Measurable residual disease, conditioning regimen intensity, and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: A registry analysis of 2292 patients by the Acute Leukemia Working Party European Society of Blood and Marrow Transplantation

Abstract

Patients with acute myeloid leukemia (AML) in morphological first complete remission (CR1) pre-allogeneic hematopoietic cell transplantation (HCT) may have measurable residual disease (MRD) by molecular and immunophenotyping criteria. We assessed interactions of MRD status with HCT conditioning regimen intensity in patients aged <50 years (y) or ≥50y. This was a retrospective study by the European Society for Blood and Marrow Transplantation registry. Patients were >18y with AML CR1 MRD NEG/POS and recipients of HCT in 2000-2015. Conditioning regimens were myeloablative (MAC), reduced intensity (RIC) or non-myeloablative (NMA). Outcomes included leukemia free survival (LFS), overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), chronic graft-vs-host (cGVHD), and GVHD-free and relapse-free survival (GRFS). The 2292 eligible patients were categorized into four paired groups: <50y MRD POS MAC (N = 240) vs RIC/NMA (N = 58); <50y MRD NEG MAC (N = 665) vs RIC/NMA (N = 195); ≥50y MRD POS MAC (N = 126) vs RIC/NMA (N = 230), and ≥50y MRD NEG MAC (N = 223) vs RIC/NMA (N = 555). In multivariate analysis RIC/NMA was only inferior to MAC for patients in the <50y MRD POS group, with worse RI (HR 1.71) and LFS (HR 1.554). Patients <50Y MRD NEG had less cGVHD after RIC/NMA HCT (HR 0.714). GRFS was not significantly affected by conditioning intensity in any group. Patients aged <50y with AML CR1 MRD POS status should preferentially be offered MAC allo-HCT. Prospective studies are needed to address whether patients with AML CR1 MRD NEG may be spared the toxicity of MAC regimens. New approaches are needed for ≥50y AML CR1 MRD POS.

Allogeneic stem cell transplantation following relapse post autologous stem cell transplantation in adult patients with acute myeloid leukemia: A retrospective analysis of 537 patients from the Acute Leukemia Working Party of the EBMT

“…This finding is in accordance with the results of another recent EBMT study of the impact of conditioning with RIC and MAC and MRD status at time of allotransplant in 2292 adult patients with AML in CR1. In this study, MAC and RIC gave similar outcomes except in younger patients (less than 50 years of age) with MRD positive detection, where MAC was associated with lower RI and better outcome . This finding might probably also apply to relapses post ASCT where a positive MRD status in younger patients in CR would favor a MAC regimen.…”

Cytogenetic risk score maintains its prognostic significance in AML patients with detectable measurable residual disease undergoing transplantation in remission: On behalf of the acute leukemia working party of the European society for blood and marrow transplantation

“…These data provide a bona fide preliminary indication that additional pre‐transplant therapy for MRD positive patients may provide clinical benefit and improve post‐transplant outcomes. And, the data complement a recent ALWP/EBMT analysis suggesting superior outcomes for MRD positive patients younger than 50 years of age, with a myeloablative conditioning approach 9 . Alternatively, one may consider that the therapeutic intervention for MRD positive patients should not be in the form of additional therapy, but rather in guided donor selection as suggested by publications demonstrating that choice of alternative donors, namely umbilical cord grafts 30 or haploidentical donors 31,32 may improve on historical results with traditional donors.…”

“…Indeed, a recently published survey indicates that nearly 70% of leukemia physicians in the US use MRD on a routine basis in the clinic 1 . However, while determination of MRD status provides robust prognostic information in AML patients following induction chemotherapy, consolidation therapy prior to allogeneic stem cell transplantation (allo‐SCT), and post‐transplant, 2‐10 the role positive MRD status should play in clinical decision making remains currently undefined, reflected also in recently published guidelines 11 . Whereas a number of recent studies clearly implicate pretransplant MRD persistency in inferior patient outcome, 12,13 the notion that additional therapy prior to transplant would decrease relapse has not thus far been tested in a scientifically rigorous manner.…”

Molecular minimal residual disease negativity and decreased stem cell mobilization potential predict excellent outcome after autologous transplant in NPM1 mutant acute myeloid leukemia

“…The implementation of mutated NPM1 as target for minimal residual disease (MRD) has greatly consolidated the armamentarium how best to advise cytogenetically normal AML patients [6]. It was suggested that AML patients <50 years in CR1 with MRD-negativity may have no benefit from allogeneic SCT, whereas patients with MRD-positivity after induction may benefit from myeloablative conditioning [7]. At our center, we consistently consolidate NPM1mut/FLT3wild-type patients with autologous SCT, but also NPM1mut/FLT3-ITD-positive patients in the absence of an available donor or according to patient preference [4,[8][9][10].…”