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Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.

Results of two parallel phase II trials of transplantation of unrelated umbilical cord blood or bone marrow from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18-70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo cord blood (n=186) or haploidentical (n=182) transplant. Reduced intensity conditioning comprised total body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for cord blood transplantation was cyclosporine and mycophenolate mofetil and for haploidentical transplantation, post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil. The primary endpoint was 2-year progression-free survival. Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease and disease status at randomization. Two-year progression-free survival was 35% (95% CI, 28-42%) compared to 41% (95% CI, 34-48%) after cord blood and haploidentical transplants, respectively (p=0.41). Pre-specified analysis of secondary endpoints recorded higher 2-year non-relapse mortality after cord blood, 18% (95% CI, 13-24%) compared to haploidentical transplantation, 11% (95% CI, 6-16%), p=0.04. This led to lower 2-year overall survival after cord blood compared to haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49-64%), respectively (p=0.04). The trial did not demonstrate a statistically significant difference in the primary endpoint, 2-year progression-free survival, between the donor sources. While both donor sources extend access to reduced intensity transplantation, analyses of secondary endpoints, including overall survival, favor haploidentical bone marrow donors. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute; ClinicalTrials.gov number, NCT01597778).

Background: Limited studies report a wide range of venous thromboembolism (VTE) incidence among allogeneic hematopoietic cell transplant (alloHCT) recipients. Chronic GVHD (cGVHD) is an immune mediated complication after alloHCT associated with vascular endothelial damage and prolonged systemic inflammation. We hypothesized that patients developing cGVHD are a subgroup at particularly high risk for VTE. Aims: To assess VTE incidence, sites of involvement, and risk factors in patients with cGVHD and to examine the impact of VTE on clinical outcomes after alloHCT. Methods: We performed a retrospective cohort study of all 145 patients who developed cGVHD after a matched sibling (MSD) and umbilical cord blood (UCB) donor alloHCT from 2010 to 2018. VTE was defined as a new confirmed event by imaging at any time after cGVHD diagnosis. VTE sites were categorized as upper extremity (UE), lower extremity (LE) deep vein thrombosis (DVT) or pulmonary embolus (PE). We assessed the cumulative incidence of VTE treating non-VTE mortality as a competing risk. Multivariate regression was used to evaluate the independent association of risk factors with the incidence of VTE using predefined factors in our model including gender, age, DRI, cGVHD severity, days to cGVHD from transplant and platelet level. We accounted for multiple events of VTE using PWP regression. Cox and Fine and Gray regressions were used to evaluate the independent association of time-dependent VTE on overall survival (OS) and non-relapse mortality (NRM), respectively using propensity scoring to control for confounding.. Results: Median age at time of cGVHD diagnosis was 52 years (range 19-74). 104 (72%) patients received MSD and 41 (28%) UCB alloHCT. Of the 145 patients with cGVHD, 32 (22%) developed either 1 or 2 VTE events and 14 (10%) developed 2 VTE events. The first VTE events were PE (n=6, 19%), and DVT (n=26, 81%; n=17 LE, n= 8 UE and n=5 catheter related UE DVT); one patient developed an IVC thrombus. The second VTE events were PE (n=2, 14%), and DVT (n=12, 86%; n=5 LE, n= 7 UE and n=4 catheter related UE DVT). Most patients were on corticosteroids at the first (n=28, 88%) and second (n=10, 71%) VTE with a median dose of (0.3 and 0.2 mg/kg/day, respectively) ± additional immunosuppression therapies. The cumulative incidence of VTE through 5 years post cGVHD diagnosis was estimated at 22% (95% CI: 15-29%) with median time from cGVHD diagnosis to VTE of 234 days (IQR 85-599). Median time to the development of LE DVT or PE was shorter than UE DVT (107 vs 450 days, respectively). Incidence was higher in males (24% vs 18%), and was not significantly different by age (< or ≥50), BMI (< or ≥30), HCT- comorbidity index, donor type, conditioning regimen and GVHD prophylaxis. Cumulative incidence was higher (50%) in patients with high/very high risk DRI compared to 19% in those with low and intermediate risk DRI. VTE incidence was highest in patients with de novo cGVHD (25%) compared to quiescent (20%) and progressive type (17%). Cumulative incidence was 9%, 17% and 38% in those with mild, moderate and severe GVHD respectively. Patients with lung, gastrointestinal, genitourinary and liver cGVHD had a higher incidence of VTE. Patients developing cGVHD >6 months from HCT had a higher incidence of VTE (24% vs 19%). In multivariate analysis, high/very high risk DRI was associated with higher risk of VTE (HR 2.5; 95% CI; 1.2-5.3) (Figure 2). VTE was not associated with a significantly higher 2-year NRM (HR 1.2; 95% CI; 0.4-3.6) or 5 year OS (HR 1.4; 95% CI; 0.7-3.0). Conclusion: Patients who develop cGVHD after alloHCT have a high incidence VTE. Identifying a subgroup at a particularly high risk for VTE could inform thromboprophylaxis and other supportive care strategies for prevention of such events. Disclosures Bachanova: Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; FATE: Research Funding; BMS: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. Blazar:Tmunity: Other: Co-founder; Magenta Therapeutics: Consultancy; KidsFirst Fund: Research Funding; Fate Therapeutics Inc.: Research Funding; Childrens' Cancer Research Fund: Research Funding; BlueRock Therapeuetic: Consultancy; BlueRock Therapeutics: Research Funding. Brunstein:Astex: Research Funding; AlloVir: Other: Advisory board; Magenta: Research Funding; Gamida: Research Funding. Holtan:CSL Behring: Other: Clinical trial data adjudication; BMS: Consultancy; Generon: Consultancy; Incyte: Consultancy. Janakiram:Takeda, Fate, Nektar: Research Funding. Gangaraju:Sanofi Genzyme, Consultant for Cold Agglutinin Disease: Consultancy. MacMillan:Talaris Therapeutics, Inc: Consultancy; Angiocrine Biosciences, Inc.: Consultancy; Equillium, Inc.: Consultancy; Fate Therapeutics, Inc.: Consultancy; Mesoblast: Consultancy. Rashidi:Synthetic Biologics: Other: DSMC member (1 trial) and related honorarium. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy. Arora:Pharmacyclics: Research Funding; Fate Therapeutics: Consultancy; Kadmon: Research Funding; Syndax: Research Funding.

