Logan, Brent R.

Background: Recent advances in the treatment of myelodysplastic syndrome (MDS) have improved patient survival and quality of life (QOL), while reducing transfusion burden. However, allogeneic hematopoietic cell transplantation (HCT), widely used in younger MDS patients, remains the only curative therapy for MDS. While transplantation outcomes among selected older patients with MDS are similar to younger patients with MDS, early transplantation for older patients is infrequently offered since the relative benefits of HCT over non-HCT therapy in have not been well defined in this patient group. We conducted a multi-center, biologic assignment trial in older individuals with high risk MDS to define the benefit of HCT over non-HCT therapy. Methods: The study was a multicenter, biologic assignment trial in subjects aged 50-75 with higher risk de novo MDS (IPSS Intermediate-2 (Int-2) or High) who were candidates for reduced-intensity conditioning (RIC) allogeneic HCT, comparing outcomes of those with a suitable 8/8 HLA-matched donor to those without a donor. The trial was conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1102, NCT02016781). Eligible subjects were enrolled prior to a formal donor search, and before or after MDS treatment was initiated. Biological assignment to the Donor or No Donor arm was based on high-resolution HLA typing of eligible family members and a search of the unrelated donor registries. Subjects were initially assigned to the No Donor arm and re-assigned to the Donor arm when a suitable donor was identified. Subjects who died or whose 90-day donor search ended without identifying a suitable donor remained in the No Donor arm. Subjects in the Donor arm were expected to undergo RIC HCT within 6 months of enrollment. Subjects underwent RIC HCT or non-HCT therapy according to institutional standards. The primary analysis compared three-year overall survival (OS) between arms using adjusted survival estimates to account for the potential bias resulting from biological assignment. The sample size was selected to provide at least 80% power to detect a difference of 15% in 3-year OS. Between January 2014 and November 2018, 384 subjects (Donor n=260, No Donor n=124) were enrolled at 34 centers. The study arms were well balanced for age, gender, KPS, IPSS risk, MDS disease duration and responsiveness to hypomethylating therapy (Table). The median follow-up time for surviving patients was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No Donor arm. Results: In an intent-to-treat analysis, adjusted OS at 3 years from study enrollment in the Donor arm was 47.9% (95% CI: 41.3%-54.1%) compared with 26.6% (95% CI: 18.4%-35.6%) in the No Donor arm (p=0.0001, absolute difference 21.3%, 95% CI: 10.2%-31.8%)(Figure). A sensitivity analysis excluding subjects assigned to the No Donor arm who died or withdrew prior to the end of the 90-day search window showed no effect on outcome (Adjusted OS: 48.0% vs. 28.1%, p=0.0004). Leukemia-free survival (LFS) at 3 years was greater in the Donor arm (35.8%, 95% CI: 29.8%-41.8%) compared with the No Donor arm (20.6%, 95% CI: 13.3%-29.1%, p=0.003), with no changes in the sensitivity analysis. An OS and LFS benefit was seen across all subgroups tested (Figure). There were no clinically significant differences in QOL between Donor and No Donor arms as measured by the FACT-G, the MOS-SF36 Physical and Mental Component Scores and the EQ-5D utility score at all time points. The overall non-compliance rate for the trial was 26.3%. Reasons for non-compliance included the use of myeloablative conditioning or failure to proceed to RIC transplant in the Donor arm, and the use of alternative donors in the No Donor arm. In an as-treated analysis, comparison of the HCT and No HCT arms demonstrated a significant advantage in 3-year OS (47.4% vs. 16.0%, p<0.0001) and LFS (39.3% vs. 10.9%, p<0.0001) for subjects who underwent HCT. Conclusions: We observed a significant OS advantage in older patients with Int-2 and High IPSS risk de novo MDS who are RIC HCT candidates and have an HLA-matched donor, when compared with those without a donor. The benefit of having a matched donor was seen across subgroups, including those who were of Medicare age (>65) and below. HCT should be offered to all individuals between the ages of 50-75 with Int-2 and High IPSS risk MDS in whom a suitable donor can be identified. Table Disclosures Nakamura: Magenta Therapeutics: Other: Advisory board meeting; Kyowa-Kirin: Other: Support on a meeting presentation; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; NapaJen