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1047 A Phase I Study of Nivolumab in Combination with Ipilimumab for the Treatment of Patients with High Risk or Refractory/Relapsed Acute Myeloid Leukemia Following Allogeneic Stem Cell Transplantation

Program: Oral and Poster Abstracts
Type: Oral
Session: 723. Allogeneic Transplantation: Long-Term Follow up and Disease Recurrence: Novel Therapies to Prevent and Treat Disease Relapse
Hematology Disease Topics & Pathways:
Research, Clinical trials, Combination therapy, Clinical Research, Treatment Considerations, Measurable Residual Disease
Monday, December 9, 2024: 5:00 PM

Gheath Alatrash, PhD, DO1,2, Cristina Knape3*, Laura Whited, PharmD4, Dawen Sui, MS5*, Cara L Haymaker, PhD6*, Jason Yeh, pharmd4*, Megan Marcotulli, MS, PA-C4*, Pariya Sukhumalchandra2*, Lisa St. John, PhD7*, Hsinyi Lu8*, Daniela E. Duenas, MD6*, Ignacio Wistuba, MD9*, Julia Mendoza Perez8*, Beatriz Sanchez Espiridion8*, Roland L. Bassett, MS5*, Tapan M. Kadia, MD10, Courtney D. DiNardo, MD, MSc11, Farhad Ravandi, MBBS12, Jeremy Ramdial, MD1, Rohtesh S. Mehta, MD, MPH1*, Amin M. Alousi, MD1*, Betul Oran, MD, MS1, Issa F. Khouri, MD1, Qaiser Bashir, MD1, Chitra Hosing, MD1, Muzaffar H. Qazilbash, MD1, Jin S. Im, MD, PhD1, Partow Kebriaei, MD13, Pavan Bachireddy, MD14, Jeffrey J. Molldrem, MD15, Jeffrey L. Jorgensen, MD16, Sa A. Wang, MD16, Wei WANG17*, Uday Popat, MD1, Elizabeth J. Shpall, MD1, Richard E. Champlin, MD1, Hagop M. Kantarjian, MD10 and Naval Daver, MD18

1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Hematopoietic Biology and Malignancy, University of Texas MD Anderson Cancer Center, Houston
3The University of Texas MD Anderson Cancer Center, Houston
4University of Texas MD Anderson Cancer Center, Houston, TX
5Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
6Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
7Department of Hematopoietic Biology and Malignancy, University of Texas M. D. Anderson Cancer Center, Houston, TX
8University of Texas MD Anderson Cancer Center, Houston
9Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX
10Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
11Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX
12Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
13M.D. Anderson Cancer Center, Houston, TX
14Department of Hematopoietic Biology & Malignancy, The University of Texas M.D. Anderson Cancer Center, Houston, TX
15Departments of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX
16Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
17Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Harbin, China
18MD Anderson Cancer Center, Houston, TX

Background: The prognosis for patients with AML and MDS who relapse after allogeneic stem cell transplant (allo-SCT) is dismal. AML is susceptible to immunotherapy, as evidenced by the success of allo-SCT. Enhancing graft-versus-leukemia effect of allo-SCT is a major area of focus. We investigated combination immune checkpoint inhibition (ICI) using ipilimumab (Ipi) and nivolumab (Nivo) in a phase I dose escalation trial enrolling AML/MDS patients who relapsed after allo-SCT.

Patients and Methods: For AML, evidence of relapse included bone marrow blast count ≥5% and/or presence of extramedullary disease and/or presence of marrow measurable residual disease (MRD) by multicolor flow cytometry. For MDS, evidence of relapse included appearance of dysplastic changes in the marrow, with or without increase in marrow blast count. Patients, ≥18 years-old, with a matched or haploidentical related donor, or 8/8 HLA matched unrelated donor (MUD) received Nivo (1mg/Kg) monotherapy administered on Day 1 and 15 of a 4 week cycle; ipilimumab (1mg/Kg) monotherapy administered on day 1 of a 3 week cycle; or combination Nivo (1 or 3 mg/Kg) + Ipi (1 or 3 mg/Kg), with Nivo and Ipi administered on day 1, followed by Nivo on days 15 and 29 of a 6 week cycle. Drug(s) were started > 42 days after stem cell infusion. Graft versus host disease (GVHD) prophylaxis was post-transplant cyclophosphamide 50 mg/kg on day +3 and +4, and tacrolimus ± MMF. Patients with history of >grade 2 GVHD were excluded. The primary outcome was to determine maximum tolerated dose (MTD) and dose limiting toxicity of monotherapy and combination Ipi + Nivo. ClinicalTrials.gov: NCT03600155.

Results: 29 patients, 10 females and 19 males, with a median age of 59 (27-76) years were enrolled between April 2019 and May 2023. Of the 29 patients, 20 (69%) had AML, 7 (24%) had MDS, and 2 patients (7%) had CMML. Twenty-six (90%) patients had marrow disease only, 1 patient (3%) had extramedullary disease, and 2 patients (7%) had involvement of both. Twenty-two (76%) patients with AML and MDS had morphologic relapse, and 7 (24%) AML patients had MRD by flow cytometry. Five patients (33%) had a history of grade I GVHD and 10 (67%) patients had a history of grade II GVHD; in all cases, symptomatic GVHD resolution was achieved prior to study initiation. The median time from administration of SCT to study drug infusion was 179 days (range, 54-987). Seventeen (59%) patients were on GVHD prophylaxis during the study. Twenty-seven patients (93%) had received post SCT cyclophosphamide.

