Chronic Lymphocytic Leukemia Treatment (PDQ®)

General Information About Chronic Lymphocytic Leukemia (CLL)
Incidence and Mortality
Estimated new cases and deaths from CLL in the United States in 2014:
  • New cases: 15,720.
  • Deaths: 4,600.

Related Summaries
Other PDQ summaries containing information about CLL include the following:
  • Adult Non-Hodgkin Lymphoma Treatment
  • Hairy Cell Leukemia

Stage Information for CLL
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. 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
Stage 0 CLL is characterized by absolute lymphocytosis (>15,000/mm3) without adenopathy, hepatosplenomegaly, anemia, or thrombocytopenia.

Stage I
Stage I CLL is characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.

Stage II
Stage II CLL is characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy.

Stage III
Stage III CLL is characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly.

Stage IV
Stage IV CLL is characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.

Binet Classification
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.

Prognostic factors
New prognostic markers are now available to the clinician and investigator. 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. Prospective trials to verify and establish the role of these prognostic markers are ongoing. No large multivariable analyses exist as yet to test the relative power of these individual prognostic variables. Prognostic indices are under evaluation and will require prospective validation.
  • Immunoglobulin variable region heavy chain gene (IgVH) mutation. The finding of significant numbers of mutations in this region is associated with a median survival in excess of 20 to 25 years. The absence of mutations is associated with a median survival of 8 to 10 years.
  • ZAP-70. ZAP-70 has been proposed as a surrogate for the mutational status. ZAP-70 positivity for previously untreated and asymptomatic patients (>30%) is associated with a more unfavorable median survival (6–10 years), while a negative ZAP-70 is associated with a median survival of more than 15 years. A prospective evaluation of these markers in a randomized study of fludarabine-based chemotherapy (E2997 [NCT00003764]) failed to show any difference in response rates, response duration, progression-free survival, or overall survival (OS).
  • Chromosomal abnormalities by fluorescent in situ hybridization (FISH). FISH chromosomal abnormalities were associated with prognosis in retrospective and prospective studies and clonal evolution has been seen over time. 13q- is favorable (with a 17-year median OS in a prospective study). Trisomy 12 and 11q- have less favorable prognoses (with a 9- to 11-year median OS in a prospective study). In particular, 17p- is associated with mutated TP53 and with poor response rates and short duration of response to the standard therapeutic options. 17p- is associated with the most unfavorable prognosis (with a 7-year median OS in one prospective trial). The combination of adverse cytogenetics such as 11q- or 17p- (suggesting a worse prognosis) with ZAP-70 negativity (suggesting a better prognosis) in the same patients resulted in a poor prognosis. These findings emphasize the need for prospective studies of combinations of these prognostic markers.
  • CD38 immunophenotype. CD38 positivity (>30%) correlates with a worse prognosis, but there is a 30% false-positive rate and a 50% false-negative rate using IgVH mutational status as the gold standard for prognosis.
Other prognostic factors include:
  • Stage. (Refer to the Rai staging system section and the Binet classification section of this summary for more information.)
  • Lymphocyte doubling time (doubling of the white blood cell count in excess of 1 year implies a favorable prognosis).
  • Beta-2-microglobulin (higher levels imply a worse prognosis).

Treatment Option Overview for CLL
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 IgVH 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.
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, prior to administering marrow-suppressive chemotherapy because such 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. 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.
Gribben JG, O'Brien S: Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 29 (5): 544-50, 2011.Del Giudice I, Chiaretti S, Tavolaro S, et al.: Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood 114 (3): 638-46, 2009.Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst 91 (10): 861-8, 1999.Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. N Engl J Med 319 (14): 902-7, 1988.Griffiths H, Brennan V, Lea J, et al.: Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors. Blood 73 (2): 366-8, 1989.Weeks JC, Tierney MR, Weinstein MC: Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia. N Engl J Med 325 (2): 81-6, 1991.Maddocks-Christianson K, Slager SL, Zent CS, et al.: Risk factors for development of a second lymphoid malignancy in patients with chronic lymphocytic leukaemia. Br J Haematol 139 (3): 398-404, 2007.Robertson LE, Pugh W, O'Brien S, et al.: Richter's syndrome: a report on 39 patients. J Clin Oncol 11 (10): 1985-9, 1993.Mauro FR, Foa R, Cerretti R, et al.: Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 95 (9): 2786-92, 2000.Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333 (16): 1052-7, 1995.Kaufman M, Limaye SA, Driscoll N, et al.: A combination of rituximab, cyclophosphamide and dexamethasone effectively treats immune cytopenias of chronic lymphocytic leukemia. Leuk Lymphoma 50 (6): 892-9, 2009.Cheson BD, Frame JN, Vena D, et al.: Tumor lysis syndrome: an uncommon complication of fludarabine therapy of chronic lymphocytic leukemia. J Clin Oncol 16 (7): 2313-20, 1998.Hoyer JD, Ross CW, Li CY, et al.: True T-cell chronic lymphocytic leukemia: a morphologic and immunophenotypic study of 25 cases. Blood 86 (3): 1163-9, 1995.Eichhorst BF, Fischer K, Fink AM, et al.: Limited clinical relevance of imaging techniques in the follow-up of patients with advanced chronic lymphocytic leukemia: results of a meta-analysis. Blood 117 (6): 1817-21, 2011.

