Abstract: Introduction Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for many high-risk hematologic malignancies. Myeloablative conditioning is currently the standard of care for young and fit patients; however, graft-versus-host disease (GVHD) continues to be a major limitation to the success of HCT, increasing post-transplant morbidity and mortality. An ideal HCT is one combining strategies that reduce incidence and severity of GVHD, without compromising graft-versus-tumor effect. We hypothesized that GVHD prophylaxis regimen consisting of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) will reduce the incidence of chronic GVHD in patients receiving a standard hematopoietic myeloablative HCT without an increase in risk of malignant relapse. Methods This is an interim analysis of a phase II study using a myeloablative preparative regimen of either: 1. total body irradiation (TBI, total dose 1320 cGy administered twice a day from days -4 to -1) or 2. Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 µmol/min/L) plus fludarabine 160mg/m 2 days -5 to -2 for patients unable to receive further radiation, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment at 1 year post-transplant. Patient and disease characteristics are detailed in Table 1. Eligibility included: age ≤ 60 years, malignant or non-malignant diagnosis, matched related (MRD) or unrelated (MUD) donor with either a bone marrow (BM) or filgrastim-mobilized peripheral blood (PB) graft. Results Through October 2020 we treated 63 patients with a median follow up of 502 days post-transplant. Of those, 48% were female and n=11 (17%) younger than 18 with median age at HCT of 36 years (range, 2-55; Interquartile range [IQR], 20-48). Donor source was 8/8 MRD in 44 patients (70%), 8/8 MUD in 18 (29%), and one with 7/8 MUD. Graft source was BM in n=28 (44%) and PB in n=35 (56%). Preparative regimen was TBI in 94% of patients. All patients achieved primary neutrophil engraftment by 42 days, median 16 days (range, 13-27). Overall, 94% achieved platelet engraftment by 6 months, median 25 days (range, 16-98). At day 100, 48 patients (86%) achieved full donor bone marrow chimerism ( & gt;95% donor DNA); 29 (52%) and 52 (95%) achieved full donor peripheral blood CD3 and CD33 chimerism (defined as & gt;95% donor). 42 patients (66%) required total parenteral nutrition (TPN) for oral mucositis and regimen-related toxicities during their initial transplant admission. Cumulative incidence of Grade II-IV acute GVHD by 100 days post-transplant was 14% overall (95% confidence interval CI: 6-23%), 7% for MRD and 32% for the MUD group; Grade III-IV acute GVHD was 5% overall (CI: 0-10%), similar for both MRD and MUD group. At 1 year, only two patients receiving a PBSC graft developed chronic GVHD requiring immune suppression, for a cumulative incidence of 3% overall, one in the MRD group and one in the MUD group. Two-year cumulative incidence of relapse was estimated at 21% overall, 22% and 16% for the MRD and MUD groups, respectively. Two year cumulative incidence of non-relapse mortality was 13% overall, 15% and 5% for MRD and MUD, respectively. Estimated 2-year overall survival was 79% overall (CI: 65-88%), 75% for the MRD group and 95% for MUD. Estimated 2-year GVHD-free relapse free survival (GRFS) was 57% overall (CI: 42-69%), 56% and 63% in the MRD and MUD groups, respectively. Discussion Myeloablative transplantation with a TBI preparative regimen, followed by a GVHD prophylaxis regimen of PTCy, Tac, and MMF results in very low incidence of chronic GVHD. Importantly, this regimen is feasible and effective for pediatric and adult patients. Further improvement in outcomes can be achieved by incorporating post-transplant relapse mitigating strategies as well as supportive care measures to decrease regimen-related toxicities. Figure 1 Figure 1. Disclosures Arora: Kadmom: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding. Janakiram: Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria; FATE, Nektar Therapeutics: Research Funding. Smith: Astellas Gene Therapies: Current Employment. Bachanova: Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brunstein: BlueRock: Research Funding; AlloVir: Consultancy; FATE: Research Funding; NANT: Research Funding; GamidaCell: Research Funding. MacMillan: Equilium: Other: DSMB member; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Miller: Sanofi: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vycellix: Consultancy; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; Wugen: Membership on an entity's Board of Directors or advisory committees. 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: Mitobridge, an Astellas Company: Consultancy, Research Funding; CSL Behring: Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Holtan: Generon: Consultancy; Incyte: Consultancy, Research Funding.

Abstract: 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 ( & lt; or ≥50), BMI ( & lt; 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 & gt;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.

Abstract: Introduction: Chronic Graft-versus-Host Disease (cGvHD) frequently requires prolonged immune suppressive therapy (IST) with & gt; 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 & gt; 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.