Exocytosis of cytotoxic granules (CG) by lymphocytes is required for the elimination of infected and malignant cells. Impairments in this process underly a group of diseases with dramatic hyperferritinemic inflammation termed hemophagocytic lymphohistiocytosis (HLH). Although genetic and functional studies of HLH have identified proteins controlling distinct steps of CG exocytosis, the molecular mechanisms that spatiotemporally coordinate CG release remain partially elusive. We studied a patient exhibiting characteristic clinical features of HLH associated with markedly impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell exocytosis functions, who beared biallelic deleterious mutations in the gene encoding the small GTPase RhoG. Experimental ablation of RHOG in a model cell line and primary CTLs from healthy individuals uncovered a hitherto unappreciated role of RhoG in retaining CGs in the vicinity of the plasma membrane (PM), a fundamental prerequisite for CG exocytotic release. We discovered that RhoG engages in a protein–protein interaction with Munc13-4, an exocytosis protein essential for CG fusion with the PM. We show that this interaction is critical for docking of Munc13-4(+) CGs to the PM and subsequent membrane fusion and release of CG content. Thus, our study illuminates RhoG as a novel essential regulator of human lymphocyte cytotoxicity and provides the molecular pathomechanism behind the identified here and previously unreported genetically determined form of HLH.

Post transplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has allowed haploidentical (Haplo) transplantation to be performed with results similar to that after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD versus Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate containing GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults between 2011 and 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced intensity regimens were analyzed separately. Among recipients of reduced intensity regimens, 2-year graft failure (3% versus 11%), acute grade II-IV GVHD (HR 0.70, p=0.022), acute grade III-IV GVHD (HR 0.41, p=0.016) and non-relapse mortality (HR 0.43, p=0.0008) were lower after MUD compared to Haplo transplantation. Consequently, disease-free (HR 0.74, p=0.008; 55% versus 41%) and overall survival (HR 0.65, p=0.001; 67% versus 54%) were higher after MUD compared to Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% versus 88%) was higher and grade III-IV acute (HR 0.39, p=0.07) and chronic GVHD (HR 0.66, p=0.05) were lower after MUD compared to Haplo transplantation. There were no differences in graft failure, relapse, non-relapse mortality, disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced intensity conditioning regimens.

BACKGROUND: Our group recently reported on the results of Blood and Marrow Transplant (BMT) Clinical Trials Network (CTN) 1101 a randomized comparison between double umbilical cord blood (dUCB) and haploidentical bone marrow (haplo) with post-transplant cyclophosphamide (ptCy) in the nonmyeloablative setting that showed similar progression free survival (PFS) between the two treatment groups, but lower non-relapse mortality (NRM) and better of overall survival (OS) in the haplo arm. In this secondary analysis we sought to investigate if transplant center experience with haplo and or cord blood HCT had an impact on outcomes. PATIENTS AND METHODS: All patient randomized in BMT CTN 1101 were included. In order to determine the transplant center experience with either haplo or dUCB we queried the Center for International Blood and Marrow Transplant Research (CIBMTR) for number of transplants with each platform in the year prior to initiation of the study. Centers were then grouped as dUCB center (> 10 dUCB, n=117, 10 centers), Haplo center (>10 haplo and ≤10 dUCB, n=110, 2 centers), and ≤10 haplo and ≤10 dUCB HCTs (other center, n=140, 21 centers). Further analysis considered the alternative cut-off for haplo (> 5 vs ≤ 5) experience, and considered the outcomes based on the donor experience vs. others (e.g. dUCB > 10 vs. ≤ 10; haplo > 5 vs. ≤ 5). RESULTS: The effect of center experience on HCT outcomes shown in Figure, below . After adjusting for age, Karnofsky performance score and, disease risk index we found that there was no difference in outcomes between haplo and dUCB for centers that were experienced with dUCB or had limited to no experience with either dUCB or haplo. In contrast, in centers that were primarily experienced with haplo had better outcomes with this donor type, as compared to dUCB. The higher risk of treatment failure (relapse or death) and overall mortality in dUCB in haplo experienced centers was driven by significantly higher risk of relapse. We then considered the transplant experience with each of the donor types separately. In transplant centers that had performed > 10 dUCB, there were similar outcomes for recipients of both dUCB and haplo. Similarly, centers that had ≤ 5 haplo HCTs had no difference in outcomes between donor types suggesting an overlap with centers that had performed > 10 dUCB HCTs. Overall mortality was higher among dUCB recipients in centers that had performed ≤ 10 dUCB. Notably, the hazard ratio of non-relapse mortality favored haplo in all four donor experience type of transplant center, albeit not statistically significant. CONCLUSION: Except for dUCB recipients in centers with < 10 dUCB/year had worse overall mortality, primarily driven by relapse, the transplant center experience in the year prior to the initiation of BMT CTN 1101 had limited impact on the outcomes of this randomized clinical trial. Figure 1 Figure 1. Disclosures Brunstein: NANT: Research Funding; FATE: Research Funding; GamidaCell: Research Funding; BlueRock: Research Funding; AlloVir: Consultancy. Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria. Cutler: Deciphera: Consultancy; Cimeio: Consultancy; Editas: Consultancy; Kadmon: Consultancy; Pfizer: Consultancy; Mallinckrodt: Consultancy; CareDx: Consultancy; Incyte: Consultancy; Omeros: Consultancy; Syndax: Consultancy; Mesoblast: Consultancy; Jazz: Consultancy. Horowitz: Sobi: Research Funding; Regeneron: Research Funding; Orca Biosystems: Research Funding; Tscan: Research Funding; Xenikos: Research Funding; Miltenyi Biotech: Research Funding; Stemcyte: Research Funding; Medac: Research Funding; Vor Biopharma: Research Funding; Kite/Gilead: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Kiadis: Research Funding; Seattle Genetics: Research Funding; Mesoblast: Research Funding; GlaxoSmithKline: Research Funding; Sanofi: Research Funding; Pfizer, Inc: Research Funding; Omeros: Research Funding; Magenta: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; Vertex: Research Funding; Genentech: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Shire: Research Funding; Gamida Cell: Research Funding; Daiicho Sankyo: Research Funding; CSL Behring: Research Funding; Chimerix: Research Funding; Bristol-Myers Squibb: Research Funding; bluebird bio: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Allovir: Consultancy; Actinium: Research Funding. Horwitz: Gamida Cell: Research Funding. McGuirk: Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Pluristem Therapeutics: Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astelllas Pharma: Research Funding; Gamida Cell: Research Funding; Fresenius Biotech: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau. Rezvani: US Department of Justice: Consultancy; Kaleido: Other: One-time scientific advisory board; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding. Rybka: Spark Therapeutics: Consultancy; Merck: Consultancy. Vasu: Kiadis, Inc.: Research Funding; Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees.

Background: Severe organ damage from acute graft-versus-host disease (aGVHD) results in a high risk of morbidity and mortality. Treatments that focus on immunosuppression alone do not consistently improve long-term survival. Modalities that aid in inflammation resolution, immune tolerance, and tissue repair may improve outcomes beyond high-dose corticosteroids and other broad immunosuppressants for life-threatening aGVHD. We studied the addition of urinary-derived human chorionic gonadotropin/epidermal growth factor (uhCG/EGF, Pregnyl®, Organon, USA) to standard aGVHD therapy in a prospective Phase 2 clinical trial (NCT02525029) conducted at the University of Minnesota and Rush University, extending from our previously published Phase 1 study results (Holtan et al, Blood Advances, 2020) showing uhCG/EGF to be safe and preliminarily efficacious as aGVHD therapy. Methods: Patients with new onset Minnesota (MN) high risk aGVHD (N=22) or with aGVHD requiring 2nd line therapy (N=22) received methylprednisolone 48 mg/m2/day plus 2,000 units/m2 of uhCG/EGF subcutaneously (SQ) every other day for 1 week (high risk arm). Patients in need of 2nd line aGVHD therapy received 2,000 - 5,000 units/m2 SQ every other day, with dose depending on organ severity, for 2 weeks plus standard of care immunosuppression (anti-thymocyte globulin (N=4), etanercept (N=1), ruxolitinib (N=5), sirolimus (N=4), steroid boost (N=8)). Patients who achieved a complete or partial response (CR/PR) after their initial course of therapy received twice weekly maintenance doses for the next 5 weeks. Exploratory metabolomic profiling was performed using mass spectrometry. Results: The median age was 61 years (range 2 years - 72 years, 75% male). The majority of patients had stage 3-4 lower GI GVHD (52%) and overall grade III-IV aGVHD (75%) at time of enrollment, with a median baseline albumin of 2.6 g/dl (range 0.9 - 4 g/dl) and median baseline Karnofsky performance status of 50 (range 20-100). The proportion of patients with a response (CR/PR) at day 28 (primary endpoint) was 68% (57% CR, 11% PR, Figure 1A). Among MN high risk patients receiving 1st line steroids, 64% achieved a CR at day 28 (0% PR). Among patients receiving 2nd line therapy, 50% achieved a CR and 23% PR at day 28. The median overall survival for the entire cohort was 1.2 years (Figure 1B), with a 2-year survival of 67% for responders and 12% for non-responders (p Conclusion: Our Phase 2 study demonstrates that uhCG/EGF is a promising addition to systemic therapy in patients with life-threatening aGVHD. The overall survival result is encouraging considering historical median survival of Figure 1 Figure 1. Disclosures Holtan: Incyte: Consultancy, Research Funding; Generon: Consultancy. Ustun: novartis: Honoraria; Blueprint: Honoraria. Arora: Pharmacyclics: Research Funding; Syndax: Research Funding; Kadmom: Research Funding. Bachanova: Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Betts: Patent Disclosures: Patents & Royalties: B.C.B. holds a patent (WO2015120436A2) related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD. B.C.B. additionally holds a provisional patent (WO2017058950A1) related to the use of JAK inhibitors for rejection and GVHD prevention. . Vercellotti: CSL Behring: Research Funding; Mitobridge, an Astellas Company: Consultancy, Research Funding. Brunstein: GamidaCell: Research Funding; NANT: Research Funding; FATE: Research Funding; BlueRock: Research Funding; AlloVir: Consultancy. Janakiram: FATE, Nektar Therapeutics: Research Funding; Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. MacMillan: Equilium: Other: DSMB member; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. OffLabel Disclosure: uhCG/EGF has FDA orphan drug designation to treat acute GVHD.

