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Incidence and Mortality
Estimated new cases and deaths from CLL in the United States in 2020:
CLL is a disorder of morphologically mature but immunologically less mature lymphocytes and is manifested by progressive accumulation of these cells in the blood, bone marrow, and lymphatic tissues.
Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.
The clinical course of this disease progresses from an indolent lymphocytosis without other evident disease to one of generalized lymphatic enlargement with concomitant pancytopenia. Complications of pancytopenia, including hemorrhage and infection, represent a major cause of death in these patients. Immunological aberrations, including Coombs-positive hemolytic anemia, immune thrombocytopenia, and depressed immunoglobulin levels may all complicate the management of CLL.
Diagnostic Evaluation and Differential Diagnosis
Tests and procedures used to diagnose CLL include the following:
In this disorder, lymphocyte counts in the blood are usually greater than or equal to 5,000/mm3 with a characteristic immunophenotype (CD5- and CD23-positive B cells).[6,7] As assays have become more sensitive for detecting monoclonal B-CLL–like cells in peripheral blood, researchers have detected a monoclonal B-cell lymphocytosis in 3% of adults older than 40 years and in 6% of adults older than 60 years. Such early detection and diagnosis may falsely suggest improved survival for the group and may unnecessarily worry or result in therapy for some patients who would have remained undiagnosed in their lifetime, a circumstance known in the literature as overdiagnosis or pseudodisease.[9,10]
Confusion with other diseases may be avoided by determination of cell surface markers. CLL lymphocytes coexpress the B-cell antigens CD19 and CD20 along with the T-cell antigen CD5. This coexpression occurs in only one other disease entity, mantle cell lymphoma. CLL B cells express relatively low levels of surface-membrane immunoglobulin (compared with normal peripheral blood B cells) and a single light chain (kappa or lambda). CLL is diagnosed by an absolute increase in lymphocytosis and/or bone marrow infiltration coupled with the characteristic features of morphology and immunophenotype, which confirm the characteristic clonal population. In a database analysis, for up to 77 months before diagnosis, almost all patients with a CLL diagnosis had prediagnostic B-cell clones that were identified in peripheral blood (when available).[7,13]
About 1% of morphologic CLL cases express T-cell markers (CD4 and CD7) and have clonal rearrangements of their T-cell receptor genes. These patients have a higher frequency of skin lesions, more variable lymphocyte shape, and shorter median survival (13 months) with minimal responses to chemotherapy and B-cell receptor inhibitors.
The differential diagnosis must exclude the following:
Cladribine (2-chlorodeoxyadenosine) appears to be an active agent (60% complete remission rate) for patients with de novo B-cell PLL.[Level of evidence: 3iiiDiv] Anecdotal responses have been seen with venetoclax.[Level of evidence: 3iiiDiv] Alemtuzumab, an anti-CD52 humanized monoclonal antibody, has been used for 76 patients with T-cell PLL after failure of previous chemotherapy (usually pentostatin or cladribine) with a 51% response rate (95% confidence interval, 40%–63%) and median time to progression of 4.5 months (range, 0.1–45.4 months).[Level of evidence: 3iiiDiv] These response rates have been confirmed by other investigators. Patients with CLL who show prolymphocytoid transformation maintain the classic CLL phenotype and have a worse prognosis than PLL patients.
Prognostic markers help stratify patients in clinical trials, assess the need for therapy, and select the type of therapy.[2,30,31] Prognostic factors that may help predict clinical outcome include cytogenetic subgroup, immunoglobulin mutational status, and CD38 immunophenotype.[2,32,33,34,35,36,37,38,39,40]
Prognostic markers include the following:
These findings emphasize the need for prospective studies of combinations of these prognostic markers.
Other prognostic factors include the following:
An international prognostic index (IPI) for CLL (CLL-IPI) identified four prognostic subgroups on the basis of IgVH mutational status, clinical stage, age (≤65 years vs. >65 years), and TP53 status (no abnormalities vs. del(17p) or TP53 mutation or both).
Follow-up After Treatment
CT scans have a very limited role in monitoring patients after completion of treatment; the decision to treat for relapse was determined by CT scan or ultrasound in only 2 of 176 patients in three prospective trials for the German CLL Study Group.
Chronic lymphocytic leukemia (CLL) does not have a standard staging system. The Rai staging system (Table 1) and the Binet classification (Table 2) are presented below.[1,2] A National Cancer Institute (NCI)-sponsored working group has formulated standardized guidelines for criteria related to eligibility, response, and toxic effects to be used in future clinical trials in CLL.
