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Chronic Lymphocytic Leukemia

Lead: David Spaner
Date of last revision: June 25, 2020

Terms of use

These guidelines are a statement of consensus of the OCC Hematology site group regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. Use of this site and any information on it is at your own risk.

  1. Diagnosis and pathologic classification:

    CLL: A diagnosis of chronic lymphocytic leukemia (CLL) requires the sustained presence of ≥5x109/L light-chain restricted clonal B lymphocytes in the blood for at least 3 months. CLL cells co-express the surface antigen CD5 with CD19, CD20, and CD23. Surface immunoglobulin, CD20, and CD79b levels are characteristically low compared to normal B cells.1 The differential diagnosis includes mantle cell lymphoma and rarer CD5+ lymphoproliferative disorders such as marginal zone lymphoma (particularly splenic marginal zone lymphoma), lymphoplasmacytic lymphoma and B-prolymphocytic leukemia. An extended phenotype by flow cytometry for CLL/SLL is positivity for CD5, CD19, CD23, CD43, and CD200, with dim expression of CD20, CD22, CD79b and surface kappa or lambda.29 By immunohistochemistry on tissue specimens, expression of LEF1 supports the diagnosis of CLL/SLL.30

    MBL: Monoclonal B lymphocytosis (MBL) is a precursor to CLL defined by the presence of <5x109/L clonal B lymphocytes without lymphadenopathy or organomegaly (as detected by physical examination or imaging studies), disease-related cytopenias, or symptoms. When there are 2 MBL populations (e.g. one kappa and one lambda) the definition of CLL will be based on the total clonal B cell burden.

    MBL progresses to symptomatic CL at a rate of 1% to 2% per year. Cytopenias from marrow infiltration establish the diagnosis of CLL regardless of the number of peripheral blood B cells or lymph node involvement.1

    SLL: Small lymphocytic lymphoma (SLL) is defined by the presence of lymphadenopathy, absence of cytopenias caused by a clonal marrow infiltrate, and <5x109/L circulating B cells. The diagnosis should be confirmed by a lymph node or other biopsy.1

  2. Baseline Testing 

    Baseline testing should include: 
    • CBC and differential count,
    • immunophenotyping of peripheral blood lymphocytes,
    • serum chemistry (creatinine, bilirubin, lactate dehydrogenase, transaminases, alkaline phosphatase, β2-microglobulin)
    • serum immunoglobulin with consideration of haptoglobin and a direct antiglobulin test (DAT).
    • Immunoglobulin heavy chain variable gene (IGHV) and TP53 mutation testing are currently supported by Janssen and should be obtained at diagnosis for prognostic purposes, using the HSNgenomics Testing Order Form CLL Prognostic Markers. This test can be ordered for MBL as well as CLL. Since the IGHV mutation status will not change but CLL cells can acquire additional genetic mutations over time, cytogenetic analysis with FISH is not recommended until treatment is indicated.
    • Bone marrow aspirate and biopsy are generally unnecessary.

      Physical examination should record bi-dimensional diameters of the largest palpable cervical, axillary, and inguinal lymph nodes along with dimensions of the liver and spleen below their respective costal margins, as assessed by palpation. Staging of CLL relies on physical exam and blood counts and CT scans are generally not required for initial evaluation or follow-up.1

      Positron emission tomography (PET) is not useful except in patients with proven or suspected Richter transformation. Magnetic resonance imaging (MRI) is generally not more useful than CT scans and not recommended outside of clinical trials. Abdominal ultrasounds to measure spleen size may be useful on an individual basis.

  3. Staging and key prognostic factors:

    1. Staging: The Rai and Binet classifications are both used since CLL does not have a universally applied staging system.

