List of Abbreviations
AV block – atrioventricular block
AH – arterial hypertension
BP – blood pressure
ALT – alanine aminotransferase
ARB – angiotensin II receptor blockers
AST – aspartate aminotransferase
aPTT – activated partial thromboplastin time
BAL – bronchoalveolar lavage
ESBL – extended-spectrum β-lactamases
PAD – peripheral artery disease
PFS – progression-free survival
HIV – human immunodeficiency virus
HSC – Hematopoietic Stem Cells
CI – confidence interval
DNA – deoxyribonucleic acid
ACEI – ACE (angiotensin-converting enzyme) inhibitors
CHD – coronary heart disease
CAG – Coronary angiography
CFU — colony-forming unit
CT – computed tomography
Total CK – total creatine phosphokinase
CK-MB – a fraction of creatine kinase that is a specific and sensitive indicator of myocardial injury.
SLL – small lymphocytic lymphoma
LDL – low-density lipoproteins
MBL – monoclonal B-cell lymphocytosis
IU – international unit
INR – international normalized ratio
MRD – minimal residual disease
IPI – International Prognostic Index
MIC – minimum inhibitory concentration
MRI – magnetic resonance imaging
OS – overall survival
AML – acute myeloid leukemia
ACS – acute coronary syndrome
ARF – acute renal failure
HR – hazard ratio
PCT – polychemotherapy
PCR – polymerase chain reaction
rRNA – ribosomal ribonucleic acid
GVHD – graft-versus-host disease
CSF – cerebrospinal fluid
HSCT – hematopoietic stem cell transplantation
LVEF – left ventricular ejection fraction
AF – atrial fibrillation
US – ultrasound examination
CKD – chronic kidney disease
CLL – chronic lymphocytic leukemia
CRF – chronic renal failure
CHF – chronic heart failure
CVC – central venous catheter
CNS – central nervous system
TEE – transesophageal echocardiography
HR – heart rate
ECG – electrocardiography
EchoCG – echocardiography
A. baumannii – Acinetobacter baumannii
C. albicans – Candida albicans
S. albidus – Cryptococcus albidus
C. difficile – Clostridioides difficile
C. gattii – Cryptococcus gattii
C. glabrata – Candida glabrata
C. krusei – Candida krusei
C. laurentii – Cryptococcus laurentii
C. neumonia – Chlamydophila neumonia
Chl-G – immunochemotherapy regimen including obinutuzumab** and chlorambucil** (for treatment regimens, see Appendix A3.3)
Chl-R – immunochemotherapy regimen including rituximab** and chlorambucil** (for treatment regimens, see Appendix A3.3)
CIM – carbapenem inactivation method
CMV – cytomegalovirus
CTC – Common Terminology Criteria for Toxicity
E. faecalis – Enterococcus faecalis
E. faecium – Enterococcus faecium
E. coli – Escherichia coli
EBV – Epstein-Barr virus
FCR – immunochemotherapy regimen including rituximab**, fludarabine**, and cyclophosphamide** (for treatment regimens, see Appendix A3.3)
FCR-Lite – immunochemotherapy regimen including rituximab**, fludarabine**, and cyclophosphamide** with dose reduction of antineoplastic drugs (for treatment regimens, see Appendix A3.3)
FISH – fluorescence in situ hybridization
HHV-6 – Human herpes virus 6
HSV – Herpes simplex virus
HZV – Herpes zoster virus
IGHV – immunoglobulin heavy chain variable region genes
IWCLL – International Workshop on Chronic Lymphocytic Leukemia
K. pneumonia – Klebsiella pneumonia
KPC – Klebsiellap neumonia carbapenemase
L. pneumophila – Legionella pneumophila
L. monocytogenes – Listeria monocytogenes
mCIM – modified carbapenem inactivation method
M. furfur – Malassezia furfur
M. pachydermatis – Malassezia pachydermatis
M. pneumonia – Mycoplasma pneumonia
NDM – New Delhi metallo-β-lactamase
OXA-48 – oxacillinase-48
QTc – corrected QT interval on the electrocardiogram
R. glutinis – Rhodotorula glutinis
P. jirovecii – Pneumocystis jirovecii
R. minuta – Rhodotorula minuta
R. mucilaginosa – Rhodotorula mucilaginosa
R. rubra – Rhodotorula rubra
RB – immunochemotherapy regimen including rituximab** and bendamustine** (for treatment regimens, see Appendix A3.3)
S. aureus – Staphylococcus aureus
S. boulardii – Saccharomyces boulardii
S. capitata – Saprochaete capitata
S. maltophilia – Stenotrophomonas maltophilia
S. prolificans – Scedosporium prolificans
Terms and Definitions
ECOG – assessment of the patient's general condition according to the scale developed by the Eastern Cooperative Oncology Group (see Appendix G1).
B-symptoms – nonspecific symptoms of tumor intoxication, including fever (body temperature above 38°C) for more than 2 consecutive weeks without signs of inflammation, profuse night sweats, and weight loss of 10% of body weight over the last 6 months.
Small lymphocytic lymphoma – a B-cell neoplasm composed of small B-lymphocytes with the immunophenotype of chronic lymphocytic leukemia, characterized by lymphadenopathy and/or splenomegaly with a peripheral blood B-lymphocyte count ≤5×109/L without morphological evidence of bone marrow involvement.
Richter syndrome – the development of diffuse large B-cell lymphoma in the setting of chronic lymphocytic leukemia.
Hodgkin transformation – the development of Hodgkin lymphoma in the setting of chronic lymphocytic leukemia.
Chronic lymphocytic leukemia – a neoplasm of small B-lymphocytes characterized by the proliferation and accumulation of aberrant lymphoid cells in the bone marrow, blood, and lymphoid tissues; the diagnostic criterion is the presence of absolute B-cell lymphocytosis in the blood (>5×109/L monoclonal B-lymphocytes). Chronic lymphocytic leukemia and small lymphocytic lymphoma represent different manifestations of the same disease, which standardizes therapeutic approaches.
Transformation – the development of diffuse large B-cell lymphoma or Hodgkin lymphoma in the setting of chronic lymphocytic leukemia or small lymphocytic lymphoma.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are B-cell neoplasms composed of small B-lymphocytes. CLL and SLL are biologically the same nosological entity. The difference between them is that CLL presents with prominent lymphocytosis in the blood (≥5,000 monoclonal B-lymphocytes), whereas SLL shows involvement of lymph nodes and spleen, but the clonal B-cell count in the blood is ≤5×100/L [Note: keeping original tag index placement].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
The molecular pathogenesis of CLL is a complex, multi-step process leading to the replication of the B-lymphocyte clone [1–3]. In almost all cases, chronic lymphocytic leukemia is preceded by monoclonal B-cell lymphocytosis (MBL), which is detected by high-precision immunophenotyping methods in 5–15% of individuals over 40 years of age; the risk of developing MBL increases with age [4]. MBL is initiated by a combination of factors, including mutations in a number of genes, antigenic stimulation, microenvironmental signals, epigenetic modifications, and finally, cytogenetic abnormalities. As a result, a lymphocyte clone with the phenotype of CLL cells appears. Given the vastly higher frequency of MBL, additional genetic alterations lead to the development of CLL in 1 out of 100 cases of MBL. CLL cells significantly influence the microenvironment, initiating the emergence of a specific microenvironment and even specialized cells (nurse-like cells) that determine their clonal expansion and allow them to survive genotoxic stresses. Time and chemotherapy lead to clonal evolution with the accumulation of genetic abnormalities that make CLL cells increasingly autonomous, rapidly dividing, and refractory to therapy.
CLL/SLL cells express B-cell antigen receptors with a restricted repertoire of specificity. Continuous signaling through these receptors and the nature of this signaling is a key factor determining the survival of CLL cells and the pattern of tumor development. It is suggested that the B-cell receptor signaling pathway is antigen-independent but operates autonomously, possibly through the interaction of CLL cells with each other [5, 6].
1.3 Epidemiology of the Disease or Condition
CLL is the most common type of leukemia in adults. In European countries, the incidence is 5 cases per 100,000 population per year. The incidence increases with age. In individuals over 70 years of age, it is more than 20 cases per 100,000 population per year. The median age at diagnosis in European countries is 69 years [7–10]. In the Russian Federation, CLL is detected less frequently: in 2017, the incidence was 2.95 cases per 100,000 population, and the median age at diagnosis was 68 years [11].
1.4 Features of Coding the Disease or Condition
C91.1 – Chronic lymphocytic leukemia
1.5 Classification of the disease or condition
CLL can be classified by stage (see section 1.5.1 Staging) and by risk groups (see section 1.5.2 Determination of risk groups) [12].
1.5.1. Staging
The stage of CLL is established based on physical examination and blood counts according to J.L. Binet criteria (Table 1) [12]. Computed tomography (CT), X-ray, and ultrasound examination (US) are not required for staging. The stage is determined at the current moment, indicated in the diagnosis, and serves as a guide when determining indications for therapy.
SLL staging is performed based on examination results in accordance with the Ann Arbor classification criteria (see section 7.1 of these guidelines) [13].
Table 1. Stages of chronic lymphocytic leukemia according to Binet
Stage | Characteristics | Median survival, months | Proportion of patients at presentation, % |
A | Hemoglobin >100 g/L, platelets >100×109/L, <3 lymph node areas involved* | >120 | 60 |
B | Hemoglobin >100 g/L, platelets >100×109/L, >3 lymph node areas involved* | 61 | 30 |
C | Hemoglobin <100 g/L or platelet count <100 × 109/L | 32 | 10 |
*Lymph node areas: cervical lymph nodes, axillary lymph nodes (unilateral or bilateral), inguinal lymph nodes (unilateral or bilateral), liver, spleen.
1.5.2. Risk group determination
The Chronic Lymphocytic Leukemia International Prognostic Index (CLL-IPI) was developed based on the survival analysis of 3,472 patients included in 8 studies conducted in Europe and the USA [14]. The index accounts for 5 parameters:
1) presence of del(17p) and/or TP53 mutations,
2) mutational status of immunoglobulin variable region genes (IGHV),
3) β2-microglobulin level,
4) stage,
5) patient age.
Each of these parameters is assigned a score reflecting the hazard ratio (HR) for progression or death (Table 2). The CLL-IPI stratifies patients into 4 risk groups: low progression risk (0–1 points), intermediate progression risk (2–3 points), high progression risk (4–6 points), and very high progression risk (7–10 points). Overall survival (OS) in these groups is presented in Section 7.2 of these guidelines.
It should be noted that this scale is applicable only to untreated patients and patients who received chemoimmunotherapy (CIT) or chemotherapy prior to the advent of novel targeted therapies in CLL, which have neutralized the significance of many adverse prognostic factors.
Table 2. International Prognostic Index
Parameter | Negative value | Hazard ratio | Points |
TP53 (17p) | Deletion/mutation | 4,2 | 4 |
IGHV status | Unmutated | 2,6 | 2 |
β2-Microglobulin level, mg/L | >3,5 | 2,0 | 2 |
Grade | Binet stage B/C or Rai stage I-IV | 1,6 | 1 |
Age | 65 years | 1,7 | 1 |
Possible scale values | 0-10 | ||
When using obinutuzumab** and venetoclax** combination as first-line therapy, predictors of adverse outcomes include 17p deletion, IGHV unmutated status, and lymph node size >5 cm. The presence of these features favors the choice of a Bruton's tyrosine kinase (BTK) inhibitor. Predictive markers for first-line BTK inhibitor therapy are less well established.
1.6 Clinical presentation of the disease or condition
The disease may be asymptomatic or manifest with lymphadenopathy, tonsillar enlargement, splenomegaly, hepatomegaly, and nonspecific symptoms caused by anemia (fatigue, malaise), thrombocytopenia (hemorrhagic syndrome), immunosuppression (infectious complications), or intoxication (B symptoms: body temperature >38 °C for more than 2 consecutive weeks without signs of inflammation, drenching night sweats, 10% weight loss over the last 6 months).
2. Diagnostics, medical indications and contraindications for diagnostic methods
Criteria for diagnosis/condition establishment
Diagnosis of CLL requires a complete blood count and immunophenotyping using multi-color flow cytometry, which is preferably performed on peripheral blood.
Diagnostic criteria for CLL (WHO, 2016) [15]:
MBLC >5,000 per µL of blood;
Phenotype CD19+, CD5+, CD23+, CD79b+dim, CD20+dim, CD22+dim, sIg dim, CD81dim, CD160dim;
Light chain restriction (kappa or lambda);
>30% lymphocytes in the bone marrow;
A diagnosis of CLL is not established in the presence of cytopenia or disease-related symptoms if the monoclonal B-lymphocyte count is <5,000/µL.
