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Chronic lymphocytic leukemia



CLL is a lymphoproliferative malignancy characterized by peripheral lymphocytosis due to the proliferation of clonal B cells.
CLL is caused by somatic gene mutations involving multipotent and self-renewing hematopoietic stem cells, which leads to clonal proliferation and accumulation of mature B cells.
The incidence of CLL in the US is estimated at 4.83 per 100,000 person-years.
Disease course
Accumulation of B cells in the bone marrow, blood, lymph nodes, and spleen can result in cytopenias, lymphadenopathy, splenomegaly, hepatomegaly, susceptibility to infection, bone marrow failure, and death.
Prognosis and risk of recurrence
The overall survival at 5-years for patients with low-risk, intermediate-risk, high-risk, and very-high risk CLL is 93.2%, 79.4%, 63.6%, and 23.3%, respectively.


Key sources

The following summarized guidelines for the evaluation and management of chronic lymphocytic leukemia are prepared by our editorial team based on guidelines from the British Society for Haematology (BSH 2022,2018), the European Society of Medical Oncology (ESMO 2021), the International Workshop on Chronic Lymphocytic Leukemia (iwCLL 2018), and the American Academy of Family Physicians (AAFP 2014). ...
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Screening and diagnosis

Indications for screening: as per ESMO 2021 guidelines, do not obtain routine screening for CLL in the general population nor in relatives of patients with CLL.
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  • Diagnostic criteria

  • Patients with Richter's transformation (biopsy)

  • Differential diagnosis

Diagnostic investigations

History and physical examination: as per ESMO 2021 guidelines, elicit history and perform physical examinations, including careful palpation of all lymph node areas, spleen, and liver, in asymptomatic patients with early-stage disease,
as well as before initiating treatment in patients with advanced or symptomatic stage disease.

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  • Laboratory testing

  • Screening for viral infections

  • Diagnostic imaging

Diagnostic procedures

As per ESMO 2021 guidelines:
Consider performing lymph node biopsy and/or bone marrow biopsy if immunophenotyping is not conclusive for the diagnosis of CLL.
Consider performing bone marrow examination for the diagnostic evaluation of unclear cytopenia or in the presence of a non-conclusive phenotype before initiating treatment in patients with advanced or symptomatic stage disease. Consider performing a bone marrow biopsy as a baseline parameter to assess treatment response.

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  • Cytogenetic analysis

Medical management

General principles
As per BSH 2018 guidelines:
Decide on treatment choice and aims in discussion with the patient and a CLL expert
and based on the patient's wishes, comorbidities, and potential drug side effects.
Offer the opportunity to participate in a clinical trial, where available, in all patients with CLL.

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  • Watchful waiting

  • Indications for treatment

  • Initial treatment

  • CAR therapy

  • Management of cytopenias

  • Management of hypogammaglobulinemia

  • Management of tumor lysis syndrome

  • Management of infection

Therapeutic procedures

Stem cell transplantation: as per BSH 2022 guidelines, consider offering allo-SCT in suitable patients with high-risk CLL defined by either of the following:
failed two out of chemoimmunotherapy, B-cell receptor inhibitors or BCL-2 inhibitors irrespective of TP53 status
failed either B-cell receptor inhibitors or BCL-2 inhibitors therapy and harboring a TP53 disruption.

Specific circumstances

Frail patients: as per BSH 2018 guidelines, consider offering chlorambucil monotherapy in extremely frail patients intolerant to anti-CD20 antibodies or when IV therapy is deemed unsuitable. Consider offering corticosteroid monotherapy.
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  • Patients with chronic hepatitis B or C

  • Patients with CMV infection

  • Patients with autoimmune hemolytic anemia or immune thrombocytopenia

  • Patients with COVID-19 infection

  • Patients with Richter's transformation (biopsy)

  • Patients with Richter's transformation (mutational analysis)

  • Patients with Richter's transformation (screening for viral infections)

  • Patients with Richter's transformation (enrollment in clinical trials)

  • Patients with Richter's transformation (systemic therapy)

  • Patients with Richter's transformation (stem cell transplantation)

  • Patients with Richter's transformation (palliative care)

Preventative measures

Routine immunizations: as per BSH 2022 guidelines, offer routine immunizations at diagnosis in all patients, keep a vaccine logbook, and avoid administering live vaccines.
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  • Antimicrobial prophylaxis

Follow-up and surveillance

Assessment of treatment response
As per ESMO 2021 guidelines:
Obtain response assessment with a careful physical examination and blood cell count. Perform a bone marrow biopsy and obtain minimal residual disease assessment to define complete remission and minimal residual disease status within clinical trials,
as well as obtain CT.
Do not obtain routine minimal residual disease measurement, except after allo-SCT.

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  • Management of relapsed/refractory disease

  • Surveillance for malignancy