Pharma: Consultancy; Kadmon Corporation: Other: Advisory board meeting; Celgene: Other: Support on seminar; Viracor: Consultancy. Scott:Alexion, Incyte, Novartis, Regeneron: Consultancy; Agios, BMS: Honoraria; BMS, Novartis: Research Funding. Oran:ASTEX: Research Funding; Celgene: Consultancy; Arog Pharmaceuticals: Research Funding. Maziarz:Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and AlloVir: Consultancy; Novartis and Athersys: Other: DSMB participant; Athersys: Patents & Royalties; Incyte, Kite, BMS/Celgene, PACT Pharma, Orca BioSystems, and Omeros: Honoraria; Novartis and Juno: Research Funding. McGuirk:Allo Vir: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; Bellicum Pharmaceutical: Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cutler:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction: Cryopreservation of peripheral blood stem cell (PBSC) or bone marrow (BM) grafts is rarely performed, thus information about the effect of cryopreservation on graft characteristics and HCT outcomes is limited. Given the global pandemic leading to changing practices for donor graft collection and increasing utilization of cryopreservation, we evaluated the outcomes of HCT recipients who received either fresh or cryopreserved allogeneic BM or PBSC grafts. The primary endpoint was engraftment. Secondary endpoints were incidence of acute graft-vs.-host disease (aGVHD), relapse, transplant related mortality (TRM), disease free survival (DFS), and overall survival (OS). Methods: We included 7397 patients transplanted between 2013 and 2018. 1883 cryopreserved graft recipients were divided into three cohorts based on graft source and donor type: matched related (MRD) PBSC (n=1,051), matched unrelated (MUD) PBSC (n=678), and matched related or unrelated bone marrow donors (n=154). All patients received conventional calcineurin-based GVHD prophylaxis strategies. Patients who received cryopreserved grafts were matched with 5514 patients who received fresh adjusting for graft type (BM vs. PB), donor source (MRD vs. 8/8 MUD), Disease Risk Index (DRI, low risk vs. intermediate risk vs. high risk), recipient age (within 5-years) and propensity score (within 1 standard deviation from pooled sample). The propensity score was based on age, Karnofsky score, diagnosis, disease risk index, HCT-comorbidity index, and conditioning intensity. The level of statistical significance for the main analyses was p<0.01 due to multiple comparisons. The reason for cryopreservation was available on a subset of URD product recipients. Results: Baseline characteristics for all cohorts are shown in Table 1. CD34+ doses reflect enumeration at infusion. In univariate analyses, rates of graft failure and neutrophil recovery at day 28 were similar for cryopreserved and fresh grafts for BM or related PBSC recipients but differed in cryopreserved vs. fresh MUD PBSC (5% vs 2%, p<0.001 and 87 vs 94%, p<0.001, respectively). Rates of platelet recovery within 28 days were similar in marrow cohorts, but lower with cryopreserved related (92% vs 96%, p<0.001) and MUD PBSC (87 vs 94%, p<0.001) grafts. In matched pair multivariable analyses, there were no significant differences in any outcomes with cryopreserved vs fresh BM grafts, irrespective of donor type. With related donor PBSC, cryopreservation was associated with decreased platelet recovery (HR=0.73, CI=0.68-0.78, p<0.001) and an increased risk of both grade II-IV (HR=1.27, CI=1.09-1.48, p=0.002) and grade III-IV (HR=1.48, CI=1.19-1.84, p<0.001) aGVHD, but had no impact on other outcomes. In contrast, with MUD PBSC grafts, cryopreservation was associated with delayed engraftment of neutrophils (HR=0.77, CI=0.71-0.84, p<0.001) and platelets (HR=0.61, CI=0.56-0.66, p<0.001), an increased risk of TRM (HR=1.4, CI=1.18-1.66, p<0.001) and relapse (HR=1.32, CI=1.11-1.58, p=0.002), and decreased DFS (HR=1.36, CI=1.20-1.55, p<0.001) and OS (HR=1.38, CI=1.22-1.58, p<0.001) but did not affect the incidence of aGVHD. In a subset analysis of 299 URD recipients, the most common reason for cryopreservation was delays due to patient-related events, eg., additional chemotherapy, infection. These recipients had decreased OS compared to products cryopreserved for non-patient reasons (HR=0.65, CI=0.44-0.96, p=0.029). Conclusions: The retrospective nature of this analysis, and the fact that cryopreservation is likely to have been performed in recipients with a different (higher) risk profile compared to those receiving fresh products limits our ability to draw firm confusions. Despite these limitations, we conclude