Prospective phase II study of prophylactic low-dose azacitidine and donor lymphocyte infusions following allogeneic hematopoietic stem cell transplantation for high-risk acute myeloid leukemia and myelodysplastic syndrome

Abstract

Thirty patients, with high-risk acute myeloid leukemia (AML, n = 20) or myelodysplastic syndrome (MDS, n = 10), were enrolled in a phase II trial entailing prophylactic post-transplant azacitidine (AZA) plus escalated doses of donor lymphocyte infusion (DLI). The median number of AZA cycles was 5 (1-12) with 10 patients (33%) completing the 12 projected cycles. DLI were performed in 17 patients: 5 received one DLI, 2 received 2 DLI and 8 received 3 infusions. AZA was well tolerated, but discontinued in 20 patients primarily due to graft-versus-host disease (GvHD) and relapse. The cumulative incidence (CI) of grade 1-3 acute GvHD was 31.5% and the chronic GvHD CI was 53% at 2 years. At a median follow-up of 49 months (27-63), 18 patients are alive. The overall and disease-free survivals are 65.5% (CI 95% = 48.2-82.8) at 2 years. Cause of death was mainly relapse for 9 patients. The median time to relapse was 7 months (2.5-58) and the cumulative incidence of relapse at 2 years was 27.6% (CI 95% = 12.8-44.6). These results confirm that AZA is well tolerated as a prophylactic treatment to reduce the risk of post-transplantation relapse and compared favorably to those of patients who receive no post-transplant maintenance.

Molecular Detection of Minimal Residual Disease before Allogeneic Stem Cell Transplantation Predicts a High Incidence of Early Relapse in Adult Patients with NPM1 Positive Acute Myeloid Leukemia

“…Although alloHSCT improves outcomes, the therapeutic benefit of alloHSCT in patients with persistent MRD positivity is only partial, which is mainly due to a high risk of relapse during the first year after alloHSCT. Thus, an effective prophylactic or preemptive therapy in post-transplantation might be important in order to reduce the rate of relapse [14,15,16,17,18]. Moreover, although the relatively small number of patients precludes drawing definitive conclusions, among patients who were MRD-positive after two consolidation cycles, we observed a negative effect of increasing levels of MRD on OS and DFS.…”

Measurable residual disease (MRD) testing for acute leukemia in EBMT transplant centers: a survey on behalf of the ALWP of the EBMT

“…This will likely increase the predictive value of pretransplant MRD status on relapse risk and OS above what has been observed with MRD positivity as currently ascertained in the EBMT registry database. Further, having these data in the registry will also benefit to study assessing the impact of prophylactic intervention such as posttransplant immunosuppression discontinuation, donor lymphocyte infusion, or targeted low-intensity therapies on leukemia progression [34][35][36][37][38][39].…”

Immune escape and immunotherapy of acute myeloid leukemia

“…More recently, studies performed in epithelial malignancies demonstrated that HMAs can promote reactivation of dormant human endogenous retroviruses, which, upon transcription, elicit innate immune sensing and induction of adaptive responses (110,111). In addition, azacitidine was shown to improve T cell repertoire in MDS (112), and its efficacy in combination with donor lymphocyte infusion in the post-alloHSCT setting supports azacitidine's ability to induce tumor-specific responses (113)(114)(115).…”