Early Lenalidomide Maintenance to Prevent Relapse of High-Risk MDS and AML Patients with Del(5q) Following Allogeneic HCT - Results of the “LENAMAINT” Trial

Chromosome 5 abnormalities in patients (pts) with acute myeloid leukemia (AML) or advanced myelodysplastic syndrome (MDS) are mostly associated with a poor outcome. Although allogeneic hematopoietic stem cell transplantation (HCT) is the treatment approach with the highest curative potential, early relapse rates following HCT are still considerably high. Since therapeutic options in these pts are often limited, the prevention of relapse represents a major challenge. Lenalidomide (LEN) has been successfully used in MDS pts with del(5q) cytogenetic abnormalities. Besides a direct anti-proliferative effect on del(5q) progenitors, its immunmodulatory function might also enhance T-or NK cell mediated GVL effects. Therefore it could be an effective maintenance drug to prevent relapse after allogeneic HCT in pts with MDS or AML and del(5q) abnormalities.

We report results of a prospective multicenter phase II clinical trial evaluating the efficacy to prevent relapse as well as safety of LEN maintenance following HCT in pts with MDS or AML and cytogenetic abnormalities including del(5q). Only pts achieving a complete hematological remission (CR) after HCT were eligible. In the absence of toxicity or relapse pts could receive up to 12 cycles of LEN maintenance at a dose of 10 mg/day orally, for 21 days, with 7 days rest (28 day cycle).

Ten pts with either MDS (n=1, RAEB-1) or AML (n=9) with a median age of 65 years (range 40–72) were included. The disease status prior to allogeneic HCT were CR in 4 pts, relapse/refractory disease in 3 pts, unknown in 2 pts while the MDS pt had not received any prior therapy. A complex aberrant karyotype including del(5q) was documented in 5 pts. Two pts had an additional cytogenetic abnormality besides del(5q) and 3 pts displayed single del(5q). While three pts underwent allogeneic HCT from a matched sibling donor, four pts were transplanted from a matched unrelated and three from a mismatched unrelated donor (single allele or antigen mismatch). Conditioning was of reduced intensity and was followed by the infusion of peripheral blood stem cells in all pts. LEN maintenance therapy was started after complete hematopoietic recovery with documented complete remission at a median of 2.5 months (range 2–4 months) following HCT. After a median of 4 cycles 8 of 10 pts (80%) had to discontinue LEN treatment due to relapse (n=4), development of severe GvHD grade 2–4 (n=2) or other adverse events (n=2). Altogether, 6 of 10 pts (60%) developed severe acute GvHD grade 3–4 within the first 2 cycles of LEN maintenance. All pts were still under systemic immunosuppression at the time of GvHD appearance. Other common adverse events were gastrointestinal side effects (nausea) and myelotoxicity. Reversible neutropenia grade 3/4 was documented in 3 of 10 (30%) of the pts while thrombocytopenia grade 3/4 occurred in 4 of 10 (40%) of them. During the treatment course specific T cell responses against different tumor/leukemia-associated antigens (TAAs/LAAs) using ELISpot analysis for Interferon alpha and granzyme B were measured. Sufficient T cells before and during LEN treatment were only available in one pt, who showed an increase of specific T cell responses against the TAAs/LAAs. With a median follow-up of 254 days (range 32–677) from the start of LEN maintenance, 5 of 10 pts (50%) are currently alive with four pts in continuous CR since the time of HCT. The study was stopped prematurely because of suspected induction of GVHD by LEN.

Early LEN maintenance to prevent relapse following HCT in pts with MDS or AML and del(5q) may be associated with the induction of severe acute GVHD.

Kobbe:Celgene: Consultancy, Research Funding; Ortho Biotec: Consultancy. Germing:Celgene: Consultancy, Research Funding. Bornhaeuser:Celgene: Honoraria. Platzbecker:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.