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 B-cell lymphoma-2 (BCL-2), with or without chemotherapy.
(See also Overview of Leukemia.)
Chronic lymphocytic leukemia is the most common type of leukemia in the Western world. In the United States in 2025 there were approximately 23,690 new cases of CLL and approximately 4460 deaths; most cases and almost all deaths were in adults. The average age of a patient with CLL is 70 years; CLL is extremely rare in children. In the United States, the average lifetime risk of CLL in both sexes is approximately 0.5% (1 in 200) (1).
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 (2). CLL is more common among people with Ashkenazi Jewish ancestry (3).
General references
1. American Cancer Society. Key Statistics for Chronic Lymphocytic Leukemia (CLL). Accessed February 6, 2026.
2. Yang S, Varghese AM, Sood N, et al. P. Ethnic and geographic diversity of chronic lymphocytic leukaemia. Leukemia. 2021;35(2):433-439. doi: 10.1038/s41375-020-01057-5
3. Zada M, Lerner D, Piltz Y, et al. Familial chronic lymphocytic leukemia in Israel: A disproportionate distribution among Ashkenazi Jews. Eur J Haematol. 2017;99(1):51-55. doi: 10.1111/ejh.12889
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 immune thrombocytopenia.
Chronic lymphocytic leukemia can evolve into B-cell prolymphocytic leukemia and can transform to a higher grade nonHodgkin lymphoma. Approximately 2 to 10% of CLL cases develop into diffuse large B-cell lymphoma (called Richter syndrome) (1, 2, 3).
Pathophysiology references
1. Shadman M. Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Review. JAMA. 2023;329(11):918-932. doi:10.1001/jama.2023.1946
2. Jain N, Wierda WG, O'Brien S. Chronic lymphocytic leukaemia. Lancet. 2024;404(10453):694-706. doi:10.1016/S0140-6736(24)00595-6
3. Al-Sawaf O, Robrecht S, Bahlo J, et al. Richter transformation in chronic lymphocytic leukemia (CLL)-a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials. Leukemia. 2021;35(1):169-176. doi:10.1038/s41375-020-0797-x
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). Approximately 1 to 2% of monoclonal B-cell lymphocytosis cases progress to CLL per year (1, 2). Bone marrow aspirate and biopsy are not required for the diagnosis of CLL. However, if performed, 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 performed 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 ).
Clinical Staging of Chronic Lymphocytic Leukemia*
Classification and Stage | Description |
|---|---|
Rai | |
Stage 0 | Absolute lymphocytosis of > 10,000/mcL (> 10 × 109/L) in blood and ≥ 30% lymphocytes in bone marrow |
Stage I | Stage 0 plus enlarged lymph nodes |
Stage II | Stage 0–I plus hepatomegaly or splenomegaly |
Stage III | Stage 0–II plus anemia with hemoglobin < 11 g/dL (< 110 g/L) |
Stage IV | Stage 0–III plus thrombocytopenia with platelet counts <100,000/mcL (< 100 × 109/L) |
Binet | |
Stage A | Absolute lymphocytosis of > 10,000/mcL (> 10 × 109/L) in blood and ≥ 30% lymphocytes in bone marrow Hemoglobin ≥ 10 g/dL ( ≥ 100 g/L) Platelets ≥100,000/mcL (≥ 100 × 109/L) ≤ 2 involved sites* |
Stage B | As for stage A, but 3–5 involved sites |
Stage C | As for stage A or B, but hemoglobin < 10 g/dL (< 100 g/L) or platelets < 100,000/mcL (100 × 109/L) |
* Sites considered: Cervical, axillary, and inguinal lymph nodes; liver; and spleen. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46(2):219-234. Blood. 2016;128(17):2109. doi:10.1182/blood-2016-08-737650 Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48(1):198-206. doi:10.1002/1097-0142(19810701)48:1<198::aid-cncr2820480131>3.0.co;2-v | |
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. doi: 10.1056/NEJMoa075290
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. 2023;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 available therapy; treatment is aimed at symptom amelioration with attempts to prolong survival. 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
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 (1). 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 (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 (2). The E1912 study examined the efficacy of treatment with FCR versus the combination of ibrutinib, an oral inhibitor of Bruton tyrosine kinase (BTK), and rituximab in patients < 70 years of age with previously untreated CLL( ). The E1912 study examined the efficacy of treatment with FCR versus the combination of ibrutinib, an oral inhibitor of Bruton tyrosine kinase (BTK), and rituximab in patients < 70 years of age with previously untreated CLL(3). The results demonstrated superior progression-free and overall survival in patients who received ibrutinib plus rituximab as compared to standard chemoimmunotherapy.
Other 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 (Other 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 (4). Given the advent of targeted therapy for use in upfront treatment of CLL, several studies have examined a "time limited" approach to treatment (5). The oral BCL-2 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 (). The oral BCL-2 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 (6). 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 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 lengthen 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) in combination with rituximab 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.In patients who received upfront chemoimmunotherapy, treatment with a BTK inhibitor can improve response rate and lengthen 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) in combination with rituximab 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. 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 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 (7) and zanubrutinib (8, 9) 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 (8, 9).