Stage 0 CLL
Because of the indolent nature of stage 0 chronic lymphocytic leukemia (CLL), treatment is not indicated. 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 will be superior to a watchful waiting approach is uncertain.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 chronic lymphocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.

Stage I, II, III, and IV CLL
Several decades of large, randomized, prospective trials of previously untreated patients have demonstrated statistically significant improvements in response rates, event-free survival (EFS), and progression-free survival (PFS) with comparison of combinations of drugs versus single-agent alkylators, but only two trials have shown statistically significant improvement in overall survival (OS).
The first trial, a comparison of chlorambucil versus fludarabine, after 15 years of median follow-up, showed improved median OS for patients on the fludarabine regimen at 63 months versus 59 months (P = .04), and an improved percentage of patients were alive at 8 years (31% vs. 19%, P = .04).[Level of evidence: 1iiA]
The second trial, which had 817 patients, compared FCR (fludarabine + cyclophosphamide + rituximab) versus FC (fludarabine + cyclophosphamide) with a median follow-up of 38 months and showed improved OS at 3 years for the rituximab combination (i.e., 87% vs. 83%, P = .01.[Level of evidence: 1iiA] Yet neither fludarabine nor FCR has been compared in a randomized study against watchful waiting in asymptomatic or minimally affected patients.
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 OS by multivariate analysis. The surrogate endpoint of such clearance of residual disease, while prognostic, has not been shown to improve 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.
The sequencing of the following treatment options cannot be determined from the current set of completed clinical trials. When patients become symptomatic or require treatment, FCR has become the most frequently chosen option outside of a clinical trial, mostly on the basis of the previously described prospective study.
Treatment options:
Note: Standard options are roughly ordered by level of toxic effects, starting with the least toxic options. More recently discovered options are mentioned at the end of the list.
  • Observation in asymptomatic or minimally affected patients. Outside of the context of a clinical trial, treatment for asymptomatic or minimally affected patients with chronic lymphocytic leukemia (CLL) is observation. No data exist as yet 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.
  • Rituximab is a murine anti-CD20 monoclonal antibody. When used alone, higher doses of rituximab or increased frequency or duration of therapy is required for comparable responses to those seen for other indolent lymphomas.
  • Ofatumomab is a human anti-CD20 monoclonal antibody. A trial of 138 patients, who were previously treated with fludarabine and alemtuzumab, showed overall response rates around 50% in patients refractory to fludarabine and with prior exposure to rituximab.[Level of evidence: 3iiiDiv]
  • Obinutuzumab is a human anti-CD20 monoclonal antibody. 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 ) (hazard ratio [HR], 0.18; 95% confidence interval [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]
  • Idelalisib is an oral inhibitor of the delta isoform of the phosphatidylinositol 3-kinase, which is located in the B-cell receptor-signaling cascade. 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]
  • Ibrutinib is a selective irreversible inhibitor of Bruton tyrosine kinase, a signaling molecule located upstream in the B-cell receptor-signaling cascade. Trials of previously untreated patients and of patients with relapsed or refractory CLL showed durable responses to the oral agent in phase I and II studies.[Level of evidence: 3iiiDiii] A phase Ib–II trial (NCT01105247) of 85 patients with relapsed or refractory CLL showed a 26-month PFS rate of 75% and included patients with 17p- or unmutated IgVH fluorescence in situ hybridization testing.[Level of evidence: 3iiiDiii]
  • Oral alkylating agents with or without corticosteroids. 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]
  • Fludarabine, 2-chlorodeoxyadenosine, or pentostatin as seen in the CLB-9011 trial, for example. 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. 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.[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.
    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.
  • Bendamustine is a cytotoxic agent with bifunctional properties of an alkylator and a purine analog. In previously treated and untreated patients, bendamustine with rituximab has shown response rates around 70% to 90%.[Level of evidence: 3iiiDiii]
    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 is comparing bendamustine plus rituximab versus FCR as first-line therapy in patients with CLL who require therapy.
  • Lenalidomide is an oral immunomodulatory agent with response rates over 50%, with or without rituximab, for patients with previously treated and untreated disease.[Level of evidence: 3iiiDiv] Prolonged, lower-dose approaches and attention to prevention of tumor lysis syndrome are suggested with this agent. Combination therapy and long-term toxicities from using lenalidomide (such as increased myelodysplasia, as seen in myeloma patients) remain undefined for patients with CLL.
  • Combination chemotherapy. A trial of 817 patients comparing FCR versus FC with a median follow-up of 38 months showed improved OS at 3 years for the rituximab combination (87% vs. 83%, P = .01).[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. A cumulative incidence of 6% to 8 % for myelodysplasia is seen at 5 to 7 years in patients who received fludarabine plus cyclophosphamide, with or without rituximab.