Four patients (14%) developed GVHD on study. Of the 4 patients who developed GVHD, 2 (50%), 1 (25%) and 1(25%) patients developed grade II (skin and upper GI [UGI]), III (UGI and lower GI [LGI]) and IV (LGI) GVHD, respectively. Twenty-nine (100%), 28 (97%), 29 (100%), 16 (55%), and 7 (24%) patients experienced grades I, II, III, IV and V toxicities, respectively. Typical adverse events associated with ICI included: pneumonitis (n=3; 10%), 2 (7%) grade II and 1 (3%) grade III; colitis (n=3; 10%), 1 (3%) grade II, 1 (3%) grade III and 1 (3%) grade IV; hepatitis (n=6; 21%), 2 (7%) grade 1, 2 (7%) grade II, 1 (3%) grade III and 1 (3%) grade IV; endocrinopathy (n=3; 10%), 1 (3%) grade I, 1 (3%) grade II, and 1 (3%) grade III; dermatitis (n=4; 14%), 1(3%) grade 1, and 3 (10%) grade III. Dose limiting toxicities were noted at combination nivo 1 mg/Kg + Ipi 3 mg/Kg, mandating Ipi dose reduction to 1mg/Kg.

During the study period, median follow-up was 65 days (range, 9-277 days); 13 patients experienced disease progression, GVHD, or death. Median PFS, estimated using Kaplan-Meier method, was 109 days (95%CI: 48 - NA days). Nine (31%) patients achieved stable disease or remission: 4 patients on Nivo 1 mg/Kg arm, 2 patients on Ipi 1 mg/Kg arm, 2 patients on Nivo + Ipi 1 mg/Kg arm, and 1 patient on the Nivo 3 mg/Kg + Ipi 1 mg/Kg arm. Patients with MDS had a longer PFS (HR = 0.15; CI, 0.02-1.18; p=0.03) vs. patients with AML. Of patients with extramedullary disease, 1 patient had CR of skin lesions and the second patient had a mixed response; both patients received Nivo 1mg/Kg + Ipi 1mg/Kg arm.

Comprehensive immune profiling using CyTOF enabled the identification of distinct stem cell subsets and myeloid and lymphoid populations in bone marrow aspirates and circulating blood.


Conclusion: This study met its primary objective of determining the MTD of the combination regimen with encouraging safety and efficacy outcomes. Our results warrant further study of this regimen.

Disclosures: Kadia: Regeneron: Research Funding; Sellas: Consultancy, Research Funding; Amgen: Research Funding; DrenBio: Consultancy, Research Funding; AstraZeneca: Research Funding; Rigel: Honoraria; Incyte: Research Funding; Pfizer: Research Funding; ASTEX: Research Funding; Ascentage: Research Funding; JAZZ: Research Funding; Servier: Consultancy; Novartis: Honoraria; BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Cellenkos: Research Funding. DiNardo: BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Astex: Research Funding; ImmuneOnc: Research Funding; Cleave: Research Funding; Stemline: Consultancy; Foghorn: Research Funding; Jazz: Consultancy, Honoraria; Loxo: Research Funding; Gilead: Consultancy; Rigel: Research Funding; Immunogen: Honoraria; Notable Labs: Honoraria; Genetech: Honoraria; Riegel: Honoraria; Amgen: Consultancy; Astellas: Consultancy, Honoraria; GenMab: Consultancy, Honoraria, Other: data safety board; GSK: Consultancy, Honoraria; Schrodinger: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding. Ravandi: BMS: Consultancy, Honoraria; Syndax: Honoraria; Syros: Consultancy, Honoraria, Research Funding; Prelude: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Xencor: Research Funding; Amgen: Research Funding; Astyex/Taiho: Research Funding. Khouri: Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Bashir: Pfizer, Inc.: Research Funding; GSK PLC: Research Funding; Stemline Therapeutics, Inc.: Research Funding. Qazilbash: Janssen Pharmaceuticals: Research Funding; NexImmune: Research Funding; Amgen: Research Funding; Angiocrine Bioscience: Research Funding; BioLineRx: Research Funding. Kebriaei: Pfizer: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Bachireddy: Allogene Therapeutics: Research Funding; Amgen: Current equity holder in publicly-traded company; BioNTech: Current equity holder in publicly-traded company; Agenus: Current equity holder in publicly-traded company; Johnson & Johnson: Current equity holder in publicly-traded company; Exelixis: Current equity holder in publicly-traded company. Popat: T Scan: Research Funding; Bayer: Research Funding; Incyte: Research Funding; Abbvie: Research Funding. Shpall: National Marrow Donor Program: Other: Board of Directors/Management; Adaptimmune Limited: Other: Scientific Advisor; FibroBiologics: Other: Scientific Advisor; Zelluna Immunotherapy: Other: Scientific Advisor; Axio Research: Current Employment, Other: Scientific Advisor. Kantarjian: AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Daver: Syndax: Consultancy; Glycomimetics: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Shattuck Labs: Consultancy; Hanmi: Research Funding; Trovagene: Research Funding; Trillium: Consultancy, Research Funding; Menarini Group: Consultancy; Celgene: Consultancy; KITE: Research Funding; Agios: Consultancy; Arog: Consultancy; Novartis: Consultancy; Jazz: Consultancy; FATE Therapeutics: Other: Consulting Fees, Research Funding; Novimmune: Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

*signifies non-member of ASH