Marginal Zone Lymphoma: Clinical Guidelines

List of Abbreviations

MZL – marginal zone lymphoma

MALT – mucosa-associated lymphoid tissue lymphoma

NHL – non-Hodgkin lymphomas

DLBCL – diffuse large B-cell lymphoma

FC – flow cytometry immunophenotyping

BM – bone marrow

CT – computed tomography

RT – radiotherapy

MRI – magnetic resonance imaging

CR – complete remission

SFD – single fractional dose

TFD – total fractional dose

SE – splenectomy

US – ultrasound examination

FL – follicular lymphoma

CVC – central venous catheter

ECG – electrocardiography

Echo-CG – echocardiography

IPSID – immunoproliferative small intestinal disease

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

Terms and Definitions

ECOG – Eastern Cooperative Oncology Group performance status scale – see Appendix G1.

B symptoms – nonspecific symptoms of tumor intoxication, including fever above 38°C for at least three consecutive days without signs of inflammation; profuse night sweats; weight loss of 10% of body weight over the last 6 months.

Evidence-based medicine is an approach to medical practice where decisions regarding the use of preventive, diagnostic, and therapeutic measures are made based on available evidence of their efficacy and safety, and such evidence is sought, compared, synthesized, and widely disseminated for use in the best interest of patients.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Marginal zone lymphomas (MZLs) represent a group of malignant B-cell neoplasms originating from CD20-expressing B lymphocytes normally found in the marginal zone of lymphoid follicles in lymph nodes (LNs), spleen, and lymphoid tissues [1–3].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

According to current views, the main etiological factor of MZL is chronic immune stimulation (infection, autoimmune diseases). A proven association exists between Helicobacter pylori infection and gastric MALT lymphoma, Borrelia burgdorferi and cutaneous MZL, Chlamydophila psittaci and orbital MZL, Campylobacter jejuni and immunoproliferative small intestinal disease, hepatitis C virus and splenic MZL, as well as MALT lymphomas of other localizations.

1.3 Epidemiology of the Disease or Condition

The incidence of marginal zone lymphomas is 6.7%. However, it varies across different regions of the globe: for example, 11.5% in Japan and 6% in the UK. Mucosal MZLs (MALT lymphomas) are the most common, accounting for up to 50–70% of all MZLs.

1.4 Features of Coding the Disease or Condition

C83.0 – Marginal zone lymphoma

1.5 Classification of the disease or condition

Three types of MZL are distinguished:

• Nodal – 2% of non-Hodgkin lymphomas (NHLs)

• Extranodal mucosa-associated (MALT) – 8% of NHLs

• Splenic – 1% of NHLs

1.6 Clinical presentation of the disease or condition

The clinical presentation of MZL depends on the site of involvement. Extranodal MALT lymphomas most frequently involve the gastrointestinal tract (GIT) at approximately 50%. Among GI organs, gastric MALT lymphoma accounts for up to 80%. In addition, involvement of the orbit, lung, and skin is common. Nodal MZLs present with peripheral lymphadenopathy. Splenomegaly is the main symptom in splenic marginal zone lymphoma. Other clinical symptoms may be absent for a long time. Over time, B symptoms may develop, such as fatigue, sweating, weight loss, and pruritus. The disease is generally characterized by a prolonged indolent course, although an aggressive course of lymphoma is possible in some cases (especially if MZL transforms into diffuse large B-cell lymphoma [DLBCL]).

2. Diagnostics, medical indications and contraindications for diagnostic methods

Many recommended diagnostic methods for the disease and related conditions have a limited evidence base (according to the trustworthiness of evidence and recommendation grading scales) due to the lack of dedicated clinical studies. Despite this, they are necessary components of patient evaluation to establish a diagnosis and select treatment tactics, as more effective and evidence-based methods have not yet been developed.

Criteria for diagnosis/condition establishment: the diagnosis of MZL is established based on pathomorphological examination of biopsy material using immunohistochemical methods and formulated in accordance with the 2017 WHO classification of tumours of hematopoietic and lymphoid tissues [1,4].

It is also necessary to examine all parts of the digestive tract in patients with gastric involvement.

2.1 Complaints and Anamnesis

• For patients with suspected MZL, as well as patients with verified MZL, at each medical appointment it is recommended to take a medical history to assess the patient's condition and to identify factors that may influence the patient's treatment strategy [3–5].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: taking complaints and medical history will help determine the nature of the disease course (indolent or aggressive), as well as differentiate symptoms associated with MZL from manifestations of other concomitant diseases and conditions.

2.2 Physical Examination

• For patients with suspected MZL, or with diagnosed MZL, at the initial or follow-up appointment, during follow-up examinations, and when relapse/progression of the disease is suspected, it is recommended to perform a general physical examination, palpation, and auscultation to clarify the extent of the disease and assess the patient's condition by organ systems [3–5].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: during the examination, it is necessary to evaluate the patient's general condition using the ECOG scale (see Appendix G1), as well as inspect the skin, tonsils, and oral cavity; palpation must include all accessible peripheral lymph node groups, the liver, and the spleen.

• When examining patients with nodal MZLs, it is recommended to thoroughly examine the areas adjacent to the site of nodal involvement to exclude infiltration of surrounding tissues and LNs [5]:

  • cervical LNs – eyes, parotid and other salivary glands, thyroid gland;

  • axillary LNs – lungs, mammary gland, skin;

  • mediastinal LNs – lungs, pleura;

  • abdominal LNs – spleen and GIT;

  • inguinal and iliac LNs – GIT and skin

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

2.3 Laboratory Diagnostics

• For patients with suspected or confirmed MZL at the initial or follow-up visit, before starting each new treatment cycle, when assessing remission after completion of therapy, before splenectomy and in the early postoperative period in case of fever, during follow-up examinations, and when disease relapse is suspected, it is recommended to perform the following diagnostic tests to clarify the patient's condition, plan the therapeutic strategy and determine the need for its modification, as well as to determine the need for supportive and concomitant therapy [3–5]:

  • complete blood count (CBC) with differential, including determination of total hemoglobin, erythrocytes, platelets, and leukocyte levels in the blood, differential leukocyte count (leukocyte formula), reticulocyte count, and erythrocyte sedimentation rate;

  • general (clinical) urinalysis;

  • general clinical blood biochemistry analysis including determination of the activities of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase in the blood, levels of urea, creatinine, glucose, albumin, total protein, total bilirubin, (potassium, sodium, total calcium, chlorides, beta-2-microglobulin and other biochemical blood parameters as clinically indicated);

  • coagulogram (exploratory hemostasis study) including the following parameters: prothrombin, activated partial thromboplastin time (APTT), fibrinogen, thrombin time, D-dimer, and, where possible, international normalized ratio (INR), antithrombin III, plasminogen [6,7].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: the scope of the study includes differential blood cell counting using an automated analyzer; review of the blood smear to analyze abnormalities in erythrocyte, platelet, and leukocyte morphology, and optical platelet counting (Fonio method) if necessary.

• All previously untreated patients with MZL before first-line antineoplastic therapy or before splenectomy to assess the feasibility of blood transfusion if indicated, before, during, or after therapy are recommended [3,4]:

  • determination of major blood groups by the AB0 system, determination of the D antigen of the Rhesus system (Rh factor);

  • determination of the subgroup and other minor blood groups A-1, A-2, D, Cc, E, Kell, Duffy;

  • determination of alloimmune antibodies against granulocyte antigens using at least 3 test erythrocyte samples.

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: if the results of erythrocyte antigen determination for Cc, E, Kell performed twice in the organization carrying out clinical use of donor blood and its components match, the Cc, E, Kell erythrocyte antigens are considered established and are not determined further.

For the use of donor blood components, see Appendix A3.5.

• All previously untreated patients with MZL before first-line antineoplastic therapy or before splenectomy are recommended to undergo the following tests to clarify the presence of concomitant infectious diseases and plan the necessary supportive therapy [3–5]:

  • molecular biological blood testing for Hepatitis B virus and Hepatitis C virus;

  • molecular biological blood testing for Human immunodeficiency virus HIV-1.

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: values of hepatitis B virus markers are presented in Appendix A3.4

• All patients with MZL, prior to starting antineoplastic therapy, are recommended where possible to perform immunochemical studies of serum and urine proteins to rule out monoclonal pathological secretion [8].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• In the event of a severe infection episode, where possible, it is recommended to determine blood immunoglobulin G, A, and M levels to clarify the risk of infectious complications and the need for appropriate prophylaxis [9].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: if IgG <4 g/L, the clinical situation is regarded as symptomatic hypogammaglobulinemia. In such cases, immunoglobulin replacement therapy is indicated (see section «Concomitant and Supportive Therapy»)

• If anemia and thrombocytopenia are detected in the complete blood count, as well as an elevated reticulocyte level, it is recommended to determine anti-erythrocyte antibodies and perform direct and indirect Coombs tests prior to initiating specific therapy to rule out an immune component (hemolysis) [10].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: if the immune component is confirmed, dynamic monitoring is required after completion of therapy.

2.4 Instrumental Diagnostics

• All patients with newly diagnosed marginal zone lymphoma (MZL), prior to splenectomy and in the early postoperative period in the event of fever, when assessing treatment response, and when disease relapse is suspected, are recommended to undergo computed tomography (CT) of the neck, chest, abdominal cavity, and pelvis (with contrast) for disease staging and to determine the presence, size, and extent of tumor lesions [4,5,11].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• Patients with contraindications to CT, or if CT is not feasible, upon establishment of the MZL diagnosis, prior to splenectomy and in the early postoperative period in the event of fever, when assessing treatment response, and when disease relapse is suspected, are recommended to undergo the following diagnostic examinations for disease staging and to determine the presence, size, and extent of tumor lesions [4]:

  • chest X-ray in two projections;

  • ultrasound examination of lymph nodes and internal organs.

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• All patients with newly diagnosed gastric MALT lymphoma, when assessing treatment response and when disease relapse is suspected, as well as patients with MZL prior to splenectomy, are recommended to undergo esophagogastroduodenoscopy and, if possible, endoscopic ultrasonography of the stomach with multiple biopsies of the affected mucosal areas [3,12,13].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

• Patients with gastric MALT lymphoma are recommended to undergo fiberlaryngoscopy [3,12,13].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

• Patients with MZL presenting with neurological symptoms prior to treatment initiation are recommended to undergo brain MRI and lumbar puncture to rule out dural MZL [14].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

• All patients with newly diagnosed MZL, when assessing treatment response, and when disease relapse is suspected, are recommended, if available, to undergo whole-body positron emission tomography with tumor-tropic radiopharmaceuticals (fluorodeoxyglucose [18F]) for more precise disease staging and better evaluation of the therapeutic effect [15].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: positron emission tomography combined with computed tomography (PET/CT) is a highly informative diagnostic method. PET/CT performed before treatment initiation not only allows for staging refinement, but also more accurately determines the localization of lesions, especially extranodal involvements that may be poorly diagnosed on CT, which is essential for the subsequent assessment of induction therapy efficacy, high-quality planning of subsequent radiation therapy, and minimization of radiation to healthy tissues. If PET/CT is available, it can be used in accordance with revised response criteria, primarily in patients with low tumor burden, as well as considering potential treatment modifications.

If technical capabilities are available, PET/CT should be evaluated using the Deauville scale (see Appendix G2).

• All patients with a confirmed diagnosis of MZL presenting with neurological symptoms prior to treatment initiation are recommended to undergo brain CT or MRI to rule out dural MZL and to plan antineoplastic therapy [4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• All patients with a confirmed diagnosis of MZL scheduled for treatment of newly diagnosed disease or relapse are recommended to undergo the following examinations for the timely detection of comorbid cardiovascular, respiratory, and digestive disorders and to determine the need for their prevention or treatment [4]:

  • electrocardiography recording, analysis, description, and interpretation;

  • echocardiography;

  • ultrasound duplex scanning of lower extremity vessels (arteries and veins) (to detect deep vein thrombosis of the lower extremities) [16].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

2.5 Other Procedures

• All patients with suspected MZL or suspected MZL relapse are recommended to undergo a biopsy of a lymph node or other lesion site, along with pathomorphological examination of the biopsy (surgical) material using immunohistochemical methods to verify the diagnosis [4,17].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: the choice of tissue and biopsy volume must be adequate for the diagnostic task. If a lymph node is accessible for biopsy, its complete removal is advisable.

Fine-needle biopsies of lymphoid tissue can be diagnostically significant, but not always.

Marginal biopsies of lymphoid tissue have low diagnostic value.

Tissue fragmentation severely impedes its evaluation.

Tissue samples for histological examination must be placed in fixative as quickly as possible. Drying of the tissue must be avoided.

The ratio of the volume of the fixative medium to the volume of the fixed object must be at least 10:1.

Fixation time must not be less than 12 and more than 48 hours.

Inadequate (weak or excessive) fixation alters the morphological properties of the tissue and leads to artifactual IHC results.

Histological material must be accompanied by a referral form containing information about the patient, duration and nature of the disease, localization of the lesion site, and a description of the biopsy [18].

Histological and immunohistochemical characteristics of MZL, as well as mandatory requirements for the pathomorphological report, are presented in Section 7.1 of these guidelines. A description of the pathomorphological and immunohistochemical features of MZL is provided in Section 7.2 of these guidelines.

• Patients with gastric MALT lymphoma are recommended, if available, to undergo pathomorphological examination of the biopsy (surgical) material using fluorescence in situ hybridization (FISH) to rule out t(11;18) [3,5,11].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: t(11;18) is an adverse prognostic factor for response to antibacterial therapy and requires the selection of an alternative treatment method.

• All patients with suspected or confirmed MZL initially (for disease staging), after completion of therapy (to assess antitumor response), and upon suspicion of disease relapse are recommended to undergo [4]:

  • bone marrow aspiration to obtain a cytological bone marrow preparation, cytological examination of the bone marrow smear (myelogram), and, in case of an increased number of lymphoid cells, presence of atypical lymphocytes, or cells with blastic morphology in the bone marrow, analysis of the biological material (bone marrow aspirate) by flow cytometry;

  • obtaining a bone marrow histological specimen (trephine biopsy), and pathological examination of bone marrow biopsy (surgical) material using immunohistochemical methods.

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: bone marrow examination (aspirate and trephine biopsy) is also recommended upon the onset of clinically unexplained cytopenia and fever (regardless of the presence of initial involvement).

• All patients with newly diagnosed gastric MZL are recommended to undergo microbiological (culture) examination of a gastric wall biopsy specimen for Helicobacter pylori with susceptibility testing to antibacterial drugs [3,19].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• All patients with newly diagnosed gastric MZL with negative results from the microbiological (culture) examination of the gastric wall biopsy specimen for Helicobacter pylori are recommended to undergo blood testing for anti-Helicobacter pylori antibodies, fecal Helicobacter pylori antigen testing, and a 13C-urea breath test for Helicobacter pylori [3,19].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• All patients with cutaneous MZL are recommended, if available, to undergo molecular biological testing of blood and skin biopsy specimens for tick-borne borreliosis agents of the Borrelia burgdorferi sensu lato complex to identify the infectious agent associated with the disease [3,12].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• Patients with MZL in complex diagnostic cases, with ambiguous results from morphoimmunohistochemical and immunophenotypic studies, are recommended to undergo additional determination of B-cell clonality by PCR on biopsy material [20].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• Patients with verified MZL undergoing initial evaluation and treatment planning are recommended to have consultations (examinations) with a cardiologist, endocrinologist, neurologist, infectious disease specialist, and other medical specialists depending on comorbidities to determine the need for treatment of concurrent conditions [4].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• For patients with verified recommended LVSD at initial examination and treatment planning, it is Khorana to assess the risk of venous thromboembolism (VTE risk assessment scale per — see Appendix G2 of these guidelines) to identify patients requiring prescription and determination of methods for thrombotic complications prophylaxis during cytostatic therapy [6,7,21–23].

GGR BLOC 3Grade of recommendation B (Level of evidence 3).

• All women of childbearing potential with newly diagnosed MZL, as well as relapsed MZL, are recommended to undergo a set of pregnancy tests prior to therapy initiation in order to adjust the therapeutic strategy and consult an obstetriciangynaecologist if pregnancy is present and the patient wishes to preserve it [4,24].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• For women of childbearing potential with indolent marginal zone lymphoma (MZL) who wish to preserve their fertility, an obstetrician-gynecologist consultation is recommended to address the possibility of oocyte cryopreservation before starting chemotherapy and subsequent ovarian protection [4,24].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• For patients with MZL who have an indication for central venous catheter placement, a chest X-ray or, preferably, contrast-enhanced computed tomography (CT) of the chest, as well as duplex ultrasonography of the upper extremity arteries, is recommended prior to catheterization [25–30].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

When choosing tactics and administering therapy, it should be taken into account that the patient may present with atypical disease manifestations or a combination of a specific disease with other pathologies, which may dictate changes by the attending physician in the algorithm for selecting optimal diagnostic and treatment tactics.

The patient discontinues treatment according to the protocol in cases of disease progression or toxic effects that preclude continuing chemotherapy at the required dose.

3.1 Treatment of patients with early (IE1, IE2, IIE) stages of gastric MALT lymphoma

The choice of treatment strategy for patients with early-stage gastric MALT lymphoma depends on H. pylori infection status.

• For patients with verified early-stage gastric MALT lymphoma who are infected with H. pylori, H. pylori eradication therapy is recommended in accordance with the clinical guidelines for peptic ulcer disease in adult patients [31].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comment: endoscopic confirmation of H. pylori eradication is required at 3 months or earlier if lymphoma symptoms persist despite antibiotic therapy.

• For patients with verified early-stage gastric MALT lymphoma and detected t(11;18) translocation who are infected with H. pylori, after completion of H. pylori eradication therapy regardless of its efficacy, radiotherapy (RT), #rituximab** monotherapy, or immunochemotherapy is recommended [5,11,12,32–34].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: RT is administered at a total dose of 24–30 Gy (see Appendix A.3.2). #Rituximab** monotherapy is administered in accordance with drug treatment regimens (see Appendix A3.1). Immunochemotherapy is administered according to regimens for advanced stages of follicular lymphoma (FL) grade I–II (drug treatment regimens: BR, R-CVP, R-CHOP, combination of #rituximab** with #chlorambucil** (see Appendix A3.1)).

• For patients with verified early-stage gastric MALT lymphoma who are infected with H. pylori, upon morphologically proven lymphoma regression and H. pylori eradication at 3 months post-eradication therapy, active surveillance is recommended [31].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• For patients with verified early-stage gastric MALT lymphoma who are infected with H. pylori, if H. pylori infection persists at 3 months post-eradication therapy, second-line anti-Helicobacter therapy is recommended until complete eradication of the infection (in accordance with specialized guidelines for the treatment of gastric ulcer) [5,11,12].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• For patients with verified early-stage gastric MALT lymphoma who are infected with H. pylori, if H. pylori is eradicated but the lymphoma persists without clinical symptoms, a wait-and-watch approach with regular esophagogastroduodenoscopy (every 3 months) is recommended [5,11,12].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: if the patient shows clinical and endoscopic improvement with persisting histological signs of lymphoma following eradication therapy, it is advisable to continue active surveillance for up to 12 months before initiating alternative treatment. In this case, endoscopic examinations are recommended every 3 months.

• For patients with verified early-stage gastric MALT lymphoma in whom H. pylori and its antibodies are not detected, H. pylori eradication therapy is also recommended in accordance with the clinical guidelines for peptic ulcer disease in adult patients [5,31].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: In cases of HP-negative gastric MALT lymphoma, achieving remission is less likely. However, starting treatment with eradication therapy is still recommended because false-negative HP test results or infection with less common HP species are possible.

• For patients with verified early-stage gastric MALT lymphoma in whom H. pylori and its antibodies are not detected, in the absence of improvement upon repeat endoscopy at 3–6 months after the start of H. pylori eradication therapy, specific antitumor treatment (radiotherapy (RT), #rituximab** monotherapy, or immunochemotherapy) is recommended [5,11,12,32–34].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: RT is administered at a total dose of 24–30 Gy (see Appendix A.3.2). #Rituximab** monotherapy is administered in accordance with drug treatment regimens (see Appendix A3.1). Immunochemotherapy is administered according to regimens for advanced stages of follicular lymphoma (FL) grade I–II (drug treatment regimens: BR, R-CVP, R-CHOP, combination of #rituximab** with #chlorambucil** (see Appendix A3.1)).

• For patients with verified early-stage gastric MALT lymphoma presenting with an ulcerated, bleeding tumor, surgical treatment is recommended [5,35].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: surgical treatment is recommended to be performed to a minimum extent and only when conservative therapy fails [5].

3.2 Treatment of patients with early-stage MALT lymphoma of other sites

• For patients with MALT lymphoma of other sites, the initiation of specific therapy is recommended if any of the following symptoms are present [5,11,12]:

  • pain syndrome,

  • organ function impairment,

  • bleeding,

  • massive involvement

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: in the absence of indications, active surveillance is possible (if feasible) with a specialist consultation (attending physician) at least once every 3 months during the first year after diagnosis, and at least once every 6 months thereafter.

• For patients with early-stage MALT lymphoma of other sites who have indications for the initiation of therapy, RT to involved fields at a total dose of 30–36 Gy is recommended [5,11,12].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: when administering RT to patients with orbital MALT lymphoma, the irradiation volume includes the entire orbit and manifest or suspected extraorbital lesions. In conjunctival involvement, the clinical target volume includes the entire conjunctival sac. The anterior segments of the eye should be shielded to reduce radiation exposure to the lens, without compromising the delivery of an adequate dose to the tumor [36,37].

Recommended RT doses are 24–30 Gy, with fractional doses of 1.5–2 Gy

RT complications occur in 8–12% of cases and are dose-dependent [38]. When choosing RT, it is necessary to consider the probability of post-radiation reactions and complications, as well as the inclusion of adjacent organs in the irradiation field with impairment of their functions. Complications (including irreversible ones) most commonly occur during irradiation of the accessory apparatus of the eye, e.g., cataract, xerophthalmia, radiation retinopathy.

Lung irradiation may be complicated by radiation pneumonitis; brain irradiation (in leptomeningeal MZL) by cerebral edema and radiation necrosis; pelvic irradiation (in intestinal or reproductive organ MZL) by post-radiation cystitis, proctitis, formation of ureterovaginal and ureteroabdominal fistulas, etc. At the same time, in cutaneous or soft tissue MZL, reactions occurring during irradiation do not lead to serious complications, and local focal irradiation in these cases can be considered the therapy of choice.

• For patients with early-stage MALT lymphoma of other sites who have indications for treatment initiation and have contraindications to or are unable to undergo RT, #rituximab** monotherapy or immunochemotherapy is recommended [5,11,12,32–34].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: #rituximab** monotherapy is conducted in accordance with drug treatment regimens (see Appendix A3.1). Immunochemotherapy is administered according to regimens for advanced stages of follicular lymphoma (FL) grade I–II (drug treatment regimens: BR, R-CVP, R-CHOP, combination of #rituximab** with #chlorambucil** (see Appendix A3.1)).

• For fully staged patients with a solitary MALT lymphoma lesion in an organ such as the lung, breast, thyroid gland, or colon, a surgical consultation and, if feasible, surgical tumor removal is recommended [12].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: the detection of lymphoma cells at the resection margin dictates the need for loco-regional RT.

• For patients with verified advanced-stage MALT lymphoma of other sites, immunochemotherapy is recommended in accordance with the recommendations for advanced stages of FL grade I–II [5,11,12].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: local RT directed only at the tumor-affected part of the organ may be administered as palliative or symptomatic therapy; the dose is determined based on the location and patient tolerance.