Introduction: Post-transplant cyclophosphamide (PT-Cy) in HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) results in acceptable engraftment and graft-versus-host disease (GVHD). Results of BMT CTN 1203 that compared matched unrelated donor (MUD) HCT with PT-Cy containing to calcineurin inhibitor (CNI) containing GVHD prophylaxis following reduced intensity conditioning, showed better 1-year GVHD free relapse free survival with PT-Cy. The relative value of a MUD versus a Haplo donor in the context of PT-Cy is not known. In this study we compared outcomes after Haplo- and MUD HCT with PT-Cy containing GVHD prophylaxis. Methods: Eligible patients were aged >18 years and received haplo-HCT or MUD HCT for AML, ALL and MDS in the US from 2011-2018. Patients received myeloablative (n=1001) or reduced intensity (n=1398) regimens and were analyzed separately. All recipients of haplo-HCT and reduced intensity conditioning MUD HCT received PT-Cy + CNI + mycophenolate mofetil (MMF) for GVHD prophylaxis. Among recipients of myeloablative conditioning MUD HCT, 55% received PT-Cy + CNI + MMF and 45%, PT-Cy + CNI. Cox regression models were built to compare outcomes between donor types. As PT-Cy containing GVHD prophylaxis for myeloablative conditioning MUD HCT is recent; therefore, outcomes were censored at 1-year. A p-value ≤0.01 was considered significant. Results: Myeloablative conditioning regimen: Age at transplant, sex, performance score, co-morbidity and CMV serostatus did not differ between recipients of haplo- and MUD HCT. Haplo-HCT recipients were less likely to be Caucasian (69% vs. 91%). They were also more likely to have AML (55% vs. 47) and less likely to have MDS (13% vs. 31%). Disease risk index did not differ between treatment groups. The predominant conditioning regimen for haplo-HCT was total body irradiation (TBI) + fludarabine (44%) for Haplo-HCT and for MUD HCT, fludarabine + busulfan ± thiotepa (59%). Engraftment rates did not differ between groups. Results of multivariate analyses are shown in Table 1. Compared to Haplo-HCT, grade II-IV acute GVHD risk was higher after MUD-HCT with PT-Cy + CNI GVHD prophylaxis. There were no differences in grade III-IV acute or chronic GVHD risk between treatment groups. Non-relapse mortality, relapse, disease-free and overall survival did not differ between treatment groups. Reduced intensity conditioning regimen: Age at transplant, sex, performance score, co-morbidity and CMV serostatus did not differ between recipients of haplo- and MUD HCT. Haplo-HCT recipients were less likely to be Caucasian (72% vs. 95%). Haplo-HCT recipients were less likely to have MDS (19% vs. 24%). Disease risk index did not differ between treatment groups. The predominant conditioning regimen was TBI 200 cGy + fludarabine + cyclophosphamide (88%) for Haplo-HCT and for MUD HCT, TBI 200 cGy + fludarabine + cyclophosphamide (37%) and fludarabine + melphalan (33%). Engraftment rates did not differ between groups. Results of multivariate analyses are shown in Table 2. Compared to Haplo-HCT acute and chronic GVHD risks did not differ between treatment groups. However, non-relapse mortality was lower after MUD-HCT which led to higher disease-free and overall survival. Conclusion: In patients who received myeloablative conditioning and PT-Cy + CNI + MMF GVHD prophylaxis, haploidentical related and matched unrelated donors are comparable. However, in patients who received less intense conditioning regimens, disease free and overall survival was higher after MUD HCT compared to Haplo-HCT. Disclosures Arora: Fate Therapeutics: Consultancy; Pharmacyclics: Research Funding; Kadmon: Research Funding; Syndax: Research Funding. Al Malki:Neximmune: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Rigel Pharma: Consultancy. Brunstein:Magenta: Research Funding; Gamida: Research Funding; Astex: Research Funding; AlloVir: Other: Advisory board. Grunwald:Merck: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Premier: Consultancy; Amgen: Consultancy; Amgen: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Cardinal Health: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Premier: Consultancy; Trovagene: Consultancy; Astellas: Consultancy; Astellas: Consultancy; Premier: Consultancy; Trovagene: Consultancy; Trovagene: Consultancy; Genentech/Roche: Research Funding; Janssen: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Research Funding; Forma Therapeutics: Research Funding; Merck: Research Funding; Janssen: Research Funding; Forma Therapeutics: Research Funding; Forma Therapeutics: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy. Kekre:Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. McGuirk:Juno Therapeutics: Consultancy, Honoraria, Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Bellicum Pharmaceutical: Research Funding. Mehta:CSL Behring: Research Funding; Incyte: Research Funding; Kadmon: Research Funding. Modi:MorphoSys: Membership on an entity's Board of Directors or advisory committees. Reshef:Gilead: Consultancy, Honoraria, Other: Travel support, Research Funding; Immatics: Research Funding; Celgene: Consultancy; Takeda: Research Funding; Monsanto: Consultancy; Incyte: Research Funding; Shire: Research Funding; Novartis: Honoraria; Pharmacyclics: Research Funding; Magenta: Consultancy; Bristol-Myers Squibb: Research Funding; Kiadis: Research Funding; Bluebird: Research Funding; Atara: Consultancy, Research Funding. Schroeder:Partners Therapeutics: Other; Gilead Sciences Inc: Other; Pfizer: Other; Genentech Inc: Research Funding; Incyte Corporation: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Novo Nordisk: Other; Merck: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; GSK: Other; FlatIron Inc: Other; Dova Pharmaceuticals: Other; Astellas: Other; Janssen: Research Funding; Genzyme Sanofi: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; PBD Incorporated: Research Funding; Celgene: Research Funding; Amgen: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Seattle Genetics: Research Funding; Fortis: Research Funding; Cellect Inc: Research Funding. Soiffer:alexion: Consultancy; Rheos Therapeutics: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; VOR Biopharma: Consultancy; Gilead: Consultancy; Be the Match/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Consultancy; Mana Therapeutics: Consultancy; Cugene: Consultancy; Juno: Membership on an entity's Board of Directors or advisory committees. Waller:Verastem Oncology, Inc: Consultancy, Research Funding.

Introduction: Chronic Graft-versus-Host Disease (cGvHD) frequently requires prolonged immune suppressive therapy (IST) with > 50% still on IST at 5 years. The IST typically involves a slow taper of steroids often with flare of cGvHD, necessitating augmentation of previous therapy or addition of new IST. Studies describing cGvHD flares are limited. We analyzed patients with cGvHD who flared during the treatment with systemic IST, their overall survival (OS) and non-relapse mortality (NRM). Methods: This study included all adult patients with cGvHD (n=145) following an allogeneic transplant (2010 - 2017) from a matched sibling donor peripheral blood stem cell transplant (MSD, n=104 (72%) or double/single umbilical cord blood transplant (UCBT, n=41 (28%). The 2014 NIH Consensus Criteria were used to classify organ/overall cGvHD severity. Flare of cGvHD was defined as progression in cGvHD manifestations (after initial response), which was less severe than at diagnosis. Multivariate regression of flares was based on the Prentice, Williams and Peterson model for ordered multiple events (flares). Time-dependent effects on OS and NRM were analyzed by Cox and Fine and Gray regression with propensity scoring to control for confounding. Results: Flares occurred in 87 patients; the cumulative incidence of flares was 60% (95% CI: 51-70%) at a median of 188 days (range 16-751) after diagnosis of cGvHD. The median dose of prednisone was 1 mg/kg/day (range 0-4.2) at diagnosis of cGvHD. At the diagnosis of flare, 36 (41%) of the patients were off prednisone, 50 (57%) were receiving 0.1-0.5 mg/kg /day, and 2 patients > 0.5 mg/kg /day. Thirty two of the 87 (36%) patients experienced multiple flares (2 to 4). The most common organs involved at cGvHD flare were skin (n=45; 51%), mouth (n=27; 31%), GI tract (n=22; 25%) and liver (n=12; 14%); often in combinations of skin/mouth in 11 cases (13%), skin/GI in 6 (7%) and liver/mouth in 4 (5%) cases. Treatment for flare was mostly increase in dose of prednisone to 0.5 mg/kg/day (range 0.3-1.0) in 77 patients (88%) plus the addition of another line of IST in 48 patients (55%). In multiple