The diagnosis is established when >5,000 B-lymphocytes per µL of peripheral blood are detected, provided that lymphocytosis persists for more than 3 months. B-cell clonality must be confirmed by immunophenotyping.
SLL is diagnosed in the presence of lymphadenopathy, splenomegaly, and/or bone marrow-induced cytopenia, provided that the absolute count of monoclonal B-lymphocytes in the blood does not exceed 5,000 per µL. The immunohistochemical phenotype of the tumor B-lymphocytes corresponds to CLL. The diagnosis must be confirmed by biopsy of a lymph node, bone marrow, or affected organ.
2.1 Complaints and Anamnesis
All patients with suspected CLL, as well as all patients with verified CLL at each hematologist appointment, are recommended to undergo history taking and symptom assessment regarding blood and hematopoietic organ disorders to evaluate the patient's condition and identify factors that may influence treatment strategy [12, 16].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: when taking the medical history, it is necessary to check for a family history of blood and hematopoietic disorders. Symptoms may be absent, in which case signs of the disease are discovered incidentally during routine examination. Asymptomatic enlargement of lymph nodes in any location may be detected. Any symptoms related to organ and tissue involvement may be present. During symptom assessment, special attention should be paid to identifying nonspecific intoxication symptoms (body temperature >38 °C for more than 2 consecutive weeks without signs of inflammation, drenching night sweats, and 10% weight loss over the past 6 months). In the presence of fever, which may serve as an indication for initiating specific therapy, thorough screening is required to rule out infectious pathology.
2.2 Physical Examination
All patients with suspected or confirmed CLL/SLL at initial or follow-up visits, during routine check-ups, and when recurrence/progression of the disease is suspected, are recommended to undergo a physical examination (visual inspection, palpation, and auscultation) to determine the extent of the disease and assess the patient's general condition, including specific organs and systems [12, 16].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: during the examination, the patient's general condition should be assessed using the ECOG scale (see Appendix G1), and the tonsils and oral cavity should be inspected; palpation must include all accessible peripheral lymph node groups, the liver, and the spleen.
2.3 Laboratory Diagnostics
2.3.1. Laboratory tests to assess the general condition of the patient
All patients with suspected or confirmed CLL/SLL at initial or follow-up visits, before initiating antineoplastic therapy, during treatment, when assessing remission after therapy completion, during follow-up monitoring, and when disease relapse or refractory course is suspected at any stage of the disease, are recommended to undergo a complete blood count (CBC) with differential white blood cell count, determining total hemoglobin, red blood cells, platelets, leukocytes, and reticulocytes, to verify diagnosis, assess disease activity, determine treatment eligibility, and/or (in previously treated patients) monitor treatment-related adverse events [12, 16].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: in stained peripheral blood smears, CLL cells exhibit the morphology of small lymphocytes with a narrow rim of cytoplasm, dense nuclei, clumped chromatin, and no distinct nucleoli. Activated lymphocyte morphology with a broader rim of blue cytoplasm or marginal basophilia is less common. Atypical cells (with cleaved, folded nuclei) and prolymphocytes—larger cells with unevenly distributed nuclear chromatin and 1–2 nucleoli—may account for about 5% of lymphocytes, which does not contradict the diagnosis of CLL. Smudge cells (Gumprecht shadows) are characteristic of CLL. The detection of more than 20% prolymphocytes in the blood indicates prolymphocytic transformation of CLL. B-cell prolymphocytic leukemia was excluded from the 2022 WHO classification.
All patients with CLL/SLL at initial diagnosis or relapse, during follow-up monitoring, before antineoplastic therapy, during treatment, when evaluating treatment efficacy, or in case of refractory disease at any stage, are recommended to undergo the following laboratory tests to assess general condition and determine the need for supportive/concomitant therapy or dose reductions:
general clinical blood chemistry panel (determining serum levels of lactate dehydrogenase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, uric acid, urea, creatinine, total protein, albumin, total bilirubin, potassium, sodium, chlorides, total calcium, and beta-2-microglobulin) [12, 16];
coagulation profile (screening hemostasis test): determination of prothrombin (thromboplastin) time in blood or plasma, fibrinogen, antithrombin III activity, plasminogen, D-dimer concentration, international normalized ratio (INR), activated partial thromboplastin time (APTT), and thrombin time [12, 16];
direct antiglobulin test (direct Coombs test) to determine predisposition to hemolytic complications of CLL [12, 16];
general (clinical) urinalysis [12, 16].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
All patients with CLL/SLL or suspected CLL/SLL presenting with anemia are recommended to undergo the following laboratory tests for differential diagnosis of anemia [17]:
serum iron test
serum ferritin test
serum folic acid test
blood vitamin B12 (cyanocobalamin) level test
blood erythropoietin level test
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
2.3.2. Laboratory tests for diagnosis verification and prognostic factor assessment
In suspected CLL in patients with a B-lymphocyte count ≥5000/μl, it is recommended to perform flow cytometry of biological material (blood lymphocytes) to verify the diagnosis [18].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Comments: the diagnosis of CLL is established when ≥5000 B-lymphocytes per 1 μl of peripheral blood are detected, provided that lymphocytosis persists for more than 3 months. B-lymphocyte clonality must be confirmed by immunophenotyping. The minimum diagnostic panel recommended for CLL diagnosis should include the following markers: CD19, CD5, CD23, CD20, kappa, lambda. CD43, CD200, CD79b, and CD81 are recommended as additional diagnostic markers. Frequently recommended, but optional markers for the diagnosis and monitoring of the CLL tumor population include: CD22, FMC7, CD38. The classic CLL cell phenotype is characterized by the expression of B-cell antigens CD19, CD20, CD22, CD79b combined with the "T-cell" marker CD5 and the activation marker CD23. Tumor cells express a single immunoglobulin light chain type (kappa or lambda). The expression intensity of B-cell antigens (CD20, CD22, CD79b) as well as surface immunoglobulins on CLL cells is lower than on normal B-lymphocytes. Nevertheless, there are many cases where the tumor cell phenotype does not entirely correspond to CLL. In such cases, determining the expression of CD200, which is always brightly expressed on CLL cells, is of critical importance.
In suspected SLL in patients without clinical blood lymphocytosis, as well as in patients with CLL/SLL suspected of transformation, it is recommended to perform a lymph node biopsy (or biopsy of another lesion site) followed by cytological examination of the biopsy specimens (or other lesion site) and pathomorphological examination of the biopsy (surgical) material of the lymph node (or other lesion site) using immunohistochemical methods to verify the diagnosis [12, 16].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: in histological preparations, the morphological substrate is represented by diffuse growth of small lymphoid cells with rounded nuclei, clumped chromatin, and without distinct nucleoli. Lymph node tissue sections frequently contain follicle-like structures—pseudofollicles, so-called proliferation centers, represented by an increased number of paraimmunoblasts and cells with prolymphocyte morphology featuring visible nucleoli. A detailed description of the morphological picture is given in the relevant sections of the guidelines. During CLL progression, the size of these pseudofollicles increases, and they may coalesce. Diffuse large B-cell lymphoma or Hodgkin lymphoma develops in 3-5% of patients with CLL and SLL. The appearance of large cell lymphoma against the background of CLL is termed Richter syndrome. A distinguishing feature of the cells is the preservation of the phenotype of the original population. The appearance of Hodgkin lymphoma against the background of CLL is termed Hodgkin transformation. In all cases of localized rapid enlargement of lymph nodes or significant changes in the clinical picture of the disease (appearance of B-symptoms—sudden weight loss, night sweats), a biopsy of the lymph node, bone marrow, or extranodal lesion must be performed. Richter syndrome is diagnosed solely based on histological examination.
All patients with CLL/SLL, 2 months after completion of therapy, when feasible, are recommended to undergo immunophenotyping of biological material by flow cytometry to detect markers of minimal residual disease (MRD) in hemoblastoses [20].
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
Comments: the optimal (most informative) material for the study is bone marrow.
When finally assessing the response after completion of immunochemotherapy, MRD allows predicting the time to relapse and OS. Most prognostic schemes are based on assessing MRD in blood, whereas bone marrow examination allows reliable confirmation of MRD-negative complete remission.
It has been repeatedly shown that the quantitative characteristic of blood MRD upon completion of therapy correlates with survival and can therefore be used as a guide for action. A residual population of CLL cells in the blood >1% predicts an early relapse and may serve as a rationale for changing therapy. A residual population of CLL cells in the blood of 0.90–0.01% characterizes a patient group with a median progression-free survival (PFS) of about 3 years; maintenance therapy can be considered for this category of patients. A residual population of CLL cells in the blood <0.01% indicates a high probability of a long-term remission (>5 years).
When administering targeted therapy with a BCL-2 anti-apoptotic protein inhibitor (L01XX Other antineoplastic agents), Bruton's tyrosine kinase (BTK) inhibitors with obinutuzumab**, as well as the combination of ibrutinib** + venetoclax**, MRD monitoring is initiated from the 9th month of therapy start [21–24].
Following allogeneic hematopoietic stem cell transplantation, MRD is determined every 3 months for one year or until relapse.
In patients with suspected CLL/SLL, to assess the extent of bone marrow involvement and the state of other hematopoietic lineages, rule out bone marrow involvement by other tumors and infections, and obtain a baseline bone marrow sample required for comparison with the post-therapy sample, it is recommended to: 1) obtain a bone marrow cytologic preparation via puncture (sternal puncture), followed by cytologic (myelogram) and immunophenotypic examination of the biological material (bone marrow) by flow cytometry, or 2) obtain a bone marrow histologic preparation (trephine biopsy), followed by pathomorphological examination of the bone marrow biopsy (surgical) material using immunohistochemical methods in the following cases [18]:
prior to initiating therapy in treatment-naive patients (optional, but preferred);
when transformation is suspected.
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Comments: the histological diagnosis of CLL is established upon the presence in the bone marrow of a diffuse lymphoid infiltrate composed of monomorphic small cells with rounded nuclei, clumped chromatin, depending on fixation conditions—with indistinct nucleoli or without them, and thin-walled capillary/venular type vessels; large cells with paraimmunoblast morphology are usually sparsely scattered, and pseudofollicles (proliferation centers) are sometimes present. Upon immunohistochemical examination, the lymphoid infiltrate is characterized by the expression of CD20 (heterogeneous in intensity, predominantly weak membranous reaction), CD79a, IgM, nuclear expression of PAX 5, LEF1 (nuclear reaction), co-expression of CD5 (membranous reaction) and CD23 (membranous reaction), CD43, while lacking the expression of CD10, BCL-6, and Cyclin D1. LEF1 expression (nuclear expression) is more intensely pronounced in the cells of proliferation centers and in cells with prolymphocyte morphology. Proliferation center cells are characterized by more intense expression of CD20, IgM, and LEF1; sometimes a portion of pseudofollicle (proliferation center) cells expresses cyclin D1 (weak nuclear reaction). The Ki-67 proliferative activity index is low, typically 5–15% of positive cells in areas of diffuse small-cell infiltrate. Immunohistochemical examination of paraffin-embedded material may show a lack of CD5 expression (up to 20–25% of cases). BCL-2 expression characterizes all variants of small B-cell lymphomas; co-expression of IgM and IgD is characteristic of lymphocytic lymphoma and mantle cell lymphoma. LEF1 expression is characteristic of lymphocytic lymphoma transformed into diffuse large B-cell lymphoma (Richter syndrome) and allows for differential diagnosis from CD5+ diffuse large B-cell lymphoma.
Obtaining a histological bone marrow preparation (bone marrow trephine biopsy) is not required to confirm and formulate the diagnosis of CLL/SLL.
Bone marrow biopsy is an optional but recommended procedure prior to initiating therapy. CLL is frequently associated with other malignancies that may metastasize to the bone marrow, be detected only on biopsy, and even cause cytopenia. Immunochemotherapy with fludarabine-containing regimens is frequently complicated by cytopenia. Having a baseline bone marrow sample allows for the differentiation of disease progression, aplasia, development of myelodysplastic syndrome/acute myeloid leukemia, and autoimmune cytopenias.
In all patients with CLL/SLL prior to initiating the 1st and all subsequent lines of therapy, it is recommended whenever possible to perform a molecular cytogenetic study (FISH method) for one chromosome pair (17p deletion) and molecular genetic testing for TP53 gene mutations in the blood, as well as (if available) a cytogenetic study (karyotype) to rule out a complex karyotype [14].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
Comments: 17p deletion is the major cytogenetic marker directly influencing therapeutic tactics. Screening for 17p deletion is recommended in all patients who have indications for the initiation of therapy and/or in case of failure of standard therapy, especially in patients younger than 55 years who may be candidates for allogeneic transplantation.