3.3 Treatment of patients with advanced (III-IV stages) MALT lymphoma

• For patients with verified advanced stages of MALT lymphoma, it is recommended to initiate specific therapy in the presence of any of the following symptoms [5,11,12]:

  • pain syndrome,

  • constitutional B-symptoms

  • organ function impairment,

  • bleeding,

  • massive involvement

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: if there are no indications for treatment, active surveillance is an option.

• For patients with verified advanced stages of MALT lymphoma who have indications for therapy, it is recommended to administer immunochemotherapy or #rituximab** monotherapy [5,11,12,32–34]

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: #rituximab** monotherapy is administered in accordance with drug regimens (see Appendix A3.1). Immunochemotherapy is performed according to regimens for advanced stages of follicular lymphoma (FL) grade I-II (drug regimens BR, R-CVP, R-CHOP, combination of #rituximab** with #chlorambucil** (see Appendix A3.1).

• For patients with MALT lymphoma in whom immunohistochemistry reveals a large-cell component, regardless of the disease stage, it is recommended to administer immunochemotherapy in accordance with the guidelines for DLBCL (see clinical practice guidelines for the treatment of aggressive B-cell lymphomas) [12].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

3.4 Treatment of patients with nodal marginal zone lymphoma

• For patients with verified nodal marginal zone lymphoma, it is recommended to administer #rituximab** monotherapy or immunochemotherapy [5,11,12,32–34].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: #rituximab** monotherapy is administered in accordance with drug regimens (see Appendix A3.1). Immunochemotherapy is performed according to regimens for advanced stages of follicular lymphoma (FL) grade I-II (drug regimens BR, R-CVP, R-CHOP, combination of #rituximab** with #chlorambucil** (see Appendix A3.1).

3.5 Treatment of patients with splenic marginal zone lymphoma

• For patients with verified splenic marginal zone lymphoma, it is recommended to initiate specific therapy in the presence of indications [5,11,12]:

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: indications for initiating therapy in splenic marginal zone lymphoma are:

• symptomatic and progressive splenomegaly

• progressive cytopenia (hemoglobin ˂100 g/L, platelets ˂80 ◊ 109/L, neutrophils ˂1.0 ◊ 109/L)

• autoimmune complications (AIHA, idiopathic thrombocytopenic purpura).

If there are no indications, active surveillance is possible.

• For patients with verified splenic marginal zone lymphoma and hepatitis C, it is recommended to administer hepatitis C antiviral therapy in accordance with the clinical guidelines for the treatment of hepatitis C [5,11,12]

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• For patients with verified splenic marginal zone lymphoma who have indications for treatment, negative screening results for hepatitis C, or contraindications to antiviral treatment, it is recommended to administer #rituximab** monotherapy, immunochemotherapy, or splenectomy [5,11,12,32–34,39].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: #rituximab** monotherapy is administered in accordance with drug regimens (see Appendix A3.1) [32,33,40,41]. Immunochemotherapy is administered according to regimens for advanced stages of follicular lymphoma (FL) grade I-II (drug regimens BR, R-CVP, R-CHOP, combination of #rituximab** with #chlorambucil** (see Appendix A3.1) [42–46].

Splenectomy is performed in accordance with indications (see Appendix A3.3) [39].

Standard indications for splenectomy (SE) in patients with verified splenic marginal zone lymphoma include:

• significant or rapidly progressive splenomegaly (including risk of rupture or splenic infarction);

• profound cytopenia (not an absolute indication);

• contraindications to immunotherapy or immunochemotherapy.

Vaccination against encapsulated bacteria (Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae) is recommended at least 14 days before (preferably) or after SE [47].

In most patients, SE is followed by a rapid recovery of hemogram parameters, resolution of symptoms related to organomegaly (pain, heaviness, dyspnea, etc.), and disappearance of B-symptoms. On the other hand, SE is major surgery associated with the development of severe and potentially fatal early and late complications. Furthermore, SE does not achieve complete tumor remission; the lymphoma persists in the bone marrow, lymph nodes, etc.

3.6 Remission consolidation in MZL patients older than 18 years

• For MZL patients who have achieved complete or partial remission after first-line therapy with #rituximab** monotherapy or #rituximab**-containing polychemotherapy, maintenance therapy with #rituximab** at 375 mg/m2 every 2 months for 2 years (12 infusions in total) may optionally be recommended to maintain remission [40,41,48].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: if signs of progression appear, maintenance therapy should be discontinued. For patients who received the BR regimen, maintenance therapy with #rituximab** increases the risk of infectious complications; therefore, in the event of complete remission, maintenance therapy after BR is not indicated [49].

3.7 Treatment of relapsed and refractory forms of MZL

• For patients with relapsed and refractory MZL who have indications for treatment, it is recommended to administer therapy in accordance with the guidelines for relapsed and refractory FL grade I-II (drug regimens – see Appendix A3.1) and radiotherapy, if not previously administered [5,11,12].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• For patients with MZL relapse occurring less than 6 months after #rituximab**-containing immunochemotherapy, who have indications for treatment initiation, alternative chemotherapy options (e.g., #bendamustine** after CHOP) combined with another anti-CD20 mAb (e.g., #obinutuzumab** after #rituximab**) may be recommended. Obinutuzumab is administered at a dose of 1000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2–6), and bendamustine at a dose of 90 mg/m(2) per day (days 1 and 2, cycles 1–6) [50].

Level of Recommendation ALevel of Evidence 2Level of recommendation A (level of evidence 2).

• For patients with relapsed and refractory MZL who have already received at least one course of #rituximab**, if there are indications for treatment, ibrutinib** therapy may be recommended as one of the treatment options (drug regimens – see Appendix A3.1) [5,11,51].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• For patients with relapsed and refractory MZL who have already received at least one course of #rituximab**-containing drug therapy, if there are indications for treatment, #zanubrutinib at 160 mg twice daily until disease progression or unacceptable toxicity may be recommended as one of the treatment options [52].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• For patients with MZL relapse occurring at any time, if there are indications for treatment initiation, the combination of rituximab** and lenalidomide** may be recommended as one of the therapeutic options (drug regimens – see Appendix A3.1) [53].

GGR ALOC 2Grade of recommendation A (Level of evidence 2).

Comment: according to a large international randomized phase III study AUGMENT (N=358) comparing the efficacy of the combination of lenalidomide**+#rituximab** (R2) versus #rituximab**+placebo (control group) in patients with relapsed/refractory FL and marginal zone lymphoma (MZL), lenalidomide** therapy had a positive impact on progression-free survival (PFS), overall response rate (ORR), and time to next antilymphoma therapy.

Lenalidomide** was administered at a dose of 20 mg/day on days 1 to 21 of a 28-day cycle (12 cycles); if the creatinine clearance was from 30 to <60 ml/min, the dose of lenalidomide** was 10 mg/day. #Rituximab** was prescribed at a dose of 375 mg/m2 on days 1, 8, 15, and 22 of the first cycle and on day 1 of cycles 2-5.

The study demonstrated a statistically significant improvement in progression-free survival (PFS) in the group of patients treated with the R2 regimen. The median PFS with the R2 combination compared to the control group was 39.4 months and 14.1 months, respectively (p = < 0.0001). The ORR in the R2 group was 78% versus 53% in the control group (p = 0.001). The duration of response in the R2 group was 36.6 months, compared to 21.7 months in the control group (p = < 0.0015). The time to next antilymphoma therapy was not reached in the R2 group. In the control group, this parameter was 32.3 months (p = < 0.0007).

• For MZL patients who are candidates for transplantation and experience a relapse occurring less than 24 months after the start of induction therapy (POD24), or who have refractory disease, it is recommended to administer therapy according to protocols for relapsed DLBCL (R-GEMOX, R-ICE, R-DHAP, R-GDP, etc.) (see clinical guidelines for the treatment of aggressive non-Hodgkin lymphomas) and, if a response to relapse therapy is achieved, to perform high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation for remission consolidation (auto-HSCT, see Appendix A3.11) [11,17,54,55].

LoR CGoE 3Level of Recommendation C (Level of Evidence 3).

• For MZL patients who are candidates for transplantation and develop an early aggressive relapse following autologous stem cell transplantation, allogeneic hematopoietic stem cell transplantation should be recommended if feasible (allo-HSCT, see Appendix A3.11) [56–58].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• For MZL patients who have relapsed and responded to relapse therapy including #rituximab**, maintenance therapy with rituximab** 375 mg/m2 once every 2 months for 2 years may be recommended as an option [11,17,41].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comments: for patients who received the BR regimen, maintenance therapy with #rituximab** increases the risk of infectious complications; therefore, in case of achieving complete remission, maintenance therapy after BR is not indicated [49].

3.8 Response assessment

• For all MZL patients receiving anti-tumor treatment, after completing the entire treatment program, it is recommended to assess the response to therapy in accordance with standard lymphoma response criteria (see section 7.4 of these guidelines) [4,59].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

3.9 Concomitant and supportive care

• For MZL patients with bulky tumor lesions receiving anti-tumor therapy, it is recommended to provide prevention and treatment of tumor lysis syndrome: #allopurinol** 10 mg/kg/day and infusion therapy 3 L/m2/day with alkalinization using #sodium bicarbonate** solution 40–80 mmol/L under the control of diuresis and laboratory monitoring of acid-base balance, with the scheduled administration of #furosemide** at a dose of 1 to 10 mg/kg if necessary, until a diuresis of 200–250 ml/hour is achieved [60,61].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• For MZL patients receiving anti-tumor chemotherapy or radiotherapy, for the prevention of nausea and vomiting, it is recommended to use appropriate medications (see Appendix A3.8 of these guidelines) [62–65].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• For MZL patients receiving glucocorticoids, it is recommended to carry out prophylaxis of gastric and duodenal ulcers (see Appendix A3.9 of these guidelines) [66].

GCR BLOCE 3Grade of Recommendation B (Level of Evidence 3)

• For MZL patients undergoing immunochemotherapy courses (R-CHOP, G-CHOP) with a high risk of febrile neutropenia (FN) exceeding 20%, or with an intermediate risk of FN of 10–20% in the presence of risk factors, primary prophylaxis of febrile neutropenia with colony-stimulating factors is recommended [67–70].

LoR CGoE 3Level of Recommendation C (Level of Evidence 3).

Comments: risk factors include, in particular, age > 65 years; severe comorbidities; renal or hepatic impairment; hemoglobin less than 12 g/dL; malnutrition; history of prolonged neutropenia or FN; lack of antimicrobial prophylaxis; ECOG ≥2; open wounds or wound infection; recent major surgery; female sex; chemoradiotherapy; cytopenia due to bone marrow tumor involvement; HIV infection.

Colony-stimulating factors (G-CSF, L03AA according to the ATC classification) are prescribed prophylactically in the following regimen: filgrastim** 5 mcg/kg subcutaneously (s/c) 24–72 hours after the completion of chemotherapy administration and until normal neutrophil count recovers after the nadir, or pegfilgrastim at a dose of 6 mg, or empegfilgrastim** at a dose of 7.5 mg subcutaneously, once, at least 24 hours after the completion of chemotherapy administration in accordance with the instructions for medical use, for the purpose of preventing the development and treating neutropenia caused by cytotoxic tumor chemotherapy.

• For MZL patients after a previously documented episode of FN, dose-limiting afebrile neutropenia (after a single episode of interval prolongation between courses and/or dose reduction), secondary prophylaxis of febrile neutropenia with G-CSF is recommended [67–69].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• For MZL patients with symptomatic hypogammaglobulinemia, as well as patients suffering from severe or recurrent infections when antibacterial drugs are ineffective, replacement therapy with #normal human immunoglobulin** 0.2–0.4 g/kg i.v. every 3–4 weeks or 0.05–0.1 g/kg s/c weekly for 12 months is recommended for the treatment of secondary immunodeficiency [9,71–74].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: therapy is performed under the control of IgG levels every 6 months, dose adjustment every 6 months. After completion of therapy, lifelong monitoring of IgG levels is carried out 1 time per year; in case of a repeated decrease in IgG < 4 g/L, repeated courses of replacement therapy with a similar drug in a similar regimen are performed for 12 months.

Subcutaneous administration of Ig causes fewer systemic adverse events, provides stable Ig levels, and self-administration of Ig at home is an advantage for a number of patients [75].

• For MZL patients receiving lenalidomide** treatment, thrombosis prophylaxis is recommended with low doses of #acetylsalicylic acid** (75–325 mg per day for patients at standard risk of venous thromboembolism (VTE) or with low-molecular-weight heparins (LMWH) (from the B01AB heparin group according to the ATC classification) for patients at high risk of VTE throughout the entire period of therapy (see Appendix A3.10 of these guidelines) [76,77].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: if the patient develops symptoms of VTE, lenalidomide** treatment must be discontinued and standard anticoagulant therapy prescribed. After the patient's condition stabilizes on anticoagulant therapy and VTE symptoms are resolved, lenalidomide** treatment can be resumed at the same dose upon a favorable benefit-risk assessment. The patient should continue anticoagulant therapy throughout the remainder of lenalidomide** treatment.

• For MZL patients with symptomatic anemia or thrombocytopenia, transfusions of blood components are recommended (see Appendix A.5) [24].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: transfusions are carried out in accordance with clinical indications, with monitoring for potential complications (in particular, volume overload, dyspnea, post-transfusion hypotension, delayed serologic transfusion reaction, transmission of transfusion-transmitted infections).

• For MZL patients undergoing platelet transfusion, in cases where individual matching of donor platelets fails to achieve a sufficient platelet increment and clinical effect from platelet concentrate transfusions, plasmapheresis is recommended to improve the efficiency of donor-recipient pair matching (see Appendix A3.6) [78–81].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• For MZL patients with an increased risk of perioperative thrombotic complications scheduled for splenectomy, the administration of LMWH (from the B01AB heparin group according to the ATC classification) in prophylactic doses is recommended (see Appendix A3.10) [82].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• For all MZL patients at all stages of disease therapy, as well as after the completion of drug treatment, comprehensive rehabilitation and, if necessary, maintenance therapy are recommended [83].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: there are no special rehabilitation methods for MZL. Rehabilitation of MZL patients should be comprehensive, covering not only medical but also social and psychological aspects of the patient's adaptation to normal life. Such rehabilitation requires, in addition to medical care, the mandatory participation of social workers and psychologists. Rehabilitation programs are developed individually, depending on the identified complications of drug treatment, comorbid conditions, and social and psychological problems.

Rehabilitation for complications arising during the course of the disease and treatment is carried out within the framework of the respective nosologies.

5. Prevention and Dispensary Observation

There are currently no methods for the prevention of MZL, as the etiological factors leading to the development of the disease are unknown.

• For adult patients who have completed treatment for MZL with the achievement of CR, a follow-up visit (examination, consultation) by an oncologist or hematologist is recommended with the following frequency of patient examinations: during the first year after completion of therapy every 3 months, the 2nd year every 6 months, thereafter annually, and after 5 years every 2 years [4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: dispensary observation should include a thorough collection of complaints, clinical examination of the patient, chest X-ray control, ultrasound of the abdominal cavity and peripheral lymph node groups; in the presence of extranodal sites at onset, corresponding CT/MRI/ultrasound studies to monitor extranodal localizations.

6. Organization of Medical Care

Indications for planned hospitalization:

• Administration of therapy in cases requiring round-the-clock patient monitoring due to the severity of the condition caused by the tumor, or due to the risk of complications associated with the treatment program or comorbid conditions.

• Patient examination, including biopsy and invasive interventions, in cases where it cannot be performed on an outpatient basis.

Indications for emergency hospitalization:

• Development of infection (hospitalization in a hematology inpatient facility is not mandatory).

• Development of life-threatening cytopenias (profound anemia, hemorrhagic syndrome, neutropenia).

• Development of life-threatening MZL complications.

• Development of therapy complications, including tumor lysis syndrome, severe infusion reactions, myelotoxic agranulocytosis with fever, and other life-threatening complications.

Indications for patient discharge from the hospital:

• Completion of a treatment course or one of the stages of specialized, including high-tech, medical care in a round-the-clock or day hospital, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting.

• Refusal of the patient or their legal representative from specialized, including high-tech, medical care in a round-the-clock or day hospital setting established by the concilium of the medical organization providing oncological care, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting.

• The need to transfer the patient to another medical organization in the relevant medical specialty.

• The medical commission's decision on the absence of indications for the patient to stay in the hospital due to the futility of treatment and the need to provide palliative care only.

The conclusion regarding the feasibility of transferring the patient to a specialized medical organization is drawn after a preliminary consultation based on the provided medical documents and/or a preliminary examination of the patient by medical specialists of the medical organization to which the transfer is planned.

7. Additional Information

7.1 General requirements for morphological diagnosis of lymphomas

Before lymph node biopsy, a complete blood count with differential must be performed to rule out biopsy in patients with chronic lymphocytic leukemia, monoclonal B-cell lymphocytosis, acute leukemias, or lymphocytosis of infectious (HIV, EBV, CMV infection, pertussis, viral hepatitis, toxoplasmosis, etc.) or other etiology (post-vaccination, drug reaction, smoking, thymoma, stress-induced lymphocytosis).

The diagnosis of marginal zone lymphoma is established on the basis of pathomorphological examination of biopsy or surgical material using immunohistochemical methods. In some cases, molecular biological and genetic tests are required. Cytological examination of punctates or touch imprints of lymph nodes or other tumor foci is an auxiliary research method and cannot serve as a sufficient basis for the diagnosis of lymphoma and its nosological verification.

During the initial examination of a patient, histological and immunohistochemical examination of the material from an incisional or excisional biopsy of the pathological focus, or of surgical material, is mandatory in all cases, with the mandatory provision to the pathologist of an extract from the patient's outpatient record/medical history. Lymph nodes should not be punctured for cell suspension aspiration. In exceptional cases (tumor localization in hard-to-reach anatomical areas, severity of the patient's condition) with justification for the impossibility of performing an excisional biopsy (reflected in the medical documentation), the object of study may be tissue material obtained using a core-needle biopsy. Suitable for examination is a biopsy specimen with a diameter of at least 16 G and a length of tumor infiltrate in the tissue of at least 1.5 cm. The volume of the immunohistochemical study is determined by the pathologist during the histological examination of the material. Splitting the material between different laboratories is strictly unacceptable. The pathological anatomy report must contain:

• Macroscopic description of the material submitted for examination; when examining prepared blocks and microslides, the report must indicate the quantity and identification numbers of all submitted objects.

• Histological description of the lymphoma indicating the growth type (diffuse, nodular, etc.), characteristics of the cell composition (small, large cells, polymorphic composition, anaplastic, blastic/blastoid morphology, presence of multinucleated forms, nuclear characteristics), and the presence of reactive and residual components.

• Results of the immunohistochemical study indicating the antibodies used and staining details pointing to the specific nature of the reaction (e.g., nuclear staining in reactions with antibodies to TdT, BCL-6, Cyclin D1; cytoplasmic in reactions for CD79a; granular cytoplasmic reaction for cytotoxic molecules; cytoplasmic or membrane staining in reactions with antibodies to CD3, heavy or light chains of immunoglobulins; membrane staining for CD20, CD10), intensity, and features of immunohistoarchitecture. Presenting immunohistochemical test results only as "crosses" ("pluses") and a list of antibodies is unacceptable.

• Pathological conclusion formulated in accordance with the current edition of the classification of tumors of hematopoietic and lymphoid tissues (WHO, 2017).

A mandatory component of determining the extent of the tumor process (stage) is the histological examination of a bone marrow trephine biopsy. During the initial examination, it is recommended to perform a bilateral biopsy.

Pathological examination of bone marrow aspirate (sternal or other) does not replace the histological examination of the trephine biopsy.

If lymphocytosis is present in the complete blood count or myelogram, regardless of the leukocyte count, as well as in the case of a predominance of lymphoid cell elements, atypical lymphocytes, or cells with blastic morphology in the pleural, ascitic, or other biological fluids, immunophenotyping by flow cytometry must be performed. Flow cytometry allows for the rapid differential diagnosis of tumor and reactive lymphocytosis, which is important for determining further patient management strategies. Materials for flow cytometry analysis can include blood cells, bone marrow, effusion fluids, bronchoalveolar lavage, cerebrospinal fluid, homogenized tissue samples (spleen, lymph nodes, etc.), and cell suspension obtained by fine-needle aspiration biopsy of lymph nodes.

When staging the tumor process, a biopsy of other affected sites may be required if their neoplastic nature cannot be ruled out by other means.

In case of relapse or disease progression, a repeat biopsy and pathological examination of the affected lymph nodes or extranodal foci are mandatory. A repeat biopsy is also indicated in the presence of residual foci to confirm remission. Performing a repeat biopsy of the pathological focus is mandatory in primary refractory disease or disease relapse to confirm the diagnosis or verify tumor transformation, as well as to exclude a second tumor or infectious process.

Repeat bone marrow aspiration and trephine biopsy are performed for planned evaluation of treatment results and upon the appearance of clinically unjustified cytopenia and fever. Bone marrow aspirate can be informative for assessing regeneration and dysplastic changes in myelopoiesis. In patients with bone marrow involvement, cytological examination of the aspirate to assess changes in the volume of tumor infiltration is not always informative.

7.2 Pathological and immunohistochemical diagnosis of MZL

The marginal zone lymphoma (MZL) group includes the following types: nodal MZL, extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma), and splenic MZL.

MZLs are B-cell lymphomas with nodular, intrafollicular, marginal, diffuse, and intrasinusoidal growth patterns. The cellular composition is polymorphic: small lymphocyte-like cells, centrocytic-like cells, lymphoid cells with signs of plasmacytic differentiation, mature plasma cells, sparsely located large cells with centroblast and immunoblast morphology are present; in extranodal localization, clusters of tumor cells with monocytoid B-cell morphology are often present.

Immunohistochemically, the diagnosis of MZL is established by excluding other variants of small B-cell lymphomas and requires the use of a wide panel of antibodies. The immunophenotype of the tumor is characterized by the expression of pan-B-cell antigens, in particular CD20 (intense membrane expression). In general, the immunophenotype of nodal and extranodal B-cell MZLs is identical: CD20+, CD19+, CD22+, CD5-, CD10-, CD23-, BCL-2+/-, BCL-6-, MUM.1 -/+ (weak nuclear expression in lymphoid cells of the tumor infiltrate). In complex cases with a predominance of diffuse growth, additional study of CD38 expression (usually absent) and CD44 expression (often present) is recommended. Residual germinal centers of follicles with signs of colonization are visualized using antibodies to CD10, BCL-6, and CD23 (follicular dendritic cell network). In splenic MZL, co-expression of CD5 may be observed (up to 20% of cases). A "unique" diagnostic marker for MZL is lacking. In the 2017 WHO classification, antibodies to MNDA are included in the immunohistochemical panel, but the expression of this marker can also be observed in certain nodal small B-cell lymphomas.

Transformation into diffuse large B-cell lymphoma is established in the presence of large focal clusters of large cells with centroblast/immunoblast morphology.

7.3 Staging of MZL

Gastric MALT lymphomas are staged according to the Lugano gastrointestinal lymphoma staging system (Table 7.3.1). Other MZLs are staged according to the Ann Arbor classification (Table 7.3.2).

Table 7.3.1. Gastric lymphoma staging: classification comparison

Table 7.3.2. Ann Arbor lymphoma staging (Lugano modification, 2014) [32]:

Comments: tonsils, Waldeyer's ring, and spleen are considered nodal structures

7.4 Response evaluation in lymphomas

Response to treatment is assessed in accordance with the updated criteria proposed by the International Working Group on Lymphoma in 2007 [59].