that cryopreservation in some patient populations may have a negative impact on engraftment and transplant outcomes. The decision to cryopreserve donor grafts, particularly PBSC grafts, should be carefully considered and highlights the need for further investigation of the effect of cryopreservation of allogeneic grafts where patient factors can be controlled for. Disclosures Farhadfar: CSL Behring: Research Funding; Incyte pharmaceutical: Other: Member of GVHD advisory forum. Frey:Kite Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Syntax: Consultancy, Honoraria. Devine:Magenta Therapeutics: Consultancy. Shaw:Orca Bio: Consultancy. Wingard:Shire: Other: Personal Fees - serve on data monitoring committee for clinical trial; Ansun: Other: Personal Fees - serve on data monitoring committee for clinical trial; Merck: Other: Personal Fees - serve on data monitoring committee for clinical trial; Cidara: Other: Personal Fees - serve on data monitoring committee for clinical trial; ReViral: Other: Personal Fees - serve on data monitoring committee for clinical trial.

Abstract INTRODUCTION: Obesity is increasingly common in the US and is frequently associated with co-morbid medical conditions that may increase the risk of HCT, often the optimal treatment for AML. HCT risk and outcomes for AML on the basis of body mass index (BMI) have not been well-characterized. Using data from the Center for International Blood and Marrow Transplant Research (CIBMTR), we have previously shown no significant difference in outcomes for autologous HCT for lymphoma among normal weight, overweight, and obese patients (pts) but worse outcomes for underweight pts (Navarro et al, BBMT 2006, 12(5): 541–51). Here, we compare outcomes by weight groups for AML patients who underwent autologous, related, or unrelated HCT. METHODS: Our final population included patients age ≥ 18 who underwent myeloablative unpurged autologous or allogeneic HCT for AML in 1st or 2nd complete remission, primary induction failure, or 1st relapse reported to the CIBMTR from 1995 to 2004. Cord blood HCTs were excluded. Four weight groups were defined based on BMI (BMI=weight (kg)/ height (m2)): underweight <18; normal=18–25; overweight >25–30; and obese >30. Treatment-related mortality (TRM), relapse, leukemia-free survival (LFS), and overall survival (OS) were compared using multivariable proportional hazards regression analysis accounting for patient, disease and HCT-related variables. RESULTS: We included 373 autologous, 2041 related, and 1801 unrelated transplant recipients. Patient-, disease-, and transplant characteristics were well-matched across weight groups and transplant types. Multivariable analysis examining risks (95% confidence intervals) relative to the normal weight group are: HCT Type Normal Underweight Overweight Obese -- =not done due to insufficient number of pts; NS=not significant; treatment failure = death or recurrence of disease. Autologous n=164 n=5 n=112 n=81 Death -- NS NS Treatment failure -- NS NS Relapse -- NS NS TRM -- NS NS Related Allogeneic n=1161 n=31 n=543 n=268 Death 1.86 (1.24–2.78) NS 1.23 (1.04–1.47) Treatment failure 2.08 (1.37–3.15) NS 1.19 (1.00–1.42) Relapse 2.02 (1.18–3.47) NS NS TRM 2.22 (1.17–4.22) NS 1.32 (1.02–1.70) Unrelated Allogeneic n=846 n=31 n=523 n=368 Death NS NS NS Treatment failure NS NS NS Relapse NS 0.82 (0.68–0.99) 0.76 (0.60–0.96) TRM NS NS NS CONCLUSIONS: There were no significant differences in risk of TRM, LFS, relapse or OS for normal weight, overweight or obese patient groups who received autologous HCT. Obese recipients of related HCT for AML had increased risk of death, treatment failure, and TRM, though the magnitude was small, an effect was not seen in the unrelated HCT group. Underweight patients who received a related, but not unrelated HCT, fared substantially worse than normal weight patients for all outcomes. It may be that the higher risk of the unrelated HCT procedure masks important but less obvious risks associated with being underweight whereas in the related donor HCT setting, such risks become manifest. Small numbers of patients limit the ability to better characterize this finding in underweight patients. Disproportionately, fewer transplants have been reported in underweight patients which suggest they experience disease and patient-related factors that preclude transplantation. No differences were observed for incidence of acute or chronic GVHD for any weight group. Overweight and obesity should not be a barrier to HCT; however, caution should be exercised in selecting underweight patients for HCT.

