Lenalidomide As a Second-Line Therapy after Failure of Hypomethylating Agents in Patients with Myelodysplastic Syndrome

Background: There is no standard therapy after the failure of hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS) without only providing supportive cares including transfusion or cytokine therapies when the patient is not eligible for allogeneic hematopoietic cell transplantation. Lenalidomide is the treatment of choice in case of MDS with 5q deletion. A study of lenalidomide for non-5q deletion MDS patients showed that transfusion independency rate was 26% which was relatively acceptable and suggested that lenalidomide could be used for non-5q deletion MDS patients.

Method: We conducted the prospective phase II trial to evaluate the efficacy of lenalidomide for patients who failed to HMA (ClinicalTrials.gov Identifier: NCT01673308). Patients took lenalidomide 10mg daily for 3 weeks and rested for a week. New cycle began every 4 weeks. The primary objective was the objective response rate (ORR; CR+PR+marrow CR+HI). Unknown or not evaluable response were regarded as failure. The planed sample size was 29 (P0: 10%, P1: 30%, α-error:0.5, β-error:0.2) patients. The major inclusion criteria were adult MDS by WHO classification and they should be treatment failure after HMAs (azacitidine or decitabine) which were defined as either intolerant to HMAs or progressive disease after HMA.

Results: Total 31 patients were included in this analysis. Among them, 1 patient didn’t receive study drug at all. Male was 21 (67.7%) patients. Median age was 68 (range 40-82) years. Reasons for stopping HMA were no response in 10, progression in 14, adverse events in 3 and other causes in 4 patients. WHO classification was follows; RA in 4, RARS in 1, RCMD in 8, RAEB-1 in 4, RAEB-2 in 8, MDS with 5q deletion in 2 and not known in 4 patients. IPSS at study enrollment were low (n=4), INT-1 (n=12), INT-2 (n=9), high risk (n=3) and unknown (n=3) risk. Revised IPSS were very low (n=3), low (n=3), intermediate (n=5), poor (n=2), very poor (n=8) and unknown risk (n=3). Median cycles of lenalidomide was 3 (range 0-21). The responses after 4 cycles were CR in 5, PR in 2, SD in 5, failure in 12, unknown in 7 patients. The maximal responses were CR in 5, marrow CR in 1, PR in 4, HI-E in 1, SD in 5, failure in 14 patients. Best ORR was 11/31 (35.5%) patients, with 16/31 receiving clinical benefit (52%, inclusive of SD). The toxicity profile was tolerable except for hematological toxicities including neutropenia and thrombocytopenia. Among 2 patients with 5q deletion, 1 patient achieved CR but 1 patient failed. Median overall survival was 8.936 (95% CI 0.0-19.685) months which compares with a historical estimate in HMA failures of 4.3-5.6 months. Two patients received alloHCT after progression or failure to lenalidomide. Causes of death were infection (n=8) and bleeding (n=1). Patients who failed to benefit from lenalidomide showed significantly poorer survival when comparing with patients who achieved ORR or SD (median overall survival 2.990 vs. 17.774 months; p=0.010). Among 17 patients who had achieved ORR or SD, 6 patients didn’t progress while 8 patients progressed and 3 patients were lost to follow up.

Conclusion: Lenalidomide showed reasonable response and excellent overall survival after failure of HMA in adult MDS with tolerable toxicities. Therefore, lenalidomide can be a promising option after failure of HMA even in non-5q deletion MDS.