Current Clinical Trials

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:

Among all of the large randomized prospective trials of untreated patients, almost all have demonstrated statistically significant improvements in response rates, event-free survival, and progression-free survival, but no trial has shown patients with statistically significant improvement in overall survival (OS).[1] Improvements in response rates that maximize the clearance of minimal residual disease have not translated into demonstrable survival benefits on the basis of any randomized study.[1] More intensive regimens carry the risk of more substantial toxic effects without a demonstrated survival benefit; their use is unproven.[2]

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

1. Observation in asymptomatic or minimally affected patients.[3] Outside of the context of a clinical trial, treatment for asymptomatic or minimally affected patients with chronic lymphocytic leukemia 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, an anti-CD20 monoclonal antibody.[4-7] 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. Oral alkylating agents with or without corticosteroids.[8] The French Cooperative Group on Chronic Lymphocytic Leukemia randomized 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment and found no survival advantage for chlorambucil.[9][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.[3][Level of evidence: 1iiA]



4. Fludarabine, 2-chlorodeoxyadenosine, or pentostatin as seen in the CLB-9011 trial, for example.[10-15]

   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.[16-19] All of these trials showed higher or equivalent response rates for the purine analog and most showed an improvement in progression-free survival, though none showed an advantage in OS.[16-20][Level of evidence: 1iiDiii] All of the trials demonstrated higher toxic effects with the purine analogs, especially granulocytopenic infections, herpes infections, autoimmune hemolytic anemia, and persistent thrombocytopenia.[21] The increased risk of infection may persist for months or years after treatment with a purine analog.[20,22] 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.[22] Purine analogs cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines.[19]




5. Combination chemotherapy.

   Among all of the large randomized prospective trials of untreated patients (such as GCLLSG-CLL4, ECOG-2997 and LRF-CLL4), for example, almost all have demonstrated statistically significant improvements in response rates, event-free survival, and progression-free survival, but no trial has shown patients with statistically significant improvement in OS.[23-25] Improvements in response rates that maximize the clearance of minimal residual disease have not translated into demonstrable survival benefits on the basis of any randomized study. More intensive regimens carry the risk of more substantial toxic effects without a demonstrated survival benefit; their use is unproven.[2]

   • Fludarabine plus rituximab as seen in the CALGB-9712 and CALGB-9011 trials.[26]
   • Fludarabine plus cyclophosphamide plus rituximab.[27,28]
   • Fludarabine plus cyclophosphamide versus fludarabine plus cyclophosphamide plus rituximab as seen in the NCT00090051 trial.
   • Pentostatin plus cyclophosphamide plus rituximab as seen in the MAYO-MC0183 trial, for example.[29,30]
   • CVP: cyclophosphamide plus vincristine plus prednisone.[31]
   • CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[32]
   • Fludarabine plus cyclophosphamide versus fludarabine as seen in the LRF-CLL4 trial, for example.[24,25]
   • Fludarabine plus chlorambucil as seen in the CALGB-9011 trial, for example.[33]

   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.[3][Level of evidence: 1iiA]




6. Involved-field radiation therapy. Relatively low doses of radiation therapy will effect 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).



7. Alemtuzumab (campath-1H), the monoclonal antibody directed at CD52, has been used as first-line therapy and after relapse from prior chemotherapy.[34-37] 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 progression-free survival favored alemtuzumab (hazard ratio [HR] = 0.58; 95% confidence interval [CI], 0.43–0.77; P = .0001).[34][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 progression-free survival. This agent shows activity (>50% response rate in 91 previously treated patients) in the setting of chemotherapy-resistant disease.[38] The subcutaneous route of delivery is preferred to the intravenous route to avoid acute allergic reactions. Profound and long-lasting immunosuppression has been seen, which mandates monitoring for reactivation of cytomegalovirus and prophylaxis for pneumocystis and herpes virus infections.



8. Bone marrow and peripheral stem cell transplantations are under clinical evaluation.[39-44] Patients younger than 60 years with adverse prognostic factors are very likely to die from chronic lymphocytic leukemia. These types of patients are candidates for clinical trials that employ high-dose chemotherapy and immunotherapy with autologous peripheral stem cell support.[45] Myeloablative and nonmyeloablative allogeneic peripheral stem cell transplantation are also under clinical evaluation.[39-44,46-51] 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.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References

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39. Doney KC, Chauncey T, Appelbaum FR, et al.: Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplant 29 (10): 817-23, 2002.  [PUBMED Abstract]
    
    
40. Schetelig J, Thiede C, Bornhauser M, et al.: Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol 21 (14): 2747-53, 2003.  [PUBMED Abstract]
    
    
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42. Moreno C, Villamor N, Colomer D, et al.: Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol 23 (15): 3433-8, 2005.  [PUBMED Abstract]
    
    
43. Khouri IF, Keating MJ, Saliba RM, et al.: Long-term follow-up of patients with CLL treated with allogeneic hematopoietic transplantation. Cytotherapy 4 (3): 217-21, 2002.  [PUBMED Abstract]
    
    
44. Pavletic SZ, Khouri IF, Haagenson M, et al.: Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research. J Clin Oncol 23 (24): 5788-94, 2005.  [PUBMED Abstract]
    
    
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