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Chronic Lymphocytic Leukemia (CLL)

By

Ashkan Emadi

, MD, PhD, University of Maryland;


Jennie York Law

, MD, University of Maryland, School of Medicine

Reviewed/Revised Oct 2023 | Modified Nov 2023
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Topic Resources

Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow, spleen, and lymph nodes. Symptoms and signs may be absent or may include lymphadenopathy, splenomegaly, hepatomegaly, fatigue, fevers, night sweats, unintentional weight loss, and early satiety. Diagnosis is by flow cytometry and immunophenotyping of peripheral blood. Treatment is delayed until symptoms develop and generally involves chemotherapy and immunotherapy. However, treatments are evolving, and first-line regimens may include targeted agents such as inhibitors of Bruton tyrosine kinase (Btk) and Bcl-2, with or without chemotherapy.

Chronic lymphocytic leukemia is the most common type of leukemia in the Western world. The American Cancer Society estimates that in the United States in 2023 there will be almost 19,000 new cases of CLL and about 4500 deaths; most cases and almost all deaths will be in adults. The average age of a patient with CLL is 70 years; CLL is extremely rare in children. In the US, the average lifetime risk of CLL in both sexes is about 0.57% (1 in 175).

Although the cause of CLL is unknown, some cases appear to have a hereditary component. CLL is rare in Japan and China, and the incidence does not seem to be increased among people who are of Japanese descent living in the United States, suggesting the importance of genetic factors. CLL is more common among people with Ashkenazi Jewish ancestry.

Pathophysiology of CLL

In chronic lymphocytic leukemia, CD5+ B cells undergo malignant transformation. The B cells become continuously activated by acquisition of mutations that lead to monoclonal B-cell lymphocytosis (MBL). Further accumulation of genetic abnormalities and subsequent oncogenic transformation of monoclonal B cells leads to CLL. Lymphocytes initially accumulate in the bone marrow and then spread to lymph nodes and other lymphoid tissues, eventually inducing splenomegaly, hepatomegaly, and systemic symptoms such as fatigue, fever, night sweats, early satiety, and unintentional weight loss.

As CLL progresses, abnormal hematopoiesis results in anemia, neutropenia, thrombocytopenia, and decreased immunoglobulin production. Hypogammaglobulinemia can develop in up to two thirds of patients, increasing risk for infectious complications. Patients have increased susceptibility to autoimmune hemolytic anemia (with a positive direct antiglobulin test) and autoimmune thrombocytopenia.

CLL can evolve into B-cell prolymphocytic leukemia and can transform to a higher grade non-Hodgkin lymphoma Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the... read more Non-Hodgkin Lymphomas . About 2 to 10% of CLL cases develop into diffuse large B-cell lymphoma (called Richter's transformation).

Symptoms and Signs of CLL

Patients are often asymptomatic early on, with insidious onset of nonspecific symptoms (eg, fatigue, weakness, anorexia, weight loss, fever, and/or night sweats) that may prompt evaluation. More than 50% of patients have lymphadenopathy. Lymphadenopathy can be localized (with cervical and supraclavicular nodes being the most commonly involved) or generalized. Splenomegaly and hepatomegaly are less common than lymphadenopathy. Skin involvement (see photo ) is rare.

Diagnosis of CLL

  • Complete blood count (CBC) and peripheral smear

  • Flow cytometry of peripheral blood

  • Immunophenotyping

The diagnosis of chronic lymphocytic leukemia is first suspected when an absolute peripheral lymphocytosis of > 5000/mcL (> 5 × 109/L)) is found. Peripheral blood flow cytometry can confirm clonality in circulating B cells. The circulating lymphocytes should express CD5, CD19, CD20, CD23, and kappa or lambda light chains. Patients with an absolute lymphocyte count < 5000/mcL (< 5 × 109/L) but evidence of clonality are diagnosed with monoclonal B cell lymphocytosis (MBL). About 1 to 2% of monoclonal B-cell lymphocytosis cases progress to CLL per year (1, 2 Diagnosis references Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more ). Bone marrow aspirate and biopsy are not required for the diagnosis of CLL. However, if done, the marrow often demonstrates > 30% lymphocytes.

Other findings at diagnosis can include hypogammaglobulinemia (< 15% of cases), elevated lactate dehydrogenase (LDH), elevated uric acid, elevated hepatic enzymes, and rarely, hypercalcemia. Cytogenetic and molecular studies done from a peripheral blood sample at the time of diagnosis help in determining prognosis.

Classification uses the Rai or Binet staging systems. Neither system effectively predicts early disease progression. Routine imaging is not recommended for initial staging (see table ).

Table

Diagnosis references

  • 1. Rawstron AC, Bennett FL, O'Connor SL, et al: Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med 359(6):575–583, 2008.

  • 2. Semenzato G, Ghobrial IM, Ghia P: Monoclonal B-cell lymphocytosis, monoclonal gammopathy of undetermined significance, and T-cell clones of uncertain significance: are these premalignant conditions sharing a common identity? Lancet Haematol 10(7):e549–e556, 2023. doi:10.1016/S2352-3026(23)00086-8

Treatment of CLL

  • Chemoimmunotherapy, targeted therapy, and sometimes radiation therapy

  • Supportive care

Chronic lymphocytic leukemia is considered incurable with the current standard of care; treatment is aimed at symptom amelioration. Thus, treatment is withheld until patients have one of the following:

  • Symptoms attributed to CLL

  • Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period

  • Lymphocyte doubling time (increase of ≥ 100%) < 6 months

Symptoms that prompt treatment in patients with CLL include

  • Constitutional symptoms (fever, night sweats, extreme fatigue, weight loss)

  • Significant hepatomegaly, splenomegaly, or lymphadenopathy

  • Recurrent infections

  • Symptomatic anemia and/or thrombocytopenia

Disease-directed treatment options include

  • Chemoimmunotherapy

  • Targeted therapy

  • Radiation therapy

Supportive care includes

  • Transfusion of packed red blood cells for anemia

  • Platelet transfusions for bleeding associated with thrombocytopenia

  • Antimicrobials for bacterial, fungal, or viral infections

Because neutropenia and hypogammaglobulinemia limit bacterial killing, antibiotic therapy should be bactericidal. Gamma-globulin infusions should be considered for treatment in patients with hypogammaglobulinemia and refractory infections or for prophylaxis when 2 severe infections occur within 6 months.

Initial therapy

The intent of initial therapy is to

  • Relieve symptoms

  • Induce durable remissions

  • Prolong survival

Patients are observed until symptoms develop at which point treatment consists of a targeted therapy in combination with a monoclonal antibody directed against B cells.

Studies have suggested that targeted therapy is as efficacious if not superior to upfront chemoimmunotherapy for most patients. Selection of initial therapy depends on patient characteristics, disease-specific features such as presence of del(17p), and the overarching goals of therapy.

Previously, purine analogs (eg, fludarabine) as well as alkylating agents (eg, bendamustine, chlorambucil, cyclophosphamide) have been used in combination with the anti-CD20 monoclonal antibody, rituximab. The combination of fludarabine, cyclophosphamide, and rituximab (FCR) was the prior standard of care for upfront treatment in most medically fit patients. In the past, older untreated patients were offered bendamustine and rituximab as this regimen was easier to tolerate (1 Treatment references Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more ). The landmark E1912 study examined the efficacy of treatment with FCR versus the novel combination of ibrutinib, an oral inhibitor of Bruton tyrosine kinase (Btk) and rituximab in patients < 70 years of age with previously untreated CLL. The results demonstrated superior progression-free and overall survival in patients who received ibrutinib plus rituximab as compared to standard chemoimmunotherapy (2 Treatment references Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more ).

More recent trials in treatment-naive patients suggest that the combination of acalabrutinib, a second-generation oral Btk inhibitor and obinutuzumab, a glycoengineered monoclonal antibody against CD20, is as efficacious and potentially better tolerated than conventional chemoimmunotherapy (3 Treatment references Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more ). Given the advent of targeted therapy for use in upfront treatment of CLL, several studies have examined a "time limited" approach to treatment. The oral Bcl2 inhibitor venetoclax (an oral inhibitor of Bcl-2) has been used in combination with obinutuzumab to effectively treat patients for a fixed duration of 12 months (4 Treatment references Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more ). More research is needed regarding use of monitoring minimal residual disease (MRD) in CLL and how MRD changes may guide treatment resumption.

Relapsed or refractory CLL

Relapsed or refractory CLL should be confirmed histologically before restarting treatment. Transformation to large cell lymphoma (Richter's transformation) should be specifically excluded. Asymptomatic patients with recurrent CLL are monitored closely for symptoms that warrant treatment. Factors that influence choice of treatment at relapse include

  • Initial therapy used

  • Initial duration of response

In patients who received upfront chemoimmunotherapy, treatment with a Btk inhibitor can improve response rate and progression-free survival in relapsed or refractory CLL. Btk inhibitors are continued until toxicity develops or disease progresses. Other effective targeted therapies for relapsed CLL included idelalisib (an oral inhibitor of phosphoinositide 3'-kinase [PI3K] delta) and venetoclax. Venetoclax can be used for patients with del(17p) who have received at least one prior therapy. The advent of upfront targeted therapy may make selection of optimal therapy challenging in patients with relapsed CLL. When applicable, clinical trial enrollment is encouraged.

Monotherapy with an anti-CD20 monoclonal antibody (rituximab, ofatumumab, obinutuzumab) may transiently palliate symptoms.