Complete remission (CR):

• Complete disappearance of all evidence of disease, including findings detected by laboratory and imaging diagnostic methods, as well as clinical symptoms, if present before treatment initiation.

• Lymph node dimensions:

  • ≤ 1.5 cm in greatest dimension, if lymph node sizes were greater than 1.5 cm before treatment start

  • ≤ 1.0 cm in greatest dimension, if lymph node sizes were 1.5–1.1 cm before treatment start

• Liver and spleen, if enlarged before treatment, are no longer palpable, and imaging reveals no focal lesions within them.

• Bone marrow with no evidence of tumor involvement. If the bone marrow morphological examination result is equivocal, the presence or absence of involvement must be determined immunohistochemically.

Unconfirmed complete remission (CRu) is stated only in patients who did not undergo PET-CT for response evaluation:

• Residual changes detected exclusively by imaging methods (especially residual masses at the site of bulky disease, most commonly in the mediastinum), provided the tumor has regressed by more than 75% from its baseline size based on the sum of the two largest perpendicular diameters. These residual changes must not increase in size for more than 3 months.

• Other parameters: meeting the criteria for complete remission.

Partial remission (PR):

• A reduction in the sum of diameters of all measurable target lesions (lymph nodes and/or extranodal lesions) by at least 50%. If the dimensions of the involved lesions are less than 3 cm in greatest diameter, then the 2 largest lesions must decrease by at least 50% in greatest diameter. If there are more than 6 target lesions larger than 3 cm, evaluation of the 6 largest lesions clearly measurable in two perpendicular directions is sufficient. If mediastinal and/or retroperitoneal target lesions are present, they must be included in the measurements.

• No appearance of new lesions, and no evidence of enlargement of any previously diagnosed lesions.

• In cases of baseline bone marrow involvement, the bone marrow status is not significant for determining PR. However, if bone marrow involvement persists during and/or after completion of treatment, characterization of the tumor cells is mandatory. Patients with baseline bone marrow involvement who achieve clinical CR after treatment completion but have persistent bone marrow involvement or unevaluable bone marrow are classified as having PR.

Stable disease

Tumor parameters do not meet the criteria for CR, PR, or progression.

Relapse (after CR) or progression (after PR or stable disease)

• Appearance of new lesions (enlarged lymph nodes or extranodal masses) greater than 1.5 cm in the greatest dimension during or after treatment completion, regardless of changes in the size of other lesions.

• An increase of at least 25% in any previously documented lesion from its nadir size. For lesions less than 1 cm in the greatest dimension, an increase to 1.5 cm or more.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

• Ptushkin Vadim Vadimovich – MD, PhD, Professor, Deputy Chief Medical Officer for Hematology at Botkin City Clinical Hospital, Chief Freelance Hematologist of the Moscow Healthcare Department, member of the National Hematological Society and the Russian Society of Oncohematology.

• Poddubnaya Irina Vladimirovna – Academician of the Russian Academy of Sciences, Honored Worker of Education of the RF, MD, PhD, Professor, Head of the Department of Oncology and Palliative Medicine, Vice-Rector for Clinical Work and International Cooperation at RMANPO of the Russian Ministry of Health, Chairperson of the Russian Society of Oncohematology.

• Babicheva Lali Galimovna – PhD in Medical Sciences, Associate Professor at the Academician A.I. Savitsky Department of Oncology and Palliative Medicine at RMANPO of the Russian Ministry of Health, member of the Russian Society of Oncohematology.

• Nesterova Ekaterina Sergeevna – PhD in Medical Sciences, Researcher, Hematologist at the Department of Intensive High-Dose Chemotherapy of Hemoblastoses with Day and 24-Hour Patient Care, National Research Center for Hematology of the Russian Ministry of Health, member of the Association for the Promotion of Development of Hematology and Bone Marrow Transplantation "National Hematological Society".

• Osmanov Evgeny Alexandrovich – MD, PhD, Professor, Head of the Department of Hematology and Bone Marrow Transplantation at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Professor at the Department of Oncology at Sechenov First Moscow State Medical University of the Russian Ministry of Health, Board Member of the Russian Society of Oncohematology.

• Kravchenko Sergey Kirillovich – PhD in Medical Sciences, Associate Professor, Head of the Department of Intensive High-Dose Chemotherapy with 24-Hour and Day Hospital, National Medical Research Center for Hematology of the Russian Ministry of Health, member of the National Hematology Society Association for the Promotion of Development of Hematology and Bone Marrow Transplantation

• Smolyaninova Anna Konstantinovna – PhD in Medical Sciences, Hematologist at the Department of Hematology and Lymphoma Chemotherapy with a Bone Marrow and Hematopoietic Stem Cell Transplantation Unit, National Medical Research Center for Hematology of the Russian Ministry of Health, member of the National Hematology Society Association for the Promotion of Development of Hematology and Bone Marrow Transplantation

• Al-Radi Lyubov Sattarovna – PhD in Medical Sciences, Senior Researcher at the Department of Diagnostics and Treatment of Hematological Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health, member of the National Hematology Society Association for the Promotion of Development of Hematology and Bone Marrow Transplantation

• Falaleeva Natalia Aleksandrovna – MD, PhD, Head of the Antitumor Drug Therapy Department, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, member of the Russian Society of Clinical Oncology and the Russian Association of Therapeutic Radiation Oncologists.

• Stefanov Dmitry Nikolaevich – Researcher, Head of the Scientific and Organizational Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, member of the Russian Society of Oncohematology

• Baykov Vadim Valentinovich – MD, PhD, Professor at the Department of Pathological Anatomy, Head of the Laboratory of Pathomorphology, R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, First Saint Petersburg State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health, member of the Presidium of the Russian Society of Pathologists, member of the Board of the Russian Society of Oncohematology.

• Kovrigina Alla Mikhailovna – Doctor of Biological Sciences, Professor at the Department of Pathological Anatomy, Cytology and Molecular Pathology, Institute for Advanced Training of the Federal Medical-Biological Agency of Russia, Head of the Department of Pathology, National Medical Research Center for Hematology of the Russian Ministry of Health, member of the Presidium of the Russian Society of Pathologists, member of the Board of the Russian Society of Oncohematology.

• Krivolapov Yury Aleksandrovich – MD, PhD, Professor, Head of the Department of Pathology of Clinical Molecular Morphology at the E.E. Eichwald Clinic, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, member of the Pathology Panel of the European Lymphoma Research Network, member of the European Bone Marrow Working Group, member of the Presidium of the Russian Society of Pathologists

• Konovalov Dmitry Mikhailovich – PhD in Medical Sciences, Head of the Pathology Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, member of the Presidium of the Russian Society of Pathologists

• Trofimova Oksana Petrovna – MD, PhD, Professor at the A.I. Savitskiy Department of Oncology and Palliative Medicine, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation

• Sotnikov Vladimir Mikhailovich – MD, PhD, Head of the Methodological Accreditation and Simulation Center for Radiotherapy, Russian Scientific Center of Roentgenology and Radiology of the Ministry of Health of the Russian Federation

• Vinogradova Yulia Nikolaevna – MD, PhD, Associate Professor, Head of the Department of Radiation and Combined Treatment Methods, A.M. Granov Russian National Research Center of Radiology and Surgical Technologies of the Russian Ministry of Health

• Ilyin Nikolay Vasilievich – MD, PhD, Professor, Chief Researcher at the Department of Fundamental Research Methods, A.M. Granov Russian National Research Center of Radiology and Surgical Technologies

Conflict of interest: none declared

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Hematologists.

2. Oncologists.

4. Radiologists.

5. Medical students.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision — at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1 Medical treatment regimens for MZL

During chemotherapy, it is necessary to monitor the patient's weight and recalculate chemotherapy drug doses when the weight changes.

Rituximab monotherapy** [32,33,40,41]

• #Rituximab** 375 mg/m² IV infusion, once weekly for 4 weeks

R-chlorambucil** [84–86]

• #Rituximab**

  • 375 mg/m² IV infusion on days 1, 8, 15, 22, then on day 1 of the corresponding cycles of #chlorambucil** administration (weeks 9, 13, 17, 21)

or

• 375 mg/m² IV infusion on days 1, 8, 15, 22, then #rituximab** 1400 mg SC on day 1 of the corresponding cycles of #chlorambucil** administration (weeks 9, 13, 17, 21) [87–90]

• #Chlorambucil** 6 mg/m² orally daily for one week, weeks 1–6, 9–10, 13–14, 17–18, 21–22

R-CHOP [42,43]

• #Rituximab**

  • 375 mg/m² IV infusion, day 0 or 1 for all cycle courses

or

• 375 mg/m² IV infusion for cycle 1, then #rituximab** 1400 mg SC, day 0 or 1 [87–90]

• Doxorubicin** 50 mg/m² IV infusion, day 1

• Cyclophosphamide** 750 mg/m² IV infusion, day 1

• #Vincristine** 1.4 mg/m² (total dose not exceeding 2 mg) IV, day 1

• #Prednisolone** 100 mg orally, days 1–5

• Filgrastim** 5 mcg/kg subcutaneously (SC) 24–72 hours after the completion of chemotherapy administration and until neutrophil counts recover to normal levels after the nadir, or pegfilgrastim at a dose of 6 mg or empegfilgrastim** at a dose of 7.5 mg subcutaneously, single dose, at least 24 hours after the completion of chemotherapy administration [67–70]

Treatment is resumed on day 22

R-CVP [42,44]

• #Rituximab**

  • 375 mg/m² IV infusion, day 0 or 1 for all cycle courses

or

• 375 mg/m² IV infusion for cycle 1, then rituximab** 1400 mg SC, day 0 or 1 [87–90]

• Cyclophosphamide** 750 mg/m² IV infusion, day 1

• #Vincristine** 1.4 mg/m² (total dose not exceeding 2 mg) IV, day 1

• #Prednisolone** 100 mg orally, days 1–5

Treatment is resumed on day 22

RB [45,46]

• #Rituximab**

  • 375 mg/m² IV infusion, day 0 or 1 for all cycle courses

or

• 375 mg/m² IV infusion for cycle 1, then #rituximab** 1400 mg SC, day 0 or 1 [87–90]

• #Bendamustine** 90 mg/m² IV infusion, days 1, 2

Treatment is resumed on day 22

R2 [53,91]

• Rituximab** 375 mg/m² IV infusion, days 1, 8, 15, 22 of cycle 1 and on day 1 of cycles 2–5

• Lenalidomide** 20 mg/day orally (at a creatinine clearance of 30–60 ml/min – 10 mg/day), days 1–21

Treatment is resumed on day 29. A total of 12 cycles are administered.

Ibrutinib monotherapy** [51]

• Ibrutinib** – 560 mg/day (4 capsules) orally once daily until disease progression or unacceptable toxicity occurs.

Appendix A3.2 Radiotherapy for marginal zone lymphoma.

Radiotherapy parameters are determined depending on the initial extent of the process, localization, and volume of the tumor lesion. Initial target lesions must be identified using contrast-enhanced computed tomography and positron emission tomography.

To reduce the incidence of locoregional recurrences, modern 3D-conformal external beam radiotherapy (EBRT) using linear electron accelerators with multileaf collimators or a proton accelerator with a proton beam should be used. In the absence of linear electron accelerators, external beam radiotherapy is recommended to be performed using teletherapy gamma units. Special immobilization devices must be used during radiotherapy to improve setup accuracy and reproducibility. Volumetric planning with contouring of the lung, heart tissues, and contralateral breast must be performed to minimize dose exposure to them. The dose to the prescribed target is calculated according to the recommendations of the International Commission on Radiation Units and Measurements ICRU-50, 62, and 83 [92]; doses to normal tissues are recommended to be limited according to QUANTEC data, but without compromising the coverage of the planned treatment volume [93].

Due to frequent multifocal involvement, the radiation field must include the entire stomach from the gastroesophageal junction to beyond the bulb of the duodenum and perigastric lymph nodes (even without signs of involvement).

Involved or suspicious lymph nodes of the hepatic hilum and para-aortic lymph nodes must also be included in the treatment volume.

At-risk organs include the kidneys, liver, heart, lungs, intestines, and spinal cord. For example, during gastric radiotherapy, the left kidney falls into the radiation field, which risks the development of radiation nephropathy or hypertension of renal origin.

Pre-radiation preparation and treatment of patients with gastric lymphoma should preferably be performed on an empty stomach (at least 4 hours after a meal). Examination of the excretory function of both kidneys is mandatory before starting treatment. It is advisable to evaluate lung motion and perform radiotherapy with an inspiratory breath hold (respiratory gating).

Total doses are 24–30 Gy with a fraction dose of 1.5–2 Gy (to minimize gastrointestinal toxicity) ± a "boost" of 6 Gy to the measurable tumor; in individual cases, total doses may reach 36 Gy. The use of advanced radiotherapy technologies, such as 3D conformal radiotherapy and its variants (IMRT, VMAT), makes it possible to deliver a high dose to the target organ while reducing it to organs at risk [36].

3–6 months after the completion of radiotherapy, restaging with an endoscopic examination and biopsy of the involved areas is necessary. In case of complete remission (CR), follow-up examinations are recommended every 3–6 months and annually thereafter. Persistence or progression of lymphoma 3–6 months after radiotherapy serves as the basis for chemotherapy according to regimens for follicular lymphoma (FL) of histological grades I–II.

Appendix A.3.3. Splenectomy in splenic MZL

The choice of access for splenectomy (laparoscopic or open laparotomy) is determined by the size of the spleen, topographic and anatomical relations with other organs, and the presence of pronounced adhesions to surrounding organs and tissues (tumor invasion of the spleen) [94–101].

Laparoscopic access to the spleen reduces the number of intraoperative and postoperative complications, decreases postoperative pain, shortens hospital stay, improves cosmetic outcomes, and enhances patients' quality of life [94–101].

Factors complicating laparoscopic splenectomy include portal hypertension, perisplenitis, massive splenomegaly, and previous surgeries [94–101].

1. Splenectomy planning

The hematologist determines the indications for splenectomy. The feasibility and timing of the surgical intervention, necessary preoperative preparation measures, as well as patient management tactics before and after the surgery must be determined jointly by a hematologist, surgeon, anesthesiologist-resuscitologist, and transfusiologist.

2. Preparation for splenectomy

• Transfusion strategy [82,94–96,100]:

Severe thrombocytopenia of less than 20 ◊ 109/L is not a contraindication for splenectomy. The number of platelet transfusion units depends on the complete blood count parameters, the presence of hemorrhagic syndrome, and the infectious process (see Appendix A3.6). A platelet count of more than 50 ◊ 109/L is sufficient to ensure hemostasis.

• Prophylaxis of thrombotic complications [82]:

Elastic compression of the lower extremities (elastic bandages or stockings) is performed in the morning on the day of the surgical intervention.

• An enema is administered in the evening on the eve of the surgery.

• Premedication is administered the evening before as prescribed by the anesthesiologist-resuscitologist.

3. Intraoperative management [82,94,96,101,102]:

Splenectomy can be performed either laparoscopically or via laparotomy; the decision on the optimal surgical access is made by the surgeon depending on the size of the spleen, clinical situation, and comorbidities.

The surgical intervention is performed under combined endotracheal anesthesia. Throughout the entire surgery, a deep level of neuromuscular blockade is required, which involves monitoring of neuromuscular transmission by the anesthesiologist.

For patients without severe cytopenia (hemoglobin > 80 g/L, platelet count > 50 ◊ 109/L) and severe coagulation disorders, all the above-mentioned blood components must be kept in reserve.

To ensure intraoperative hemostasis, monitoring of the main coagulogram parameters (exploratory study of the hemostatic system) is necessary, preferably with the simultaneous use of integral methods for studying the hemostatic system (thromboelastography, thromboelastometry).

One hour before the start of the surgical intervention, a broad-spectrum antibacterial drug is administered. Possible options: Cefazolin** 2 g ± Metronidazole** 0.5 g, Cefuroxime** 1.5 g ± Metronidazole** 0.5 g, Amoxicillin+clavulanic acid** 1.2 g, Amoxicillin+sulbactam 3 g, #Ertapenem** 1 g in case of colonization by resistant microorganisms. In case of allergy to beta-lactams: #Clindamycin** 0.9 g [103].

If blood loss exceeds 1500 ml, repeated administration of a systemic antibacterial drug is recommended. Subsequently, antibacterial therapy is carried out only if infectious complications are detected.

4. Postoperative period [82,94,96,97,100]

Daily monitoring in the postoperative period must be carried out jointly by the surgeon and the hematologist. Monitoring in an intensive care unit (intensive care ward) for 2 hours after surgery is mandatory. Further stay in the intensive care unit depends on the patient's age and somatic status, the volume of blood loss, and the presence of infectious complications.

Measures aimed at early mobilization of the patient are carried out. After 2–4 hours, the patient is allowed to sit and stand by the bed; in the absence of dyspeptic symptoms, oral fluid intake is permitted, and nutrition is resumed 12–24 hours after surgery.

In the early postoperative period, it is necessary to monitor the complete blood count, coagulogram (exploratory study of the hemostatic system), and, if necessary, administer prophylactic anticoagulant/antiplatelet therapy.

If there are risks of thrombotic complications (obesity, hemoblastoses, autoimmune hemolysis), anticoagulant therapy may be prescribed on the first day after surgery. The decision to prescribe anticoagulant therapy is made individually in each specific case. When prescribing anticoagulant therapy, the platelet count, the rate of platelet increase, complete blood count parameters, and the severity of hemorrhagic syndrome should be taken into account. The dose of LMWH (from the B01AB group according to the ATC classification) is calculated depending on body weight (see Appendix A3.10).

5. Algorithm of actions in case of fever in the early postoperative period after splenectomy [95]

The most likely causes of hyperthermia in the postoperative period: postoperative pneumonia, portal system vein thrombosis, subphrenic abscess.

Regardless of the cause of the fever, empirical antimicrobial therapy is advisable; upon identification of an infectious agent and ineffectiveness of the antibacterial therapy, the antibacterial therapy is adjusted taking into account susceptibility to antibacterial drugs. If there is no effect from empirical antibacterial therapy, additional bacteriological studies are recommended after 3 days: nasopharyngeal swabs, microbiological (culture) examination of feces/rectal swab, microbiological (culture) blood examination, microbiological (culture) urine examination, microbiological (culture) examination of lavage fluid (as indicated), and the prescription of antibacterial therapy taking into account the sensitivity of the isolated microflora [95,96,104].

For all patients after splenectomy receiving antibacterial therapy, it is necessary to choose drugs that have activity against pneumococcal infection, regardless of the timing of the infection's development.

If portal vein thrombosis is detected, effective anticoagulant therapy aimed at achieving thrombus recanalization should be administered (see Appendix A3.10) [82,94,100].

When pancreatic-type fluid collections form, ultrasound-guided drainage of pancreatic cysts and ultrasound-guided drainage of abdominal abscesses are advisable [94,96,99].

6. Criteria for discharge from the hospital

Discharge from the hospital is performed upon stabilization of the condition and the absence of the need for round-the-clock surgical observation and care, which is determined by the nature of the pathology, the presence or absence of complications, and the effect of the surgery.

Ambulatory monitoring of the complete blood count and continuation of prophylaxis for thrombotic complications in the presence of indications are necessary.

Indications for initiating specific therapy for a hematological disease are determined by the hematologist and started within the timeframe established in accordance with clinical guidelines depending on clinical indications.

Revaccination against Streptococcus pneumoniae is recommended every 5 years [95,104].

Appendix A3.4 Significance of hepatitis B virus markers in MZL

The significance of HBV infection markers and proposed actions are presented in Table 3.2.1

Table A3.2.1. Significance of hepatitis B virus markers

* If it is necessary to prescribe anti-CD20 in the case of active viral hepatitis B, consultation with an infectious disease specialist or a gastroenterologist specializing in the treatment of hepatitis is indicated, along with continuous intake of Entecavir** 0.5 mg/day [105]. Entecavir** is prescribed for the entire period of treatment/maintenance therapy and for at least 1 year after the completion of immunosuppressive therapy, provided there are repeated negative results of testing for hepatitis B virus DNA in the blood. The optimal duration of Entecavir** therapy after completion of rituximab** therapy has not been determined. If a patient with LMD does not have an indication for specific therapy, there is no need for prophylactic administration of Entecavir** . If resistance to Entecavir** develops, a switch to Tenofovir** is indicated.

Appendix A3.3 Concomitant therapy during the administration of anti-CD20 monoclonal antibodies (#rituximab**, #obinutuzumab**)

Rituximab** [106]

Intravenous administration:

The standard single dose of the drug is 375 mg/m2. The required amount of the drug is withdrawn under aseptic conditions and diluted to the calculated concentration (1–4 mg/ml) in an infusion bottle (bag) with 0.9% sodium chloride** solution for injection or 5% dextrose** solution (solutions must be sterile and pyrogen-free). The prepared infusion solution is stable for 12 hours at room temperature or for no more than 24 hours at a temperature of 2 to 8 °C. The drug is administered intravenously as an infusion (slowly) through a separate catheter. The drug must not be administered as an IV bolus or IV injection.

The recommended initial rate of the first infusion is 50 mg/h; subsequently, it can be increased by 50 mg/h every 30 min, reaching a maximum rate of 400 mg/h. Subsequent infusions can be started at a rate of 100 mg/h and increased by 100 mg/h every 30 min up to a maximum rate of 400 mg/h.

Before each infusion of #rituximab**, premedication (analgesic/antipyretic, antihistamine, glucocorticoid) must be administered 30–60 minutes prior to the infusion.

In the majority of patients, the first infusion is accompanied by a mild-to-moderate infusion-related reaction complex manifested by fever and chills/rigors. Other frequently observed infusion-related symptoms include nausea, pruritus, angioedema, asthenia, hypotension, headache, bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, dizziness, and hypertension. Typically, these reactions occur within 30–120 minutes after the start of the first infusion and resolve upon slowing or interrupting the infusion and administering supportive care (including IV administration of 0.9% sodium chloride**, clemastine/diphenhydramine**, ketoprofen**/paracetamol**). Mild or moderate reactions can be managed by reducing the infusion rate, which can be increased again after symptoms resolve. Patients who develop grade 1–3 infusion reactions should have their infusion rate reduced upon resumption. If an anaphylactoid/anaphylactic reaction or a life-threatening grade 4 infusion reaction develops, the administration of rituximab must be permanently discontinued and necessary emergency care provided.

Due to the risk of hypotension, discontinuation of antihypertensive medications is recommended 12 hours prior to the start of and throughout the entire #rituximab** infusion.

Subcutaneous administration

#Rituximab** in the subcutaneous solution dosage form (1400 mg) may be administered after the full first dose has been given intravenously, including in patients with difficult venous access. The subcutaneous needle should be attached to the syringe immediately prior to administration to prevent potential needle clogging. The drug is administered subcutaneously into the anterior abdominal wall over 5 minutes, avoiding areas with hematomas, induration, hyperesthesia, erythema, birthmarks, and scar tissue. If the injection is interrupted, it can be resumed at the same site or, if necessary, the injection site can be changed. The subcutaneous solution formulation and other subcutaneously administered drugs should be injected into different sites whenever possible. Premedication (analgesic/antipyretic, antihistamine) must be administered before each use of the drug. If the drug is not used in combination with glucocorticoid-containing chemotherapy, glucocorticoids must also be included in the premedication regimen.

