Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial

Abstract

A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

Fig. 1. CONSORT diagram.

Two hundred patients were registered. Sixteen patients were ineligible. Seven patients appeared to be higher risk IPSS 1.5 and two patients were not treated with standard ESA/G-CSF before study entry. One patient appeared to be not lenalidomide-naïve. In three patients the diagnosis of MDS could not be confirmed, one patient suffered from a second active malignancy, one patient had ANC counts < 0.8 at study entry and one patient was registered twice.

Fig. 2. Progression-free survival and overall survival.

Kaplan–Meier-estimated progression-free survival (PFS, panel A) and overall survival (OS, panel B) by arm A vs. arm B (HOVON89).

Fig. 3. Determinants of response to lenalidomide by flow cytometry in non-del(5q) MDS.

Kaplan–Meier-estimated erythroid hematological Improvement (HI-E) according to IWG2006; A percentages of BM progenitor B-cells; B percentages of bone marrow (BM) total lymphocytes; C combination of percentage of BM lymphocytes and progenitor B-cells.

Fig. 4. Determinants of response to lenalidomide by next-generation sequencing.

Kaplan–Meier estimated erythroid hematological Improvement (HI-E) according to IWG2006 by A number of mutations; B SF3B1 mutation; C VAF percentages i.e., < or >20% of SF3B1 mutation in non-del(5q) and del(5q) MDS; D VAF percentage i.e., < or ≥20% of SF3B1 mutation in non-del(5q) MDS only and E VAF percentage i.e. < or ≥20% of SF3B1 mutation in MDS del(5q).