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Incidence and Mortality
Estimated new cases and deaths from CLL in the United States in 2019:
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. 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).[3,4] 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 6% in 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.[6,7]
In two selected series of more than 900 patients followed prospectively for a median of 5 to 7 years, overt CLL requiring chemotherapy occurred in 7% of patients.[5,8] In a database analysis and for up to 77 months before diagnosis, almost all patients with a diagnosis of CLL had prediagnostic B-cell clones that were identified in peripheral blood when available.[4,9]
For patients with progressing CLL, treatment with conventional doses of chemotherapy is not curative; selected patients treated with allogeneic stem cell transplantation have achieved prolonged disease-free survival.[10,11,12,13,14] Antileukemic therapy is frequently unnecessary in uncomplicated early disease. The median survival for all patients ranges from 8 to 12 years in older trials with data from the 1970s through the 1990s.[15,16] There is, however, a large variation in survival among individual patients, ranging from several months to a normal life expectancy. Treatment must be individualized based on the clinical behavior of the disease.
As found in one report, CLL occurs primarily in middle-aged and elderly adults, with increasing frequency in successive decades of life. 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. Prognostic factors that may help predict clinical outcome include cytogenetic subgroup, immunoglobulin mutational status, ZAP-70, and CD38.[2,21,22,23,24,25,26,27,28,29] (Refer to the Prognostic Factors section in the Stage Information for Chronic Lymphocytic Leukemia section of this summary for more information.) Patients who develop an aggressive high-grade non-Hodgkin lymphoma, usually diffuse large B-cell lymphoma and termed a Richter transformation, have a poor prognosis. Patients with CLL are also at increased risk for other malignancies, even before therapy. A population-based analysis of almost 2 million cancer patients in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database suggests that cancer-specific survival for patients with pre-existing CLL who subsequently develop colorectal and breast cancer is significantly lower (hazard ratio [HR], 1.46; P < .001 for colorectal cancer and HR, 1.41; P = .005 for breast cancer) than cancer-specific survival for patients with colorectal and breast cancer who do not have antecedent CLL, after adjusting for age, sex, race, and disease stage, and excluding CLL-related deaths.
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 only occurs in 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.
The differential diagnosis must exclude hairy cell leukemia and Waldenström macroglobulinemia. (Refer to the PDQ summaries on Hairy Cell Leukemia and Adult Non-Hodgkin Lymphoma Treatment for more information.) Waldenström macroglobulinemia has a natural history and therapeutic options similar to CLL, with the exception of hyperviscosity syndrome associated with macroglobulinemia as a result of elevated immunoglobulin M. Prolymphocytic leukemia (PLL) is a rare entity characterized by excessive prolymphocytes in the blood with a typical phenotype that is positive for CD19, CD20, and surface-membrane immunoglobulin and negative for CD5. These patients demonstrate splenomegaly and poor response to low-dose or high-dose chemotherapy.[15,34]
Cladribine (2-chlorodeoxyadenosine) appears to be an active agent (60% complete remission rate) for patients with de novo B-cell prolymphocytic leukemia.[Level of evidence: 3iiiDiv] Alemtuzumab (campath-1H), an anti-CD52 humanized monoclonal antibody, has been used for 76 patients with T-cell prolymphocytic leukemia after failure of prior 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.
Large granular lymphocyte (LGL) leukemia is characterized by lymphocytosis with a natural killer cell immunophenotype (CD2, CD16, and CD56) or a T-cell immunophenotype (CD2, CD3, and CD8).[38,39,40] These patients often have neutropenia and a history of rheumatoid arthritis. The natural history is indolent, often marked by anemia and splenomegaly. This condition appears to fit into the clinical spectrum of Felty syndrome. A characteristic genetic finding in almost 50% of the patients with T-cell LGL involves mutations in the signal transducer and activator of the transcription 3 gene (STAT 3). Therapy includes low doses of oral cyclophosphamide or methotrexate, cyclosporine, and treatment of the bacterial infections acquired during severe neutropenia.[38,40,43,44]
Other PDQ summaries containing information about CLL include the following:
Staging is useful in chronic lymphocytic leukemia (CLL) to predict prognosis and also to stratify patients to achieve comparisons for interpreting specific treatment results. Anemia and thrombocytopenia are the major adverse prognostic variables.