#Obinutuzumab** [107]

For the administration of the first dose of 1000 mg of #obinutuzumab** in cycle 1, it is recommended to use 2 infusion bags of different sizes to distinguish between the 100 mg dose intended for administration on cycle 1, day 1 and the 900 mg dose for administration on cycle 1 on the same day or on day 2. To do this, withdraw 40 ml of drug concentrate from the vial; add 4 ml of the concentrate to a 100 ml infusion bag, and the remaining 36 ml of the concentrate to a 250 ml infusion bag containing sterile, pyrogen-free 0.9% sodium chloride solution**. Label each infusion bag.

Subsequently, for repeat administrations, a single dose of 1000 mg of the drug is administered.

The drug must be administered strictly as an intravenous infusion via a dedicated catheter. IV push or bolus administration is prohibited. Only 0.9% sodium chloride solution should be used for dilution.

During the administration of #obinutuzumab**, infusion reactions (including severe ones) may occur. The most frequent are nausea, vomiting, chills, decreased/increased blood pressure, fever, dyspnea, flushing, headache, tachycardia, and diarrhea. According to the prescribing information, to prevent infusion reactions, all patients should receive premedication with analgesics (ATC code N02), systemic antihistamines (ATC code R06A), and glucocorticoids (ATC code H02AB); antihypertensive medications (ATC code C02) should be withheld on the morning of the first infusion, and the dose should be administered step-wise during the cycle [50,107].

If an infusion reaction develops, the infusion rate should be adjusted based on the severity of the observed reaction: for grade 1–3 reactions, temporarily suspend the infusion and administer the medical therapy necessary to resolve symptoms. For a grade 4 reaction, interrupt the infusion and permanently discontinue therapy. Once infusion reaction symptoms have resolved, the infusion may be resumed (except for grade 4 events) at half the rate at which the reaction occurred. If the patient does not experience a recurrence of the same adverse event of the same severity, the infusion rate may be increased using the same increments and intervals as recommended. If the resumed infusion rate is poorly tolerated, follow the infusion rate recommendations for cycle 1, day 1 and day 2.

Blood pressure reduction may occur during the #obinutuzumab** infusion. Therefore, consideration should be given to withholding antihypertensive medications for 12 hours prior to each infusion, during each infusion, and for 1 hour after the end of the #obinutuzumab** infusion.

Anaphylaxis may develop during therapy with #obinutuzumab**; differentiating between a hypersensitivity reaction and an infusion-related reaction can be challenging in such cases. If a hypersensitivity reaction is suspected during the infusion (symptoms typically occur during subsequent administrations, very rarely during the first infusion), the infusion must be stopped and #obinutuzumab** therapy permanently discontinued.

Appendix A3.6 Use of donor blood components in hematological patients

The primary medical indication for red blood cell transfusion in hematologic patients is inadequate organ and tissue oxygenation and the associated risk of complications. Prophylactic donor platelet transfusions are administered to hematologic patients to prevent spontaneous hemorrhagic complications associated with profound thrombocytopenia induced by intensive chemotherapy, or for therapeutic purposes in patients with active bleeding. When replacement of coagulation factors is required, fresh frozen plasma (FFP) remains the universal product of choice today. Indications for its use in acute blood loss include a prolongation of coagulation assay times (coagulation screening test) by more than 1.8-fold; an isolated decrease in a single coagulation factor level by 20% or more, or a decrease in a factor complex by 40% or more. In addition to FFP, blood coagulation factors (ATC code B02BD), protease inhibitors, and antifibrinolytic agents (ATC code B02A) are used to correct hemostatic disorders in acute blood loss. FFP transfusions are also indicated for volume replacement during therapeutic plasma exchange procedures for hyperleukocytosis. The choice of a specific blood component type for transfusion (type of red blood cell component, platelet concentrate, or plasma product) is made by the attending physician or transfusionist in accordance with the clinical situation and pursuant to Order of the Russian Ministry of Health No. 1170n dated October 28, 2020, "On Approval of the Rules for the Provision of Medical Care to the Population in the Field of Transfusiology", Order of the Russian Ministry of Health No. 1134n dated October 20, 2020, "On the Procedure for Medical Examination of the Recipient and Performance of Individual Compatibility Tests, Including the Biological Test, During Transfusion of Donor Blood and/or Its Components", the guidelines "Clinical Use of Red Blood Cell Components" (2018), Decree of the Government of the Russian Federation No. 797 dated June 22, 2019, "On Approval of the Rules for Procurement, Storage, Transportation, and Clinical Use of Donor Blood and Its Components and Repealing Certain Acts of the Government of the Russian Federation", and other regulatory enactments.

Transfusions of red blood cell components (RBCC)

Required pre-transfusion tests

Upon admission to a medical organization, all hematologic patients must undergo primary blood typing in the clinical department using the ABO system and Rhesus factor determination, with the results recorded in the medical documentation.

To prevent transfusion reactions and complications, red blood cell components (RBCC) that are identical or compatible for the ABO system, Rhesus factor, and K antigen are used. For elective RBCC transfusions, donor-recipient compatibility for C, c, E, e, and CW red blood cell antigens is additionally taken into account.

Individual blood component cross-matching is performed for recipients with:

• a history of post-transfusion complications

• pregnancy

• a history of delivering children with hemolytic disease of the newborn

• alloimmune antibodies.

Individual selection does not replace the requirement for a flat-surface compatibility test at room temperature and a biological test performed by the physician conducting the transfusion.

When determining indications for transfusions of donor blood components, the following laboratory tests must be performed:

Before transfusion of cellular donor blood components (red blood cell suspension, platelet concentrate) — complete blood count (CBC).

Before transfusion of fresh frozen plasma (FFP), blood coagulation factor VIII (ATC code B02BD02), and cryosupernatant plasma — coagulogram (screening hemostasis test).

Indications for RBCC transfusion

Transfusion is indicated for patients with chronic anemia at a hemoglobin level of <60 g/L. In this case, donor red blood cell transfusion is performed solely to correct critical symptoms caused by anemia that are refractory to primary pathogenetic therapy.

Red blood cell transfusions are recommended at a hemoglobin level of <100 g/L for patients with sepsis, ischemic heart disease (including myocardial infarction, effort angina), myocarditis, and other cardiomyopathies.

Red blood cell transfusions are indicated for patients over 60 years of age at a hemoglobin level of <100 g/L.

Pregnant patients with blood disorders are recommended to maintain a blood hemoglobin level of at least 80 g/L.

Blood loss amounting to 15–30% of circulating blood volume in the presence of preexisting anemia or comorbid cardiac or pulmonary diseases.

Hemoglobin level below 70–90 g/L in active bleeding.

Hemoglobin level <100 g/L in patients with traumatic brain injury, subarachnoid hemorrhage, chronic respiratory failure, ischemic heart disease, cardiac surgery patients, and elderly patients.

Platelet concentrate transfusions

The threshold platelet count for hospitalized patients undergoing prophylactic platelet concentrate transfusions is considered to be 10 ◊ 109/L in the absence of bleeding risk factors. For outpatients, this value may be higher. Medical procedures, such as central venous catheter (CVC) placement, require prophylactic platelet concentrate transfusions when the peripheral blood platelet count is 20–30 ◊ 109/L or lower, whereas before lumbar puncture or major surgery, the threshold platelet count is raised to 50 ◊ 109/L.

In certain hematological diseases associated with an increased risk of hemorrhagic complications, the threshold platelet count should be increased. In pregnant patients with hematological malignancies, the threshold platelet count is 30 ◊ 109/L.

Platelet transfusion is not indicated for thrombocytopenia of immune origin, except in life-threatening situations involving active bleeding. In thrombocytopathies, platelet transfusion is also not routinely indicated and is performed only in emergency situations: massive bleeding, surgeries, or childbirth.

Indications for prophylactic platelet concentrate transfusion are given in Table A3.6.1.

Table A3.6.1. Indications for platelet concentrate transfusion

* Sepsis, pulmonary diseases, fever.

The presence of hemorrhagic syndrome in a patient is a direct indication for platelet concentrate transfusion regardless of laboratory parameters. The severity of hemorrhagic syndrome is assessed using the WHO scale (Table A3.4.2).

Table A3.6.2. WHO bleeding scale

Calculation of platelet concentrate dose for transfusion

The amount of platelet concentrate for transfusion should be calculated as 50–70 ◊ 109 platelets per 10 kg of recipient body weight or 200–250 ◊ 109 platelets per 1 m2 of recipient body surface area.

The optimal dose for therapeutic transfusions is a subject of debate; based on general consensus, therapeutic transfusions should increase the platelet count to a level that ensures adequate hemostasis.

Criteria for the efficacy of platelet concentrate transfusions

Clinical criteria for the efficacy of platelet concentrate transfusion include cessation or reduction in the severity of spontaneous bleeding, and the absence of fresh hemorrhages on the skin and visible mucous membranes.

Laboratory criteria for the efficacy of platelet transfusion include an increase in circulating platelet count—absolute platelet increment (API) or corrected platelet increment (CPI) at 1 hour and 18–24 hours after the end of transfusion, as well as maximum amplitude parameters on the thrombelastogram.

A transfusion is considered effective if the 1-hour absolute platelet increment is 10 ◊ 109/L above the baseline level. To standardize the evaluation of transfusion efficacy, the corrected platelet increment is calculated using a formula and expressed in calculation units (CU): CPI = (API ◊ body surface area, m2) / number of transfused platelets ◊ 1011.

A transfusion is considered effective if the 1-hour CPI is >7.5 CU and the 24-hour CPI is >4.5 CU. In case of transfusion inefficacy, potential causes must be determined. If refractory transfusions occur or if there is a history of post-transfusion reactions and complications, individual donor platelet matching and plasmapheresis are indicated.

FFP transfusions

Indications for FFP transfusion:

• Emergency reversal of vitamin K antagonist effects (ATC group B01AA); FFP is transfused at 5–8 mL/kg.

• Correction of hemorrhagic syndrome with prolonged (>1.5 times the upper limit of normal) prothrombin time or aPTT.

• Volume replacement during plasmapheresis.

• Indications for transfusion of blood coagulation factor VIII** (ATC code B02BD02)

• Hypofibrinogenemia (<1 g/L).

• Perioperative period or massive bleeding with a fibrinogen level <1.5 g/L.

The calculated dose of blood coagulation factor VIII** (ATC code B02BD02) is 1 IU per 5 kg of patient body weight or 15–20 IU for a body weight of 70 kg. One unit contains: at least 140 mg of fibrinogen and at least 70 IU of FVIII.

Quality of blood components used in supportive care for hematological patients

In hematological diseases with known indications for repeated blood component transfusions (leukemias, lymphomas, myelodysplastic syndromes, aplastic anemia, etc.), to prevent adverse reactions and complications associated with transfusions, the use of blood components with the following characteristics is recommended:

• leukoreduced — leukocyte content in the transfused medium dose is reduced to 1 ◊ 106 cells;

• irradiated red blood cells and platelets (gamma or X-ray irradiation at a dose of 25–50 Gy);

• limitation of donor plasma use through the application of additive solutions for red blood cells;

• following donor blood testing for viral infection markers using molecular biological methods.

To improve transfusion safety, the following technologies may be additionally used:

• pathogen inactivation in platelet concentrate;

• use of additive solutions to replace donor plasma in platelet concentrate;

• expansion of the panel of tested viral infection markers (cytomegalovirus, hepatitis B virus, human T-lymphotropic virus, and others).

The severity of post-transfusion reactions and complications can be determined using the scale presented in Table A3.6.4.

Table A3.6.4. Scale of reaction or complication severity

Premedication before transfusion of donor blood components

To prevent adverse transfusion reactions during repeated blood component transfusions, premedication may be required in accordance with general guidelines.

Adverse reactions associated with the transfusion of donor blood and (or) its components:

• immune:

  • transfusion-related acute lung injury

  • transfusion-associated dyspnea

• non-immune:

  • transfusion-associated circulatory overload

  • post-transfusion hypertension

  • acute non-immune hemolysis

  • septic shock

  • chronic iron overload

The decision to administer glucocorticoids and the choice of dose depend on the severity of the past transfusion reaction or complication, as well as the severity of underlying conditions such as infectious complications (especially during periods of severe neutropenia), diabetes mellitus, arterial hypertension, and others.

Therapeutic plasmapheresis in the management of platelet transfusion refractoriness

If donor platelet cross-matching fails to achieve a sufficient platelet increment and clinical response from platelet concentrate transfusions, plasmapheresis (PP) is added to the therapy to improve the effectiveness of the donor-recipient pair matching. The underlying mechanism of developing platelet concentrate transfusion refractoriness is the alloimmunization of the recipient against donor blood cell leukocyte and platelet antigens. In this case, the goal of PP is to reduce the concentration of circulating alloantibodies and immune complexes.

To overcome platelet concentrate transfusion refractoriness, it is usually sufficient to perform 5–6 PP procedures (ranging from 2 to 15 procedures) combined with individual platelet matching.

PP is performed 2–3 times a week with an interval of 2–3 days.

Volume of plasma removed: 0.5 of the circulating blood volume (CBV) is removed per procedure, with an average of 1,500 mL (1,000–2,000 mL).

To prevent additional alloimmunization by donor blood cell antigens and donor plasma proteins, the replacement of the removed plasma volume is carried out using 5%, 10%, 20% human albumin** solution and 0.9% sodium chloride** solution.

Ratio of 5% human albumin** solution to 0.9% sodium chloride** solution of 1:1 at a total protein level of ≥65 g/L:

• human albumin** 5% – (500–1000 mL), average 800 mL;

• 0.9% sodium chloride** solution – average 800 mL (500–1000 mL).

Methodological aspects of PP in thrombocytopenia refractory to platelet concentrate transfusions:

In the presence of severe thrombocytopenia (≤20 × 10⁹/L), a transfusion of 4–6 platelet doses must be administered before starting the PP procedure, and a platelet concentrate must be ordered for transfusion after the PP procedure is completed.

After the PP procedure, the plasma total protein level must be ≥50 g/L; if the plasma total protein level is lower, additional administration of albumin is required.

After every 2–3 PP procedures, monitoring of the serum protein level and coagulogram (exploratory hemostasis screening) is necessary to rule out coagulation factor deficiency and the development of hemorrhagic syndrome. If coagulation factor deficiency persists, the replacement of the removed plasma volume should be performed using FFP + 5% human albumin** solution and 0.9% sodium chloride** solution.

Ratio of FFP + 5% human albumin** solution to 0.9% sodium chloride** solution of 1:1 at a total protein level of ≥65 g/L:

• FFP – average 500 mL (500–1000 mL);

• Human albumin** 5% 200–300 mL (10–15 g);

• 0.9% sodium chloride solution – average 800 mL (500–1000 mL).

Ratio of FFP + 5% albumin solution to 0.9% sodium chloride** solution of 2:1 at a total protein level of ≤55 g/L:

• FFP – average 800 mL (500–1000 mL);

• Human albumin** 5% 200–300 mL (10–15 g);

• 0.9% sodium chloride** solution – average 500 mL (500–1000 mL).

Appendix A3.7 Vascular access provision

Securing vascular access is an essential component of modern chemotherapy in oncohematological patients. A central venous catheter (CVC) is used to administer chemotherapy drugs, correct electrolyte imbalances, provide parenteral nutrition, and draw blood samples for laboratory tests, etc.

The following features characterize vascular access in hematology: the necessity of exclusively intravenous administration of many medications, massive infusion requirements, compression of major venous vessels by enlarged lymph nodes and/or tumor mass with both intrathoracic and intraabdominal involvement (which significantly complicates vascular access [25]), a high risk of hemorrhagic syndrome (congenital and acquired coagulopathies, thrombocytopenia), thrombosis, and long treatment duration. Overall, oncohematological patients require reliable vascular access for periods ranging from several months to a year, both in inpatient and outpatient settings. The use of peripheral vascular access for this purpose is unacceptable, because most administered solutions are irritating (vesicants, irritants, exfoliants), and extravasation of such drugs into the subcutaneous tissue can lead to tissue necrosis [26]. In addition, many patients often lack accessible peripheral veins due to prior chemotherapy.

Indications for central venous catheterization.

• limited access to peripheral veins,

• need for chemotherapy or parenteral nutrition, massive infusion therapy,

• need for hemodynamic monitoring (central venous pressure),

• need for pulmonary artery pressure monitoring,

• pacemaker placement,

• need for renal replacement therapy.

Contraindications to central venous catheterization

• Absolute contraindications:

  • inflammation at the intended access site

  • recent surgery at the access site

• Relative

  • pronounced hemorrhagic syndrome (due to thrombocytopenia, hypofibrinogenemia, hereditary or acquired coagulopathies).

Thrombocytopenia is one of the most frequent causes of hemorrhagic syndrome. Although we consider a blood platelet count of >20 × 10⁹/L to be safe for catheterization, this threshold cannot be achieved in a number of patients due to various reasons, such as transfusion refractoriness. In these cases, ultrasound-guided central venous catheterization without a dilator may be safe even with a platelet count of less than 20 × 10⁹/L.

Plasma fibrinogen concentration is associated with hemorrhagic complications during CVC insertion: it is significantly lower in patients with hemorrhagic complications than in those without complications [108].

Catheter types

A CVC is a hollow tube placed into one of the central veins. CVCs are made of various materials and have different diameters. CVCs may be equipped with valves at either end, or a port at the proximal end, and may have single or multiple lumens to allow simultaneous infusions of incompatible solutions.

Non-tunneled catheters

These are polyurethane devices ranging from 20 to 30 cm in length with an outer diameter of up to 8 Fr, or 12 Fr in the case of hemodialysis catheters, which are implanted via percutaneous vein puncture (internal jugular, subclavian, axillary, or femoral vein) with the distal tip positioned at the cavoatrial junction. Outpatient use is not recommended because the risk of infection or accidental displacement/removal is higher compared to other catheter types, since they are not tunneled and are held in place by a fixation suture or a sutureless skin securement device at the puncture site [109]. Catheter versions with antimicrobial or antiseptic coatings are available. The use of coated catheters requires further study as the issues of antibiotic resistance remain unresolved.

Tunneled catheters

Tunneled catheters are implantable catheters in which the vein puncture site and the skin exit site are separated using a subcutaneous tunnel. Inside the tunnel, the catheter features a cuff that grows into the surrounding tissue, fixing the catheter within the tunnel and preventing the spread of infection [110].

Tunneled catheter types are preferable to non-tunneled ones, especially when massive infusion therapy is required for more than 3 weeks, particularly in oncohematological patients [111].

Port systems

Fully implantable venous access devices are used to provide long-term central venous access for chemotherapy, parenteral nutrition, and prophylactic administration of clotting factors in hereditary coagulopathies such as hemophilia. Port systems are completely concealed beneath the skin, do not restrict patients' physical activity, and are considered the type of CVC least susceptible to infection [112].

Currently, there are many modifications of port systems, including MRI-compatible modifications and high-flow devices that allow contrast injection using power injectors.

Peripherally inserted central catheters.

Peripherally inserted central catheters (PICCs) are long-term central venous access catheters placed through one of the peripheral veins of the arm into a central vein. PICCs are made of silicone or polyurethane, can be single-, double-, or triple-lumen, and range in diameter from 3 Fr to 7 Fr. PICCs are used for therapy (chemotherapy, hemostatic therapy, etc.) for an average of 6 months to 1 year and are considered a central venous access option that can be used in both inpatient and outpatient settings, daily or intermittently, providing the patient with safety and comfort [27,28]. PICCs have a number of advantages over conventional CVCs. Their insertion excludes the risk of pneumothorax and hemothorax, patients report greater comfort, and sometimes prefer them for cosmetic reasons. An important advantage of PICCs is also a lower rate of infectious complications. PICCs are virtually indispensable in the presence of severe hemorrhagic syndrome.

Dialysis catheters.

A separate category is represented by so-called dialysis catheters, i.e., catheters used for renal replacement therapy, as well as plasmapheresis and leukocytapheresis procedures, and collection of hematopoietic stem cells. This is due to the large diameter of the catheter, as well as the structural features of its distal tip. They are placed during the formation («maturation») of a fistula or graft in patients with chronic renal failure requiring maintenance hemodialysis, or as the sole vascular access in the presence of severe heart failure.

Complications of central venous catheterization

Early complications include those arising during the procedure:

• injury to major arteries,

• formation of a hematoma at the vascular puncture site

• development of pneumothorax, hemothorax,

• injury to the thoracic duct,

• damage to nerve plexuses,

• malposition of the catheter

Late complications, occurring during or after catheter use, are thrombotic, stenotic, and infectious.

Catheter-associated thrombosis (CAT) is defined as a combination of clinical and instrumental signs of thrombosis.

• Clinical signs: skin hyperemia, subcutaneous edema and pain, enhanced superficial venous pattern on the side of catheter insertion, impaired catheter patency, fluid leakage along the catheter tract during infusion.

• Instrumental signs: detection on ultrasound of a hyperechoic mass at the catheter insertion site that completely or partially occludes the vessel lumen, prevents vein wall coaptation during probe compression, shows complete or absence of blood flow on Doppler ultrasound, or reveals turbulent blood flow; vascular opacification defects on CT angiography or direct angiography.

CVC-associated thrombotic complications can be divided into three types:

• «fibrin sheath»,

• catheter obstruction

• mural or occlusive intravascular thrombosis.

Asymptomatic CATs are more common, but their clinical significance is unclear. The detection rate of CAT ranges, according to various sources, from 5% to 12-14% [113,114]. Factors predisposing to the development of CAT are divided into three groups:

1. patient-related (gender, age, presence of tumor disease, thrombophilia);

2. catheter-related (large diameter, catheter material, i.e., a «rigid» catheter);

3. treatment-related (chemotherapy, parenteral nutrition, and administration of other irritant substances).

The presence of an oncological disease increases the risk of thrombosis.

An important role in the formation of CAT is played by the ratio of the catheter diameter to the vein diameter, which should not exceed 1/3, otherwise additional endothelial trauma occurs [29]. When comparing silicone and polyurethane catheters placed in upper arm veins, no significant difference in the incidence of CAT was found, but endothelial damage contributing to the development of thrombosis was noted [115]. Also significant in the pathogenesis of CAT are factors such as procedural trauma, incorrect position of the distal catheter tip, left-sided catheter placement, multiple vein puncture attempts, history and number of prior catheterizations, and past episodes of CAUTI. CVC insertion is accompanied by local injury to the vein wall and endothelium and thrombus formation, with the subsequent development of a «fibrin» sheath. One of the factors in the development of venous thrombosis is the presence of venous valves, which create turbulent flow. A factor contributing to CAT is CVC positioning, as catheter migration, occlusion of the distal catheter tip by the venous wall, trauma to the venous wall by the distal tip, suction of the catheter tip against the wall during blood sample aspiration, and the administration of irritating solutions contribute to vascular wall injury [116]. CVCs are in direct contact with the inner wall of the veins; due to constant catheter movement associated with respiration, heart contractions, and head turns, further endothelial damage occurs. Endothelial trauma is aggravated if the trajectory of the catheter in the vein is characterized by one or more bends [117]. In addition to trauma, intimal inflammation occurs as a response to injury, leading to intimal hyperplasia or thrombosis. Puncture of the left internal jugular vein compared to the right jugular vein is more difficult, as in 34% of patients the left internal jugular vein is smaller than the right [118], which is especially important in diagnosing catheter-associated stenosis (CAS).

Catheter-associated stenosis (CAS) is a persistent narrowing of the vessel lumen, up to complete obliteration, detected by ultrasound at rest and during functional tests, occurring after catheterization, with or without associated CAT. In hemato-oncological patients, along with the aforementioned causes, chemotherapy plays a significant role in the formation of CAT and CAS [119].