    Other combination chemotherapy regimens include the following:
      Fludarabine plus cyclophosphamide plus rituximab.
    • Fludarabine plus rituximab as seen in the CLB-9712 and CLB-9011 trials.
    • Fludarabine plus cyclophosphamide versus fludarabine plus cyclophosphamide plus rituximab.
    • Pentostatin plus cyclophosphamide plus rituximab as seen in the MAYO-MC0183 trial, for example.
    • Ofatumumab plus fludarabine plus cyclophosphamide.
    • CVP: cyclophosphamide plus vincristine plus prednisone.
    • CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.
    • Fludarabine plus cyclophosphamide versus fludarabine as seen in the E2997 trial [NCT00003764] and the LRF-CLL4 trial, for example.
    • Fludarabine plus chlorambucil as seen in the CLB-9011 trial, for example.
    A meta-analysis of ten trials comparing combination chemotherapy (before the availability of rituximab) with chlorambucil alone showed no difference in OS at 5 years.[Level of evidence: 1iiA]
  • Involved-field radiation therapy. Relatively low doses of radiation therapy will affect an excellent response for months or years. Sometimes radiation therapy to one nodal area or the spleen will result in abscopal effect (i.e., the shrinkage of lymph node tumors 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 17p deletion or p53 mutation. 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.
    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 phase II trials.[Level of evidence: 3iiiDiv]
    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. Antibiotic prophylaxis includes trimethoprim and sulfamethoxazole, itraconazole, and acyclovir (or ganciclovir) for asymptomatic cytomegalovirus viremia.
  • Bone marrow and peripheral stem cell transplantations are under clinical evaluation. 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 fludarabine plus cyclophosphamide. Although the 3-year 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. 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]
  • 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 chimeric–antigen receptors (termed CARs).
  • Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia and stage IV chronic lymphocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Recurrent or Refractory CLL
    Clinical trials are appropriate and should be considered when possible. In small studies, response rates of more than 40% have been reported for lenalidomide and flavopiridol.[Level of evidence: 3iiiDiv] The addition of the Bcl-2 anti-sense oligonucleotide oblimersen to fludarabine/cyclophosphamide improved complete response rates in a randomized study of 241 patients with relapsed disease.[Level of evidence: 1iiDiv] Bone marrow and peripheral stem cell transplantations are under clinical evaluation.
    Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with refractory chronic lymphocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Changes to This Summary (12/05/2014)
    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.
    Stage I, II, III, and IV Chronic Lymphocytic Leukemia
    Added Strati et al. as reference 7.
    Added text to state that obinutuzumab is a human anti-CD20 monoclonal antibody treatment option and provided statistics from a randomized prospective trial (NCT01010061) of 781 previously untreated patients with coexisting medical problems who were randomly assigned to chlorambucil plus obinutuzumab versus chlorambucil plus rituximab versus chlorambucil alone (cited Goede et al. as reference 16 and level of evidence (LOE) 1iiA).
    Added text to state that idelalisib is an oral inhibitor of the delta isoform of the phosphatidylinositol 3-kinase and provided statistics from a randomized, double-blind, prospective trial (NCT01539512) of 220 patients treated mainly with fludarabine-based regimens who had coexisting medical problems and received rituximab plus idelalisib versus rituximab plus placebo (cited Furman et al. as reference 17 and LOE 1iA).
    Added O'Brien et al. as reference 19.
    Added text to state that a series of 90 patients with relapsed or refractory CLL who underwent allogeneic stem cell transplantation reported a 58% 6-year overall survival rate and a 38% 6-year event-free survival rate, which included those patients with the worst prognostic factors (cited Dreger et al. as reference 92 and LOE 3iiiD).
    Revised text to state that ongoing clinical trials are testing the concept of T-cells directed at specific antigen targets with engineered chimeric–antigen receptors (cited Maus et al. as reference 94).
    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.

    About This PDQ Summary
    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).
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    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:
    • Steven D. Gore, MD (Yale University School of Medicine)
    • Eric J. Seifter, MD (Johns Hopkins University)
    • Mikkael A. Sekeres, MD, MS (Cleveland Clinic Taussig Cancer Institute)
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    Call 1-800-4-CANCER
    For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.
    Chat online
    The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.
    Write to us
    For more information from the NCI, please write to this address:
    • NCI Public Inquiries Office
    • 9609 Medical Center Dr.
    • Room 2E532 MSC 9760
    • Bethesda, MD 20892-9760
    Search the NCI Web site
    The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.
    There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
    Find Publications
    The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).

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