Abstract Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.)

SummaryTransplant‐associated thrombotic microangiopathy (TA‐TMA) is a complication of allogeneic transplantation (allo‐HCT). The incidence and risk factors associated with TA‐TMA are not well known. A retrospective analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) was conducted including patients receiving allo‐HCT between 2008 and 2016, with the primary objective of evaluating the incidence of TA‐TMA. Secondary objectives included identification of risk factors associated with TA‐TMA, and the impact of TA‐TMA on overall survival and the need for renal replacement therapy (RRT). Among 23,665 allo‐HCT recipients, the 3‐year cumulative incidence of TA‐TMA was 3%. Variables independently‐associated with increased incidence of TA‐TMA included female sex, prior autologous transplant, primary disease (acute lymphoblastic leukaemia and severe aplastic anaemia), donor type (mismatched or unrelated donor), conditioning intensity (myeloablative), GVHD prophylaxis (sirolimus + calcineurin inhibitor), pre‐transplant kidney dysfunction and acute GVHD (time‐varying effect). TA‐TMA was associated with higher mortality (HR = 3·1, 95% Confidence Interval [CI] = 2·8–16·3) and RRT requirement (HR = 7·1, 95% CI = 5·7–311·6). This study provides epidemiologic data on TA‐TMA and its impact on transplant outcomes. Increased awareness of the risk factors will enable providers to be vigilant of this uncommon but serious transplant complication. The results will also provide benchmarking for future study designs and comparisons.

Introduction Renal dysfunction is a recognized risk factor for mortality after HCT, as it is included in the comorbidity index (HCT CI). Yet, further understanding on outcomes in patients with different level of renal dysfunction or undergoing hemodialysis (HD) at time of transplant remains scant. This study explores the impact of different levels renal dysfunction on major HCT outcomes in a large population using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods The study population included 8,102 patients age 40 years and older who received HCT for treatment of malignancies from 2008 to 2016, with available pre-transplant creatinine measurement. eGFR, calculated using CKD-EPI (CKD-epidemiology collaboration) method, was used to assigned patients in four categories: eGFR ≥ 90ml/min (eGFR≥ 90, N=4,237, reference), eGFR 60-90ml/min (eGFR 60-90, N=3,158), eGFR 45-59ml/min (eGFR 45-59, N=538) and eGFR <45ml/min(eGFR<45, N=169). A separate cohort of patients on HD at time of HCT (N=46) was analyzed independently. Multivariate analysis models were built for assessment of overall mortality, transplant-related mortality (TRM), disease relapse or progression, graft-versus-host disease (GVHD), hepatic sinusoidal obstructive syndrome (SOS), thrombotic microangiopathy (TMA), idiopathic pneumonia syndrome (IPS) and need of HD post-transplant. Common patient-, disease- and transplant-related covariates were tested on all models and HCT CI was computed without reported renal dysfunction comorbidity to avoid collinearity. Results Patient characteristics are shown in table 1. The groups were comparable on disease risk index, graft and donor source, but patients with eGFR>90 were younger and received myeloablative conditioning more frequently. The cohort of eGFR <45 had a higher proportion of patients with HCT CI ≥3. TRM and overall survival according to eGFR groups are shown in Figure. In the multivariate analysis models eGFR as the main effect was associated with TRM (p<0.0001), overall mortality (p<0.0001), and requirement of HD post HCT (p<0.0001), but not for relapse/progression (p=0.98), GVHD (grades II-IV, p=0.34; III-IV, p=0.70; and chronic, p=0.20), TMA (p=0.46), SOS (p=0.02) or IPS (p=0.06). Compared to eGFR ≥90, the hazard ratio (HR) for TRM for eGFR 60-89 was 1.12 (p=0.07), for eGFR 45-59 was 1.46 (p<0.001) and for eGFR<45 was 1.74 (p=0.004). Corresponding HRs for overall mortality were 1.0 (p=0.9), 1.17 (p=0.03) and 1.63 (p<0.0001), respectively. Similarly, for the need of HD post HCT, HR for eGFR60-89 was 1.29 (p=0.03), eGFR45-59 was 2.45 (p<0.001) and for eGFR<45 was 3.09 (p<0.0001). Only eGFR<45 was associated with higher risk of SOS (HR2.66, p=0.03). Among 46 patients on HD prior to HCT, one-year probability of overall survival was 20% (95% Confidence Interval [CI] 10-32%) and cumulative incidence of TRM at one year was 67% (95% CI, 50-81%). Conclusion These findings indicate that degree of renal dysfunction