MRD-Directed Post-Remissional Therapy Dramatically Improves Outcome of Adult Patients with High Risk AML by Implementing Allogeneic Transplant Option
Authors: Buccisano Francesco , Maurillo Luca , Principe Maria Ilaria Del , Cerretti Raffaella , Consalvo Maria Antonietta Irno , Fraboni Daniela , Panetta Paola , Campagna Selenia , Ottaviani Licia , Sarlo Chiara , Angelis Gottardo De , Ditto Concetta , Caprio Luigi Di , Cefalo Maria Giovanna , Ammatuna Emanuele , Duranti Fabio , Coco Francesco Lo , Arcese William , Amadori Sergio , Venditti Adriano 
Published: October 2019

Abstract
Abstract 2702
Despite improvements in supportive care and wider availability of novel drugs, the outcome of young adult with AML still remains unsatisfactory with a long term survival of 30–40%. Such a dismal outlook is due to the contribution of several reasons. Among these, we believe that risk-category allocation based on the sole definition of pre-treatment biological features (genetics/cytogenetics) may fail to distinguish some high-risk patients which consequently are not timely addressed to intensive treatments. Furthermore, proper treatment of patients with poor prognosis may be hampered by the limited availability of HLA full compatible sibling donors (30% of patients). For the same reasons, some low-risk patients may be misclassified and over-treated (e.g. by giving them allotransplant for the simple reason that they have a full related compatible donor) with an excessive rate of treatment related mortality. Minimal residual disease (MRD) detection promises to be a strong predictive factor in adult AML when measured after the [induction-consolidation] phase and in fact, we have demonstrated (Venditti Blood 2000, Maurillo JCO 2008, Buccisano Blood 2010) that it refines the upfront genetic/cytogenetic risk classification. Thus, we designed a risk-directed pilot study which took into account: 1) an adjusted risk-stratification based on pretreatment genetics/cytogenetics and MRD status at the end of consolidation; and 2) a fast prospective assignment of all high-risk patients to allogeneic stem cell transplantation (alloSCT) in the form of HLA full compatible sibling, matched unrelated donor, umbilical cord blood or full haploidentical donor transplant. By applying this adjusted risk-stratification, we were able to discriminate two discrete category of patients: 1) Low-risk: good and intermediate-risk karyotype (K) that were MRD negative after consolidation (MRDneg good/int-K); and 2) High-risk: adverse-risk K, FLT3-ITD mutated cases and good/intermediate-risk K that were MRD positive after consolidation (MRDpos good/int-K). We also analyzed the outcome of a matched historical cohort of high-risk patients whose post-consolidation treatment was oriented according to a “genetic randomization”: alloSCT for those with a HLA full compatible sibling and autologous stem cell transplant (auSCT) for those lacking this option. Results achieved in this retrospective cohort were compared with those generated in the analysis of the prospective one. The prospective cohort included 25 high risk patients (4 MRDpos good-K, 9 MRDpos int-K, 4 adverse-karyotype and 8 FLT3-ITD). Five of them relapsed early being 20 evaluable for this analysis. The retrospective cohort accounted for 52 high-risk patients (8 MRDpos good-K, 33 MRDpos int-K, 1 adverse-karyotype and 10 FLT3-ITD). Ten of them relapsed early being 42 evaluable for this analysis. Even though the median follow-up of the prospective cohort is still short (18 months) survival estimates were dramatically superior as compared to the retrospective one (DFS 70% vs. 20%, p=0.00047; OS 69% vs. 24%, p=0.046). Accordingly, the prospective cohort also showed a lower relapse rate (20% vs. 52%, p=0.003). The 2 cohorts were well balanced in terms of frequency of FLT3-ITD, adverse-K and treatment related mortality rate, therefore, we believe that the improvement in survival estimates is related to the higher percentage of patients who were able to receive alloSCT. In fact, in the prospective cohort 21/20 (95%) of patients entering the post-consolidation phase underwent alloSCT as compared to 12/42 (30%) in the retrospective cohort (p<0.001). Notably, in the prospective cohort, only 8/21 patients had an HLA full compatible sibling whereas in 6 and 7 an haploidentical or MUD/UCB donor was found, respectively. We conclude that: 1) risk-assessment combining upfront genetics/cytogenetics with post-consolidation MRD status improves identification of high-risk category of patients who share a very poor prognosis if not selectively submitted to alloSCT; 2) the actual risk of disease recurrence should guide alloSCT option according to a “transplant vs no transplant” rather than “donor versus no donor” approach. This implies that once high-risk patients are identified they should receive alloSCT whatever the source of stem cell and, in our experience, this is feasible in the large majority of patients.

Disclosures:
No relevant conflicts of interest to declare.