Impact of Induction Regimen and of Allogeneic Hematopoietic Cell Transplantation on the Outcome in Younger Adults Patients with Acute Myeloid Leukemia with a Monosomal Karyotype: Results from the EORTC/Gimema AML-10 and AML-12 Trials
Authors: Baron Frederic , Stevens-Kroef Marian , Meloni Giovanna , Muus Petra , Marie Jean-Pierre , Halkes Constantijn J.M. , Thomas Xavier , Vrhovac Radovan , Specchia Giorgina , Lefrere Francois , Sica Simona , Mancini Marco , Venditti Adriano , Hagemeijer Anne , Jansen Joop H. , Amadori Sergio , de Witte Theo , Willemze Roelof , Suciu Stefan 
Published: October 2019

Abstract
Background. Previous studies have demonstrated that monosomal karyotype (MK) confers a particularly poor prognosis in patients with acute myeloid leukemia (AML) (Breems et al., J Clin Oncol 2008, 26:4791-7).
Purpose of the study. To determine the impact of the type of remission-induction chemotherapy and the impact of having a donor on overall survival (OS) in younger (</=60 years of age) AML patients with a MK.
Methods. In the EORTC/GIMEMA AML-10 trial (Mandelli et al., J Clin Oncol 2009, 27:5397-403), patients were randomized to receive either daunorubicin (DNR), mitoxantrone (MTX), or idarubicin (IDA) in addition to standard-dose cytarabine (SDAC: 10 days of 100 mg/m2 per day as continuous IV infusion) and etoposide for induction chemotherapy. In the EORTC/GIMEMA AML-12 trial, (Willemze et al., J Clin Oncol 2014, 32:219-28) patients were randomized between either SDAC or high dose cytarabine (HiDAC) (3 g/m2 every 12 hours as a 3-hour IV infusion on days 1, 3, 5, and 7) induction, both with DNR, and etoposide. In both trials, a second cycle of the same remission induction chemotherapy was administered in patients who achieved a partial remission. Patients who achieved a complete remission (CR) or a CR with incomplete counts recovery (CRi) after 1 or 2 courses of induction chemotherapy received a consolidation chemotherapy with the same anthacycline as in the induction course plus intermediate dose cytarabine. Patients in both studies were then scheduled to receive an allogeneic hematopoietic stem cell transplantation (allo-HSCT) if they had a donor or an autologous HSCT (auto-HSCT) otherwise, in first CR. For the current analyses, cytogenetics were centrally reviewed and re-classified using the European Leukemia Net (ELN) definition. MK was defined as the presence of 2 or more monosomies, or a single monosomy in the presence of structural abnormalities.
Results. In the AML-10 trial, 2157 patients were randomized to receive DNR, MTX or IDA. The current analyses were performed in a subgroup of 910 patients for whom cytogenetic data were available and who did not have t(8;21), inv(16) nor t(15;17). 709 of them were classified in the ELN intermediate cytogenetic risk group and 201 in the adverse group. Out of the 910 patients, 93 had a MK. In comparison to the 817 remaining (MK-) patients, MK+ patients were less likely to achieve a CR, were more likely to have resistant disease (RD), and had worse OS and disease-free survival (DFS) (Table 1). There was no impact of the type of anthracycline on outcomes. Among the MK+ patients who achieved a CR, 5-yr OS from CR was 26% (95% CI, 10-46%) in patients with a donor (n=21, of whom, 13 received an allo-HSCT in first CR), versus 4% (95% CI, 0-18%) in those without a donor (n=24, of whom, 1 received an allo-HSCT in first CR) (P=0.07). Further, among the 10 MK+ who survived more than 1 year, 7 received an allo-HSCT in first CR (n=4) or beyond (n=3). In the AML-12 trial, 1942 patients were randomized between HiDAC or SDAC. The current analyses were performed in a subgroup of 1079 patients for whom cytogenetic data were available and who did not have t(8;21), inv(16) nor t(15;17). 893 of them were classified in the ELN intermediate cytogenetic risk group and 186 in the adverse group. Out of the 1079 patients, 98 had a MK. In comparison to the 1027 MK- patients, MK+ patients were less likely to achieve a CR, were more likely to have RD, and had worse OS and DFS (Table 1). There was a higher probability of achieving a CR and a trend for better OS in MK- patients randomized in the HiDAC arm (Table 2). In contrast, in MK+ patients, HiDAC did not increase either the CR rate as compared to SDAC, nor the 5-yr OS rate: 7% (HiDAC) vs 2% (SDAC) (Table 2). Finally, among the MK+ patients who achieved a CR, 5-yr OS from CR was 14 % (95% CI, 4-32%) in patients with a donor (n=21, of whom, 12 received an allo-HSCT in first CR), versus 4% (95% CI, 0.3-18%) in those without a donor (n=24) (P=0.60). Further, among the 4 MK+ patients who survived more than 1 year, 3 received an allo-HSCT in first CR (n=2) or beyond (n=1).
Conclusions. This analysis confirms the poor prognosis of MK in younger AML patients. Shifting DNR to IDA or MTX or administration of HiDAC in the induction course failed to improve outcome of MK+ patients. Finally, there was a suggestion for a longer OS from CR in MK+ patients who had a donor, suggesting that allo-HSCT should be offered in all fit MK+ patients.
FB & MSK contributed equally to this work

Disclosures
Thomas: Pfizer: Consultancy.