CLL has no standard staging system. The Rai staging system and the Binet classification 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
Stage 0 CLL is characterized by absolute lymphocytosis (>15,000/mm3) without adenopathy, hepatosplenomegaly, anemia, or thrombocytopenia.
Stage I CLL is characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.
Stage II CLL is characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy.
Stage III CLL is characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly.
Stage IV CLL is characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.
Clinical stage A*
Clinical stage A CLL is characterized by no anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai stages 0, I, and II).
Clinical stage B*
Clinical stage B CLL is characterized by no anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai stages I and II).
Clinical stage C
Clinical stage C CLL is characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai stages III and IV).
*Lymphoid areas include cervical, axillary, inguinal, and spleen.
The Binet classification integrates the number of nodal groups involved with the disease 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 in the Rai staging, and from 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 or 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.
New prognostic markers are now available to the clinician and investigator.[6,7,8] The use of these markers to stratify patients in clinical trials, to help assess the need for therapy, and to help select the type of therapy continues to evolve. The new prognostic markers include the following:
Other prognostic factors include:
An international prognostic index (IPI) for CLL (CLL-IPI) identified four prognostic subgroups based on immunoglobulin variable region heavy–chain gene mutation (IgVH), clinical stage, age (≤65 years vs. >65 years), and TP53 status (no abnormalities vs. del[17p] or TP53 mutation or both).
Treatment of chronic lymphocytic leukemia (CLL) ranges from periodic observation with treatment of infectious, hemorrhagic, or immunologic complications to a variety of therapeutic options, including steroids, alkylating agents, purine analogs, combination chemotherapy, monoclonal antibodies, and transplant options. 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 asymptomatic patients, treatment may be deferred until the patient becomes symptomatic as the disease progresses. Since 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.
A meta-analysis of randomized trials showed no survival benefit for immediate versus delayed therapy for patients with early-stage disease, nor for the use of combination regimens incorporating an anthracycline compared with a single-agent alkylator for advanced-stage disease.[Level of evidence: 1iiA] A variety of clinical factors, including the immunoglobulin variable region heavy–chain (IgVH) gene mutation, chromosomal abnormalities by fluorescent in situ hybridization analysis or cytogenetics, beta-2-microglobulin, and lymphocyte doubling time may be helpful in predicting progression of disease.
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.[5,6]
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, though 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.)
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 frequently advisable to control the autoimmune destruction with corticosteroids, if possible, before administering marrow-suppressive chemotherapy because the patients may be difficult to transfuse successfully with either red blood cells or platelets. Alternate therapies include high-dose immune globulin, rituximab, cyclosporine, azathioprine, splenectomy, and low-dose radiation therapy to the spleen.[10,11] Tumor lysis syndrome is an uncommon complication (presenting in 1 out of 300 patients) of chemotherapy for patients with bulky disease.
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.
Computed tomographic (CT) scans have a very limited role in following 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.
Because of the indolent nature of stage 0 chronic lymphocytic leukemia (CLL), treatment with chemotherapy is not indicated, and observation is the generally accepted approach. The French Cooperative Group on CLL randomly assigned 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment and found no survival advantage for immediate treatment with chlorambucil.[Level of evidence: 1iiA] A meta-analysis of six trials of immediate versus deferred therapy with chlorambucil (including the aforementioned trial by the French Cooperative Group) showed no difference in overall survival at 10 years.[Level of evidence: 1iiA] Whether immediate therapy with the nucleoside analogs or other newer strategies, such as ibrutinib, will be superior to observation is uncertain.
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.
Clearance of Minimal Residual Disease
The improvements in response rates from more intensive regimens have maximized the clearance of minimal residual disease (MRD). In one prospective trial of 493 patients, clearance of MRD was an independent predictor of overall survival (OS) by multivariate analysis. The surrogate endpoint of clearance of residual disease, while prognostic,[1,2] did not show improved survival in a randomized prospective trial. The necessary study would include patients who fail to completely clear the marrow with induction therapy and randomly assign them to further alternative treatment versus the same treatment later at relapse, looking at OS as the primary endpoint.[3,4]
Choice of Treatment Options
In the absence of randomized trials comparing the new B-cell receptor inhibitors and bcl-2 inhibitors to the new monoclonal antibodies and to more conventional chemotherapeutic agents, the following general principles may provide a sequencing for available therapeutic options:
Outside of the context of a clinical trial, treatment for asymptomatic or minimally affected patients with CLL is observation. No data exist to suggest any harm with a delay in therapy until the patient becomes symptomatic or develops serious cytopenias despite growth factor support. 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. 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 immunoglobulin variable region heavy–chain (IgVH) mutational status, and the presence of 11q- or 17p- deletion established by fluorescence in situ hybridization (FISH) analysis.
A phase Ib–II trial (NCT01105247) of 85 patients with relapsed or refractory CLL showed a 26-month progression-free survival (PFS) rate of 75% and included patients with 17p- or unmutated IgVH FISH testing.[Level of evidence: 3iiiDiii] Patients who discontinued ibrutinib early because of disease progression or drug intolerance had very poor outcomes, which were mainly attributable to very poor pre-existing prognostic factors.[10,11]
A prospective, randomized trial of 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma compared ibrutinib with ofatumumab. With a median follow-up of 9.4 months, the 12-month OS favored ibrutinib (90% vs. 81%) (hazard ratio [HR], 0.43; P = .005).[Level of evidence: 1iiA] Similar outcomes were seen for patients whose disease was resistant to purine analogues or who had a chromosome 17p deletion.
A prospective, randomized trial of 269 previously untreated patients who were aged 65 years or older compared ibrutinib with chlorambucil. With a median follow-up of 18 months, the 2-year OS favored ibrutinib (98% vs. 85%) (HR, 0.16; 95% CI, 0.05–0.56; P = .001).[Level of evidence: 1iiA]
A prospective, randomized trial of 578 previously treated patients compared ibrutinib plus bendamustine plus rituximab with bendamustine plus rituximab. With a median follow-up of 17 months, PFS favored the ibrutinib-combination arm at 18 months (79% vs. 24%) (HR, 0.20; 95% confidence interval [CI], 0.15–0.27; P = .0001).[Level of evidence: 1iDiii]
A phase II, multicenter study (NCT01744691) included 144 patients with relapsed or refractory disease with deletion 17p disease. With a median follow-up of 27.6 months, the objective response rate was 83% (95% CI, 76%–89%), 2-year PFS was 63% (95% CI, 54%–70%), and 2-year OS was 75% (67%–81%).[Level of evidence: 3iiiDiii]
These trials establish the rationale for first-line use of ibrutinib in patients with CLL, especially for high-risk patients with deletion 17p disease. These trials also establish the use of ibrutinib for patients with relapsed disease.
