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Abstract Introduction Follow-up is an integral part of hematopoietic cell transplant (HCT) care which ensures accurate characterization of HCT-related outcomes as well as surveillance and intervention for complications. Despite the importance of follow-up of all HCT recipients at transplant centers, they may be lost to follow-up (LTFU). HCT recipients who are LTFU may be demographically or clinically distinct from HCT recipients who maintain regular center follow-up. Using population-based data from 17,550 adult and 4,279 pediatric HCT recipients from United States centers reported to the Center for International Blood and Marrow Transplant Research (CIBMTR), we characterize the incidence of, and predictors for, becoming LTFU. Methods The study included 2-year (yr) survivors of first allogeneic (10,367 adults and 3,865 children) or autologous (7,183 adults and 414 children) HCT for malignant and non-malignant disorders in the United States from 2002-2013 reported to the CIBMTR. LTFU was defined as a patient having missed 2 consecutive follow-up reporting periods. CIBMTR follow-up forms are collected annually for the first 6 yrs post-HCT and bi-annually thereafter. The cumulative incidence of LTFU HCT recipients was calculated. Marginal Cox models allowing adjustment for center effect were fit to evaluate risk factors for becoming LTFU among adults and pediatric allogeneic and autologous HCT survivors. Risk factors evaluated included: sociodemographic (age at HCT, sex, performance status, race, distance to center, income, health insurance, marital status) and disease/HCT-related (disease type, yr of HCT) factors. Results Among 2-yr allogeneic HCT survivors, the median age at the time of HCT was 49 yrs (range, 18-81) and 7 yrs (range, <1-18) for adult and pediatric recipients, respectively. Corresponding median follow-up was 75 months (mos) (range, 12-173) and 74 mos (range, 3-173). Health insurance coverage was public (23%) or private (64%) for adult recipients, and public (40%) or private (43%) for pediatric recipients. For 2-yr autologous HCT survivors, the median age at the time of HCT was 58 yrs (range, 18-82) and 4 yrs (range, <1-18) for the adult and pediatric recipients, respectively. Corresponding median follow-up was 76 mos (range, 3-174) and 73 mos (range, 6-173). Health insurance coverage was public (27%) or private (57%) for adult recipients, and public (48%) or private (39%) for pediatric recipients. The 10-year cumulative incidence of becoming LTFU among adult and pediatric allogeneic HCT recipients was 13% (95% CI, 12-14) and 25% (95% CI, 24-27), respectively. Among autologous HCT recipients, the 10-year cumulative incidence of becoming LTFU among adults and children was 15% (95% CI, 14-16) and 23% (95% CI, 19-28), respectively. (Figure 1) Among pediatric allogeneic HCT survivors, older age, non-white race, public or no insurance (referent: private), and earlier yr of HCT were significantly associated with increased LTFU risk. However, in adult allogeneic HCT survivors, younger age, non-malignant disease, public or no insurance (referent: private), living farther from the HCT center, and unmarried were significantly associated with higher risk of LTFU (Table 1). In pediatric autologous HCT survivors, males and Non-Hodgkin lymphoma (NHL)/Hodgkin lymphoma patients (referent: central nervous system tumors) were significantly associated with higher risk of becoming LTFU (Table 1), whereas for adult autologous HCT survivors, older age and multiple myeloma (referent: NHL) were significantly associated with decreased risk of LTFU. Conclusions The incidence of LTFU is significantly higher in pediatric than adult patients, with no difference between autologous and allogeneic HCT patients, regardless of age. We identified risk factors for LTFU that differed by age and HCT donor type. A national, comprehensive, risk-based approach to long-term follow-up focusing on minimizing the attrition in high-risk groups such as adolescent and young adult-aged HCT survivors and HCT survivors with non-private health insurance is needed. Future studies incorporating patient reported outcomes may help describe reasons for lack of long-term follow-up. Collection of accurate and meaningful epidemiologic and clinical data from all survivors can help develop and refine strategies to improve long-term outcomes of this population. Disclosures Parsons: Seattle Genetics: Research Funding.

