Azacytidine (AZA) as First Line Therapy in AML: Results of the French ATU Program.
Authors: Thépot Sylvain , Itzykson Raphael , Seegers Valerie , Recher Christian , Quesnel Bruno , Delaunay Jacques , Cluzeau Thomas , Koka Anne Marfaing , Stamatoullas Aspasia , Chaury MP , Dartigeas Caroline , Cheze Stéphane , Salanoubat Celia , Morel Pierre , Plantier Isabelle , Taksin Anne-Laure , Marolleau Jean Pierre , Pautas Cecile , Wattel Eric , Isnard Francoise , Sanhes Laurence , Harel Stephanie , de Botton Stephane , Chait Yasmine , Uzunov Madalina , Guerci Agnes , Dahoun Mehdi , Vey Norbert , Dombret Herve , Dreyfus Francois , Ades Lionel , Fenaux Pierre , Gardin Claude 
Published: October 2019

Abstract
Abstract 843

Background:
AZA prolongs survival in higher-risk MDS including patients (pts) with 20-29 % marrow blasts, now considered WHO-AML ( Lancet Onc, 2009). However, no large AML cohorts (especially with '30% marrow blasts) treated upfront with AZA have been reported.

Methods:
An AZA compassionate program (ATU) was initiated in France in Dec 2004 for higher risk MDS, and AML considered not candidates or refractory to intensive chemotherapy (IC). We retrospectively analyzed WHO AML pts having received at least 1 cycle of AZA in the 42 centers with complete pt reporting, excluding those previously treated by IC, allo SCT, low dose AraC or a hypomethylating agent.

Results:
138 pts were included between Dec 2004 and Dec 2008; M/F: 86/52; median age 73 years (y) (range 31-87), 117 pts (85%) were > 65 y and 54 (40%) >75y. 65 pts (47%) had prior WHO MDS and 30 pts (22%) therapy related (tAML). 44 pts (32%) had 20-29% marrow blasts. Median WBC was 3.0 G/L [0.8-111.5]. Karyotype (MRC classification), was intermediate (int) in 60 pts,( including 38 normal (NK), and 7 isolated +8 ) adverse in 67 pts (including 42 -7/ del7q, 41 del5q/-5, 45 complex karyotype, two 3q26) and failed in 11 pts.
With a median follow-up of 11.3 months, pts received a median of 4.5 AZA cycles (range 1-26). Treatment was according to FDA-EMEA approved schedule for MDS in 95 pts (69%) and a less intensive schedule (5d/4w, or <75 mg/m2/d) in 31% pts, 29 pts (21%) received concomitant valproic acid (VPA).
First evaluation was made after 3 to 4 cycles. An overall AML response (ie according to AML-IWG criteria) was observed in 29 pts (21%) including 19 CR (14%), 3 CRp (2%) and 7 PR (5%) after a median of 3 cycles (1 – 11). An additional 25 pts (who had no CR, CRi or PR) achieved hematologic improvement (HI, according to MDS-IWG 2006 criteria). Neither any pretreatment characteristic including age, preceding MDS, tAML, karyotype, WBC, marrow blast %, combination with VPA were correlated with AML response. Median time to progression after AML response was 7.6 months
In the 138 pts, 1 y-OS was 40%, 2 y OS 18% and median OS 10.2 months. In univariate analysis, pre-treatment characteristics negatively influencing OS were higher WBC, adverse cytogenetics, higher absolute PB blasts and diagnosis of tAML. In multivariate analysis: higher WBC (p=0.018), and adverse cytogenetics (p=0.0006) retained prognostic significance for OS. In particular, pts with WBC >10 G/L (32 pts in our cohort) carried poorer prognosis ( 1 y OS of 27% vs 44% ,p=0.01); NK had better OS (1-y OS: 66%) than adverse cytogenetics (1-y OS: 30%, p=0.01) but also other “intermediate-risk” abnormalities (1-y OS: 30%, p=0.03).
Marrow blast % did not influence OS and survival, whatever the cut off chosen. In particular, pts with 20-29 % marrow blasts had 22% AML response and 1 y OS of 50%, compared to 21% and 1 y OS of 35%, respectively, in pts with >30% marrow blasts (p=NS and NS, respectively). Prior MDS also had no influence on survival.
Overall, 33 pts required hospitalization during treatment, mainly for neutropenic fever.
A landmark analysis at the time of evaluation showed that achievement of CR, CRi or PR was associated with improved OS (1y-OS 55% vs 31%,p=0.007). In pts with no AML-IWG response, however, achievement of HI also predicted better survival: 1 y-OS 55% vs 19 %, p=0.02.
In the 54 pts older than 75 y (ie pts generally considered unfit for IC), 12 (22%) had AML response including CR in 9 (17%) and 3 PR (5%). 1y-OS was 41 % vs 38% for younger pts (p=NS). Hospitalisation was needed in 31% of them vs 32% in younger pts (p=NS).

Conclusion:
In this untreated cohort of generally older AML pts considered non candidates for intensive chemotherapy, response rate was 21% and 1 y OS 40%. Higher WBC counts and adverse karyotype were associated with poorer OS, but marrow blast %, whatever the threshold chosen, had no influence on outcome. Age above 75 y was associated with similar response and 1y OS. Finally, pts without AML IWG responses but with improved cytopenias also appeared to have improved survival.

Disclosures:
Off Label Use: Azacytidine is approved by FDA and EMEA in the treatment of high risk MDS and AML up to 30% of bone marrow blast.. Fenaux:CELGENE: Research Funding; AMGEN: Research Funding.