Hairy cell leukemia: clinical guidelines

List of Abbreviations

ECOG - Eastern Cooperative Oncology Group Performance Status Scale

TRAP - tartrate-resistant acid phosphatase

HCL - hairy cell leukemia

WHO – World Health Organization

IHC – immunohistochemical study

CT – computed tomography

LU – lymph node

MRI – magnetic resonance imaging

CVC – central venous catheter

BRAF V600E mutation – heterozygous mutation of the BRAF gene resulting in the V600E amino acid substitution

** – 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

Immunophenotyping (by flow cytometry) – determination of cell phenotype by detecting CD markers (clusters of differentiation) on cells in a liquid sample (blood) or cell suspension (bone marrow, biological fluids).

Immunohistochemical study – study of cell phenotype by determining CD markers on solid samples (paraffin blocks) of bone marrow or splenic biopsy.

Interferon alfa – ATC L03AB04 #peginterferon alfa-2a (40 kDa)** or L03AB05 interferon alfa-2b**

Detection of the BRAF V600E mutation – molecular assay detecting the most common variant of BRAF mutations with a valine-to-glutamic acid substitution at codon 600.

Splenectomy – surgical removal of the spleen (laparoscopic or open procedure).

Trephine biopsy – procedure for obtaining a bone marrow sample using a trephine needle from the iliac crest of the pelvis.

Bone marrow puncture – procedure for obtaining a bone marrow sample using a special needle from the sternum or iliac crest.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder that most commonly involves the bone marrow and spleen. Its substrate consists of lymphoid cells with characteristic morphology (large size, round nucleus, cytoplasmic projections—"hairs", from which the disease derives its name) and a specific immunophenotype [1, 2].

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

The etiology of HCL, like that of other leukemias, is unknown. The activating V600E mutation of the BRAF gene plays an important role in the pathogenesis of the disease [3].

1.3 Epidemiology of the Disease or Condition

Hairy cell leukemia accounts for approximately 2% of all adult leukemias and 8% of other chronic lymphoproliferative disorders. The annual incidence of HCL in the USA is 0.32 cases per 100,000 population [4]. This type of leukemia is more common in middle-aged men (the male-to-female ratio is 2–4:1, patient age is over 50 years), although cases in young individuals (under 30–40 years of age) are known [5].

1.4 Features of Coding the Disease or Condition

C91.4 Hairy cell leukemia

1.5 Classification of the disease or condition

There is no universally accepted classification of HCL; typically, initial and advanced phases of newly diagnosed disease, remission (complete or partial), relapse (early or late), and refractory disease course are distinguished.

1.6 Clinical presentation of the disease or condition

Clinical manifestations of HCL can range from minimal or entirely absent (where the disease is an incidental finding during examination) to pronounced symptoms of splenomegaly and cytopenia [6]. HCL is characterized by leukopenia with neutropenia and monocytopenia, as well as anemia and thrombocytopenia. In 95% of cases, characteristic "hairy" / "villous" lymphocytes are detected in the patients' blood, although their count may vary. Splenomegaly, ranging from mild to massive, is typical for HCL, although variants of HCL without splenomegaly do occur. Focal splenic lesions are not typical for HCL. Peripheral lymphadenopathy is absent in HCL, but visceral lymphadenopathy is detected in 15–25% of patients. If enlargement of intrathoracic lymph nodes is detected, tuberculosis must be ruled out. Clinical symptoms of cytopenia (affecting one, two, or three lineages) depend on its severity, but overall, anemia is often compensated for prolonged periods, and thrombocytopenia is frequently asymptomatic or accompanied by a moderately severe hemorrhagic syndrome. The main life-threatening complication of HCL is inflammatory and infectious processes prone to a septic course and abscess formation. Neuroleukemia is not characteristic of HCL; meningeal symptoms require ruling out bacterial, viral, or tuberculous meningitis. Monoclonal gammopathy in HCL is rare (10–15% of cases), mostly represented by minor/trace secretion of class G paraprotein, although cases of classic HCL with monoclonal secretion of 20–30 g/L do occur. Specific involvement of non-lymphoid organs in HCL is rare; the clinical picture may be absent or depends on the site of involvement (skin, bones, lungs, kidneys, central nervous system). An exception is specific diffuse lymphoid infiltration of the liver, which is always present in HCL but usually does not lead to organ enlargement or dysfunction. Isolated extramedullary involvement, such as involvement of the axial skeleton (vertebrae, sacrum, pelvis) with a soft tissue component, is extremely rare in HCL. The presence of an extramedullary lesion must be verified by morphological, immunophenotypic (preferred), or immunohistochemical (IHC) examination, and in the case of isolated extramedullary involvement (i.e., in the absence of other typical HCL features), by molecular genetic testing for the BRAF V600 mutation.

Approximate frequency of clinical and laboratory manifestations of HCL:

• splenomegaly in 80% of patients;

• leukopenia in 70% of patients;

• neutropenia in 75% of patients;

• monocytopenia in 90% of patients;

• "hairy" lymphocytes in peripheral blood smears in 95% of patients;

• thrombocytopenia in 80% of patients;

• anemia in 70% of patients;

• abdominal lymphadenopathy in 15–25% of patients;

• monoclonal gammopathy in 10% of patients.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Many recommended diagnostic methods for the disease and related conditions have limited evidence bases (according to the scales for assessing the levels of certainty of evidence and grades of recommendation) due to the lack of dedicated clinical studies. Despite this, they are necessary elements of patient evaluation for diagnosis and treatment planning, as more effective and proven methods have not yet been developed.

Artificial intelligence technologies may be used to interpret diagnostic tests (if available and adapted for the diagnosis of hairy cell leukemia).

The diagnosis of HCL is established based on the combined laboratory and instrumental findings of blood, bone marrow, and splenic evaluations.

HCL should be suspected if a patient presents with:

1. cytopenia (one-, two-, or three-lineage);

2. lymphocytosis (regardless of leukocyte count);

3. monocytopenia;

4. splenomegaly;

5. frequent infectious and inflammatory conditions.

Criteria for establishing the diagnosis/condition:

1. "villous" lymphocytes ("hairy cells") in blood and/or bone marrow >5%;

2. immunophenotype of lymphoid cells specific for HCL: B-cell clone expressing CD19, CD20 (bright), CD22 (bright), sIg, CD25, CD11c, CD103, FMC7, CD123, and CD85 markers; typically lacking the expression of CD5, CD10, and CD23 markers;

3. typical "loose" lymphoid infiltration of the bone marrow in the trephine biopsy specimen (with expression of CD20, Annexin A1, TRAP, CD25, CD103, DBA.44 (CD72), CD11c, CD123, Cyclin D1 upon IHC testing, and absence of CD5, CD10, and CD23 expression);

4. detection of the BRAF V600E mutation in lymphoid cells.

5. positive reaction of "hairy" lymphocytes to tartrate-resistant acid phosphatase (TRAP);

6. in the case of splenectomy – characteristic lymphoid infiltration of the red pulp with expression of HCL markers upon IHC examination.

If only data (1) and (5) are present, the HCL diagnosis is probable; if data (2–4) and (6) are present, it is definite.

Differential diagnosis of HCL must be performed with all diseases presenting with cytopenia, lymphocytosis, and splenomegaly. These primarily include other lymphoproliferative disorders: splenic marginal zone lymphoma, T-cell lymphoma, splenic diffuse large B-cell lymphoma, chronic lymphocytic leukemia, splenic red pulp lymphoma, and HCL variant. The spectrum of the differential diagnosis for HCL also includes other hematological (aplastic anemia, myelodysplastic syndrome, myelofibrosis) and non-hematological (Gaucher disease, hepatitis and cirrhosis, autoimmune disorders) diseases with similar symptoms. In rare cases (approximately 1%), HCL may be combined with chronic lymphocytic leukemia, and even more rarely with another lymphoid or myeloid hematological malignancy.

The most challenging appears to be the differential diagnosis of HCL from variant HCL and splenic diffuse red pulp small B-cell lymphoma, which are clinically similar and were classified in the 2008 and 2016 World Health Organization (WHO) classifications as subvariants of a separate nosological entity — "unclassifiable splenic lymphoma/leukemia" (in the 2022 WHO classification, variant HCL was renamed to splenic B-cell lymphoma/leukemia with prominent nucleoli).

Variant HCL occurs approximately 10 times less frequently than classic HCL, and is characterized by a normal or elevated leukocyte count and the absence of the CD25 marker [7]. The disease is more commonly diagnosed in younger patients. Clinical manifestations of variant HCL are generally similar to those of classic HCL; however, variant HCL is characterized by a several-fold higher incidence of massive splenomegaly and visceral lymphadenopathy (sometimes with the formation of lymph node conglomerates), as well as a higher frequency of severe infectious complications at disease onset and in the early stages of therapy [8]. The bone marrow in variant HCL is typically hypercellular, with minimal signs of fibrosis. Morphologically, "hairy" lymphocytes in variant HCL bear a closer resemblance to prolymphocytes, and their nuclei frequently contain 1–2 large nucleoli. In contrast to classic HCL, the immunophenotype of variant HCL is characterized by the absence of CD25 and CD123 expression, while retaining other HCL-typical markers but at lower expression levels: CD11c, CD103, and FMC7. Occasionally, other lymphoid cell phenotype aberrations are noted in variant HCL. TRAP and annexin A1 are usually absent. The fact that variant HCL does not truly belong to a subtype of classic HCL is confirmed by the absence of the BRAF V600E mutation in tumor cells.

The disease responds less favorably to standard therapy, and the optimal treatment for the variant form of HCL has not yet been definitively established [9, 10]. Due to the rarity of the disease, there are no randomized clinical trials comparing the efficacy of various treatment methods in variant HCL. According to most researchers, purine analogs are less effective and more frequently achieve only partial remission or improvement. A combination of a purine analog with #rituximab** is considered preferable. Long-term therapy with interferon alfa (interferon alfa-2b** or #peginterferon alfa-2a (40 kDa)**) and RB chemotherapy regimens are used. For pronounced splenomegaly in the first line of treatment, splenectomy is employed. The efficacy of monoclonal antibodies and antibody-drug conjugates (anti-CD22 and anti-CD25 antibodies) is being studied . In young patients with a refractory disease course, allogeneic hematopoietic stem cell transplantation may be performed.

Splenic red pulp small B-cell lymphoma (SRPL) is a rare (5 times less frequent than HCL) mature small B-cell lymphoma of the spleen, localized in its red pulp. The disease is more frequently detected in older patients. Much like variant HCL, SRPL presents without leukopenia, often with marked leukocytosis, lymphocytosis due to a high number of circulating "hairy" lymphocytes (also detected upon bone marrow cytological examination), and without monocytopenia; significant splenomegaly is characteristic [11]. The immunophenotype of lymphoid cells in SRPL differs from the classic HCL phenotype by the absence of CD25 and variable low expression of CD103 and CD11c. The BRAF V600E mutation is consistently absent, and the TRAP reaction is usually negative. Interestingly, in SRPL, histological examination of the bone marrow contrasts with the myelogram—lymphoid infiltration in the trephine biopsy specimen is often quite sparse, clearly identifiable only upon immunohistochemical testing with the CD20 marker; markers such as CD25, annexin A1, and cyclin D1 are absent. Histological examination of the spleen reveals red pulp lymphoid infiltration with a phenotype only partially overlapping with HCL upon immunohistochemistry: CD20+, DBA.44+, CD25–, annexin A1–, cyclin D1–, CD103–, CD123–, with only focal CD11c+ and TRAP+.

SRPL shares clinical and laboratory features with splenic marginal zone lymphoma with hairy lymphocytes, and the only 100% definitive option in their differential diagnosis is histological and immunohistochemical examination of splenic tissue.

Based on a number of features (absence of leukopenia and monocytopenia, aberrant immunophenotype, absence of the BRAF V600E gene mutation), variant HCL and SRPL are very similar to each other; however, they differ by the presence of leukemic infiltration in the histological bone marrow specimen in variant HCL, as opposed to sparse bone marrow involvement in the trephine biopsy histological specimen in SRPL.

In the treatment of SRPL, splenectomy is used primarily, along with combination therapy with cladribine and #rituximab**; R-CHOP, R-F(M)C, R-COP, RB, and similar regimens are also employed.