Abstract Introduction: Outcome disparities related to race and area-based socioeconomic status (SES) following allogeneic hematopoietic stem cell transplantation (allo-HCT) have been identified in adult patients [Baker et al. 2009]. The relationship between SES and outcomes in pediatric allo-HCT has not been previously described. Among a large cohort of pediatric allo-HCT recipients we sought to determine the impact of area-based poverty on 5-year outcomes of overall survival (OS), acute and chronic graft-versus-host-disease (aGVHD, cGVHD); as well as the short-term outcome of infection through day 100 . Methods: We utilized the Center for International Blood and Marrow Transplant Research (CIBMTR) database to examine the association of sociodemographic variables with outcomes in two cohorts of pediatric transplant recipients aged <=18 years who received allo-HCT at U.S. centers between 2006-2015. Cohort 1 (malignant) included 2053 children who received myeloablative conditioning for any malignancy. Cohort 2 (non-malignant) included 1696 children who received myeloablative or reduced-intensity conditioning for any non-malignant disease. Zip codes of child's residence were categorized as high-poverty area (>=20% households living below 100% federal poverty level (FPL)) versus low-poverty area (<20% households below 100% FPL) by linkage to U.S. Census data [Krieger et al. 2002]. Individual-level sociodemographic variables including insurance (Medicaid-only vs Other), race (Caucasian vs Black vs Other) and ethnicity (non-Hispanic vs Hispanic) were included as covariates. Cox regression was used to examine the effect of patient-related (age, performance status, insurance, race, and ethnicity), disease-related (disease type and status), and HCT-related (donor/graft type, CMV status, stem cell source, HLA match, donor age and gender, conditioning regimen and intensity, GVHD prophylaxis, year of HCT) variables on the outcomes of interest between the two area-based poverty groups. Results: Fifteen percent (N=299) of children in Cohort 1 lived in a high-poverty area; 35% (N=711) were insured by Medicaid-only; 11% (N=227) were African-American and 20% (N=417) Hispanic. Median follow-up of survivors was 74 months. In multivariable analysis, there was no association between area-based poverty and OS; however, OS was inferior in children with Medicaid-only insurance compared to those with private insurance (HR 1.22 (95% CI 1.06-1.40), p=0.0037) and in Black children compared to Caucasian (HR 2.02 (95% CI 1.10-3.73), p=0.0234). For the secondary outcomes of aGVHD, cGVHD or infection through day 100, there were no associations between area-based poverty, insurance, race, or ethnicity in multivariable analysis. To further explore the independent association of insurance with OS, we performed an ad hoc univariate analysis that demonstrated that insurance-related differences in OS for malignant disease appear to be driven by differences in treatment-related mortality (TRM) (5-year TRM: Medicaid-only 25% (95% CI 22-28) versus 18% (95% CI 16-21) other). Thirteen percent (N=228) of children in Cohort 2 lived in a high-poverty zip code; 35% were insured by Medicaid-only (N=597); 20% (N=332) were African-American and 20% (N=344) Hispanic. Median follow-up of survivors was 74 months. In multivariable analyses, there was no association between area-based poverty, insurance, race or ethnicity and any outcome. Conclusion: Area-based poverty is not associated with disparate outcomes in pediatric allo-HCT for malignant or non-malignant disease. In the setting of malignant disease, insurance-a household-level measure of socioeconomic status-and Black race are independently associated with inferior OS. These results suggest that future prospective investigation of more refined measures of household-level socioeconomic status may identify risk-factors for treatment-related mortality in this population. Disclosures No relevant conflicts of interest to declare.

Abstract The first two authors and last two authors contributed equally. Genome-wide association studies (GWAS) have identified risk loci for Acute Lymphoblastic Leukemia (ALL), Chronic Lymphoblastic Leukemia (CLL) and Non-Hodgkin Lymphoma, however an Acute Myeloid Leukemia (AML) GWAS has not been published to date. We performed a GWAS to identify AML and Myelodysplastic Syndrome (MDS) risk loci using a nested case-control study design in the DISCOVeRY-BMT cohorts which includes almost 2000 AML and MDS patients as cases and 2813 unrelated donors as controls. Genotyping was performed using the Illumina Human OmniExpress BeadChip and imputed using the Haplotype Reference Consortium, yielding > 8 million high-quality variants for statistical analysis. Logistic regression models with AML (de novo AML with normal cytogenetics, de novo AML with abnormal cytogenetics and therapy-related AML) and MDS cases and European American healthy donor controls adjusted for age and sex were used to test the association of each SNP with disease status. To identify the strongest association signal with disease we conducted a summary statistic SNP-based association analysis (ASSET) using non-overlapping AML and MDS cases implemented in R statistical software. ASSET uses an exhaustive search for SNPs with small but common pleiotropic effects across groups of traits while accounting for the multiple tests required by the subset search, as well as any shared controls between groups. This approach allowed us to further investigate the heterogeneity within AML subtypes and to gain increased power by pooling subtypes that show pleiotropic effects. ASSET genome wide (GW) significance is defined as P<5.0x10-8, however, we present results of each subset analysis. ASSET analyses identified an association of T allele at rs12203592, Interferon Regulatory Factor 4 (IRF4), with increased risk of de novo AML and MDS (Figure 1) (OR=1.37; 95% CI, 1.25-1.51, Pmeta=1.59x10-10). The variant has been reported significant in GWAS of skin pigmentation, hair color, non-melanoma skin cancer, squamous cell carcinoma, actinic keratosis, and childhood ALL; GW case-control studies of neuroblastoma and breast cancer show suggestive association signals (P<5 x 10-6). IRF4 belongs to the IRF family of transcription factors and is a key regulator of differentiation stages in hematopoiesis. The T allele at rs12203592 is associated with significantly increased expression of IRF4 in whole blood and lung tissue and in vitro mouse studies have shown the T allele to be associated with higher levels of IRF4 transcription. rs12203592 is <80bp from an IRF4 transcription start site and in an important position within NF-κB motifs in multiple blood and immune cell lines, supporting the hypothesis that this SNP modulates NF-κB repression of IRF4 expression. Another variant in the IRF4 regulatory region, rs62389423 (A allele), showed a putative association with subsets of de novo AML and MDS (OR=1.36; 95% CI,1.21-1.52, Pmeta=1.2x10-7). Although not in linkage disequilibrium with rs12203592, the A allele has also been previously associated with susceptibility to skin cancer and melanoma in multiple GWAS. Analysis of 596 UKbiobank CLL cases and >300,000 controls, shows the A allele correlates with a 50% increased risk of CLL (95% CI, 1.32-1.73, P= 2.4x10-9).Several other GWAS also show an association between additional IRF4 variants and CLL. Analyses in individual subtypes also revealed an intronic variant, rs10098598, in RAD21 to be associated with de novo AML (OR=2.18; 95% CI, 1.60-2.97; Pmeta=8.9x10-7). RAD21, on8q24, a region known to be associated with multiple cancer types, is involved in DNA double-stranded break repair and in chromatid cohesion in mitotic cells. Loss of function would theoretically lead to chromosomal instability and tumorigenesis. Components of the cohesion complex (including RAD21) are somatically mutated in ~12% of de novo AML and MDS patients, where it is frequently an early event. We provide the first GW evidence of association between a common variant and AML susceptibility. This SNP has been shown to be associated with