Catheter-associated bloodstream infection (CABSI) is the detection of a positive blood culture in a blood sample drawn from the catheter 2 or more hours earlier than in a blood sample drawn from a peripheral vein, and the growth of microorganisms upon microbiological examination of the distal catheter tip [120].

When using tunneled catheters, the following types of infection may occur:

• Tunnel infection – local inflammation along the formed tunnel from the catheter exit site to the cuff or localized exclusively in the cuff fixation area.

• Exit-site infection – local inflammation localized exclusively at the site where the catheter exits onto the skin surface.

• Pocket infection – local inflammation localized at the port-system reservoir insertion site.

Methods for monitoring the distal tip of a CVC

Electrocardiographic method

To monitor the position of CVCs equipped with an integrated electrode, endovenous electrocardiography (ECG) is used. It allows positioning of the distal CVC tip without increasing insertion time, based on changes in the P wave of the ECG.

Radiological method

During the insertion of tunneled CVCs, PICCs, port systems, as well as in cases of atrial fibrillation or pacemaker-driven rhythm, the position of the distal CVC tip is confirmed radiologically:

- on the chest radiograph, the distal tip of the CVC should be located between the 5th and 6th thoracic vertebrae.

- another landmark for positioning the distal CVC tip is the right tracheobronchial angle, which corresponds to the upper border of the superior vena cava. The cavoatrial junction is located 3 cm below this angle.

- another radiological landmark for the entry of the SVC into the right atrium is the intersection of the arch of the right heart border and the line running along the right mediastinal border.

Patient evaluation, preparation for the procedure

To establish vascular access, a consultation with an anesthesiologist-intensivist is required.

A physical examination is performed prior to catheterization to check for inflammatory and postoperative skin changes at potential vein puncture sites, enlarged and altered lymph nodes that could impede catheterization, prominent superficial venous patterns, and clinical manifestations of superior vena cava syndrome (hoarseness, shortness of breath, cough, inability to lie flat, etc.). Anamnestic data are clarified – the number of previous catheterizations, history of catheterization complications; intensity and schedule of planned treatment, potential complications (adverse reactions) of therapy, and the feasibility of alternative treatments, such as radiation therapy.

Laboratory diagnostics.

Prior to CVC insertion, it is necessary to perform:

• a complete blood count (CBC) with differential (if necessary, with blood platelet evaluation on a blood smear)

• coagulogram (exploratory hemostasis study) including APTT, prothrombin index, fibrinogen, and platelet aggregation testing if necessary

• determination of major blood groups (AB0 system) and Rhesus D antigen (Rh factor)

Instrumental diagnostics

Prior to catheterization, it is necessary to perform:

• chest X-ray or, preferably, chest computed tomography (CT) with bolus contrast enhancement (to rule out lung injury and verify correct central venous catheter placement)

• ultrasound Doppler assessment of upper extremity arteries

• ECG

Real-time ultrasound guidance allows selecting the needle trajectory during puncture of the internal jugular, axillary, or femoral vein, thereby avoiding accidental arterial puncture [121].

The use of ultrasound guidance, even during CVC placement in patients with thrombocytopenia (<20 × 10⁹/L), helps prevent severe hemorrhagic complications.

Currently, ultrasound is considered the "gold standard" for central venous catheterization via the jugular approach, as the IJV lies close to the skin surface and there are no intervening muscles to hinder visualization [30]. In addition, the right IJV forms an almost straight line, which reduces vascular trauma and the risk of catheter-related complications.

Ultrasound guidance for central venous catheterization does not replace knowledge of anatomy and surface anatomical landmarks, which remain essential for orienting both the needle and the ultrasound probe itself. Ultrasound guidance allows visualization of not only the vein but also adjacent anatomical structures.

If mediastinal lesions are detected on imaging or in the presence of superior vena cava syndrome, chest CT with bolus contrast enhancement must be performed prior to catheterization to assess the patency of large veins and diagnose thrombotic complications.

Prevention of Complications

Methods for Preventing Early Complications

• Ultrasound guidance for central venous catheterization

Using a 10 MHz linear probe providing a scanning surface of 20–50 mm and a depth of up to 80 mm, or in Doppler mode.

Puncture of the vein is performed under continuous real-time visualization of the needle tip.

Although we consider a blood platelet count above 20 × 10⁹/L to be a safe threshold for catheterization, this target cannot be reached in certain patients due to various reasons, such as transfusion refractoriness. In such cases, central venous catheterization is performed exclusively under ultrasound guidance.

Methods for Preventing Late Complications

Upon completion of use, all catheters must be flushed with an adequate volume of normal saline (Table A3.7.1) and subsequently locked with a locking solution corresponding to the catheter volume. For short-term use (1–2 days), a "heparin lock" (heparin sodium** in normal saline at a concentration of 100 IU/mL) may be used; for long-term catheterization or in patients at high risk of catheter infection, Taurolock solution is preferred.

In case of treatment interruptions, the catheter must be flushed every 24 hours for non-tunneled CVCs, every 7 (10) days for PICCs and tunneled catheters, and every 30 days for port systems.

An aseptic dressing is applied to the catheter insertion site. The dressing must be changed and the insertion site treated according to general principles of surgical antisepsis: twice a week for non-tunneled catheters, once a week for tunneled catheters and PICCs, and as needed (Table A3.7.1). Transparent dressings are preferred to allow daily inspection of the catheter site for inflammatory signs.

Table A3.7.1. Catheter Flushing and Locking Regimens

Physician's Algorithm

The procedure is performed only after obtaining informed consent for catheterization.

1. Physical examination

2. Selection of the CVC type following physical examination, medical history review, and evaluation of laboratory and instrumental test results.

3. Duplex scanning of veins at the intended CVC insertion site (determining vein diameter, compressibility at the puncture site and along the catheter tract, presence of luminal thrombosis, and valve competence. Placing a CVC in a vein whose diameter is less than 50% of the catheter diameter and/or where thrombosis is detected is strictly prohibited).

4. CVC implantation with mandatory positioning of the distal tip at the cavoatrial junction for SVC catheterization, or at the cavoatrial junction / below the renal vein ostia for IVC catheterization.

5. Securing the catheter to the patient's skin at the exit site using suture material or sutureless securement devices.

6. Application of an aseptic dressing.

7. Completion of the catheterization protocol with mandatory documentation of early complications, number of insertion attempts, and type of CVC installed.

Additional Information on Catheter Care (Dressing Change):

1. During CVC dressing changes, the patient may sit or lie supine, with the arm on the side of the catheter positioned alongside the trunk. When using additional catheter clamps, removing the cap is independent of the respiratory phase. For procedures involving a femoral venous catheter, the foot of the bed is lowered by 25°. Removing the cap is independent of the respiratory phase.

2. When changing dressings in patients with sensitive skin, applying a sterile skin protectant barrier around the vascular catheter insertion site and allowing it to dry completely is recommended.

3. The choice of dressing should take into account the patient's individual characteristics. If risk factors for infection are present (CVC in place for more than three days; compromised immune status [oncology patients, etc.]; high risk of catheter colonization), a transparent polyurethane dressing containing a chlorhexidine-impregnated gel pad is recommended. For other cases, a standard sterile transparent dressing is the optimal choice.

4. If bleeding is observed around the catheter insertion site during the first 24 hours post-insertion, a non-woven dressing with an absorbent pad is acceptable, provided it is replaced with a transparent dressing after 24 hours.

5. Transparent polyurethane dressings on CVCs are changed every 5–7 days (provided the dressing is intact, no exudate is present, and visibility is maintained).

6. Visual inspection of the vascular catheter insertion site must be performed at least once daily.

Appendix A3.8 Prevention and treatment of nausea and vomiting

One of the frequent clinically significant side effects of chemotherapy is nausea and vomiting. These adverse events not only impair patient well-being and reduce quality of life, but also hinder oral drug administration and food intake. Although novel combinations of antineoplastic agents have improved outcomes in hemato-oncology patients, severe nausea and vomiting can limit the administration of full-dose chemotherapy and negatively affect treatment adherence. Therefore, controlling nausea and vomiting plays a vital role in supportive care for patients with hemoblastoses [62, 64, 65, 122–125].

Nausea and vomiting occur when the vomiting center is stimulated via several pathways: through the action of neurotransmitters on its receptors, or via afferent impulses from the chemoreceptor trigger zone. Chemical mediators that activate the vomiting center include dopamine, serotonin, histamine, acetylcholine, and substance P (neurokinin-1 [NK-1]). Antiemetic drugs selectively block one or more of these neurotransmitters.

Types of Nausea and Vomiting

• Acute vomiting develops within the first 24 hours after chemotherapy; it is characterized by high intensity and is rarely accompanied by nausea.

• Delayed vomiting develops on days 2–5 after the start of chemotherapy; it is less intense than acute vomiting and is often accompanied by persistent nausea.

• Anticipatory vomiting develops as a conditioned reflex to chemotherapy and/or associated procedures and the environment; the risk of its development increases with the number of chemotherapy cycles and it may persist for a long time after the end of chemotherapy.

• Uncontrolled nausea and vomiting develop despite adequate antiemetic prophylaxis and require additional management.

• Refractory vomiting occurs during subsequent courses of chemotherapy when antiemetic prophylaxis and/or rescue medications were ineffective in previous treatment courses.

Emetogenic potential of antineoplastic agents

Emetogenicity is the risk of vomiting in patients receiving an antineoplastic agent (as monotherapy, without antiemetic therapy). There are 4 grades of emetogenic potential (see Table A3.8.1) [62,64,65,122–125]:

• minimal – vomiting develops in less than 10% of patients;

• low – vomiting develops in 10–30% of patients;

• moderate – vomiting develops in 30–90% of patients;

• high – vomiting develops in more than 90% of patients.

Table A3.8.1. Emetogenicity level of individual antineoplastic agents used in the treatment of malignant lymphomas

Expert recommendations on the principles of antiemetic treatment are based on the emetogenic potential category of the antineoplastic agent [62,64,65,122–125]. The emetogenic potential of intravenous agents is usually determined for a single-day administration regimen, i.e., based on the single dose emetogenicity. The emetogenicity classification of oral agents is based on the emetogenicity of a full treatment course. The emetogenicity of a combination chemotherapy regimen is generally determined by the agent with the highest emetogenic potential. This rule holds true for regimens containing highly emetogenic cytotoxic agents. A combination of moderately emetogenic cytotoxic agents may increase the emetogenicity of the regimen as a whole.

Antiemetics

For clinical use, 5 groups of drugs with antiemetic effects are employed [62,64,65,122–125]:

• Serotonin 5-HT3 receptor blockers. This group of drugs includes ondansetron**, granisetron, tropisetron, palonosetron. The mechanism of action is due to the ability to selectively block serotonin 5-HT3 receptors, preventing the vomiting reflex triggered by the stimulation of vagal afferent fibers by serotonin released from enterochromaffin cells of the GI mucosa. 5-HT3 receptor antagonists also suppress the central components of the vomiting reflex by blocking 5-HT3 receptors in the area postrema of the fourth ventricle of the brain. The drugs are administered 30–60 minutes before chemotherapy. ECG and electrolyte monitoring is required in patients with signs of cardiac disorders. 5-HT3 receptor blockers can prolong the QT interval; therefore, 5-HT3 antagonists should be avoided in patients with congenital long QT syndrome, except for palonosetron, which has no effect on the QT interval. Palonosetron is a highly selective serotonin receptor antagonist with the longest half-life (up to 40 hours). It is administered as a single dose on Day 1 of Cycle 1 for a single-day chemotherapy course, and every other day for a multi-day chemotherapy course.

Table A3.8.2. Dosing schedule for 5-HT3 receptor antagonists

• Glucocorticoids. If the chemotherapy regimen includes glucocorticoids, additional administration of #dexamethasone** for antiemetic purposes is not required. The addition of #dexamethasone** to serotonin receptor antagonists reduces the risk of acute nausea and vomiting and prevents delayed nausea and vomiting. In addition, it has intrinsic antiemetic activity and can be used as monotherapy for the prophylaxis of acute vomiting after administration of low-emetogenicity cytotoxics. The drug is prescribed at a dose of 12 mg IV once, 30–60 minutes before chemotherapy. In the case of highly emetogenic therapy, it is prescribed orally on subsequent days at a dose of 8 mg twice daily for up to 5 days [62,123,125].

• Neurokinin-1 (NK-1) receptor antagonists – specific drugs from the group "A04AD Other antiemetics". This group includes aprepitant and fosaprepitant. Aprepitant is a selective, high-affinity central NK-1 receptor antagonist (via binding to brain NK1 receptors). The central action of aprepitant is long-lasting, and it inhibits both acute and delayed phases of vomiting, while also enhancing the antiemetic activity of serotonin 5-HT3 receptor blockers (e.g., ondansetron**) and glucocorticoids (dexamethasone**). NK1 receptor antagonists are moderate inhibitors of CYP3A4, which must be considered when co-administering drugs metabolized by the same system (e.g., aprepitant reduces the efficacy of hormonal contraceptives, thus alternative contraception methods must be used; aprepitant increases glucocorticoid concentrations, therefore the dose of #dexamethasone** must be reduced by approximately 50% when combined with aprepitant; patients receiving #warfarin** require additional monitoring of the international normalized ratio). NK1 receptor antagonists are used in combination with glucocorticoids and serotonin 5-HT3 receptor blockers. Aprepitant is taken one hour before chemotherapy, and fosaprepitant is administered 30 minutes before chemotherapy at the doses presented in Table 7.6.3.

Table A3.8.3. Dosing schedule for NK1 receptor antagonists

• Dopamine receptor blockers can be used for nausea prophylaxis during low-emetogenicity chemotherapy. This group includes GI motility stimulants (metoclopramide**), aliphatic phenothiazine derivatives (#chlorpromazine** 25 mg orally every 6 hours [62,123,125]), butyrophenone derivatives (haloperidol** 1–2 mg orally every 4–6 hours), and benzodiazepine derivatives (#lorazepam 0.5–2 mg orally or intramuscularly/intravenously, single dose 50 mcg/kg every 4–6 hours [62,123,125]). These drugs have sedative and anxiolytic properties. Metoclopramide**, previously widely used in high doses for the prophylaxis of acute nausea and vomiting after high- and moderate-emetogenicity chemotherapy, is now used less frequently because, despite comparable efficacy to serotonin receptor antagonists, it has a significant number of pronounced side effects. According to international guidelines, the use of metoclopramide** is acceptable in standard doses for the prophylaxis of acute nausea and vomiting following low-emetogenicity chemotherapy, and for the prophylaxis of delayed vomiting in combination with #dexamethasone**. The dosing regimen is 10 mg 1–3 times daily intravenously or orally. The addition of dopamine receptor blockers to the antiemetic therapy regimen is carried out according to indications at the discretion of the attending physician.

• Antipsychotics (diazepines, oxazepines, thiazepines, and oxepines – N05AH according to the ATC classification). The addition of antipsychotics to the antiemetic therapy regimen is carried out according to indications at the discretion of the attending physician (e.g., in case of uncontrolled nausea and vomiting – #olanzapine 5–10 mg daily orally [62,125]).

Principles of prophylaxis and treatment of nausea and vomiting.

Experts of the Multinational Association of Supportive Care in Cancer (MASCC) have developed principles of antiemetic therapy, according to which the following algorithm and methods for nausea and vomiting prophylaxis are used [62,125].

Algorithm for the prophylaxis and treatment of nausea and vomiting:

• Determine the emetogenic potential of the prescribed chemotherapy regimen

• Prescribe prophylactic therapy based on the emetogenicity of the chemotherapy regimen, starting from the first cycle

• Prescribe treatment if nausea and vomiting develop despite prophylactic therapy

• In case of nausea and vomiting, modify prophylactic therapy for subsequent chemotherapy cycles

• The criterion for the efficacy of antiemetic therapy is the complete absence (complete control) of vomiting and nausea for 24 hours (the period of acute vomiting development) from the moment of antineoplastic agent administration.

Prophylaxis of acute and delayed nausea and vomiting in highly emetogenic chemotherapy

Prevention of nausea and vomiting should begin before chemotherapy and continue for at least 2–3 days after its completion. Antiemetics are prescribed daily on all days of chemotherapy (exception: palonosetron — every other day) based on the emetogenic potential of the cytostatics administered on a given day. The choice of antiemetic combination is based on the chemotherapy component with the highest emetogenicity. Currently, the most effective antiemetic combination is an antiemetic drug regimen including an NK1 receptor antagonist + a serotonin 5-HT3 receptor blocker + #dexamethasone** (not added if #dexamethasone** is already included in the chemotherapy regimen). Additionally, as indicated and at the discretion of the attending physician, benzodiazepine derivatives (N03AE per ATC classification), H2-histamine receptor blockers (A02BA per ATC classification), and proton pump inhibitors (A02BC per ATC classification) may be used. Aprepitant may be prescribed at a dose of 125 mg on day 1 and 80 mg on subsequent days [62,64,65,122–125].

Prevention of acute and delayed nausea and vomiting in moderately emetogenic chemotherapy

Prevention of nausea and vomiting should begin before chemotherapy and continue, if necessary, for another 2–3 days after its completion. Currently, the most effective antiemetic combination is an antiemetic drug regimen including a serotonin 5-HT3 receptor blocker + dexamethasone**. For certain moderately emetogenic regimens containing carboplatin**, it is recommended to prescribe aprepitant/fosaprepitant in combination with a serotonin 5-HT3 receptor blocker and #dexamethasone** [62,64,65,122–125].

Prevention of acute and delayed nausea and vomiting in low-emetogenic and minimally emetogenic chemotherapy

For the prevention of nausea and vomiting in low-emetogenic chemotherapy, only one of the following drugs should be used: #dexamethasone**, a serotonin 5-HT3 receptor blocker, or metoclopramide**. With minimally emetogenic chemotherapy, prevention of nausea and vomiting is not required [62,64,65,122–125].

Prevention of nausea and vomiting during radiation therapy

When irradiating the upper torso and extremities, antiemetic therapy is generally not required. If antiemetics need to be prescribed, the emetogenic potential is determined by the maximum emetogenic impact (based on the radiation field or the medicinal product in case of combined radiation therapy and chemotherapy) and taking into account the irradiation area. Antiemetics (mainly serotonin 5-HT3 receptor blockers) are most often used via non-invasive routes (orally, rectally) 30–60 minutes before irradiation. If serotonin 5-HT3 receptor blockers are insufficiently effective as monotherapy, glucocorticoids may be added [62,64,65,122–125].

Management of uncontrolled nausea and vomiting

If uncontrolled nausea and vomiting occur despite the planned administration of standard antiemetic therapy corresponding to the emetogenicity of the given chemotherapy regimen, causes unrelated to the direct administration of cytostatics must be ruled out (gastrointestinal pathology, electrolyte disturbances, hyperglycemia, uremia, brain metastases, side effects of opioid analgesics, psychophysiological causes). If these are ruled out, the patient should be switched from a low-emetogenic to a moderately emetogenic prevention regimen, or from a moderately emetogenic to a highly emetogenic one. If uncontrolled nausea and vomiting occur against the background of standard antiemetic regimens (without the use of aprepitant or fosaprepitant), aprepitant or fosaprepitant must be introduced into the antiemetic regimen for subsequent cycles [62,64,65,122–125].

The development of uncontrolled or refractory vomiting may occur in patients with the so-called ultra-rapid metabolizer phenotype (accelerated hepatic metabolism of 5-HT3 receptor antagonists). In such cases, switching the 5-HT3 blocker to another antiemetic of this drug class is advisable.

In addition, a number of general principles for the prevention and treatment of nausea and vomiting should be followed:

• Administer antiemetics strictly on a schedule rather than upon the onset of nausea or vomiting.

• Assess the preferred route of drug administration (parenterally, via rectal suppositories, or orally).

• Provide adequate hydration and electrolyte correction.

• Add H2-histamine receptor blockers or proton pump inhibitors in case of dyspepsia.

If uncontrolled nausea and vomiting develop during a standard three-drug antiemetic regimen, there is no standard approach; adding drugs of a different class from the reserve group should be considered [62,125]:

• benzodiazepine derivatives (e.g., #lorazepam 0.5–2 mg every 4–6 h);

• #metoclopramide** 20 mg every 6 h);

• aliphatic phenothiazine derivatives (e.g. #chlorpromazine** 25 mg 4 times a day);

• butyrophenone derivatives (e.g., haloperidol** 1–2 mg every 4–6 h).

An alternative regimen for the prevention of nausea and vomiting is also possible [125]:

• #olanzapine 5–10 mg daily orally on days 1 to 3;

• palonosetron 0.25 mg IV 60 minutes before chemotherapy on day 1 once;

• #dexamethasone** 20 mg IV 30 minutes before chemotherapy on day 1.

Prevention and treatment of anticipatory nausea and vomiting

For the prevention and treatment of anticipatory nausea and vomiting, optimal prevention of nausea and vomiting in each chemotherapy cycle is of primary importance. Also, given the psychogenic mechanism, benzodiazepine derivatives are used (e.g., #lorazepam 0.5–2 mg at bedtime the night before and in the morning prior to chemotherapy), along with non-pharmacological methods such as psychotherapy, hypnosis, and systematic desensitization [62, 64, 65, 122–125].

Appendix A3.9 Prevention of gastric and duodenal ulcers during glucocorticoid therapy

The vast majority of antineoplastic treatment protocols for oncohematological diseases include high doses of glucocorticoids (GCs). Gastric or duodenal ulcer is one of the serious side effects of GC therapy. The mechanism of the ulcerogenic action of GCs includes increased hydrochloric acid secretion in the stomach, changes in the qualitative composition of mucus, and inhibition of surface epithelial regeneration. When GCs are combined with nonsteroidal anti-inflammatory drugs and anticoagulants, the risk of steroid ulcers increases. Due to their ulcerogenic potential, antisecretory therapy is necessary when using GCs to prevent steroid ulcers [66, 126].

Diagnosis of gastric and duodenal ulcers during GC use

The formation of gastrointestinal ulcers may present with dyspepsia and abdominal pain, but is often asymptomatic, manifesting as bleeding or perforation.

Esophagogastroduodenoscopy is used to diagnose gastrointestinal ulceration, with biopsy and H. pylori testing when necessary.

Prevention of gastric and duodenal ulcers during GC use.

Based on a meta-analysis of 300 studies [127], gastric and duodenal ulcers heal in almost all cases if intragastric pH is maintained above 3 for 18 hours per day. Taking this rule into account, antacids, H2-histamine receptor blockers, and proton pump inhibitors (PPIs) can currently be considered as anti-ulcer therapy. According to one of the latest meta-analyses, the use of PPIs or H2-histamine receptor blockers significantly improves ulcer healing and reduces the risk of recurrent bleeding. Only drugs from these two classes allow achieving and maintaining the required gastric pH environment for gastroduodenal ulcer healing.

Currently, two classes of drugs are used for antisecretory purposes to prevent gastric and duodenal ulcers, including during glucocorticoid therapy: proton pump inhibitors and H2-histamine receptor blockers [128, 129].

Proton pump inhibitors (PPIs)

Proton pump inhibitors (PPIs, proton pump blockers, H+/K+-ATPase blockers, hydrogen pump blockers) are antisecretory drugs that block the H+/K+-ATPase of the lining (parietal) cells of the gastric mucosa and reduce hydrochloric acid secretion by penetrating into the parietal cells of the gastric mucosa, concentrating in the secretory canaliculi, and becoming activated at an acidic pH. Upon activation, PPIs form strong covalent bonds with the mercapto groups of cysteine residues of H+/K+-ATPase, blocking the action of the proton pump so that it is irreversibly excluded from the process of hydrochloric acid secretion. The effect of PPIs on the final stage of hydrochloric acid production in the stomach is dose-dependent and provides highly effective inhibition of basal and stimulated hydrochloric acid secretion regardless of the triggering factor. The PPI group includes #omeprazole**, #lansoprazole, #pantoprazole, #rabeprazole, and zomeprazole**, which are used during courses of specific antineoplastic therapy that includes systemic GCs [128–130].