2.1 Complaints and Anamnesis

• In all patients with suspected or confirmed HCL at the initial visit, it is recommended to conduct a thorough collection of complaints and anamnesis regarding hematopoietic and blood disorders to verify the diagnosis [12, 15].

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

Comment: during the examination, it is necessary to assess the patient's general condition using the Eastern Cooperative Oncology Group (ECOG) performance status scale (see Appendix G1). With pronounced anemia, the patient may experience weakness, shortness of breath, palpitations, and dizziness, which worsen with physical exertion. With severe thrombocytopenia, a hemorrhagic syndrome may occur (rarely). With neutropenia, hyperthermia and frequent infectious-inflammatory diseases may develop, sometimes with a severe life-threatening course (abscess formation, pneumonia, sepsis). With splenomegaly, there is a sensation of fullness and heaviness in the epigastrium and left half of the abdomen. Therefore, consultation and examination by related specialists are often necessary to assess complications and comorbidities that influence the choice of further management.

It is necessary to clarify the family history regarding the presence of blood system diseases in relatives.

Since the disease in most cases develops gradually and over a long period, complaints may be absent for a long time despite pronounced cytopenia and splenomegaly.

2.2 Physical Examination

• In all patients with suspected or confirmed HCL at initial or repeat visits, follow-up examinations, and suspected disease relapse, it is recommended to perform a physical examination including inspection, palpation, and auscultation, determine the general condition using the ECOG performance status scale, and examine the tonsils and oral cavity to assess the extent, presence of complications, and severity of the disease [6, 69, 70].

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

Comment: during the examination, it is necessary to assess the patient's general condition using the ECOG scale (see Appendix G1), as well as to inspect the tonsils, oral cavity, and skin (including for concurrent infectious manifestations associated with neutropenia typical of HCL); palpation must include all accessible groups of peripheral lymph nodes, the liver, and the spleen.

2.3 Laboratory Diagnostics

• In all patients with suspected or confirmed HCL during monitoring, treatment delivery, evaluation of treatment efficacy, follow-up examinations, and suspected disease relapse, it is recommended to perform a complete (clinical) blood count with differential to establish the diagnosis, clarify the severity of the patient's condition, track disease dynamics, formulate adequate therapeutic tactics, and/or (in the case of previously administered therapy) assess the development of potential adverse treatment events [6, 12–14].

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

Comment: blood smear preparation reveals larger "hairy" lymphoid cells with homogeneous, sparse chromatin of the round or oval, less commonly kidney-shaped nucleus, with a fairly broad pale cytoplasm and an irregular, scalloped cytoplasmic border with projections or villi.

• For patients with suspected HCL or disease relapse, as well as when evaluating the effectiveness of HCL therapy, it is recommended to obtain a bone marrow cytologic preparation via puncture for cytologic examination of the bone marrow smear (myelogram), which is necessary to confirm and formulate the diagnosis [6, 12, 13].

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

Comment: the bone marrow often contains more "hairy" lymphocytes than the blood. However, bone marrow aspiration may be difficult ("dry tap") due to bone marrow fibrosis in HCL.

• For patients with suspected HCL or disease relapse, as well as when evaluating the effectiveness of HCL therapy, it is recommended, if necessary, to perform a pathomorphological examination of bone marrow biopsy (surgical) material as an important diagnostic method required to confirm and formulate the diagnosis [6, 12, 13, 15].

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

Comment: pathomorphological examination of bone marrow biopsy (surgical) material is important for establishing the diagnosis of HCL, as it allows for the detection of lymphoid infiltration with features specific to HCL, assessment of hematopoiesis reserves, and differential diagnosis with hematopoietic aplasia. In HCL, biopsy (surgical) material of the bone marrow shows a decrease in the number of normal hematopoiesis elements and diffuse or diffuse-focal infiltration of the bone marrow by "loosely" arranged medium-sized lymphoid cells with irregularly shaped nuclei and a fairly broad cytoplasm with an irregular border. Fibrosis and microcirculation disturbances in the form of hemorrhage fields and dilated sinuses are typical—a picture that allows morphological differentiation of this type of leukemia from other diseases.

• For all patients with suspected HCL or HCL relapse, it is recommended to perform a biological material study using flow cytometry (to determine lymphocyte immunophenotype) as the primary diagnostic method required to confirm and formulate the diagnosis [6, 12, 13, 16].

GCR CLEL 3Grade of Recommendation — C (Level of Evidence — 3)

Comment: determination of the immunophenotype of tumor lymphocytes is mandatory to verify the diagnosis of HCL. Two complementary methods are used for this purpose: flow cytometry and IHC. Flow cytometry is most commonly used, utilizing blood (if there is a sufficient number of pathological lymphocytes in the blood) or bone marrow as the substrate; however, it is also possible (and sometimes necessary) to analyze the tumor substrate from any localization—lymph node, spleen, tissue biopsy, pleural or cerebrospinal fluid, etc. No single marker for HCL has been identified; therefore, an accurate diagnosis requires evaluating a sufficiently broad panel of B- and T-cell CD markers, including markers typical of HCL. Flow cytometry reveals strong expression of CD19, CD20, CD22, CD79a, absence of CD5, CD10, CD23, CD43 expression, and expression of CD11c, CD25, CD103, FMC7, CD123, CD200, LAIR-1 typical of HCL. Phenotypic deviations (aberrations)—the presence of markers uncharacteristic of HCL such as CD10 (up to 20%) and CD23, and more rarely CD5—are occasionally encountered.

• For all patients with suspected HCL, it is recommended to perform a molecular genetic study for the BRAF V600E mutation in blood or bone marrow lymphocytes as the primary diagnostic method required to confirm and formulate the diagnosis [3, 6, 12, 13, 17, 18].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comment: in HCL, the BRAFV600E mutation is detected in more than 95% of cases, distinguishing it from other B-cell lymphoproliferative disorders, as well as from the variant form of HCL and splenic red pulp lymphoma. This mutation can be detected by polymerase chain reaction in cellular blood or bone marrow samples, or by IHC examination. Since the BRAFV600E mutation is a diagnostic criterion for HCL, it is advisable to test for it in all patients in the active phase of the disease, especially in diagnostically complex cases, with severe somatic status and refractory HCL, to determine the feasibility of using B-Raf (BRAF) serine-threonine kinase inhibitors.

• For all patients with suspected HCL or disease relapse with ambiguous data from previous examination stages (doubtful immunophenotyping or trephine biopsy results, absence of the BRAF mutation), it is recommended to perform a pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods as an additional diagnostic method important for confirming the diagnosis [6, 12, 13].

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

Comment: IHC examination in HCL detects the expression of CD20, Annexin A1, TRAP, CD25, CD103, DBA.44 (CD72), CD11c, CD123, Cyclin D1 (weak nuclear expression in most cases). Tumor cells do not express CD5, CD10, CD23 (weak expression on a portion of cells may occur in rare cases).

• For all patients with suspected HCL who underwent splenectomy, it is recommended to perform a pathomorphological examination of spleen biopsy (surgical) material using immunohistochemical methods as an additional diagnostic method important for confirming the diagnosis [6, 12, 13].

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

Comment: morphological examination of spleen tissue in cases of splenectomy reveals lymphoid infiltration of the red pulp, while the white pulp is usually atrophied. Tumor infiltration leads to the formation of so-called "blood lakes," which are blood-engorged sinuses. IHC examination of spleen tissue with the determination of markers characteristic of HCL helps clarify the diagnosis.

• For patients with suspected HCL who underwent a liver biopsy, it is recommended to perform a pathomorphological examination of liver biopsy (surgical) material using immunohistochemical methods as an additional diagnostic method important for confirming the diagnosis [6, 12, 13].

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

Comment: Pathomorphological examination of liver biopsy (surgical) material reveals tumor infiltration located not only in the portal tracts but also in the sinusoids. Pathomorphological examination of liver biopsy (surgical) material using immunohistochemical methods with the determination of HCL-characteristic markers helps clarify the diagnosis.

• For patients with suspected HCL, it is recommended to determine the activity level of leukocyte acid phosphatase in peripheral blood and/or bone marrow punctate as an additional diagnostic method to confirm the diagnosis [6, 12, 13].

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

Comment: cytochemical examination of lymphocytes for TRAP clearly detects TRAP in "hairy" lymphocytes. This type of enzyme can sometimes be detected in other lymphoproliferative disorders, but high TRAP activity is specifically typical of HCL and occurs in 95% of cases.

• For patients with suspected HCL, it is recommended, whenever possible, to perform a study of immunoglobulin monoclonality in blood and urine using immunofixation as an additional diagnostic method important for the differential diagnosis of HCL [6, 12, 13].

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

Comment: paraproteinemia is generally uncharacteristic of HCL, occurs rarely (up to 10%), mainly in elderly patients, and is most often trace-level, with IgG predominantly detected. The prognostic significance of monoclonal secretion has not been established. The detection of significant secretion is a reason to revise the diagnosis (secretory lymphoma, plasmacytoma, multiple myeloma).

• For all patients with HCL prior to initiating anti-tumor therapy, a general (clinical) urinalysis is recommended to assess renal function and rule out urinary tract infection [70, 71].

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

• All patients with hairy cell leukemia (HCL) before starting antitumor therapy are recommended to undergo a general general-clinical biochemical blood test (determination of blood lactate dehydrogenase activity, blood uric acid level testing, blood urea level testing, blood creatinine level testing, blood total protein level testing, blood albumin level testing, blood total bilirubin level testing, determination of blood aspartate aminotransferase activity, determination of blood alanine aminotransferase activity, determination of blood alkaline phosphatase activity, blood potassium level testing, blood sodium level testing, blood glucose level testing) to clarify the patient's somatic status, detect organ dysfunction, and develop adequate therapeutic tactics [6, 14, 19].

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

Comment: other parameters of the general-clinical biochemical blood test may be included in the study at the physician's discretion.

• All patients with HCL before starting antitumor therapy are recommended to undergo a coagulogram (indicative assessment of the hemostatic system) (determination of prothrombin (thromboplastin) time in blood or plasma or determination of international normalized ratio (INR), determination of prothrombin (thromboplastin) time in blood or plasma, blood fibrinogen level testing, determination of blood thrombin time) to clarify the state of the patient's coagulation system and develop adequate therapeutic tactics [71, 72].

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

Comment: other parameters of the coagulogram (indicative assessment of the hemostatic system) may be included in the study at the physician's discretion, according to clinical indications.

• Patients with HCL before starting antitumor therapy are recommended to undergo ABO blood group determination and Rhesus factor (Rh factor) D antigen determination to enable blood transfusion if indicated before, during, or after therapy [71].

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

• Patients with HCL before starting antitumor therapy are recommended to undergo molecular biological blood testing for Hepatitis B virus and Hepatitis C virus to clarify comorbidity and, if necessary, provide viral hepatitis reactivation prophylaxis [14, 19].

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

• Patients with HCL before starting antitumor therapy are recommended to undergo molecular biological blood testing for human immunodeficiency virus (HIV-1) to clarify the need for simultaneous antitumor and antiretroviral therapy [14, 19].

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

2.4 Instrumental Diagnostics

• Patients upon establishing the diagnosis of HCL, ruling out disease relapse, as well as when evaluating the efficacy of HCL therapy in patients with previously identified enlargement of abdominal and retroperitoneal lymph nodes are recommended to undergo computed tomography (CT) of the abdominal organs whenever possible [6, 13, 19].

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

Comment: in most cases, moderate to significant splenomegaly is detected without focal lesions of the splenic tissue. Enlargement of visceral lymph nodes is determined in approximately 20% of cases, most often insignificant, but can also present as conglomerates (especially at a young age or during disease progression); infiltration of the retroperitoneal tissue (not clearly detected by ultrasound) may also be detected, especially with a long disease history and prior splenectomy.

• All patients upon establishing the diagnosis of HCL, ruling out disease relapse, as well as when evaluating the efficacy of HCL therapy are recommended to undergo an abdominal ultrasound (complex) [6, 13, 19].

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

Comment: in most cases, ultrasound reveals moderate to significant splenomegaly, without focal lesions of the splenic tissue. Enlargement of visceral lymph nodes is determined in approximately 20% of cases, most often insignificant, but can also present as conglomerates (especially at a young age or during disease progression).

• All HCL patients (initial, in relapse, progression) with detected massive enlargement of abdominal and retroperitoneal lymph nodes or with the presence of hyperthermia, pulmonary symptoms are recommended to undergo CT of the chest organs to rule out intrathoracic lymphadenopathy, pneumonia, pleurisy, lung abscess [6, 13, 19].

