Illustrative Case Series

Current Approaches for Treating Patients with Fludarabine-resistant CLL

By Jerome Yates, MD, Hematology/Immunology Unit, National Institute on Aging, NIH. Dr. Yates reports no financial relationships relevant to this field of study.

A 58-year-old retired school principal was seen in the office because of malaise and weight loss. He had been well until 4 years ago when he was discovered, at a routine annual exam, to have lymphocytosis. At that time, he was asymptomatic and was without lymphadenopathy, splenomegaly, anemia, or thrombocytopenia. His white blood count was 17,000/cu mm, with 90% small lymphocytes. It was elected to observe initially, and he was followed at regular intervals. His white count, initially stable, rose gradually during the second year after diagnosis, and although his hemoglobin and platelet counts remained normal, he began to experience constitutional symptoms, including fatigue and night sweats. Approximately 24 months after diagnosis, he was started on chemotherapy with fludarabine, cytoxan, and rituximab (FCR). At that time, his lymphocyte count was approximately 60,000/cu mm and a CT scan revealed axillary and retroperitoneal nodes, but not bulky. The spleen was not enlarged. Peripheral blood and bone marrow were examined for prognostic markers, and his CLL cells were found to have unmutated IVGH, and approximately 40% expressed CD38. Furthermore, cytogenetic studies revealed a 17p deletion.

Chemotherapy consisted of rituximab 375 mg/m2 on day 1, fludarabine 30 mg/m2 days 1-3, and cytoxan 250 mg/m2 on days 1-3. Treatment was continued for a total of six monthly cycles; it was tolerated without delays or dose reductions. His lymphocyte count dropped to 4,000/cu mm, and there was complete resolution of lymphadenopathy (by CT). Upon completion of therapy, the patient felt well, but blood counts continued to rise, and by 3 months after chemotherapy, his lymphocyte count was 30,000 and constitutional symptoms returned. It was decided to give two additional cycles of FCR. Once again, he experienced a reduction in lymphocyte number, but the response was transient. He was seen on this occasion for consideration of second-line CLL therapy.

Case Discussion

Treatment with purine analogues, such as fludarabine, either alone or in combination, is usually highly effective in the management of chronic lymphocytic leukemia. Although in retrospect one might question the delay in starting therapy in this case, treatment delay in asymptomatic stage 0 CLL remains the standard approach.1 Choosing the FCR regimen also was most appropriate, as such treatment has been associated with overall response rates in excess of 90% and 5-year disease-free survival of approximately 70%.2,3 However, there remains much consternation on what to do when responses to FCR are sub-optimal. Responses may be achieved with other combinations, particularly with the addition of an anthracycline but, in general, the likelihood of durable remission is low with such an approach. In a patient such as the one presented, alternative approaches should be considered. Those that are currently available and that would be on my list include the following:

Alemtuzumab (Campath®) is a humanized monoclonal antibody directed at the CD52 molecule that has demonstrated activity in fludarabine-resistant CLL and is FDA approved for patients who have previously been treated with alkylating agents and for whom fludarabine has failed. In a multicenter clinical trial of such patients (n = 93), the overall response rate was 33% (2% CR, 31% PR).4 Alemtuzumab was administered on a dose-escalation schedule toward a target dose of 30 mg three times weekly, for a maximum of 12 weeks. It took, on average, 1.5 months to observe response, and the median time to disease progression, including all patients, was 4.7 months. For responders, the median time to progression was 9.5 months. A number of other trials have reported similar findings or even slightly better responses.5-7 For a review of Alemtuzumab and its use in refractory CLL, see reference 8. Notably, treatment is associated with T-cell immune deficiency, and antiviral/anti-pneumocystis prophylaxis is essential to achieve optimal results.

Lenolidomide (Revlimid®) is an immunomodulating drug with demonstrated activity for patients with multiple myeloma and myelodysplastic syndrome. Treatment with lenalidomide at 25 mg orally on days 1 through 21 of 28-day cycles produced one CR and six PRs among 23 fludarabine-resistant CLL patients,9 and similar results have been observed elsewhere.10 In general, adverse events associated with lenalidomide treatment at this dose include fatigue, thrombocytopenia, neutropenia, and gastrointestinal symptoms.

Allogeneic Stem Cell Transplant is another alternative for patients who have an appropriate matched donor and are sufficiently fit to withstand the procedure. There have been several published reports, including those using reduced-intensity conditioning regimens that have reported recurrence rates ranging from 5% to 28% at 2 years.11-13

An approach that I might take for this 58-year-old patient with fludarabine-resistant CLL would be to initiate second-line treatment with lenalidomide while performing the necessary studies to refer to a transplant center for consideration of allogeneic transplant. In my opinion, this would provide the greatest chance for achieving a durable remission.

References

1. Montserrat E, Rozman C. Current approaches to the treatment and management of chronic lymphocytic leukaemia. Drugs. 1994;47:1-9.

2. Keating MJ, et al. Early results of a chemo-immunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4079-4088.

3. Tam CS, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112:975-980.

4. Keating MJ, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: Results of a large international study. Blood. 2002;99:3554-3561.

5. Lozanski G, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004;103:3278-3281.

6. Moreton P, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol. 2005;23:2971-2979.

7. Rai KR, et al. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol. 2002;20:3891-3897.

8. Tsimberidou AM, Keating MJ. Treatment of fludarabine-refractory chronic lymphocytic leukemia. Cancer. 2009;115:2824-2836.

9. Chanan-Khan A, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006;24:5343-5349.

10. Ferrajoli A, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008;111:5291-5297.

11. Dreger P, et al. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia. 2005;19:1029-1033.

12. Schetelig J, 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. 2003;21:2747-2753.

13. Sorror ML, et al. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005;23:3819-3829.