Conditioning Intensity In Middle Aged Patients With AML In CR1. No Advantage For Myeloablative Regimens Irrespective Of The Risk Group. An Observational Analysis By The Acute Leukemia Working Party Of The EBMT
Authors: Passweg Jakob , Labopin Myriam , Cornelissen Jan J , Volin Liisa , Socié Gérard , Huynh Anne , Tabrizi Reza , Wu Depei , Craddock Charles , Schaap Nicolaas PM , Kuball Jurgen H , Chevallier Patrice , Cahn Jean-Yves , Blaise Didier , Ghavamzadeh Ardeshir , Bilger Karin , Nagler Arnon , Ciceri Fabio , Schmid Christoph , Giebel Sebastian , Mohty Mohamad 
Published: October 2019

Abstract

Introduction
In younger patients with AML achieving CR1 with intermediate or high risk disease allogeneic HSCT is the treatment of choice. Conditioning intensity is varied, reduced intensity (RIC) conditioning regimens are usually given to older patients, whereas young patients traditionally receive myeloablative regimens (MAC). In patients between the ages of 40-60 both types of regimens are used with little knowledge about factors that would lead physicians to prefer one over the other. Previous studies had shown that RIC regimens were associated with somewhat higher relapse risks but lower risks of transplant related mortality (TRM). We hypothesized that in low-intermediate risk disease based on cytogenetic classification RIC is superior to MAC whereas in high risk leukemia MAC is superior to RIC given higher antileukemic activity.

Patients and Methods
This study included 2974 of 5388 eligible patients with AML transplanted in CR1 in 2000-2011 based on the availability of cytogenetics to classify by risk status at diagnosis. Only sibling or unrelated donors and marrow or peripheral blood stem cell transplants were considered. Regimens were classified as MAC (n=1638) or RIC (n=1336) based on published criteria. Median follow-up of surviving patients was 46 and 41 months respectively. Groups differed by many variables. MAC recipients were significantly younger (37.6 vs 53.8 years), had a shorter interval from diagnosis to transplantation (143 vs 165 days), were more frequently male (53% vs 48%), had less frequently poor risk cytogenetics 19% vs 22%, received less frequently stem cells from an unrelated donor (20% vs 33%), and had more frequently marrow as a stem cell source (36% vs 7%). The Kaplan-Meier estimator, the cumulative incidence function and Cox proportional hazards regression models were used where appropriate.

Results
Table 1 shows similar overall (OS) and leukemia free survival (LFS) in both groups but a lower relapse incidence (RI) and a higher transplant related mortality incidence (TRM) in the MAC group. Acute grade II-IV GvHD was higher with MAC, incidence of chronic GvHD did not differ significantly.
In univariate analysis overall survival was higher with RIC in cytogenetic good risk AML (55±5% vs 77±7% MAC vs RIC) but not in intermediate risk (61±1% vs 62±2%) or poor risk AML (42±3% vs 40±3%). Relapse incidence was lower with MAC in poor risk AML (36±3% vs 51±3%) and intermediate risk AML (21±1% vs 30±1%) but not in good risk AML (19±4% vs 13±5%). TRM was higher in MAC vs RIC in all three cytogenetic risk groups. Multivariate analysis confirmed a significant LFS and OS advantage of RIC in good risk but not in intermediate and poor risk leukemia.

Conclusions
In patients aged 40-60 MAC conditioning has no advantage over RIC conditioning in spite of RIC transplant recipients being generally in a poorer risk category. We confirm lower relapse rates but higher TRM risks with MAC compared to RIC. We fail to show superiority of MAC in patients with high risk cytogenetics but there appears to be an advantage for RIC over MAC in the small cohort of patients with good risk leukemia.

Disclosures:
Kuball: Miltenyi: GMP product development Other.