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

Comment: if intrathoracic lymphadenopathy is detected, a phthisiatric examination is necessary to rule out tuberculosis, as patients with HCL are at high risk for developing tuberculosis. When HCL is combined with tuberculosis, treatment for both diseases must be carried out simultaneously in full, since with timely treatment and an adequate response to therapy, the prognosis for patients is favorable.

• All HCL patients with bone pain syndrome are recommended to undergo radiography, CT, or magnetic resonance imaging of bone tissue to rule out specific bone involvement [6, 13, 19].

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

Comment: specific bone involvement in HCL occurs in young patients; involvement of the axial skeleton is characteristic in the form of osteodestruction or osteosclerosis foci, sometimes with a soft tissue component; it requires histological, immunophenotypic, and molecular verification; it is usually resolved with specific HCL therapy.

• Patients upon establishing the diagnosis of HCL, as well as when evaluating the efficacy of HCL therapy, are recommended to undergo electrocardiography to assess comorbidity and rule out cardiac toxicity [71, 73].

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

Comment: Electrocardiography is necessary to rule out concomitant cardiac pathology and/or complications of HCL, as well as to assess the dynamics of the QT interval during treatment with B-Raf (BRAF) serine-threonine kinase inhibitors.

2.5 Other Procedures

• All patients with suspected extramedullary lesion site are recommended to undergo a biopsy of the probable site for verification of specific involvement [6, 19, 69, 71].

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

Comment: specific involvement of organs and tissues in HCL is proven only by morphological examination with immunophenotypic or IHC testing and, if possible, molecular genetic testing for the BRAF V600 mutation.

• All HCL patients at any stage of diagnosis, monitoring, treatment, or when infectious complications are suspected are recommended to undergo diagnostics of the infection localization and pathogen type, with dynamic monitoring during treatment [70, 71]. (see sections 7.1 and A3.1).

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

• HCL patients with anemia are recommended to undergo the following laboratory tests for the purpose of differential diagnosis of anemia [69]:

o serum iron level testing

o blood ferritin level testing

o serum folic acid level testing

o blood vitamin B12 (cyanocobalamin) level determination

o blood erythropoietin level testing (according to indications)

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

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

The prescription and use of medicinal products specified in the clinical guidelines are aimed at providing the patient with clinically effective and safe medical care; therefore, their prescription and use in a specific clinical situation may be determined not only in accordance with the instructions for use, with the implementation of precautions presented in the instructions, with possible correction of doses and administration regimens taking into account the patient's condition.

It should be taken into account that the patient may have atypical manifestations of the disease, as well as a combination of a specific disease with other pathologies, which may dictate changes in the algorithm for choosing the optimal diagnostic and treatment tactics for the attending physician.

3.1. Indications for initiation of therapy and determination of the HCL treatment strategy

• Patients with verified HCL without cytopenia or significant splenomegaly (<+2 cm from the costal margin) or with non-progressive mild cytopenia (hemoglobin >110 g/L, platelets >150´10⁹/L, neutrophils >2.0´10⁹/L), without infectious episodes and without disease symptoms, provided regular patient monitoring is possible at least once every 2 months, specific therapy is not recommended [6, 12, 13].

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

• Patients with verified HCL with significant or worsening cytopenia (hemoglobin <110 g/L, platelets <100´10⁹/L, neutrophils <2.0´10⁹/L), infectious complications, symptomatic or progressive splenomegaly are recommended to initiate specific therapy [6, 12, 13].

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

3.2 Treatment of newly diagnosed hairy cell leukemia

The primary drugs in the treatment of hairy cell leukemia (HCL), leading to long-term complete remissions in HCL, are purine analogues, specifically cladribine. Despite its high efficacy and organ non-toxicity, first-line use of cladribine usually leads to prolonged myelotoxic agranulocytosis [20], which is hazardous in immunocompromised patients with HCL. Therefore, it is preferable to use cladribine after the resolution of neutropenia using interferon-alpha (#peginterferon alfa-2a (40 kDa)** or interferon alfa-2b**) or a B-Raf (BRAF) serine-threonine kinase inhibitor #vemurafenib**. Treatment of HCL with extramedullary involvement should also be primarily systemic, using #peginterferon alfa-2a (40 kDa)** or interferon alfa-2b** and/or cladribine, optionally with the addition of #rituximab** to the therapy. Recommendations for the use of these medicinal products are presented below.

• For patients with newly diagnosed HCL with indications for specific therapy in the presence of neutropenia, therapy with #peginterferon alfa-2a (40 kDa)** or interferon alfa-2b** is recommended as the first stage of treatment [6, 21, 22, 74, 75].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comment: interferon alfa-2b** is usually administered for 12–16 weeks prior to the administration of a purine analogue (to correct neutropenia and prevent prolonged myelotoxic agranulocytosis resulting from cladribine use, typically at a dose of 2 million IU/m² (i.e., 3 million IU per administration) × 3 times a week subcutaneously. Depending on blood count parameters and individual tolerance, the dosage regimen of interferon alfa-2b** may vary. Due to the frequent development of flu-like syndrome in the initial stages of interferon alfa-2b** administration, therapy should be initiated while taking non-steroidal anti-inflammatory and antirheumatic drugs, gradually increasing the dose to the standard one (2 million IU/m² 3 times a week). In cases of profound leukopenia, interferon alfa-2b** and #peginterferon alfa-2a (40 kDa)** must be used with caution, without forcing, due to the risk of transient exacerbation of leukopenia. #Peginterferon alfa-2a (40 kDa)** is used at doses ranging from 90 to 135 mcg × once a week subcutaneously. The purpose of using interferon alfa-2b** and #peginterferon alfa-2a (40 kDa)** is to increase neutrophils by reducing the lymphocyte count in the hemogram to a level of <50%, which avoids agranulocytosis and infectious complications after a course of purine analogues. Concurrently, a reduction in spleen size typically occurs. Interferon alfa-2b** and #peginterferon alfa-2a (40 kDa)** may be omitted prior to the main course of cladribine in cases of minor lymphocytosis and minimal bone marrow infiltration.

• For patients with newly diagnosed HCL presenting with severe neutropenia (agranulocytosis) or during an active infection, the administration of #vemurafenib** at a dose of 240–960 mg/day until the resolution of neutropenia (neutrophils >1.5 × 10⁹/L) may be recommended prior to purine analogue therapy [23, 24].

GRC CLEL 4Level of Evidence Rating – C (Level of Evidence - 4)

Comment: #vemurafenib** exerts a pathogenetic effect on the abnormal BRAF kinase of tumor cells. A #vemurafenib** dose of #240–480 mg/day is usually used for an average treatment duration of up to 3–4 months (12–16 weeks).

• For patients with newly diagnosed HCL with indications for specific therapy after the completion of therapy with interferon alfa-2b** and #peginterferon alfa-2a (40 kDa)**, as well as patients with mild lymphocytosis and minimal bone marrow infiltration for whom prior administration is not indicated, cladribine therapy is recommended as the main stage of treatment [25].

GSI ALoE 2Grade of Recommendation — A (Level of Evidence — 2)

Comment: in HCL, typically 1 short course of cladribine is used at a dose of 0.1 mg/kg/day × 7 days or cladribine at 0.14 mg/kg/day × 5 days (dosages and duration of treatment are determined by the attending physician depending on the disease course and severity of the condition) [25]. Randomized studies have not revealed differences in efficacy and tolerability of the drug between different administration regimens. The equal bioavailability of cladribine upon subcutaneous and bolus administration has been confirmed by pharmacological studies. Given the convenience of daily subcutaneous administration, this regimen is preferred in the treatment of HCL. If cladribine therapy is prescribed for any reason without a preceding course of interferon alfa-2b** and #peginterferon alfa-2a (40 kDa)** and in the setting of profound neutropenia in a debilitated patient, treatment with #cladribine in a fractionated regimen may be performed: 1 administration per week up to the total cumulative dose [26].

Cladribine treatment does not require special concomitant therapy (i.e., antiemetics and hydration are not prescribed), except for the use of co-trimoxazole [Sulfamethoxazole + Trimethoprim]** and acyclovir** in accordance with the instructions for infection prevention (as indicated; mandatory in cases of neutropenia until neutrophil recovery >1.0 × 10⁹/L).

• For patients with newly diagnosed HCL presenting with symptomatic thrombocytopenia, inefficacy or intolerance of drug therapy, complications of splenomegaly (infarcts, rupture), as well as marked splenomegaly (more than 10 cm below the costal margin) combined with minimal bone marrow involvement, splenectomy is recommended [6, 70, 71].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: in HCL, removal of the spleen rapidly eliminates cytopenia, but only in 20% of patients for a long term; in the majority, the effect of splenectomy lasts less than 1 year, inevitably followed by disease progression and the need for medical therapy.

3.3 Treatment of Relapsed and Refractory Hairy Cell Leukemia

• For patients with late relapse of HCL (remission duration greater than 5 years), repeat treatment similar to the initial one is recommended [27–29].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comment: it has been shown that if the duration of remission after initial HCL treatment with a purine analogue (cladribine) is sufficient, re-administration of these drugs is also effective.

• For patients with early relapse of HCL (remission duration less than 5 years), specific treatment combined with the CD20 (cluster of differentiation 20) inhibitor #rituximab** or #obinutuzumab** is recommended [30, 31, 34, 47, 48, 49].

Level of Evidence BGrade of Recommendation 3Level of Clinical Effectiveness – B (level of evidence – 3)

Comment: in early relapses, cladribine monotherapy is of low efficacy; therefore, combined use of cladribine with a CD20 (cluster of differentiation 20) inhibitor, or #vemurafenib** with a CD20 (cluster of differentiation 20) inhibitor, or sequential use of interferon alfa-2b** and #peginterferon alfa-2a (40 kDa)** (or #vemurafenib**), cladribine, and CD20 (cluster of differentiation 20) inhibitors is indicated.

As a CD20 (cluster of differentiation 20) inhibitor, #rituximab** is usually used (first administration as a prolonged intravenous infusion; subsequent administrations: intravenous infusion or subcutaneous injection when indicated).

In the case of early relapse or refractoriness after previously administered #rituximab**, the type II CD20 (cluster of differentiation 20) inhibitor #obinutuzumab** is used.

See also A3.2 – supportive care during the administration of monoclonal antibodies – CD20 (cluster of differentiation 20) inhibitors.

• For patients with HCL who have not achieved complete remission 6–12 months after cladribine therapy, repeat cladribine therapy in the same regimen as for initial patients, with the addition of #rituximab** at a dose of 375 mg/m² for 6 administrations at 28-day intervals, is recommended [30, 31].

強B (level of recommendation — B)УДД 3Level of Recommendation — B (Level of Evidence — 3)

Comment: the myelopoiesis recovery period can be prolonged; therefore, if a patient shows a positive response after a course of purine analogue therapy—disappearance of hairy cells, a trend toward normalization of blood counts, and a reduction in spleen size—the completeness of the achieved remission is evaluated no earlier than 6–12 months post-treatment.

• For patients with HCL relapse manifested primarily by splenomegaly, splenectomy is recommended (see Appendix A4) [6, 70, 71].

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

Comment: as a rule, splenectomy alone does not lead to remission, and systemic therapy is required thereafter.

• For patients with refractory HCL with a detected BRAFV600E mutation, #vemurafenib** at a dose of 480 mg/day for 2 months or more (until remission is achieved) is recommended as one of the treatment options [32].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comment: #Vemurafenib** may be used only with a confirmed BRAFV600E mutation. There is experience of successful use of #vemurafenib** at various dosages — from 240 mg/day to 960 mg twice daily [32, 33]. Taking into account sufficient efficacy and good tolerability, a dose of 240 mg twice daily can be used. #Vemurafenib** monotherapy has lower efficacy (shorter remission), and therefore it is recommended to consider consolidation of the achieved effect with immunotherapy or immunochemotherapy (see theses below).

• For patients with refractory HCL with a detected BRAFV600E mutation receiving #vemurafenib** therapy, the addition of #rituximab** is recommended as one of the treatment options [76].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comment: #Rituximab** at a standard dose of 375 mg/m² as a prolonged intravenous infusion is used after #vemurafenib** therapy or concurrently with #vemurafenib**, for a total of up to 8 administrations with an interval ranging from weekly to monthly or less frequently (depending on the degree of cytopenia and performance status).

• For patients with refractory HCL with a detected BRAFV600E mutation after #vemurafenib** therapy, a course of cladribine + #rituximab** immunochemotherapy is recommended as one of the treatment options [6, 30, 31, 77, 78, 88].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comment: cladribine is used in a standard regimen — 1 course of cladribine at a dose of 0.1 mg/kg/day × 7 days or 0.14 mg/kg/day × 5 days (dosages and duration of treatment are determined by the attending physician depending on the disease course and severity of the condition); #rituximab** at a standard dose of 375 mg/m² as a prolonged intravenous infusion is used after cladribine therapy, usually 4–6 (rarely up to 8) administrations (the first administration is usually performed immediately after cladribine, subsequent ones at intervals ranging from weekly to monthly or less frequently, depending on the degree of cytopenia and performance status).

• For patients with refractory HCL with a detected BRAFV600E mutation after #vemurafenib** therapy, #bendamustine** + #rituximab** (RB regimen) is recommended as one of the treatment options [34, 79].

Level of Evidence BGrade of Recommendation 3Level of Clinical Effectiveness – B (level of evidence – 3)

Comment: #Rituximab** is used at a standard dose of 375 mg/m² on days 1 and 15 as a prolonged intravenous infusion, #bendamustine** is used in a standard regimen of 70 mg/m² or 90 mg/m² on days 1 and 2; up to 6 cycles are administered in total with an interval of 4 weeks.

• For patients with refractory HCL, Interferon alfa-2b** at a dose of 2 IU/m² 3 times a week is recommended as one of the treatment options [6, 70].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

• For patients with refractory HCL, the combination of #bendamustine** at a dose of 70 mg/m² on days 1–2 with #rituximab** IV at a dose of 375 mg/m² on days 1 and 15, for 6 courses with an interval of 28 days, may be recommended as one of the treatment options [34].

GPR CLoE 4Level of Recommendations Validation – C (Level of Evidence – 4) 

3.4 Supportive Care for Patients with Hairy Cell Leukemia

• For patients with HCL with the presence or suspicion of an infectious and inflammatory process, performing the examination procedures necessary to diagnose the source of infection is recommended (ultrasound, CT, microbiological (culture) blood test for sterility; microbiological (culture) urine test for bacterial pathogens using automated seeding; microbiological (culture) test of oral cavity discharge; study of intestinal microbiocenosis (dysbiosis)) to clarify the nature of the infection and develop adequate treatment tactics [20, 35, 68].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comment: To rule out infection and obtain material for microbiological and other examinations, depending on the localization of the suspected lesion, the following procedures and instrumental diagnostic methods are used: thoracoscopy, tracheobronchoscopy with bronchoalveolar lavage, esophagogastroduodenoscopy, colonoscopy, ultrasound of soft tissues, magnetic resonance imaging of the required region (soft tissues, pelvis, spine, bone, brain, etc.), computed tomography of the required region (chest, abdominal cavity, pelvis, brain, bone, etc.), pleural puncture, lumbar puncture, incision and drainage of phlegmon (abscess), incision of acute purulent paraproctitis. If necessary, a biopsy of the affected organ is performed (lymph nodes, lungs, mediastinum, liver, intestine, bone, soft tissue tumor, etc.). The obtained material is sent for cytological, histological (pathological-anatomic examination of biopsy (surgical) material, if necessary using immunohistochemical methods), microscopic, and microbiological (cultural, bacteriological) examinations.

• For patients with HCL with suspected development of an infectious and inflammatory process, urgent initiation of systemic antimicrobial therapy is recommended (see section 7.2) [8, 35, 36].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comment: when treating patients with HCL, extreme vigilance regarding infections is necessary — hyperthermia in HCL, unlike lymphomas, is not a symptom of tumor intoxication and indicates the presence of an infectious and inflammatory process, often without a clearly defined localization due to neutropenia. Patients with HCL are particularly prone to developing pneumonia, sinusitis, subcutaneous abscesses, intermuscular abscesses (especially in the leg muscles); due to neutropenia, the foci of infection in HCL tend to generalize rapidly and require urgent prescription of systemic antimicrobial therapy, including, according to indications, antibacterial, antifungal, antiviral systemic drugs and others (see section 7.2).

• For patients with HCL combined with tuberculosis, simultaneous treatment of both diseases is recommended [37].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

• For patients with HCL, colony-stimulating factor therapy is not recommended, except for patients with prolonged and profound neutropenia (agranulocytosis) with severe infectious complications [38].

強B (level of recommendation — B)УДД 3Level of Recommendation — B (Level of Evidence — 3)

• For patients with HCL with profound anemia when other causes of anemia are ruled out (iron deficiency, or vitamin B₁₂, folic acid deficiency, etc.), short-term therapy with hematopoietic stimulating agents (B03XA Other antianemic preparations) is recommended [39].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: if iron deficiency, or vitamin B₁₂, or folic acid deficiency is confirmed, appropriate therapy with hematopoietic stimulants — iron preparations, or vitamin B₁₂ and folic acid — must be administered. In the absence of a deficiency of these factors, a patient with profound anemia may receive therapy with hematopoietic stimulating agents (B03XA Other antianemic preparations).

• For patients with HCL with anemia accompanied by symptoms of hypoxemia, or thrombocytopenia with pronounced hemorrhagic manifestations, replacement hemotransfusion therapy with platelet concentrate and red blood cell components is recommended to correct symptoms of anemia or thrombocytopenia [85].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: if there are indications for repeated transfusions of blood components, in order to prevent adverse reactions and complications associated with transfusions, it is recommended to use blood components with the following characteristics: leukoreduced — leukocyte count in the dose of the transfused medium is reduced to 1 × 10⁶ cells; irradiated red blood cells and platelets (gamma radiation or X-ray radiation at a dose of 25–50 Gy); restriction of donor plasma usage by employing additive solutions for red blood cells; after testing donor blood for viral infection markers using molecular biological methods. The main reactions and complications associated with the transfusion of donor blood components are presented in section A3.3.

• For patients with HCL at risk of developing tumor lysis syndrome, syndrome prevention including adequate hydration and the prescription of anti-gout medications before starting treatment is recommended [83, 84].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: patients at risk for tumor lysis syndrome include those with a high tumor burden prior to a course of immunochemotherapy (e.g., pronounced splenomegaly and/or lymphadenopathy with lymph node conglomerates, high lymphocyte count in peripheral blood, and/or renal failure with creatinine clearance <70 ml/min). In this case, it is necessary to perform prevention of the syndrome accompanied by an increase in uric acid concentration (hyperuricemia), including adequate hydration and the prescription of anti-gout medications (e.g., #allopurinol** at a dose of 100–600 mg daily) prior to the initiation of treatment.

• For HCL patients who develop acute or chronic pain syndrome, it is recommended to diagnose the cause of the pain syndrome followed by pathogenetic or symptomatic pain therapy [6, 40, 41].

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

Comment: the most frequent cause of pain in HCL is a local inflammatory process (abscess, tissue inflammation). In this case, active treatment of the inflammation focus must be carried out (including surgical treatment if necessary). If the infectious-inflammatory nature of the pain syndrome is ruled out, the patient undergoes analgesic therapy according to existing pain management protocols (see relevant clinical guidelines for chronic pain, clinical guidelines for anesthesiology), taking into account potential contraindications associated with cytopenia and other clinical situations.

3.5 Assessment of Treatment Efficacy

• For HCL patients undergoing treatment with interferons α (interferon alfa-2b** or #peginterferon alfa-2a (40 kDa)**) or #vemurafenib**, treatment efficacy recommended to be assessed at least once a month (see Appendix A3.5) [6, 13].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: evaluation of the efficacy of interferon therapy is performed no earlier than 8 weeks after the start of treatment. Therapy is considered effective if there is positive dynamics in all or several parameters (reduction of cytopenia, lymphocytosis, and monocytopenia, decrease in spleen size and visceral lymphadenopathy). When blood lymphocytosis decreases to approximately 50% and neutrophils increase to approximately 1.5× 10⁹/L, this stage of treatment is completed and a course of cladribine chemotherapy is administered.

• For patients who have completed planned treatment for HCL, treatment efficacy recommended to be assessed 6–12 months after therapy completion according to international criteria (see Appendix A3.5) [6, 13].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

3.6 Medical Nutrition Therapy

The organization of clinical dietary nutrition for patients with hairy cell leukemia during inpatient treatment in medical organizations is carried out in accordance with current orders of the Russian Ministry of Health, taking into account the somatic status and comorbidity of the patient, as well as dietary restrictions associated with the presence and severity of cytopenia.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• For all HCL patients at all stages of disease therapy, as well as after the completion of drug treatment, comprehensive rehabilitation recommended [42].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: there are no specific rehabilitation methods for HCL. Rehabilitation of HCL patients should be comprehensive, covering medical and socio-psychological aspects of the patient's adaptation to normal life. The scope of medical rehabilitation is developed individually for each patient by a medical rehabilitation physician with the participation of a hematologist. In addition, the rehabilitation program must take into account the social and psychological problems of the patient and include (as indicated) social workers and psychologists. Rehabilitation for complications arising during the course of the disease and treatment is carried out within the framework of relevant nosologies.

5. Prevention and Dispensary Observation

There are currently no methods for preventing HCL since the etiological factor(s) leading to the development of the disease are unknown.

The high frequency of infectious complications in patients in the advanced phase of HCL (newly diagnosed or relapse, disease progression), especially during the neutropenia period, dictates the need for prescribing prophylactic drugs.

• For all HCL patients after completion of therapy, lifelong dynamic follow-up by a hematologist recommended [6].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: for the timely detection of HCL relapse, monitoring of the complete blood count at least 2 times a year and spleen size at least once a year is necessary. HCL relapses develop over time in the vast majority of cases, with a detection rate of up to 35% at a median follow-up of 5 years and up to 50% at a median of 10 years. Relapses may occur more frequently and earlier in young patients (disease onset under 45 years of age) and when only partial remission is achieved. When HCL relapse is suspected, an examination similar to the initial one at diagnosis is performed to accurately verify disease relapse and rule out other diseases (conditions) leading to cytopenia, splenomegaly, and capable of mimicking relapse.

• For HCL patients in the advanced phase of the disease (newly diagnosed, relapse, progression) with neutropenia and/or episodes of infection (including a history thereof), infection prophylaxis recommended [50–54, 70] (see section A3.1).

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: prophylaxis is indicated for infections caused by fungi and viruses, especially during prolonged neutropenia, as well as in high-risk groups, for example, with frequent and/or severe infections in history. Prophylaxis of bacterial infections becomes less relevant due to the increase in multidrug-resistant bacteria and is performed in a certain category of patients.

• For HCL patients planning a splenectomy, as well as newly diagnosed HCL patients, post-treatment, in relapse, upon progression, with neutropenia and/or episodes of Pneumocystis pneumonia (including a history thereof), vaccination against Streptococcus pneumoniae for the prevention of pneumococcal infection recommended [59, 68].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: in the absence of vaccination against Streptococcus pneumoniae prior to splenectomy, vaccination is recommended 3–6 months after splenectomy. Revaccination against Streptococcus pneumoniae is recommended every 5 years.

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Protecting Public Health in the Russian Federation", is organized and provided:

1. in accordance with the regulations on the organization of medical care by types of medical care approved by the authorized federal executive body;

2. in accordance with the procedure for the provision of care for the profile "hematology", mandatory for execution on the territory of the Russian Federation by all medical organizations;

3. based on these clinical guidelines;

4. taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by a hematologist and other medical specialists at an ambulatory hematology/oncology care center, a primary hematology/oncology office, a primary hematology department, or an outpatient department of an oncological dispensary.

When HCL is detected or suspected in a patient, general practitioners, district general practitioners, general family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for consultation to an ambulatory hematology/oncology care center or a primary hematology office, primary hematology department of a medical organization to receive primary specialized health care.

An outpatient or inpatient hematologist organizes the diagnostic tests necessary to establish the diagnosis, including disease extent and stage.

If diagnostic tests cannot be performed, the attending physician refers the patient to a medical organization providing medical care to patients with hematological diseases to establish a diagnosis and provide specialized, including high-tech, medical care.

When HCL is detected or suspected during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with hematological diseases to determine management tactics and the need for additional specialized antineoplastic treatment methods.

Specialized, including high-tech, medical care is provided by hematologists in medical organizations providing medical care to HCL patients, holding a license, the necessary material and technical base, certified specialists, in inpatient and day-hospital settings, and includes the prevention, diagnosis, treatment of hematological diseases requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing medical care to HCL patients, the tactics of medical examination and treatment are determined by hematologists with the involvement of other medical specialists if necessary, and if necessary, by holding a medical board (consilium). The decision of the medical board is formalized in a protocol, signed by the members of the medical board, and entered into the patient's medical documentation. Thus, all HCL patients with comorbidity that may affect the choice of the antineoplastic treatment program undergo an appointment (examination, consultation) with the relevant medical specialist (obstetrician-gynecologist, cardiologist, neurologist, otorhinolaryngologist, urologist, coloproctologist, endocrinologist, pulmonologist, phthisiatrician, infectious disease specialist, anesthesiologist-resuscitologist, etc.) before starting therapy as indicated.

Indications for hospitalization in a 24-hour or day hospital of a medical organization providing specialized, including high-tech, medical care in the specialty "hematology" are determined by a hematologist/medical panel with the involvement of other medical specialists if necessary.

Indications for planned hospitalization:

1. delivery of therapy in cases requiring round-the-clock patient monitoring due to the severity of the condition caused by leukemia or disease complications, or due to the risks of complications associated with the treatment program or concomitant diseases;

2. patient examination, including biopsies and invasive interventions, in cases where it cannot be performed on an outpatient basis.

Indications for emergency hospitalization:

1. development of a severe infection (due to neutropenia in HCL, the formation of a distinct focus of infection is difficult, therefore the severity of the infection is determined by hyperthermia refractory to antibacterial therapy, intoxication symptoms, signs of a septic state, respiratory failure);

2. severe condition due to decompensated, life-threatening cytopenias (symptomatic profound anemia, significant hemorrhagic syndrome, neutropenia with infectious manifestations);

3. development of HCL complications, including splenic rupture (or threat of rupture), neuroleukemia, pneumonia or pleurisy with signs of respiratory failure, paraneoplastic and autoimmune syndromes, and other life-threatening complications;

4. development of therapy complications, including myelotoxic agranulocytosis with fever, severe infusion reactions, and other life-threatening complications.

Indications for patient discharge from the hospital:

1. completion of the examination;

2. completion of the course of treatment;

3. transition to the outpatient stage of treatment;

4. achievement of the expected treatment effect;

5. in cases where, by decision of the medical commission, the patient's hospital stay is not indicated due to the futility of treatment and the need to provide only palliative care.

The conclusion on the feasibility of transferring the patient to a specialized medical organization is drawn up after a preliminary consultation based on the provided medical documents (including via telemedicine consultation) and/or a preliminary examination of the patient by medical specialists of the planned receiving medical organization.

7. Additional Information

7.1 Management of Complications of Hairy Cell Leukemia and Its Specific Treatment

7.1.1 Neutropenia in HCL

Neutropenia (as well as often monocytopenia) is characteristic of HCL and significantly increases the risk of infections, including fatal ones. Hyperthermia in this disease is not a symptom of tumor intoxication, and infections serve as the main cause of mortality in HCL; therefore, any hyperthermia not associated with a pyrogenic reaction to the use of interferons should be regarded as an infectious complication and requires immediate adequate therapy with systemic anti-infective drugs, including systemic antibacterial drugs (as indicated — systemic antiviral drugs, systemic antifungal drugs, and others). The most common occurrences are protracted bronchitis, pneumonia, soft tissue infections (abscess, phlegmon, paraproctitis), sinusitis, tonsillitis, and herpes simplex virus infection. The course of the infectious process in HCL is characterized by a tendency to generalize (sepsis) and form abscesses. Combination with tuberculosis is possible.

Antibacterial therapy and prophylaxis of fungal and viral infections are carried out in accordance with accepted protocols for the treatment of infectious complications in hematology, including during the period of agranulocytosis (see section 7.2 and A3.1). Colony-stimulating factors (ATC: L03AA) are not routinely used in HCL, but they may be used in case of severe infections, sepsis against the background of deep neutropenia and agranulocytosis.

7.1.2 Hemorrhagic Complications in HCL

Despite thrombocytopenia, prominent hemorrhagic manifestations are uncharacteristic for HCL. Usually, a moderate cutaneous hemorrhagic syndrome is observed, which is relieved by symptomatic therapy and does not require replacement platelet transfusions. In severe thrombocytopenia (<20×10⁹/L) with a pronounced hemorrhagic syndrome or against the background of an infectious process, platelet transfusions are necessary (see section A3.3).

7.1.3 Anemic Syndrome in HCL

Clinically compensated anemia in HCL with a hemoglobin level >70 g/L usually does not require replacement transfusion therapy. However, in case of decompensation associated with anemia, blood transfusions of red blood cell components are performed at any hemoglobin level (see section A3.3). It is necessary to clarify the type of anemia, as the cause of this complication may not be related to HCL (often iron or vitamin B12 deficiency), and prescribe appropriate therapy. If other causes of anemia are excluded and the hemoglobin level persistently drops to <50 g/L, the administration of hematopoiesis-stimulating agents (B03XA Other antianemic preparations) in doses corresponding to the instructions is required.

7.1.4 Infarction and Rupture of the Spleen

Splenic infarction and rupture are rare complications of HCL, despite the often significantly pronounced splenomegaly. Splenic rupture (usually after trauma) is an indication for emergency splenectomy. If a splenic infarction develops, a conservative management tactic with antibacterial therapy is possible. Recurrent splenic infarctions are also an indication for splenectomy (see section A3.4).

7.1.5. Complications associated with the administration of interferon alfa-2b** and #peginterferon alfa-2a (40 kDa)**, cladribine, and CD20 (cluster of differentiation 20) inhibitors.

Interferon alfa-2b** and #peginterferon alfa-2a (40 kDa)**

These drugs are characterized by a pyrogenic reaction (flu-like syndrome), the severity of which is individual and varies from asymptomatic subfebrile temperature to hectic fever with chills, joint and muscle pain. A moderate pyrogenic reaction is more common, the severity of which gradually decreases to a minimum within 2 weeks as "habituation" occurs. To prevent this complication, therapy with these drugs is carried out with premedication using nonsteroidal anti-inflammatory and antirheumatic drugs, starting treatment with a reduced dose of interferons, gradually increasing it over 1–2 weeks to the "working" dose of 3 million IU.

Extremely rarely, therapy with interferon alfa-2b** and #peginterferon alfa-2a (40 kDa)** leads to the development of immune complex vasculitis and indurative myositis, requiring discontinuation of the drug, glucocorticoid therapy, and plasmapheresis.

If aminotransferase activity increases during treatment with interferon alfa-2b** and #peginterferon alfa-2a (40 kDa)**, it is necessary to exclude hepatitis B and C, determine the activity of aspartate aminotransferase in the blood, and monitor alanine aminotransferase activity dynamically with temporary discontinuation of treatment if ALT and AST exceed the upper limit of normal by more than 5 times, along with hepatoprotective and detoxification therapy.

Cladribine

The drug is not toxic (in the doses used in HCL, it does not exhibit cardio-, hepato-, nephro-, or neurotoxicity) and does not cause nausea or vomiting. A rare complication (2% of cases) is non-infectious hyperthermia after administration, which is more frequently observed in tumor lysis syndrome. The drug causes myelotoxic agranulocytosis, but when used after a course of interferon therapy, this complication is observed in only 5% of cases and lasts 2–5 days. In this case, standard prevention of infectious complications is carried out; colony-stimulating factors are usually not used.

Monoclonal anti-CD20 antibodies (L01FA CD20 (cluster of differentiation 20) inhibitors)

These drugs cause standard complications, most often related to the infusion rate. Antihistamine therapy is used, glucocorticoids are prescribed, and the infusion rate of #rituximab** is reduced (see Appendix A3.2).

7.2 Diagnosis and Treatment of Infectious Complications of Hairy Cell Leukemia

Infections are the leading complications in the treatment of HCL; moreover, they are the main cause of mortality in HCL. The main factor determining the development of infectious complications is neutropenia (neutrophils <0.5×10⁹/L) or leukopenia (leukocytes ≤1,000×10⁹/L), as well as the duration of neutropenia exceeding 10 days. The risk of developing infections increases with damage to the mucous membranes of the gastrointestinal tract and the presence of a central venous catheter (CVC). Diagnosis and treatment of infectious complications that naturally arise during neutropenia in an HCL patient are carried out directly during the period of antileukemic treatment.

Characteristic features of infections during the neutropenia/leukopenia period include:

• scarcity of clinical manifestations;

• the likelihood of simultaneous presence of different pathogens and different localizations of the infectious process;

• the possibility of the emergence of other pathogens and different localization of the infectious process as the period of neutropenia lengthens.

The most frequent manifestations of clinically proven infections are pneumonia, soft tissue infection, and perineal infection (including paraproctitis). Microbiological confirmation of infection during granulocytopenia in most cases is the isolation of microorganisms from blood culture.

In all cases of probable or established infectious process, diagnostics aimed at identifying both the foci of infection and etiological agents should be actively pursued, along with the immediate collection of clinical material samples from the patient for microbiological studies (especially with a history of glucocorticoid intake and in the elderly — the possibility of septicemia with normothermia).

During neutropenia, the patient examination includes: an active interview of the patient regarding possible symptoms of infection, including the presence of pain along the esophagus and in the perineum; examination of the oral mucosa; examination of the skin (septicopyemic foci); examination of catheter insertion sites (if present); auscultation of the chest (harsh breathing in the absence of rales, minimal wet rales in a limited area may be an initial manifestation of pneumonia); palpation of the abdomen (pain or "rumbling" on palpation in the right iliac region are the first symptoms of pseudomembranous colitis).

In case of hyperthermia, the following tests are performed: microbiological (culture) blood test for sterility; microbiological test of the removed central venous catheter (if catheter-associated infection is suspected); microbiological test of smears from inflammation sites; microbiological (culture) urine test; microscopic, microbiological (culture) and molecular-biological examination of cerebrospinal fluid (if symptoms of meningitis are present, or if lesion(s) are detected in the brain on CT or MRI). Cerebrospinal fluid (CSF) examination includes cytologic examination of CSF cells, microscopic and microbiological (culture) examination of CSF, including, according to indications, for meningococcus (Neisseria meningitidis), pneumococcus (Streptococcus pneumoniae), Haemophilus influenzae, other aerobic, anaerobic and facultative anaerobic opportunistic microorganisms, as well as fungi – Cryptococcus spp., Aspergillus spp., etc.; and viruses (molecular-biological test for herpes simplex virus types 1 and 2, cytomegalovirus, Epstein-Barr virus, etc.). If enterocolitis symptoms are present, a microbiological (culture) test of feces/rectal swab for Clostridium difficile is performed with antimicrobial susceptibility testing; if this test is negative, a quantitative test is performed for opportunistic microorganisms, as well as for Salmonella spp., Shigella spp., Listeria monocytogenes, Yersinia enterocolitica, Rotavirus gr. A, Adenovirus, Candida spp. In quantitative stool examination, attention should be paid to the isolation of Pseudomonas aeruginosa strains and enterobacteria (Escherichia coli, Klebsiella spp.) producing ESBLs or carbapenemases. In patients with persistent febrile neutropenia and no positive blood cultures, these microorganisms may be the cause of infection.

In the presence of signs of stomatitis (mucositis), microbiological (culture) examination of the oral mucosa discharge and mucosal smears, nasopharyngeal discharge and scrapings is performed – culture test for gram-negative bacteria (Escherichia coli, Salmonella, Shigella and other Enterobacteriaceae, Pseudomonas, Moraxella, Helicobacter, Stenotrophomonas, Bdellovibrio, Legionella, etc.) and microbiological (culture) test of oral scrapings for yeast fungi of the genus Candida, virus tests (molecular-biological test for herpes simplex virus types 1 and 2, cytomegalovirus, Epstein-Barr virus, etc.).

In perineal infection, inflammation or damage to the rectal mucosa (fissure, paraproctitis, etc.), microbiological and molecular-biological examination of rectal mucosa discharge (rectal swabs) is performed to detect colonization of the intestinal mucosa by multidrug-resistant gram-negative bacteria and Candida fungi.

