Type: Oral
Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD and Immune Reconstitution: Monitoring, Understanding and Optimizing GVHD Interventions
Hematology Disease Topics & Pathways:
Research, Clinical Research, Real-world evidence, Registries
Endpoints for GVHD treatment trials use early response (i.e, day (D)28 of treatment) as a surrogate for long term survival. Overall response (OR) that combines complete (CR) and partial responses (PR) at day (D) 28 is the conventional endpoint for primary acute GVHD trials because of similar survival outcomes between CR and PR. D28 OR ignores symptom severity at baseline and D28, however, and the PR category encompasses a wide range of responses from minimal improvement to near complete resolution of symptoms. D28 OR is the only endpoint currently approved by the FDA for efficacy, but it has not been re-evaluated as an endpoint for primary treatment (1L) in fifteen years and little is known regarding the prognostic value of D28 OR as an endpoint for second line treatment (2L) of GVHD. We hypothesized that refinement of the current D28 OR criteria, particularly through recategorization of PR in the GI tract, the main driver of nonrelapse mortality (NRM), would more accurately reflect disease control and better predict survival outcomes than current D28 response.
Methods
The Japanese Society for Transplantation and Cellular Therapy (JSTCT) collaborated with the Mount Sinai Acute GVHD International Consortium (MAGIC) to develop and validate D28 refined response (RR) criteria for 1L and 2L treatment (tx) in patients with Grades II-IV acute GVHD. To maximize the correlation between treatment success (i.e, response) with long term survival, our primary measured metric was the negative predictive value (NPV).
We first randomly divided the 1L tx cohort of JSTCT into the training (n=2341) and validation sets (n=1156). In the training set we used a classification and regression tree (CART) algorithm to generate RR criteria that predicted 6-month (mo) NRM based on symptoms both at tx onset and D28. We then compared the two D28 response endpoints (RR vs OR) as surrogates for 6-mo NRM in two validation sets of both 1L tx (JSTCT: n=1156; MAGIC: n=1141) and 2L tx (JSTCT: n=510; MAGIC: n=196).
Results
The CART algorithm defined a RR as GVHD Grades 0/I at D28 without additional tx; all other D28 grades were considered refined nonresponses. As expected, RR successfully stratified the risk of 6-mo NRM in both 1L tx validation sets (JSTCT: 8% vs 38%, p<0.01; MAGIC: 9% vs 37%, p<0.01). We defined a discordant nonresponse as a nonresponse by RR criteria but a response by OR criteria, which accounted for the majority (~75%) of differences between RR and OR. 6-mo NRM in discordant nonresponders was four fold higher than in responders (JSTCT: 35%; MAGIC: 30%). The large majority (>80%) of discordant nonresponders had persistent GI GVHD at D28. Because the proportion of discordant nonresponders was small (<7% of the total population) in the 1L setting, the improvements of an already high NPV were small (JSTCT: 93% vs 91%; MAGIC: 91% vs 90%).
In the 2L tx validation sets, RR also stratified the risk of 6-mo NRM (JSTCT: 26% vs 56%, p<0.01; MAGIC: 13% vs 55%, p<0.01). At the time of 2L tx, the discordant nonresponders are more common and half of the discordant nonresponders experienced 6-mo NRM (JSTCT: 45%; MAGIC: 59%); as a result, RR achieved much higher NPVs than OR (JSTCT: 75% vs 66%; MAGIC: 87% vs 76%). Deaths in responders from acute GVHD (vs. other causes such as infection) were more frequent in OR than RR in both 2L tx validation sets (JSTCT: 41% vs 20%; MAGIC: 41% vs 13%) and 1L tx validation sets (JSTCT: 25% vs 18%; MAGIC: 32% vs 29%). D28 RR is superior to OR because it more accurately reflects control of serious GVHD in four independent validation cohorts, particularly in patients with GI disease.
Conclusion
We conclude that RR is a more accurate endpoint than OR in patients with grade II-IV GVHD primarily because it classifies persistent GI GVHD at D28 as a non-response instead of a response, which correlates with 6-mo NRM and achieves a higher NPV. This validated RR metric can serve as a better endpoint than OR in assessing treatment efficacy in both primary treatment trials that enrich for high risk GVHD, e.g. GI involvement, and second line treatment trials.
Disclosures: Akahoshi: Novartis: Honoraria. Inamoto: Janssen: Honoraria; Meiji Seika Pharma: Honoraria, Research Funding. Ayuk: BMS: Honoraria; Medac: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Miltenyi Biomedicine: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria; Abbvie: Honoraria. Choe: Ironwood Pharmaceuticals, Inc.: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; REGiMMUNE: Consultancy; Sanofi: Consultancy; Orca Bio: Consultancy; Incyte: Consultancy. Hexner: Disc Medicine: Consultancy. Kataoka: AbbVie: Honoraria; Pfizer: Honoraria; Nippon Shinyaku: Honoraria; Shionogi: Research Funding; Meiji Seika Pharma: Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; JCR Pharmaceuticals: Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Japan Blood Products Organization: Research Funding; Mochida Pharmaceutical: Research Funding; Celgene: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria; Asahi Kasei Pharma: Research Funding; Chordia Therapeutics: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Teijin Pharma: Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Asahi Genomics: Current equity holder in private company; Sumitomo Dainippon Pharma: Honoraria, Research Funding; SymBio Pharmaceuticals: Honoraria; Sanofi: Honoraria; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen Pharmaceutical: Honoraria. Uchida: Astellas Pharma Inc.: Consultancy; Chugai Pharmaceutical Co.: Research Funding; Fuji Pharma Co.: Research Funding; Sumitomo Pharma Co.: Research Funding; Nippon Boehringer Ingelheim Co.: Research Funding; JCR Pharmaceuticals Co.: Research Funding; CSL Behring: Honoraria; MSD (Merck & Co. Inc.): Honoraria; Asahi Kasei Pharma Co.: Honoraria; Astellas Pharma Inc.: Honoraria; AstraZeneca: Honoraria; AbbVie GK: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; Kyowa Kirin Co.: Honoraria; SymBio Pharmaceuticals: Honoraria; Daiichi Sankyo Co.: Honoraria; Takeda Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Nippon Shinyaku Co.: Honoraria; Takeda Pharmaceutical Co.: Consultancy; Novartis Pharma Co.: Honoraria. Chen: Ironwood Pharmaceuticals, Inc.: Consultancy; Vor: Consultancy; Garuda: Consultancy; Editas: Consultancy; Alexion: Consultancy; Incyte: Consultancy. Kanda: Janssen Pharmaceutical K.K.: Consultancy, Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; CSL Behring K.K.: Honoraria; MSD K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; Amgen Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb Co: Honoraria; Ono Pharma Inc.: Honoraria; ASAHI KASEI PHARMA CORPORATION: Honoraria; Sanofi K.K.: Honoraria; asclepia: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; NIPPON KAYAKU CO.,LTD.: Honoraria; Novartis Pharma K.K.: Consultancy, Honoraria; DAIICHI SANKYO Co., Ltd.: Consultancy, Honoraria; Megakaryon Co: Consultancy; SymBio Pharmaceuticals, Ltd.: Consultancy; AbbVie Inc.: Consultancy, Honoraria; Eisai: Research Funding. Nakamura: Mitarisan: Research Funding; Omeros (ended): Consultancy; Helocyte: Research Funding; Blue Bird (ended): Consultancy; Sanofi: Consultancy; Ono Pharmaceutical: Consultancy; Pfizer: Consultancy; Maat Pharma: Research Funding. Atsuta: Meiji Seika Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Speakers Bureau; Janssen Pharmaceutical K.K.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Consultancy; CHUGAI PHARMACEUTICAL CO., LTD.: Speakers Bureau; Novartis Pharma KK: Speakers Bureau. Ferrara: Allovir: Consultancy; Physician Education Resource: Consultancy; Bluebird Bio: Consultancy; Sanofi: Consultancy; Viracor: Consultancy, Patents & Royalties: GVHD biomarker patent; Medpace: Consultancy; Realta: Consultancy; Alexion: Consultancy; Inhibrx: Consultancy; X4 Pharmaceuticals: Consultancy. Kanda: Asahi-kasei, MSD, Novartis, Pfizer, Sanofi, Chugai, Astellas, Kyowa-Kirin: Honoraria; Chugai, Kyowa-kirin, Asahi-kasei, Otsuka: Research Funding. Levine: X4: Consultancy; Novartis: Consultancy; Mesoblast: Consultancy; Maat Pharma: Consultancy; Inhibrx: Consultancy; Forte Biosciences: Consultancy; Editas: Consultancy; Bluebird Bio: Consultancy; Ironwood: Consultancy; Calliditas: Consultancy; Viracor: Patents & Royalties: GVHD biomarker patent. Teshima: Janssen: Honoraria; Shionogi: Honoraria, Research Funding; Eisai: Research Funding; Symbio: Honoraria; Genmab: Honoraria; Pharma Essentia Japan: Research Funding; Chugai: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; AstraZeneca: Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Roche Diagnostics: Consultancy; Takeda: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria, Research Funding; Asahi Kasei Pharma: Honoraria, Research Funding; Nippon Kayaku: Honoraria, Research Funding; JCR Pharma: Honoraria, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; MSD: Honoraria; Fuji Pharma: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Sumitomo Pharma: Research Funding; Abbvie: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; LUCA Science: Research Funding; Novartis: Honoraria; Nippon Shinyaku: Consultancy, Honoraria.
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