Allogeneic Stem Cell Transplantation Improves Survival in Patients with FLT3-ITD-Negative and NPM1-Wild Type Intermediate Risk (ELN) Acute Myeloid Leukemia
Authors: Heidrich Katharina , Thiede Christian , Schäfer-Eckart Kerstin , Schmitz Norbert , Aulitzky Walter E , Krämer Alwin , Rösler Wolf , Hänel Mathias , Einsele Hermann , Baldus Claudia D. , Trappe Ralf U , Stölzel Friedrich , Middeke Jan Moritz , Röllig Christoph , Kramer Michael , Serve Hubert , Berdel Wolfgang E , Ehninger Gerhard , Bornhäuser Martin , Schetelig Johannes 
Published: October 2019

Abstract
Background: So called triple-negative acute myeloid leukemias (AML) form a heterogeneous subgroup of intermediate-risk AML according to ELN criteria. Molecularly this group can be defined by the absence of internal tandem duplications (ITDs) in the fms related tyrosine kinase 3 gene (FLT3), wild type (wt) nucleophosmin gene (NPM1) and wt or single (homozygously or heterozygously) mutated CCAAT/enhancer binding protein α gene (CEBPA). To date, it remains unclear whether this group of patients benefits from allogeneic stem cell transplantation (alloSCT) as consolidation strategy in first complete remission (CR1).
Aims: To evaluate the impact of alloSCT on the overall (OS) and relapse free survival (RFS) in patients with triple negative AML in first remission in comparison to post remission chemotherapy (PRT).
Methods: We performed a subgroup analysis of 3041 AML patients aged 16-60 years who were enrolled into the AML 96 and the AML 2003 trials of the Study Alliance Leukemia (SAL). Selection criteria for this subgroup were NPM1 wt, negativity for FLT3-ITD and CEPBA double mutations, a karyotype that does not define the AML as favorable or adverse according to ELN criteria and the accomplishment of CR1. Status of molecular markers was evaluated with standard PCR techniques. Within the AML2003 trial, donor status was evaluated at study entry, making these data eligible for a donor-versus-no-donor analysis. Kaplan-Meier estimates were used to report on point estimates for survival probabilities. Multivariate Cox models were fitted to analyze the impact of alloSCT as time-dependent covariate. Age, gender, white blood cell count, lactate dehydrogenase, AML type (de novo, secondary AML following MDS or MPN, or therapy-related myeloid neoplasms) and ECOG performance status at diagnosis were selected as adjusting covariables. As-treated analyses used data from both trials, AML96 and AML2003. For these analyses alloSCT or PRT were entered as time-dependent covariates into extended Cox regression models. Survival outcomes were displayed with Simon-Makuch-plots.
Results: In total, 497 patients (AML96: 217, AML2003: 280) with a median age of 47 years were evaluable for the analysis of OS from diagnosis. A total of 302 patients had reached CR1 and could be evaluated for RFS. In a multivariate donor-versus-no-donor analysis, OS of patients with a sibling donor was not significantly different to patients without a donor (HR 0.79, 95%CI 0.53 to 1.16, p=.2). Irrespective of whether the patient actually received alloSCT in CR1, the probability of OS at 5 years from study enrollment was 55% (95%CI, 45% to 67%) for patients with a sibling donor and 47% (95%CI, 40% to 54%) for patients without a donor. For RFS, the hazard ratio was 0.72 (95%CI, 0.5 to 1.05, p=0.09), with a trend in favor of better remission-control for patients with a sibling donor. At five years from CR1, RFS of patients with sibling donor was 48% (95%CI, 38% to 61%) compared to 36% (95%CI, 30% to 44%). However, the transplantation rate in the donor group was only 53% and 15% of patients in the no-donor group actually received alloSCT. Therefore, 'cross-over' effects lowered the power of donor-versus-no-donor analysis.
In the multivariable as-treated analysis including patients from AML96 and AML 2003, OS and RFS of patients with alloSCT were significantly longer (OS: HR 0.58, 95%CI, 0.37 to 0.9, p=.02, RFS: 0.51, 95%CI, 0.34 to 0.76, p=0.001) compared to the PRT group. The probability of OS at 5 years from initiation of consolidation treatment (alloSCT vs. PRT) was 66% (95%CI, 57% to 76%) for patients who received alloSCT compared to 46% (95%CI, 38% to 55%) for PRT patients. The probability of RFS at 5 years from initiation of consolidation treatment was 55% (95%CI, 46% to 67%) for alloSCT patients and 31% (95%CI, 24% to 39%) for PRT patients.
Conclusions: Due to cross-over effects which limit the power of the donor-versus-no-donor analysis we give more weight to the results of the as-treated analysis. This analysis suggests that eligible intermediate-risk AML patients with NPM1 wt and absent FLT3-ITD benefit from alloSCT in CR1. However, bias introduced by selection and confounding factors cannot be excluded for this type of analysis and could only be circumvented in randomized controlled trials.

Disclosures
Thiede: AgenDix: Employment, Other: Ownership. Rösler:Janssen: Consultancy, Other: Travel/Accommodation/Expenses. Middeke:Sanofi: Honoraria. Schetelig:Sanofi: Honoraria.