Cancer Health Center

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Treatment options:

Several decades of large, randomized, prospective trials of previously untreated patients have demonstrated statistically significant improvements in response rates, event-free survival, and progression-free survival (PFS) with comparison of combinations of drugs versus single-agent alkylators,[1,2] but only two trials have shown statistically significant improvement in overall survival (OS).[3,4]

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).[3,5][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., 84% vs. 79%, P < .01.[4][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. The surrogate endpoint of such clearance of residual disease, however, 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.[1,2] 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.[4]

Note: These options are roughly ordered by level of toxic effects, starting with the least toxic options.

1. Observation in asymptomatic or minimally affected patients.[6] 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.
2. Rituximab, a murine anti-CD20 monoclonal antibody.[7,8,9,10,11] 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.
3. Ofatumomab is a human anti-CD20 monoclonal antibody.[12] A trial of 138 patients previously treated with fludarabine and alemtuzumab showed overall response rates around 50% in a patient group that historically showed less than 20% responses to rituximab.[12][Level of evidence: 3iiiDiv]
4. Oral alkylating agents with or without corticosteroids.[13] 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.[14][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.[6][Level of evidence: 1iiA]
5. Fludarabine, 2-chlorodeoxyadenosine, or pentostatin as seen in the CLB-9011 trial, for example.[15,16,17,18,19,20]

   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.[5,21,22,23,24] All of these trials showed higher or equivalent response rates for the purine analog and most showed an improvement in PFS, with one reaching significance in OS favoring fludarabine.[3,21,22,23,24,25][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).[3][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.[26] The increased risk of infection may persist for months or years after treatment with a purine analog.[25,27] 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.[27] Purine analogs cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines.[23]

6. Bendamustine.

   Bendamustine is a cytotoxic agent with bifunctional properties of an alkylator and a purine analogue.[28] In previously treated and untreated patients, bendamustine with rituximab has shown response rates around 70% to 90%.[29,30][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.[31][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.[29]

7. 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 (84% vs. 79%, P < .01).[4][Level of evidence: 1iiA] FCR has never been compared to watchful waiting up front in asymptomatic or minimally affected patients. The improvements in response rates from more intensive regimens have maximized the clearance of minimal residual disease (MRD). But 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.[1,2]

   • Fludarabine plus cyclophosphamide plus rituximab.[32,33,34]
   • Fludarabine plus rituximab as seen in the CLB-9712 and CLB-9011 trials.[35]
   • Fludarabine plus cyclophosphamide versus fludarabine plus cyclophosphamide plus rituximab.[4,36]
   • Pentostatin plus cyclophosphamide plus rituximab as seen in the MAYO-MC0183 trial, for example.[37,38]
   • CVP: cyclophosphamide plus vincristine plus prednisone.[39]
   • CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[40]
   • Fludarabine plus cyclophosphamide versus fludarabine as seen in the E2997 trial and the LRF-CLL4 trial, for example.[41,42]
   • Fludarabine plus chlorambucil as seen in the CLB-9011 trial, for example.[43]

   A meta-analysis of ten trials comparing combination chemotherapy (before the availability of rituximab) to chlorambucil alone showed no difference in OS at 5 years.[6][Level of evidence: 1iiA]

8. 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).
9. Alemtuzumab (campath-1H), the monoclonal antibody directed at CD52, has been used as first-line therapy and after relapse from prior chemotherapy.[44,45,46,47] A prospective randomized trial of 297 previously untreated patients compared alemtuzumab given three times a week with chlorambucil given monthly; after a median follow-up of 24 months, the PFS favored alemtuzumab (hazard ratio [HR] = 0.58; 95% confidence interval [CI], 0.43-0.77; P = .0001).[44][Level of evidence: 1iiDii] However, this trial demonstrated no difference in the secondary endpoint of survival. Also, the choice of chlorambucil as the comparison arm is problematic because this drug is usually not a first-line choice today and because other standard drugs or combinations, often employing fludarabine, have a much better PFS. This agent shows activity (>50% response rate in 91 previously treated patients) in the setting of chemotherapy-resistant disease.[48] The subcutaneous route of delivery 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.[49,50,51]. Profound and long-lasting immunosuppression has been seen, which mandates monitoring for reactivation of cytomegalovirus and prophylaxis for pneumocystis and herpes virus infections.[52]
10. Bone marrow and peripheral stem cell transplantations are under clinical evaluation.[53,54,55,56,57,58] Patients younger than 60 years with adverse prognostic factors are very likely to die from CLL. These types of patients are candidates for clinical trials that employ high-dose chemotherapy and immunotherapy with autologous peripheral stem cell support or myeloablative and nonmyeloablative allogeneic peripheral stem cell transplantation.[53,54,55,56,57,58,59,60,61,62,63,64,65] Although most patients who attain complete remission after autologous stem cell transplantation eventually relapse, a survival plateau for allogeneic stem cell support suggests an additional graft-versus-leukemia effect.