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Among patients who survive over two years post-allo-HSCT, cGVHD and subsequent cancers represent a significant source of morbidity and mortality. Long-term treatment with immunosuppressive agents and cGVHD-related immune dysregulation may promote the development of subsequent cancers. The burden of subsequent cancers has not yet been described in patients with the most severe manifestations of cGVHD, who likely represent a high-risk population. 439 patients were enrolled on the prospective NIH Chronic GVHD Natural History Study from 2004 to 2019, underwent one-week evaluation by subspecialists, and were scored in accordance with 2005 NIH criteria. Follow-up data were collected by annual survey in which patients self-reported cancer diagnoses and provided consent for confirmatory medical records. Cumulative incidence was estimated for non-melanoma skin cancer (NMSC) competing with death, relapse, or cancer other than NMSC and for cancer other than NMSC competing with death or relapse using the method of Gooley. Potential predictors of subsequent cancers including demographics, transplant characteristics, and cGVHD-related factors were assessed using Gray's test in univariable analysis and Cox proportional hazards models in multivariable analysis. Patients must have been free of post-transplant relapse, NMSC (for NMSC analyses only), and cancer other than NMSC at evaluation to be included in analysis. 22 NMSC and 19 cancers other than NMSC were observed among 205 eligible patients, with cumulative incidences at 60 months of 11.2% (95% CI: 6.9-16.7) and 7.3% (95% CI 4.1-11.8), respectively. The most common cancers other than NMSC were oral squamous cell carcinoma and melanoma (n=6 each). Factors associated with NMSC in univariable analysis were older age at transplant, older age at evaluation, having received sirolimus for cGVHD, having received extracorporeal photopheresis or psoralen-ultraviolet therapy for cGVHD as well as higher CRP, higher NK cell count, and greater BMI at evaluation. Only older age at transplant (HR=2.12; 95% CI: 1.35-3.31) and higher CRP (HR=9.61; 95% CI: 1.29-71.73) remained associated in the multivariable model. Factors associated with subsequent cancers other than NMSC in univariable analysis were T-cell depletion, lymphoid malignant indication for transplant, and increasing severity of oral cGVHD by NIH score. Only lymphoid malignant indication for transplant (HR=2.58; 95% CI: 1.31-5.07) remained significant in multivariable analysis. The association of CRP with NMSC may represent an effect of cGVHD-related inflammation, with CRP previously associated with cGVHD severity. Interestingly, sirolimus was associated with increased risk of NMSC despite its purported antineoplastic effects. One study has previously reported increased risk of NMSC in allo-HSCT recipients treated with sirolimus, however, numerous studies have reported that sirolimus reduces risk of NMSC in solid organ recipients. In this study population, sirolimus was often prescribed later in patients already with refractory cGVHD and adjustment for measures of disease severity attenuated this association in multivariable modeling. The association of lymphoid indication with cancers other than NMSC may be attributable to age as patients with lymphoid malignancies were older at transplant than those with other indications. Additionally, differences in pre-transplant therapies for lymphoid vs. other indications may also contribute to this observation. Post-transplant patients with cGVHD are at high risk of developing subsequent cancers, with higher incidence of NMSC than other cancers. This study identifies potential risk groups for subsequent cancers, highlights patients who may benefit from increased surveillance, and reiterates the need for effective cGVHD therapy to mitigate risks associated with long-term immunosuppression and immune dysfunction. Disclosures Cowen: UpToDate: Other: Royalties; Elsevier: Other: Royalties.

Abstract 4631 A 44 year old African-American asplenic male with sickle cell disease (HbSS) underwent allogeneic HSCT in September 2009. Upon engraftment, the patient had 97% donor myeloid, and 30% donor lymphoid chimerism, and he was free of his sickle cell disease with HbA 97%, HbA2 2.9%,and HbF Twenty eight months later, he experienced onset of minor soft tissue hemorrhage associated with a long aPTT, and low FVIII activity (14% of normal), two weeks after an upper respiratory infection. vWF levels were elevated (antigen 263% & activity 246%), and the FIX level (113%), PT (13.2 seconds), and fibrinogen (395 mg/dL) were normal. He had stable FVIII levels of 10–14% for two months, but then had acute onset of pain, swelling and decreased grip strength in the right hand, consistent with a compartment syndrome. He was treated with Humate-P at a dose of 3000 U every 12 hours, which initially normalized the aPTT and corrected the FVIII to 121%, permitting fasciotomy of the palmar and volar surfaces of the forearm to treat his acute compartment syndrome. After 4 days' treatment on the same 3000 U Q 12 hour dose of Humate P, the recovered FVIII levels declined to only 18%. He was switched to Kogenate with no change in FVIII recovery, then rhFVIIa at doses of 90 μg/kg Q 4 hrs was started eleven days after surgery. Despite inhibitor bypassing therapy, the patient had recurrent pain, swelling, decreased grip strength, decreased range of motion, and numbness in the right hand, consistent with recurrent bleeding. His human FVIII inhibitor titer was 12 BIAU, but < 1 BIAU for porcine FVIII. Recombinant porcine FVIII (OBI-1) was obtained for use under an expanded access provision of IND 16395, and 200 units per kg were given 16 days after surgery, and a second dose of 100 units per kg was given 19 days after surgery. A FVIII level of 540 U/dL was obtained 20 minutes after the first