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2348 Lower Risk of Graft Versus Host Disease after Exposure to Checkpoint Inhibitors with the Use of Post-Transplant Cyclophosphamide Prophylaxis

Program: Oral and Poster Abstracts
Session: 704. Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
AML, Diseases, Therapies, MDS, Adverse Events, Myeloid Malignancies, Clinically relevant
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Chantal Saberian, MD1*, Noha Abdel-Wahab2*, Ala Abudayyeh, MD3*, Hind Rafei, MD4*, Jacinth Joseph, MD5*, May Daher5, Stephen K. Gruschkus, PhD, MPH6*, Cristina Knape7*, Laura Whited8*, Alison Gulbis9*, Megan Marcotulli8*, Gabriela Rondon10, Uday R. Popat, MD5, Rohtesh S. Mehta, MD, MPH, MS5, Marina Konopleva, MD, PhD11, Betul Oran, MD, MS12, Maro Ohanian, DO13*, Farhad Ravandi, MBBS14, Guillermo Garcia-Manero, MD13, Amin M. Alousi, MD15, Naval Daver, MD13, Richard E. Champlin, MD10, Adi Diab, MD16* and Gheath Alatrash17

1Melanoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX
2University of Texas MD Anderson Cancer Center, Houston, TX
3MD Anderson Cancer Center, Houston, TX
4Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
5Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
6Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
7The University of Texas MD Anderson Cancer Center, Houston, TX
8UT M.D. Anderson Cancer Center, Houston, TX
9Pharmacy, The University of Texas M.D. Anderson Cancer Center, Houston, TX
10Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
11University of Texas, MD Anderson Cancer Center, Houston, TX
12Stem Cell Transplantation and Cellular Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX
13Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
14Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
15Stem Cell Transplantation and Cellular Therapy, University of Texas M. D. Anderson Cancer Center, Houston, TX
16Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX
17Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Background: Allogeneic hematopoietic stem cell transplantation (alloHCT) remains a curative approach for patients with AML/MDS. Still, up to 50 % of patients relapse after alloHCT. Immune checkpoint inhibitors (ICI) are being used in the post-transplant setting to reverse the immune dysfunction that contributes to AML/MDS relapse. However, a major concern with using ICI post alloHCT is the increased risk of graft versus host disease (GVHD). A variety of pre- and post- transplant factors can play a crucial role in exacerbating GVHD. We performed a retrospective analysis to report our experience with ICIs used after alloHCT in AML/MDS patients with a focus on the impact of post-transplant cyclophosphamide (PTCy).

Methods: In this study, we included 16 AML and 5 MDS patients treated with single-agent anti-PD-1 (nivolumab, n=16) or anti-CTLA-4 (ipilimumab, n=5) for disease relapse after alloHCT at our institution. The primary outcome was acute GVHD (aGVHD) following ICI initiation post alloHCT. Secondary outcomes were progression-free survival (PFS) and overall survival (OS) that were estimated using the Kaplan-Meier method.

Results: Median patient age was 54 years (range, 29-77 years). Patients received a median of 2 doses of ICI therapy (range, 1 to 12). The median time from alloHCT to ICI initiation was 9.1 months (range 1.3–134.4 months). All patients had received myeloablative conditioning regimens. Donors were matched related in 9 (43%), matched unrelated in 9 (43%), and haploidentical in 3 (14%). Stem cell source was peripheral blood stem cells in 14 (67%) and bone marrow in 7 patients (33%). Twelve patients (57%) received PTCy as GVHD prophylaxis (PTCy group). Transplantation characteristics were comparable between the two groups (PTCy vs no-PTCy), except for lower median score of hematopoietic stem cell comorbidity index in PTCy group (median score of 1 (range,0-3) vs. median score of 3 (range,1-5), P=.04), and a shorter median time from alloHCT to ICI initiation (5 vs. 26 months, P=.04) noted in PTCy group. Before initiation of ICI, 5 patients (24 %) had previously had GVHD.

In the entire cohort, 4 patients (19 %) developed aGVHD following ICI initiation. All the 4 cases of aGVHD were reported following nivolumab initiation. Over a median follow up of 5.3 months, the frequency of grade 2-4 aGVHD was 19%. The frequency of grade 1 to 2 and grade 3 to 4 aGVHD were 9.5% and 9.5%, respectively, with a median time from initiation of nivolumab to onset of aGVHD of 24 days (range, 12-31 days), and a median time from alloHCT to nivolumab-related aGVHD of 188 days (range,109-419 days). The median number of nivolumab doses to aGVHD was 2 doses (range, 1-8 doses). No chronic GVHD or grade > 2 immune-related adverse events were reported.

The frequency of grade 2-4 aGVHD was not influenced by stem cell source, donor type, age at transplant, and previous history of GVHD, but was affected by post-transplant GVHD prophylaxis. Specifically, patients receiving PTCy had a lower observed cumulative incidence of grade 2 to 4 aGVHD than patients who did not receive PTCy (16% vs 22%, P=.07). After controlling for comorbidities and time from transplant to ICI initiation, we found that PTCy was significantly associated with a 90% reduced risk of aGVHD (HR= 0.1; 95% CI: 0.02 – 0.6; P=.01).

Of the 13 evaluable patients who received nivolumab, 4 patients (31%) had an objective response, including 3 patients achieving a complete response (CR) and 1 patient achieving a partial response. The other 9 patients (69%) had no response. Of the 5 patients who received ipilimumab, only 1 patient (20 %) achieved a CR. The other 4 patients (80%) had progression of disease. There was no significant difference between the clinical responses in patients who received PD-1 inhibitor versus CTLA-4 inhibitor (P= 0.65). Patients receiving PTCy had a significantly longer median PFS (22.4 vs. 5.2 months, P=.02), and a trend toward longer median OS (22.4 vs. 5.2 months, P=.08). Fourteen patients (67%) died, and no deaths were related to aGVHD.

Conclusions: The use of ICI for AML/MDS relapse after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of aGVHD in this cohort of patients. Given the small number of patients involved in our study, further investigations with a larger number of patients in prospective trials are needed to determine the magnitude of the of PTCy effect on reducing aGVHD after ICI.

Disclosures: Rafei: United States Provisiona: Patents & Royalties: I have a filed patent. Popat: Bayer: Research Funding; Novartis: Research Funding. Mehta: Kadmon: Research Funding; CSL Behring: Research Funding; Incyte: Research Funding. Konopleva: Amgen: Consultancy; Agios: Research Funding; Sanofi: Research Funding; Rafael Pharmaceutical: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Cellectis: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Kisoji: Consultancy; Ascentage: Research Funding; Eli Lilly: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; AstraZeneca: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical. Oran: Celgene: Consultancy; Arog Pharmaceuticals: Research Funding; ASTEX: Research Funding. Ravandi: Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Garcia-Manero: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Alousi: Incyte: Honoraria, Research Funding; Alexion: Honoraria; Therakos: Research Funding. Daver: Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees. Champlin: Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Omeros: Consultancy; Johnson and Johnson: Consultancy; Actinium: Consultancy; Takeda: Patents & Royalties. Diab: Bristol Myers Squibb: Research Funding; Pfizer: Research Funding; Apexigen: Research Funding; Idera Therapeutics: Research Funding; Nektar Therapeutics: Research Funding.

*signifies non-member of ASH