Rai Staging System
The Binet classification integrates the number of disease-involved nodal groups with bone marrow failure. Its major benefit derives from the recognition of a predominantly splenic form of the disease, which may have a better prognosis than was recognized in the Rai staging, and from the recognition that the presence of anemia or thrombocytopenia has a similar prognosis and does not merit a separate stage. Neither system separates immune from nonimmune causes of cytopenia. Patients with thrombocytopenia, anemia, or both, which is caused by extensive marrow infiltration and impaired production (Rai III/IV, Binet C), have a poorer prognosis than patients with immune cytopenias.
The International Workshop on CLL has recommended integrating the Rai and Binet systems as follows: A(0), A(I), A(II); B(I), B(II); and C(III), C(IV). The NCI-sponsored working group has published guidelines for the diagnosis and treatment of CLL in both clinical trial and general practice settings. Use of these systems allows comparison of clinical results and establishment of therapeutic guidelines.
Treatment of chronic lymphocytic leukemia (CLL) must be individualized on the basis of the clinical behavior of the disease. Because this disease is generally not curable, occurs in an elderly population, and often progresses slowly, it is most often treated in a conservative fashion.
In older trials with data collected from the 1970s through the 1990s, the median survival for all patients ranged from 8 to 12 years.[3,4] However, with the introduction of the B-cell receptor inhibitors and targeting of BCL2, the median survival for all patients has not been reached with over 10 years of follow-up.
Treatment of CLL ranges from observation with treatment of infectious, hemorrhagic, or immunologic complications to a variety of therapeutic options administered as single agents or combination therapy. In asymptomatic patients, treatment may be deferred until the disease progresses and symptoms occur. Because the rate of progression may vary from patient to patient, with long periods of stability and sometimes spontaneous regressions, frequent and careful observation is required to monitor the clinical course. Although even asymptomatic patients with del(17p) on fluorescence in situ hybridization (FISH) analysis (or TP53 mutation) may be followed with watchful waiting, frequent monitoring may be required to avert rapid progression. A meta-analysis of randomized trials showed no survival benefit for immediate versus delayed therapy for patients with early-stage disease.[Level of evidence: 1iiA] For patients with progressing CLL, treatment will not be curative in most cases. Selected patients treated with allogeneic stem cell transplantation have achieved prolonged disease-free survival (DFS); sometimes exceeding 20 years.[7,8,9,10,11] Prolonged DFS was also noted in young patients (<60 years) with IgVH hypermutation who received the FCR regimen (fludarabine, cyclophosphamide, and rituximab).[12,13,14]
The following clinical factors may be helpful in predicting progression of disease:
Symptomatic or progressive CLL is defined as the following by the International Workshop on Chronic Lymphocytic Leukemia:
Considerations for the Selection of Therapy
The following general principles may provide a sequencing for available therapeutic options:
Adverse Sequelae of the Disease and Therapy
Infectious complications in advanced disease are in part a consequence of the hypogammaglobulinemia and the inability to mount a humoral defense against bacterial or viral agents. Herpes zoster represents a frequent viral infection in these patients, but infections with Pneumocystis carinii and Candida albicans may also occur. The early recognition of infections and the institution of appropriate therapy are critical to the long-term survival of these patients. A randomized study of intravenous immunoglobulin (400 mg/kg every 3 weeks for 1 year) in patients with CLL and hypogammaglobulinemia produced significantly fewer bacterial infections and a significant delay in onset of first infection during the study period. There was, however, no effect on survival. Routine chronic administration of intravenous immunoglobulin is expensive, and the long-term benefit (>1 year) is unproven.[19,20]
Autoimmune hemolytic anemia and/or thrombocytopenia can occur in patients with any stage of CLL. Initial therapy involves corticosteroids with or without alkylating agents (fludarabine can worsen the hemolytic anemia). It is often necessary to control the autoimmune destruction with corticosteroids, if possible, before administering marrow-suppressive chemotherapy because it may be difficult for a patient to successfully receive a red blood cell or platelet transfusion. Alternate therapies include high-dose immune globulin, rituximab, cyclosporine, azathioprine, splenectomy, and low-dose radiation therapy to the spleen.[3,22] Tumor lysis syndrome is an uncommon complication (presenting in 1 of 300 patients) of chemotherapy for patients with bulky disease.
Second malignancies and treatment-induced acute leukemias may also occur in a small percentage of patients. Transformation of CLL to diffuse large cell lymphoma (Richter syndrome) carries a poor prognosis with a median survival of less than 1 year, although 20% of the patients may live more than 5 years after aggressive combination chemotherapy. (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
Because of its indolent nature, treatment for asymptomatic or minimally affected patients with chronic lymphocytic leukemia (CLL) with chemotherapy is not indicated, and observation is the generally accepted approach. 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. One nomogram to predict time-to-first treatment relies on the number of lymph node sites, size of cervical lymph nodes, lactate dehydrogenase level, the IgVH mutational status, and the presence of del(11q) or del(17p) established by fluorescence in situ hybridization analysis.
Despite many therapeutic options, observation should be considered for asymptomatic or minimally affected patients, even in the context of adverse prognostic findings. Therapy begins when patients develop profound cytopenias or when symptoms adversely impact quality of life.
To date, there are no clinical trial results that confirm that immediate treatment of asymptomatic or minimally affected patients with the B-cell receptor inhibitors or BCL2 inhibitors is superior to observation.
Clinical trials will need to establish improved outcomes using the newer biologic therapies in asymptomatic patients before observation or watchful waiting is abandoned.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
The following regimens are considered first-line approaches for patients with chronic lymphocytic leukemia (CLL) who are experiencing symptomatic progression:
Several large prospective clinical trials have compared these approaches. A chemotherapy-free approach for first-line therapy is usually preferred for most patients, but is mandatory for patients with del(17p) or TP53 positive disease.[1,2,3,4,5]
Anti-CD20 monoclonal antibodies are often combined with venetoclax, ibrutinib, acalabrutinib, or chemotherapy regimens. The three monoclonal antibodies typically used include rituximab, obinutuzumab, and ofatumumab.[6,7,8,9]
Ibrutinib is a selective irreversible inhibitor of Bruton's tyrosine kinase, a signaling molecule located upstream in the B-cell receptor-signaling cascade.
Summary: These trials establish the use of venetoclax with rituximab or obinutuzumab, or the use of ibrutinib or acalabrutinib (with or without rituximab or obinutuzumab) as first-line therapy in previously untreated patients with CLL. Unlike ibrutinib or acalabrutinib, which are applied continuously until relapse, venetoclax may be stopped after 12 months, with durable maintenance of remission. Venetoclax can be subsequently reapplied with success, if needed. The combination of venetoclax and ibrutinib needs to be evaluated in prospective randomized trials versus either agent alone. The considerable financial toxicity of this combination mandates verification of superior efficacy. These trials further establish the rationale for a chemotherapy-free approach for first-line therapy for CLL instead of the previous standard of BR and FCR (which proved more efficacious than chlorambucil regimens).
The same regimens considered for first-line therapy can be applied subsequently in a sequential fashion. These regimens are described in more detail under first-line therapy. (Refer to the Symptomatic or Progressive CLL Treatment section of this summary for more information.)
In the relapsed setting, venetoclax showed similar efficacy and safety even after previous therapy with ibrutinib or idelalisib (the phosphatidylinositol 3-kinase delta inhibitor).[1,2]
Similarly, in a trial reported in abstract form, ibrutinib and acalabrutinib showed similar efficacy and safety after previous therapy with venetoclax. Sequencing these novel agents showed efficacy in the relapsed/refractory setting.
Chimeric Antigen Receptor (CAR) T-Cell Therapy
Autologous T cells were modified by a lentiviral vector to incorporate antigen receptor specificity for the B-cell antigen CD19 and then infused into a previously treated patient. A dramatic response lasting 6 months has prompted larger trials of this concept.[Level of evidence: 3iiiDiv] Ongoing clinical trials are testing the concept of T cells directed at specific antigen targets with engineered CARs.[6,7]
Idelalisib or Duvelisib
Idelalisib is an oral inhibitor of the delta isoform of the phosphatidylinositol 3-kinase (PI3K inhibitor), which is in the B-cell receptor-signaling cascade. Duvelisib is an oral dual inhibitor of the delta and gamma isoforms of PI3K.
Lenalidomide is an oral immunomodulatory agent with response rates of more than 50%, with or without rituximab, for patients with previously treated and untreated disease.[14,15,16,17,18,19][Level of evidence: 3iiiDiv] Prolonged, lower-dose approaches and attention to prevention of tumor lysis syndrome are suggested with this agent.[14,20] Combination therapy and long-term toxicities from using lenalidomide (such as increased myelodysplasia, as seen in myeloma patients) remain undefined for patients with CLL.
