In recent years there has been considerable progress in our understanding of the biology of chronic lymphocytic leukemia (CLL) and the possible causes of the molecular basis of resistance to therapy. Furthermore, the development of prognostic indicators has led to the development of new therapeutic strategies and a better understanding of disease progression.
In this issue of ONCOLOGY, Dr. Lin provides an excellent and comprehensive review of both the historic approaches and newer therapeutic options of front-line therapy for CLL. He presents data that support the superiority of fludarabine to older chemotherapy regimens (ie, clorambucil [Leukeran], CAP [cyclophosphamide, doxorubicin [Adriamycin], prednisone], or CHOP [cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone]) in terms of achievement of complete remissions and prolongation of progression-free survival, although no significant advantage in overall survival has been demonstrated.
In addition, Dr. Lin present's the results of studies combining fludarabine with cyclophosphamide and/or riuximab (Rituxan). The combination of FCR (fludarabine, cyclophosphamide, rituximab) administered to 300 previously untreated CLL patients resulted in an overall response rate of 94%, with a 72% complete response rate, 4-year relapse-free survival rate of 77%, and 4-year overall survival rate of 83%.
In order to decrease the toxicity associated with the current doses used in the FCR regimen, we conducted a prospective study at the University of Pittsburgh Cancer Institute using different doses of the FCR combination. We reduced the fludarabine dose from 25 g/m2 to 20 mg/m2 and the cyclophosphamide dose from 250 mg/m2 to 150 mg/m2, and increased the rituximab dose to 500 mg/m2 every other week (FCR-Lite). The increased rituximab dose was based on studies suggesting that higher doses of rituximab are more effective in CLL.[1,2]
A total of 50 patients entered this study, and 42 are evaluable to date. Grade 3/4 neutropenia occurred during 29 courses (12%), with two episodes of neutropenic fever. Grade 3/4 neutropenia was noted in 51% of courses of FCR. The overall response rate among 40 evaluable patients was 100%, with 85% complete responses. All of the patients showing a complete response were tested by flow cytometry and had < 1% CD5+/CD19+ cells in their blood and bone marrow. These results suggest that FCR-Lite is highly effective, while producing considerably less neutropenia than FCR. The fact that none of the responders had residual detectable CD5/CD19-positive cells was promising, and minimal residual disease testing is currently ongoing.
To date, as pointed out by Dr. Lin, no data support the possibility that any of these combination therapies will improve overall survival, although early data suggest that establishing minimal residual disease will ultimately translate into prolonged survival and may serve as a surrogate endpoint for survival.
Other Chemotherapy Options
Dr. Lin also presents data suggesting that pentostatin may substitute for fludarabine in the FCR regimen and may be better tolerated by elderly patients, with what appears to be near comparable efficacy. Finally, the issue of alemtuzumab (Campath) either as a single agent in front-line therapy or as a consolidation therapy following chemoimmunotherapy is discussed as another option. Alemtuzumab is a highly active agent for CLL but has the disadvantage of being immunosuppressive. On the other hand, it has the advantage of being active in patients with deletion 17(p13) whose disease is not responsive to the above therapies.
1. Byrd JC, Murphy T, Howard RS, et al: Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 19:2153-2164, 2001.
2. O'Brien SM, Kantarjian H, Thomas DA, et al: Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 19:2165-2170, 2001.
3. Ahmad A, Tarhini AA, Land S, et al: Final results of lower dose fludarabine (F) and cyclophosphamide (C) and high dose rituximab (R), (FCR-Lite) for patients with untreated chronic lymphocytic leukemia (CLL) (abstract 2037). Blood 110(11 suppl), 2007.
4. Dreger P, Corradini P, Kimby E, et al: Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: The EBMT transplant consensus. Leukemia 21:12-17, 2007.