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, a noncovalent reversible BTK inhibitor, is available for treatment of relapsed CLL after failure of ≥ 2 prior therapies, including a BTK inhibitor and BCL-2 inhibitor (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, a noncovalent reversible BTK inhibitor, is available for treatment of relapsed CLL after failure of ≥ 2 prior therapies, including a BTK inhibitor and BCL-2 inhibitor (10). Resistance to covalent BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) often arises from the C481S mutation, which prevents irreversible binding. However, pirtobrutinib retains potent activity against both wild-type BTK and C481-mutant BTK. Lisocabtagene maraleucel, a type of cell therapy that produces autologous anti-CD19 targeting ). Resistance to covalent BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) often arises from the C481S mutation, which prevents irreversible binding. However, pirtobrutinib retains potent activity against both wild-type BTK and C481-mutant BTK. Lisocabtagene maraleucel, a type of cell therapy that produces autologous anti-CD19 targetingchimeric antigen receptor T (CAR-T) cells, has also shown efficacy when combined with the BTK inhibitor venetoclax, leading to long-term remissions in some "double-refractory" patients ((CAR-T) cells, has also shown efficacy when combined with the BTK inhibitor venetoclax, leading to long-term remissions in some "double-refractory" patients (11).
Allogeneic stem cell transplantation should be considered for patients who are fit and whose leukemia is refractory to novel combinations of targeted therapies with immunotherapies and emerging cellular therapies.
Treatment references
1. Shadman M. Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Review. JAMA. 2023;329(11):918-932. doi:10.1001/jama.2023.1946
2. 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. 2016;17(7):928-942. doi: 10.1016/S1470-2045(16)30051-1
3. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443. doi: 10.1056/NEJMoa1817073
4. 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. 2020;395(10232):1278-1291. doi: 10.1016/S0140-6736(20)30262-2
5. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia. N Engl J Med. Published online December 6, 2025. doi:10.1056/NEJMoa2515458
6. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi: 10.1056/NEJMoa1815281
7. 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. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355
8. 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
9. 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. 2023;41(5):1035-1045. doi:10.1200/JCO.22.00510
10. Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(1):33-44. doi:10.1056/NEJMoa2300696
11. 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. 2023;402(10402):641-654. doi:10.1016/S0140-6736(23)01052-8
Prognosis for CLL
The natural history of chronic lymphocytic leukemia is highly variable. Survival ranges from approximately 2 to > 20 years, with a median of approximately 10 years. Patients presenting as Rai stage 0 to II may survive for 5 to 20 years without treatment (1).
Risk stratification of CLL is based on the following clinical and genetic factors:
Age: Younger patients (age < 65 years) generally have better tolerance of therapy and longer survival.
Performance status
Lymphocyte doubling time: 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.
Serum beta-2 microglobulin: > 3.5 mg/L (297 nmol/L)
Rai and Binet staging: Early-stage (Rai 0; Binet A) have favorable prognosis; advanced-stage (Rai III to IV; Binet C) have poor prognosis
Immunoglobulin heavy chain variable region (IGHV) mutation status: IGHV-unmutated CLL often presents with more aggressive disease, shorter duration of complete remission time after first treatment and, in general, carries inferior overall survival compared with IGHV-mutated CLL (2, 3).
Karyotyping and mutations: del(17p)/TP53 deletion or TP53 mutation (with or without 17p deletion) has very poor prognosis and is associated with resistance to chemoimmunotherapy; del(11q) carries unfavorable prognosis and is often associated with bulky lymphadenopathy; trisomy 12 carries intermediate prognosis; del(13q) as sole abnormality carries favorable prognosis; normal fluorescence in situ hybridization (FISH) is considered intermediate prognosis.
High expression of ZAP70 is associated with higher risk disease.
NOTCH1 and/or SF3B1-mutated disease is associated with more rapid disease progression.
The CLL International Prognostic Index (CLL-IPI) is a risk stratification tool that takes into consideration clinical staging as well as biochemical and genetic markers to provide treatment recommendations based on risk category (see table ) (4).
Chronic Lymphocytic Leukemia International Prognostic Index
Risk Category* | Points | Treatment |
|---|---|---|
Low risk | (0–1 points) | No treatment recommended |
Intermediate risk | (2–3 points) | No treatment recommended, unless patient is symptomatic |
High risk | (4–6 points) | Treatment recommended, unless the patient is asymptomatic |
Very high risk | 7–10 points | Treatment with novel agents or in a clinical trial (preferred over chemotherapy) |
CLL-IPI Prognostic Factor Point Value: Age > 65 years = 1 point; CLL-IPI Prognostic Factor Point Value: Rai stage I-IV or Binet stage B-C = 1 point; Unmutated IGHV = 2 points; serum beta-2 microglobulin > 3.5 mg/L = 2 points; TP53 mutation or deletion 17p = 4 points. * For each CLL-IPI risk category, the overall survival (without treatment) at 5 years (p < 0.001 for all) is estimated to be: low-risk: 93% (95% CI 91-96); intermediate risk: 79% (95% CI 76-83); high risk: 63% (95% CI 58-69); very-high risk: 23% (95% CI 13-34) CLL = chronic lymphocytic leukemia; IGHV = immunoglobulin heavy chain variable region; IPI = international prognostic index. International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779-790. doi:10.1016/S1470-2045(16)30029-8 | ||
Prognosis references
1. American Cancer Society. Key Statistics for Chronic Lymphocytic Leukemia (CLL). February 6, 2026.
2. Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94(6):1840-1847.
3. Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848-1854.
4. International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779-790. doi:10.1016/S1470-2045(16)30029-8
Key Points
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy involving mature lymphocytes, which predominantly affects older adults.
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 and targeted therapy decrease symptoms and prolong 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