A prospective trial of 263 patients in partial response or complete response after a first course or second course of induction therapy randomly assigned patients to 2 years of maintenance therapy with rituximab versus observation. With a median follow-up of 34 months, median PFS favored the rituximab arm at 47.0 months versus 35.5 months (HR, 0.50; 95% CI, 0.33–0.75; P = .0008) but with no difference in OS.[Level of evidence: 1iiDiii]
In a randomized prospective trial (NCT01010061), 781 previously untreated patients with coexisting medical problems were randomly assigned to chlorambucil and obinutuzumab versus chlorambucil and rituximab versus chlorambucil alone. The median PFS was best for the obinutuzumab arm (26.7 months) versus the rituximab arm (16.3 months) versus chlorambucil alone (11.1 months) (HR, 0.18; 95% CI, 0.13–0.24; P < .001) for obinutuzumab and chlorambucil versus chlorambucil alone; for rituximab and chlorambucil versus chlorambucil alone (HR, 0.44; 95% CI, 0.34–0.57; P < .001). The 2-year OS was significantly improved for the obinutuzumab arm (91%) versus chlorambucil alone (80%) (HR, 0.41; 95% CI, 0.23–0.74; P = .002). Patients who received obinutuzumab did not have improved survival compared with those who received rituximab alone.[Level of evidence: 1iiA]
A prospective, randomized trial of 447 patients who were previously untreated compared ofatumumab plus chlorambucil with chlorambucil alone. With a median follow-up of 2 years, median PFS favored the ofatumumab arm at 22.4 months versus 13.1 months (HR, 0.57; 95% CI, 0.45–0.72; P = .0001) but with no difference in OS.[Level of evidence: 1iiDiii]
A prospective trial of 474 previously treated patients who attained partial or complete remission to second- or third-line chemotherapy were randomly assigned to 2 years of maintenance therapy with ofatumumab versus observation. With a median follow-up of 19 months, median PFS favored the ofatumumab maintenance arm at 29.4 months versus 15.2 months (HR, 0.50; 95% CI, 0.38–0.66; P < .0001) but with no difference in OS.[Level of evidence: 1iiDiii]
In phase I and phase II studies, previously treated patients received venetoclax, resulting in an 80% response rate, including patients with adverse prognosis resistant to fludarabine or with 17p deletion.[25,26,27][Level of evidence: 3iiiDiv] These data led to FDA approval for use in relapsed disease.
In a randomized, double-blind, prospective trial (NCT01539512), 220 patients treated mainly with fludarabine-based regimens and who had coexisting medical problems, such as renal dysfunction, received rituximab and idelalisib versus rituximab and placebo. With a median follow-up of less than 1 year, the PFS rate at 24 weeks favored the rituximab and idelalisib arm (93%) versus the rituximab and placebo arm (46%) (HR, 0.15; 95% CI, 0.08–0.28; P < .001), and the OS rate at 1 year was significantly better for the rituximab and idelalisib arm (92%) versus the rituximab and placebo arm (80%) (HR, 0.28; 95% CI, 0.09–0.86; P = .02).[Level of evidence: 1iA] In 64 previously untreated patients, the combination of idelalisib plus rituximab resulted in a PFS rate of 83% at 3 years.[Level of evidence: 3iiiDiii]
The French Cooperative Group on CLL randomly assigned 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment and found no survival advantage for chlorambucil.[Level of evidence: 1iiA] A meta-analysis of six trials of immediate versus deferred therapy with chlorambucil (including the aforementioned trial by the French Cooperative Group) showed no difference in OS at 10 years.[Level of evidence: 1iiA]
Several randomized trials have compared the purine analogs with chlorambucil; with cyclophosphamide, doxorubicin, and prednisone; or with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in previously untreated patients.[38,39,40,41,42] All of these trials showed higher or equivalent response rates for the purine analog, and most showed an improvement in PFS; one reached significance in OS favoring fludarabine.[38,40,41,42,43,44][Level of evidence: 1iiDiii]
A comparison of chlorambucil versus fludarabine, after 15 years' median follow-up, showed patients with improved median OS with fludarabine at 63 versus 59 months (P = .04) and an improved percentage of patients alive at 8 years (31% vs. 19%, P = .04).[Level of evidence: 1iiA] All of the trials demonstrated higher toxic effects with the purine analogs, especially granulocytopenic infections, herpes infections, autoimmune hemolytic anemia, and persistent thrombocytopenia. The increased risk of infection may persist for months or years after treatment with a purine analog.[44,46]
Although empiric evidence is lacking, some investigators recommend prophylaxis with trimethoprim-sulfa during therapy and for 6 to 12 months afterwards to prevent pneumocystis infection. In a similar way, other investigators employ prophylaxis (e.g., acyclovir) for the herpes viruses. Purine analogs cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines.
