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62 Ivosidenib Monotherapy Is Effective in Patients with IDH1 Mutated Myelodysplastic Syndrome (MDS): The Idiome Phase 2 Study By the GFM Group

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Low Risk Myelodysplastic Syndrome Prognosis and Treatment
Hematology Disease Topics & Pathways:
Clinical Trials, Clinical Research
Saturday, December 11, 2021: 9:45 AM

Marie Sebert, MD, PhD1*, Thomas Cluzeau, MD, PhD2*, Odile Beyne Rauzy3*, Aspasia Stamatoulas Bastard, MD4*, Sophie Dimicoli-Salazar, MD5*, Sylvain Thepot, MD6*, Pierre Peterlin7*, Sophie Park, MD, PhD8, Marie-Pierre Gourin, MD9*, Oana Brehar4*, Cécile Bally10*, Sébastien Maury11*, Gaelle Fossard, MD12*, Lamya Ait Si Selmi13*, Cendrine Chaffaut14*, Emmanuelle Clappier, PhD, PharmD15*, Raphael Itzykson16*, Fatiha Chermat17*, Sylvie Chevret, MD, PhD18*, Pierre Fenaux, MD, PhD19 and Lionel Ades, MD, PhD20

1Department of Clinical Hematology, Hôpital saint louis, Paris, France
2Centre Hospitalier Universitaire de Nice, Nice, France
3Oncopôle Toulouse, Toulouse, France
4Henri Becquerel Center, Rouen, France
5Department of Clinical Hematology, Bordeaux University Hospital, Pessac, France
6Department of Clinical Hematology, Angers University Hospital, Angers, France
7Clinical Hematology, HOPITAL HOTEL DIEU ET HME, NANTES CEDEX 1, France
8Department of Clinical Hematology, CHU Grenoble, Grenoble Cedex 9, France
9Department of Clinical Hematology, Limoges University Hospital, Limoges, France
10Necker Hospital, hematological department, Paris, FRA
11Service d’Hématologie clinique, Hôpitaux universitaires Henri-Mondor (AP-HP), Créteil, FRA
12Hematology, Centre Hospitalier Lyon Sud, Pierre Benite, France
13GFM, Paris, France
14Division of Biostatistics, Saint-Louis Hospital, APHP, Paris, France
15Hematology Laboratory, Hôpital Saint Louis, Paris, France
16INSERM U944, Paris, FRA
17Groupe Francophone des Myélodysplasies (GFM), Paris, France
18Division of Biostatistics, Saint-Louis Hospital, APHP, Paris, France, Paris, France
19Service d'Hématologie, Assistance Publique des Hôpitaux de Paris/ Hôpital Saint-Louis / Université Paris 7, Paris, France
20Institut Univeristaire d'Hematologie, Hopital Saint Louis, Paris, France

Background: Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of mutant IDH1 approved in the US for adult patients with unfit or relapse/refractory AML with IDH1 mutation. Little is known on its efficacy in patients with IDH1 mutated MDS. Here we report interim results of a Phase 2 study evaluating safety and efficacy of IVO in three different cohorts of MDS patients: Higher risk MDS having failed azacytidine (AZA) (cohort A, n=29), untreated higher risk MDS without life threatening cytopenias (ie ANC < 500/mm3 or any recent severe infections and/or platelets below 30,000/mm3 and any bleeding symptom,) as a first line treatment (cohort B, with the addition of AZA in non-Responders after 3 cycles, n=29) and lower risk MDS having failed EPO (cohort C, n=10). (ClinicalTrials.gov NCT03503409).

Methods: Subjects enrolled in cohort A, B or C received continuous 28-day cycles of IVO - 500 mg orally QD. In cohort B, AZA (75 mg/m2/d x 7 days, SC) was added to IVO after 3 cycles, only in the absence of IWG 2006 response (absence of CR, PR or HI). The primary endpoint was overall hematological response rate (ORR) at 3 and 6 months (including CR, PR, stable disease with HI according to IWG 2006). All responders allowed to continue treatment until loss of response. Secondary endpoints included safety, duration of response, EFS, overall survival and translational project evaluating the role of biomarkers on response. We report the preliminary results on the first 26 pts enrolled.

Results: At data cut off (6/15/2021), 32 patients had been enrolled, including 26 who were evaluable for the primary endpoint. 13, 11 and 2 were enrolled in cohort A, B and C respectively. Median age was 76 years and 50% were female. WHO was MDS-MLD, MDS-EB1, MDS-EB2, CMML and low blast count AML in 2, 2, 12, 1 and 9 patients respectively. IPSS-R was low, intermediate, high and very high in 2, 6, 5 and 13 resp. IDH1 mutation was p.R132C in 15 patients, p.R132H in 7, p.R132G/S in 3 and not specified in 1.

The ORR was 69% (18 patients) including 12 CR (46%), 1 PR and 5 HI. Most patients achieved response after 3 cycles (17/18). Response was achieved in 7 (54%), 10 (91%) and 1 (50%) in cohort A, B and C respectively. Moreover, CR was achieved in 3, 8 and 1 in cohort A, B and C respectively. In cohort B, AZA was added to IVO in one patient after 3 cycles, without additional response.

With a median follow up of 9.1 months, the median duration of response of the 18 responders was 7.4 months, 9 of them lost their response, and two had died without loss of response (from bleeding and after HSCT, respectively). IPSS-R was the only prognostic factor of response after 6 cycles.

At data cut off, 12 patients had progressed (9 in cohort A, 2 in cohort B and 1 in cohort C) and 11 (42%, 10 in cohort A and 1 in cohort C) patients had died, mostly of relapse/progression (n=5/11), infection in 1, suicide in 1, hemorrhage in 1 and other unrelated causes in 3.

Median overall survival was 14 months in the whole cohort, 7.7 and not reached in cohort A and B resp.

The most common treatment-related serious adverse event (SAE) was differentiation syndrome (4/5), one died and three resolved without sequelae. One patient had febrile neutropenia related to IVO, resolved without sequelae.

Conclusion: IVO was well tolerated in MDS patients with significant responses in all the cohorts. With a response rate of 91%, IVO was particularly effective in treatment naïve higher risk MDS patients with IDH1 mutations (cohort B). These encouraging preliminary results have to be confirm in more patients. The IDIOME study is still ongoing, and molecular monitoring results of IDH1 mutations will be presented.

Disclosures: Sebert: BMS: Consultancy; Abbvie: Consultancy. Cluzeau: Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Agios: Honoraria; Amgen: Speakers Bureau; Takeda: Other: travel, accommodations, expenses; Astellas: Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Other: travel, accommodations, expenses. Stamatoulas Bastard: Pfizer: Other: Travel Support; Celgene: Membership on an entity's Board of Directors or advisory committees. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Ades: Abbvie: Honoraria; Takeda: Honoraria; Novartis: Honoraria; JAZZ: Honoraria; Celgene: Honoraria, Research Funding.

*signifies non-member of ASH