Augmented Reduced-Intensity Regimen Does Not Improve Postallogeneic Transplant Outcomes in Acute Myeloid Leukemia

Abstract

PURPOSE Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia: Who, When, and How?

“…This identified a poor prognostic impact of a 0.2% threshold of residual disease. However, even in the MRD positive arm, only approximately 50% of patients relapsed: not only suggesting further strategies to identify patients at risk of relapse are required (14), but contrary to previously held opinions, this sizeable proportion of patients with high risk AML may be salvageable with an allo-SCT.…”

“…This debate has been reinvigorated in recent years by two key innovations: the widespread use of MRD technologies in patients with AML (80) and the increasing availability of novel pharmacological agents that may be applied at different treatment stages (81) (Figure 2). The adverse impact of pre-transplant MRD on post-transplant outcomes has been increasingly widely recognized (14,82) and this may inform pretransplant treatment strategies. Furthermore, emerging data suggest that conditioning intensity and potentially graft-versushost disease prophylaxis strategies may influence the poor prognostic impact of pre-transplant MRD (83).…”

“…This draws comparison to the outcomes of younger adults with a partial response to the first cycle of induction chemotherapy who have a similar overall outcome as compared to patients who have a CR or CRi but have MFC MRD positivity (10). Two prospective studies have demonstrated the importance of pre-transplant MRD (14,83) in patients with AML or high risk MDS. The FIGARO study investigated the impact of pretransplant MFC MRD in 244 patients entered into a randomized comparison between FLAMSA-Bu-RIC regimen and a control RIC arm.…”

“…The high relapse rates associated with RIC regimens, for patients with high risk AML resulted in the development of the FIGARO study, which compared the outcomes of a standard RIC arm with an augmented RIC schedule with sequential chemotherapy (FLAMSA-Bu) which had shown promising results in early studies in patients with primary refractory disease (112). However, this randomized controlled study demonstrated no improvement in relapse risk from the FLAMSA-Bu regimen as compared to a standard control arm (14).…”

“…Accurate prediction of these parameters has been refined by progress in both risk stratification utilizing clinical, cytogenetic and molecular genetic data as well as advances in prediction of the risk of allo-SCT (5)(6)(7)(8)(9). Increasingly, randomized controlled trials are informing critical questions concerning relapse risk in patients treated with IC alone (10) and informing the personalization of transplant strategies (11)(12)(13)(14). Cooperative transplant trials networks such as the US BMT CTN and the UK transplant cooperative IMPACT will play an increasingly important role in optimizing outcomes after allo-SCT in AML (15).…”