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.

FIG 1.

Trial CONSORT diagram. FBA, fludarabine/busulphan/alemtuzumab; FB-ATG, fludarabine/busulphan/antithymocyte globulin; FMA, fludarabine/melphalan/alemtuzumab; FLAMSA-Bu, fludarabine/amsacrine/cytarabine-busulphan.

FIG 2.

(A) OS, (B) EFS, and (C) CIR by conditioning regimen in the intention-to-treat population. 85% CIs are reported for overall survival to align with the type I error rate applied in the sample size calculation (described in the Data Supplement). CIR, cumulative incidence of relapse; EFS, event-free survival; FLAMSA-Bu, fludarabine/amsacrine/cytarabine-busulphan; HR, hazard ratio; OS, overall survival.

FIG 3.

(A) CIR by conventional MFC-MRD status, (B) CIR by conventional MFC-MRD with 0.2% cutoff, (C) CIR by unsupervised (computational) MFC-MRD with 1% cutoff, (D) CIR by unsupervised (computational) combined MFC-MRD test status. Impact of flow cytometric MRD on outcomes of transplanted patients are shown with comparison of results from conventional and unsupervised (computational) analysis approaches. Unsupervised MFC-MRD cutoff is higher than conventional MFC-MRD as the former values summate all quantifiable nonoverlapping abnormal blast subpopulations from an antibody combination, whereas conventional MFC-MRD values are from a single LAIP. UnSup-combined MRD is unsupervised MRD applying criteria of MRD-positive = aberrant blasts in at least two of the three antibody combinations (standard and stem cell) and MRD-negative or equivocal = aberrant blasts in 0-1 of 3 antibody combinations. CIR, Cumulative incidence of relapse; LIAP, leukemia-associated immunophenotype; MFC-MRD, flow cytometric measurable residual disease; UnSup, unsupervised (computational) MRD analysis.

FIG 4.

(A) OS by month 3 Chimerism with pretransplant MRD status and (B) CIR by month 3 Chimerism with pretransplant MRD status. Outcomes are for transplanted patients who were alive and relapse-free at day + 100. MRD status is by conventional flow MRD. Negative—full, pretransplant MRD-negative and month 3 full donor T-cell chimerism. Positive—full, pretransplant MRD-positive and month 3 full donor T-cell chimerism. Negative—mixed, pretransplant MRD-negative and month 3 mixed donor T-cell chimerism. Positive—mixed, pretransplant MRD-positive and month 3 mixed donor T-cell chimerism. CIR, Cumulative incidence of relapse; MRD, measurable residual disease; OS, overall survival.