regression analysis, only donor type was significant predictor of flare in cGvHD. UCBT was associated with 2-fold lower probability of flaring (HR 0.5; 95% CI: 0.3-0.9; p=0.03) compared to MSD. cGvHD severity, organ involvement, platelet count at diagnosis and type of onset were not significant predictors of cGvHD flares. At 2 years after the initial flare, the OS was 77% (95% CI: 66-84%) and NRM 19% (95% CI: 11-28%). Multiple regression analysis evaluating OS and NRM from onset of cGvHD comparing flare to non-flare were performed using flare as a time dependent variable. Compared to cGvHD patients without flare at 2 years, those with flare of cGvHD had a similar risk of NRM (HR 1.2; 95% CI: 0.2-6.1, p=0.86) and OS (HR 0.9; 95% CI: 0.4-2.3, p=0.85). At 2 years from cGvHD onset, the cumulative incidence of resolved cGvHD (durable discontinuation of steroids for ≥ 6 consecutive months) was 31% (95% CI: 21-41%) in those who flared vs. 86% (95% CI: 75-96%) in those without flare. Conclusions: Though cGvHD patients with flare had similar risk of NRM and OS as those without a flare, patients with flare required extended steroids, along with clinical monitoring and intensified IST. cGvHD after UCBT was associated with significantly lower risk of flaring compared to MSD. The ongoing burden of IST, risk of infection and morbidity of cGvHD is substantial and needs better approaches than chronic slow taper of steroids. Disclosures Weisdorf: Incyte: Research Funding; FATE Therapeutics: Consultancy. Wagner:Novartis: Research Funding; Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company; Magenta Therapeutics: Consultancy, Research Funding; BlueRock: Research Funding; Gadeta: Membership on an entity's Board of Directors or advisory committees. Blazar:Fate Therapeutics Inc.: Research Funding; Childrens' Cancer Research Fund: Research Funding; BlueRock Therapeutics: Research Funding; BlueRock Therapeuetic: Consultancy; Magenta Therapeutics: Consultancy; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder. MacMillan:Mesoblast: Consultancy; Angiocrine Biosciences, Inc.: Consultancy; Equillium, Inc.: Consultancy; Talaris Therapeutics, Inc: Consultancy; Fate Therapeutics, Inc.: Consultancy. Holtan:Generon: Consultancy; BMS: Consultancy; CSL Behring: Other: Clinical trial data adjudication; Incyte: Consultancy. Brunstein:AlloVir: Other: Advisory board; Gamida: Research Funding; Astex: Research Funding; Magenta: Research Funding. Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. Bachanova:FATE: Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Rashidi:Synthetic Biologics: Other: DSMC member (1 trial) and related honorarium. Arora:Fate Therapeutics: Consultancy; Kadmon: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding.

Familial hemophagocytic lymphohistiocytosis (F-HLH) and Griscelli syndrome type 2 (GS) are life-threatening immunodeficiencies characterized by impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell lytic activity. In the majority of cases, these disorders are caused by biallelic inactivating germline mutations in genes such as RAB27A (GS) and PRF1, UNC13D, STX11, and STXBP2 (F-HLH). Although monoallelic (ie, heterozygous) mutations have been identified in certain patients, the clinical significance and molecular mechanisms by which these mutations influence CTL and NK cell function remain poorly understood. Here, we characterize 2 novel monoallelic hemophagocytic lymphohistiocytosis (HLH)-associated mutations affecting codon 65 of STXPB2, the gene encoding Munc18-2, a member of the SEC/MUNC18 family. Unlike previously described Munc18-2 mutants, Munc18-2(R65Q) and Munc18-2(R65W) retain the ability to interact with and stabilize syntaxin 11. However, presence of Munc18-2(R65Q/W) in patient-derived lymphocytes and forced expression in control CTLs and NK cells diminishes degranulation and cytotoxic activity. Mechanistic studies reveal that mutations affecting R65 hinder membrane fusion in vitro by arresting the late steps of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-complex assembly. Collectively, these results reveal a direct role for SEC/MUNC18 proteins in promoting SNARE-complex assembly in vivo and suggest that STXBP2 R65 mutations operate in a novel dominant-negative fashion to impair lytic granule fusion and contribute to HLH.

Background: Prolonged thrombocytopenia after hematopoietic stem cell transplant is a relatively common complication associated with intricate mechanisms including impaired thrombopoiesis and increased platelet turnover. Platelet recovery is particularly delayed after umbilical cord blood transplant (UCBT). Romiplostim is a thrombopoietin receptor agonist that is FDA approved for the treatment of chronic ITP. Although an increasing number of studies recently show promising results on the use of romiplostim in chemotherapy induced thrombocytopenia, the effect of romiplostim on platelet recovery in patients with persistent thrombocytopenia after UCBT remains unknown. Objectives: The primary objective of the study was to determine the maximum tolerated dose (MTD) of romiplostim in patients who failed to achieve platelet recovery by day +28 after UCBT. Secondary objectives were to determine if romiplostim influences the speed of platelet recovery, decreases the risk of thrombocytopenia related complications or affects the incidence of bone marrow (BM) fibrosis or relapse. Methods: This was a single center dose escalation trial of weekly romiplostim in patients >18 years who failed to achieve an untransfused platelet count (PLT) of 20 x 109/L by day +28 after myeloablative (MA) or nonmyeloablative (NMA) UCBT. A total of 21 patients were enrolled from April 2015 to December 2018. One patient withdrew and was replaced so 20 patients are included in the analysis. Romiplostim was administered at the assigned dose as 6 weekly injections beginning by day +42 post UCBT with an end date by day +100. Four dose levels (4, 6, 8, and 10 mcg/kg/dose) were evaluated. There was no intra-patient dose escalation. The MTD of romiplostim was determined by the Continual Reassessment Method, with a goal to identify a dose level which corresponds to the desired toxicity rate of £ 20%. Toxicities of interest included thrombosis, PLT>400x109/L and any grade 4-5 adverse event (AE) attributed to romiplostim. The comparison group were historical controls selected from our prospectively collected database based on age, gender, underlying disease, conditioning intensity and transplant type (1:1 matching). Results: Median (range) age of the patients was 59.5 (18-68) years and 60% were female. Ten patients had AML, 5 ALL, 3 MDS, 1 NHL and 1 MM. Of those, 11 received NMA double UCBT, 7 MA single UCBT and 2 received NMA single UCBT. Two patients received 4 mcg/kg/dose, two 6 mcg/kg/dose, four 8 mcg/kg/dose and the remaining 12 received 10 mcg/kg/dose. Only 5 patients completed the full 6 doses of treatment. Of the 15 patients who received less than 6 doses, 12 were due to a PLT>100×109/L, 2 due to PLT>400×109/L, and 1 was due to physician choice after the subject developed right upper extremity edema (without thrombosis). As shown in figure 1, 100% of romiplostim treated patients achieved platelet engraftment to 20 x 10^9/L at a median of 45 days post UCBT compared to 85% of controls who achieved platelet engraftment at a median of 49 days (p=0.07). Similarly, 90% of romiplostim treated patients achieved platelet engraftment to 50 x 10^9/L at a median of 48 days compared to 70% of historical controls who achieved platelet engraftment at a median of 52 days (p=0.04). The most common AEs were insomnia (30%), arthralgia (25%), myalgia (20%), headache (20%), dizziness and abdominal pain (15%). Only three patients experienced serious AEs requiring discontinuation of the drug: two had a PLT>400x109 /L (without complications) and one developed right upper extremity edema. Bleeding episodes improved with the use of the drug as well as need of transfusions (patients vs controls, p All study patients were evaluated for BM fibrosis and relapse at regular intervals. There were no BM findings suggestive of increased fibrosis or relapse by day +100, and peripheral blood morphology was normal (no significant dacryocytosis, normal platelet morphology). Conclusion: Our study showed that romiplostim was well tolerated and accelerates platelet engraftment in patients undergoing UCBT, with the MTD being 10mcg/kg/dose. These results indicate that romiplostim is safe and potentially effective therapy to improve platelet recovery after UCBT. Further studies in larger numbers of patients are needed to confirm these observations. Disclosures Wagner: BlueRock: Research Funding; Rocket Pharmaceuticals: Consultancy; Novartis: Research Funding; Magenta: Consultancy, Research Funding; Gadeta: Membership on an entity's Board of Directors or advisory committees. Brunstein:Gamida: Research Funding; Magenta: Research Funding; Astex: Research Funding. Bejanyan:Kiadis Pharma: Other: advisory board. Smith:Amgen: Research Funding; Jazz Pharmaceuticals: Research Funding. OffLabel Disclosure: Romiplostim (Nplate) is an FDA approved drug for chronic ITP. In this study (phase I trial) we aimed to evaluate the safety and effectiveness of romiplostim on platelet recovery following UCBT.

Although some data (Scott, JCO 2017) suggest that myeloablative conditioning (MAC) is preferred for allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), these data were not informed by analysis of disease specific risk factors. We analyzed AML and MDS HCT outcomes stratified by the disease risk index (DRI) in order to identify the preferred transplant conditioning intensity (reduced-intensity conditioning [RIC] vs. MAC). In this large CIBMTR registry study we identified 4387 adult patients (age 40-65 years) who received HCT for AML (68%) or MDS (32%) between 2009 and 2015. DRI was stratified as low/ intermediate risk (1539 MAC and 999 RIC) and high/ very high risk (1121 MAC and 728 RIC). Examining the low/ intermediate risk DRI cohort (Table), RIC was associated with lower risk of TRM (HR=0.74, 95% CI 0.62-0.88; p In this large study of HCT for AML or MDS stratified by DRI, RIC was independent predictor of lower TRM, but significantly higher risk of relapse. The MAC was an independent predictor of lower relapse in both low/ intermediate and high/very high DRI groups. However, MAC only resulted in RFS benefit in the low/ intermediate group where the magnitude of impact on relapse was not offset by the higher TRM. In adults with AML or MDS aged 40-65 years, these data support MAC as the preferred conditioning intensity for low/ intermediate risk DRI, whereas MAC does not provide significant benefit in those with high/ very high risk DRI. Safer, yet still potent MAC regimens could benefit this higher risk group. Disclosures Bejanyan: Kiadis Pharma: Other: advisory board. Brunstein:Gamida: Research Funding; Astex: Research Funding; Magenta: Research Funding. Kebriaei:Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria; Pfizer: Honoraria; Kite: Honoraria. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding.

