Allogeneic Hematopoietic Stem Transplantation Does Not Erase the Impact of the New Prognosis Classification in AML and the Negative Influence of Evi1 and Flt3 ITD Mutations.
Authors: Michallet Mauricette , Sobh Mohamad , Hayette Sandrine , Charlot Carole , El Hamri Mohamed , Tedone Nathalie , Nicolini Franck Emmanuel , Cannas Giovanna , Chelghoum Youcef , Nicolas-Virelzier Emmanuelle , Ducastelle Sophie , Baracco Fiorenza , Tigaud Isabelle , Thomas Xavier 
Published: October 2019

Abstract
Abstract 4678
Improvement of survival in AML patients remains an important objective to achieve; recently better therapeutic strategies were defined according to the stratification of different markers. According to cytogenetics and molecular markers we determined 2 groups of patients: a good prognosis group for patients who had good cytogenetics [inv 16 and t (8, 21)]and intermediate 1 (normal cytogenetics associated to either NMP1+ with ITD- or CEBPα +ITD-) and a poor prognosis group for patients classified as in intermediate 2 (normal cytogenetics associated to other molecular markers) and unfavourable cytogenetics. To see if allogeneic hematopoietic stem cell transplantation had an impact on these groups, we studied 78 patients who underwent an allogeneic HSCT for AML and for whom we had cytogenetics and molecular markers. There were 73 de novo and 5 secondary AML, FAB classification showed 9 M0, 11 M1, 15 M2, 8 M4, 24 M5, 3 M6, 1M7, 7 patients were unclassified. Regarding cytogenetics and molecular markers: 6 were in favourable, 29 in intermediate and 38 in unfavourable group and we found 5 Flt3 mutated, 22 Flt3 ITD+, 4 MLL mutated, 13 Hoxa9 mutated, 10 Evi1 mutated, 34 Wt1 mutated and 17 NMP mutated. Using the new classification, 11 patients were in the good prognosis group and 61 in the poor prognosis group (6 patients have not been classified due to cytogenetics failure and/or missing data of molecular markers). At transplant, 42 patients were in CR1, 22 in > CR1 and 14 in progressive disease, 49 received a myelo-ablative and 29 a non myelo-ablative conditioning. As HSC source, 27 received PBSC, 46 bone marrow and 5 cord blood cells. At the last follow-up, 28 have relapsed, 38 patients are alive (36 in CR and 2 in relapse) and 40 died. With a median follow-up of 32 months, the 3-years overall survival was 45%±12 with no significant impact of age, FAB classification, kind of AML (de novo vs secondary), HSC source (PBSC vs BM), Flt3, MLL, HoxA9, NMP and WT1 mutations. We found a difference of survival but not reaching the significance for Flt3 ITD [27.5% ±20 (mutated)vs 52% ±12 (non mutated), p=0.09] and a significant difference of survival for Evi1 [48.5%±14 (non mutated) vs 22.5% ±26 (mutated), p=0.04]. We also showed a difference of survival not reaching the significance according to cytogenetics with 83%±30 for favourable, 53%±20 for intermesiate and 28%±16 for unfavourable although we observed a very significant difference of OS according to the new prognosis classification between the good prognosis group with 81%±24 and the poor prognosis group with 38%±14 (p=0.04). In addition, we found a significant better survival for patients in 1st CR (60%±16) vs > CR1 (31%±22) or in progressive disease (24%±22)(p=0.009) and a significant difference of survival according to conditioning with 54%±16 for myelo-abative vs 11%±18 for RIC ( p<0.0001). But, for patients receiving a nonmyelo-ablative conditioning, we noted that the majority of patients presented poor risk factors with 12 and 13 (86%) among the 29 patients belonging to intermediate and unfavourable cytogenetics groups, 25 (86%) were in poor prognosis and 19 patients (65%) were in progressive disease or in > CR1 at transplant. The multivariate analysis showed a significant impact on OS of the new prognosis classification [HR=3.62 [95%CI 2.89-4.35] (p=0.03)], disease status at transplant [HR=151 [95%CI 1.28-1.74] (p=0.07)], kind of conditioning [HR=0.32 [95%CI 0-0.7] (p=0.003)], Evi1 [HR=0.33[95%CI 0-0.8] (p=0.02)] and Flt3 ITD [HR=0.43 [95%CI 0.07-0.78] (p=0.02)]. This study showed the importance of the new prognosis classification in terms of OS for AML and allogeneic HSCT did not erase the impact of this parameter, the OS after allogeneic HSCT remains very poor for patients having Evi1 mutation and Flt3ITD for whom it is fundamental to propose new strategy of allogeneic HSCT in 1st CR as for example allotransplant after FLAMSA regimen or haplo-identical allogeneic HSCT.

Disclosures:
No relevant conflicts of interest to declare.