The time of day and food intake do not affect PPI activity. Dose adjustment is not required in renal impairment. If oral administration is not feasible, PPIs are administered intravenously.

H2 histamine receptor blockers

Gastric secretory responses to exogenous or endogenous histamine are mediated through H2 histamine receptors. Histamine H2 receptor blockers are competitive antagonists of histamine and suppress hydrochloric acid secretion induced by various stimuli by displacing histamine from its bond with H2 receptors on parietal cells. Drugs in this group maintain intragastric pH values > 3 throughout the day. The use of H2 histamine receptor blockers for 1–1.5 months leads to the healing of ulcer defects in 70–80% of patients with duodenal ulcers and 55–60% of patients with gastric ulcers. Nevertheless, following the introduction of PPIs into clinical practice as baseline antisecretory therapy, H2 blockers are used less frequently, mainly when PPIs cannot be used [128–130].

Appendix A3.10 Prevention of thrombotic complications

The incidence of VTE in lymphomas ranges from 1.5 to 59.5% and depends on the lymphoma variant, disease stage, and localization [131, 132]. In high-grade lymphomas, the risk of VTE is higher than in low-grade lymphomas (8.3% vs. 6.3%). Compression of venous vessels by tumor mass, which occurs in 22% of lymphoma patients, contributes to the development of VTE [131, 132].

In lymphomas, risk factors for VTE include age over 60 years, intoxication syndrome, as well as chemotherapy and radiation therapy. In particular, after chemotherapy, VTE is recorded in more than 70% of patients during the first 3 months of treatment. Lenalidomide** therapy is associated with an increased risk of VTE and therefore strictly requires prophylaxis for thrombotic complications.

When deciding on prophylaxis, individual VTE risk must be taken into account (Table 7.5.1).

Table A3.10.1. Assessment of VTE risk in patients with lymphomas

The determination of the duration of antithrombotic prophylaxis should be based on assessing the persistence/cessation of risk factors for thrombosis. These factors primarily include the activity of the underlying disease, chemotherapy and radiation therapy, patient mobility restriction, the presence of inflammatory activity of infectious or non-infectious origin, and respiratory or heart failure. If thrombosis-provoking factors are not fully resolved and a high risk of VTE persists, antithrombotic prophylaxis must be continued. At the initial stage of antithrombotic prophylaxis in patients with 0–1 VTE risk factors, acetylsalicylic acid** may be used; in patients with ≥ 2 risk factors, the drugs of choice are low-molecular-weight heparins (LMWHs – specific drugs from the B01AB heparin group, including #dalteparin sodium 100 IU/kg twice daily or 200 IU/kg once daily, #enoxaparin sodium** 100 IU/kg twice daily or 150 IU/kg once daily, #nadroparin calcium 86 IU/kg twice daily or 172 IU/kg once daily, parnaparin sodium**, bemiparin sodium), vitamin K antagonists (VKAs – warfarin**), or direct oral anticoagulants (DOACs – B01AE direct thrombin inhibitors [#dabigatran etexilate**], B01AF #rivaroxaban** B01AF01, #apixaban** B01AF02, direct factor Xa inhibitors, and B01AX other antithrombotic agents [fondaparinux sodium]) [133]. There are no clear advantages of certain LMWHs, VKAs, or DOACs over others.

Table. Recommended direct oral anticoagulants for the treatment of venous thromboembolic events in cancer patients

Warfarin** should be taken once a day at a fixed time (preferably in the evening) after meals. The dose of warfarin** is adjusted based on the INR value. The target INR values during warfarin** therapy are 2–2.5. In patients with artificial heart valves, the INR during warfarin** therapy should be 3.0–4.0. The starting dose for patients who have not previously used warfarin** is 2.5–5.0 mg/day. For patients who have previously used warfarin**, the recommended starting dose is double the known maintenance dose of the drug and is prescribed during the first 2 days. If it is necessary to switch a patient from LMWH injections (from the B01AB group according to the ATC classification) to long-term VKA administration, it is recommended to continue LMWH injections (from the B01AB group according to the ATC classification) at a prophylactic dose for the first 4–5 days of warfarin** administration to avoid thrombotic complications due to VKA-induced suppression of protein C activity. The first INR check should be performed 24–48 hours after starting warfarin**. During the first week, INR determinations are recommended daily. After 3–4 days of concurrent administration of warfarin** and heparin sodium**, an INR test is performed. When the INR reaches 2.0 or higher, heparin sodium** is discontinued. If the INR is less than 2.0, the warfarin** dose is increased by 0.5 tablets, and concurrent administration of warfarin** and heparin sodium** is continued for 3 days. The INR test is repeated. If the INR is 2.0 or higher, heparin sodium** is discontinued. Thereafter, laboratory monitoring is performed regularly every 4–8 weeks.

Table A3.10.3. Warfarin** dose adjustment based on INR

If pathological bleeding occurs during warfarin** treatment, Quick's prothrombin (INR) must be determined, and warfarin** must be discontinued. Prothrombin complex concentrates or fresh frozen plasma (FFP) are used in the treatment of severe warfarin-induced bleeding.

Switching patients from parenteral drugs to direct oral antithrombotic agents can be performed according to the following algorithm:

• treatment with direct oral anticoagulants should be started 0–2 hours before the next scheduled parenteral anticoagulant administration;

• replacement of a scheduled dose of the parenteral drug with an oral anticoagulant dose: for LMWHs and fondaparinux sodium – after 24 hours, for UFH – after 8 hours (for #rivaroxaban** [B01AF01 according to the ATC classification] – oral administration immediately after discontinuing UFH).

VKA and DOAC preparations can be used as monotherapy for the prophylaxis of thrombotic disorders during chemotherapy and other types of specific treatment.

Currently, switching patients from oral anticoagulants to parenteral anticoagulants is carried out according to the following algorithm:

• for dabigatran etexilate** (B01AE07 according to the ATC classification) or #rivaroxaban** (B01AF01 according to the ATC classification), a 24-hour break from the last dose is required, after which a parenteral anticoagulant must be administered;

• for #apixaban** (B01AF02 according to the ATC classification), wait 12 hours from the last dose and administer a parenteral anticoagulant.

Appendix A3.11 Autologous hematopoietic stem cell transplantation

Mobilization and collection of peripheral blood hematopoietic stem cells

Mobilization is a sharp increase in the number of hematopoietic stem cells (HSCs) in the peripheral blood under the influence of growth factors.

Historically, mobilization regimens were based on the use of chemotherapeutic agents, as a temporary increase in the circulation of stem cells in the blood was observed during hematopoiesis recovery. However, the results of HSC collection were unsatisfactory. The first mentions of the presence of factors affecting hematopoiesis in the blood date back to the early last century. In the mid-20th century, two groups of researchers from the USA and Australia developed an agar culture system in which the growth of hematopoietic progenitor cell colonies was observed upon the addition of certain substances. These substances were named colony-stimulating factors (CSFs). Their further study made it possible to isolate several types of CSF: granulocyte (G-CSF), granulocyte-macrophage (GM-CSF), macrophage (M-CSF), as well as interleukin-3 (IL-3) [134].

In clinical practice, recombinant G-CSF preparations have become the most widely used as stimulators of leukopoiesis. Currently, the use of G-CSF is the standard for HSC mobilization.

Several HSC mobilization regimens used in oncohematology have been developed, each of which employs G-CSF.

Decision-making algorithm prior to HSC mobilization

• assessment of the patient's status (presence of indications for autologous hematopoietic stem cell transplantation (auto-HSCT), standard examination to exclude factors preventing high-dose treatment, comorbidities, patient consent, review of prior therapy - number of courses and dates of treatment completion, use of radiation therapy)

• assessment of disease status - depth of antitumor response, presence of remission, time to achievement;

• assessment of hematopoiesis (bone marrow biopsy to detect hematopoietic lineage suppression as well as bone marrow infiltration by tumor cells)

The most accessible immunological marker of hematopoietic progenitors is the expression of the CD34 antigen. This molecule is present on both the most primitive stem cells and differentiated progenitors, whereas mature hematopoietic cells do not express CD34.

It is precisely the total pool of CD34+ cells that determines the timing of hematopoietic recovery after transplantation [135,136]. Repeated attempts have been made to establish the number of CD34+ cells required for rapid and successful hematopoietic recovery after transplantation [136–139].

Currently, it is generally accepted that the minimum number of cells required to perform a single autologous transplantation is 2×10⁶ CD34+ cells/kg of the patient's weight, and the optimal number is 3–5 × 10⁶ CD34+ cells/kg. Some studies indicate that when using a graft containing more than 5×10⁶ CD34+ cells/kg, a shorter duration of neutropenia and thrombocytopenia is observed.

However, no carefully planned prospective randomized trials have been conducted, so it is not possible to determine the effect of high doses of CD34+ cells on engraftment kinetics [136].

Risk factors for ineffective HSC mobilization

Despite the improvement of techniques and the introduction of new drugs, HSC mobilization failure remains a problem for patients with oncohematological diseases [140]. The Italian research group GITIMO defined criteria for proven and probable risk of HSC mobilization failure in patients with MM and NHL.

Proven risk factors for failure include two parameters: if circulating blood CD34+ counts do not reach 20 cells per 1 µL on days 4–6 after the start of G-CSF, or if fewer than 2 × 10⁶ CD34+ cells/kg are harvested over 3 leukapheresis procedures.

Criteria for probable risk of HSC mobilization failure include a history of prior ineffective HSC mobilization; prolonged chemotherapy or radiation therapy; the use of lenalidomide** at previous stages of treatment; an advanced phase of the disease requiring at least two lines of chemotherapy. Bone marrow cellularity of less than 30% at the time of mobilization and age over 65 years are also risk factors for ineffective mobilization [141].

In the case of an insufficient number of harvested HSCs, the issues of growth factor dose escalation, repeated mobilization using a different regimen, and bone marrow harvest are discussed. Currently, peripheral blood-derived HSC transplantation is displacing bone marrow transplantation. This is because methods for collecting cells from the peripheral blood are less invasive, and hematopoietic recovery after HSC transplantation occurs faster than after bone marrow transplantation.

The goal of mobilization is to harvest an adequate number of CD34+ cells, sufficient to perform one or two transplantations.

Below is a detailed description of drugs that stimulate the release of HSCs into the peripheral blood.

Drugs used for HSC mobilization.

Granulocyte colony-stimulating factor

G-CSF is a glycoprotein that accelerates the proliferation of neutrophil progenitor cells in the bone marrow, their differentiation into mature neutrophils, and their release from the bone marrow into the peripheral blood. The use of G-CSF, both following a course of chemotherapy (CT) and independently of it, leads to the mobilization of hematopoietic progenitor cells into the peripheral blood.

G-CSF significantly increases the peripheral blood neutrophil count within the first 24 hours after administration. Following the discontinuation of G-CSF, the neutrophil count in the peripheral blood decreases by 50% within 1-2 days and returns to normal values within 1-7 days.

Pharmacokinetic studies of G-CSF have shown that the drug is rapidly eliminated from the body, which necessitates multiple injections. To prolong its duration of action, a polyethylene glycol (PEG)-conjugated form of G-CSF was developed. In this pegylated drug, PEG is covalently attached to the N-terminal peptide of the molecule, increasing its size, which leads to a slowdown in renal clearance. The circulation time of the pegylated form in the blood increases from 3.5 hours to 42 hours. Following a single injection of the drug, high neutrophil levels are maintained in the blood for 9 days [142].

G-CSF dosing regimen for HSC mobilization

Filgrastim** is administered at a dose of 5 or 10 mcg/kg/day subcutaneously, depending on the HSC mobilization regimen. Pegylated G-CSF (empegfilgrastim**) is administered as a single subcutaneous dose of 7.5 mg [143].

Special instructions for G-CSF administration

An increase in spleen size is observed during G-CSF therapy. During clinical trials, splenomegaly was detected by palpation in 31% of patients with severe chronic neutropenia. Radiography revealed that spleen enlargement occurred shortly after the administration of G-CSF and subsequently tended to stabilize. It was established that reducing the dose of the drug halted splenomegaly; splenectomy was required in 3% of patients. It is necessary to regularly monitor spleen size during HSC mobilization.

The efficacy and safety of G-CSF in patients with severe renal or hepatic impairment have not been studied; therefore, caution should be exercised when using the drug in this category of patients [144].

Side effects of G-CSF

Adverse events following administration occur in 30% of cases, both in patients and in healthy donors.

The most common complications are bone pain, headaches, and generalized fatigue. Myalgia, anxiety, insomnia, hyperhidrosis, fever, nausea, and injection site skin reactions are less common [145].

Ossalgia is associated with changes in bone tissue metabolism under the action of G-CSF. The pain can be intense and throbbing in nature, most frequently localized in the spine and pelvic bones. Pronounced bone pain syndrome during HSC mobilization requires adequate analgesia.

Plerixafor

Bone marrow stromal cells secrete stromal cell-derived factor-1α (SDF-1α, CXCL12). The receptor for SDF-1α is CXCR4, which is present on the surface of HSCs. The interaction between SDF-1α and its receptor CXCR4 is essential for "retaining" the stem cell in the bone marrow.

Plerixafor is a selective reversible antagonist of the chemokine receptor CXCR4. It blocks CXCR4 by binding to SDF-1α, as a result of which HSCs "detach" from the bone marrow stroma and enter the peripheral blood.

It is believed that plerixafor-induced leukocytosis and an increase in the number of circulating hematopoietic progenitor cells are the result of disrupting the bond between CXCR4 and its ligand, which leads to the appearance of both mature and multipotent cells in the systemic circulation. CD34+ cells mobilized using plerixafor are functional and capable of engraftment, with long-term potential for population reconstitution [146].

Plerixafor is used to enhance the mobilization of hematopoietic stem cells into the peripheral blood for their collection and subsequent autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with lymphoma and multiple myeloma, in combination with G-CSF.

Plerixafor dosing regimen

The recommended dose of plerixafor is 0.24 mg/kg/day. The drug is administered subcutaneously 6-11 hours before the start of apheresis, following preliminary 4-day therapy with G-CSF. In clinical trials, the drug was typically used for 2-4 consecutive days (up to 7 days of continuous administration).

In patients with renal impairment and a glomerular filtration rate (GFR) of less than 50 mL/min, the dose of plerixafor should be reduced by 1/3 to 0.16 mg/kg/day. Clinical data on the use of the adjusted dose of the drug are limited. Current clinical experience with plerixafor does not allow for dosing recommendations in patients with a GFR of less than 20 mL/min.

Special precautions for the use of plerixafor

Thrombocytopenia.

Thrombocytopenia is a known complication of apheresis and is observed in patients receiving both G-CSF and plerixafor.

Potential for tumor cell mobilization in patients with lymphoma.

The consequences of potential tumor cell reinfusion have not been adequately studied. When plerixafor is used in combination with G-CSF for hematopoietic stem cell mobilization in lymphoma, tumor cells may be released from the bone marrow and subsequently collected during leukapheresis. The clinical significance of the potential risk of tumor cell mobilization has not been fully determined. In clinical trials involving patients with non-Hodgkin lymphoma, tumor cell mobilization was not observed with plerixafor administration.

Vasovagal reactions

Vasovagal reactions, orthostatic hypotension, and/or syncope may occur following subcutaneous injection of the drug.

Splenomegaly

In clinical trials, the effect of plerixafor on spleen size was not specifically evaluated. Given that the use of G-CSF can provoke splenomegaly, as well as the combined use of plerixafor and G-CSF, regular monitoring of spleen size is necessary.

Adverse effects of plerixafor

The most frequent complications include musculoskeletal pain, headaches, dizziness, insomnia, general fatigue, diarrhea, and nausea. Flatulence, constipation, dry mouth, hyperhidrosis, and injection site skin reactions also occur.

HSC mobilization regimens

Currently, the following HSC mobilization regimens are widely used in oncohematology:

1. G-CSF monotherapy

2. G-CSF following myelosuppressive chemotherapy (CT + G-CSF)

3. G-CSF combined with plerixafor

G-CSF monotherapy

This regimen is also referred to as "mobilization under steady-state hematopoiesis," since the patient does not develop myelotoxic agranulocytosis (MTA).

Indications

• HSC mobilization in healthy donors;

• HSC mobilization in patients with oncohematological diseases;

• HSC mobilization in patients for whom the "chemotherapy + G-CSF" regimen is not safe (in the presence of comorbidities, cardiac pathology, dialysis-dependent renal failure);

• Re-mobilization following initial HSC mobilization failure using regimens that include myelosuppressive drugs.

HSC mobilization regimen

Filgrastim** is prescribed at a dose of 10 mcg/kg/day, administered subcutaneously in the morning (or 5 mcg twice daily). Leukapheresis begins on the fourth day of G-CSF administration, provided there is an adequate number of CD34+ cells in the peripheral blood. When their count exceeds 10–20 cells/mcL, cell separation is initiated. If peripheral blood CD34+ cells are less than 10 cells/mcL, leukapheresis should be omitted and cell counts repeated the following day. The number of leukapheresis sessions depends on the HSC collection results; harvesting the optimal number of CD34+ cells requires 2–4 procedures (ranging from 1 to 5). On the final day of leukapheresis, G-CSF is not administered (Table 1).

Table 1. "G-CSF monotherapy" HSC mobilization regimen

G-CSF after myelosuppressive chemotherapy

Indications

• HSC mobilization in patients with oncohematological diseases

"Chemotherapy + G-CSF" HSC mobilization regimen

Myelosuppressive chemotherapy stimulates the proliferation of stem and progenitor cells, leading to an increased release of HSCs from the bone marrow into the blood. The principle of this HSC mobilization regimen is as follows: the patient is administered a chemotherapeutic agent (or multiple agents) according to the corresponding treatment protocol, and then, after the development of myelotoxic agranulocytosis (MA), leukopoiesis stimulation with filgrastim** is initiated at a dose of 5 mcg/kg/day.

Provided that peripheral blood leukocytes recover and an adequate number of CD34+ cells are present among them, HSC collection procedures are initiated (typically on days 6–8 of G-CSF administration).

Figure 1 shows the algorithm for determining the indications for the first leukapheresis. The number of leukaphereses depends on the HSC collection result (from 1 to 5). On the final day of leukapheresis, G-CSF is not administered.

G-CSF combined with plerixafor

Indications

• Remobilization after failure of the first HSC mobilization using regimens that include myelosuppressive drugs combined with G-CSF or G-CSF monotherapy in patients with lymphomas and multiple myeloma (MM);

• Suboptimal results of current mobilization in patients with lymphomas and MM.

Unsatisfactory results of current mobilization:

• peripheral blood CD34+ cell count on the day of the planned first leukapheresis is less than 10 cells/µL (for a planned single autologous transplantation) and 10–20 cells/µL (for a planned tandem autologous transplantation);

• less than 30–50% of the required number of CD34+ cells is harvested during the first leukapheresis.

HSC mobilization regimen

Filgrastim** is prescribed at a dose of 10 mcg/kg/day, administered subcutaneously in the morning. On the fourth day of filgrastim** administration, plerixafor is administered 12 hours prior to leukapheresis at a dose of 240 mcg/kg subcutaneously. Based on the leukapheresis results, the need for repeated administration of plerixafor is determined (Table 2). Multiple doses of plerixafor may be used.

Table 2. "G-CSF + plerixafor" HSC mobilization regimen

Comparative characteristics of HSC mobilization regimens

No prospective randomized trials comparing mobilization methods (growth factor alone vs. combination of G-CSF with myelosuppressive chemotherapy) in the same patient cohort have been conducted, and direct comparison of different studies is difficult. Therefore, the optimal HSC mobilization method cannot be definitively determined.

Each HSC mobilization regimen has certain advantages and disadvantages; therefore, an individualized approach is taken in selecting the treatment scheme for each specific situation (Table 3). For instance, using G-CSF monotherapy shortens hospitalization times, avoids complications typical of the MA period, and eliminates the need for transfusion therapy. This regimen is relatively safe in patients with dialysis-dependent renal failure and cardiac pathology.

However, in patients with a long treatment history, the likelihood of a suboptimal HSC collection result is high. The "chemotherapy + G-CSF" regimen frequently allows for the harvesting of an adequate number of cells, but is associated with the development of infectious and toxic complications during the MA period, and requires the administration of intensive supportive care, which prolongs hospitalization.

Table 3. Comparative characteristics of HSC mobilization regimens

Chemotherapy – chemotherapy, RT – radiation therapy

Numerous studies aimed at optimizing stem cell mobilization regimens are ongoing, the possibilities of using new growth factors are being discussed, and various doses of cytotoxic drugs are being tested.

Features of supportive care during HSC mobilization

G-CSF monotherapy and G-CSF combined with plerixafor

• If peripheral venous access is difficult, a central venous perfusion catheter is placed prior to initiating HSC collection;

• For the prevention of thrombotic complications, #enoxaparin sodium** 40 mg or its equivalent is administered subcutaneously once daily at a prophylactic dose during G-CSF administration and for 2–3 days after its discontinuation [147];

• Adequate analgesia for bone pain caused by G-CSF administration. Opioids are preferred (trimeperidine** 10 mg IV, tramadol** 100 mg IV, fentanyl** 25 mcg/h transdermally); in the absence of myelotoxic agranulocytosis, nonsteroidal anti-inflammatory and antirheumatic drugs may be used.

"Chemotherapy + G-CSF" regimen:

• placement of a central venous catheter (CVC) is necessary to ensure vascular access. If there are difficulties with peripheral venous access, the central catheter is replaced with a perfusion catheter before initiating HSC collection;

• continuous infusion of #heparin sodium** around the clock for the prevention of thrombotic complications. The initial dose of #heparin sodium** is 12,000 IU/day, followed by monitoring of aPTT (aPTT 1.5–2 times the upper limit of normal) [147];

• the administration of chemotherapy drugs is accompanied by massive hydration at a rate of 1.5–3 L/m2, along with hypouricemic therapy (except for regimens containing methotrexate**), and diuretic therapy.

• if ifosfamide** or cyclophosphamide** is included in the chemotherapy regimen, mesna** is administered on the day of drug administration at a dosage in accordance with the product labeling to protect the mucosa of the urinary bladder and urinary tract;

• if methotrexate** is included in the chemotherapy regimen, calcium folinate** is administered 12 hours after its completion at a dose of 25 mg orally and intravenously 6 times a day for 4 days or until blood methotrexate concentrations fall below 0.1 mcmol/L.

• antiemetic therapy (see Appendix A3.8);

• prophylaxis of gastric and duodenal ulcers (see Appendix A3.9);

• ovarian protection is performed in women of reproductive age.

Leukapheresis and cryopreservation

Leukapheresis

Leukapheresis is a semi-selective method of extracorporeal hemocorrection based on the separation of plasma and blood cells under centrifugal force and the isolation of the leukocyte fraction from the blood [148].

As mentioned above, the primary criterion for predicting a successful HSC collection is the peripheral blood CD34+ cell count on the day of the anticipated first leukapheresis. If HSC collection is initiated too early, a greater number of procedures will be required, leading to increased financial and labor costs. Furthermore, an increased number of leukaphereses results in a larger total volume of the harvested product. Consequently, a greater amount of cryoprotectant (dimethyl sulfoxide – DMSO) is used, which can cause adverse effects upon subsequent intravenous infusion during auto-HSCT [149].