Taking into account the isolated microorganisms, correction of antimicrobial therapy may be performed in the absence of diagnostically significant results from clinically significant samples in patients with persistent febrile neutropenia. Attention is drawn to the isolation of multidrug-resistant gram-negative bacteria – P. aeruginosa, A. baumannii, S. maltophilia, and enterobacteria producing ESBLs or carbapenemases.

In the presence of septicemic skin lesions (dermal infiltrates of any size that developed during hyperthermia), a microbiological (culture) skin scraping test for bacteria, fungi, and tuberculosis is performed; microscopic examination with Gram, Ziehl-Neelsen, and calcofluor white stains.

In the presence of lung abnormalities, bronchoalveolar lavage may be performed with microscopic and microbiological (culture) examination of the bronchoalveolar lavage fluid for various pathogens (bacteria, fungi, viruses), including microbiological (culture) examination of bronchoalveolar lavage fluid for Pneumocystis carinii cysts, microbiological (culture) examination of lavage fluid for aerobic and facultative anaerobic microorganisms, microbiological (culture) examination of bronchoalveolar lavage fluid for Mycoplasma pneumoniae, microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeasts and molds), Chlamydophila pneumoniae by PCR, and detection of herpes virus and respiratory virus DNA (Influenza, Parainfluenza, RSV, Coronavirus, Human metapneumovirus, H1N1) by PCR. In the presence of pneumonia with consolidation foci, determination of legionellosis pathogen antigen (Legionella pneumophila) in urine is performed. In patients with prolonged neutropenia and characteristic radiological signs, invasive aspergillosis, invasive candidiasis, and cryptococcosis must be ruled out. Determination of class M and G antibodies (IgM, IgG) to Mycoplasma pneumoniae in blood and antibodies to Chlamydophila pneumoniae in blood is performed in community-acquired pneumonia.

Table 1 (Section A.3.1) summarizes diagnostic tests in patients with hematological diseases and infections.

Indications for first-line antibacterial therapy

On the first day, as a rule, the only symptom of an infectious complication is merely an elevated body temperature, and information about bacteremia or pneumonia in patients with neutropenia cannot be obtained earlier than on the second day of the infectious episode. Therefore, the main principle of treating infectious complications in hematological patients with febrile neutropenia, especially from the risk group, which includes patients with leukemias and lymphomas (oncohematology, immunodeficiency states), is an empirical approach to prescribing systemic antibacterial drugs, applying them at the first signs of infection and fever before pathogen identification. At the same time, the empirical approach to prescribing systemic antibacterial drugs is relative, since the choice of systemic antibacterial drugs is determined by a retrospective analysis of verified pathogens and their antibiotic susceptibility.

Indications for prescribing systemic antibacterial drugs are an increase in temperature ≥38.0 °C persisting for 2 hours and not associated with the administration of pyrogenic agents (e.g., blood components, growth factors, etc.) or the presence of a focus of infection (e.g., pneumonia, paraproctitis, etc.) regardless of temperature readings.

For upper and lower respiratory tract infections and urinary tract infections, first-line treatment involves intravenous systemic antibacterial drugs active against gram-negative bacteria, including Pseudomonas aeruginosa: Piperacillin+[Tazobactam] (4.5 g × 3 times) or Cefoperazone+[Sulbactam]** (4 g × 2 times). In clinics with a low detection rate of ESBL-producing enterobacteria, Cefepime** (2 g × 2 times) or Ceftazidime** (2 g × 3 times) is acceptable. The drug of choice for pregnant women with blood system disorders is Cefepime**. In case of ineffectiveness and lack of informative microbiological tests in lower respiratory tract, urinary tract, or bloodstream infections (bacterial septicemia), first-line systemic antibacterial drugs are replaced with an antipseudomonal carbapenem (Imipenem+[Cilastatin]**, Meropenem**, or Doripenem for hospital-acquired pneumonia, complicated intra-abdominal and urinary infections). Ceftriaxone**, Cefoperazone, and fluoroquinolones are not prescribed as first-line therapy for febrile neutropenia.

Indications for prescribing antipseudomonal carbapenems (Imipenem+[Cilastatin]**, Meropenem**, Doripenem) as first-line therapy include severe respiratory and urinary tract infections, bacterial endocarditis, bacterial septicemia (sepsis); ventilator-associated pneumonia (VAP), and other severe infections.

Modification of antimicrobial therapy is based on clinical symptoms, instrumental examinations, and microbiological tests. If carbapenems are ineffective and neutropenia persists, systemic antifungals are added—including for the treatment of esophageal candidiasis and for prophylaxis of candidiasis when neutropenia lasts longer than 10 days—echinocandins (J02AX Other systemic antifungals) (caspofungin**, micafungin**, or anidulafungin); including for the prevention of invasive fungal infections and treatment of severe fungal infections—voriconazole**, amphotericin B**; and for oropharyngeal candidiasis and esophagitis—fluconazole**.

Empirical prescription of systemic antifungals

Empirical prescription of systemic antifungals for candidiasis prophylaxis or in case of esophageal candidiasis and invasive candidiasis is performed in patients with HCL and a history of candidiasis who present with persistently prolonged febrile neutropenia. The drug of choice is caspofungin** (70 mg on day 1, followed by 50 mg IV once daily), micafungin** (100 mg once daily IV), anidulafungin (200 mg on day 1, followed by 100 mg once daily IV); alternatives include voriconazole** (6 mg/kg IV twice daily on day 1, followed by 4 mg/kg IV twice daily on subsequent days, with transition to oral administration at 200 mg twice daily), amphotericin B [liposomal] (starting at a daily dose of 1.0 mg/kg, increasing up to 3.0 mg/kg if necessary; the maintenance dose is 1.0–3.0 g), amphotericin B [lipid complex] (starting at 0.25–0.3 mg/kg, with a gradual increase to 0.5–0.7 mg/kg IV once daily; dose selection is individual depending on the severity of the infection). As a rule, temperature normalizes within the first three days of systemic antifungal administration, and the total duration of their use is 10–14 days.

Criteria for discontinuing antimicrobial therapy

In fever of unknown origin during neutropenia/leukopenia, systemic antibacterials are discontinued after 72 hours if the patient has had no episodes of hemodynamic instability during the current infection episode and normothermia is maintained for 48 hours.

In clinically and microbiologically proven infection, the duration of systemic antibacterial therapy is at least 7 days, provided that normal body temperature is observed for at least 4 days, infection foci have completely regressed, and microbiological eradication of the confirmed infection pathogen has been achieved (or is anticipated). After discontinuing systemic antibacterials, the patient with neutropenia/leukopenia is monitored for the subsequent 24–48 hours, and if fever recurs, systemic antibacterials are re-administered.

Outpatient management of patients

Outpatient management of infectious complications during neutropenia/leukopenia is carried out in most cases provided that the expected duration of neutropenia does not exceed 5–10 days and the only symptom of infection is a temperature below 39.0 °C; there are no significant pulmonary changes according to radiological imaging; arterial hypotension and respiratory failure are absent; there are no clinical signs of decompensation of chronic pulmonary diseases and diabetes mellitus; consciousness is not impaired; bleeding is absent; and invasive aspergillosis did not occur during previous chemotherapy courses. In case of clinical deterioration, the patient must be urgently hospitalized in an inpatient facility at any time of day.

Outpatient treatment for upper and lower respiratory tract infections, otitis media, urogenital tract infections, skin and soft tissue infections (including complicated skin and skin structure infections), odontogenic infections, and others involves a combination of amoxicillin + [clavulanic acid]** (625 mg orally 3 times daily) with ciprofloxacin** (0.5 g orally twice daily) or levofloxacin** (0.5 g orally once daily) or moxifloxacin** (0.4 g orally once daily).

Perianal infection

Perianal infection is very common in neutropenic patients with HCL, while the formation of inflammatory changes in tissues may be delayed and present with atypical forms; thus, abscess formation under neutropenic conditions is rare, and tissue changes may manifest as inflammatory infiltrates and necrosis. Additional mechanisms of infection include the spread of microorganisms into tissues and the bloodstream from the intestinal mucosa, through skin lesions of the anal canal and perianal region. The danger of perianal infection in HCL against the background of neutropenia is due to a high (up to 30%) probability of sepsis. Diagnosis and treatment of perianal infection in patients with HCL are carried out directly during the course of anti-leukemic treatment.

Clinical presentation.

Signs of perianal infection are typically anorectal pain and fever. Assessment of the nature of tissue changes forms the basis for selecting treatment tactics.

Diagnosis.

1. Initial appointment (examination, consultation) by a coloproctologist, follow-up appointment (examination, consultation) by a coloproctologist

2. Pelvic MRI.

3. Pelvic CT / SCT

4. Pathogen identification

The diagnosis of perianal infection is established clinically based on symptoms characterizing inflammation: perianal pain, erythema, fluid collection, or fistula formation. Since invasive diagnostic procedures (digital rectal examination and rectoscopy) in HCL patients are associated with the risk of bleeding and dissemination of infection into tissues and the bloodstream, pelvic MRI or CT/SCT is performed in case of doubtful clinical presentation. MRI signs of perianal infection include cavities in the pararectal tissue, fluid collections, rectal wall defects, and fistulous tracts. In neutropenic patients with appropriate clinical data, the presence of pararectal tissue edema is a sufficient MRI sign of perianal infection. To determine the microflora profile and to prescribe or modify antibacterial therapy, pathogen identification is performed using microbiological, molecular, and other studies of rectal mucosal swabs, fistula discharge, wound surface, and perianal skin scrapings.

Treatment

1. Antibacterial therapy (see above)

2. Surgical intervention

For HCL patients, anorectal infections are regarded as a condition requiring emergency treatment with systemic antibacterials, which halts the progression of the anorectal infection and sepsis. The initial step involves the administration of systemic antimicrobials active against gram-negative bacteria, including *Pseudomonas aeruginosa*; systemic antimicrobials are administered exclusively orally and intravenously.

Indications for surgery include abscess formation or necrosis. Cavity drainage and necrectomy are performed. In some cases (pelvic phlegmon, grade 3–4 complex fistulas), surgical drainage is combined with a diverting colostomy. Surgical intervention must be performed against the background of antibacterial therapy under general anesthesia. Antibacterial therapy should be continued in the postoperative period until signs of infection disappear.

Patients with an absolute neutrophil count greater than 1000 × 10⁹/L have higher cure rates with surgical drainage, whereas patients with a lower neutrophil count and/or absence of fluctuation are more successfully treated with systemic antimicrobials alone.

7.3 Treatment of Hairy Cell Leukemia During Pregnancy

When HCL is diagnosed in a pregnant woman, treatment tactics are determined by the gestational age and the severity of disease symptoms.

In the case of pregnancy in an HCL patient without indications for urgent treatment (with mild cytopenia and minor splenomegaly, without infectious manifestations), observation is an option. At the same time, passive management of patients with deepening cytopenia is extremely dangerous—on the contrary, a prompt choice of adequate treatment tactics is necessary to minimize complications and risks of pregnancy and childbirth for both mother and child [43]. The main approach to treating HCL during pregnancy is the use of interferons, but splenectomy is also possible, and less commonly—after carefully weighing all risk and prognostic factors—the use of #cladribine or #rituximab**.

A history of HCL diagnosis and treatment, including with purine analogs and #rituximab**, is not an obstacle to pregnancy and childbirth during remission. The recommended contraception period is 6–12 months.

• Female patients with newly diagnosed HCL or HCL relapse during pregnancy who have clinical indications for HCL treatment may be recommended the use of interferons (#interferon alfa-2b** (or #peginterferon alfa-2a (40 kDa)) [43, 44].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comment: the use of interferons (#interferon alfa-2b** (or #peginterferon alfa-2a (40 kDa)) during pregnancy is safe; #interferon alfa-2b** is used in the same dosage regimen as in non-pregnant patients – 3 million IU x 3 times/week subcutaneously, since this drug has no negative impact on the course of pregnancy, childbirth, or fetal development.

• For patients with newly diagnosed HCL or HCL relapse in early pregnancy, if there are clinical indications for HCL treatment, splenectomy may be recommended [80].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comment: when splenectomy is performed in early pregnancy, subsequent monitoring is carried out to determine indications for systemic treatment of HCL during pregnancy with interferons (#interferon alfa-2b** (or #peginterferon alfa-2a (40 kDa)), or delaying treatment until delivery.