is an independent predictor of OS, TRM, probability of receiving HD and SOS when adjusted for other risk factors. The impact of eGFR on the need of HD, a complication that increases morbidity post HCT is an important finding. Additionally, the outcomes of a subset of patients on HD at time of transplants are dismal. These results can further assist the prognostic assessment of candidates for an allogeneic HCT. Disclosures Stadtmauer: Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding. Wingard:Ansun: Consultancy; Pluristem: Consultancy; Celgene: Consultancy; Merck: Consultancy; Shire: Consultancy. Ganguly:Seattle Genetics: Speakers Bureau; Daiichi Sankyo: Research Funding; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. Pasquini:Pfizer: Other: Advisory Board; Amgen: Consultancy; Medigene: Consultancy; BMS: Research Funding; Novartis: Research Funding; Kit Pharma: Research Funding.

Abstract Abstract 2877 FLC assay measures circulating unbound k and l light chains and is of diagnostic and prognostic value in plasma cell disorders. Normalization of FLC ratio is considered a higher level of complete response (CR) in MM but this has not been well validated prospectively. HLC is a novel antibody based assay that targets the unique junctional epitopes between the heavy chain and light chain constant regions of intact immunoglobulin (Ig) molecules. It separately measures in pairs the light chain types of each immunoglobulin class generating ratios of monoclonal Ig/background polyclonal Ig concentrations (i.e IgGκ/IgGλ, IgAκ/IgAλ and IgMκ/IgMλ); potentially simplifying assessment of monoclonal protein response. To assess the prognostic impact of these assays and to correlate them with electrophoretic/immunofixation (SPE/IFE) assessment, we analyzed 497 stored serum samples from patients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 clinical trial, sponsored by the NHLBI and NCI, of tandem autologous (autoHCT) vs. tandem autoHCT- allogeneic (alloHCT). Samples were collected prior to the first autoHCT and analyzed for FLC (Freelite™) and HLC (Hevylite™) at The Binding Site, UK. Corresponding disease status determination was centrally performed by an expert data review committee using uniform response criteria and correlated with FLC and HLC results. HLC remission was defined as normalization of composite heavy and light chain ratios across all 3 measured heavy/light chain pairs or the normalization of clonal isotype with normal ratios of uninvolved pairs. The demographics of 497 patients with HLC/FLC samples at baseline were concordant with the main study and showed similar patient proportions from the 2 study arms. Of the 211 pts with baseline SPE response better than or equal to a very good partial response (>VGPR), 188 also had an HLC remission (Sensitivity=89%). Comparison of the HLC remission with the >VGPR disease state also identified a specificity of 52%, positive predictive value (PPV) of 58% and a negative predictive value (NPV) of 87%. Similarly, all 56 patients in complete remission (CR) by SPE/IFE were in HLC remission. Compared with conventional CR assessment, sensitivity of HLC remission was 100%, specificity 39%, PPV and NPV values of 17% and 100% respectively. FLC remission correlated with >VGPR disease state had a sensitivity of 47%, specificity of 81% and a PPV and NPV of 64% and 67% respectively. Multivariate models for post transplant progression free survival (PFS) indicated that baseline disease response (>VGPR vs. partial remission (PR) or<PR) was associated with longer PFS. Adjusted models including baseline response, myeloma stage and study arm were used to compare the predictive utility of HLC and FLC assays. There was a lower risk of treatment failure (HR 0.74, p=0.02) and superior PFS for patients who achieved an HLC remission. When stratified by baseline disease response states, there was no additional prognostic impact for HLC remissions on PFS. Normalization of FLC ratio among patients with >VGPR disease state did not impact PFS (HR 0.96, p=0.83). Abnormal HLC after induction therapy has a high negative predictive value (100%) for identifying patients not achieving CR by uniform response criteria and is also associated with shorter PFS after transplant. FLC ratio normalization had no impact suggesting that stringent CR criteria may need further validation. Disclosures: Krishnan: Celgene: Speakers Bureau; Millenium: Speakers Bureau. Alvi:the binding site: Employment. Harding:The Binding Site Group Ltd: Employment. Maloney:Cellgene: Consultancy.