      Rai: The modified Rai classification defines:

      • Low-risk: Patients who have lymphocytosis with leukemia cells in blood and/or marrow (formerly considered Rai stage 0).
      • Intermediate-risk: Patients with peripheral blood lymphocytosis, enlarged lymph nodes in any site, and splenomegaly and/or hepatomegaly (lymph nodes being palpable or not) (formerly considered Rai stage I or II).
      • High-risk: Includes patients with disease-related anemia (defined by hemoglobin (Hb) <100 g/L) (formerly stage III) or thrombocytopenia (defined by a platelet count <100x109/L; formerly stage IV).1

        Binet: The Binet staging system is based on the number of involved lymphoid areas defined by lymph nodes ≥1 cm in diameter or organomegaly and presence of anemia or thrombocytopenia. Areas of involvement for staging include:

        • head and neck, including the Waldeyer ring (this counts as 1 area, even if ≥1 group of nodes is enlarged),
        • axillae (involvement of both axillae counts as just 1 area),
        • inguinal nodes including superficial femorals (involvement of both groins counts as just 1 area), 4. spleen, and
        • liver.

      • Stage A is defined as Hb ≥100 g/L and platelets ≥100x109/L and up to 2 lymphoid areas involved.
      • Stage B is defined as Hb ≥100 g/L and platelets ≥100x109/L and 3 or more lymphoid areas involved. Stage C is defined as Hb <100 g/L and/or platelet count <100x109/L.
    2. Prognostic factors: The clinical course of CLL is heterogeneous and a number of prognostic parameters can help risk stratify patients.
      • Higher Rai or Binet stages generally predict patients will ultimately require treatment while a subgroup of Rai stage 0 patients may never progress or need treatment in their lifetime.2
      • Serum β2 microglobulin levels >3.5 mg/L are associated with more aggressive disease although the result must be interpreted with caution in the presence of renal disease.
      • The lymphocyte doubling time (LDT) provides a good idea of clinical aggression and an LDT < 6 months is an indication for treatment. The LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. Patients with initial blood lymphocyte counts <30x109/L may require a longer observation period to determine an accurate LDT.1 Confounding factors that cause lymphocytosis such as infections and glucocorticoids must be excluded. LDTs less than 1 year generally indicate treatment will be needed sooner rather than later.
      • High CD38, ZAP-70, and CD49d expression on CLL cells measured by flow cytometry are also associated with more aggressive clinical behavior.3 CD38 levels are provided on the diagnostic flow cytometry report but are not very sensitive and the others are not generally offered at Sunnybrook. The most clinically relevant prognostic parameters are the presence of del(17p) and/or TP53 mutations and IGHV mutational status. Genetic aberration of TP53 is usually associated with high-risk CLL. CLL patients with higher degrees of somatic mutation in IGHV, defined as more than 2% difference from the germline sequence, generally have a more indolent course than germline or unmutated IGHV patients. Mutated IGHV CLL cells may arise from memory B cells while unmutated IGHV cells represent transformed transitional B cells to account for the differences in clinical behavior.6 CLL cells with unmutated IGHV genes do not generally exhibit deep responses to chemoimmunotherapy.7 Prior to the availability of novel agents like the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and BCL-2 inhibitor venetoclax, patients whose CLL cells expressed a mutatedIGHV had a median overall survival (OS) of >20 years compared to those with unmutated IGHV whose median OS was only 8 years.4,5
      • Common cytogenetic abnormalities found in CLL by FISH testing offer prognostic information. Prior to the newer therapies, patients with del(17p13) had the shortest OS (~3 years), followed by patients with del(11q23) (~6.5 years), trisomy 12 (~9.2 years), negative FISH (~9.5 years), and del(13q14) (~11 years).8 FISH testing should be performed only before a treatment decision as the presence of del(17p13) where TP53 resides or a TP53 mutation, determined in a separate assay, in more than 10% of CLL cells are contraindications for chemoimmunotherapy. For decisions about retreatment, only FISH for del(17p) should be ordered and not the full CLL FISH panel.
      • Next-generation DNA sequencing has detected around 50 somatic mutations that act to drive the growth of CLL cells and disease progression. Identification of these genetic changes will affect prognosis and therapeutic decisions in the near future but the technology is not readily available in Canada at this time. These mutations affect DNA damage and cell cycle control (ATM, TP53, RB1), Notch signaling (NOTCH1, NOTCH2, FBXW7), cytokine signaling (NRAS, KRAS, BRAF), inflammatory pathways (MYD88, DDX3X, MAPK1, BIRC3), and RNA splicing and export (SF3B1, U1, XPO1).9 Howthese genes affect the pathogenesis and course of CLL are current research questions. For example, CLL patients who harbor NOTCH1mutations (mostly in patients with trisomy 12), SF3B1 mutations (mostly in patients with del13q14), and TP53 mutations exhibit shorter times to first therapy, progression-free survival (PFS), and OS.7 Factors such as IGHV gene family usage have also been shown to provide important information about time to first therapy and OS.6

    3. CLL International Prognostic Index (CLL-IPI): 

      Risk Points 5-year OS
      Low 0-1 93%
      Intermediate 2-3 79%
      High 4-6 63%
      Very high 7-10 23%
      Note that very high-risk disease requires an abnormality of TP53.

      The CLL-IPI does not consider somatic genetic mutations or patient co-morbidities and was developed before the newer therapies so OS predictions are no longer valid. However, it can predict time to first therapy in previously untreated patients.

  4. Treatment

    1. 4.1. Indications for treatment:

      Treatment for CLL remains essentially palliative and is reserved to improve symptoms from active disease. Older studies showed treatment of early-stage disease did not yield a survival benefit11 and there is no reason to think the newer agents will change this result.7,12 Active disease is defined by at least one of following criteria1:

      1. Progressive marrow failure. Cutoff levels of Hb <100 g/L or platelet counts <100x109/L are generally regarded as indication for treatment. However, some patients tolerate lower Hb levels and platelet counts <100x109/L may be stable over a long period and do not automatically require therapeutic intervention.
      2. Massive (≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
      3. Massive nodes (≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
      4. Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids
      5. Progressive lymphocytosis with an increase of ≥50% in 2-months or LDT <6 months.
      6. Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, spine).
      7. Disease-related symptoms defined by any of the following:
        • Unintentional weight loss ≥10% within the previous 6 months.
        • Significant fatigue (i.e. ECOG performance scale 2 or worse; cannot work or unable to perform usual activities).
        • Fevers ≥ 38.0°C for 2 or more weeks without evidence of infection.
        • Night sweats for ≥1 month without evidence of infection.

          The absolute lymphocyte count alone is not used as an indicator for treatment.

    2. 4.2. Watch and wait:

      Because the rate of progression may vary, with long periods of stability and sometimes spontaneous regressions, frequent and careful observation is required to monitor the clinical course of CLL patients. Patients with low-risk disease can be seen at yearly or longer intervals while those with high-risk disease should be seen more frequently. While no active treatment is administered during "watch and wait", it makes sense for patients to follow AICR/WCRF cancer prevention guidelines as they may prolong time-to-first treatment.13

    3. 4.3. First line therapy:

      Clinical trials should always be considered as better treatments are needed for all lines of therapy in CLL. First-line regimens currently funded by CCO include fludarabine, cyclophosphamide, and rituxan (FCR), fludarabine plus rituxan (FR), chlorambucil plus obinotuzumab (C/O), and ibrutinib. Venetoclax and acalabrutinib are likely to be funded in the next few years. Bendamustine plus rituxan provides the same CR and overall response rate with slightly longer progression free survival (PFS) than C/O but this regimen is not funded by CCO.31 Cytogenetic abnormalities, TP53 mutations, IGHV mutation status and co-morbidities guide the choice of regimen. Chemoimmunotherapy is ineffective in the presence of chromosome 17p deletions or TP53 mutations and only induces prolonged remissions in patients with mutated IGHV genes.5

      1. Initial treatment of fit IGHV mutated patients without TP53 disruption: FCR is recommended as initial therapy for fit patients without TP53 disruption outside clinical trials.15 Several studies have shown IGHV mutated patients who receive FCR experience a long PFS (that can exceed 10 years).16 Patients with unmutated IGHV genes do not experience such long remissions and are eligible for ibrutinib as first-line treatment in Ontario (see iii below). FCR is recommended only in young (generally <65 years) and otherwise fit patients who can tolerate this intensive regimen. The long-term outcomes of patients who achieve a state of minimal residual disease (MRD) in the bone marrow at the end of 3 cycles of FCR, defined by four-color flow cytometry as <.01% CLL cells in at least 10,000 leukocytes, are similar to patients given 6 cycles, suggesting it is possible to minimize the cumulative toxicity and leukemogenic potential of this regimen.17

