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3246 Phase I/II Clinical Trial Evaluating Azacitidine + Venetoclax + Donor Lymphocyte Infusion in Post-Transplant Relapse Myelodysplastic Syndromes and Acute Myeloid Leukemia: Preliminary Results of Ventograft, a GFM Study

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
AML, clinical trials, Acute Myeloid Malignancies, Research, Combination therapy, Clinical Research, Diseases, Therapies, Myeloid Malignancies
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Thomas Cluzeau, MD, PhD1, Marie Sebert, MD, PhD2*, Michael Loschi, MD, PhD3*, Lionel Ades, MD, PhD4, Sylvain Thepot, MD5*, Martin Carre, MD6*, Nicolas Duployez, MD7*, Rosa Sapena, PhD8*, Fatiha Chermat9*, Claude Preudhomme, PharmD, PhD10*, Pierre Fenaux, MD, PhD11 and Marie Robin, MD12*

1Nice University Hospital, Nice, Provence Alpes Cote d'Azur, France
2Hôpital Saint-Louis, Paris, France
3Centre Hospitalier Universitaire de Nice, Nice, France
4Hôpital Saint-Louis, Hematology Department, Hopital Saint Louis, Paris, France
5Department of Clinical Hematology, Angers University Hospital, ANGERS, NA, France
6Clinical Hematology Department, CHU Grenoble Alpes - Université Grenoble Alpes, Grenoble, France
7Hematology Laboratory, CHRU Lille, Lille, France
8Groupe Francophone des Myelodysplasies, Paris, France, Paris, France
9Groupe Francophone des Myelodysplasies, Paris, France
10Hematology Laboratory, CHU Lille, Lille, France
11Hôpital Saint-Louis, Hematology Department, AP-HP, Paris, France
12Hopital Saint-Louis, Paris, France


Azacitidine (AZA) is approved for the treatment of patients with high-risk MDS and in combination to Venetoclax (VEN) in AML. Beyond direct cytotoxic/epigenetic effects of AZA and ability to induce remissions even in patients refractory to chemotherapy, AZA has been shown to increase the immunogenicity of AML blasts by reexpression of key antigens [Schroeder et al. Leukemia 2013]. Moreover, VEN imparts distinct cell death sensitivity and adaptivity patterns in T cells (Ludwig et al. Cell Death Dis 2021). DLI have shown efficacy to treat or prevent relapse of AML or MDS following allogeneic stem cell transplantation (allo-SCT) in 20-40% of the cases [Castagna et al. Transfusion and Apheresis 2016]. A german retrospective study showed an overall response rate (ORR) of 33% (including 27% CR and 6% PR), to AZA and DLI following relapse after allo-SCT in AML and MDS [Schroeder et al. BBMT 2015], a regimen used since in many centers. We present here preliminary results of a phase I/II evaluating the combination of AZA/VEN/DLI in relapse MDS/AML.

Patients and Methods:

In this open label multicenter phase I/II study, MDS and AML patients relapsing post allo-SCT, without active graft versus host disease (GVHD) and active infections, are treated with VEN during 14 days in combination with AZA at 75 mg/m²/day for 5 days for each cycle (or 50 mg/m²/day for 5 days each cycle if relapse occurs less than 4 months after allo- SCT), and VEN orally at escalating dose (step 1: VEN 100mg/d; step 2: VEN 200mg/d and step 3: VEN 400mg/d) in the phase I part and at maximal tolerated dose (MTD) on days 1-14 of each cycle in the phase II part. Cycles are administered every 28 day (or delayed until day 42 in case of hematological toxicity). DLI are started at least 8 weeks after immunosuppressive therapy discontinuation, if chimerism in <90% recipient, and administered on day 15 every two cycles (C2, C4, C6, C8) in the absence of GVHD. Patients receive at least 8 cycles of AZA/VEN + DLI unless progression occurs. Response is assessed after 4, 6 and 8 cycles. Patients achieving a response receive 12 cycles of AZA + VEN followed by cycles of AZA alone. In the absence of response after 8 cycles, patients stop treatment.


From November 2022 to June 2023, 9 patients were included in part 1 of VENTOGRAFT. M/F was 8/1. Median age 57 years (range 18-71). Two patients had MDS and 7 patients had AML at diagnosis. Five patients had MDS (IPSS-R was low (1), intermediate (2) and very high (2)), and 3 patients had AML (ELN2017 was intermediate (1) and unfavorable (2) and molecular relapse (1)) at the time of relapse. Median interval between allo-SCT and relapse was 44 months (range 2-181). At data cut-off, 3 patients had been treated in step 1, 3 patients in step 2 and 3 patients in step 3 (AZA + VEN 400mg/d D1-14)). Median number of AZA + VEN cycles was 3 (range 1-8) and median number of DLI infused was 1 (range 0-3). One dose limiting toxicity (No ANC recovery on D42 and one patient still neutropenic at D28) was observed in step 3 leading to inclusion 3 more patients on this step. Other adverse events observed were grade 1/2 nausea (2 patients), grade 1 skin lesions (1 patient), ALAT increase grade 3 (1 patient), febrile neutropenia grade 3 (2 patients), grade 3 abdominal pain (1 patient) and grade 3 gastrointestinal bleeding (2 patients). GVHD was seen in 1/9 (11%) patients). CMV and EBV reactivation were observed in 0 and 2 patients, respectively. Overall response rate was 6/9 (67%) patients 67% including 22% complete remission (CR), 22% of CR with incomplete recovery (CRi) and 33% of morphologic leukemia-free state (MLFS). Full donor chimerism was obtained in all patients obtaining a response.

Conclusion: The combination of AZA at 75mg/m²/d D1-5 and VEN at 100 to 400mg/d D1-D14 (400mg/d ongoing) was safe, showed a promising ORR of 67%. Final results of the phase 1 and first patients treated in this phase 2 will presented at the ASH meeting.

Disclosures: Cluzeau: Keros: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; BMS: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Syros: Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau. Sebert: Abbvie: Honoraria; Servier: Honoraria, Research Funding; Jazz pharmaceuticals: Honoraria; Gilead: Honoraria; Novartis: Honoraria; BMS: Honoraria. Loschi: Alexion: Honoraria; AstraZeneca: Honoraria; BMS: Honoraria; Gilead: Honoraria; GSK: Honoraria; Jazz: Honoraria; Kartos: Honoraria; Medac: Honoraria; MSD: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Sobi: Honoraria; Telios: Honoraria. Ades: Abbvie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; KEROS: Consultancy; ROCHE: Honoraria; Novartis: Consultancy, Research Funding; jazz: Honoraria; AMGEN: Consultancy. Fenaux: AbbVie: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; French MDS Group: Honoraria.

*signifies non-member of ASH