Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial

Abstract

This study evaluated azacitidine as treatment of minimal residual disease (MRD) determined by a sensitive donor chimerism analysis of CD34+ blood cells to pre-empt relapse in patients with CD34+ myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). At a median of 169 days after HSCT, 20/59 prospectively screened patients experienced a decrease of CD34+ donor chimerism to <80% and received four azacitidine cycles (75 mg/m2/day for 7 days) while in complete hematologic remission. A total of 16 patients (80%) responded with either increasing CD34+ donor chimerism to ⩾80% (n=10; 50%) or stabilization (n=6; 30%) in the absence of relapse. Stabilized patients and those with a later drop of CD34+ donor chimerism to <80% after initial response were eligible for subsequent azacitidine cycles. A total of 11 patients (55%) received a median of 4 (range, 1–11) additional cycles. Eventually, hematologic relapse occurred in 13 patients (65%), but was delayed until a median of 231 days (range, 56–558) after initial decrease of CD34+ donor chimerism to <80%. In conclusion, pre-emptive azacitidine treatment has an acceptable safety profile and can substantially prevent or delay hematologic relapse in patients with MDS or AML and MRD after allogeneic HSCT.

Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT

“…Most patients (if not all) will progress after AZA, even those patients who could achieve an initial response. Early administration of AZA after transplant may allow to improve these results as suggested by Platzbecker et al, 27 who have shown that preemptive AZA therapy rather than salvage therapy could delay hematological relapse. With this background, we are currently conducting a prospective trial using the combination of early preemptive administration of AZA followed by DLI in high-risk myeloid malignancies.…”

Prognostic and therapeutic implications of minimal residual disease at the time of transplantation in acute leukemia

“…35,39,[87][88][89][90] Additional (pre-emptive) post-HCT therapy Useful additional post-HCT therapy could encompass conventional chemotherapies (ideally non-cross-resistant to those used for prior therapies), Ab-based therapeutics, epigenetic modifying drugs and/or molecularly targeted agents. Supporting this strategy, Platzbecker et al 91 observed that 16 out of 20 patients with CD34 þ AML or myelodysplastic syndromes who received the DNA methyltransferase I inhibitor, azacitidine, after they experienced a decrease in CD34 þ donor chimerisms to o80% responded with either increasing donor chimerism or stabilization thereof. Although, at the time of data cutoff, 13 of 20 patients had relapsed within a median of 231 (range, 56-558) days, a comparison with historic controls suggested that azacitidine could at least substantially delay, and in some cases possibly prevent, relapses.…”

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation

“…In this regard, several groups are investigating the role of 5-azacytidine as part of a maintenance treatment after allogeneic hematopoietic cell transplantation in high-risk AML patients as demethylating agents have been shown to increase the GvL effect while reducing GvHD. 18,19 The role of lenalidomide as potential immunomodulator after allogeneic hematopoietic cell transplantation remains controversial as it not only increased the GvL effect, but also resulted in increased GvHD. 20 Finally, a promising approach in reducing relapse rates could be vaccination concepts with peptides such as WT-1, which is highly expressed in the majority of AML.…”