• For patients with newly diagnosed HCL or HCL relapse in early pregnancy, if there are clinical indications for HCL treatment and no alternative treatment options, the use of #cladribine at a dose of 0.1 mg/kg/day for a 5-day course may be recommended [82, 86].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comment: the use of the purine analogue #cladribine during pregnancy is not routinely recommended, but may be performed for vital indications using the same dosage regimens as in non-pregnant patients with HCL – 0.1 mg/kg/day x 5 days.

• For patients with newly diagnosed HCL or HCL relapse during pregnancy, if there are clinical indications for HCL treatment, the use of #rituximab** in special cases may be recommended [43].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comment: the use of #rituximab** during pregnancy is not routinely recommended, but may be performed for vital indications in the same dosage regimens as in non-pregnant patients with HCL - 375 mg/m2 4 infusions at 3-month intervals.

The use of #vemurafenib** (ATC group: L01EC B-Raf serine-threonine kinase (BRAF) inhibitors) during pregnancy in HCL has not been described and is not routinely recommended; there is limited positive experience with the drug in pregnant patients with other malignancies harboring the BRAFV600E mutation (metastatic melanoma) in the absence of alternative treatment options for vital indications [81].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Al-Radi Lyubov Sattarovna, Candidate of Medical Sciences, Senior Researcher, National Medical Research Center for Hematology of the Russian Ministry of Health, member of the Association for the Promotion of Hematology, Transfusion Medicine and Bone Marrow Transplantation "National Hematology Society"

2. Baykov Vadim Valentinovich, Doctor of Medical Sciences, Hematologist, Professor at the Department of Pathological Anatomy, Head of the Pathomorphology Laboratory, R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, First St. Petersburg State Medical University named after Academician I.P. Pavlov, Member of the Presidium of the Russian Society of Pathologists, Member of the Russian Society of Oncohematology

3. Kovrigina Alla Mikhailovna, Doctor of Medical Sciences, Pathomorphologist, Professor at the Department of Pathological Anatomy, Cytology and Molecular Pathology, Institute for Advanced Training of the Federal Medical and 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 Management Board of the Russian Professional Society of Oncohematology, Member of the Association for the Promotion of Hematology, Transfusion Medicine and Bone Marrow Transplantation "National Hematology Society"

4. Krivalapov Yury Alexandrovich, Doctor of Medical Sciences, Professor, Pathologist, Head of the Department of Clinical Molecular Morphology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, Member of the Presidium of the Russian Society of Pathologists

5. Moiseeva Tatyana Nikolaevna, Candidate of Medical Sciences, Hematologist, Head of the Department of Chemotherapy for Hematological Diseases with Day Hospital, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the Association for the Promotion of Hematology, Transfusion Medicine and Bone Marrow Transplantation "National Hematology Society"

6. Nikitin Evgeny Alexandrovich, Doctor of Medical Sciences, Professor, Hematologist, Professor at the Department of Hematology and Transfusion Medicine, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Head of the Day Hospital of Hematology, Oncology and Chemotherapy, City Hematology Center, S.P. Botkin City Clinical Hospital of the Moscow Healthcare Department, Member of the Management Board of the Russian Society of Oncohematology, Member of the Association for the Promotion of Hematology, Transfusion Medicine and Bone Marrow Transplantation "National Hematology Society"

7. Pivnik Alexander Vasilyevich, Doctor of Medical Sciences, Professor, Head of the Department of Oncohematology and Secondary Immunodeficiency Diseases, A.S. Loginov Moscow Clinical Scientific Center of the Moscow Healthcare Department, Member of the European Hematology Association

8. Stadnik Elena Alexandrovna, Candidate of Medical Sciences, Hematologist, Associate Professor at the Department of Faculty Therapy, First St. Petersburg State Medical University named after Academician I.P. Pavlov, Senior Researcher at the Research Laboratory of Oncohematology, V.A. Almazov National Medical Research Centre of the Russian Ministry of Health, Member of the Russian Society of Oncohematology

9. Dzhulyakyan Unan Levonovich, Candidate of Medical Sciences, Scientific Secretary, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the Association for the Promotion of Hematology, Transfusion Medicine and Bone Marrow Transplantation "National Hematology Society"

10. Nevolskikh Alexey Alekseevich, Doctor of Medical Sciences, Deputy Director for Medical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

11. Ivanov Sergey Anatolyevich, Professor of the RAS, Doctor of Medical Sciences, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

12. Khaylova Zhanna Vladimirovna, Candidate of Medical Sciences, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

13. Gevorkyan Tigran Gagikovich, Deputy Director of the Research Institute of Clinical and Economic Research, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Conflict of interests – none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• hematologists;

• oncologists.

Methodology for evidence collection

Methods used for evidence collection/selection:

Search for publications in specialized periodical printed publications.

Search in electronic databases

Databases used for evidence collection/selection:

• the evidence base for the recommendations consists of publications included in the PubMed and Medline databases. The search depth was 30 years.

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• assessment of the significance of evidence in accordance with the rating scheme for evidence (Tables A1–A4).

Table A1. Levels of Evidence (LoE) rating scale for diagnostic methods (diagnostic interventions)

Table A2. Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table A3. Scale for assessing 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 3 years, as well as when new data emerge from the perspective of evidence-based medicine 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. Prophylaxis of Infectious Complications in Hairy Cell Leukemia

Infectious complications in patients with hairy cell leukemia (HCL) are characterized by diversity in both etiology and localization of the infectious process. The high incidence of severe infectious complications in patients with HCL (from 10 to 30%; higher during the remission induction period, in the resistant variant of the disease, with concomitant hypogammaglobulinemia, and during periods of forced immobility), especially during neutropenia, dictates the need to prescribe prophylactic medications. Prophylaxis is indicated for fungal and viral infections in the high-risk group. Prophylaxis of bacterial infections is becoming less relevant due to the increase in multi-drug resistant bacteria and is performed in a specific category of patients. Thus, HCL patients with neutropenia and/or episodes of Pneumocystis pneumonia (including a history thereof) receive Pneumocystis pneumonia prophylaxis with co-trimoxazole [Sulfamethoxazole+Trimethoprim]** 480 mg 2 times/day (the drug can be used during cytostatic therapy and throughout the entire period of neutropenia; it simultaneously prevents infections caused by Toxoplasma gondii, Listeria monocytogenes, Nocardia asteroides [50, 70]. Also, HCL patients with neutropenia and/or episodes of fungal infection (including a history of acute or chronic disseminated candidiasis, mucormycosis, or invasive aspergillosis) receive antifungal prophylaxis and therapy – administration of the drug with which recovery from the invasive mycosis was achieved, usually one of the following drugs – fluconazole** (400 mg daily, intravenously or orally); for patients with febrile neutropenia when fungal infection is suspected – caspofungin** (50 mg daily intravenously); micafungin** (50 mg daily intravenously, with a possible dose increase to up to 100 mg daily); with a history of invasive aspergillosis, one of the following drugs is usually used – voriconazole** (200 mg twice daily orally or intravenously); posaconazole** (suspension, 200 mg 3 times daily orally); itraconazole (suspension, 200 mg twice daily orally); with a history of mucormycosis – posaconazole** (suspension), 200 mg 3 times daily orally [51, 52, 70].

HCL patients with neutropenia and/or episodes of viral infection (including a history thereof) receive viral infection prophylaxis – for example, acyclovir** (intravenously 250 mg/m² or 5 mg/kg every 12 hours); acyclovir** (400 mg tablets x 2 times); valacyclovir (500 mg tablets x 2 times); famciclovir (500 mg tablets 2 times). Antiviral prophylaxis is usually used during specific therapy and after it until neutrophil recovery to > 1.0 – 1.5 x 10⁹/L; switching from oral to intravenous formulation is performed in patients with mucositis [53, 54, 70].

Table A3.1.1 Algorithm of diagnostic tests in patients with hairy cell leukemia and infections.

Appendix A3.2. Supportive care during the administration of CD20 (cluster of differentiation 20) inhibitors in hairy cell leukemia.

It is known that even in complete clinical and hematological remission following purine analogue therapy, HCL patients retain a minimal tumor cell clone in the bone marrow. Subsequently, disease relapse is reported in approximately 25% of HCL patients at 5 years and 40% of HCL patients at 10 years of follow-up. For the treatment of refractory or relapsed HCL, a combination of purine analogues with CD20 (cluster of differentiation 20) inhibitors has been used since the mid-2000s. Over the past decade, targeted therapy methods for tumor cells in hematological malignancies have demonstrated high efficacy and have been included in numerous national guidelines for the treatment of hemoblastoses, both in the relapse setting and as first-line therapy.

Given that monoclonal antibodies are protein molecules capable of causing adverse reactions, primarily infusion-related, an algorithm has been developed to eliminate adverse events associated with the administration of therapeutic monoclonal antibodies and antibody-drug conjugates. Monoclonal antibodies and antibody-drug conjugates cause a wide range of side effects: from headache and rash to anaphylaxis and toxicoderma. Infusion reactions to monoclonal antibodies and antibody-drug conjugates are presumed to be driven by immune mechanisms: massive cytokine release and IgE-mediated pathways.

To prevent the development of infusion reactions, premedication is recommended immediately prior to the administration of monoclonal antibodies and antibody-drug conjugates.

If infusion reactions occur—nasal congestion, cough, allergic rhinitis, chills, sore throat, dyspnea, nausea, edema, blood pressure changes—of any severity, the infusion of the drug must be stopped immediately and the symptoms managed by administering glucocorticoids, oxygen, medications for obstructive airway diseases, systemic antihistamines, after which the possibility of resuming the infusion should be evaluated. In the event of severe or refractory infusion reactions, an anesthesiologist-resuscitologist must perform an evaluation. If anaphylactic shock develops, epinephrine** and fluid challenge are administered first, followed by dexamethasone** or prednisolone**.

A3.2.1 #Rituximab** [30, 31, 34, 75, 76, 82, 88]

The use of #rituximab** in HCL enhances the anti-tumor effect of treatment, including achieving MRD-negativity in some cases.

#rituximab** administration may be accompanied by infusion reactions, mainly chills, weakness, dyspnea, dyspepsia, nausea, rash, arterial hypotension or hypertension, fever, pruritus, urticaria, tachycardia, which requires standard premedication (30–60 min before the infusion, nonsteroidal anti-inflammatory and antirheumatic drugs, systemic antihistamines, and glucocorticoids are administered), adherence to the drug administration timing (the solution is stable for 12 h at room temperature or for no more than 24 h at 2 to 8 °C); adherence to administration rules (slow intravenous infusion at an initial rate of 50 mg/h for the first infusion, with subsequent escalation by 50 mg/h every 30 min up to a maximum rate of 400 mg/h), and administration of antiallergic and anti-shock therapy if necessary. Mild or moderate reactions can be managed by reducing the infusion rate, which can be increased again once the symptoms resolve. For subcutaneous administration of subsequent doses in patients with difficult venous access, standard premedication is also performed (nonsteroidal anti-inflammatory and antirheumatic drugs, systemic antihistamines, glucocorticoids). Due to the risk of hypotension, discontinuation of antihypertensive agents is recommended 12 h before and throughout the infusion of #rituximab**.

A3.2.2 #Obinutuzumab** [47-49]

The use of #obinutuzumab**, due to its increased affinity for CD20 cell receptors, may lead to a deeper anti-tumor response, justifying its use in HCL in cases of refractory disease or relapsing disease with short-lived remissions.

Infusion reactions (including severe ones) may occur during the administration of #obinutuzumab**. The most frequent are nausea, vomiting, chills, blood pressure decrease/increase, fever, dyspnea, flushing, headache, tachycardia, and diarrhea. To prevent infusion reactions, all patients should receive premedication with analgesics (ATC code N02), systemic antihistamines (ATC code R06A), and glucocorticoids (ATC code H02AB); discontinue antihypertensive drugs (ATC code C02) on the morning of the first infusion, and administer the dose step-wise during cycle 1.

If an infusion reaction develops, the infusion should be temporarily suspended, medical therapy for complications administered, and the infusion rate subsequently adjusted based on the severity of the observed reaction.

Blood pressure reduction may occur during the infusion of #obinutuzumab**; therefore, treatment with antihypertensive medications should be suspended for 12 hours prior to each infusion, during each infusion, and for 1 hour following the administration of #obinutuzumab**.