When evaluating the number of progenitor cells, special attention should be paid to the quantification method. The results of flow cytometric analysis of CD34+ cell counts vary depending on the specific methodology, and recommendations regarding cell counts based on studies conducted in other laboratories should be interpreted with caution.

On the day of the anticipated first collection, a complete blood count and flow cytometric CD34+ blood cell count are performed.

The absolute count of CD34+ HSCs in the blood is calculated using the formula:

Absolute CD34+ cell count in blood (cells/µL) =

fraction of CD34+ cells (%) × leukocyte count (10^9/L) × 10

If the peripheral blood CD34+ cell count is greater than 10–20/µL, the first leukapheresis can be initiated.

If the absolute CD34+ cell count in the blood exceeds 20/µL, there is a high probability of graft harvesting within 1–2 leukapheresis procedures.

If CD34+ cells are detected in the blood in a quantity of 10–20/µL, 2–4 leukapheresis procedures are typically required.

If the CD34+ cell count is less than 10/µL, it is advisable to refrain from cell collection on that day and repeat the analysis the following day.

If the CD34+ cell count is less than 5/µL, the option of discontinuing mobilization or potentially using plerixafor should be discussed.

The leukapheresis procedure can be performed in either automatic or semiautomatic mode. When the leukocyte count exceeds 20 × 10^9/L, the semiautomatic mode is preferred to allow manual adjustment of the interface boundary.

Absolute contraindications for leukapheresis include severe decompensated somatic diseases and life-threatening conditions.

Examples of relative contraindications include a significant decrease in hemoglobin or platelet counts, which can be compensated by transfusion support prior to the procedure. Immediately before the procedure, it is necessary to measure blood pressure, assess the patient's general condition, and review the results of biochemical blood tests and a coagulogram (exploratory hemostasis screening).

The HSC collection procedure takes about 3–4 hours. During leukapheresis, if hypocalcemia develops (manifested by paresthesia of the lips, tongue, and fingertips), the blood return rate must be slowed down. To prevent citrate reactions, it is recommended to administer 10 ml of a 10% calcium gluconate solution** or 5 ml of a 10% calcium chloride solution** per 200 ml of citrate solution for patients with a body weight <60 kg, or per 400 ml for patients with a body weight >70 kg [150].

An HSC sample is taken from the harvested product to determine the CD34+ cell content using a flow cytometer. There are many recommended protocols for counting CD34+ HSCs, the most well-known being the ISHAGE protocol (International Society of Hematotherapy and Graft Engineering) [151].

Thus, for a successful HSC collection, the timely initiation of the first leukapheresis procedure and a well-established laboratory technique including flow cytometric analysis are essential.

Graft Cryopreservation

In parallel with the CD34+ cell count, fractionation of the obtained leukapheresis product is performed. First, a two-chamber polymer bag is labeled (the first chamber for "plasma", the second for "hematopoietic stem cells"), the leukoconcentrate is transferred into the HSC bag under aseptic conditions, and centrifugation (2000 rpm) is carried out for 15 min.

Fractionation is performed under aseptic conditions, for example, in a Class II biological safety cabinet. Next, CD34+ cells are counted in the obtained leukoconcentrate. Having obtained the fraction of CD34+ cells out of all leukocytes in the leukoconcentrate, the number of CD34+ cells per 1 kg of the patient's body weight is calculated.

The cryopreservation process includes several stages. First, the required amount of DMSO solution to be added to the HSCs is calculated. The obtained biomaterial with the cryoprotectant is transferred into a cryopreservation bag, and air bubbles are thoroughly removed.

Freezing and storage of the biomaterial are carried out in a container with liquid nitrogen vapors.

Patient evaluation prior to mobilization and HSC collection

Before initiating hematopoietic stem cell mobilization, it is necessary to determine the phase of the disease, assess the patient's somatic status, and evaluate hematopoiesis. To this end, all patients undergo a routine evaluation panel comprising both laboratory and instrumental methods.

General examination methods

1. Complete blood count (CBC) with differential

2. Biochemical blood test (general clinical) with mandatory determination of total protein, albumin, creatinine, uric acid, potassium, calcium, and lactate dehydrogenase levels

3. Urinalysis

4. Blood glucose test

5. Coagulogram (exploratory hemostasis study)

6. Acquisition of bone marrow cytologic specimen via puncture, bone marrow smear cytologic examination (myelogram)

7. Obtaining a bone marrow histological specimen, pathomorphological examination of bone marrow biopsy (surgical) material (including the use of immunohistochemical methods)

8. Examination of biological material (bone marrow) by flow cytometry to determine minimal residual disease markers

9. Determination of main ABO blood groups, Rhesus D antigen (Rh factor), and determination of subgroups and other minor blood groups A-1, A-2, D, Cc, E, Kell, Duffy

10. Molecular biological blood test for Hepatitis B virus and Hepatitis C virus; molecular biological blood test for Human immunodeficiency virus HIV-1

11. Electrocardiography

12. Echocardiography

13. Holter ECG monitoring – in case of rhythm and conduction disorders detected on the ECG

14. Abdominal ultrasound (comprehensive)

15. Ultrasonic Dopplerography of lower extremity vessels (arteries and veins) – if necessary

16. Esophagogastroduodenoscopy with biopsy – in case of a history of dyspeptic disorders or gastric/duodenal ulcer

17. Brain MRI

18. Chest computed tomography

19. Lumbar puncture followed by cytological, comprehensive immunochemical, and immunophenotypic examination of the cerebrospinal fluid if central nervous system involvement is suspected

20. Obstetrician-gynecologist examination and pelvic ultrasound – for women

21. Positron emission tomography combined with CT

22. Clonality testing (B/T depending on the disease variant) in peripheral blood and bone marrow by polymerase chain reaction

23. Determination of blood immunoglobulin G, A, and M levels

24. Peripheral lymph node ultrasound

25. CT of the chest/abdomen/pelvis – to assess antitumor response if PET/CT is not feasible or contraindicated

Contraindications to auto-HSCT

Absolute contraindications to auto-HSCT

- progression/relapse of the underlying disease;

- infectious diseases in the acute stage;

- diseases of the musculoskeletal system, circulatory system, digestive and respiratory organs, urogenital, endocrine, and nervous systems, as well as diseases of other organs and systems in the acute stage accompanied by persistent functional impairment;

- presence of "second" malignant neoplasms not in remission;

- therapy with immunosuppressive or other medicinal products that may affect the self-renewal capacity and pluripotency of hematopoietic stem cells;

- mental disorders and behavioral disorders in the acute stage and/or posing a danger to the patient and others;

- mental and behavioral disorders caused by psychoactive substance use;

- cachexia;

- pregnancy;

- early postoperative period with potential risks of postoperative wound infection during the period of myelotoxic agranulocytosis.

- absence of signed informed consent for transplantation.

Relative contraindications for auto-HSCT

- infectious diseases not in the acute stage (infection foci requiring sanitization);

- diseases of the musculoskeletal system, circulatory system, digestive and respiratory organs, urogenital, endocrine, and nervous systems, as well as diseases of other organs and systems in the compensated stage;

- age over 65 years.

- presence of human immunodeficiency virus markers in the blood;

Evaluation of patients prior to auto-HSCT

Before performing autologous hematopoietic stem cell transplantation, it is necessary to determine the phase of the disease, assess the patient's performance status and hematopoiesis. To this end, all patients undergo a routine set of examinations, including both laboratory and instrumental methods.

General examination methods

1. Complete blood count (CBC) with differential

2. Biochemical blood test (general clinical) with mandatory determination of total protein, albumin, creatinine, uric acid, potassium, calcium, and lactate dehydrogenase levels

3. Urinalysis

4. Blood glucose test

5. Coagulogram (exploratory hemostasis study)

6. Acquisition of bone marrow cytologic specimen via puncture, bone marrow smear cytologic examination (myelogram)

7. Obtaining a bone marrow histological specimen, pathomorphological examination of bone marrow biopsy (surgical) material (including the use of immunohistochemical methods)

8. Examination of biological material (bone marrow) by flow cytometry to determine minimal residual disease markers

9. Determination of main ABO blood groups, Rhesus D antigen (Rh factor), and determination of subgroups and other minor blood groups A-1, A-2, D, Cc, E, Kell, Duffy

10. Molecular biological blood test for Hepatitis B virus and Hepatitis C virus; molecular biological blood test for Human immunodeficiency virus HIV-1

11. Electrocardiography

12. Echocardiography

13. Pulmonary function testing

14. Holter ECG monitoring – in case of rhythm and conduction disorders detected on the ECG

15. Abdominal ultrasound (comprehensive)

16. Ultrasonic Dopplerography of lower extremity vessels (arteries and veins) – if necessary

17. Esophagogastroduodenoscopy with biopsy – in case of a history of dyspeptic disorders or gastric/duodenal ulcer

18. Brain and paranasal sinus MRI to identify latent foci of infection

19. Chest computed tomography

20. Lumbar puncture followed by cytological, comprehensive immunochemical, and immunophenotypic examination of the cerebrospinal fluid if central nervous system involvement is suspected

21. Dentist examination.

22. Obstetrician-gynecologist examination and pelvic ultrasound – for women.

23. Positron emission tomography combined with CT.

24. Clonality testing (B/T depending on the disease variant) in peripheral blood and bone marrow by polymerase chain reaction.

25. Determination of polyclonal immunoglobulin levels (A, G, M).

26. Contrast-enhanced chest CT for primary mediastinal involvement.

27. Peripheral lymph node ultrasound.

28. Lactate dehydrogenase activity.

29. Chest/abdominal/pelvic CT – to assess antitumor response if PET/CT is not feasible or contraindicated.

Pre-transplantation conditioning regimens for auto-HSCT

The goal of high-dose chemotherapy is to eliminate tumor cells remaining after antitumor therapy with minimal toxic impact on organ systems.

For conditioning regimens prior to transplantation in NHL, HL, and plasmablastic lymphoma, the BEAM conditioning regimen is used, which consists of BCNU (300 mg/m² × 1, day -6), VP (200 mg/m², days -5 to -2), Ara-C (200 mg/m² twice daily, days -5 to -2), and MEL (140 mg/m²/day × 1, day -1) [152–154]. Administration schedules and doses are presented in Table 4.

Early toxicity of the BEAM regimen includes severe mucositis, nausea and vomiting, diarrhea, hepatotoxicity, nephrotoxicity, and non-infectious pulmonary complications.

Late toxicity includes pulmonary complications such as chronic interstitial fibrosis and decreased diffusing capacity of the lungs (21%), infection (30%), metabolic syndrome (17%), cardiovascular complications (12%), and secondary malignancies (20%).

Table 4. BEAM pre-transplant conditioning regimen [152–156]

To reduce the toxicity of the BEAM conditioning regimen, lomustine (CEAM / LEAM) is used instead of carmustine in certain cases. The drug administration schedule and doses are presented in Table 5.

Table 5. CEAM/LEAM conditioning regimen [152,156–159]

The efficacy of the Benda-EAM conditioning regimen in lymphoproliferative disorders has been confirmed in a number of clinical trials. The drug administration schedule and doses are presented in Table 6.

Table 6. Benda-EAM conditioning regimen [160,161]

Autologous hematopoietic stem cell infusion.

Hematopoietic stem cell infusion is performed into a central venous catheter observing aseptic and antiseptic principles.

The time interval from the completion of chemotherapy to HSC infusion must be at least 24 hours.

Before starting the transplantation procedure, the physician must inspect the cryopreserved bags containing HSCs, verify that the packaging is intact and undamaged, and match the identification data on the packaging with the patient's data.

For the first infusion, the bag with the highest cellularity is selected. Metal objects (clamps, forceps, etc.) must not be used when handling the bag. If there are multiple cryopreserved HSC bags, it is advisable to take breaks between infusions. In some cases, HSC administration over 2 days is permissible (elderly, debilitated patients).

Cryopreserved HSCs are thawed in a water bath or automated thawer at a temperature of 37 °C. After thawing, the physician must ensure that there are no ice fragments or clots in the bag. Afterwards, the physician connects the bag to the infusion set.

In some cases, premedication using standard doses of promedol is performed prior to the administration of the leukocyte concentrate into the central venous catheter.

The initial infusion rate of HSCs is 3–5 mL/min (4–5 minutes), after which the rate can be increased to the maximum possible. Vital signs (blood pressure, heart rate, respiratory rate) are monitored during and after HSC infusions.

If hemolysis develops, the infusion of the next bag is suspended until complications are resolved.

Upon completion of the infusion, the CVC lumen is flushed with sodium chloride**.

Two hours after the completion of the infusion, a general clinical biochemical blood test is performed (assessment of electrolytes), and urine color is evaluated to rule out hemolysis.

An operation protocol is completed in the medical chart, indicating the stages of HSC administration, time intervals, and the patient's condition.

A general (clinical) urinalysis is performed the next day.

Supportive care in auto-HSCT.

Infusion therapy

Infusion therapy is administered to all patients to reduce conditioning toxicity and prevent tumor lysis syndrome.

Basic principles of infusion therapy during auto-HSCT:

• All infusions are performed via a central venous catheter.

• During the pre-transplantation conditioning phase, the volume of infusion therapy is 2–3 liters per day; after transplantation, the infusion volume should be at least 1.5 liters per day, with fluid loading distributed evenly throughout the day.

• In patients on hemodialysis, the volume of saline solutions should not exceed 1 liter per day, while potassium chloride** is prescribed only if hypokalemia develops.

• To assess fluid balance and prevent volume overload, the patient should be weighed daily, and central venous pressure, blood pressure, diuresis, and fluid balance should be monitored.

• If febrile neutropenia develops, the volume of infusion therapy should be increased to 3–4 liters per day under fluid balance monitoring.

• Regular monitoring of electrolytes (potassium, sodium, calcium, chloride, magnesium) is necessary to adjust infusion therapy; in cases of severe hypocalcemia or hypomagnesemia, intravenous calcium and magnesium preparations are prescribed.

• Hypouricemic therapy is administered during pre-transplantation conditioning.

• The administration of diuretics for forced diuresis is recommended during pre-transplantation conditioning.

Antisecretory therapy

Currently, two classes of drugs are used for antisecretory purposes: proton pump inhibitors (PPIs) and H2-histamine receptor blockers [66,126]. PPIs can be administered at any time of day, and food intake does not affect drug activity. Dose adjustment is not required in renal failure. If oral administration is not possible, PPIs are administered intravenously.

Currently, PPIs are the mainstay of therapy. The results of randomized comparative studies indicate the high efficacy of PPIs compared to H2-blockers [130]. PPIs are almost 1.5 times more effective than H2-blockers regarding the epithelialization of ulcer defects [129].

Patients undergoing courses of specific antitumor therapy may also be prescribed medications from the H2-histamine receptor blocker group for prophylactic purposes.

Antimicrobial therapy

According to various authors, the use of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation leads to infectious complications in more than 90% of patients [162–166].

The main factors determining the development of infections in immunocompromised patients are neutropenia (depth, duration, and rate of onset), impaired cellular and humoral immunity, damage to the gastrointestinal mucosa, and the presence of a CVC.

The highest incidence of infectious complications is observed in patients with a duration of neutropenia of 10 days or more [166].

Clinical manifestations of the infectious process in this category of patients, especially during the neutropenic period, are extremely scarce. Previously, fever of unknown origin (elevated body temperature without any other manifestations of infection) was the most frequent manifestation of febrile neutropenia (≈ 50% of cases) [167].

Microbiologically and clinically proven infections were less common. Clinically proven infections are those that can be verified using physical or instrumental diagnostic methods in the absence of microbiological confirmation. The microbiological confirmation of an infection during granulocytopenia in most cases is the isolation of microorganisms from blood cultures.

Recently, diagnostic capabilities for infectious complications have expanded significantly, both through the introduction of new methods and the improvement of previously used ones, as well as the reduction of turnaround time in microbiology due to the introduction of automated analyzers and new technologies for microorganism identification into laboratory practice.

During the first 24 hours, the only symptom is typically an elevated temperature, and information about bacteremia or pneumonia in neutropenic patients is usually not obtained until the second day of the infectious episode. Therefore, the main principle of treating infectious complications in patients with febrile neutropenia is an empirical approach to prescribing antibacterial drugs, applying them at the first signs of infection or fever before the causative agents are identified. At the same time, the empirical approach to prescribing systemic antibacterial drugs is relative, since their choice is determined by a retrospective analysis of verified pathogens and their antibiotic susceptibility.

Diagnostic tests performed for fever in LPD patients during auto-HSCT [147]

In all cases of an infectious process, diagnostics aimed at identifying both the sites of infection and the etiological agents should be actively pursued.

When infection is suspected, clinical samples from patients must be taken promptly. Special emphasis should be placed on the need for close attention and thorough microbiological studies in patients receiving glucocorticoids and in elderly individuals.

In this group of patients, septicemia may occur without fever (which occurs in 70% of severely ill patients aged 66 years and older), or the fever may be only subfebrile.

Table 9. Algorithm for the diagnosis of infectious complications in LPD patients during auto-HSCT.

Daily patient examination

In neutropenia, a thorough patient examination is performed daily, which, along with standard therapeutic examination protocols, includes the following approaches:

• Active questioning of the patient regarding possible symptoms of infection, including pain along the esophagus and in the perineum.

• Daily examination of the oral mucosa in neutropenia, especially the periodontium. Attention is paid to friability, mucosal edema (mucositis), plaque, and ulcers.

• Examination of the skin for the possible appearance of septicopyemic lesions in case of fever, even in the absence of patient complaints. During glucocorticoid therapy, septicopyemic lesions may occur even at normal body temperature.

• Inspection of the venous catheter insertion site.

• Careful auscultation of the chest. Harsh breathing in the absence of rales, or a minimal number of moist rales in a limited area, may be an initial manifestation of pneumonia.

• Thorough palpation of the abdomen. The first symptoms of pseudomembranous colitis are the appearance of pain or "gurgling" upon palpation in the right iliac fossa (region of the cecum).

Microbiological blood culture

Indications: temperature ≥ 38°C or the presence of septicopyemic skin lesions.

Venous blood is drawn before antibiotic administration into two bottles (aerobes/anaerobes or aerobes/aerobes) simultaneously from a vein and from a central venous catheter (CVC) or from different veins; in peritonitis or abdominal surgery, into two different bottles (for aerobes and anaerobes); in infective endocarditis, 3 times at intervals of 1–2 hours; in suspected catheter-related bloodstream infection, simultaneously from a vein and a CVC into bottles for an automated blood culture analyzer (Bactec or other automated analyzers). Based on the time difference (2 hours or more) in the appearance of microbial growth, venous catheter infection can be suspected. In catheter-related infection, a positive blood culture from the CVC precedes a positive blood culture from the vein by 2 hours or more.

Blood collection for microbiological examination should be performed during a temperature spike (≥ 38°C) with strict adherence to aseptic rules to eliminate the likelihood of culture media contamination by skin microflora. The nurse must wear gloves and a mask during blood collection; the patient's skin at the venipuncture site is thoroughly treated with a disinfectant solution (the disinfectant solution must dry); after skin disinfection, repeated palpation of the vein to locate the venipuncture site is not performed.

It is extremely important to obtain a sufficient volume of blood for blood culture – for a single test in adults, a total of 20–30 ml of blood is drawn into 2–3 bottles (10 ml each bottle).

Blood cultures from a CVC without a concomitant peripheral blood culture should not be sent to the laboratory.

Blood culture bottles must not be placed in a refrigerator.

Isolation of coagulase-negative staphylococci (the majority of which is Staphylococcus epidermidis) must be confirmed by two blood cultures, due to the high probability of contamination of the blood samples by these microorganisms (obligate microflora). This also applies to Corynebacterium spp. A repeat test should be performed as close in time to the initial test as possible.

Microbiological blood culture drawn simultaneously from a vein and a central venous catheter in suspected catheter-related infection

Indications:

• Hyperemia (infiltrate) at the catheter insertion site.

• Fever associated with infusions through the catheter.

• Poor catheter patency (difficulties in flushing or blood withdrawal from the catheter).

• Onset of fever >38°C upon neutrophil recovery (granulocyte count >0.5 × 109/L).

• Onset of fever >38°C outside of neutropenia (granulocyte count >0.5 × 109/L) in a patient with a central venous catheter in place for ≥ 7 days.

Catheter-related bloodstream infection most commonly develops outside the period of neutropenia or during neutrophil recovery.

In persistent fever (≥ 38°C), blood cultures are repeated every 4–5 days.

Microbiological examination of the central venous catheter

The catheter is removed and sent for examination to the bacteriology laboratory.

Indications:

• Suspicion of catheter-related infection.

• Isolation of yeast or mold fungi from the blood.

• Transfer of a patient from another hospital with a CVC.

• Granulocyte recovery in patients with sepsis caused by gram-negative bacteria.

If a patient is transferred from another hospital with a CVC, the catheter is removed on the day of admission to the new clinic.

For bacteriological examination, an aseptically removed distal catheter segment 5–6 cm long is used. The removed catheter segment is placed in a Petri dish or another sterile container and immediately delivered to the laboratory for analysis. Storage and subsequent examination of a removed catheter is unacceptable.

The examination is carried out using a semi-quantitative (Maki roll plate method) or quantitative method. Diagnostic significance (confirming catheter infection) in the semi-quantitative method is the isolation of microorganisms at ≥15 CFU, and in the quantitative method at ≥103 CFU/mL. To diagnose a catheter-related infection, in addition to isolating microorganisms in diagnostically significant quantities from the removed catheter, the same microorganism must be isolated from the blood.

If signs of inflammation and discharge appear at the venous catheter insertion site, a microbiological examination of the discharge must be performed; if these changes persist or become chronic, testing for non-tuberculous mycobacteria should be performed.

Routine testing of all removed catheters is not performed.

Microbiological urine analysis

Indications:

• Symptoms of urinary tract infection.

• Leukocyturia.

• Prolonged fever of unknown origin.

The morning midstream urine sample is submitted for analysis; urine delivery to the laboratory must be immediate, with the maximum allowable time from collection to delivery being 2 hours.

Microbiological examination of urine collected from a Foley catheter or urine collection bags is not performed due to plastic contamination. Urine testing in these cases should be performed on the day the urinary catheter is placed. Microbiological examination of a removed Foley catheter is also not performed.

Bacteriuria is diagnostically significant if a single microorganism is isolated at a concentration of ≥103 CFU/mL.

If two microorganisms are isolated at concentrations of ≥103 CFU/mL, the microbiological urine analysis is repeated the following day. Repeated isolation of the same microorganisms (except for bacteria specified in the footnote) confirms a urinary tract infection.

Any amount of bacteria in urine obtained by suprapubic bladder aspiration is considered significant bacteriuria.

Bacteriuria is considered asymptomatic if the same pathogen is detected at a concentration of ≥105 CFU/mL in two consecutive samples collected more than 24 hours apart.

The most common causative agents of urinary tract infections are Enterobacteriaceae, predominantly Escherichia coli, followed by Staphylococcus saprophyticus (more frequently in young women), Enterococcus spp., and Pseudomonas aeruginosa.

When coagulase-negative staphylococci are isolated from urine in monoculture (≥104 CFU/mL), additional testing is performed to identify Staphylococcus saprophyticus.

A high count of Staphylococcus epidermidis (≥105 CFU/mL) is diagnostically significant.

