Outcomes of Chronic Graft-Versus-Host Disease (cGVHD) Following Matched Sibling Donor (MSD) Versus Umbilical Cord Blood Transplant (UCBT)
Authors: Okoev Grigori , Weisdorf Daniel J. , Wagner John E. , Blazar Bruce R. , MacMillan Margaret L. , DeFor Todd E. , Lazaryan Aleksandr , El Jurdi Najla H , Holtan Shernan , Brunstein Claudio G , Betts Brian C. , Takahashi Takuto , Bachanova Veronika , Warlick Erica D. , Rashidi Armin , Arora Mukta 
Published: November 2019

Introduction: Chronic Graft-Versus-Host Disease (cGVHD) is a leading cause of late non-relapse mortality (NRM) and morbidity after allogeneic hematopoietic cell transplant (alloHCT).Though the incidence of cGVHD is reported to be lower after umbilical cord blood transplantation (UCBT), studies describing its clinical presentation, response to treatment, duration of immune suppression (IST) and NRM following diagnosis of cGVHD are limited. We hence performed a retrospective cohort study of patients who developed cGVHD following a UCBT and compared to matched sibling donor peripheral blood stem cell transplant (MSD PBSCT) treated uniformly in a similar manner at a single center.
Methods: This single center retrospective cohort study included all adult patients who underwent an allogeneic HCT at University of Minnesota between the years 2010 and 2017 from an MSD PBSCT or double/single UCBT and developed cGVHD (n=145). The 2014 NIH Consensus Criteria (Jagasia et al. Biol Blood Marrow Transplant 21 (2015) 389-401) were used to retrospectively classify organ/overall cGVHD severity, and response (Lee at al. Biol Blood Marrow Transplant 21 (2015) 984-999) to IST.
Results: Of 145 patients, 104 (72%) received MSD PBSCT and 41 (28%) UCBT. The median age (range) at HCT was 54y (23-74y) vs. 50y (19-69y) in MSD PBSCT and UCBT, respectively. The median time from HCT to cGVHD was similar at 216 days in MSD PBSCT vs. 224 days in UCBT. cGVHD onset was progressive in 22% of MSD PBSCT vs. 29% of UCBT. Overlap cGVHD was similar at 32% in MSD PBSCT vs. 37% in UCBT respectively (p=0.58). Thrombocytopenia (platelet count <100,000/μl at diagnosis of cGVHD) was similar in MSD PBSCT (24%) vs. 32% in UCBT. Severe cGVHD (classified per 2014 NIH criteria) was more common following MSD PBSCT (p=0.02, Figure 3). Involvement of > 3 organs with cGVHD was more frequent in MSD PBSCT (Figure 1). Amongst organ involvement, liver was significantly more frequently involved in MSD PBSCT, whereas GI involvement was significantly more frequent in UCBT (both p<0.01; Figure 2).
No difference was seen in response (complete or partial: CR or PR) at 6 months (78% vs. 78%, p=0.98), 1 year (80% vs. 78%, p=0.78) or 2 years (67% vs. 67%, p=0.99) between MSD PBSCT or UCBT. In multivariate analysis of response at one year using NIH criteria, UCBT recipients had similar odds of a CR or PR (OR: 0.9 (95% CI: 0.4-2.1, p = 0.9). Karnofsky performance score (KPS) of > 90 at diagnosis of cGVHD was associated with 3-fold higher odds of response (95% CI: 1.42-10.0, p <0.01).
The overall cumulative incidence of 2-year NRM following cGVHD diagnosis was 15% (95% CI: 9-21%). The 2-year cumulative incidence of NRM following MSD was 13% (95% CI: 7-20%), vs. 20% in UCBT (95% CI: 8-33%). In multivariate analysis UCBT recipients had a similar risk of NRM at 2 years as compared to MSD recipients (RR: 1.9, 95% CI: 0.8-4.3, p=0.15). Across both cohorts KPS < 90 was associated with an 8.8-fold higher risk of NRM (95% CI: 3.1-24.9, p < 0.01) and platelet count of < 100,000/μl was associated with 3-fold higher risk of NRM (95% CI: 1.25-10, p= 0.01).
The cumulative incidence of durable discontinuation of all IST (discontinuation of all IST without restarting for at least 6 months) at 2 years was 42% (95% CI: 32-51%). There was no difference noted between MSD (39%, 95% CI: 28-49%) vs. UCBT recipients (50%, 95% CI: 32-69%), p= 0.63 (Figure 4).
Conclusions: cGVHD following UCBT differed in presentation from MSD PBSCT. cGVHD following UCBT was less severe and had more frequent GI involvement and less frequent liver involvement as compared to MSD PBSCT. Despite the differences in clinical presentation, cGVHD following UCBT had similar treatment responses and NRM to that following MSD PBSCT. High risk groups including those with platelet count of <100,000/μl and KPS< 90, need careful monitoring and possibly intensified therapy.

Disclosures
Weisdorf: Pharmacyclics: Consultancy; Incyte: Research Funding; Fate Therapeutics: Consultancy. Wagner:Rocket Pharmaceuticals: Consultancy; Gadeta: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy, Research Funding; BlueRock: Research Funding. Blazar:Kamon Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Five Prime Therapeutics Inc: Co-Founder, Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics and BlueRock Therapeuetics: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc.: Research Funding; RXi Pharmaceuticals: Research Funding; Alpine Immune Sciences, Inc.: Research Funding; Abbvie Inc: Research Funding; Leukemia and Lymphoma Society: Research Funding; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-Founder; BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees. MacMillan:Equillium: Membership on an entity's Board of Directors or advisory committees; Angiocrine: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Alpine Immune Sciences: Consultancy. Lazaryan:Kadmon: Consultancy. Holtan:CSL Behring: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy. Brunstein:Astex: Research Funding; Gamida: Research Funding; Magenta: Research Funding. Bachanova:Kite: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Research Funding; GT Biopharma: Research Funding; Celgene: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Incyte: Research Funding.