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Chlorambucil, rituximab and lenalidomide in CLL
in combination with rituximab was previously described and was proven to be safe and effective.15,24
Following induction-I, patients received an additional six cycles of monotherapy with lenalidomide 10 mg/day. As previously reported, responses can improve with lenalidomide consolidation treatment.11,25-27 In addition, the CLLM1 study showed that lenalidomide (5-10-15 mg/day) can be efficaciously used as maintenance treat- ment, prolonging the time to progression as compared with placebo, in first-line patients with CLL who do not achieve minimal residual disease negativity following chemoimmunotherapy induction.25
Although lenalidomide-specific toxicity remains a con- cern, an individualized dose-escalation schedule is feasi- ble and results in an acceptable toxicity profile and less frequent occurrence of tumor lysis syndrome and tumor flare reactions. Grade 3-4 toxicities were reported in 26 (49%) patients. The most frequently reported toxicities were infections and gastrointestinal disorders. Despite prophylaxis with granulocyte colony-stimulating factor, 64% and 73% of patients developed grade 3-4 neutrope- nia. Similar percentages were observed in the GIMEMA trial, in which patients were treated with a combination of fludarabine, lenalidomide and rituximab.9 The rate of grade 3-4 toxicities reported with ofatumumab and chlo- rambucil in the COMPLEMENT-1 trial was 50%,21 which is comparable to the rate in our study. Treatment with ibrutinib, as described in the PCYC-1102/1103 studies,4 was less toxic than treatment with chlorambucil, ritux- imab and lenalidomide.
The ORIGIN study, in which lenalidomide monothera- py was compared with chlorambucil, was stopped pre- maturely after an imbalance in deaths and treatment-
emergent adverse events in the lenalidomide arm.10 Based on these observations, lenalidomide monotherapy was not recommended as first-line treatment in CLL patients, particularly in those who are elderly and/or frail. Although our study has shown that adverse events and deaths can be reduced by using individualized dose schedules, intensive monitoring is required. The high death rate observed in the ORIGIN study in lenalido- mide-treated patients10 was not replicated in our study.
Due to rapid developments, the clinical impact of our study might be limited. Although chemo-immunothera- py is still considered a standard first-line option in CLL patients without del17p/TP53 mutation, phase 2 as well as phase 3 studies examining new chemotherapy-free regimens show a high proportion of minimal residual dis- ease-negative responses.28 Nevertheless, data currently available imply that patients will relapse even following treatment with novel agents. Based on the findings of this study and on lenalidomide’s unique mechanisms of action,6 there might be a role for this drug or for the newer immunomodulatory treatments either in combina- tion with novel agents, or in patients who are not eligible for novel therapies such as ibrutinib.
In conclusion, our study showed that triple treatment with chlorambucil, rituximab and lenalidomide is an effec- tive therapy in previously untreated elderly and FCR-unfit patients with CLL. Intensive monitoring is of paramount importance to minimize toxicity and ensure safety.
Acknowledgments
The authors would like to thank the HOVON109-trial team of the Hovon Data Centre for their help with the trial manage- ment and central data management.
References
1. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting condi- tions. N Eng J Med. 2014;370(12):1101- 1110.
2. Hallek M. Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratifica- tion, and treatment. Am J Hematol. 2017;92(9):946-965.
3. Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015;29:16024.
4. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Eng J Med. 2015;373(25):2425-2437.
5. Landau DA, Sun C, Rosebrock D, et al. The evolutionary landscape of chronic lympho- cytic leukemia treated with ibrutinib tar- geted therapy. Nat Commun. 2017;8(1): 2185.
6. Kater AP, Tonino SH, Egle A, Ramsay AG. How does lenalidomide target the chronic lymphocytic leukemia microenvironment? Blood. 2014;124(14):2184-2189.
7. Itchaki G, Brown JR. Lenalidomide in the treatment of chronic lymphocytic
leukemia. Expert Opin Investig Drugs.
2017;26(5):633-650.
8. Browning RL, Byrd WH, Gupta N, et al.
Lenalidomide induces interleukin-21 pro- duction by T cells and enhances IL21-medi- ated cytotoxicity in chronic lymphocytic leukemia B cells. Cancer Immunol Res. 2016;4(8):698-707.
9. Mauro FR, Carella AM, Molica S, et al. Fludarabine, cyclophosphamide and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia. A multicenter phase I–II GIMEMA trial. Leuk Lymphoma. 2017;58(7):1640-1647.
10. Chanan-Khan A, Egyed M, Robak T, et al. Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial). Leukemia. 2017;31(5):1240.
11. Chen CI, Paul H, Wang T, et al. Long term follow up of a phase 2 trial of single agent lenalidomide in previously untreated patients with chronic lymphocytic leukaemia. Br J Haematol. 2014;165(5):731-733.
12. Badoux XC, Keating MJ, Wen S, et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood. 2011;118(13):3489-3498.
13. Ferrajoli A, Lee B-N, Schlette EJ, et al. Lenalidomide induces complete and partial
remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008;111(11):5291-5297.
14. James DF, Werner L, Brown JR, et al. Lenalidomide and rituximab for the initial treatment of patients with chronic lympho- cytic leukemia: a multicenter clinical-trans- lational study from the chronic lymphocyt- ic leukemia research consortium. J Clin Oncol. 2014;32(19):2067-2073.
15. Thompson PA, Rozovski U, Keating MJ, et al. The addition of CD20 monoclonal anti- bodies to lenalidomide improves response rates and survival in relapsed/refractory patients with chronic lymphocytic leukaemia relative to lenalidomide monotherapy–the MD Anderson Cancer Center experience. Br J Haematol. 2015;171(2):281-284.
16. Ferrajoli A, Badoux XC, O'Brien S, et al. Combination therapy with lenalidomide and rituximab in patients with relapsed chronic lymphocytic leukemia (CLL). Blood. 2009;114(22):206-206.
17. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;111 (12):5446-5456.
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