Background. HSC dose and HLA match are independent risk factors that impact non-relapse mortality in children and adults undergoing umbilical cord blood (UCB) transplant for acute leukemia (Eapen et al. Blood 2014 123:133-140). Low number of CD34+ HSCs results in prolonged periods of cytopenia and higher risk of graft failure. To reduce these risks, a minimum cell dose threshold, e.g. 3.0 x 107 total nucleated cells (TNC)/kilogram (kg), has generally been required in CBU selection. While beneficial in terms of hematopoietic recovery, this cell dose threshold markedly limits the number of available cord blood units (CBUs) particularly for larger adolescent and adult recipients, thus reducing the probability of identifying a 7-8/8 HLA-matched graft. In addition, a second UCB unit is often required for adults as a single unit may not meet the cell dose threshold. MGTA-456 is an expanded CD34+ HSC product utilizing an AHR antagonist in the presence of SCF, Flt-3L, IL-6 and TPO. In previous studies with fresh MGTA-456, 36 patients with hematologic malignancies demonstrated rapid neutrophil recovery and sustained engraftment in all patients. The aims of this study (NCT03674411) were to evaluate the safety and efficacy of cryopreserved MGTA-456 as well as the effectiveness of lowering the minimum cell dose threshold of the selected CBU from 3.0 x 107 to 1.0 x 107 TNC/kg to improve donor-recipient HLA match. Patients and Methods: Ten patients with high-risk hematologic malignancy were enrolled with 9 transplanted to date. Conditioning consisted of cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2 and total body irradiation 1320 cGy (total doses) with cyclosporine and mycophenolate mofetil as immunoprophylaxis. G-CSF was initiated on the day after infusion and continued until the neutrophil count exceeded 2500/uL for 3 consecutive days. Results: Cryopreserved MGTA-456 contained a median of 1.9 x 109 CD34+ cells (range, 1.1-6.2) after expansion culture (a 491-fold expansion of CD34+ cells [range, 219-672]). As shown in Table 1, neutrophil recovery occurred in 100% of patients (with one pending after recent transplant) at a median of 15 days (range, 0-31), similar to recipients of fresh MGTA-456 in a prior study (median 14 days, range 7-32) and significantly faster than in recipients of unmodified UCB (median 25 days). Platelet recovery (>20,000/uL for 7 days without transfusion) was also comparable in recipients of cryopreserved and fresh MGTA-456 (median 42 [range 27-53] vs 45 days [range 28-54], respectively), and again faster relative to recipients of unmodified CBUs (median 64 days). In line with preclinical experiments in NSG murine recipients that demonstrates all engrafting cells are retained in the CD34+CD90+ subpopulation, CD34+CD90+ content strongly correlated with speed of neutrophil recovery in recipients of MGTA-456 (cryopreserved and fresh) as shown in Figure 1. As expected, lowering the cell dose requirement from 3.0 x 107 to 1.0 x 107 TNC/kg for UCB unit selection prior to expansion culture improved HLA match and/or eliminated the need for double UCB transplant in 5 of 6 adults (Table 1). As a result, all but one patient received an 8/8 (n=5) and 7/8 (n=4) HLA matched UCB graft, potentially contributing to the low incidence of acute GVHD with only one patient of the 7 out >42 days having grade 2 acute GVHD. This low rate of GVHD compares favorably to that observed in the prior study of fresh MGTA-456. With a follow-up of 19-187 days (median 89), all patients are alive. Conclusion: Transplantation of cryopreserved MGTA-456 resulted in complete engraftment and rapid recovery with speed of neutrophil recovery correlating with the CD34+CD90+ cell dose. Based on the marked expansion that is now possible, units with fewer cells can now be considered, increasing the probability of finding a better HLA matched unit, particularly for adults. Availability of MGTA-456 could reduce the barriers associated with cell dose and poor HLA match previously limiting the successful use of UCB in transplantation. Disclosures Stefanski: Novartis: Consultancy, Speakers Bureau. Brunstein:Magenta: Research Funding; Gamida: Research Funding; Astex: Research Funding. McKenna:Icahn School of Medicine, New York, New York: Consultancy; CIBMTR BMT CTN (NIH): Other: Medical Monitor; National Eye Institute (NIH): Other: DSMB (2); Magenta Therapeutics: Research Funding; Gamida: Research Funding; NMDP: Other: Donor and Patient Safety Monitoring Advisory Group; Fate Therapeutics: Research Funding; Intima: Patents & Royalties: Royalities, Research Funding. Miller:Dr. Reddys Laboratory: Membership on an entity's Board of Directors or advisory committees; Moderna: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc: Consultancy, Research Funding; GT BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CytoSen: Membership on an entity's Board of Directors or advisory committees; OnKImmune: Membership on an entity's Board of Directors or advisory committees. Blazar:KidsFirst Fund: Research Funding; Childrens' Cancer Research Fund: Research Funding; Abbvie Inc: Research Funding; Leukemia and Lymphoma Society: Research Funding; Kamon Pharmaceuticals, Inc: 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; 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; Alpine Immune Sciences, Inc.: Research Funding; RXi Pharmaceuticals: Research Funding; Fate Therapeutics, Inc.: Research Funding; Tmunity: Other: Co-Founder; BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Davis:Magenta Therapeutics: Employment, Equity Ownership. Wagner:Rocket Pharmaceuticals: Consultancy; Magenta: Consultancy, Research Funding; BlueRock: Research Funding; Gadeta: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding.

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 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 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 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 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.