Abstract BMT CTN 0201 was a randomized study of unrelated donor bone marrow (BM) vs. peripheral blood (PB) (N=551) in hematopoietic cell transplantation (HCT) for hematologic malignancies. The primary analysis after 2 years of follow up showed similar survival, disease-free survival and treatment-related mortality between the graft types. There was a higher rate of graft failure with bone marrow (9% vs. 3%, p=0.002) and a higher rate of chronic GVHD with peripheral blood (53% vs. 41%, p=0.01). (Anasetti et al, NEJM 2012) Patient reported outcomes (PROs) were collected from patients > 16 years old at enrollment and 0.5, 1, 2 and 5 years after transplantation with the Functional Assessment of Cancer Therapies - Bone Marrow Transplant (FACT-BMT), Mental Health Inventory (MHI), and Lee chronic graft-versus-host disease (cGVHD) symptom scale. At 5 years, 102 BM and 93 PB participants were alive and eligible for the quality of life (QOL) study. Clinically meaningful differences (changes in scores that are noticeable to patients) were considered 0.5 x standard deviation of the total population based on the distribution method. Results: Data as of 5/25/15 were analyzed. 70% completed the pre-randomization assessment, and 74-78% of adult survivors completed the 5 year assessment. Age < 30 at transplant and high risk disease were associated with missing 5 year data, but not graft source. Response rates at 0.5, 1 and 2 years were 28-43% of survivors. There are no differences in any of the primary QOL scores in the first two years after HCT using univariate comparisons, although missing data severely limit conclusions during this period. At 5 years, the FACT-Trial Outcome Index (TOI), the MHI Psychological Well-Being, and the cGVHD symptom scale scores are all significantly better for BM patients, although only the latter two are still significant after adjustment for multiple testing (p<0.0125 because of 4 primary QOL variables). Results were similar when tested in multivariate models adjusting for baseline patient-reported scores and also imputing missing values based on patient characteristics (Table). Of the 7 chronic GVHD subscales, symptoms in the eye, lung, and energy were significantly better with BM (p<0.01). A diagnosis of cGVHD was highly associated with patient-reported cGVHD symptoms but not with QOL or psychological status. Inclusion of extensive cGVHD in the multivariate models did not change the significance of PRO differences suggesting that differences in cGVHD incidence do not explain the PRO findings. With a median follow up of 73 months for survivors, no difference in survival between PB and BM is observed (p=0.84, Figure). Conclusion: At 5 years after transplant, recipients of unrelated donor BM have better psychological well-being and less burdensome chronic GVHD symptoms than recipients of PB. Survival rates are similar. Table. Comparisons of primary QOL variables at 5 years, adjusted for QOL values at baseline and missing data using inverse probability weighting using significant clinical characteristics. QOL scale Bone marrow (n=102) Peripheral blood (n=93) P value Clinically significant difference* Difference between BM and PB (95% CI) FACT-BMT TOI, mean +/- SE (higher scores better) 76.7 +/- 1.6 (n=79) 70.5 +/- 1.9 (n=69) 0.014 8.5 6.2 (1.3-11.1) MHI - Psychological well-being, mean +/- SE (higher scores better) 78.9 +/- 1.7 (n=80) 72.2 +/- 1.9 (n=72) 0.011 8.4 6.7 (1.6-11.8) MHI-Psychological Distress, mean +/- SE (lower scores better) 16.0 +/- 1.3 (n=80) 19.0 +/- 1.5 (n=71) 0.128 6.5 -3.0 (-6.8,0.9) Chronic GVHD symptoms, mean +/- SE (lower scores better) 13.1 +/- 1.5 (n=80) 19.3 +/- 1.6 (n=72) 0.004 7.1 -6.3 (-10.5, -2.0) SE, standard error *0.5 x STD Figure 1. Figure 1. Disclosures Lee: Bristol-Myers Squibb: Consultancy; Kadmon: Consultancy. Maziarz:Athersys: Consultancy, Patents & Royalties, Research Funding; Novartis: Consultancy.

