Treatment of Progression of Myeloproliferative Disorders(MPD) to MDS/AML by Azacytidine (AZA) : A Preliminary Report on 17 Patients (pts)
Authors: Thépot Sylvain , Itzykson Raphael , Raffoux Emmanuel , Roussel Murielle , Dartigeas Caroline , Dreyfus Francois , Recher Christian , Pilorge Sylvain , Cassinat Bruno , Beve Blandine , Mbida Rose-Marie , Kiladjian Jean-Jacques , Ades Lionel , Fenaux Pierre 
Published: April 2020

Abstract
Background: MDS or AML occurring during the course of MPD carry a very poor prognosis and current treatments, with the exception of allogeneic SCT, have very limited efficacy. AZA significantly improves survival in higher risk MDS (ASH 2007, abstr n° 817) and in some AML, but its use has not been extensively reported so far in MDS and AML post MPD.
Methods: The French health agency (AFSSAPS) designed a still ongoing pt named program (ATU) of AZA in higher risk MDS and poor risk AML. 17 pts with MDS or AML post MPD, included in this program in 5 centers (Paris-Avicenne, Paris St Louis, Paris-Cochin, Tours and Toulouse), before April 08 and having completed ≥ 1 cycle of AZA (75 mg/m2/d during 7 days per 28 d cycle) are analysed here. Response was evaluated according to IWG 2006 criteria for MDS and IWG-AML 2003 criteria for AML.
Results: median age was 68y (range 38–83), M/F: 7/10. The initial MPD was Polycythemia Vera (PV) in 6 pts, Essential Thrombocytopenia (ET) in 7 pts, primary myelofibrosis (MF) in 2 pts and unclassified in 2 pts. Median interval from diagnosis to progression was 10 years (range 7 months-22 years). 10/16 (62%) pts had JAK2-V617F mutation. Treatment of MPD had consisted of HU in 7 pts, pipobroman in 4 pts, both in 4 pts, imatinib in 1 pt and Interferon Alfa in 1 pt. At the time of inclusion, WHO classification was AML in 8 pts, and MDS in 9 pts (RAEB-2 in 8pts, RAEB-1 in 1pt) Karyotype was normal (n=2), isolated −7/7q- (n=3), isolated del 5q (n=1), + 8 (n=2), isolated −17 (n=1), t[1;7] (n=2), complex (n=3) including −7 (3), −5(2) and +8(1), and a failure (n=3). Before AZA, 2 pts had received intensive chemotherapy (1 CR, 1 failure) followed by allo SCT in 1 of them (who subsequently relapsed).
The median number of cycles of AZA administered was 4 (range 1–9). 2 pts received only 1 cycle due to early death (from aspergillosis and unknown cause). The overall response rate (ORR, including CR, PR, CRi) was 10/17 (59%). In the 15 pts who received more than 1 cycle, 4/8 MDS achieved CR (including one cytogenetic CR) and 2/8 achieved PR. RBC and platelet transfusion independence were achieved in 4/8 and 6/8 respectively (resp). In AML, 1/7 pts achieved CR and 3/7 achieved CRi. 2 of the 10 responders relapsed (after 5 and 12 months resp) and the other 8 remained responders after 1+ to 12 + months (median 3.5). 9/10 responders were still alive after 2 to 16 months (median 5.5). Interestingly, in 3 pts with a very long history of MPD (15, 16 and 22 years) treated with HU or pipobroman, who at progression had MDS and cytopenias, response to AZA was associated to recurrence of MPD (2 TE and 1 PV) requiring restart of cytoreductive therapy in 2 of them.
Conclusion: 5 AZA gives encouraging results in MDS or AML occurring in the course of MPD with an overall response rate of 59%. An update, with cases recently included in the program, will be presented.