A phase 2 trial of high dose lenalidomide in patients with relapsed/refractory higher‐risk myelodysplastic syndromes and acute myeloid leukaemia with trilineage dysplasia

Abstract

Limited therapies exist for patients with refractory and relapsed (RR) higher-risk myelodysplastic syndromes (HR-MDS) and acute myeloid leukaemia with trilineage dysplasia (AML-TD). High dose (HD) lenalidomide (50 mg) has activity as frontline therapy in elderly AML but there is limited data in the RR setting. This phase II trial included patients with RR HR-MDS or AML-TD at 2 doses of lenalidomide (15 or 50 mg) on days 1-28 of 42-day cycles. The primary endpoint was response rate using the 2006 International Working Group criteria. Overall survival (OS) was estimated by Kaplan-Meier methods. Of 27 patients enrolled, 59% had HR-MDS and 31% AML-TD. No patient had isolated del5q; 41% had poor-risk karyotype. Of 9 patients treated at 15 mg, 56% completed ≥2 cycles with no responses. Of 18 patients treated at 50 mg, 39% completed ≥2 cycles and 11% responded but all experienced grade 3/4 neutropenic fever/infection. The 60-day mortality rate was 30%. Median OS was 114 days with 19% surviving ≥1 year. The study was terminated due to lack of robust clinical activity. In conclusion, lenalidomide at 15 mg is ineffective in RR myeloid malignancies. Continous high dosing schedules are poorly tolerated and minimally active. Further evaluation should be considered in upfront intensive chemotherapy-ineligible patients.

How I treat MDS after hypomethylating agent failure

“…In highrisk MDS after HMA failure, treatment with standard-(15 mg) or high-dose (50 mg) lenalidomide resulted in scarce/absent clinical activity and extreme toxicity. 56 However, there are reports of higher response rates (40%) in HMA-refractory MDS patients, with CR in those carrying del5q. 57 High doses of lenalidomide induced mCR in 33% and HI in 8% of HMA-refractory patients.…”

Heterogeneity in refractory acute myeloid leukemia

“…The findings herein suggest that small-molecule inhibitors targeting aberrant biological pathways can produce antiproliferative effects in otherwise refractory leukemia cells. Drugs with apparently low efficacy using this ex vivo methodology, such as venetoclax and lenalidomide, may be effective clinically, however, as combination treatment or in specific disease subsets (34,52). An assay with viability as the read-out may underestimate the efficacy of drugs with noncytotoxic mechanisms of action.…”

Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications

“…Given the successful application of lenalidomide in low and intermediate‐1 risk MDS, several trials have examined the potency of lenalidomide monotherapy in intermediate‐2 and HR‐MDS (Table ) . In a phase 2 study, low dose lenalidomide (10 mg) was shown to result in transfusion independence in 26% of patients with intermediate‐2 and HR‐MDS with 5q− (Table ) .…”

“…Encouraged by these results, a phase 2 clinical trial recently examined the efficacy of even higher doses of lenalidomide (15 mg and 50 mg) in patients with HR‐MDS and AML with trilineage dysplasia . Unfortunately, only a minority of patients had a clinical response at the cost of high rates of toxicity (Table ).…”