multiple phenotypes, suggesting that there are pleiotropic effects at work. Our RAD21 finding is consistent with the role of cohesion in leukemogenesis and provides some evidence of its role in de novo AML susceptibility. Replication and further subset analyses with genome-wide data in >2000 AML cases are ongoing. Disclosures Griffiths: Alexion Inc.: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Celgene, Inc: Honoraria, Research Funding; Novartis, Inc.: Research Funding; Pfizer, Inc.: Research Funding. McCarthy:Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Abstract Background Current literature suggests that the presence and quality of social support may provide meaningful benefits in overall survival of HCT recipients. Further, studies in general oncology and renal transplantation population suggest that married patients have favorable outcomes. Caregivers of HCT recipients are an important source of both instrumental and emotional support, and a reasonable surrogate for presence of social support. Using data from Center for International Blood and Marrow Transplant Research (CIBMTR), we examined the potential influence of marital status (surrogate for caregiver) at the time of HCT on outcomes of HCT. Methods Patients, >40 years of age who underwent either autologous or allogeneic-HCT from 2008 to 2015 were included. Marital status was defined as either 1) Married, 2) Single, never married, 3) Separated/divorced, and 4) Widowed. The probability of OS at 5 years, Grade 2-4 acute GVHD at 100 days and chronic GVHD at 2 years were estimated as appropriate using the Kaplan-Meier method with the log-rank test used for univariate comparisons. Multivariate analysis was performed to determine the association of marital status with these outcomes, while adjusting for clinical and sociodemographic variables. Results We identified 10,226 allogeneic and 5,714 autologous HCT patients; the median follow-up of survivors was 37 months (range 1-102 months) and 40 months (range 1-106 months) respectively. In the allogeneic population, there were n=7,999 married, n=741 single, n=1,175 separated/divorced and n=311 widowed patients. There were n=4,308, n=478, n=695 and n=233 respectively in the autologous population. The baseline characteristics amongst the 4 groups of marital status were comparable. In the allogeneic population, the 5-year probability of OS, 100-day Grade 2-4 acute GVHD, 2-year probability of chronic GVHD were 38% [95%CI (36-39%)], 16% [95%CI (15-17%)]and 46% [95%CI (45-47%)] respectively; while the 5-year probability of OS in the autologous population was 63% [95%CI (61-64%)]. When compared with married patients, single, separated/divorced and widowed patients were not at an increased risk of death [HR 1.09, 95%CI (0.98-1.2); HR 1.01, 95%CI (0.93-1.09); HR 1.09, 95%CI (0.98-1.2)] in the allogeneic setting. Similarly, there was no association of marital status and OS in the autologous setting [HR 1.10, 95%CI (0.92-1.33); HR 1.17, 95%CI (1.01-1.36); HR 1.08, 95%CI (0.86-1.37)] respectively. In contrast, marital status in the allogeneic setting was associated with an increased risk of grade 2-4 acute GVHD in patients who are divorced/separated as compared to married patients [HR 1.13, 95%CI (1.03-1.24)] but not chronic GVHD [HR 0.90, 95%CI (0.80-1.02); HR 0.94, 95%CI (0.86-1.04); HR 0.82, 95%CI (0.68-0.99)] respectively. We did not identify an interaction between marital status and gender. Conclusions Our data suggest the marital status in patients undergoing either autologous or allogeneic HCT is not associated with overall survival or chronic GVHD, while the risk of acute GVHD maybe increased in patients who are divorced/separated. Taken together, the effect of marital status on post-HCT outcomes is negligible when other patient, disease and transplant variables are considered. Alternatively, marital status maybe an imperfect marker for positive social support. Future research should consider measuring social support using validated scales and assess health related quality of life together with health care utilization outcomes to better appreciate the potential impact of social support. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 3094 The HLA class II DRB1 antigen DR15 is an important immunobiologic marker in immune mediated marrow failure states. DR15 has also been reported in small studies to be associated with favorable outcomes (reduction in acute GVHD and reduced relapse resulting in improved overall survival) after allogeneic hematopoietic cell transplant. To elucidate the impact of DR15 on major transplant outcomes, we conducted a retrospective study of 2, 891 recipients of first marrow or mobilized peripheral blood stem cell transplantation for the treatment of acute myeloid leukemia (n=1038), acute lymphoblastic leukemia (n=700), chronic myeloid leukemia (n=948), or myelodysplastic syndrome (n=205) between 1990–2008 and reported to the CIBMTR registry. Selection was confined to HLA-identical sibling transplantation to avoid HLA-disparity as a driving force for observed differences. All patients received conventional myeloablative conditioning, T-replete grafts and cyclosporine plus methotrexate- based GVHD prophylaxis. DNA-based HLA typing allowed categorization of 732 (25.3%) patients as positive and 2159 (74.7%) patients as negative for DRB1*15 :01 or *15 :02 (DR15). There were no significant differences in baseline characteristics between the HLA DR15-positive and -negative groups. In univariate analysis, HLA-DR15 status had no impact on neutrophil engraftment, acute graft-versus-host disease (GvHD) II-IV or III-IV, chronic GVHD, treatment related mortality, relapse, disease-free survival or overall survival. Confining the univariate analysis to myeloid malignancies did not alter these findings. Multivariate analysis models were constructed with DR15 status forced into the models in all steps of model building and the final model regardless of its statistical significance. Other variables tested included: donor/recipient age, CMV status, disease, disease stage, graft source, Karnofsky score, race and year of transplant. Variables that attained a p-value ≤0.05 were held in the final multivariate models. In multivariate analysis, DR15 status showed no significant difference in the primary outcomes of acute GVHD II-IV or III-IV, chronic GVHD, overall survival, or relapse. In conclusion, DR15 status had no impact on major HLA-matched sibling donor hematopoietic cell transplantation outcomes in this large and homogenous cohort of leukemia and MDS patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 897 Recent changes in allogeneic hematopoietic cell transplantation (HCT) including increased use of reduced-intensity conditioning, peripheral blood cells as the graft source (PB) and unrelated donors (URD) warrant re-evaluation of risk factors for acute graft-versus-host disease (aGVHD) and its impact on overall survival (OS). Risk factors for these outcomes were analyzed using more recent data from CIBMTR observational database. Methods: The cohort included adult patients ≥ 20 y transplanted from an HLA-identical sibling (SD) (n=3191) or URD (N=2370) for acute myelogenous leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), or myelodsyplastic syndrome (MDS) using a T-cell replete graft from 1999–2005. Six groups were created to evaluate the impact of conditioning [(myeloablative (MA) and reduced-intensity or non-myeloablative (RIC)], total-body irradiation (TBI) and graft source [(bone marrow (BM) or PB] as follows: MA+TBI+PB (group 1), MA+TBI+BM (group 2) MA+ no TBI+PB (group 3), MA+ no-TBI+BM (group 4), RIC+PB (group 5) and RIC+BM (group 6). Separate analyses were performed for SD and URD. IBMTR grade was used to classify aGVHD. A p-value of ≤ 0.01 was considered significant. Results: Among the SD cohort, the probability of aGVHD grade B-D and grade C-D at 100 days was 39% (95% CI, 37–41%) and 16% (95% CI, 14–17%). In multivariate analyses, non-TBI based MA regimens with a BM graft (group 4), RIC conditioning with PB (group 5) and tacrolimus plus methotrexate aGVHD prophylaxis were associated with lower odds ratio of grade B-D aGVHD (Table 1). The probability of OS was 51% (95% CI: 49–53%) at 3 y and 46% (95% CI: 44–49%) at 5 y. In multivariate