In a randomized comparison with chlorambucil in 319 previously treated patients, bendamustine showed a better response rate (68% vs. 31%, P < .0001) and PFS (21.6 months vs. 8 months) with a median follow-up of 35 months.[Level of evidence: 1iiDiii] The German CLL Study Group compared bendamustine plus rituximab (BR) versus fludarabine plus cyclophosphamide plus rituximab (FCR) as first-line therapy in patients with CLL who required therapy. With a 37.1-month median follow-up, the median PFS was better for FCR (55.2 months vs. 41.7 months) (HR, 1.64; 90% CI, 1.31–2.06; P = .001), but there was no difference in OS at 3 years (91% vs. 92%, not significant).[Level of evidence: 1iiDiii]
In patients older than 65 years, there was no difference in PFS between the two arms, but more infections occurred with FCR than with BR (grade 3 to 5 infection, 47% vs. 27%).
Combination chemotherapy was used in a trial of 817 patients that compared FCR with fludarabine plus cyclophosphamide (FC) and at a median follow-up of 5.9 years showed improved OS at 6 years for the rituximab combination (69% vs. 62%) (HR, 0.68; 95% CI, 0.54–0.89; P = .001).[Level of evidence: 1iiA] FCR has never been compared with watchful waiting up front in asymptomatic or minimally affected patients. The improvements in response rates from more intensive regimens have maximized the clearance of MRD. However, the surrogate endpoint of MRD clearance has not been proven to be a valid surrogate for improved survival in a randomized, prospective trial; the necessary study would take patients who fail to completely clear the marrow with induction therapy and randomly assign them to further alternative treatment versus the same treatment later at relapse looking at OS as the primary endpoint.[3,4] A cumulative incidence of 6% to 8% for myelodysplasia is seen at 5 to 7 years in patients who received FC, with or without rituximab.[60,61]
Other combination chemotherapy regimens include the following:
A meta-analysis of ten trials compared combination chemotherapy (before the availability of rituximab) with chlorambucil alone and showed no difference in OS at 5 years.[Level of evidence: 1iiA]
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.[84,85,86][Level of evidence: 3iiiDiv]; [Level of evidence: 1iiDiii]
In a randomized prospective study, 335 previously treated patients received intravenous alemtuzumab plus fludarabine versus fludarabine alone. With a median follow-up of 30 months, the combination of fludarabine plus intravenous alemtuzumab had better PFS, with a median of 23.7 months versus 16.5 months (HR, 0.61; 95% CI, 0.47–0.80; P = .0003); and better OS, with a median not reached, versus 52.9 months (HR, 0.65; 95% CI, 0.45–0.94; P = .021).[Level of evidence: 1iiA] Profound and long-lasting immunosuppression has been seen, which mandates monitoring for reactivation of cytomegalovirus and prophylaxis for pneumocystis and herpes virus infections.[89,90] Antibiotic prophylaxis includes trimethoprim and sulfamethoxazole, itraconazole, and acyclovir (or ganciclovir) for asymptomatic cytomegalovirus viremia.
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).
In a prospective randomized trial, 241 previously untreated patients younger than 66 years with advanced-stage disease received induction therapy with a CHOP-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 aracytin, and cisplatin reinduction followed by either ASCT or 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.[91,92,93,94,95,96,99,100,101,102,103,104,105,106] 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.
Patients with recurrent or refractory chronic lymphocytic leukemia (CLL) are eligible for clinical trials or can be offered alternative therapies as described in the section for treatment options for Stages I, II, III, and IV CLL. (Refer to the Treatment options section in the Stages I, II, III, and IV CLL section of this summary for more information.)
These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of chronic lymphocytic leukemia treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for chronic lymphocytic leukemia. 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)
Updated statistics with estimated new cases and deaths for 2019 (cited American Cancer Society as reference 1).
Stages I, II, III, and IV CLL
Editorial changes were made to this section.
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:
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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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The preferred citation for this PDQ summary is:
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: 2019-03-05
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