Appendix A3.3. Main reactions and complications associated with the transfusion of donor blood components

The main medical indication for blood transfusions in HCL patients is inadequate oxygenation of organs and tissues, and hemorrhagic complications. The choice of a specific type of blood component for transfusion (type of red blood cell component, type of platelet concentrate, type of plasma product) is made by the attending physician or transfusiologist in accordance with the clinical situation and based on regulatory documents.

Transfusions of red blood cell components (RBCC)

To prevent transfusion-related reactions and complications, RBCCs are used that are identical or compatible in the ABO system, Rh factor, and K (if possible, by erythrocyte antigens C, c, E, e, C^W). Individual selection of blood components is carried out for recipients with: a history of post-transfusion complications; pregnancy; a history of children born with hemolytic disease of the newborn; alloimmune antibodies.

Indications for RBCC transfusion

• In HCL with chronic anemia: at a hemoglobin level <60 – 80 g/L.

• In HCL with sepsis, coronary artery disease (including myocardial infarction, effort angina), myocarditis, and other cardiomyopathies: at a hemoglobin level of <80 – 100 g/L.

• In HCL in patients older than 60 years: at a hemoglobin level <80 – 100 g/L.

• In HCL and pregnancy: recommended hemoglobin level is at least 80 g/L.

• In HCL with blood loss of 15–30% of circulating blood volume in the presence of preexisting anemia or concomitant cardiac or pulmonary diseases; hemoglobin below 70 – 90 g/L with active bleeding; hemoglobin <100 g/L in traumatic brain injury, subarachnoid hemorrhage, chronic respiratory failure.

Platelet concentrate transfusions

The threshold platelet count for prophylactic platelet concentrate transfusion in HCL patients is 20-30 x10⁹/L provided there are no bleeding risk factors. Prophylactic platelet concentrate transfusion is performed in HCL patients during invasive medical procedures (CVC placement, puncture, biopsy, etc.) and a platelet count of less than 30-50 x10⁹/L. In pregnant HCL patients, the threshold platelet count is 30-50 x10⁹/L. Bleeding, severe or progressive hemorrhagic syndrome in HCL is a direct indication for platelet concentrate transfusion regardless of laboratory parameters.

Indications for prophylactic platelet concentrate transfusion are given in Table A3.3.1.

Table A3.3.1. Indications for platelet concentrate transfusion

* Sepsis, pulmonary diseases, fever.

Indications for therapeutic platelet concentrate transfusion.

The presence of hemorrhagic syndrome in a patient is a direct indication for platelet concentrate transfusion regardless of laboratory parameters. Assessment of the severity of hemorrhagic syndrome is carried out according to the WHO scale (Table A3.3.2).

Table A3.3.2. WHO bleeding scale

Clinical criteria for the effectiveness of platelet concentrate transfusion are the cessation or reduction of spontaneous bleeding, absence of fresh hemorrhages on the skin and visible mucosa.

Laboratory criteria for the effectiveness of platelet transfusion are an increase in the number of circulating platelets — absolute platelet increment at 1 hour and 18–24 hours after the end of transfusion, as well as maximum amplitude indicators on the thromboelastogram. In case of refractoriness to transfusions or a history of post-transfusion reactions and complications, individual selection of donor platelets and plasmapheresis are indicated.

Quality of blood components used in supportive care for hematological patients

If there are indications for repeated blood component transfusions, in order to prevent adverse reactions and complications associated with transfusions, the use of blood components with the following characteristics is recommended:

• Leukoreduced — the leukocyte content in the dose of the transfused medium is reduced to 1x10⁶ cells.

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

• Limitation of donor plasma use through the use of additive solutions for red blood cells.

• Following testing of donor blood for markers of viral infections 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).

To prevent adverse transfusion reactions during repeated blood component transfusions, premedication may be required in accordance with general recommendations. The severity of transfusion reactions and complications can be assessed using the corresponding scale (see Appendix G2.1).

Appendix A.3.4. Splenectomy in HCL

Indications for splenectomy in hairy cell leukemia (HCL) are determined by a hematologist. The feasibility and timing of the surgical intervention, preoperative preparation measures, and management tactics for the patient before and after surgery are determined jointly by a hematologist, surgeon, anesthesiologist-resuscitologist, and transfusiologist.

The choice of access for splenectomy (laparoscopic or laparotomic) under combined endotracheal anesthesia is determined by the size of the spleen, topographic and anatomical relationships with other organs, and the presence of pronounced adhesions with surrounding organs and tissues [58–65]. During the splenectomy, an open marginal liver biopsy is performed; in the presence of abdominal lymphadenopathy, a lymph node biopsy or biopsy of another accessible lesion is performed, if possible. The obtained material is sent for cytological, histological (pathological and anatomical examination of biopsy (surgical) material, including using immunohistochemical methods), microscopic, and, if necessary, microbiological (cultural, bacteriological) examinations.

Profound thrombocytopenia of less than 20 ´ 10⁹/L is not a contraindication for performing a splenectomy. The number of transfused platelet doses depends on the complete blood count parameters, the presence of hemorrhagic syndrome, and the infectious process. To ensure hemostasis, a platelet count of more than 50 ´ 10⁹/L is sufficient [57, 58–60, 64]. It is necessary to have a reserve of blood transfusion products for use if needed (red blood cell-containing media, platelet concentrate, fresh frozen plasma); preoperative preparation is carried out, including the administration of low-molecular-weight heparin (B01AB Heparin group) in prophylactic doses in patients at high risk of perioperative thrombotic complications; premedication on the eve of surgery as prescribed by the anesthesiologist-resuscitologist.

To ensure intraoperative hemostasis, monitoring of the main coagulogram parameters (exploratory study of the hemostatic system) is performed, if possible 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 (e.g., 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 with resistant microorganisms. In case of allergy to beta-lactam antibacterial drugs: penicillins: #clindamycin** 0.9 g [67]. If intraoperative blood loss exceeds 1500 ml, repeated administration of a systemic antibacterial drug is recommended. Further antibacterial therapy is carried out only if infectious complications are detected.

In the postoperative period, daily monitoring is carried out jointly by the surgeon and hematologist. Monitoring in the intensive care unit (intensive care ward) for 2 hours after surgery is mandatory. Further stay in the intensive care unit depends on the age and somatic status of the patient, the volume of blood loss, and the presence of infectious complications. Early mobilization of the patient is routinely performed — sitting and standing at the bedside are allowed after 2–4 hours; in the absence of dyspeptic symptoms, oral fluid intake is permitted, with resumption of nutrition 12–24 hours after surgery. In the early postoperative period, monitoring of the complete blood count, coagulogram (exploratory study of the hemostatic system), and, if necessary, preventive anticoagulant/antiplatelet therapy in the presence of risks of thrombotic complications (obesity, hemoblastoses, autoimmune hemolysis) is carried out, taking into account the count and rate of increase in complete blood count parameters and the severity of hemorrhagic syndrome. The dose of LMWH (B01AB Heparin group) is calculated based on body weight [57, 58, 60, 61, 64].

In case of hyperthermia in the postoperative period, an examination is performed to exclude the most likely complications: postoperative pneumonia, portal vein thrombosis, subphrenic abscess, and initiation of empirical antimicrobial therapy with subsequent correction based on identified pathogens and activity against pneumococcal infection (see Appendix A3.1) [59, 60, 67]. In case of postoperative portal vein thrombosis, anticoagulant therapy is performed for thrombus recanalization [57, 58, 64]. In case of pancreatic pseudocyst formation or abdominal cavity abscesses, ultrasound-guided drainage of cysts and abscesses is performed [58, 60, 63].

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.

Appendix A3.5. Evaluation of Treatment Efficacy in Hairy Cell Leukemia

The effect of HCL treatment manifests gradually, as lymphoid infiltration in the bone marrow and spleen decreases and normal hematopoiesis elements recover in parallel; therefore, the effectiveness of therapy must be judged by the dynamics of laboratory parameters and spleen size over a long period of time.

Evaluation of the effectiveness of interferons or #vemurafenib** is carried out no earlier than 8 weeks after the start of treatment; therapy is considered effective if there is positive dynamics in all or several parameters (reduction of cytopenia, lymphocytosis, and monocytopenia, reduction in spleen size and visceral lymphadenopathy). When blood lymphocytosis decreases to approximately 50% and neutrophils increase to approximately 1.0–1.5 × 10⁹/L, interferon-alfa therapy is completed and a course of cladribine chemotherapy is administered.

During the course of cladribine treatment, a regular lymphopenia and simultaneously an increase in platelets and hemoglobin levels are observed. During the first month, an increase in formed blood elements is noted, but complete restoration of the hemogram may take several months; therefore, in the presence of positive blood parameter dynamics, the completeness of bone marrow remission is evaluated no earlier than 6–12 months after the end of chemotherapy.

Currently, the following criteria for remission and minimal residual disease are accepted (proposed in 2006 and modified in 2011) [5, 12]:

Criteria for complete remission:

• absence of cytopenia: hemoglobin levels >120 g/L, neutrophils >1.5 × 10⁹/L, platelets >100 × 10⁹/L;

• absence of organomegaly: normalization of spleen size, visceral lymph nodes;

• absence of villous lymphocytes in peripheral blood and <1% in bone marrow.

Some researchers distinguish complete remission with residual disease in the presence of 1–5% villous lymphocytes in the bone marrow.

Criteria for partial remission:

• absence of cytopenia: hemoglobin levels >120 g/L, neutrophils >1.5 × 10⁹/L, platelets >100 × 10⁹/L;

• reduction of organomegaly and bone marrow infiltration by more than 50%;

• absence of villous lymphocytes in peripheral blood, but >5% in bone marrow.

Improvement is considered to be the normalization of one of the parameters without deterioration of others.

HCL remission lasting more than 5 years is considered prolonged.

Resistance (refractoriness)

Since in HCL the effectiveness of therapy is evaluated dynamically over several weeks of treatment, resistance to interferons can be judged no earlier than 2 months of continuous therapy, and resistance to cladribine therapy no earlier than 1 month after completing the course (provided that villous lymphocytes disappear from the blood during treatment).

Criteria for resistance to therapy:

• hemoglobin level <120 g/L, neutrophil count <1.5 × 10⁹/L, platelet count <100 × 10⁹/L;

• >5% "hairy cells" in the blood;

• decrease in the number of "hairy cells" in the bone marrow by less than 50%;

• decrease in spleen size by less than 50% or increase in spleen size, development of visceral lymphadenopathy despite treatment.

Relapse criteria:

• presence of a lymphocyte clone with HCL markers in the blood, bone marrow, or other sites;

• increase in spleen size due to leukemic infiltration.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Hairy cell leukemia is a chronic disease. This means that currently there is no cure for this condition. However, enormous progress has been made in the treatment of HCL: a combination of medications has been selected that allows more than 95% of patients to achieve remission, often long-term, during which no treatment is required and the disease does not interfere with a normal life in any way.

The only life-threatening risk is infection during periods of severe leukopenia. Therefore, it is important to follow all medical recommendations during treatment and immediately report any changes in condition, especially an elevated body temperature. When treatment is successfully completed, it is important to remain under the supervision of a hematologist, regularly undergo blood tests, and assess the size of the spleen. This makes it possible to timely detect the onset of disease relapse even before symptoms appear, and to administer a short course of treatment to induce remission once again. If necessary, the physician will suggest additional treatment options (e.g., splenectomy).

A patient in HCL remission can lead a normal lifestyle—play sports, work, have children, etc.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. ECOG Performance Status Scale. Clinical evaluation of the general condition of a patient with HCL is performed using the scale developed by the Eastern Cooperative Oncology Group [45]

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. Vol. 5, № 6. P. 649–65 [45]

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation:

Appendix G2.1 Assessment of Severity of Post-Transfusion Reactions and Complications

Assessment of the severity of reactions and complications in recipients associated with the transfusion of donor blood and (or) its components is carried out in accordance with the appendix to Order No. 1128n dated October 20, 2020, "On the procedure for submitting information on reactions and complications occurring in recipients in connection with the transfusion of donor blood and (or) its components to the authorized federal executive body exercising the functions of organizing the activities of the blood service."

Source: Website of the Russian Ministry of Health. Registered on 06.11.2020 No. 60773. Publication number: 0001202011060026. Publication date: 06.11.2020

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation:

Table G2.1. Severity of reactions and complications occurring in recipients in connection with the transfusion of donor blood and (or) its components