Bone marrow or peripheral stem cell transplantation
Bone marrow or peripheral stem cell transplantation is under clinical evaluation for patients with advanced-stage disease or adverse prognostic factors.[21,22,23,24,25,26,27]
In a prospective randomized trial, 241 previously untreated patients younger than 66 years with advanced-stage disease received induction therapy with a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based regimen followed by fludarabine. Complete responders (105 patients) were randomly assigned to undergo autologous stem cell transplantation (ASCT) or observation, while the other 136 patients were randomly assigned to receive dexamethasone, high-dose cytarabine, and cisplatin reinduction followed by either ASCT or fludarabine plus cyclophosphamide (FC). Although the 3-year event-free survival (EFS) favored ASCT in complete responders, there was no difference in OS in any of the randomized comparisons.[Level of evidence: 1iiDi]
Patients with adverse prognostic factors are very likely to die from CLL. These patients are candidates for clinical trials that employ high-dose chemotherapy and immunotherapy with myeloablative or nonmyeloablative allogeneic peripheral stem cell transplantation.[21,22,23,24,25,26,29,30,31,32,33,34,35,36] Although most patients who attain complete remission after ASCT eventually relapse, a survival plateau for allogeneic stem cell support suggests an additional graft-versus-leukemia effect. A series (NCT00281983) of 90 patients with relapsed or refractory CLL who underwent ASCT reported a 58% 6-year OS rate and a 38% 6-year EFS rate, which included those patients with the worst prognostic factors (such as TP53 gene mutation).[Level of evidence: 3iiiD] Patients who relapse after ASCT may respond well and durably to salvage regimens.
Ofatumumab is a humanized anti-CD20 monoclonal antibody.
Evidence (ofatumumab alone and in combination with chlorambucil):
Involved-Field Radiation Therapy
Relatively low doses of radiation therapy can be applied to problematic areas of lymphadenopathy causing problems due to size or encroachment on adjacent organs. Sometimes radiation therapy to one nodal area or the spleen will result in an abscopal effect (i.e., the shrinkage of lymph nodes in untreated sites).
Alemtuzumab, the monoclonal antibody directed at CD52, shows activity in the setting of chemotherapy-resistant disease or high-risk untreated patients with del(17p) or TP53 mutation.[41,42,43] As a single agent, the subcutaneous route of delivery for alemtuzumab is preferred to the intravenous route in patients because of the similar efficacy and decreased adverse effects, including less acute allergic reactions that were shown in some nonrandomized reports.[43,44,45,46,47]
In a combination regimen, subcutaneous alemtuzumab plus fludarabine (with or without cyclophosphamide) or intravenous alemtuzumab plus alkylating agents have resulted in excess infectious toxicities and death, with no compensatory improvement in efficacy in three phase II trials and one randomized trial.[48,49,50][Level of evidence: 3iiiDiv]; [Level of evidence: 1iiDiii]
Alemtuzumab is no longer available commercially in the United States for neoplastic indications but can be obtained from the pharmaceutical company on a compassionate-use basis (U.S. Campath Distribution Program).
These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of chronic lymphocytic leukemia (CLL) treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for CLL. Listed after each reference are the sections within this summary where the reference is cited.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Chronic Lymphocytic Leukemia (CLL)
Added Staber et al. as reference 17.
Added text to state that anecdotal responses have been seen with venetoclax (added Boidol et al. as reference 20 and level of evidence 3iiiDiv).
Selection of Therapy for CLL
Revised text to state that cutoff levels of hemoglobin less than 10 g/dL or platelet counts less than 50 × 109 /L are generally regarded as an indication for treatment.
Revised text to add acalabrutinib as one of the new biologic agents that are approved by the U.S. Food and Drug Administration for first-line use in newly diagnosed patients with CLL who require therapy; also added it as an agent that should be considered in patients with adverse prognostic factors.
Symptomatic or Progressive CLL Treatment
This section was extensively revised.
Recurrent or Refractory CLL Treatment
Added text to state that in a trial reported in abstract form, ibrutinib and acalabrutinib showed similar efficacy and safety after previous therapy with venetoclax. Sequencing these novel agents showed efficacy in the relapsed/refractory setting (cited 2019 Mato et al. as reference 3 and 2017 Mato et al. as reference 4).
Added Patel et al. as reference 8.
Added text to state that in a prospective randomized trial, 261 patients with previous therapy were randomly assigned to receive idelalisib plus ofatumumab versus ofatumumab alone. With a median follow-up of 16.1 months, the median progression-free survival favored the idelalisib combination at 16.3 months versus 8.0 months (cited Jones et al. as reference 13 and level of evidence 1iiDiii).
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic lymphocytic leukemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Chronic Lymphocytic Leukemia Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ® Adult Treatment Editorial Board. PDQ Chronic Lymphocytic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389470]
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Last Revised: 2020-03-20
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