Currently, deep sequencing methods have established that the majority of refractory cases are caused by the loss of TP53, either through deletion combined with mutations or through gene mutations. Therefore, performing FISH for the 17p deletion alone is currently insufficient. To identify the largest number of patients resistant to immunochemotherapy, it is also necessary to test for TP53 gene mutations. The presence of a mutation is established when the mutant allele burden exceeds 10%.
A complex karyotype is defined as the presence of 3 or more aberrations in patients with del(17p) or 5 or more aberrations in patients without the deletion.
In all patients with CLL/SLL at the time of diagnosis, it is recommended whenever possible to determine IGHV gene mutations to refine the prognosis of the disease [14].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
Comments: IGHV gene mutations have prognostic significance. Currently, the prognosis in patients with CLL is assessed using the CLL International Prognostic Index (see section 5.1). The index requires evaluation of beta-2-microglobulin levels, Ighv mutation status, and cytogenetic testing. Determination of these parameters is desirable. Given their high predictive value regarding time to treatment, efficacy of immunochemotherapy, and time to relapse, determining the mutation status of IGHV genes is recommended, as this forms the basis for first-line therapy selection and the early prescription of a BCL-2 anti-apoptotic protein inhibitor (L01XX Other antineoplastic agents and Bruton's tyrosine kinase (BTK) inhibitors in cases of unmutated variant.
2.3.2. Other mandatory laboratory studies
In all patients with CLL/SLL prior to 1st-line antineoplastic therapy, it is recommended to determine AB0 blood groups, Rh blood group antigen D (Rh factor), subgroups and other minor blood groups A-1, A-2, D, Cc, E, Kell, Duffy, and to determine the phenotype for antigens C, c, E, e, Cw, K, k to enable blood transfusion if indicated before, during, or after therapy [16].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
In all patients with CLL/SLL prior to therapy with CD20 (cluster of differentiation 20) inhibitors, in order to clarify the risk and, if necessary, prevent the reactivation of viral hepatitis, it is recommended to perform virological testing to detect hepatitis B virus markers, which should include the determination of [25]:
hepatitis B virus surface antigen (HBsAg) in the blood;
antibodies to hepatitis B virus surface antigen (anti-HBs) in the blood;
antibodies to hepatitis B virus core antigen (anti-HBc) in the blood;
hepatitis B virus DNA in the blood by polymerase chain reaction (qualitative assay).
GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).
Comments: the values of viral hepatitis B markers are presented in Appendix A3.1.
Reactivation of viral hepatitis B during therapy with CD20 (cluster of differentiation 20) inhibitors is associated with B-cell depletion and, consequently, a drop in the titer of controlling anti-HBs antibodies. Recovery of the antibody titer occurs 6 months after the last drug administration. The presence of hepatitis is not a contraindication to initiating CLL therapy with CD20 (cluster of differentiation 20) inhibitors, but it requires supportive therapy with systemic antiviral agents and careful monitoring of liver function.
In all patients with CLL/SLL at the diagnostic stage and, if indicated, at any stage of monitoring or treatment, it is recommended to perform molecular biological blood testing for human immunodeficiency virus (testing for the level of IgM and IgG antibodies to human immunodeficiency virus HIV-1/2 and antigen p24 in the blood) to clarify comorbidity and the need for antineoplastic and antiretroviral therapy [16].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
In all patients with CLL/SLL at the time of diagnosis, after each immunosuppressive therapy, and after each severe bacterial infection, it is recommended whenever possible to test blood levels of immunoglobulins A, M, and G to clarify the indications for intravenous immunoglobulin use [12, 16].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
2.4 Instrumental Diagnostics
In all patients at the diagnostic stage, prior to initiating CLL/SLL therapy, during response assessment 2 months after completion of therapy (if mediastinal and/or pulmonary lymph node involvement was present), as well as in case of suspected relapse/disease progression, it is recommended to perform the following diagnostic examinations to clarify the presence and extent of lymphadenopathy or to evaluate the antitumor effect if the study is performed dynamically [12, 16]:
CT of the chest organs, CT of the abdominal organs, and CT of the pelvic organs;
Targeted chest X-ray in 2 projections (if chest CT is not available);
Ultrasound of lymph nodes (peripheral, intra-abdominal, and retroperitoneal) and, in the absence of abdominal CT, ultrasound of internal organs (complex abdominal ultrasound and complex pelvic ultrasound).
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
In patients with suspected CLL/SLL or a confirmed diagnosis of CLL/SLL who present with clinical signs of Richter's syndrome or Hodgkin transformation (progressive enlargement of lymph nodes, weight loss, persistent fever without signs of infection, high lactate dehydrogenase levels, hypercalcemia), it is recommended to perform positron emission tomography combined with computed tomography using tumor-tropic FDG ([18F]fluorodeoxyglucose) to identify areas of probable transformation and select the optimal site for biopsy [26].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Comments: at SUV values <5, the probability of Richter's syndrome is about 3% [27]. SUV values >15% are typical for Richter's syndrome. If the radiotracer uptake intensity varies markedly across different areas, a biopsy of the most active node or lesion must be performed.
In all patients with verified CLL/SLL at initial diagnosis or diagnosis of disease relapse, during follow-up examinations in the course of dynamic monitoring, prior to antineoplastic therapy, during treatment, when assessing treatment efficacy, or in refractory disease at any stage, in order to timely detect concomitant cardiovascular, respiratory, and digestive pathology and determine the need for their prevention or treatment, it is recommended to perform the following tests [16]:
electrocardiography recording (for all);
echocardiography (as indicated);
vascular ultrasound (arteries and veins) of the lower extremities (as indicated);
chest X-ray (as indicated);
computed tomography of the chest organs (as indicated);
ultrasound examination of abdominal organs (comprehensive) (as indicated);
computed tomography of the abdominal organs (as indicated);
esophagogastroduodenoscopy (as indicated);
colonoscopy (as indicated);
sigmoidoscopy (as indicated).
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
2.5 Other Procedures
In all patients with CLL/SLL and comorbidity that may affect the choice of the antineoplastic treatment regimen, prior to initiating therapy, an initial consultation (examination, assessment) by the relevant specialist physician (obstetrician-gynecologist, cardiologist, neurologist, otorhinolaryngologist, urologist, coloproctologist, endocrinologist, pulmonologist, phthisiatrician, infectious disease specialist, etc.) is recommended [16].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
All patients with CLL/SLL at any stage of diagnosis, follow-up, treatment, or when an infectious complication is suspected, are recommended to undergo diagnostic tests to clarify the localization of the infection, the type of infectious agent, and for dynamic monitoring during treatment [28, 29].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1. Indications for initiating therapy for B-cell CLL
All patients with verified CLL/SLL are recommended to start specific therapy only if there are indications in accordance with the IWCLL 2018 criteria (see Appendix A3.2) [12, 16].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: about 30% of patients have a slowly progressive course of CLL, and their life expectancy is close to that of the general population. The presence of such a group of patients justifies a watch-and-wait strategy until indications for therapy arise. CLL therapy should be initiated when indications are present according to the IWCLL 2018 criteria. Stage A patients with autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura should receive treatment for these complications. If an autoimmune complication responds poorly to glucocorticoid therapy, CLL-directed immunochemotherapy can be used. Asymptomatic hypogammaglobulinemia and the presence of monoclonal protein alone are not indications for treatment. The detection of negative prognostic markers, including 17p deletion, is not an indication to start therapy.
Considering the limited data on the management of pregnancy in CLL, the decision for pregnant patients with CLL regarding the possibility of prolonging the pregnancy or the need for its termination, the timing of initiation, and the treatment regimen is determined individually, depending on the presence or absence of indications for starting specific leukemia therapy, involving an multidisciplinary team, preferably with consultation from specialists at federal medical institutions.
3.2. First-line CLL treatment
The choice of first-line therapy depends on the presence of adverse prognostic factors (17p deletion or TP53 mutations, complex karyotype, unmutated IGHV variant), concomitant diseases, and to a lesser extent on chronological age.
The results of major clinical trials from the 2000s convincingly demonstrate the low efficacy of immunochemotherapy in patients with 17p deletion and TP53 mutations. 17p deletion is detected before 1st-line therapy in 7% of patients. Most patients with 17p deletion detected in more than 20% of cells simultaneously harbor TP53 mutations. In addition, 5–7% have only TP53 mutations without deletion. A special group consists of patients with a complex karyotype. Today it is proven that a complex karyotype is an independent predictor of poor prognosis in patients receiving immunochemotherapy. Thus, in a prospective study of CLL patients receiving chlorambucil**-based first-line regimens, Herling et al. showed that a complex karyotype (n = 30 of 154, 19.5%) was associated with shorter overall survival in multivariate analysis (P=0.004) [81]. Le Bris et al. found that a complex karyotype was associated with shorter PFS and 5-year OS in a cohort of CLL patients receiving first-line FCR [82]. In the era of targeted therapy, a complex karyotype becomes even more important: while PFS and OS significantly increase in the general patient group, the prognosis in patients with a complex karyotype is significantly worse [22, 83].
To date, there is no convincing data on the superiority of any single therapy regimen in patients with a complex karyotype, but the best results are achieved in patients receiving combination therapy with Bruton's tyrosine kinase (BTK) inhibitors and venetoclax** [84].
When choosing 1st-line therapy, patients can be divided into 4 groups.
1. The 1st group includes patients with 17p deletion and/or TP53 mutation and/or complex karyotype, regardless of age and comorbidity. The therapy of choice for these patients is the use of Bruton's tyrosine kinase (BTK) inhibitors: acalabrutinib** as monotherapy or in combination with #obinutuzumab**[21], #zanubrutinib as monotherapy[30,31], ibrutinib** as monotherapy or in combination with #obinutuzumab**[32–35],venetoclax** in combination with a Bruton's tyrosine kinase (BTK) inhibitor[23,24,36,37](drugs are listed in alphabetical order; in clinical practice, individual patient characteristics and drug availability should be considered). The use of venetoclax** in combination with #obinutuzumab** is possible, but the number of relapses within 5 years will be significantly higher[22]. According to a pooled analysis of 4 studies, when a Bruton's tyrosine kinase (BTK) inhibitor is prescribed as monotherapy or in combination with monoclonal antibodies and antibody-drug conjugates in the first line for patients with 17p deletion or TP53 mutations, the 4-year PFS and OS are 79% and 88%, respectively [85]. According to a large Italian study, in patients with TP53 aberrations receiving ibrutinib** therapy in the 1st line, the 2-year time to treatment discontinuation was 63.4%, and overall survival was 82.6% [87]. Due to these data, allogeneic transplantation as consolidation of remission after 1st-line Bruton's tyrosine kinase (BTK) inhibitor therapy is not advisable. Therapy is continued until progression. If progression develops, switching to a venetoclax**-containing regimen and performing allogeneic transplantation, if available, is advisable. Whenever possible, all patients should undergo complex karyotype testing. A complex karyotype is an independent predictor of prognosis in patients receiving ibrutinib**. In this subgroup of patients, the optimal combination is venetoclax** in combination with a Bruton's tyrosine kinase (BTK) inhibitor[23,24,36,37], acalabrutinib** +/- #obinutuzumab** can be effective[21], venetoclax** in combination with #obinutuzumab**[22], #zanubrutinib as monotherapy[30, 31], ibrutinib** as monotherapy or in combination with #obinutuzumab**[32–35](drugs are listed in alphabetical order; in clinical practice, individual patient characteristics and drug availability should be considered). The use of finite therapy (venetoclax** + #obinutuzumab**) should be considered on an individual basis, taking into account the potential prognosis and risk of disease progression. In the subgroup of patients with a complex karyotype, the combination of #venetoclax** and ibrutinib** can be considered as preparation for transplantation, as it allows achieving undetectable MRD and/or CR in a significant number of patients.
2. The 2nd group includes patients without TP53 aberrations and complex karyotype who belong to the less favorable prognostic group due to the presence of the unmutated IGHV CLL variant. In this patient subgroup, targeted drugs have demonstrated high efficacy: acalabrutinib** +/- #obinutuzumab** [21], venetoclax** in combination with #obinutuzumab** [22], #zanubrutinib as monotherapy [30, 31], ibrutinib** as monotherapy or in combination with #obinutuzumab** [32–35] (drugs are listed in alphabetical order; in clinical practice, individual patient characteristics and drug availability should be considered). A high rate of achieving MRD-negative status can be expected when using venetoclax** with obinutuzumab** [22]. The anti-apoptotic BCL-2 protein inhibitor (L01XX Other antineoplastic agents) and Bruton's tyrosine kinase (BTK) inhibitors have a different toxicity profile compared to chemotherapy and can therefore be used regardless of age. In young patients, fixed-duration therapy and achieving MRD-negative remission are preferred. Therefore, the optimal regimens are venetoclax** combined with monoclonal antibodies and antibody-drug conjugates. In elderly patients, continuous therapy until progression or unacceptable toxicity can be used.
3. The third group includes patients without TP53 aberrations and complex karyotype, belonging to the favorable prognostic group due to the presence of the mutated IGHV variant of CLL. Most of these patients achieve long-term remission after immunochemotherapy. Therefore, immunochemotherapy remains the primary choice for these patients. FCR-containing regimens are significantly less tolerated by elderly patients; therefore, distinguishing between young and elderly patient subgroups is fundamental in this group.
3.1. In young patients (under 65 years of age) without significant comorbidity and with the mutated IGHV variant, course immunochemotherapy with FCR or BR regimens is preferred.
3.2. In elderly patients (over 65 years of age) with significant comorbidity, chlorambucil** + obinutuzumab**, BR, and low-intensity FCR-like regimens can be used [38,39].
4. The 4th group includes very elderly patients with frailty and geriatric syndromes, dementia, and patients with uncontrolled organ failures. In this group of patients, the goal of therapy is exclusively palliative.
For patients with verified CLL/SLL with 17p deletion and/or TP53 mutation and/or complex karyotype, regardless of age and comorbidity, targeted therapy according to one of the following regimens is recommended as a 1st-line therapy option (drugs are listed in alphabetical order; in real-world practice, individual patient characteristics and drug availability should be considered):
acalabrutinib** monotherapy 100 mg (1 capsule) twice daily until disease progression or unacceptable toxicity, or in combination with #obinutuzumab** 100 mg IV over 4 hours on day 1, 900 mg IV on day 2, 1000 mg IV on days 8–15 (cycle 2), 1000 mg IV on day 1 (cycles 3–7), cycle repeated on day 29 (for treatment regimens, see Appendix A3.3) [21];
#venetoclax** + ibrutinib**: ibrutinib** at a dose of 420 mg/day (3 capsules) orally once daily for 3 cycles, #venetoclax** in combination with ibrutinib** starting from day 1 of cycle 4 of ibrutinib** in a ramp-up schedule: 20 mg/day for week 1, 50 mg/day for week 2, 100 mg/day for week 3, 200 mg/day for week 4, 400 mg/day for week 5 and thereafter at a #venetoclax** dose of 400 mg/day in combination with ibrutinib** for 12 cycles (for treatment regimens, see Appendix A3.3) [23, 24]; This regimen is preferred in patients with a complex karyotype.
venetoclax** + #obinutuzumab**: venetoclax** 20 mg/day on days 22–28 of cycle 1; 50 mg/day on days 1–7 of cycle 2; 100 mg/day on days 8–14 of cycle 2; 200 mg/day on days 15–21 of cycle 2; 400 mg/day on days 22–28 of cycle 2, then 400 mg/day for 12 cycles + obinutuzumab** 100 mg on day 1 of cycle 1; 900 mg on day 2 of cycle 1; 1000 mg on day 8 of cycle 1; 1000 mg on day 15 of cycle 1; 1000 mg on day 1 of cycle 2; 1000 mg on day 1 of cycles 3–6 (for treatment regimens, see Appendix A3.3) [22];
#zanubrutinib monotherapy 160 mg (2 capsules) twice daily until disease progression or unacceptable toxicity (for treatment regimens, see Appendix A3.3) [30, 31];
ibrutinib** monotherapy or in combination with #obinutuzumab** until progression or unacceptable toxicity at a dose of 420 mg/day (3 capsules) orally once daily (for treatment regimens, see Appendix A3.3) [34, 40].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
In young patients with verified CLL/SLL without significant comorbidity, with del(17p) and complex karyotype, after 1st-line therapy with acalabrutinib**, venetoclax**, #zanubrutinib, or ibrutinib** and upon achieving complete remission, it is recommended to consider allogeneic hematopoietic stem cell transplantation as consolidation [41, 42].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Comments: the optimal timing for transplantation is considered to be the 2nd year of therapy with ibrutinib** or acalabrutinib** or achieving MRD-negative remission on venetoclax**.
For patients with verified CLL/SLL without TP53 aberrations and complex karyotype, with unmutated IGHV CLL, if available, one of the following treatment options is recommended as a 1st-line therapy option to achieve remission (drugs are listed in alphabetical order; individual patient characteristics and drug availability should be considered in real-world practice) (for treatment regimens, see Appendix A3.3):
acalabrutinib** monotherapy 100 mg (1 capsule) twice daily until disease progression or unacceptable toxicity, or in combination with #obinutuzumab** 100 mg IV over 4 hours on day 1, 900 mg IV on day 2, 1000 mg IV on days 8–15 (cycle 2), 1000 mg IV on day 1 (cycles 3–7), cycle repeated on day 29 [21];
venetoclax** in combination with #obinutuzumab**: venetoclax** 20 mg/day on days 22–28 of cycle 1; 50 mg/day on days 1–7 of cycle 2; 100 mg/day on days 8–14 of cycle 2; 200 mg/day on days 15–21 of cycle 2; 400 mg/day on days 22–28 of cycle 2, then 400 mg/day for 12 cycles + #obinutuzumab** 100 mg on day 1 of cycle 1; 900 mg on day 2 of cycle 1; 1000 mg on day 8 of cycle 1; 1000 mg on day 15 of cycle 1; 1000 mg on day 1 of cycle 2; 1000 mg on day 1 of cycles 3–6 [22];
#venetoclax** + ibrutinib**: ibrutinib** at a dose of 420 mg/day (3 capsules) orally once daily for 3 cycles, #venetoclax** in combination with ibrutinib** starting from day 1 of cycle 4 of ibrutinib** in a ramp-up schedule: 20 mg/day for week 1, 50 mg/day for week 2; 100 mg/day for week 3; 200 mg/day for week 4; 400 mg/day for week 5 and thereafter at a #venetoclax** dose of 400 mg/day in combination with ibrutinib** for 12 cycles [23, 24, 43]
#zanubrutinib monotherapy 160 mg (2 capsules) twice daily until disease progression or unacceptable toxicity [30, 31];
ibrutinib** monotherapy or in combination with #obinutuzumab** until disease progression or unacceptable toxicity: ibrutinib** 420 mg/day (3 capsules) orally once daily, daily; obinutuzumab** 1000 mg IV on day 1 (100 mg over 4 hours), day 2 (900 mg), days 8 and 15 (cycle 1), day 1 (cycles 2–6) [32, 34, 40].
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
In the absence of availability of B-cell lymphoma 2 (BCL-2) anti-apoptotic protein inhibitors (L01XX Other antineoplastic agents) or Bruton's tyrosine kinase (BTK) inhibitors, patients with unmutated IGHV CLL may undergo immunochemotherapy (FCR, RB, FCR-Lite, chlorambucil**, including in combination with rituximab** or obinutuzumab**) [44, 45].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
For patients with verified CLL/SLL younger than 65 years without significant comorbidity (physically active, without severe concomitant diseases, with normal renal function), with mutated IGHV, without TP53 aberrations and complex karyotype, one of the following treatment options is recommended as 1st-line treatment to achieve remission:
FCR: (rituximab** – cycle 1: 375 mg/m2 IV infusion on day 1, subsequent cycles: rituximab** 500 mg/m2 IV infusion or #rituximab** 1600 mg SC on day 1; #fludarabine** – 25 mg/m2 IV infusion on days 1–3; #cyclophosphamide** – 250 mg/m2 IV infusion on days 1–3). (for treatment regimens, see Appendix A3.3) [46–48];
RB (rituximab** – cycle 1: 375 mg/m2 IV infusion on day 1, subsequent cycles: rituximab** 500 mg/m2 IV infusion; #bendamustine** – 90 mg/m2 IV infusion on days 1, 2) to achieve remission (for treatment regimens, see Appendix A3.3) [38, 49];
venetoclax** in combination with #obinutuzumab**: venetoclax** 20 mg/day on days 22–28 of cycle 1; 50 mg/day on days 1–7 of cycle 2; 100 mg/day on days 8–14 of cycle 2; 200 mg/day on days 15–21 of cycle 2; 400 mg/day on days 22–28 of cycle 2, then 400 mg/day for 12 cycles + #obinutuzumab** 100 mg on day 1 of cycle 1; 900 mg on day 2 of cycle 1; 1000 mg on day 8 of cycle 1; 1000 mg on day 15 of cycle 1; 1000 mg on day 1 of cycle 2; 1000 mg on day 1 of cycles 3–6 [22].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
For patients with verified CLL/SLL older than 65–70 years, with severe comorbid conditions or renal impairment, with mutated IGHV, without TP53 aberrations and complex karyotype, 1st-line therapy is recommended using one of the following cytostatic regimens depending on the preferences and experience of the medical center and the attending physician (drugs are listed in alphabetical order) (for treatment regimens, see Appendix A3.3):
#bendamustine** 90 mg/m2 IV infusion on days 1, 2 ± rituximab** cycle 1: 375 mg/m2 IV infusion on day 1, subsequent cycles: rituximab** 500 mg/m2 IV infusion. Treatment is resumed on day 29, for a total of 6 cycles [38, 48–50];
GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)
FCR-Lite regimen (rituximab** – cycle 1: 375 mg/m2 IV infusion on day 1, subsequent cycles: rituximab** 500 mg/m2 IV infusion; #fludarabine** – 20 mg/m2 orally on days 1–3; #cyclophosphamide** – 150 mg/m2 orally on days 1–3. Treatment is resumed on day 29), for a total of 6 cycles [44, 51];
GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).
#chlorambucil** 10 mg/m2 orally on days 1–7 + rituximab** cycle 1: 375 mg/m2 IV infusion on day 1, subsequent cycles: rituximab** 500 mg/m2 IV infusion. Treatment is resumed on day 29, for a total of 6 cycles [53];
Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)
#chlorambucil** 0.5 mg/kg orally on days 1, 15 + #obinutuzumab** 1000 mg IV on days 1, 8, 15 (cycle 1), day 1 (cycles 2–6). Treatment is resumed on day 29, for a total of 6 cycles [54].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
For patients older than 75–80 years with verified CLL/SLL and low life expectancy due to age, refractory organ failure, dementia, and geriatric syndromes, the least toxic therapy options are recommended [44, 45]:
Best supportive care, including blood transfusions as indicated, systemic antibacterial drugs for therapeutic and prophylactic purposes, and colony-stimulating factors.
#chlorambucil** monotherapy 70 mg/m2 orally daily for 2–4 weeks followed by dose adjustment [55];
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
CD20 (cluster of differentiation 20) inhibitor monotherapy – rituximab** at the appropriate registered package insert dosage [56];
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
3.3. Selection of therapy for relapsed CLL (2nd and subsequent lines)
Choice of therapy for relapsed CLL depends on the following factors:
presence of high-risk markers (del(17p), TP53 mutations, complex karyotype);
Previous therapy;
Time to relapse;
Comorbidities and concomitant therapy.
In relapsed therapy, just as in first-line therapy, determining the presence of del(17p), TP53 mutations, and a complex karyotype is of fundamental importance. If these markers are detected, as in first-line therapy, the most justified approach is the administration of BTK inhibitors: acalabrutinib**, #zanubrutinib, ibrutinib** (drugs are listed in alphabetical order), as well as combination regimens including Bruton's tyrosine kinase (BTK) inhibitors and venetoclax**. In clinical practice, individual patient characteristics and drug availability should be considered if they have not been used previously.
In patients with progression who developed it while receiving continuous therapy with a Bruton's tyrosine kinase (BTK) inhibitor, the most preferable option is the use of venetoclax** in combination with monoclonal antibodies and antibody-drug conjugates. Venetoclax**-containing regimens significantly outperform immunochemotherapy, especially if the Bruton's tyrosine kinase (BTK) inhibitor was prescribed for relapse.
In patients who discontinued therapy with a Bruton's tyrosine kinase (BTK) inhibitor due to adverse events, it is possible to use an alternative Bruton's tyrosine kinase (BTK) inhibitor or switch therapy to venetoclax**-containing regimens. Immunochemotherapy is less preferable, especially if it has been previously administered. Second-line therapy is prescribed when there are indications for treatment. These may be present at the time of discontinuation due to toxicity or may appear over time.
When prescribing therapy in patients with relapse occurring after venetoclax** therapy, the time of relapse onset is taken into account. In late relapses developing more than 2–3 years after therapy, returning to a venetoclax**-containing regimen is possible. In case of progression during treatment or early relapse occurring within 2 years after completing a venetoclax**-containing regimen, switching to a Bruton's tyrosine kinase (BTK) inhibitor is advisable.
When prescribing therapy in patients with relapse occurring after immunochemotherapy who lack TP53 aberrations and a complex karyotype, the time of relapse onset is taken into account. In late relapses developing more than 3 years after therapy, repeating the same or an alternative chemotherapy regimen is possible. In case of progression during treatment or early relapse occurring within 3 years after immunochemotherapy, switching to a Bruton's tyrosine kinase (BTK) inhibitor or venetoclax** is advisable.
For patients with CLL/SLL who experienced a relapse while receiving a Bruton's tyrosine kinase (BTK) inhibitor, if feasible, it is recommended to administer venetoclax** as monotherapy or in combination with rituximab** [57, 58].
venetoclax** + rituximab**: venetoclax** 20 mg/day (week 1), 50 mg/day (week 2), 100 mg/day (week 3), 200 mg/day (week 4), 400 mg/day (week 5 and onward), administered for 24 months starting from Day 1 of Cycle 1 of rituximab** therapy, and rituximab** 375 mg/m2 IV infusion 1 week after reaching the venetoclax** dose of 400 mg/day, followed by rituximab** 500 mg/m2 IV infusion monthly, for a total of 6 administrations [57];
GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)
Venetoclax** administered until disease progression or unacceptable toxicity at a dose of 400 mg/day, starting from the dose-escalation phase.
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Comments: relapse or refractory disease during therapy with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib** may be associated with BTK gene mutations; therefore, it is advisable to test for the p.C481S mutation in the BTK gene, which is most frequently associated with resistance to ibrutinib**.
For patients with CLL/SLL under 65 years of age without significant comorbidities who achieved remission after switching to venetoclax** following progression on continuous BTK inhibitor therapy, it is recommended to consider allogeneic hematopoietic stem cell transplantation as consolidation [41, 42].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
For patients with CLL/SLL and relapse developing after discontinuation of BTK inhibitor therapy due to toxicity, one of the following treatment options is recommended (for treatment regimens, see Appendix A3.3):
acalabrutinib** 100 mg (1 capsule) twice daily as monotherapy regardless of food intake until disease progression or unacceptable toxicity [59];
#zanubrutinib as monotherapy 160 mg (2 capsules) twice daily until disease progression or unacceptable toxicity [30, 31, 52];
venetoclax** + rituximab**: venetoclax** 20 mg/day (week 1), 50 mg/day (week 2), 100 mg/day (week 3), 200 mg/day (week 4), 400 mg/day (week 5 and onward), administered for 24 months starting from Day 1 of Cycle 1 of rituximab** therapy, and rituximab** 375 mg/m2 IV infusion 1 week after reaching the venetoclax** dose of 400 mg/day, followed by rituximab** 500 mg/m2 IV infusion monthly, for a total of 6 administrations [57];
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
For patients with CLL/SLL and early relapse developing after discontinuation of venetoclax** therapy or progression during a venetoclax**-containing regimen, one of the following treatment options is recommended (for treatment regimens, see Appendix A3.3):
acalabrutinib** 100 mg (1 capsule) twice daily as monotherapy regardless of food intake until disease progression or unacceptable toxicity [59];
#zanubrutinib as monotherapy 160 mg (2 capsules) twice daily until disease progression or unacceptable toxicity [60];
ibrutinib** 420 mg/day (3 capsules) orally once daily until disease progression or unacceptable toxicity [34].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
For patients with CLL/SLL and late relapse developing after discontinuation of venetoclax** therapy, one of the following treatment options is recommended (for treatment regimens, see Appendix A3.3):
acalabrutinib** 100 mg (1 capsule) twice daily as monotherapy regardless of food intake until disease progression or unacceptable toxicity [59];
#zanubrutinib as monotherapy 160 mg (2 capsules) twice daily until disease progression or unacceptable toxicity [60];
ibrutinib** 420 mg/day (3 capsules) orally once daily until disease progression or unacceptable toxicity [34];
venetoclax** + rituximab**: venetoclax** 20 mg/day (week 1), 50 mg/day (week 2), 100 mg/day (week 3), 200 mg/day (week 4), 400 mg/day (week 5 and onward), administered for 24 months starting from Day 1 of Cycle 1 of rituximab** therapy, and rituximab** 375 mg/m2 IV infusion 1 week after reaching the venetoclax** dose of 400 mg/day, followed by rituximab** 500 mg/m2 IV infusion monthly, for a total of 6 administrations [57].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
For patients with late relapse of CLL/SLL after immunochemotherapy (>24 months from the last chemotherapy) in the absence of del(17p) and TP53 mutations, one of the following treatment options is recommended (for treatment regimens, see Appendix A3.3):
repeat first-line immunochemotherapy [61];
alternative immunochemotherapy regimen [61, 62];
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
acalabrutinib** 100 mg (1 capsule) twice daily as monotherapy regardless of food intake until disease progression or unacceptable toxicity [59];
venetoclax** + rituximab**: venetoclax** 20 mg/day (week 1), 50 mg/day (week 2), 100 mg/day (week 3), 200 mg/day (week 4), 400 mg/day (week 5 and onward), administered for 24 months starting from Day 1 of Cycle 1 of rituximab** therapy, and rituximab** 375 mg/m2 IV infusion 1 week after reaching the venetoclax** dose of 400 mg/day, followed by rituximab** 500 mg/m2 IV infusion monthly, for a total of 6 administrations [57];
#zanubrutinib as monotherapy 160 mg (2 capsules) twice daily until disease progression or unacceptable toxicity [52, 60];
ibrutinib** 420 mg/day (3 capsules) orally once daily throughout the course and thereafter (after completion of BR cycles) until disease progression or unacceptable toxicity ± BR (#bendamustine** – 70 mg/m2 IV infusion, days 2–3 of cycle 1; days 1–2 of cycles 2–6; rituximab** – 375 mg/m2 IV infusion, day 1 of cycle 1; thereafter – rituximab** 500 mg/m2 IV infusion monthly, for a total of 6 administrations. Treatment is resumed on day 29 [63, 64].
GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).
Comments: in patients with late relapse, the choice of therapy depends on the type, outcomes, and tolerability of previous therapy, the patient's general condition and comorbidities, as well as the preferences and capabilities of the clinic. Repeated fludarabine**-containing courses are possible provided that this therapy as a first-line treatment was not associated with significant toxicity—severe prolonged cytopenias leading to months-long treatment breaks, or severe infectious complications. The same regimen can be used as second-line therapy. Phase II studies have provided convincing data on the efficacy of the BR (bendamustine** + rituximab**) regimen. In patients previously treated with chlorambucil**, therapy with bendamustine**, BR regimens, and FCR-Lite may be effective.
For patients with CLL/SLL with early (<24 months after completion of first-line therapy) relapse with indications for treatment or disease progression, who have not previously received novel targeted agents, therapy with the following drugs is recommended whenever possible (drugs are listed in alphabetical order. In clinical practice, individual patient characteristics and drug availability should be considered):
acalabrutinib** 100 mg (1 capsule) twice daily as monotherapy regardless of food intake until disease progression or unacceptable toxicity [59];
venetoclax** + rituximab**: venetoclax** 20 mg/day (week 1), 50 mg/day (week 2), 100 mg/day (week 3), 200 mg/day (week 4), 400 mg/day (week 5 and onward), administered for 24 months starting from Day 1 of Cycle 1 of rituximab** therapy, and rituximab** 375 mg/m2 IV infusion 1 week after reaching the venetoclax** dose of 400 mg/day, followed by rituximab** 500 mg/m2 IV infusion monthly, for a total of 6 administrations [57];
#zanubrutinib as monotherapy 160 mg (2 capsules) twice daily until disease progression or unacceptable toxicity [52, 60];
ibrutinib** 420 mg/day (3 capsules) orally once daily throughout the course and thereafter (after completion of BR cycles) until disease progression or unacceptable toxicity ± BR (#bendamustine** – 70 mg/m2 IV infusion, days 2–3 of cycle 1; days 1–2 of cycles 2–6; rituximab** – 375 mg/m2 IV infusion, day 1 of cycle 1; thereafter – rituximab** 500 mg/m2 IV infusion monthly. Treatment is resumed on day 29, for a total of 6 cycles) [63, 64].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
For patients with CLL/SLL under 65 years of age without significant comorbidities who received targeted therapy due to early relapse or the detection of del(17p) and/or a TP53 mutation at relapse, it is recommended to consider allogeneic hematopoietic stem cell transplantation as consolidation upon achieving complete remission [41, 42].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
For patients receiving rituximab** for relapsed or refractory CLL/SLL, if venous access is difficult, starting from the 2nd dose, it is recommended to use the subcutaneous form of rituximab** at a fixed dose of 1600 mg (for treatment regimens, see Appendix A3.3) [48].
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
3.4. Concomitant and supportive therapy
For patients with CLL/SLL at any stage of diagnosis, monitoring, or treatment, upon suspicion of or diagnosed infectious complication, it is recommended to administer medical therapy for the infectious complication depending on the pathogen and the site of infection (see Appendix A3.5) [28, 29, 65, 66].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
For patients with CLL/SLL at any stage of treatment who have an immunoglobulin G level <5 g/L (with severe secondary hypogammaglobulinemia) and recurrent bacterial infections, it is recommended to provide continuous replacement therapy with intravenous immunoglobulin (ATC: J06B), if feasible, to reduce the risk of infectious complications [67].
GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).
Comments: infections are the leading cause of death in 10-15% of patients with CLL. Several randomized studies have shown that continuous replacement therapy with intravenous immunoglobulin effectively reduces the frequency of bacterial infections. The effect is most significant in the subgroup of patients with hypogammaglobulinemia and recurrent infections, which is why replacement therapy is currently recommended only for this category of patients.
Normal human immunoglobulin** in the form of a solution for infusion is prescribed as single injections at a dose of 200-400 mg/kg once a month for a year. The goal of therapy is to maintain the IgG level at >5 g/L. When selecting the dose and frequency of administration, clinicians are guided by the peak and trough concentrations of IgG. Monitoring of the peak IgG concentration is carried out no earlier than 24 hours after the 1st intravenous administration of immunoglobulin. The trough concentration is determined immediately before the next administration of immunoglobulin. The trough IgG concentration should be >5 g/L. Repeat determinations of the trough concentration are performed every 3-6 months. Continuous immunoglobulin replacement therapy is discontinued in the absence of severe bacterial infections for a year.
All patients with CLL/SLL after diagnosis are recommended to undergo vaccination in the absence of contraindications [68–71]:
seasonal vaccination with influenza vaccine [live]** or influenza vaccine [inactivated]** (only after recovery of B-lymphocyte counts, i.e., 9 months after therapy with CD20 (cluster of differentiation 20) inhibitors);
two-dose vaccination against pneumococcal infections in the absence of contraindications;
vaccination against herpes zoster, in the absence of contraindications.
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: pneumococcal immunization is carried out in two doses. First, a polysaccharide, conjugated, adsorbed pneumococcal vaccine containing 13 pneumococcal antigens is administered. After 2 months, a pneumococcal vaccine containing 23 pneumococcal antigens is administered. Pneumococcal revaccination is performed once every 5 years.
The use of vaccines against encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis is recommended in many countries for patients with CLL prior to chemotherapy (at least 2 weeks before) or after immune system recovery following therapy (no earlier than 3 months after). This is especially important for patients with functional asplenia or those scheduled for splenectomy. The sequential two-dose vaccination schedule was developed empirically based on the observation that the response to the 23-valent vaccine is weaker than to the 13-valent one. On the other hand, the 23-valent vaccine broadens and enhances the immune response.
The vaccine for the prevention of herpes zoster (recombinant, adjuvanted) is administered in two doses with an interval of 2–6 months.
Vaccinations for epidemiological indications are carried out using appropriate (non-live) vaccines.
For all patients with CLL/SLL at any stage of treatment who develop clinically significant anemia, it is recommended to administer red blood cell component transfusion therapy (see Appendix A3.6) [72].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
For all patients with CLL/SLL at any stage of treatment who develop clinically significant thrombocytopenia, it is recommended to administer platelet concentrate replacement therapy (see Appendix A3.6) [73].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
3.5. Assessment of treatment response
For all patients with CLL/SLL, it is recommended to evaluate therapy response using the IWCLL 2018 criteria (see Section 7.3 of these guidelines) for finite-duration therapy (at least 2 months after its completion), and for continuous or maintenance therapy (at least 2 months after achieving the maximum response) [12].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: the maximum response is defined as a response that does not improve further over the last 2 months of therapy. Bruton's tyrosine kinase (BTK) inhibitors cause redistribution lymphocytosis. Persistent lymphocytosis during ibrutinib** therapy is not a sign of refractoriness. This condition is referred to as a partial response with lymphocytosis. The time to normalization of lymphocyte counts varies across studies from 4 to 12 months; however, with ibrutinib**, lymphocytosis may persist for 12 months or more, which does not affect prognosis. In some patients, lymphocyte counts never return to normal.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
For all patients with CLL/SLL at all stages of disease therapy, as well as upon completion of medical treatment, comprehensive rehabilitation and, if necessary, maintenance therapy are recommended to improve treatment outcomes and the patient's quality of life [74].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: there are no special rehabilitation methods for CLL/SLL. Rehabilitation of patients with CLL should be comprehensive, covering not only medical but also social and psychological aspects of the patient's adaptation to normal life. Such rehabilitation requires, in addition to medical care, the mandatory participation of social workers and psychologists. Rehabilitation programs are developed individually depending on the identified complications of medical treatment, comorbidities, and social and psychological problems.
Rehabilitation for complications of the disease and treatment is carried out within the framework of the respective nosologies.
Maintenance therapy, if necessary, is carried out locally under the supervision of a hematologist or oncologist. The local hematologist or oncologist follows the recommendations provided by the specialists of the treatment center.
5. Prevention and Dispensary Observation
Currently, there are no methods for preventing CLL/SLL, as the etiological factor or factors leading to the development of the disease are unknown.
All patients with CLL/SLL throughout their lives (both during and outside treatment periods) are recommended to undergo follow-up monitoring by a hematologist [12, 16].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: during the 1st year after completion of treatment, the patient should be monitored by a hematologist at least once every 3 months. Thereafter, the frequency of monitoring is determined by the hematologist individually depending on the patient's general condition and well-being, complications of the therapy, and the achieved response to therapy, but should not be less than once a year.
During follow-up monitoring, in addition to physical examination and medical history taking, it is necessary to perform a general (clinical) blood test with differential leukocyte count (leukocyte formula), and, if the disease was accompanied by lymphadenopathy, instrumental examination of peripheral lymph nodes (ultrasound or CT). Other diagnostic methods may be used at the discretion of the hematologist.
Patients who have received or are receiving treatment for CLL/SLL are recommended to undergo regular routine screening examinations due to the increased risk of developing second malignancies [75, 76].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
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, which is approved by the authorized federal executive body;
2) in accordance with the procedure for the provision of care in the specialty "hematology", mandatory for implementation across 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 CLL is detected or suspected in a patient, general practitioners, district general practitioners, general family practitioners, specialists, and mid-level medical personnel shall refer the patient in the established manner for a consultation at an outpatient hematology/oncology care center or to a primary hematology office or 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 CLL is detected or suspected during the provision of emergency medical care, the patient is transferred or referred to medical organizations that provide medical care to patients with hematological diseases to determine management tactics and the need for additional specialized anti-tumor treatment methods.
Specialized, including high-tech, medical care is provided by hematologists in medical organizations that provide medical care to CLL patients, hold the necessary license, have the appropriate material and technical base and certified specialists, in inpatient and day-hospital settings, and includes the prevention, diagnosis, and treatment of hematological diseases requiring special methods and complex unique medical technologies, as well as medical rehabilitation.
In a medical organization providing medical care to patients with CLL, the tactics of medical examination and treatment are determined by hematologists, involving other medical specialists if necessary, and through a medical board (consilium) when required. The decision of the medical board is formalized in a protocol, signed by the participating physicians, and entered into the patient's medical documentation.
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 emergency hospitalization:
1. Development of a severe infection (hospitalization in a hematology department is optional).
2. Development of life-threatening cytopenias (profound anemia, hemorrhagic syndrome, neutropenia).
3. Development of CLL complications, including Richter syndrome, symptomatic lymphadenopathy and organomegaly with the risk of severe complications, neuroleukemia, specific pleurisy and chylothorax with signs of respiratory failure, paraneoplastic and autoimmune syndromes, and other life-threatening complications.
4. Development of therapy complications, including tumor lysis syndrome, severe infusion reactions, myelotoxic agranulocytosis with fever, and other life-threatening complications.
Indications for planned hospitalization:
1. Administration of therapy in cases requiring round-the-clock patient monitoring due to the severity of the condition caused by the tumor or due to the risk of complications associated with the treatment regimen or comorbid conditions.
2. Patient examination, including biopsy and invasive interventions, in cases where it cannot be performed on an outpatient basis.
Indications for patient discharge from a medical organization:
1. Completion of a course of treatment or one of the stages of specialized, including high-tech, medical care in an inpatient or day-hospital setting, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting.
2. Refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day-hospital setting prescribed by the medical board of the oncological healthcare organization, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting.
3. The need to transfer the patient to another medical organization according to the relevant medical specialty profile.
4. Decision of the medical commission regarding the absence of indications for the patient's stay in the hospital due to the futility of treatment and the need to provide palliative care only.
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 and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.
7. Additional Information
7.1. Staging of small lymphocytic lymphoma
Staging of malignant lymphomas is carried out based on the examination results in accordance with the Ann Arbor classification criteria (Table 7.1) [13].
Table 7.1. Ann Arbor staging of lymphomas, Cotswold modification
Stage I |
|
Stage II |
|
Stage III |
|
Stage IV |
|
For all stages | |
A |
|
C | One or more of the following symptoms:
|
E | Localized extranodal involvement (in stages I–II):
|
[1] Lymphatic structures include lymph nodes, spleen, thymus, Waldeyer's ring, appendix, Peyer's patches.
7.2. Overall survival of patients across IPS groups
Table 7.2. Overall survival of patients in MPI groups
Risk group | Score | Number of patients, abs. (%) | 5-year OS, % |
Low | 0-1 | 340 (29) | 93,2 |
Intermediate | 2-3 | 464 (39) | 79,4 |
High | 4-6 | 326 (27) | 63,6 |
Very high | 7-10 | 62 (5) | 23,3 |
7.3. Assessment of treatment response in CLL
Response assessment to treatment is carried out in accordance with the updated criteria proposed by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) in 2018 (Table 7.3) [12].
Table 7.3. Treatment response assessment in chronic lymphocytic leukemia
Indicator | Complete remission | Partial remission | Progression |
A. Parameters characterizing tumor burden | |||
Lymphadenopathy | Absence of nodes >1.5 cm | Reduction ≥50% | Increase ≥50% |
Hepatomegaly | No | Reduction ≥50% | Increase ≥50% |
Splenomegaly | Craniocaudal spleen size <13 cm | Reduction ≥50% of the baseline enlargement value | Increase ≥50% |
Blood lymphocytes | <4×109/L | Reduction ≥50% from baseline | Increase ≥50% from baseline |
Bone marrow | Normocellular, <30% lymphocytes, no nodular involvement | Reduction of bone marrow infiltration by 50% | – |
Constitutional symptoms | No | Any | Any |
A. Parameters characterizing bone marrow function | |||
Platelets | >100×109/L | >100×109/L or an increase ≥50% from baseline | Decrease ≥50% from baseline due to CLL |
Hemoglobin | >110 g/L (without transfusions and erythropoietins (B03XA Other antianemic preparations)) | >110 g/L or an increase ≥50% from baseline | Decrease ≥20 g/L from baseline due to CLL |
Neutrophils | >1.5×109/L | >1.5×109/L or increase of >50% from baseline | – |
Disease stabilization is established in situations that do not meet the criteria for either partial remission or progression.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Performance evaluation |
1 | Detailed complete (clinical) blood count performed (at diagnosis, during follow-up assessments, after completion of therapy, and when disease relapse is suspected) | Yes/No |
2 | Peripheral blood flow cytometry performed in the presence of absolute lymphocytosis (at diagnosis or when disease relapse is suspected) | Yes/No |
3 | Lymph node (target lesion) biopsy performed (when small lymphocytic lymphoma is suspected without blood lymphocytosis or when transformation is suspected) | Yes/No |
4 | Pathological examination of bone marrow biopsy (surgical) material performed using immunohistochemical methods | Yes/No |
5 | Computed tomography of the chest or targeted chest X-ray performed (before starting therapy, after completion of therapy, and when disease relapse is suspected) | Yes/No |
6 | Computed tomography of the abdomen, ultrasound of the lymph nodes, or comprehensive ultrasound of the abdominal organs performed (before starting therapy, after completion of therapy, and when disease relapse is suspected) | Yes/No |
7 | Antitumor therapy administered (if indicated) | Yes/No |
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Appendix A1. Working Group Composition
Lyubov S. Al-Radhi, Cand. Sci. (Med.), Deputy Head of the Consultative Hematological Department with a Day Hospital for Intensive High-Dose Therapy, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematological Society
Tatyana E. Byalik, Cand. Sci. (Med.), Onco-Hematologist, Assistant Professor at the Department of Oncology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).
Kamil D. Kaplanov, Cand. Sci. (Med.), Head of Hematology Department No. 11, S.P. Botkin City Clinical Hospital of the Moscow Healthcare Department, Member of the Russian Society of Oncohematology, Member of the National Hematological Society.
Tatyana N. Lopatkina, Cand. Sci. (Med.), Physician, Gastroenterologist, Associate Professor at the Department of Therapy, Occupational Diseases, and Pulmonology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University).
Svetlana A. Lugovskaya, Dr. Sci. (Med.), Professor at the Department of Clinical Laboratory Diagnostics, Russian Medical Academy of Continuous Professional Education (RMAPO) of the Russian Ministry of Health, Member of the National Hematological Society.
Olga V. Mukhortova, Dr. Sci. (Med.), Highest Category Radiologist, Senior Researcher at the Department of Nuclear Diagnostics (PET Center) at the A.N. Bakulev National Medical Research Center of Cardiovascular Surgery of the Russian Ministry of Health.
Evgeny A. Nikitin, Dr. Sci. (Med.), Professor, Head of the Day Hospital for Hematology, Oncology, and Chemotherapy at the City Hematology Center, S.P. Botkin City Clinical Hospital of the Moscow Healthcare Department, Board Member of the Russian Society of Oncohematology, Board Member of the National Hematological Society.
Evgeny A. Osmanov, Dr. Sci. (Med.), Professor, Head of the Department of Hematology and Bone Marrow Transplantation, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Professor at the Department of Oncology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Board Member of the National Hematological Society.
Irina V. Poddubnaya, Academician of the Russian Academy of Sciences, Honored Worker of Education of the Russian Federation, Dr. Sci. (Med.), Professor, Head of the Department of Oncology and Palliative Medicine, Vice-Rector for Clinical Work and International Cooperation, Russian Medical Academy of Continuous Professional Education (RMAPO) of the Russian Ministry of Health, Chair of the Russian Society of Oncohematology.
Olga S. Samoylova, Cand. Sci. (Med.), Hematologist, Head of the Hematology Department, N.A. Semashko Nizhny Novgorod Regional Clinical Hospital, Chief freelance hematologist of the Volga Federal District, Member of the Russian Society of Oncohematology, Member of the National Hematological Society.
Elena A. Stadnik, Cand. Sci. (Med.), Associate Professor at the Department of Faculty Therapy, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, Senior Researcher, V.A. Almazov National Medical Research Centre of the Russian Ministry of Health, Member of the Russian Society of Oncohematology.
Dmitry N. Stefanov, Researcher at the Scientific and Organizational Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Resident Physician at the Department of Pathology, Sheba Medical Center Tel HaShomer, Member of the Russian Society of Oncohematology
Natalya A. Falaleeva, Dr. Sci. (Med.), Head of the Antitumor Drug Therapy Department, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Member of the Association of Oncologists of Russia and the Russian Association of Therapeutic Radiation Oncologists.
Vadim V. Baykov, Dr. Sci. (Med.), Professor at the Department of Pathological Anatomy, Head of the Pathomorphology Laboratory at the Research Institute of Pediatric Oncology, Hematology and Transplantation named after R.M. Gorbacheva, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, Presidium Member of the Russian Society of Pathologists, Board Member of the Russian Society of Oncohematology.
Alla M. Kovrigina, Dr. Sci. (Biol.), Professor at the Department of Pathological Anatomy, Cytology and Molecular Pathology, Institute of Advanced Training of the Federal Medical-Biological Agency of the Russian Federation, Head of the Pathological Anatomy Department, National Medical Research Center for Hematology of the Russian Ministry of Health, Presidium Member of the Russian Society of Pathologists, Board Member of the Russian Society of Oncohematology.
There is no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience of these clinical guidelines:
hematologists;
oncologists;
medical students.
Methodology for evidence collection
Methods used for collecting/selecting evidence: searching for publications in specialized peer-reviewed periodicals with an impact factor >0.3.
Search in electronic databases.
The evidence base for the recommendations includes publications from the Cochrane Library, 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;
evaluation of the significance of evidence in accordance with the evidence rating scheme (Tables A1–A3).
These clinical guidelines provide levels of evidence certainty and recommendation grades in accordance with the guidelines for the development and updating of clinical guidelines (Order of the Russian Ministry of Health No. 103n dated February 28, 2019).
Table A1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without sequential reference-standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table A2. Levels of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)
LoE | Definition |
1 | Systematic review of RCTs incorporating meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table A3. Grades of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Methodology for validation of guidelines
Validation methods:
external expert review;
internal expert review.
Description of the guideline validation methodology
The preliminary version of these recommendations was reviewed by independent experts who were asked to comment on the quality of evidence interpretation and guideline development. An expert review of the presentation of the recommendations and their readability was also carried out.
The guidelines were discussed and approved by leading specialists of specialized federal centers of the Russian Federation and practicing physicians. The draft clinical guidelines were reviewed at working group meetings in 2017–2018, at the "Lymphoforum" expert forum on the diagnosis and treatment of malignant lymphoproliferative disorders, the annual Russian conference with international participation "Malignant Lymphomas", and within the framework of the IV Congress of Hematologists of Russia.
Procedure for updating clinical guidelines
Updating is carried out at least once every 3 years or upon the emergence of new information on the diagnosis and management of patients with CLL/SLL, but no more frequently than once every 6 months. The decision to update is made by the Russian Ministry of Health based on proposals from medical professional non-profit organizations. The formulated proposals must take into account the results of a comprehensive evaluation of medicines and medical devices, as well as the results of clinical approbation.
Appendix A3. Reference Materials
Appendix A3.1. Significance of hepatitis B virus markers in CLL
CLL cells can serve as an additional reservoir for the hepatitis B virus. Latent HBV infection is more frequently detected in patients with CLL. The significance of HBV infection markers and recommended actions are presented in Table 3.1.
Table A3.1. Significance of hepatitis B virus markers
Definition | HBs-Ag | Anti-HBc | Anti-HBs | HBV DNA | Actions |
No previous contact with HBV | – | – | – | – | Vaccination is indicated. No contraindications to CD20 (cluster of differentiation 20) inhibitors |
Vaccination completed | – | – | + | – | No contraindications to CD20 (cluster of differentiation 20) inhibitors |
Convalescent | – | + | + | – | No contraindications to CD20 (cluster of differentiation 20) inhibitors |
Possible latent HBV carrier state | – | + | – | +/- | HBV DNA monitoring every 2 months during therapy with CD20 (cluster of differentiation 20) inhibitors; initiation of antiviral therapy upon appearance of HBsAg or HBV DNA |
Inactive HBsAg carrier state | + | ± | – | ± | Prescription of systemic antiviral drugs during therapy with CD20 (cluster of differentiation 20) inhibitors + 1 year after completion |
Chronic hepatitis B | + | * | * | ± | Avoid CD20 (cluster of differentiation 20) inhibitors, or administer antiviral therapy before treatment, throughout the entire treatment period, and for 1 year after completion* |
* If administration of CD20 (cluster of differentiation 20) inhibitors is necessary, continuous administration of entecavir** at 0.5 mg/day is indicated. Entecavir** is prescribed for the entire period of treatment/maintenance therapy and for at least 1 year after completion of immunosuppressive therapy, provided there are repeated negative results for hepatitis B virus DNA testing in the blood. The optimal duration of entecavir** therapy after completion of rituximab** therapy has not been established. If a patient with CLL does not require specific therapy, there is no need for prophylactic administration of entecavir**. Lamivudine** should not be used in patients with CLL, as this always involves long-term administration of systemic antiviral drugs. By the end of the 2nd year of lamivudine** administration, more than 40% of HBV strains are resistant to this drug, and by the end of the 4th year, 70% of HBV strains. If resistance to entecavir** develops, switching to tenofovir** is indicated.
Appendix A3.2. Indications for initiating treatment of CLL/SLL
Therapy for CLL/SLL should be initiated in the presence of at least 1 of the following criteria according to IWCLL 2018 guidelines [12]:
Binet stage C.
One or more B-symptoms:
weight loss >10% over 6 months (if the patient was not intentionally trying to lose weight);
fatigue (ECOG performance status ≥2, inability to work);
low-grade fever for ≥2 weeks without signs of infection;
night sweats persisting for more than 1 month, without signs of infection.
Progressive anemia and/or thrombocytopenia caused by bone marrow infiltration.
Autoimmune anemia and/or thrombocytopenia resistant to prednisolone.
Massive splenomegaly (>6 cm below the costal margin), marked enlargement of the organ.
Massive (≥10 cm in maximal diameter) and/or progressive lymphadenopathy.
Lymphocyte doubling time of less than 6 months.
Extranodal involvement that is symptomatic or affecting the function of the affected organ.
Appendix A3.3. Drug treatment regimens for CLL
Monotherapy
Chlorambucil** monotherapy – course format [81];
#Chlorambucil** – 10 mg/m2 orally on days 1–7.
Treatment is resumed on day 29.
#Chlorambucil** monotherapy – continuous format [55];
#Chlorambucil** – 60–70 mg/m2 orally daily for 2–4 weeks, followed by dose adjustment.
#Bendamustine** monotherapy [77]
#Bendamustine** – 100 mg/m2 IV on days 1, 2.
Treatment is resumed on day 29.
Ibrutinib** monotherapy [32].
Ibrutinib** – 420 mg/day (3 capsules) orally once daily until disease progression or unacceptable toxicity.
Acalabrutinib monotherapy** [59];
Acalabrutinib** – 100 mg (1 capsule) orally twice daily until disease progression or unacceptable toxicity.
Venetoclax** monotherapy [78]
Venetoclax** – 20 mg/day (wk 1), 50 mg/day (wk 2), 100 mg/day (wk 3), 200 mg/day (wk 4), 400 mg/day (wk 5 and thereafter), until disease progression or unacceptable toxicity.
#Zanubrutinib monotherapy [30, 31]
#Zanubrutinib – 160 mg (2 capsules) twice daily until disease progression or unacceptable toxicity.
Combination chemotherapy
Intravenous FCR [32, 44, 46]
Rituximab** – cycle 1: 375 mg/m2 IV infusion, day 1; subsequent cycles: rituximab** 500 mg/m2 IV infusion or #rituximab** 1600 mg SC, day 1 [48].
#Fludarabine** – 25 mg/m2 IV infusion, days 1–3.
#Cyclophosphamide** – 250 mg/m2 IV infusion, days 1–3.
Treatment is resumed on day 29.
Recommended number of cycles: 6.
Oral FCR [44]
Rituximab** – cycle 1: 375 mg/m2 IV infusion, day 1; subsequent cycles: rituximab** 500 mg/m2 IV infusion or #rituximab** 1600 mg SC, day 1 [48].
#Fludarabine** – 40 mg/m2 orally, days 1–3.
#Cyclophosphamide** – 250 mg/m2 orally, days 1–3.
Treatment is resumed on day 29.
FCR-Lite [44, 51]
Rituximab** – cycle 1: 375 mg/m2 IV infusion, day 1; subsequent cycles: rituximab** 500 mg/m2 IV infusion.
#Fludarabine** – 20 mg/m2 orally, days 1–3.
#Cyclophosphamide** – 150 mg/m2 orally, days 1–3.
Treatment is resumed on day 29.
RB [38, 49, 50]
Rituximab** – cycle 1: 375 mg/m2 IV infusion, day 1; subsequent cycles: rituximab** 500 mg/m2 IV infusion.
#Bendamustine** – 90 mg/m2 IV infusion, days 1, 2.
Treatment is resumed on day 29.
Chl-R [53]
Rituximab** – cycle 1: 375 mg/m2 IV infusion, day 1; subsequent cycles: rituximab** 500 mg/m2 IV infusion.
#Chlorambucil** – 10 mg/m2 orally, days 1–7.
Treatment is resumed on day 29.
Chl-G [21, 40, 54]
Obinutuzumab** – 1000 mg IV, day 1 (100 mg over 4 hours), day 2 (900 mg), days 8, 15 (cycle 1), day 1 (cycles 2–6).
#Chlorambucil** – 0.5 mg/kg orally, days 1, 15.
Treatment is resumed on day 29.
Acalabrutinib** + #obinutuzumab** [21, 36]
Acalabrutinib** – 100 mg (1 capsule) orally twice daily until disease progression or unacceptable toxicity.
#Obinutuzumab** – 100 mg, day 1 of cycle 2; 900 mg, day 2 of cycle 2; 1000 mg, day 8 of cycle 2; 1000 mg, day 15 of cycle 2; 1000 mg, day 1 of cycles 3–7.
Treatment is resumed on day 29, for a total of 7 cycles.
Venetoclax** + rituximab** [57, 78]
Venetoclax** – 20 mg/day (wk 1), 50 mg/day (wk 2), 100 mg/day (wk 3), 200 mg/day (wk 4), 400 mg/day (wk 5 and thereafter), administered for 24 months starting from day 1 of cycle 1 of rituximab** therapy.
Rituximab** – 375 mg/m2 IV infusion 1 week after reaching the venetoclax** dose of 400 mg/day, then rituximab** 500 mg/m2 IV infusion monthly, for a total of 6 administrations.
Venetoclax** + #obinutuzumab** [22]
#Obinutuzumab** – 100 mg, day 1 of cycle 1; 900 mg, day 2 of cycle 1; 1000 mg, day 8 of cycle 1; 1000 mg, day 15 of cycle 1; 1000 mg, day 1 of cycle 2; 1000 mg, day 1 of cycles 3–6.
Venetoclax** – 20 mg/day, days 22–28 of cycle 1; 50 mg/day days 1–7 of cycle 2; 100 mg/day days 8–14 of cycle 2; 200 mg/day days 15–21 of cycle 2; 400 mg/day days 22–28 of cycle 2, then 400 mg/day for 12 cycles of 28 days each.
#Venetoclax** + ibrutinib** [23, 24]
Ibrutinib** – 420 mg/day (3 capsules) orally once daily for 3 cycles, then in combination with venetoclax** for 12 cycles.
#Venetoclax** – 20 mg/day week 1, 50 mg/day week 2; 100 mg/day week 3; 200 mg/day week 4; 400 mg/day week 5 and thereafter 400 mg/day, starting from day 1 of cycle 4 of ibrutinib**.
Ibrutinib** + BR [63, 64]
Ibrutinib** – 420 mg/day (3 capsules) orally once daily every day throughout the entire course and thereafter (after completion of BR cycles) until disease progression or unacceptable toxicity.
#Bendamustine** – 70 mg/m2 IV infusion, days 2–3 of cycle 1; days 1, 2 of cycles 2–6.
Rituximab** – 375 mg/m2 IV infusion, day 1 of cycle 1; rituximab** 500 mg/m2 IV infusion.
Treatment is resumed on day 29, for a total of 6 cycles.
Ibrutinib** + #obinutuzumab** [40]
Ibrutinib** – 420 mg/day (3 capsules) orally once daily every day throughout the entire course and thereafter (after completion of BR cycles) until disease progression or unacceptable toxicity.
#Obinutuzumab** – 100 mg, day 1 of cycle 1; 900 mg, day 2 of cycle 1; 1000 mg, day 8 of cycle 1; 1000 mg, day 15 of cycle 1; 1000 mg, day 1 of cycle 2; 1000 mg, day 1 of cycles 3–6.
Appendix A3.4. Supportive care during the administration of monoclonal antibodies and antibody-drug conjugates in patients with CLL/SLL.
Monoclonal antibodies and antibody-drug conjugates are a class of drugs with high selectivity for a molecular target that is typically one of the key components of the pathological process. Antibodies have the ability to bind precisely to an antigen due to special antigen-binding sites with high specificity for it.
Over the past decade, targeted treatment methods against tumor cells in hematological malignancies have demonstrated high efficacy and have been included in numerous national guidelines for the treatment of hemoblastosis, both in relapse and in first-line therapy.
Considering that monoclonal antibodies and antibody-drug conjugates are protein molecules capable of causing adverse reactions, mainly infusion-related, an algorithm has been developed to eliminate side effects 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 the administration of monoclonal antibodies and antibody-drug conjugates are presumed to be based on immune mechanisms: massive cytokine release and IgE-mediated mechanisms.
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, changes in blood pressure—of any severity, the administration of the drug should be stopped immediately and the symptoms eliminated by administering glucocorticoids, oxygen, medications for obstructive airway diseases, systemic antihistamines, and then the possibility of continuing the administration should be evaluated. In case of severe or refractory infusion reactions, an initial assessment (consultation) by an anesthesiologist-resuscitologist is performed. In the event of anaphylactic shock, epinephrine** and fluid challenge are administered first, followed by dexamethasone** or prednisolone**.
A3.4.1. Rituximab**
The administration of rituximab** may be accompanied by infusion reactions: chills, fatigue, dyspnea, dyspepsia, nausea, rash, arterial hypotension or hypertension, fever, pruritus, urticaria, pharyngeal irritation, rhinitis, tachycardia, vomiting, pain, signs of tumor lysis syndrome. The drug is administered according to the instructions.
In the majority of patients, the first infusion is accompanied by a mild to moderate infusion complex consisting of fever and chills/shaking. Other frequently observed infusion symptoms include nausea, pruritus, angioedema, asthenia, hypotension, headache, bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, dizziness, hypertension. As a rule, these reactions occur within 30–120 minutes after the start of the first infusion and disappear after slowing or interrupting the drug administration and implementing supportive measures. Mild to moderate reactions can be resolved by reducing the infusion rate, which can be increased again after symptoms subside. Patients who develop grade 1–3 infusion reactions should have the infusion rate reduced upon resumption. In the event of an anaphylactic reaction or a life-threatening grade 4 infusion reaction, the administration of rituximab** must be permanently discontinued, and necessary emergency care must be provided.
Due to the risk of hypotension, discontinuation of antihypertensive drugs is recommended 12 hours before the start and throughout the entire duration of the rituximab** infusion.
A3.4.2. Obinutuzumab**
The recommended dose of obinutuzumab** in chronic lymphocytic leukemia is 1000 mg intravenously on days 1 (or 1 + 2), day 8, and day 1 of the 1st 28-day cycle (Table 3), then 1000 mg in cycles 2–6; in lymphomas, the dose of obinutuzumab** is 1000 mg in each treatment cycle. The drug is administered according to the instructions.
When using obinutuzumab**, infusion reactions may occur (including severe ones). The most frequent ones are nausea, vomiting, chills, blood pressure decrease/increase, fever, dyspnea, flushing, headache, tachycardia, and diarrhea. In accordance with the instructions for medical use, to prevent infusion reactions, all patients should be premedicated with analgesics (ATC N02), systemic antihistamines (ATC R06A), and glucocorticoids (ATC H02AB); antihypertensive drugs (ATC C02) should be withheld on the morning of the first infusion, and the dose should be escalated stepwise in cycle 1.
If an infusion reaction develops, the infusion rate should be adjusted depending on the severity of the observed reaction: for grade 1–3 reactions, the infusion should be temporarily suspended and medical therapy necessary to resolve the symptoms administered. For grade 4 reactions, the infusion should be interrupted and therapy permanently discontinued. After resolution of the infusion reaction symptoms, the infusion can be resumed (except for grade 4 cases) at half the rate at which the reactions occurred. If the patient does not experience a recurrence of the same adverse event of the same severity, the infusion rate can be increased with the same steps and intervals as recommended. If the resumed infusion rate is poorly tolerated, the infusion rate recommendations for cycle 1, day 1, and day 2 must be followed.
A decrease in blood pressure may occur during the infusion of obinutuzumab**. Therefore, the possibility of withholding antihypertensive medications for 12 hours prior to each infusion, during each infusion, and for 1 hour following the administration of obinutuzumab** should be considered.
Anaphylaxis may develop during obinutuzumab** therapy, and differential diagnosis between hypersensitivity reactions and infusion reactions may be difficult. If a hypersensitivity reaction is suspected during the infusion (symptoms typically occur during subsequent administrations, very rarely during the first infusion), the infusion must be stopped, and obinutuzumab** therapy should be discontinued.
Patients at risk for tumor lysis syndrome (with high tumor burden and/or high peripheral blood lymphocyte count and/or renal impairment with creatinine clearance <70 mL/min) must receive prophylaxis for the syndrome, including adequate hydration and the administration of uric acid synthesis inhibitors prior to the start of the infusion.
Appendix A3.5. Prophylaxis of infectious complications
Infections are leading complications in the treatment of CLL/SLL, with the incidence of infectious complications ranging from 10 to 30%. It is higher during the remission induction period, in refractory disease, in the presence of concomitant hypogammaglobulinemia, and during periods of forced physical inactivity and strict bed rest. An important 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—the incidence of infections increases significantly when neutropenia lasts longer than 10 days. The risk of infections increases with impaired neutrophil phagocytic function, cellular and humoral immunity defects, damage to the gastrointestinal mucosa (especially grade III–IV mucositis), and the presence of a central venous catheter (CVC). The source of infection is typically the gastrointestinal tract, where active translocation of microorganisms occurs from the mucosa damaged as a result of chemotherapy. Other major portals of entry for infection in neutropenia include the CVC. Infectious complications in patients with CLL/SLL are characterized by diversity in both the etiology and localization of the infectious process.
The high frequency of infectious complications in hematological patients, especially during neutropenia, necessitates the administration of prophylactic drugs. 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-resistant bacteria and is performed in a specific category of patients.
Pneumocystis pneumonia prophylaxis [65, 66]:
Indications:
Glucocorticoid therapy.
Treatment with drugs that lead to a decrease in the CD4 lymphocyte count.
Patients with a history of pneumocystis pneumonia.
One of the following drugs is prescribed:
Co-trimoxazole [Sulfamethoxazole + Trimethoprim]** is prescribed at 800 mg + 160 mg once daily for 7 days. In case of poor drug tolerance, a reduction of the daily dose to 400 mg + 80 mg daily can be considered.
#Dapsone** 100 mg orally daily.
The drugs may be used during cytostatic therapy and throughout the entire period of neutropenia.
The use of Co-trimoxazole [Sulfamethoxazole + Trimethoprim]** simultaneously prevents infections caused by Toxoplasma gondii, Listeria monocytogenes, Nocardia asteroides.
Antifungal prophylaxis [65]:
Administered to patients with a burdened medical history (acute disseminated candidiasis, chronic disseminated candidiasis, mucormycosis, or invasive aspergillosis).
The drug that was used to achieve a cure for invasive mycosis is prescribed.
Patients with a history of acute or chronic disseminated candidiasis (usually one drug from the list) at dosages according to the instructions for use:
Fluconazole**, 400 mg daily, intravenously or orally;
#Micafungin**, 50 mg daily intravenously;
Patients with a history of invasive aspergillosis (usually one drug from the list) at dosages according to the instructions for use:
#Voriconazole**, 200 mg twice daily orally (in tablets, on an empty stomach) or 3–4 mg/kg twice daily intravenously;
Posaconazole**, 200 mg 3 times daily orally (after meals);
#Itraconazole, 5 mg/kg twice daily orally (on an empty stomach).
Patients with a history of mucormycosis:
Posaconazole** (suspension), 200 mg 3 times daily orally (after meals).
Viral infection prophylaxis [65]:
Indicated for patients with a burdened medical history (frequent, recurrent episodes of herpetic infections).
The following drugs are used for viral infection prophylaxis at dosages according to the instructions for use:
#Acyclovir**;
Valacyclovir**;
#Famciclovir.
Antiviral prophylaxis is used for 3–5 weeks starting from the 1st day of specific therapy. Switching from the oral to the intravenous form is performed in patients with mucositis.
Appendix A3.6. Use of donor blood components
The use of donor blood components in patients with chronic lymphocytic leukemia is regulated by Orders of the Russian Ministry of Health 797, 1170n, 1134n, 1128n.
The main medical indication for red blood cell transfusion in hematological patients is inadequate oxygenation of organs and tissues and the associated risk of complications. Donor platelet transfusions are performed in hematological patients to prevent spontaneous hemorrhagic complications against the background of profound thrombocytopenia induced by intensive chemotherapy, or for therapeutic purposes in patients with existing hemorrhagic complications.
Appendix B. Physician Action Algorithms
Appendix B1. Algorithm for selecting first-line therapy for patients with CLL/SLL
Appendix B2. Algorithm for selecting relapse therapy for CLL/SLL
Appendix C. Patient Information
Chronic lymphocytic leukemia (CLL) is a cancer that affects blood and bone marrow cells. In chronic CLL, the bone marrow produces pathologically altered lymphocytes that are unable to perform their functions. They accumulate in the blood and various organs and crowd out normal blood cells. The word "chronic" in the name indicates that this disease has an indolent course.
Small lymphocytic lymphoma (SLL) is a specific manifestation of chronic CLL in which pathological lymphocytes accumulate not in the blood or bone marrow, but in the lymph nodes.
Just 10 years ago, it was believed that CLL/SLL mainly affected older adults. However, as diagnostics improved, it turned out that this disease can also occur in young adults (40–50 years old), and at this age, it has a less favorable course.
Your doctor may suspect CLL/SLL based on your complaints and by finding corresponding symptoms during an examination. In this case, it will be necessary to undergo a series of examinations, including blood and bone marrow tests. In CLL, the most important test is a blood test; the diagnosis is not made without it. The blood test reveals an increased lymphocyte count. The diagnosis is necessarily confirmed by a special test—lymphocyte immunophenotyping. Other diagnostic clarification tests may also be required. In SLL, the diagnosis is made based on the results of histological and immunohistochemical examination of the affected lymph node.
Unfortunately, CLL/SLL is currently incurable. However, some patients never need treatment—CLL/SLL can remain stable for many years or even decades. Many studies have compared watchful waiting and early initiation of therapy (immediately after diagnosis). It turned out that early treatment provides no benefit but causes toxic effects. Therefore, the management strategy for CLL/SLL is tailored to the course of the disease—treatment is applied as needed, since it is inherently unsafe, and the watchful waiting strategy remains the standard for many patients.
If there are clear signs of disease progression—steady growth of lymphocytosis, enlargement of lymph nodes and the spleen, the onset of anemia and thrombocytopenia—the doctor will offer a specific course of treatment.
When choosing treatment, the physician takes into account:
the status of the disease (clinical picture and prognostic factors);
the patient's condition (age, comorbidities);
what treatment was previously administered and when relapse occurred.
As a result, the disease can be effectively controlled with modern medications in the majority of patients.
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 CLL/SLL is performed using the scale developed by the Eastern Cooperative Oncology Group [79].
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
Type: rating scale
Purpose: clinical assessment of the patient's general condition
Content and interpretation:
Status (scores) | Description of the patient's general condition |
0 | Fully active, able to carry on all pre-disease performance without restriction |
1 | Patient is unable to do heavy work, but can carry out light or sedentary work (e.g., light housework or office work) |
2 | The patient is treated on an outpatient basis, is capable of self-care, but cannot work. Spends more than 50% of waking hours active – upright. |
3 | Capable of only limited self-care; confined to bed or chair more than 50% of waking hours |
4 | Completely disabled; cannot carry on any self-care; totally confined to bed or chair |
5 | Dead |
Appendix G2. CIRS comorbidity rating scale
Clinical evaluation of comorbidity in a patient with CLL/SLL can be performed using the Cumulative Illness Rating Scale [80].
Original title: Cumulative Illness Rating Scale
Source: Linn, B. et al. Cumulative Illness Rating Scale. Journal of the American Geriatrics Society.
Type: rating scale
Purpose: clinical evaluation of comorbidity
Content and interpretation:
Score | |||||
0 | 1 | 2 | 3 | 4 | |
Heart disease | |||||
Vascular disease (blood and lymphatic vessels) | |||||
Hematological disease (bone marrow, spleen, and peripheral blood) | |||||
Respiratory disease (trachea, bronchi, and lungs) | |||||
Eye, ear, nose, throat, and larynx disease | |||||
Upper GI disease (esophagus, stomach, duodenum, pancreas (excluding DM), and gallbladder) | |||||
Lower GI disease (small and large intestines) | |||||
Liver disease | |||||
Renal disease | |||||
Genitourinary disease (ureters, bladder, urethra, prostate, and genitals) | |||||
Musculoskeletal (muscles, joints, bones) and integumentary (skin) disease | |||||
Diseases of the central and peripheral nervous system (brain, spinal cord, and nerves) | |||||
Diseases of the endocrine system and metabolic disorders (including diabetes mellitus) | |||||
Mental disorders | |||||
Total score | |||||
Evaluation of organs and systems:
0 points: no diseases in this organ system or presence of a pathology that does not interfere with normal daily functioning, does not affect prognosis, and does not require treatment.
1 point: mild deviations from the norm or past diseases.
2 points: a disease requiring pharmacological therapy.
3 points: a disease that has caused disability.
4 points: a life-threatening disease requiring emergency therapy.