analyses, grade B-D aGVHD was associated with a higher risk of death. Other independent risk factors for OS are shown in Table 2. Among the URD cohort, the probability of aGVHD grade B-D and C-D at 100 days was 59% (95%, CI 57–61%) and 32% (30-34%). In multivariate analysis, BM with MA (TBI and no TBI) or RIC conditioning (groups 2, 4 and 6) were significantly associated with lower odds ratio of grade B-D aGVHD (Table 1). Other independent risk factors included a diagnosis of CML. HCT from a 7/8 HLA-mismatched URD showed a trend for higher incidence of aGVHD (p=0.02). The probability of OS was 38% (95% CI: 35–40%) at 3 y and 33% (95% CI: 31–35%) at 5 y. In multivariate analysis, grade B-D aGVHD was associated with a higher mortality. Table 2 shows other independent risk factors for OS. Conclusion: Intensity of the conditioning regimen, TBI and the graft source has a combined effect on the risk of aGVHD. In both SD and URD cohorts, BM with MA, non-TBI regimens were associated with lower risk of aGVHD. In URD cohort, BM after a RIC also was associated with a reduced risk of aGVHD. Modulation of these risk factors is needed to reduce acute GVHD incidence and death after allogeneic transplantation. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4112 We report the characterization of BMS-911543, a potent and functionally selective small molecule inhibitor of the Janus kinase family (JAK) member, JAK2. BMS-911543 is a reversible inhibitor of JAK2 with a biochemical IC50 of 0.001 μ M and Ki of 0.48 nM. It has over 74- and 350-fold selectivity against the other JAK family members, JAK3 and JAK1, respectively. Further, examination of > 450 other kinases did not reveal significant inhibitory activity for this JAK2 inhibitor. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in mutated JAK2-expressing cell lines dependent upon JAK2-STAT signaling and had little activity in cell types dependent upon other pathways such as JAK1 and JAK3. BMS-911543 was evaluated in colony growth assays using primary progenitor cells isolated from patients with JAK2V617F-positive myeloproliferative disease (MPD) and resulted in an increased anti-proliferative response in MPD cells as compared with those from healthy volunteers. Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2-pSTAT signaling in multiple species (mouse, rat, dog and monkey) with sustained pathway suppression being observed after a single oral dose. Additionally, BMS-911543 was evaluated for effects in a JAK2V617F-expressing SET-2 xenograft model system and displayed a minimally effective dose of <2 mg/kg on pSTAT5 pathway suppression, which lasted up to 8 hours. BMS-911543 was also compared to pan-JAK inhibitors in a mouse model of immunosuppression. At low dose levels active in JAK2-dependent PD models, no effects were observed on antigen-induced IgG and IgM production whereas a pan-JAK family inhibitor showed pronounced effects at all dose levels tested. The mechanistic selectivity of BMS-911543 to pan-JAK family inhibitors was extended through comparative analysis of these inhibitors in whole genome gene expression profiling experiments performed in sensitive cell types. In this comparison, BMS-911543 modulated a distinct subset of transcriptional changes as compared to pan-JAK inhibitors, thereby defining a minimal set of transcriptional changes underlying the pharmacologic effects of JAK2 inhibition. Collectively these results define the mechanistic basis for a differential therapeutic index between selective JAK2 and pan-JAK family inhibition pre-clinically and suggest a therapeutic rationale for the further characterization of BMS-911543 in patients with MPD and in other disorders characterized by constitutively active JAK2 signaling. Disclosures: Purandare: Bristol-Myers Squibb: Employment. McDevitt:Bristol-Myers Squibb: Employment. Gottardis:Bristol-Myers Squibb: Employment. You:Bristol-Myers Squibb: Employment. Lombardo:Bristol_Myers Squibb: Employment. Penhallow:Bristol-Myers Squibb: Employment. Vuppugalla:Bristol-Myers Squibb: Employment. Trainor:Bristol-Myers Squibb: Employment. Lorenzi:Bristol-Myers Squibb: Employment.