Repeated isolation of Candida spp. from urine in patients with febrile neutropenia without a urinary catheter indicates a high probability of disseminated invasive candidiasis.

Isolation of microorganisms such as diphtheroids, viridans group streptococci, lactobacilli, and coagulase-negative staphylococci (except for Staphylococcus saprophyticus) from urine indicates sample contamination (skin, vagina).

Microbiological examination of cerebrospinal fluid

Indications:

• Symptoms of meningitis.

• "Cerebral" symptoms accompanied by fever and neutropenia.

• Detection of brain lesion(s) on CT or MRI.

The material must be delivered to the laboratory immediately in a sterile tube or in a syringe with a capped tip.

CSF samples should not be refrigerated.

A complete examination (bacteria, fungi, antigens) requires 2 ml of CSF. The minimum volume required for microbiological testing is 0.5–1 ml.

CSF samples obtained from the first tube of a lumbar puncture should not be sent to the laboratory, as there is a high probability of sample contamination with skin microorganisms, which will certainly cause interpretation issues if coagulase-negative staphylococci are isolated. The first CSF sample can be used for cytological examination.

CSF is examined for bacteria (microscopy, culture, antigen testing), mycobacteria (microscopy, mycobacterial DNA detection), viruses (DNA detection of herpesviruses, CMV), fungi (microscopy, culture, antigens), Cryptococcus spp. and Aspergillus spp. antigens (in the presence of invasive pulmonary or paranasal sinus aspergillosis), and, if necessary, bacterial antigens (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, group B streptococci - Streptococcus agalactiae). In patients with brain lesions and severe immunodeficiency (prolonged neutropenia), Toxoplasma gondii DNA in CSF should be determined (PCR).

Microbiological examination of stool

Indication — diarrhea.

Clostridium difficile toxin testing should be performed in all cases.

If this test is negative, quantitative testing for opportunistic microorganisms, as well as for Cryptosporidium parvum, Salmonella spp., Shigella spp., Listeria spp., Yersinia spp., and viruses (rotaviruses, adenoviruses) is performed. Enterocolitis can be caused by Candida spp. Quantitative stool testing should focus on the isolation of Pseudomonas aeruginosa and Enterobacteriaceae (Escherichia coli, Klebsiella spp.) producing ESBL or carbapenemases. In patients with persistent febrile neutropenia and negative blood cultures, these microorganisms may be the cause of infection.

Testing for intestinal dysbiosis in patients without diarrhea is a practice adopted only in Russia; it is labor-intensive and has low diagnostic value, especially in non-neutropenic patients.

Microbiological examination of oropharyngeal swab

Indication — signs of stomatitis.

In neutropenia, attention is paid to the isolation of Candida spp., Gram-negative bacteria, especially Pseudomonas aeruginosa or Stenotrophomonas maltophilia, and ESBL- or carbapenemase-producing Enterobacteriaceae (Escherichia coli, Klebsiella spp.).

It should be remembered that bacteria such as Enterococcus spp. and viridans group streptococci are normal components of the oropharyngeal microflora. Vancomycin should not be added to empiric therapy for febrile neutropenia based solely on the isolation of these bacteria in the absence of signs of mucositis.

Yeasts of the genus Candida are found in 30% of healthy individuals.

Microbiological examination of esophageal material

Indications — pain along the esophagus.

Esophagoscopy is performed (platelet count must be at least 50 × 10⁹ /L).

Esophageal mucosal scraping (using a brush method in neutropenia) or biopsy (in the absence of neutropenia) is performed.

Samples are examined in microbiological (bacteria, fungi), virological (HSV DNA, CMV), and histological laboratories.

Microbiological examination of rectal swab

Indications:

• Inflammation or damage to the rectal mucosa (anal fissure, paraproctitis, etc.).

• In patients with febrile neutropenia lasting more than 3–4 days.

Antimicrobial therapy may be adjusted based on isolated microorganisms in patients with persistent febrile neutropenia when clinically significant samples fail to yield diagnostic results.

Attention is focused primarily on the isolation of multidrug-resistant Gram-negative bacteria - Pseudomonas aeruginosa and ESBL- or carbapenemase-producing Enterobacteriaceae (Escherichia coli, Klebsiella spp.).

Microbiological examination of the nasal passage mucosa

Indications — presence of nasal mucosal necrosis.

Testing is performed exclusively for mold (mycelial) fungi.

Routine testing of material from the nasopharynx, oropharynx, rectum, as well as routine urine culture in the absence of signs of infection, has limited clinical value.

Microbiological examination of skin biopsies

Indications — presence of septicopryemic foci (infiltrates within the skin—in the dermis—of any size, painful on palpation, developed during fever) or other skin lesions.

Biopsy should be performed on lesions that are 1–2 days old. The biopsy must include the dermis.

Histological and microbiological examinations are performed to detect bacteria (including mycobacteria) and fungi. In addition to culture, microscopy of all samples is performed (Gram staining, Ziehl–Neelsen staining, calcofluor white).

Computed tomography of the lungs

Indications:

• Fever of unknown origin ≥ 5 days during neutropenia with normal physical findings in the lungs.

• Monitoring of detected pulmonary changes (the first follow-up examination is performed 7 days after the diagnosis of pneumonia and the initiation of antibacterial or antifungal therapy, followed by subsequent scans as clinically indicated).

Chest CT should be performed without prior chest radiography.

Chest CT for fever during neutropenia is performed regardless of auscultatory findings in the lungs.

Chest radiography has low diagnostic utility in neutropenia. It fails to timely diagnose invasive aspergillosis or interstitial lung diseases (viral, fungal). This imaging modality should be omitted when searching for a pulmonary infectious process in neutropenic patients.

Bronchoalveolar lavage

Indications: pulmonary abnormalities on CT.

List of diagnostic tests:

• Examination of bronchoalveolar lavage (BAL) fluid:

• Cytology of smears.

• Smear microscopy (Gram staining, Ziehl–Neelsen staining).

• Fluorescence microscopy for fungi using calcofluor white.

• Microbiological culture for bacteria, including Nocardia, and fungi (mandatory for molds — culture on Czapek medium).

• Microbiological culture for Legionella spp.

• Mycobacterial testing (PCR).

• Fluorescence microscopy for Pneumocystis jirovecii.

• Pneumocystis jirovecii DNA detection (PCR).

• Aspergillus antigen (galactomannan) assay in BAL fluid.

• Legionella pneumophila antigen assay in urine.

• Mycoplasma pneumoniae and Chlamydophila pneumoniae DNA detection in BAL fluid.

• Detection of viral DNA (CMV, influenza viruses, parainfluenza viruses, respiratory syncytial virus, coronaviruses, human metapneumovirus, human herpesvirus type 6) in BAL fluid (PCR).

• Fungal antigen detection

• Aspergillus antigen (galactomannan)

• Detection of Aspergillus antigen is included in the diagnostic criteria for invasive aspergillosis.

Specimens for testing:

• blood;

• BAL fluid;

• CSF.

The Aspergillus antigen test result is considered positive in blood at an optical density index ≥ 0.5, in BAL fluid ≥ 1.0, and in CSF ≥ 0.5.

Aspergillus antigen testing is performed in patients with clinical signs (or risk factors) of suspected invasive mycosis.

Aspergillus antigen detection

Detection of Aspergillus antigen (galactomannan) is indicated in autologous hematopoietic stem cell transplant recipients with suspected invasive aspergillosis based on CT lung findings and risk factors predisposing to invasive aspergillosis (neutropenia for 10 days or more, glucocorticoid therapy, fludarabine or alemtuzumab therapy).

In such cases, a single Aspergillus antigen test is performed in BAL fluid, or, if the patient has neutropenia (granulocytes <0.5 × 109 /L), Aspergillus antigen is tested in 2–3 blood samples (not just one!) drawn within 24 hours or over 2 days.

Aspergillus antigen testing should be performed prior to the administration of systemic antifungal agents active against molds.

In this category of patients (with lymphomas, multiple myeloma, autologous hematopoietic stem cell transplant recipients), the probability of developing invasive aspergillosis is 1–5%.

Candida antigen (mannan) and anti-Candida antibodies (antimannan)

The test specimen is blood.

A test result is considered positive at the following values:

• Candida antigen (mannan): ≥125 pg/mL;

• anti-Candida antibodies (antimannan): ≥10 IU.

Indications for the test:

• multiple lesions in the liver and/or spleen (suspected hepatosplenic candidiasis);

• suspected invasive candidiasis.

Sensitivity and specificity of the test are approximately 50–60%. Results should be interpreted with caution due to the high rate of false-positive results. Patients with mucosal Candida colonization test positive for antimannan.

Cryptococcus antigen (glucuronoxylomannan)

Detection of Cryptococcus antigen (glucuronoxylomannan) is included in the diagnostic criteria for invasive cryptococcosis.

Specimens for testing:

• blood;

• BAL fluid;

• CSF;

• urine.

The latex agglutination test demonstrates high sensitivity and specificity (qualitative assay — positive or negative).

Indications for Cryptococcus antigen (glucuronoxylomannan) testing:

• testing of all initial CSF samples in patients with hematological malignancies presenting with CNS infection symptoms;

• testing of a second cerebrospinal fluid sample in refractory CNS infection;

• testing for Cryptococcus antigen (glucuronoxylomannan) in blood in suspected cryptococcal infection.

Cryptococcosis develops primarily in patients with T-cell immunodeficiency (lymphoma, chronic lymphocytic leukemia). Risk groups include patients receiving treatment with glucocorticoids, fludarabine, alemtuzumab, or cyclosporine.

Blood test for Mycoplasma pneumoniae antibodies (IgM, IgG) and Chlamydia pneumoniae antibodies (IgM, IgG)

Indication — pneumonia.

If IgG is positive and fever is present, the test is repeated in 10–14 days.

Brain MRI

Indication — onset of neurological symptoms or signs of meningitis. Development of cerebral symptoms in the setting of febrile neutropenia.

If a lesion or lesions are identified in the brain parenchyma, lumbar puncture must be performed followed by cytological and microbiological studies.

Abdominal ultrasound or computed tomography

Indication — persistent fever (temperature fluctuations between 37 and 39°C over 24 hours) during neutrophil recovery (granulocyte count >0.5 × 109 /L).

Ultrasound and CT in hepatosplenic candidiasis are not mutually exclusive diagnostic procedures. In some patients, hepatic and/or splenic lesions may be detected only by ultrasound, while in others only by CT. MRI of the liver and spleen has the highest diagnostic value.

When diagnosing hepatosplenic candidiasis, follow-up imaging should be performed no earlier than 3–4 weeks after starting systemic antifungal therapy due to the extremely slow regression of lesions.

The status of hepatic and splenic lesions (size, density) must always be assessed when the granulocyte count is >0.5 × 109 /L. Performing imaging during neutropenia yields false information indicating a smaller lesion size.

Additional tests

In the case of sudden-onset neutropenia or thrombocytopenia, or prolonged unexplained neutropenia or thrombocytopenia, CMV testing (CMV DNA detection in blood) must be performed, especially in patients with lymphoproliferative disorders and those on long-term glucocorticoid therapy.

In severe infection, particularly bacteremia, levels of C-reactive protein, interleukins (IL-6, IL-8), and procalcitonin may change. However, these markers do not always rise, especially in viral or fungal infections. Detection of biologically active compounds in the blood or an increase in their levels is not an indication to prescribe antimicrobial drugs or alter infectious complication therapy in a clinically stable patient during neutropenia. Procalcitonin and other markers should not be measured within the first few hours of fever onset, as an antibiotic will be prescribed for febrile neutropenia regardless, and procalcitonin values do not influence the choice of antimicrobial agent.

Prevention of infectious complications

Antifungal prophylaxis [147]

Administered to patients with a burdened medical history (acute disseminated candidiasis, chronic disseminated candidiasis, mucormycosis, or invasive aspergillosis).

The drug that was used to achieve a cure for invasive mycosis is prescribed.

Patients with a history of acute or chronic disseminated candidiasis (typically one agent from the list):

• Fluconazole**, 400 mg daily, intravenously or orally.

• Micafungin**, 50 mg daily intravenously.

• #Anidulafungin, 100 mg daily intravenously.

Patients with a history of invasive aspergillosis (typically one agent from the list):

• Voriconazole**, 200 mg twice daily orally (in tablets, on an empty stomach) or 3–4 mg/kg twice daily intravenously.

• Posaconazole** (suspension), 200 mg 3 times daily orally (after meals).

• Itraconazole (suspension), 5 mg/kg twice daily orally (on an empty stomach).

Patients with a history of mucormycosis:

Antiviral prophylaxis [168]

Indicated for patients with a burdened medical history (frequent, recurrent episodes of herpetic infections).

Oral G05AB antiviral prophylaxis (e.g., with #valacyclovir at a dose of 500 mg twice daily) is administered starting from the initiation of pre-transplant conditioning.

Pneumocystis jirovecii pneumonia prophylaxis [147,169]

Indications:

• Glucocorticoid therapy.

• Treatment with drugs that lead to a decrease in the CD4 lymphocyte count.

• Patients with a history of pneumocystis pneumonia.

One of the following drugs is prescribed:

• Co-trimoxazole [Sulfamethoxazole+Trimethoprim]** is prescribed at 480 mg daily.

• Dapsone, 100 mg orally daily.

The drugs are used during the period of cytostatic therapy and throughout the period of neutropenia.

The simultaneous use of co-trimoxazole [sulfamethoxazole+trimethoprim]** prevents infections caused by Toxoplasma gondii, Listeria monocytogenes, and Nocardia asteroides.

Patients infected with Pneumocystis jiroveci must not be accommodated in the same room with other immunocompromised patients.

Normal human immunoglobulin**

Secondary immunodeficiency develops in patients after auto-HSCT. Human immunoglobulin preparations are used to correct hypogammaglobulinemia. By replenishing the antibody deficiency, human immunoglobulin reduces the risk of infections in patients with secondary immunodeficiency.

Before the patient is discharged from the bone marrow transplantation unit, intravenous drip administration of the drug at a dose of 0.4 g/kg weekly is recommended. For severe bacterial and viral infections, 0.4–1 g/kg daily for 1–4 days is recommended. Before administration, the drug should be warmed to room temperature or body temperature. The initial infusion rate is 30 drops/min (1.65 ml/min); after 10 minutes, the rate is increased to 40 drops/min (2.2 ml/min).

Laboratory and instrumental monitoring in the early post-transplantation period

All patients in the early post-transplantation period regularly undergo a complete (clinical) blood count (to correct anemia and thrombocytopenia), general therapeutic blood biochemistry panel (to correct electrolyte imbalance and hypoalbuminemia), coagulogram (screening test of the hemostatic system) to monitor hemostasis, urinalysis, electrocardiogram recording, and other diagnostic methods as clinically indicated, including chest CT, brain MRI, and Holter heart rhythm monitoring.

The frequency of testing these parameters may vary depending on the specific clinical situation.

• Complete (clinical) blood count every 2–3 days.

• General therapeutic blood biochemistry panel every 2–3 days.

• Coagulogram (screening test of the hemostatic system) every 3–4 days.

• Blood glucose testing every 3–4 days.

• Urinalysis - weekly.

• Electrocardiogram recording – weekly.

Nutritional therapy

High-dose chemotherapy followed by auto-HSCT, prolonged granulocytopenia, infectious complications, and a lengthy hospital stay are the main reasons leading to reduced nutrient intake and, consequently, general weakness, decreased physical activity, and significant weight loss.

Nutrition should be considered inadequate if the patient is unable to independently cover more than 60% of their energy requirements for 1–2 weeks [170,171].

According to ESPEN, 46% to 88% of cancer patients require additional nutritional support during anti-tumor treatment [171,172].

Nutritional support is a method of providing adequate nutrition to patients using special formulas that are maximally balanced in quantitative and qualitative terms. Nutritional support is necessary not only to maintain the body's metabolic reserves, but also to increase its resistance to ongoing therapy [170,173].

Goals of nutritional support [170,171]:

• Maintaining optimal body weight.

• Preventing or correcting macro- and micronutrient deficiencies.

• Increasing tolerance to high-dose chemotherapy.

• Reducing the severity of chemotherapy side effects.

• Improving quality of life.

Indications for nutritional support

Nutritional screening should be performed throughout the entire treatment period. Many criteria have been proposed for diagnosing the severity of malnutrition, the main ones being:

• body mass index <20 kg/m2;

• rate of weight loss;

• hypoproteinemia <60 g/l or hypoalbuminemia <30 g/l.;

• inability to maintain adequate enteral nutrition;

• side effects of high-dose chemotherapy:

• nausea,

• vomiting,

• loss of appetite,

• dysphagia,

• mucositis of varying severity,

• taste and smell disorders,

• moderate to severe necrotizing enteropathy.

Timely identification of patients at nutritional risk helps protect them from progressive weight loss and the development of refractory cachexia. For initial screening, well-established scales can be used, such as NRS-2002, nutritional risk index (NRI according to Buzby G.P.), the A.B.V.G. scoring system (ESMO, 2008), Quetelet body mass index, and others [170–172].

In cases where enteral nutrition is impossible or ineffective, parenteral nutrition must be prescribed [174]. Protein delivery should be at least 1 g/kg/day, but strive for 1.5 g/kg/day when possible.

In patients with concomitant chronic renal failure, protein intake should not exceed 1–1.2 g/kg/day. The energy supply for a cancer patient should be maintained at 25–30 kcal/kg/day [170,171].

Types of nutritional support [170,171,173]

There are three types of nutritional support:

• oral nutritional supplements (sip feeding) – oral intake of medical (specialized) nutrition in small sips;

• enteral nutrition – possible via a nasogastric/nasointestinal tube or via a stoma (percutaneous, endoscopic, laparoscopic, laparotomic);

• parenteral nutrition.

Enteral nutrition is the preferred method of nutritional support due to its physiological nature, ability to maintain bowel function, reduce the hypermetabolic response to injury, and reduce bacterial and toxin translocation from the gut.

Enteral nutrition can be administered if at least partial gastrointestinal function is present. The absence of audible peristalsis is not a contraindication for enteral nutrition.

Classification of enteral nutrition formulas [170]

• polymeric: consist of intact proteins, fats, and carbohydrates;

• oligomeric (semi-elemental): consist of hydrolyzed proteins and simple carbohydrates, and contain medium-chain triglyceride oils;

• disease-specific formulas tailored to the needs of a particular patient suffering from a specific condition (diabetes mellitus, kidney, liver, or lung diseases).

Contraindications to enteral nutrition [170,172]

• mechanical intestinal obstruction;

• severe nausea and vomiting unresponsive to antiemetic therapy;

• hypoxia (PaO2 < 70 mmHg).

An indication for parenteral nutrition is the inability to maintain adequate enteral nutrition for more than 3 days [171]. Depending on the duration, parenteral nutrition is classified as:

• short-term PN (10–15 days):

  • acute and severe mucositis, ileus, intractable vomiting;

• prolonged (more than 30 days):

  • severe malabsorption;

  • subacute or chronic enteritis;

  • severe enteropathy [170,175].

Nutrients required by the body are administered directly into the bloodstream. The main components of parenteral nutrition are:

• energy sources: 10–20% carbohydrate solutions, fat emulsions;

• plastic material sources: crystalline amino acid solutions;

• multivitamin complexes for parenteral administration: – water-soluble vitamin preparations; – fat-soluble vitamin preparations; – water- and fat-soluble vitamin preparations; – trace element complexes for parenteral administration [171].

Parenteral nutrition systems [170,173]

• "modular" – using separate bottles with amino acids, glucose, and fat emulsions (the main disadvantage of this method is the varying infusion rate of the preparations);

• "all-in-one" system involves the use of two- and three-component containers with a pre-calculated required quantity and metabolically correct ratio of amino acids, glucose, lipids, and electrolytes.

Contraindications to parenteral nutrition [170,173]

• ability to receive enteral nutrition;

• inability to secure adequate vascular access;

• absence of signs of protein-energy malnutrition;

• hypoxia ($PaO_2 < 70$ mm Hg, serum lactate > 3 mmol/L);

• anuria or hyperhydration without dialysis.

Mixed nutrition [170,172]

Enteral and parenteral nutrition may be prescribed to patients simultaneously if one of these methods is insufficiently effective (failing to provide more than 60% of energy requirements).

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Lymphomas are tumors of lymphoid cells. Lymphoma is not a single disease; it is a large group comprising more than 30 different diseases that differ from one another in their manifestations, clinical course, and treatment response. The main thing to understand is that lymphomas behave and are treated completely differently. Therefore, simply saying "lymphoma" tells you nothing—to understand how to treat it, you need to know the specific subtype of lymphoma.

The most common symptom of lymphoma is enlarged lymph nodes. However, this symptom is not the only one and is not even mandatory, as lymphomas can originate in any organ. Therefore, the symptoms of lymphoma can be very diverse, virtually anything.

Lymphoma is frequently diagnosed at an advanced stage. This is because lymphoid cells circulate throughout the body via the bloodstream and lymphatic flow. However, the fact that most lymphomas are diagnosed at advanced stages does not imply a poor prognosis. Lymphomas respond to therapy significantly better than many other tumors, and many variants of lymphoma can be completely cured today.

The clinical course of non-Hodgkin lymphomas also varies. Some present with an indolent course lasting years or decades and do not even require treatment. Others are characterized by a more aggressive course. Based on their clinical course, non-Hodgkin lymphomas are subdivided into aggressive and indolent.

Some lymphomas frequently involve the bone marrow and blood, though this is not critically important. What matters more is the cell of origin and the genetic aberrations they carry.

Marginal zone lymphomas also belong to the group of indolent lymphomas. They are subdivided into three categories depending on the localization of the lymphoma.

The first group comprises lymphomas originating from mucosa-associated lymphoid tissue (MALT). They are often referred to as MALT lymphomas or maltomas. All surfaces and mucosal membranes through which a human interacts with the external environment (the lining of the respiratory tract, lungs, gastrointestinal tract, urinary tract, genital tract, and ocular epithelium) contain lymphoid tissue. Mucosa-associated lymphoid tissue protects us from numerous bacteria. Some common pathogens are so difficult to eradicate that they persist in a given location (e.g., in the stomach or intestine) for a very long time—years. Today we know that *Helicobacter pylori*, a bacterium residing in the stomach and serving as a leading cause of gastric ulcers, can lead to the development of gastric lymphomas. *Chlamydia psittaci* can cause orbital MALT lymphomas. Infection caused by *Borrelia burgdorferi* is associated with cutaneous MALT lymphomas, and *Campylobacter jejuni* with small intestinal MALT lymphomas. MALT-type lymphoid tissue can form de novo in virtually any organ in an adult. Therefore, MALT lymphomas can arise in any organ. Most commonly, they develop in the gastrointestinal tract, eyes, thyroid gland, salivary glands, and skin. Many individuals who develop such lymphomas have autoimmune diseases.

The second group of marginal zone lymphomas comprises lymphomas growing within lymph nodes. They differ from other nodal lymphomas in their microscopic appearance and molecular features.

Finally, the third variant of marginal zone lymphoma arises in the spleen. Splenic marginal zone lymphoma has very characteristic features.

Marginal zone lymphomas usually have a favorable prognosis.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Eastern Cooperative Oncology Group (ECOG) Performance Status Scale

Original title: The ECOG Scale of Performance Status

Source: Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. 1982;5(6):649–65 [176]

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation:

Appendix G2. Khorana Scale for VTE Risk Assessment in Patients Receiving Chemotherapy

Original title:

Source: Development and Validation of a predictive model for chemotherapy associated thrombosis. Blood. 2008;111(10):4902-4907 [177]

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation: