- •These updated ESMO Clinical Practice Guidelines provide key recommendations on the management of chronic lymphocytic leukaemia (CLL)
- •Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe
- •Recommendations are provided, including levels of evidence and grades of recommendation where applicable
- •Prognosis and treatment decisions in CLL depend on genetic and clinical factors including age, stage and comorbidities
- •Therapies targeting B-cell receptor pathway or defect mechanism of apoptosis induce long lasting remissions
Incidence and epidemiology
- •Routine screening for CLL is not recommended either in the general population or in relatives of patients with CLL [V, E].
Diagnosis and pathology/molecular biology
- •Presence of ≥5 × 109/l monoclonal B lymphocytes in the peripheral blood. The clonality of the circulating B lymphocytes needs to be confirmed by demonstrating light chain restriction using flow cytometry.
- •The leukaemia cells found in the blood smear are characteristically small, mature-appearing lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli and having partially aggregated chromatin. Larger, atypical lymphocytes or prolymphocytes may be seen but must not exceed 55%.1
- •Diagnosis is usually possible by immunophenotyping of peripheral blood only [III, A].
- •LN biopsy and/or bone marrow biopsy may be helpful if immunophenotyping is not conclusive for the diagnosis of CLL [IV, A].
Staging and risk assessment
Early, asymptomatic stage
|Binet A||Hb ≥100 g/l (6.21 mmol/l), platelets ≥100 × 109/l|
<3 involved lymphoid sites
|Binet B||Hb ≥100 g/l (6.21 mmol/l), platelets ≥100 × 109/l|
≥3 involved lymphoid sites
|Binet C||Hb <100 g/l (6.21 mmol/l), platelets <100 × 109/l|
|Low-risk||Rai 0||Lymphocytosis >5 × 109/l|
|Intermediate-risk||Rai I||Lymphocytosis and lymphadenopathy|
|Rai II||Lymphocytosis and hepatomegaly and/or splenomegaly with/without lymphadenopathy|
|High-risk||Rai III||Lymphocytosis and Hb <110 g/l (6.83 mmol/l) with/without lymphadenopathy/organomegaly|
|Rai IV||Lymphocytosis and platelets <100 × 109/l with/without lymphadenopathy/organomegaly|
- •History and physical examinations including a careful palpation of all LN areas, spleen and liver;
- •Complete blood cell count and differential count.
|Initial staging at diagnosis||Pre-treatment evaluation||Staging at the end of therapy||Follow-up|
|History, physical examination and performance status||+||+||+||+|
|Complete blood count and differential||+||+||+||+|
|Serum chemistry including serum immunoglobulin and direct antiglobulin test||−||+||+||+|
|Cytogenetics (FISH) and molecular genetics for TP53 mutation or del(17p)||(+)|
|IGHV mutational status||(+)|
|Marrow aspirate and biopsy||−||+|
|HBV, HCV, CMV and HIV serology||−||+||−|
|Radiological imaging (CT scan)||−||+|
Advanced or symptomatic stage
- •History and physical examination including a careful palpation of all LN areas, spleen and liver;
- •Complete blood cell count and differential count;
- •Serum chemistry including lactate dehydrogenase (LDH), bilirubin, serum Igs, direct antiglobulin test (DAT) and haptoglobin. Other parameters in order to exclude other reasons for existing anaemia may be carried out. In addition, kidney and liver function should be tested before starting systemic therapy;
- •The history and status of relevant infections [i.e. hepatitis B (HBV) and C (HCV), cytomegalovirus (CMV), human immunodeficiency virus (HIV)] should be evaluated to prevent virus reactivation;
- •FISH for detection of deletion of the chromosome 17 [del(17p)] affecting the tumour protein p53 expression and, in the absence of del(17p), TP53 sequencing for detection of TP53 gene mutation (at least exons 4-10, exons 2-11 recommended) [III, A].6Array-based techniques might be used alternatively to FISH in the future,7but most data for the prognostic and predictive value of TP53 deletion are based on FISH. As genetic lesions may evolve throughout the disease, the analysis should be carried out as close as possible (e.g. <6 months) to initiation of therapy (Table 3);Table 3Personalised medicine synopsis
Biomarker Method Use LoE, GoR TP53 mutation or del(17p) FISH and Sanger or NGS Strongest prognostic and predictive relevance together with del(17p) III, A IGHV Sanger or NGS Strong prognostic evidence; predictive evidence for CIT III, A Complex karyotype Chromosome banding Possible prognostic and predictive relevance but not yet established prospectively IV, CCIT, chemoimmunotherapy; GoR, grade of recommendation; IGHV, immunoglobulin heavy chain variable; LoE, level of evidence; NGS, next-generation sequencing.
- •Chest imaging: see section ‘Imaging’.
- •Although a bone marrow examination is not required for diagnosis, it is recommended for the diagnostic evaluation of unclear cytopaenia or in the presence of a non-conclusive phenotype. A marrow biopsy may be considered as a baseline parameter to assess treatment response;
- •An extended FISH analysis (or array-based analysis) before therapy may allow the detection of additional cytogenetic abnormalities [e.g. del(11q) or trisomy 12];
- •Hepatitis E testing is optional but should particularly be considered if the patient is positive for HBV;10
- •Serum β2-microglobulin (B2M) is an important prognostic marker, which is part of the CLL-International Prognostic Index (IPI).11
Goals of therapy
- •Binet and Rai staging systems with clinical symptoms are relevant for treatment indication [III, A].
- •del(17p), TP53 mutations and IGHV status are relevant for choice of therapy and should be assessed before treatment [III, A].
- •Routine evaluation of del(17p), TP53 mutation and IGHV status in early and asymptomatic stage is not recommended [V, D].
- •Routine imaging during a watch-and-wait period is not recommended unless there are clinical symptoms [V, E].
Management of early disease
Binet stage A and B without active disease; Rai 0, I and II without active disease
- •The standard treatment of patients with early asymptomatic disease is a watch-and-wait strategy [I, A].
Management of advanced disease
Binet stage A and B with active disease or Binet stage C; Rai 0-II with active disease or Rai III-IV
- •Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopaenia. Cut-off levels of haemoglobin (Hb) <100 g/l (<6.21 mmol/l) or platelet counts <100 × 109/l are generally regarded as indications for treatment. However, it should be pointed out that in some patients, platelet counts <100 × 109/l may remain stable over a long period of time; this situation does not automatically require therapeutic intervention;
- •Massive (i.e. ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly;
- •Massive (i.e. ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy;
- •Progressive lymphocytosis with an increase of ≥50% over a 2-month period, or lymphocyte doubling time (LDT) of <6 months. LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts (ALCs) obtained at intervals of 2 weeks over an observation period of 2-3 months; patients with initial blood lymphocyte counts of <30 × 109/l may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis other than CLL (e.g. infections, steroid administration) should be excluded particularly when LDT is the only criterion to start therapy;
- •Autoimmune complications including anaemia or thrombocytopaenia poorly responsive to corticosteroids;
- •Symptomatic or functional extranodal involvement (e.g. skin, kidney, lung, spine);
- •Disease-related symptoms as defined by any of the following:
- ○Unintentional weight loss ≥10% within the previous 6 months;
- ○Significant fatigue [i.e. European Cooperative Oncology Group performance status (ECOG PS) 2 or worse; cannot work or unable to perform usual activities];
- ○Fevers ≥38.0°C for ≥2 weeks without evidence of infection;
- ○Night sweats for ≥1 months without evidence of infection.
- Eichhorst B.
- Fink A.M.
- Bahlo J.
- et al.
Treatment of relapse and refractory disease
- •The PI3K inhibitor idelalisib in combination with rituximab [II, B];58
- •CIT unless a TP53 mutation or del(17p) is found and no other treatment options with inhibitors or cellular therapy are available; a response to prior BR should have lasted at least 3 years to justify re-administration [II, B]. Repeated administration of FCR is not recommended due to increased toxicity rates and risk of secondary myeloid neoplasm [V, B].
- •Treatment duration (no termination versus fixed duration);
- •Administration [oral (p.o.) versus i.v.];
- •Compliance (i.v. versus p.o.);
- •Evidence (currently, more data exist on ibrutinib first-line followed by venetoclax second-line than on the reverse sequence);
- •Risk of complications (in particular in the presence of specific comorbidities: bleeding and cardiac comorbidities with ibrutinib or other BTKis versus impaired renal function and neutropaenia with venetoclax);
- •Response to and side-effects of prior therapies;
- •Number and complexity of clinical controls (2-4 weeks for ibrutinib versus dose ramp-up with three controls every week for 5 weeks to prevent TLS and potential hospitalisation in case of high TLS risk with venetoclax).
Role of haematopoietic stem cell transplantation and cellular therapies
- •Patients refractory to CIT with TP53 mutation or del(17p), but fully responsive to novel inhibitor therapy. AlloSCT should be discussed with the patient as an option for curative treatment if risk of transplantation is low;65
- •Patients refractory to CIT and to novel inhibitor therapy, even for patients with a higher risk of non-relapse mortality [haematopoietic cell transplant comorbidity index (HCT-CI) score of ≥3] [III, B];65
- •Patients with Richter's transformation in remission after therapy and clonally related to CLL.
- •Lower non-relapse mortality and different, mostly acute, toxicity (cytokine release syndrome; CAR-T-cell-related encephalopathy syndrome) which renders this approach available to patients with some comorbidities;
- •Uncertain long-term curative potential.
Treatment of CLL complications
- •Decision for type of front-line treatment is based on TP53 mutation or del(17p), IGHV mutational status, age, comorbidities and comedication [II, A].
- •CLL with unmutated IGHV status and without TP53 mutation or del(17p) (if there was similar efficacy, panel is giving preference to time-limited therapies):
- ○Fit patients: ibrutinib [I, A] (data for other BTKis for fit patients are still pending); CIT should be avoided due to survival disadvantage, but may be used if other options are not available [I, A]. Venetoclax plus obinutuzumab might be an alternative to BTKis, but data for fit patients are still pending [III, A].
- ○Unfit patients: venetoclax plus obinutuzumab or ibrutinib or acalabrutinib [I, A] or chlorambucil plus obinutuzumab.
- •CLL with mutated IGHV status and without TP53 mutation or del(17p) (if there was similar efficacy, panel is giving preference to time-limited therapies):
- ○Fit patients: CIT according to age (FCR or BR) or ibrutinib [I, A]. Venetoclax plus obinutuzumab might be an alternative to BTKis, but data for fit patients are still pending [III, A].
- ○Unfit patients: venetoclax plus obinutuzumab [I, A] or chlorambucil plus obinutuzumab or ibrutinib or acalabrutinib [I, A].
- •TP53 mutation or del(17p): ibrutinib or acalabrutinib or venetoclax plus obinutuzumab or venetoclax alone or idelalisib plus rituximab [III, A].
- •Early relapse: change of therapy to venetoclax plus rituximab or ibrutinib or acalabrutinib or another BTKi if approved and available [I, A].
- •Late relapse and no del(17p) or TP53 mutation: ibrutinib or venetoclax plus rituximab or repeat front-line therapy [II, B].
- •Autoimmune cytopaenia should be treated with corticosteroids. In patients not responding to corticosteroids, treatment of CLL based on anti-CD20 antibodies or also BCRis should be considered [IV, A].
- •Except after alloSCT, MRD measurement is not yet recommended as a clinical routine test [IV, C].
Follow-up, long-term implications and survivorship
- Cwynarski K.
- van Biezen A.
- de Wreede L.
- et al.
- •The transformation into DLBCL occurs in 2%-15% of CLL patients during the course of their disease, in particular after several lines of CIT. The diagnosis of transformation must be confirmed by histopathology exam of an LN (biopsy or excision). A PET-CT scan can be useful to guide biopsy [IV, C].
- •Response duration of Richter's transformation is typically short, and alloSCT should be recommended to all patients with clonally-related Richter's transformation with an available donor and sufficient fitness [IV, B].
- •In clonally unrelated disease, DLBCL should be treated as a de novo DLBCL.
- •Transformation of CLL into the HL variant should be treated with conventional ChT against HL.
- Dykewicz C.A.
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Approved by the ESMO Guidelines Committee: August 2003, last update June 2020. This publication supersedes the previously published version—Ann Oncol 2015; 26 (Suppl 5): v78-v84.
These Clinical Practice Guidelines are endorsed by the European Hematology Association (EHA) through the Scientific Working Group on CLL/European Research Initiative on CLL (ERIC)