Efficacy of Azacitidine (AZA) in Autoimmune and Inflammatory Disorders (AID) Associated with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)
Authors: Fraison Jean-Baptiste , Mekinian Arsène , Grignano Eric , Kahn Jean-Emmanuel , Arlet Jean-Benoît , Decaux Olivier , Guillaume Denis , Buchdahl Anne-Laure , Omouri Mohamed , Maigne Gwenola , Aouba Achille , Leon Nathalie , Berthier Sabine , Liozon Eric , Park Sophie , Gardin Claude , Lortholary Olivier , Rossignol Julien , Fenaux Pierre , Fain Olivier , Braun Thorsten 
Published: October 2019

Abstract
Background: AID are seen in 10-30% of MDS and CMML. After initial response to steroids, AID are often poorly controlled and steroid-sparing drugs are difficult to use due to the underlying MDS/CMML. Some case reports suggest a beneficial role of AZA treatment in AID associated to MDS/CMML.
Methods: We retrospectively analyzed 22 MDS/CMML patients (pts) with AID who received AZA in French centers between January 2007 and May 2014.
Results: Median age of the 22 pts was 70y (range 41-84), including 6F/16M. Diagnosis of MDS/CMML preceded AID (n=8) by a median of 17 months (mo), was concomitant with (n=7) or followed AID (n=7) by a median of 20 mo. 14 pts had lower risk IPSS and 8 higher risk IPSS. AID diagnosis included: Behçet's disease (n=4), polymyalgia rheumatica (n=4), relapsing polychondritis (RP) (n=4), giant cell arteritis (n=2), Sweet's syndrome (n=2), SLE (n=2), Sjögren's (n=1), adult onset Still's disease (n=1), unclassified small vessel vasculitis (n=1) and seronegative polyarthritis (n=1). One pt presented with both RP and Sweet's syndrome. 12 (55%) AID were considered atypical and 10 (45%) fulfilled complete diagnostic criteria. Before AZA, 21 pts (96%) had received steroids and 16 (73%) a median of 2 immunomodulatory drugs (IMD) (range 1-6) in addition to steroids.
At AZA onset, AID was still active (n=14), in PR (n=6) and in CR (n=2). 19 pts still reported asthenia (n=17), weight loss (n=8), fever >38°5 (n=8), rheumatologic signs (n=15), skin involvement (n=10), oral aphtosis (n=4). 9 pts were steroid dependent or resistant. 20 pts were treated with steroids (91%, median dose of 23 mg/d). 13 pts were non-responders to IMD and 11 received concomitant IMD, without efficacy in 7 pts.
AZA was the first-line treatment of MDS/CMML in 13 pts (59%) and was in 9 pts preceded by: intensive chemotherapy (n=3), LEN (n=2), HY (n=2), allo SCT (n=2) and LDaraC (n=2). Median interval between MDS/CMML diagnosis and AZA onset was 9 mo (range 1-93). At AZA onset, IPSS was low (n=4), int-1 (n=7), int-2 (n=8) and high (n=3). Pts received a median of 6 cycles of AZA (range 3-14); 1 pt received 3 cycles, 5 received 5 cycles; 9 pts received more than 6 cycles. Complete remission (CR) of AID was observed in 16 pts (73%), partial remission (PR) in 3 pts (14%) and no effect or worsening of AID in 3 pts (14%). All responses were observed within 3 cycles, but 8 PR of AID after 3 cycles became CR after 6 mo. Discontinuation of steroids was possible in 3 pts (14%) and dose reduction in 14 pts (64%), to a median of 9 mg/d, (range 0-30), (p=0.001). Discontinuation of IMD was possible in 7 pts (32%). Altogether, dose reduction or discontinuation of steroids and/or IMD after AZA was possible in 16 cases (73%). Good response of AID symptoms (including PR and CR) or discontinuation of IST was noted in 19 patients (86%). Median CRP decreased from 40 mg/L to 15 mg/L (p=0.28). Response of MDS/CMML to AZA (IWG2006 criteria) was seen in 12 pts (55%), including CR in 9 pts (41%), PR in 1, SD+HI-E in 1, mCR in 1, SD in 8 and PD in 2. No uncommon side effects to AZA were seen.
MDS/CMML and AID evolution was concordant in 13 pts (59%): both improved (n=11) or worsened (n=2). AID improved while MDS worsened (n=8) and vice versa (n=1). With a median FU from response to AZA of 8 mo, only 3 relapses of AID were seen after 3 (n=1) and after 19 mo (n=2), and 5 pts had a response > 12 mo. Seven pts (32%) progressed to AML and 10 pts (45%) had died, with 8 deaths occurring in IPSS high or int 2 pts. Median survival from AZA onset was 16 months in IPSS high or int-2 MDS and was not reached in IPSS low and int-1 MDS.
Conclusions: AZA frequently seems effective in controlling steroid-dependent AID associated with MDS/CMML, but prospective studies are necessary to confirm those findings.

Disclosures
Fenaux: JANSSEN: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding.