5-Azacytidine (5-AZA) Salvage Therapy for Very High Risk Acute Myeloid Leukemia (AML): Response After 3 Cycles Is the Major Determinant for Outcome.
Authors: Ayari Sameh , Chevallier Patrice , Guillaume Thierry , Brissot Eolia , Gouill Steven Le , Mohty Mohamad , Blin Nicolas , Gastinne Thomas , Moreau Philippe , Harousseau Jean Luc , Delaunay Jacques 
Published: October 2019

Abstract
Abstract 2044
Poster Board II-21
Very high risk AML can be categorized into three groups: i) group I: AML in second relapse or refractory after 2 induction regimens and AML in relapse after stem cell transplantation in patients aged <60 years, ii) group II: AML in first relapse in patients aged >60 years or secondary AML with unfavourable karyotype, iii) group III: AML in patients aged >70 years with either unfavourable karyotype or secondary AML. In this subgroup of very high risk AML, results of conventional chemotherapy are very poor and overall survival (OS) does not exceed a few weeks. Recently, an ever-growing body of evidence suggested that 5-AZA, a hypomethylating agent approved in high risk myelodysplastic syndromes, might also have some potent anti-leukemic activity. The aim of this pilot study was to assess the feasibility and efficacy of 5-AZA in a single centre cohort of 58 patients with very high risk relapsed or refractory AML.
Between 2006 and 2009, 58 consecutive patients received 5-AZA subcutaneously (75 mg/m2/d) for 7 days every 4 weeks (one cycle= 7 days of treatment). Response after 3 cycles was assessed by marrow examination according to the IWG criteria. 5-AZA was continued after 3 cycles, if patients were at least in stable disease and/or until progression.
In this series, the median age was 66 years (range, 28-80; 32 males and 26 females). AML features were: favourable and intermediate karyotype, 59% (n=34); unfavourable karyotype, 38% (n=22); secondary AML, 57% (n=33). Distribution according to AML risk groups were: group I, 26% (n=15); group II, 50% (n=29); group III, 24% (n=14). Of note, 16% of patients (n=9) from the entire cohort had received and failed a previous stem cell transplant.
In all, a mean of 4.5 cycles (range, 1-14) of 5-AZA could be administered. 48% of patients (n=28) could achieve an overall response (OR) including CR, complete remission with incomplete blood recovery (CRi), partial remission (PR) and stable disease (SD). The “CR+CRi” rate was 19% (n=11). Interestingly, 13 patients (22%) were not able to receive the full first 3 cycles of 5-AZA, with 8 early deaths and 5 treatment discontinuation before evaluation. The main causes of early death and treatment discontinuation were severe infections and/or haemorrhage. In univariate analysis, age, AML risk group, karyotype, secondary AML feature, did not prove to be significantly associated with the rate of OR.
With a median follow-up of 10,5 (range, 0,6-36) months, the Kaplan-Meier estimate of OS was 13% (95%CI, 3.4-30%) at 24 months. The median OS was 13.5 (95%CI, 11-not reached) months for patients achieving at least a stable disease after 3 cycles of 5-AZA versus 4 (95% CI, 3.29-5.44) months (p<0.0001) for the rest of the cohort. In multivariate analysis including response to 3 cycles of 5-AZA, cytogenetics, secondary AML featureand AML risk group only achievement of an OR after 3 cycles of therapy and a favourable karyotype, proved to be significantly associated with an improved OS (HR=0.10, p<0.001; and HR=0.36, p=0.012; respectively).Among patients achieving CR or CRi,6 patients were able to proceed to allogeneic stem cell transplantation and are currently alive in sustained CR.
We conclude that 5-AZA is a feasible salvage therapy for relapsed or refractory AML with a relatively acceptable toxicity. Survival advantage is mainly observed in those patients achieving at least a stable disease after 3 cycles of therapy, and in patients who can proceed to consolidation with allogeneic stem cell transplantation, highlighting the need for large scale multicenter prospective studies assessing the role of 5-AZA as salvage therapy for high risk AML.

Disclosures:
No relevant conflicts of interest to declare.