General AML

GVL effect of Allogenic HSCT and MRD in AML patients in CR1

In Acute Myeloid Leukemia (AML), Minimal Residual Disease (MRD) assessment after induction therapy has been shown to predict for relapse and overall outcome irrespective of the type of Post-Remission Therapy (PRT) used. Furthermore, PRT with Allogenic Hematopoietic Stem Cell Transplantation (allo-HSCT) may lead to a strong reduction of relapse (Graft-versus-Leukemia [GVL] effect) in AML patients. However, it is not known whether and how the presence or absence of MRD should guide the use of allo-HSCT as PRT.

Jurjen Versluis from the Erasmus University Medical Center Cancer Institute, Rotterdam, Netherlands, and colleagues evaluated whether allo-HSCT reduces relapse compared to conventional PRT in upfront-treated patients with MRD positive or MRD negative AML in First Complete Remission (CR1). The results of the study were published in the Journal of Clinical Oncology: Precision Oncology on 15th September 2017.

Overall, 547 AML patients in CR1 after induction in three prospective, consecutive Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and the Swiss Group for Clinical Cancer Research AML trials (AML42, AML92, and AML102) and had available MRD data before PRT were included in this study. Patients were either MRD positive (n = 129, median age = 49 years) or MRD negative (n = 418, median age = 51 years). Patients received PRT consisting of allo-HSCT (n = 282), conventional PRT by a third cycle of chemotherapy (n = 160) or Autologous Hematopoietic Stem Cell Transplantation (AuSCT).

The key results of the study were:
  • 4-year Overall Survival (OS) in MRD negative and positive patients; 65% ± 2% vs 50% ± 5%, P = 0.002
  • 4-year Relapse Free Survival (RFS) in MRD negative and positive patients; 58% ± 3% vs 38% ± 4%, P < 0.001
  • Non Relapse Mortality (NRM) was not significantly different between MRD positive and MRD negative patients
  • 4-year Cumulative Incidence of Relapse (CIR) in MRD negative and positive patients; 32% ± 2% vs 54% ± 4%, P < 0.001
  • Compared to chemotherapy or AuSCT, allo-HSCT significantly reduced the incidence of relapse (Hazard Ratio [HR] of GVL effect of allo-HSCT = 0.36, P < 0.001) and also in MRD negative (HR = 0.38, P < 0.001) and MRD positive (HR = 0.35, P < 0.001) patients

The key finding was that “the GVL effect of allo-HSCT is similar in MRD positive and MRD negative patients”.

Versluis et al. concluded by noting that “a personalized application of allo-HSCT should take MRD response into account” as well as “the counterbalancing risk of NRM”. They further suggested that additional prospective studies are required to assess “whether the conversion of MRD positivity into an MRD-negativity remission before allo-HSCT further optimizes outcomes” and to explore “how the GVL effect after allo-HSCT can be optimized”.

The results of this study were presented at the 22nd Congress of the European Hematology Association (EHA) Congress, Madrid, Spain, which the AGP reported on here.

Abstract
Purpose

The detection of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) may improve future risk-adapted treatment strategies. We assessed whether MRD-positive and MRD-negative patients with AML benefit differently from the graft-versus-leukemia effect of allogeneic hematopoietic stem-cell transplantation (alloHSCT).

Methods

A total of 1,511 patients were treated in subsequent Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research AML trials, of whom 547 obtained a first complete remission, received postremission treatment (PRT), and had available flow cytometric MRD before PRT. MRD positivity was defined as more than 0.1% cells with a leukemia-associated immunophenotype within the WBC compartment. PRT consisted of alloHSCT (n = 282), conventional PRT by a third cycle of chemotherapy (n = 160), or autologous hematopoietic stem-cell transplantation (n = 105).

Results

MRD was positive in 129 patients (24%) after induction chemotherapy before proceeding to PRT. Overall survival and relapse-free survival were significantly better in patients without MRD before PRT compared with MRD-positive patients (65% ± 2% v 50% ± 5% at 4 years; P = .002; and 58% ± 3% v 38% ± 4%; P < .001, respectively), which was mainly because of a lower cumulative incidence of relapse (32% ± 2% compared with 54% ± 4%; P < .001, respectively). Multivariable analysis with adjustment for covariables showed that the incidence of relapse was significantly reduced after alloHSCT compared with chemotherapy or autologous hematopoietic stem cell transplantation (hazard ratio [HR], 0.36; P < .001), which was similarly exerted in both MRD-negative and MRD-positive patients (HR, 0.38; P< .001; and HR, 0.35; P < .001, respectively).

Conclusion

The graft-versus-leukemia effect of alloHSCT is equally present in MRD-positive and MRD-negative patients, which advocates a personalized application of alloHSCT, taking into account the risk of relapse determined by AML risk group and MRD status, as well as the counterbalancing risk of nonrelapse mortality.

References
  1. Versluis J. et al. Graft-Versus-Leukemia Effect of Allogeneic Stem-Cell Transplantation and Minimal Residual Disease in Patients With Acute Myeloid Leukemia in First Complete Remission. JCO Precision Oncology. 2017 Sep 15. DOI: 10.1200/PO.17.00078.