GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia

Adriano Venditti,Giovanni Martinelli,William Arcese,Edoardo La Sala,Gabriella Storti,Serena Lavorgna,Paolo De Fabritiis,Paola Fazi,Roberto Cairoli,Nicola Stefano Fracchiolla,Mario Luppi,Maria Paola Martelli,Alessia Tieghi,Marco Vignetti,Anna Candoni,Prassede Salutari,Patrizio Mazza,Antonio Cuneo,Francesco Buccisano,Maria Teresa Voso,Francesco Albano,Valeria Calafiore,Caterina Alati,Luca Maurillo,Tiziana Ottone,Debora Capelli,Alfonso Piciocchi,Robin Foà,Maria Ilaria Del Principe,Anna Chierichini,Sergio Amadori,Lorella Melillo,Agostino Tafuri,Francesco Lanza,Francesco Fanfani ,Maria Irno‐Consalvo ,Francesco Lo‐Coco

doi:10.1182/blood.2018886960

Abstract

AbstractWe designed a trial in which postremission therapy of young patients with de novo acute myeloid leukemia (AML) was decided combining cytogenetics/genetics and postconsolidation levels of minimal residual disease (MRD). After induction and consolidation, favorable-risk patients (FR) were to receive autologous stem cell transplant (AuSCT) and poor-risk patients (PR) allogeneic stem cell transplant (AlloSCT). Intermediate-risk patients (IR) were to receive AuSCT or AlloSCT depending on the postconsolidation levels of MRD. Three hundred sixty-one of 500 patients (72%) achieved a complete remission, 342/361 completed the consolidation phase and were treatment allocated: 165 (48%) to AlloSCT (122 PR, 43 IR MRD-positive) plus 23 rescued after salvage therapy, for a total of 188 candidates; 150 (44%) to AuSCT (115 FR, 35 IR MRD-negative) plus 27 IR patients (8%) with no leukemia-associated phenotype, for a total of 177 candidates. Overall, 110/177 (62%) and 130/188 (71%) AuSCT or AlloSCT candidates received it, respectively. Two-year overall (OS) and disease-free survival (DFS) of the whole series was 56% and 54%, respectively. Two-year OS and DFS were 74% and 61% in the FR category, 42% and 45% in the PR category, 79% and 61% in the IR MRD-negative category, and 70% and 67% in the IR MRD-positive category. In conclusion, AuSCT may still have a role in FR and IR MRD-negative categories. In the IR MRD-positive category, AlloSCT prolongs OS and DFS to equal those of the FR category. Using all the available sources of stem cells, AlloSCT was delivered to 71% of the candidates.This trial was registered at www.clinicaltrials.gov as #NCT01452646 and EudraCT as #2010-023809-36.

Highlights

Despite the continuously growing knowledge about the genetic and molecular landscape of acute myeloid leukemia (AML),1-6 the paradigm of treatment of young adults with AML is still largely based on the “one-size-fits-all” approach, with postremission strategies still depending on donor availability rather than on the actual risk of disease relapse
Untreated patients with a diagnosis of de novo AML according to the World Health Organization diagnostic criteria21 were recruited to the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) AML1310 Study (EudraCT #2010-023809-36; www.clinicaltrials.gov Identifier #NCT01452646) provided they met the criteria for eligibility
When splitting the survival analysis according to the identified categories of risk, 2-year overall survival (OS) was 42% for National Comprehensive Cancer Network (NCCN)-PR patients, 58% for NCCN-IR patients, 74% for NCCN-FR patients, and 50% for NCCN-IR-no leukemia-associated immunophenotypes (LAIPs) patients (P, .0001) (Figure 3)

Summary

Introduction

Despite the continuously growing knowledge about the genetic and molecular landscape of acute myeloid leukemia (AML), the paradigm of treatment of young adults with AML is still largely based on the “one-size-fits-all” approach, with postremission strategies still depending on donor availability rather than on the actual risk of disease relapse. In the short term, this has led to satisfactory rates of complete remission (CR) (70%-80%), but in the long-term survival, estimates are still disappointing, with ,30% to 40% of patients becoming long-term survivors.8,9dealing with the high propensity for relapse and the considerable genetic heterogeneity of AML requires either development of new agents or adoption of modern, risk-adapted therapeutic programs. FR patients achieve overall survival (OS) and disease-free survival (DFS) rates of 50% to 60% at 3 to 5 years with standard chemotherapy, whereas those with adverse risk show OS and DFS rates of 5% to 20% at 3 to 5 years if not submitted to allogeneic stem cell transplantation (AlloSCT).. FR patients achieve overall survival (OS) and disease-free survival (DFS) rates of 50% to 60% at 3 to 5 years with standard chemotherapy, whereas those with adverse risk show OS and DFS rates of 5% to 20% at 3 to 5 years if not submitted to allogeneic stem cell transplantation (AlloSCT).7,11,13 It appears that in FR and adverse-risk patients, the sole genetic/cytogenetic profile, regardless of the MRD levels, is helpful enough to guide decisions for the delivery of AlloSCT in the postremission phase. There are no accepted criteria to direct the decision-making process after consolidation for patients in the IR category: for these patients, evaluation of the MRD status appears appropriate to extrapolate those at high (MRD positive) or low (MRD negative) risk of relapse, for whom differentiated treatments may be adopted

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Results