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3697 A Phase II Study of the Efficacy and Tolerance of Azacytidine (AZA) in Steroid Dependent/Refractory Systemic Autoimmune and Inflammatory Disorders (SAID) Associated with MDS or CMML (GFM- AZA-SAID –trial)

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes — Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Clinical Trials, Workforce
Monday, December 13, 2021, 6:00 PM-8:00 PM

Arsène Mékinian1*, Lin-Pierre Zhao, MD2*, Kristell Desseaux3*, Rose Rose4*, Laurent Pascal, MD, PhD5*, Pierre Peterlin6*, Thibault Comont7*, Alexandre Maria8*, Louis Terriou, MD9*, Maud d'Aveni10*, Marie-Pierre Gourin, MD11*, Norbert Vey, MD12, Odile bayne Rouzy13*, Sophie Dimicoli Salazar14*, Anne Banos, MD15*, Stefan Wickenhauser16*, Benoit De Renzis, MD17*, Eric Durot18,19*, Shanti Ame20*, Laurent Voillat, MD21*, Fatiha Chermat22*, Anne Vekhoff, MD23*, Karine Lemaire24*, Vincent Jachiet25*, Sylvie Chevret, MD, PhD26*, Lionel Ades, MD, PhD27*, Olivier Fain, MD28* and Pierre Fenaux, MD, PhD29

1APHP, Hôpital Saint Antoine, Service d'Hématologie Clinique et de Thérapie cellulaire, Paris, France
2saint louis, Paris, France
3Kristell Desseaux , Kristell Desseaux , France
4lille, lille, France
6Clinical Hematology, HOPITAL HOTEL DIEU ET HME, NANTES CEDEX 1, France
7Comont Thibault , toulouse, France
8montpellier, paris, France
9Hôpital Claude Huriez, Lille, France
10Nancy hospital, hematological department, Nancy, France
11Department of Clinical Hematology, Limoges University Hospital, Limoges, France
12Institut Paoli Clamettes, Marseille, France
13toulose, toulouse, France
14abanos@ch-cotebasque.fr, Pessac, FRA
16HôPital Caremeau, Nimes Cedex 9, FRA
17Service d'Hématologie Clinique Adulte, Clermont Ferrand, FRA
18Service d'Hématologie, saint louis, Reims Cedex, France
19CHU Reims, Hôpital Robert Debré, Reims, France
20anne.vekhoff@aphp.fr, Strasbourg, FRA
21Laurent.Voillat@ch-chalon71.fr, g, France
22Groupe Francophone des Myélodysplasies (GFM), Paris, France
23Department of Clinical Hematology and Cellular Therapy, Saint Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Sorbonne Université, Paris, France
24zaer, paris, France
25HôPital Saint Antoine, Paris, FRA
26APHP, Saint-Louis University Hospital, Department of Biostatistics, PARIS, France
27AP-HP, Hôpital Saint Louis and University of Paris, and INSERM U944, Paris, France
28int atnoine, saint antoine, paris, France
29Service d'Hématologie, Assistance Publique des Hôpitaux de Paris/ Hôpital Saint-Louis / Université Paris 7, Paris, France

Background: Systemic autoimmune and inflammatory diseases (SAIDs) occur in 10-15% of MDS or CMML patients. They are often severe, difficult to treat and steroid resistant/dependent disorders. In a retrospective report of 22 patients with steroid-dependent MDS/CMML associated SAID, we observed promising results with azacytidine (AZA) on the SAID component (Fraison et al, Leuk Res, 2016). In this prospective French nationwide trial, we aimed at confirming this effect prospectively.

