For decades, initial therapy for chronic lymphocytic leukemia (CLL) consisted of alkylators such as chlorambucil (Leukeran). The introduction of nucleoside analogs such as fludarabine and monoclonal antibodies such as rituximab (Rituxan) markedly changed the initial therapy of CLL, particularly in the United States. Fludarabine and combination regimens such as fludarabine/cyclophosphamide (FC) have achieved higher complete response (CR) rates and progression-free survival (PFS) than chlorambucil in previously untreated CLL, but long-term overall survival has not improved, due to concurrent improvement in salvage therapy of relapsed CLL patients. Upfront chemoimmunotherapy regimens such as fludarabine/rituximab (FR) and fludarabine/cyclophosphamide/rituximab (FCR) have similarly improved CR rates and PFS in previously untreated CLL patients, but it is unclear whether overall survival is improved. Advances in cytogenetic analysis and other biologic prognostic factors have greatly enhanced clinicians' ability to risk-stratify newly diagnosed CLL patients, and knowledge of such prognostic factors is necessary to properly interpret results of clinical treatment studies. The choice of initial therapy for an individual patient should depend upon the patient's age and medical condition, cytogenetic and other prognostic factors, and whether the goal of therapy is maximization of CR and PFS or palliation of symptoms with minimal toxicity.
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.
Dr. Lin states that patients may be resistant to subsequent therapy after they have been treated successfully with combination regimens such as FCR. Perhaps lower doses of chemotherapy and fewer cycles of chemotherapy may allow patients to be responsive to subsequent salvage therapies. In addition, with a wide variety of new agents under development that are not cross-resistant with nucleosides or alkylating agents, there may be many new options for salvage therapies in the future.
Stem Cell Transplant
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a curative option for CLL via the graft-vs-leukemia-effect. The use of allogeneic transplantation is limited because of the advanced age of most patients and the higher associated nonrelapse mortality. Thus, allo-HSCT is not being used as first-line therapy. However, the evolution of risk stratification and prognostic factors in CLL and the ongoing improvements in transplantation techniques may provide the ability to better select patients earlier for allo-HSCT. As Dr. Lin mentions, patients with deletion 17(p13) are resistant to current chemotherapy regimens. These patients should be treated up-front with regimens that include alemtuzumab or, if appropriate candidates, should be considered for allo-HSCT.
With current therapies, complete remission or even a complete molecular remission does not guarantee either cure or prolongation of overall survival. Fludarabine combined with cyclophosphamide and/or rituximab has been shown to lead to longer failure-free survivals than fludarabine alone and should be used as first-line therapy in patients who can tolerate the possible associated toxicities.
For elderly patients with comorbid conditions, lower doses of chemotherapeutic drugs and fewer cycles should be considered. For patients with del(17p) who are at high risk of not responding to initial treatment or of relapsing soon after achieving remission with initial treatment, the use of alemtuzumab or early allo-HSCT should be considered.
-Michael Boyiadzis, MD, MHSC
-Steven Pavletic, MD
-Kenneth A. Foon, MD
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.