Acalabrutinib and zanubrutinib covalently inhibit the Btk enzyme but have less off target effects than ibrutinib on the non-Btk targets, and their use therefore results in fewer adverse effects. Acalabrutinib (5 Treatment references Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more ) and zanubrutinib (6, 7 Treatment references Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more ) have been shown in head-to-head randomized trials to have improved tolerability, lower discontinuation rates, and better safety profiles compared to ibrutinib. Zanubrutinib also showed improved efficacy compared to ibrutinib in patients with relapsed CLL, including in those with high-risk disease (6, 7 Treatment references Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more ).

Patients with relapsed CLL after Btk inhibitors and venetoclax ("double refractory ") have poor clinical outcomes, and development of therapeutic options for these patients is an unmet clinical need. Pirtobrutinib is a selective and non-covalent Btk inhibitor with efficacy in such patients (8 Treatment references Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more ). Lisocabtagene maraleucel, an autologous anti-CD19 targeting chimeric antigen receptor T Modified T cells Systemic cancer therapy includes chemotherapy (ie, conventional or cytotoxic chemotherapy), hormone therapy, targeted therapy, and immune therapy (see also Overview of Cancer Therapy). The number... read more (CAR-T) cells, has also shown efficacy in patients after treatment with covalent Btk inhibitor/venetoclax with long-term remissions observed in some "double-refractory" patients (9 Treatment references Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more ).

Radiation therapy

Palliative irradiation may be given to areas of lymphadenopathy or for liver and spleen involvement that does not respond to chemotherapy. Total body irradiation in small doses is occasionally successful in temporarily relieving symptoms.

Treatment references

  • 1. Eichhorst B, Fink AM, Bahlo J et al: First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): An international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 17:928–942, 2016.

  • 2. Shanafelt TD, Wang XV, Kay NE, et al: Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med 381:432–443, 2019. doi: 10.1056/NEJMoa1817073

  • 3. Sharman JP, Egyed M, Jurczak W, et al: Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet 395(10232):1278–1291, 2020. doi: 10.1016/S0140-6736(20)30262-2

  • 4. Fischer K, Al-Sawaf O, Bahlo J, et al: Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 380(23):2225–2236, 2019. doi: 10.1056/NEJMoa1815281

  • 5. Ghia P, Pluta A, Wach M, et al: ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 38(25):2849–2861, 2020. doi:10.1200/JCO.19.03355

  • 6. Brown JR, Eichhorst B, Hillmen P, et al: Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 388(4):319–332, 2023. doi:10.1056/NEJMoa2211582

  • 7. Hillmen P, Eichhorst B, Brown JR, et al: Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: Interim analysis of a randomized phase III trial. J Clin Oncol 41(5):1035–1045, 2023. doi:10.1200/JCO.22.00510

  • 8. Mato AR, Woyach JA, Brown JR, et al: Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med 389(1):33–44, 2023. doi:10.1056/NEJMoa2300696

  • 9. Siddiqi T, Maloney DG, Kenderian SS, et al: Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet 402(10402):641–654, 2023. doi:10.1016/S0140-6736(23)01052-8

Prognosis for CLL

The natural history of chronic lymphocytic leukemia is highly variable. Survival ranges from about 2 to > 20 years, with a median of about 10 years. Patients presenting as Rai stage 0 to II may survive for 5 to 20 years without treatment.

Other prognostic features of CLL include

  • Lymphocyte doubling time

  • Specific genetic abnormalities

Lymphocyte doubling time is the number of months it takes the absolute lymphocyte count to double. Untreated patients with a lymphocyte doubling time < 12 months have a more aggressive clinical course.

Specific high-risk cytogenetic abnormalities include del(17p) and del(11q). Other adverse prognostic features include an unmutated immunoglobulin heavy chain variable gene, presence of CD38 on flow cytometry, and expression of ZAP-70.

Key Points

  • Chronic lymphocytic leukemia (CLL) is an indolent lymphoproliferative malignancy involving mature lymphocytes, which predominantly affects older individuals.

  • CLL is the most common type of leukemia in the Western world.

  • Natural history is highly variable.

  • Treatment is generally not curative and so is not initiated until symptoms develop.

  • Chemoimmunotherapy decreases symptoms and prolongs survival.

More Information

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

Drugs Mentioned In This Article

Drug Name Select Trade
Fludara, Oforta
BELRAPZO, BENDEKA, Treanda, VIVIMUSTA
Leukeran
Cyclophosphamide, Cytoxan, Neosar
RIABNI, Rituxan, RUXIENCE, truxima
Imbruvica
CALQUENCE
GAZYVA
Venclexta, VENCLEXTA Starting Pack
ZYDELIG
Arzerra, Kesimpta
BRUKINSA
Jaypirca
BREYANZI
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