Treatment of Advanced CMML by Azacitidine (AZA) In a Compassionate Program. the GFM Experience In 38 Patients (pts)
Authors: Wolfromm Alice , Dreyfus Francois , Vey Norbert , Delaunay Jacques , Stamatoullas Aspasia , Banos Anne , Marfaing-Koka Anne , de Botton Stephane , Bordessoule Dominique , Legros Laurence , Rauzy Odile Beyne , Gyan Emmanuel , Makhoul Pascale Cony , Thepot Sylvain , Itzykson Raphael , Fenaux Pierre , Ades Lionel 
Published: October 2019

Abstract
Abstract 4023

Background:
Treatment of CMML remains difficult, with no drug having shown a clear clinical benefit. AZA has demonstrated a survival benefit in higher risk MDS, in a study that included a small number of CMML (Lancet Oncol, 2009). Several small series of CMML treated by Decitabine (Wijermans, Leuk Res. 2008, Aribi A, Cancer. 2007 and Kantarjian H, Blood. 2007), and AZA (Scott, Br J Haematol. 2010) have been reported, but pts were often very heterogeneous in terms of risk factors and treatment, while in the AZA paper, patients also received etanercept in combination.

Methods:
The French health agency (AFSSAPS) designed, between 2004 and 2008, a pt named program (ATU) of AZA in higher risk MDS and poor risk AML. 38 pts with CMML or AML arising from CMML included in this program before April 08 and having completed ≥ 1 cycle of AZA (75 mg/m2/d during 7 days every 28 d) are analysed here. As CMML has features of both MDS and MPD, its risk factors are somewhat composite. Based on our previous experience (JCO 1988 6:1417, Blood 1996 88:2480) and on IPSS, pts with WBC <13 G/L were classified according to IPSS, and, in those with WBC > 13 G/L, risk factors were based on: marrow blasts≥5%, Hb<10g/dl, plts<100G/l, abnormal cytogenetics, splenomegaly > 5cm below costal margin (SMG> 5cm) and extramedullary disease (EMD). Response was evaluated according to IWG 2006 criteria in pts with WBC <13G/L, also took into account “proliferative” features of CMML (splenomegaly, increased WBC and blood monocytes, extra medullary disease) in pts with WBC > 13G/L, and IWG-AML 2003 criteria for AML.

Results:
median age was 71 y (range 50–87), M/F: 28/10. Median interval from diagnosis to treatment was 22 months (range 0.2–74 months). Previous treatment was low dose chemotherapy (CT) (n= 10, low dose Arac n=2, HU n=8), Intensive CT (n=12), allogeneic SCT (n=1), ATO (n=2). At inclusion, 9 pts had CMML-1, 17 CMML-2 and 12 AML secondary to CMML according to WHO. Karyotype was normal (n=16), isolated –7/7q- (n=2), +8 (n=1), del 20q (n=1), complex (n=2), -Y (n=2) and a failure (n=2). In the 14 CMML with WBC <13G/L, IPSS was low in 1, int-1 in 3 pts, int-2 in 8 pts and High in 2 pts. In the 12 CMML with WBC > 13G/L, 10 had more than 3 risk factors defined in Blood 1996 88:2480. The median number of cycles of AZA administered was 4 (range 1–26). 6 pts received also HU during the first cycles to reduce WBC count. 9 pts received less than 4 cycles due to early death (n=4), progression (n=3) and haematological toxicity (n=2). 20 pts (53%) responded including 9 CR, 3 marrow CR,8 HI-E and 1 partial remission. 19 (68%) of the 28 pts who received more than 4 cycles responded, including 9 CR, 3 mCR, 1 PR and 6 HI. Of the 26 CMML without AML progression, 15 (58%) responded (7 CR, 2 marrow CR and 6 HI-E).
Of the 12 AML arising from CMML, 5 (42%) responded (2 CR, 1 marrow CR, 1 PR and 1 HI-E).
Median number of cycles of AZA to achieve best response was 4 (range 3–12). Age (p=0.38), WBC count (p=0.76), Hb level (p=0.987), platelet count (p=0.07), blood monocytes (p=0.4823), Sex (p=0.28), CMML 1 vs 2 (p=0.48), splenomegaly (p=0.7), normal karyotype (p=1), -7/del7q(p=0.65), concomitant treatment with HU (p=0.6), >3 risk factors in CMML with WBC>13 G/l, and previous treatment (p=0.506) had no impact on response.
9 of the 20 responders relapsed after a median of 10.6 months (range 3–23), including 4/9 (44%), 1/3 (33%), 0/1, 4/8 (50%) of the pts who had achieved CR, mCR, PR and HI respectively, 10 remained responders after a median of 26 months (16-35) and 1 pt with HI died without relapse. Median overall survival (OS) was 24 months in CMML compared to 7 months in AML arising from CMML (p= 0.0081). Presence of splenomegaly, WBC>13 G/l, previous treatment (excluding ESA), Sex, -7/del7q and normal karyotype had no impact on OS.

Conclusion:
In this series of CMML which had on average more unfavourable prognostic factors than in previous series of CMML treated with Decitabine or AZA (10/14 with WBC <13G/L were IPSS int 2 or high, 10/12 with WBC > 13 G/L had at least 3 risk factors, and 12 had progressed to AML), AZA showed clear efficacy, but mainly in pts who had not progressed to AML.

Disclosures:
Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.