Minimal Residual Disease (MRD) Based Preemptive 5–Azacytidine Treatment Can Prevent or Delay Imminent Relapse In Patients with High-Risk MDS or AML After Allogenic HSCT – Results of the “RELAZA” Trial

Besides GVHD, relapse is one of the major challenges in the care of patients with MDS or AML undergoing allogeneic hematopoietic stem cell transplantation (HSCT). However, relapse can be predicted in case of CD34-expression on the leukemic clone by a sensitive chimerism analysis in sorted CD34+ peripheral blood cells. If CD34+ donor cells drop below 80%, relapse is inevitable within 6–8 weeks in the absence of interventions like immediate cessation of immunosuppressive drugs or the administration of DLI. However, both approaches often result in clinically significant GVHD.

We report results of an ongoing phase II clinical trial evaluating the efficacy of 5-azacitidine (5-aza) to treat MRD and thus prevent hematological relapse in patients with CD34+ AML or MDS and a decreasing CD34-donor chimerism after allogenic HSCT. Therefore, a total of 60 patients with CD34+ MDS (n=5) or AML (n=55) were prospectively screened after HSCT for a decreasing chimerism of donor CD34+ cells in the peripheral blood. In case of MRD and consequently imminent relapse, defined as a drop of donor CD34+ cells below 80%, 5-aza was given at a dose of 75mg/m²/d s.c. day 1–7. A total of 4 cycles every 28 days were allowed. Patients showing either insufficient CD34-chimerism response, i.e. an increase but below 80%, or again decreased below the cut-off were eligible for a second treatment phase.

A median of 158 days after HSCT, 20 (CR1: n=3, CR2: n=4, PR1: n=3, PR2: n=1, PD: n=3 prior to HSCT) out of 59 patients screened entered the treatment phase of the study with a median of 21% (range 0–79%) CD34+ donor cells in the peripheral blood (PB). However, a complete overall PB donor chimerism and less than 5% marrow blasts were documented in all patients before 5-aza treatment.

Currently, 19 patients are evaluable for response one month after the 4^th cycle of 5-aza. As a result, 10 out of 19 patients (53%) showed a complete clearance of MRD defined as an increase of CD34-donor chimerism > 80%. In 2 patients (10%) an increase in CD34-donor cells but to less than 80% was observed. Additionally, 3 patients (16%) demonstrated no increase in CD34-donor chimerism but did not develop hematological relapse while on therapy. Four patients (21%) relapsed during therapy (between cycle 2 and 4). Out of the 10 complete responders, there were 3 patients (30%) again showing an increase in MRD after a median of 139 days after the end of 5-aza treatment with all again responding to repeated 5-aza treatment.

Reversible neutropenia grade 3/4 occurred in 76% of the patients whereas thrombocytopenia grade 3/4 was observed in 65%. There were 7 patients who showed clinical signs of graft versus host disease (GvHD) under therapy with 5-aza, which in 6 of them already existed before the initiation of 5-aza treatment.

Preemptive treatment with 5-aza seems to be a potent strategy to prevent or delay hematological relapse of patients with MDS or AML and MRD after allogeneic HSCT.

Platzbecker:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.