Patients and Methods: This open-label, single-arm multicenter, phase II study included MDS/CMML patients with IPSS/CPSS int 2 or high, or lower IPSS/CPSS but with significant cytopenias, especially ESA resistant anemia (or, for CMML, proliferative features) and SAID with steroid dependence and/or resistance. The primary endpoint was response rate (RR, including CR and PR) of SAID after 6 cycles of AZA. Secondary endpoints included RRof SAID after 3 cycles of AZA, response of MDS, time to MDS progression (including to AML), overall survival (OS) and safety. AZA was used at 75 mg/m²/d x 7 days, every 4 weeks for a minimum of 6 cycles (unless overt disease progression occurred before). At the onset of AZA, prednisone (PRED) was administered at 1 mg/kg during 1 month and then decreased progressively over 6 months.

Results: 30 patients were included between July 2017 and June 2020 , 29 of whom received AZA and were considered evaluable: median age 72 [range 68-78], 69% males; WHO: MDS ML (n=11; 41%), CMML (n=11, 41%), MDS-RS (n=2, 7%), EB-1 (n=1) and EB-2 (n=1), unclassified (n=3); IPSS-R : good (n=15, 54%), very good (n=3; 11%, each), intermediate (n=7; 25%) and very poor profile (n=3; 11%) (all CMML had WBC <13G/l and could be classified by IPSS-R). SAIDs features included non-infectious fever (n=5; 17%), skin lesions (n=14; 48%), joint involvement (n=18; 68%), chondritis (n=6; 21%) and peripheral nervous system impairment (n=3; 10%). 11 (38%) /28 tested patients had UBA1 mutation (VEXAS syndrome), while inin the remaining cases SAID was vasculitis (n=5), rheumatic disease (n=6), neutrophilic dermatosis (n=2) and others (n=5).

19 patients (65.5%, IC95% []) obtained a SAID response after 6 cycles (including 8 CR and 11 PR), while 17 (58.6% (IC95% [38.9; 76.5]) patients achieved an IWG 2006 hematological response (7 CR, 9 SD with HI and 1 marrow CR). All the 13 patients who received 12 cycles of AZA achieved SAID CR or PR at 12 months, and 10 of them had a hematological response (6 CR, 1PR, 2 HI, 1 marrow CR). The SAID response rate at 12 month was at 72.4% (IC95% : [51.3;85.6]). SAIDs complete/partial response occurred in 3/9 (33%) UBAI-positive versus 8/19 (42%) non-mutated cases. No significant prognostic factor of SAID response after 6 cycles, including sex, age, WHO classification, IPSS-R, UBA1 and TET-2 mutation status was found. With a median follow-up of 18.5 months [11.8; 24.3], 9 (31%) patients had died, with a 1-year OS of 82.3% (IC95% [69.4; 97.7]. At least one SAE occurred in 23 patients, with a median of 2 events/patient [1.5; 5.5]. Death was due to infection (n=5, two of them in patients with good IPSS-R, but severe steroid dependent SAID), MDS progression (n=2), or unrelated causes (n=2).

Conclusion We confirmed prospectively an effect of AZA on the autoimmune/inflammatory component in two thirds of MDS/CMML patients with steroid dependent / refractory concomitant systemic autoimmune/inflammatory disease. No significant difference in AZA response was noted between UBA1 mutated and unmutated MDS patients. The adverse events and mortality rates, often from infectious origin, appear to be those expected in such an MDS population, potentially worsened by the associated SAID and background of immunosuppressive treatment (especially steroids)

Disclosures: Terriou: Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vey: JAZZ PHARMACEUTICALS: Honoraria; SERVIER: Consultancy; NOVARTIS: Consultancy, Honoraria, Research Funding; BIOKINESIS: Consultancy, Research Funding; BMS: Honoraria; Amgen: Honoraria; JANSSEN: Consultancy, Honoraria; Abbvie: Honoraria. Ades: ABBVIE: Honoraria; TAKEDA: Honoraria; CELGENE/BMS: Honoraria; NOVARTIS: Honoraria; JAZZ: Honoraria, Research Funding; CELGENE: Research Funding. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria.

*signifies non-member of ASH