        Prior to treatment with FCR, patients should be evaluated for hepatitis B (HBV) or hepatitis C virus (HCV) due to the risk of reactivation.1 Chronic HBV carriers, as defined by positive surface antigen, HB core antibody, and/or low HBV titers in serum, should receive prophylactic antiviral drugs during treatment.182 Patients with high HBV or HCV DNA titres should first be treated with antivirals. Patients should receive pneumocystis jiroveci pneumonia (PJP) and herpes virus prophylaxis for at least one year after starting FCR.15

      2. Initial treatment of less-fit IGHV mutated patients without TP53disruption: C/O is recommended for patients older than 65 years or with at least one significant co‐morbidity who cannot tolerate FCR.18 Co‐morbidity scores to define fitness objectively such as the Cumulative Illness Rating Scale (CIRS)18 are used in clinical trials but not routinely in clinical practice.15

        Chlorambucil is dosed at 0.5 mg/kg orally on days 1 and 15 of each cycle based on a prior trial showing noninferiority of chlorambucil to fludarabine in elderly CLL patients. Obinutuzumab is injected at a dose of 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15 of cycle 1 and day 1 of cycles 2 through 6. Prophylaxis for infusion-related reactions and tumor lysis syndrome include fluid intake and premedication with allopurinol, acetaminophen, antihistamines, and glucocorticoids. Overall response (OR) rates of 77%, CR rates of 27.2%, and PFS of 27.2 months are expected with C/O in this situation.18 Chlorambucil may cause myelosuppression and gastrointestinal toxicity and obinutuzumab alone is effective if chlorambucil must be held.19 For very unfit frail patients, options also include single agent chlorambucil at lower doses and glucocorticoids.15 At the time of writing this guideline, venetoclax plus obinotuzumab as first-line treatment for patients who are not eligible for fludarabine-based therapy has been approved by Health Canada and will likely be an option in the near future.
      3. Initial treatment of unmutated IGHV patients: Such patients are less susceptible to cytotoxic chemotherapy, meaning they will be subjected to mutagenic toxicity without the possibility of a long-term remission. A prospective randomized trial of 529 previously untreated CLL patients compared ibrutinib and rituximab followed by ibrutinib maintenance in 354 patients versus six cycles of FCR in 175 patients.20 PFS was significantly longer with ibrutinib (90.7% vs. 62.5% at 3 years) for patients with unmutated IGHV disease but no different than FCR for IGHV mutated patients. In another prospective trial of 547 previously untreated patients assigned randomly to a chemotherapeutic regimen versus ibrutinib alone versus ibrutinib plus rituximab, there was no difference between PFS and OS of the two ibrutinib groups.28 Accordingly, ibrutinib at 420 mg daily until progression is recommended for such patients and funded by CCO.
      4. Treatment of patients with TP53 deletions and/or mutations: 5-10% of patients have TP53 aberrations at the time of first treatment. Chemoimmunotherapy yields short PFS and OS and is not recommended for these patients.21 Ibrutinib is the treatment of choice as it produces an OR rate, cumulative incidence of progression at 2-years, and estimated 2-year OS of 84%, 97%, 9%, and 97%, respectively.21 Idelalisib combined with rituximab is also approved by CCO and a suitable alternative when ibrutinib is deemed inappropriate, such as in the presence of significant cardiac disease or with concomitant use of vitamin K antagonists.22 Patients on idelalisib should be given PJP prophylaxis. Regular clinical and laboratory (eg. monthly) monitoring for CMV is recommended in patients with a history of CMV infection or positive CMV serology at the start of treatment with idelalisib.22 Venetoclax and acalabrutinib are also likely to soon be available in Ontario for these patients.

  5. Response Assessment

    Response assessment is based on evaluation of the blood and bone marrow and physical examination of lymph nodes around 2 months after completing treatment according to IWCLL guidelines.1 CT scans can be used to assess response but are required mainly for clinical trials.

    • Complete responses (CRs) require normalization of lymphocytosis (circulating lymphocytes below 4x109/L) and cytopenias, decrease in all lymph nodes below 1.5 cm, decrease in spleen size below 13 cm, improvement in constitutional symptoms, and clearance of CLL cells from the bone marrow. To define a CR, the cytological or pathological evaluation of the bone marrow smear or biopsy must be at least normocellular for age, without evidence for typical CLL lymphocytes by morphological criteria. This evaluation is not based on a flow cytometry–based MRD assessment.
    • Some patients fulfill criteria for a CR but have persistent cytopenias apparently related to drug toxicity and not CLL. These patients should be classed as CR with incomplete marrow recovery (CRi). Partial responses (PRs) require a 50% or greater decrease in blood lymphocytes, lymphadenopathy, and splenomegaly compared to pre-treatment values with no increase in lymph node size >1.5 cm. Abnormal Hb and platelet values prior to treatment must also increase by 50% without transfusions or erythropoietin support.
    • Progressive disease (PD) during or after therapy occurs if there is an appearance of a new lymph node >1.5 cm, an increase in previous lymphadenopathy or spleen size of 50%, occurrence of neutropenia, anemia, or thrombocytopenia attributable to CLL and unrelated to autoimmune cytopenias, or an increase in blood lymphocytes by >50% with at least 5x109/L B lymphocytes.
    • Patients who have not achieved a CR or PR, and who have not exhibited PD, are considered to have stable disease (SD), which is equivalent to a non-response.
    • Similar response criteria are used for BTK inhibitors with the exception that lymphocytosis is not the sole criteria for progression as it represents an on-target effect of this class of drugs7 and may persist for a number of years. In such cases, a partial response to a BTK inhibitor based on changes in lymphadenopathy and improvement in cytopenias is characterized as a PR with lymphocytosis.

      Measurement of minimal residual disease (MRD)

      MRD at the end of CLL therapy may be measured by multiparameter flow cytometry or allele-specific polymerase chain reaction to detect 1 leukemic cell in 10,000 leukocytes (0.01% level). MRD is a powerful prognostic tool that predicts time to next therapy and OS in many studies12 but is not readily available in Ontario at this time.

  6. Follow-up

    Management of CLL patients after treatment reverts to the "watch and wait" approach with frequency of clinic visits based on the expected duration of response. Patients with a CR might be seen every 6 months or longer while patients with incomplete responses should probably be seen every 3-4 months as they are likely to soon develop symptomatic disease. Indications for second-line treatment are the same as first-line treatment described above.

  7. Second line therapy

    Prior to instituting second-line treatment, it should be confirmed the problem remains CLL and is not another blood cancer. FISH testing can be repeated but is more to estimate PFS as the major choices for relapsed disease (i.e. BTK inhibitors vs. venetoclax) work well despite a TP53 abnormality. Even if an initial response lasted several years, retreatment with chemoimmunotherapy is generally not indicated as the second response will be shorter and lead to more mutagenicity and second cancers. Choices for second-line treatment are dependent on the nature of the first-line treatment.

    1. Mutated IGHV patients: CCO funded options for second-line treatment for IGHV mutated patients include:

      1. Ibrutinib (420 mg daily until progression)
        3 year PFS is around 60% but shorter (around 40 months) in patients with complex karyotypes (>3 cytogenetic abnormalities), TP53, SF3B1, and XPO1 mutations, more than 2 previous treatments, and baseline b2-microglobulin levels >3.5 mg/L. PFS is not reached after 4 years in patients without these factors.7 However, the CRi rate is only 9%. In addition to disease progression, many patients (12%) discontinue treatment due to adverse effects including atrial fibrillation.7
      2. Venetoclax plus rituxan (venetoclax (400 mg daily) plus rituxan x 6 cycles and then venetoclax for a total of 2 years).
        PFS at 4 years is also around 60%. CR rates are much higher than with ibrutinib and nearly 50% of patients do not have detectable disease at the end of treatment.12
      3. Acalabrutinib (200 mg BID until progression)
        Acalabrutinib is touted to have similar efficacy to ibrutininb with fewer side-effects.23 Acalabrutinib is available on a compassionate program and expected to be CCO-funded in a couple of years.

        Ibrutinib and venetoclax appear to have equivalent efficacy in patients who relapse after chemoimmunotherapy. The choice between these agents depends on patient preference and comorbidities. In patients with significant cardiovascular disease, on anticoagulants, or with a high risk of bleeding, venetoclax may be more appropriate than ibrutinib. Ibrutinib may be more appropriate for patients with significant tumor bulk (>10 cm lymph nodes) as they can develop tumor lysis syndrome with venetoclax, although this risk can be amelioriated by prior debulking with glucocorticoids. A major advantage of venetoclax is that it is time-limited, in contrast to ibrutinib or acalabrutinib that must be taken continuously until disease progression.