treatment, and the volume of distribution was 2652 mL and the half life was 16.3 hrs. Within 8 hours the pain was diminished (4/10 vs. 7/10), and grip strength measured by dynamometer went from 8 lbs to 55 lbs (compared to unaffected left hand grip strength of 110 lbs). After the 2nd dose of OBI-1 a FVIII level of 621 U/dL was obtained 20 minutes later, and the volume of distribution was 2287 ml, and the half life was 14.7 hrs. Within two weeks the patient had improved range of motion, pain free status, and right hand grip strength of 82 lbs. The patient's grip strength was restored to 101 lbs, 76 days later with physiatry and occupational therapy hand program. Immunosuppression with rituximab and high dose corticosteroids was begun at the onset of OBI-1 porcine factor VIII treatment; cyclophosphamide was not used to minimize risk for loss of the stem cell graft that cured his sickle cell disease. The inhibitor titer to human FVIII declined from 12 BIAU to less than 0.5 BIAU within three weeks, and there was no loss of donor erythropoiesis (HbA remained >96%). Concomitantly, the patient's endogenous FVIII rose to >100% of normal by day 22, and remained normal after completion of three doses of rituximab and a complete taper of prednisone over the next two months. The patient had an H2 FVIII haplotype sequence, whereas his donor was heterozygous for the FVIII H1 and H2 haplotypes. A study of stored samples showed that at the onset of mild soft tissue hemorrhage the Bethesda inhibitor titer against a recombinant FVIII with H2 haplotype sequence (Recombinate) was higher (4.2 BIAU) than that against H1 (Kogenate) or “mixed” haplotypes derived from pooled plasma (1.9 BIAU). However, by the time of his compartment syndrome hemorrhage the differential reactivity of neutralizing titers to the H2 haplotype FVIII was not as pronounced (5.2 BIAU for H2 haplotype vs. 4–4.5 BIAU for all other haplotypes/products), suggesting that any initial specificity for the H2 FVIII haplotype had been diminished. No inhibition of OBI-1 porcine factor VIII was seen prior to treatment, or in the 90 day period after treatment. Interestingly, FVIII binding antibodies could be detected prior to the viral infection preceding the overt clinical inhibitor and soft tissue hemorrhage. In summary we demonstrate use of recombinant porcine FVIII in a patient with a compartment syndrome due to acquired hemophilia, and elimination of the inhibitor, while preserving the transplant that corrected his sickle cell disease. Disclosures: Lee: Inspiration Biopharmaceuticals Inc: Employment.

Abstract 2243 Poster Board II-220 Introduction: Although a low platelet count in chronic graft-versus-host disease (cGVHD) patients is a consistent negative survival predictor across many cGVHD studies, this association is poorly understood. Additionally, a subgroup of cGVHD patients has elevated platelets, which is also unexplained. We hypothesized that such platelet abnormalities may reflect the pathophysiology of cGVHD and therefore be associated with specific clinical manifestations. This exploratory study was conducted to investigate determinants and clinical significance of platelet counts in a large cohort of cGVHD patients. Patients and Methods: cGVHD patients were enrolled in the ongoing cross sectional National Cancer Institute protocol (clinicaltrials.gov#NCT00331968). A detailed history, physical and extensive laboratory evaluations were obtained using standardized methods. National Institutes of Health (NIH) severity scores were based on the extent of cGVHD manifestations, degree of functional impairment and the number of affected organs. Wilcoxon rank sum test, Kruskal-Wallis test, and Jonckheere -Terpstra trend test were used in statistical analyses. Results with p-values Results: The cohort included 120 adult cGVHD patients (median age 48 years, 53% male (M), 47% female (F)). Median time from transplantation to study enrollment was 2.7 years. Median time of cGVHD diagnosis was 0.5 year after transplantation, and median time from cGVHD diagnosis to enrollment was 1.6 years. 75% of subjects received related donor transplant; 84% received peripheral blood stem cells and 16% bone marrow; 63% had a history of acute GVHD (skin 88%, gastrointestinal 45%, liver 22%). Median total NIH organ severity score was 6 (range 2-14), median average total NIH organ severity score was for F 0.750 (range 0.250-1.625), and for M 0.857 (range 0.286-2.000), and median number of organs involved was 4 (range 1-8). Median platelet count was 239,000/μL (range 33,000/μL-648,000/μL). F had significantly higher platelet counts than M (median 275,500 /μL vs. 221,500/μL, p=0.004). Time from transplantation (r=0.35) and time from cGVHD diagnosis (r=0.32) correlated positively with platelet counts (p=0.001). Patients who received TBI based conditioning tended to have higher platelet counts (median 279,000/μL vs. 211,000/μL, p=0.021). Platelet counts varied among the four recipient-donor gender pairings (M recipient/M donor had median platelets 199,500/μL, M recipient/F donor had median platelets 239,500/μL, F recipient/F donor had median platelets 257,000/μL, F recipient/M donor had median platelets 301,000/μL, p=0.010). Among patients with history of acute GVHD, those with liver acute GVHD tended to have higher platelet counts (292,000/μL vs. 226,500 /μL, p=0.027). Absolute lymphocyte count (r=0.35), absolute CD3s (r=0.31), absolute CD4s (r=0.31), absolute NK cells count (r=0.32), and calcium levels (r=0.33) correlated positively with platelet counts (p Conclusions: This exploratory analysis demonstrates strong positive association of platelet counts with the lymphocyte counts and with the average total NIH cGVHD organ severity scores. These data implicate abnormalities of platelet counts in cGVHD pathophysiology and warrant further research. Disclosures: No relevant conflicts of interest to declare.