Abstract Both genome wide association studies (GWAS) of common variation and exome wide association studies (EXWAS) of rare variation have successfully identified disease susceptibility variants for a variety of diseases. One GWAS of inherited susceptibility to Acute Myeloid Leukemia (AML) has been conducted, but no EXWAS have been performed to measure risk of AML attributable to low-frequency constitutional genetic variation. We performed the first EXWAS of risk of AML as a nested case-control study in the DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to one-Year mortality after BMT) cohorts. The DISCOVeRY-BMT parent study examined transplant-related mortality in leukemia patients undergoing unrelated donor allogeneic BMT. To identify low frequency variants and genes contributing to increased susceptibility to AML we used genotype data from the Illumina HumanExome BeadChip typed in the DISCOVeRY-BMT cohorts; the HumanExome BeadChip contains 242,901 variants, which are mainly protein-coding variants. The optimal sequence kernel association test (SKAT-O) was used to analyze gene-level associations with risk of AML. These gene-based tests evaluate the cumulative effects of multiple single gene variants on risk of AML. Analyses were performed in all European American AML cases and two subtypes: 1) de novo AML, 2) de novo AML with normal cytogenetics. Models were adjusted for age at transplant and principal components to control for population stratification. For gene-based tests at least 2 variants with minor allele frequency (MAF) ≤ 5%, were required to be present in the gene. This yielded a total of 13,687 genes tested, and a Bonferroni corrected significance level of P<3.65 x 10-6. Association tests were performed in 1,189 AML cases reported to CIBMTR 2000-08 (Cohort 1) and 327 AML cases reported to CIBMTR from 2009-11 (Cohort 2). Controls in Cohorts 1 (n=1,986) and 2 (n= 515) were 10/10 HLA-matched unrelated donors who passed a comprehensive medical exam and deemed healthy. We used metaSKAT to combine Cohorts 1 and 2 and obtain p-values of association with AML. We present the results of gene-level tests significant in both cohorts. The likely pathogenicity of these variants was determined in silico using SIFT, PolyPhen and MutationTaster. Patient characteristics are in Table 1. DNMT3A, on chromosome 2, was associated in the gene-based test with risk of AML (Pmeta=1.70x10-9, Table 2). Three missense variants at MAF <1% comprise both overall AML and de novo AML gene-based association: exm177559 (Asn->Ser), exm177507 (Arg->His), and exm177543 (Arg->Trp). Normal cytogenetics de novo AML gene-based assocations consisted of only 2 of these variants: exm177559 and exm177507 (Table 2). While prevalence of exm177507 is <1% for all AML cases, in de novo AML with normal cytogenetics the MAF was higher at 3%. The other 2 variants had a MAF<1% irrespective of subtype. Somatically, DNMT3A is most frequently mutated in hematologic malignancies, with >30% of de novo AML cases with a normal karyotype and >10% of MDS patients having DNMT3A mutations. Although these are germline gene associations all three of the variants found have been reported somatically in hematologic malignancies. In 200 AML cases from The Cancer Genome Atlas (TCGA) p.R882H (represented as exm177507 on the exome chip) was a frequent somatic mutation (25%). Exm177543 (p.R635W) and exm177559 (p.N501S) are reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) as somatic mutations involved in hematopoietic and lymphoid tissue in both cell lines and humans. Exm177507 and exm177543 show evidence of pathogenicity in all three in silico tools, while exm177559 was reported as deleterious and disease causing by Sift and MutationTaster, respectively. Our results show that multiple potentially pathogenic missense germline variants in DNMT3A comprise the gene-based association with AML, specifically de novo AML with normal cytogenetics. Given the functional nature of these variants it is possible germline risk stratification could be informative in determining AML risk, and subsequently development of AML harboring DNMT3A mutations. Confirmation of these findings in additional cohorts could have implications for individualized risk screening, prediction and prognosis. Additional cytogenetic subgroup analyses, including treatment-related AML, are underway. Disclosures Hahn: Novartis: Equity Ownership; NIH: Research Funding. McCarthy:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sucheston-Campbell:NIH/NCI: Research Funding.