        Idelalisib with rituximab is also approved for relapsed CLL but the associated toxicities make it less attractive than the other options.22

    2. Unmutated IGHV and disrupted TP53 patients:
      If these patients were treated first-line with chemoimmunotherapy, venetoclax, ibrutinib, or acalabrutinib remain treatment options for relapsed disease. However, if patients develop progressive disease on ibrutinib, this drug is no longer an option. It seems unlikely acalabrutinib will be of much use in this situation and idelalisib is not funded for ibrutinib-resistant disease. Accordingly venetoclax and rituxan is recommended in this situation. However PFS for ibrutinib-resistant CLL cells may not be as long as for ibrutinib-naïve cells and there are no funded options for progressive CLL once ibrutinib and venetoclax are no longer effective. Use of venetoclax plus rituxan in this situation should be considered a bridge to allo-transplant for eligible patients with a suitable donor.

  8. Beyond second-line

    IGHV mutated patients who progress on second-line ibrutinib should be treated with venetoclax and rituxan and considered for allo-SCT if suitable. For patients who have progressed on both a BTK-inhibitor and venetoclax, there is no accepted third-line treatment. Possibilities include chimeric antigen receptor (CAR) T-cells, the PI3K inhibitor duvelisib, lenalidomide, involved-field radiation, alemtuzumab, and high-dose glucocorticoids.23

  9. Supportive care

    occur in the "watch and wait" phase.14 All patients should be counseled about their risk of infections and to have seasonal influenza and pneumococcal vaccinations.15 Patients with reduced IgG (<5 g/l) and recurrent infections who have failed a 3-month trial of broad spectrum prophylactic antibiotic (according to local antimicrobial protocols) should be offered immunoglobulin replacement therapy (IRT).15 Use of subcutaneous immunoglobulin (SCIG) is generally preferred over intravenous immunoglobulin (IVIG) as trough IgG levels are more stable and to conserve transfusion clinic resources.

    Cancer screening: CLL patients are at increased risk of non-hematologic malignancy including skin cancers and should be encouraged to follow age-appropriate cancer screening and discuss with their family physician a need for yearly full body skin exams by dermatology.3,15

    Transfusion Considerations:
    The following patients with CLL require irradiated red blood cells and platelets:

    • Allogeneic stem cell transplant recipients starting at time of conditioning regimen
    • Prior or current treatment with a purine analog (fludarabine, cladribine, clofarabine, nelarabine, pentostatin), anti-thymocyte globulin (ATG), alemtuzumab or bendamustine for 1 year after last dose

    Patients with autoimmune hemolytic anemia require specially matched blood cells

  10. Special situations

    1. Richter’s transformation: Richter’s transformation is the development of an aggressive B-cell neoplasm in CLL patients. The most common histology is diffuse large B-cell lymphoma (DLBCL) with Hodgkin’s disease occurring in around 10% of cases.24 If DLBCL is not clonally related to the CLL clone, it may respond to R-CHOP as successfully as primary DLBCL. If DLBCL arises from the CLL clone, the prognosis is much poorer. Treatment with R-CHOP or infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) may be appropriate, especially if the patient has not previously been exposed to such drugs in the course of CLL treatment. Patients who respond to these treatments should be offered allo-SCT if they are suitable candidates. PD1 inhibitor therapy may have activity in some cases but is not funded in Ontario.25 Palliative care may be the best approach for less fit patients. For transformation to Hodgkin’s disease, ABVD remains the standard of care. Outcomes are better for this form of Richter’s transformation but significantly worse than for de novo Hodgkin’s disease.26
    2. Autoimmune hemolytic anemia (AIHA) and thrombocytopenia (ITP): These cytopenias occur in ~5–10% CLL patients27 and respond to corticosteroids, splenectomy, or single-agent rituximab in the absence of significant CLL tumor burden. When CLL therapy is indicated or when the cytopenias are refractory to first-line therapy, treatment with C/O is often very effective.27

      Useful links: 

References

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