Abstract Introduction: Depression is associated with increased mortality among healthy individuals and patients with various medical conditions including cardiovascular disease and cancer. The impact of an existing diagnosis of depression prior to autologous and allogeneic hematopoietic stem cell transplantation (HCT) on clinical outcomes including overall survival has not been studied. Methods: We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry to compare overall survival and hospital-length-of-stay during the first 100 days after autologous (n= 3786) or allogeneic (n = 7433) HCT for adult (≥ 18 years) patients with hematologic malignancies with an existing diagnosis of pre-transplant depression requiring treatment vs. those without pre-transplant depression. Data regarding an existing diagnosis of pre-transplant depression requiring treatment were collected from medical chart reviews and reported to the CIBMTR. Data for autologous and allogeneic HCT were analyzed separately. Using Cox proportional hazards regression models adjusting for patient-, disease-(including the disease risk index for allogeneic HCT), donor-(for allogeneic HCT), and transplant-related variables, we compared overall survival between patients with or without pre-transplant depression. To account for early deaths, we compared the number of days alive and out of the hospital in the first 100 days post-transplantation using Poisson models adjusting for patient-, disease-, and transplant-related variables. Among patients undergoing allogeneic HCT, we also compared the risk of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD among patients with or without pre-transplant depression using Cox proportional hazard regression analyses controlling for significant confounders. Results: We included 1116 (15%) patients with pre-transplant depression and 6317 (85%) patients without pre-transplant depression who underwent allogeneic HCT between 2008 and 2012. Patients with pre-transplant depression were similar to those without pre-transplant depression with regards to age, disease distribution, disease risk index, time from diagnosis to transplant, conditioning regimen, receipt of total body irradiation, graft type, donor type, and donor source, but they were more likely to be female, white, divorced, less educated, not working full-time, and had lower performance status and higher number of comorbid conditions. In multivariable analyses, pre-transplant depression was associated with higher overall mortality (HR 1.13, 95% CI 1.04-1.23, p = 0.004) and higher risk of grade II-IV acute GVHD (HR 1.25, 95%CI 1.14-1.37, p < 0.0001), but similar risk of chronic GVHD (HR 1.06, 95% CI 0.96-1.16, p = 0.26). Pre-transplant depression was associated with fewer days alive and out-of-the hospital (Means Ratio (MR) = 0.97, 95% CI 0.95-0.99, P = 0.004). Among patients undergoing autologous HCT, we included 512 (13.5%) patients with pre-transplant depression and 3274 (86.5%) patients without pre-transplant depression between 2007 and 2012. Patients with pre-transplant depression were similar to those without pre-transplant depression with regards to disease distribution, disease status prior to HCT, time from diagnosis to transplant, conditioning regimen, and year of transplant, but they were slightly younger, more likely be to female, white, divorced, less educated, not working full-time, and had lower performance status and higher number of comorbid conditions. Pre-transplant depression in autologous HCT recipients was not associated with overall survival in multivariable analyses (HR 1.15, 95% CI 0.98-1.34, p = 0.096), but was significantly associated with fewer days alive and out of the hospital (MR = 0.98, 95% CI 0.97-0.99, p = 0.002). Conclusion: Pre-transplant depression was associated with higher mortality and higher risk of acute GVHD among patients undergoing allogeneic HCT. Moreover, pre-transplant depression is associated with a longer hospital-length-of stay during the first 100 days after autologous and allogeneic HCT. Therefore patients with pre-transplant depression represent a highly vulnerable population at risk for post-transplant mortality and complications, and they may benefit from more intensive interventions to mitigate the risk of depression on their post-transplant outcomes. Disclosures Chen: Bayer: Consultancy, Research Funding. Lee:Bristol-Myers Squibb: Consultancy; Kadmon: Consultancy. Hahn:Novartis: Equity Ownership; NIH/NHLBI: Research Funding.

Family caregiver engagement in clinical encounters can promote relationship-centered care and optimize outcomes for people with Alzheimer’s disease and related dementias (ADRD). Little is known, however, about effective ways for health care providers to engage family caregivers in clinical appointments to provide the highest quality care. We describe what caregivers of people with ADRD and people with mild cognitive impairment (MCI) consider potential best practices for engaging caregivers as partners in clinical appointments. Seven online focus groups were convened. Three groups included spousal caregivers ( n = 42), three included non-spousal caregivers ( n = 36), and one included people with MCI ( n = 15). Seven potential best practices were identified, including the following: “acknowledge caregivers’ role and assess unmet needs and capacity to care” and “communicate directly with person with ADRD yet provide opportunities for caregivers to have separate interactions with providers.” Participants outlined concrete steps for providers and health care systems to improve care delivery quality for people with ADRD.