Abstract HCT entails substantial TRM justifying continued efforts to better risk stratify patients. Single institutional studies have suggested several clinically available biomarkers of CRP, ferritin and albumin influence TRM if not overall survival (OS). We sought to confirm the independent prognostic value of these biomarkers in a large multi-institutional cohort. The study population consisted of 784 adults with AML in remission (80%) or MDS (20%) undergoing unrelated donor HCT between 2008 and 2010 and available cryopreserved samples through the Center for International Blood and Marrow Transplant Research (CIBMTR) repository. CRP and ferritin were centrally quantified by ELISA from cryopreserved plasma whereas albumin levels obtained from center reported data. Correlation studies for biomarkers required log transformation of CRP and ferritin to produce a normal distribution. Multivariate models were fitted separately for each biomarker applying protocol specified thresholds generated from the literature of CRP > 10 mg/L, ferritin > 2500 ng/mL, albumin < 3.5 g/dL on TRM. Further analysis explored optimal cutpoints for this cohort for all significant clinical variables for TRM. HCT characteristics included a median age of 50 (range 18-78) years, HCT-CI (co-morbidity index) 3 or more in 35%, single allele/antigen mismatch (7/8) in 23%, PB as stem cell source in 83%, and myeloablative conditioning in 72%. Biomarker data were available in 783, 781 and 695 cases for CRP, ferritin and albumin respectively. The median values and ranges for each biomarker were as follows: 5.0 mg/L (0.3 - 316) for CRP, 1148 ng/mL (51 – 14,298) for ferritin and 3.6 g/dL (0.6-5.3) for albumin. Log transformed CRP and ferritin showed a modest correlation (r=0.35, P<0.001), and log CRP was marginally associated with albumin (r=-0.12, P=0.002). HCT-CI had no correlation to CRP and albumin. Higher ferritin was associated with HCT-CI (P=0.014) and disease (P<.001). In the entire population, TRM and overall survival (OS) at 2 years were 23% and 54%, respectively. The table shows the independent association of each biomarker with TRM and OS. Ferritin had no association with these outcomes but only 12% had levels above 2500 by ELISA. The optimal cutpoints for TRM were defined as follows: CRP > 3.67 (HR=1.75, P=0.001); albumin < 3.4 (HR 1.70, P <0.001); and ferritin as a continuous variable (HR 1.30, P = 0.008). A risk score was created modeling optimal biomarker thresholds to predict TRM based on the following formula: risk score = 0.44633*I(CRP>3.67)+0.18330*ln(Ferritin)+0.44730*I(albumin<3.4), where “I” is an indicator function and represent 1 or 0 depending on the presence of the abnormal biomarker level in parenthesis. The risk score included adjustment for HCT-CI. The biomarkers did not influence the incidence of relapse or graft-versus-host disease with any of these models. Elevated CRP and ferritin and decreased albumin prior to HCT were associated with impaired transplant survival, primarily through higher TRM. Integration of a biomarker panel in clinical practice once validated can enhance risk-stratification, improve adjustment for comparative studies and point towards the design of biomarker driven trials. Abstract 422. Table: Multivariate analysis of TRM and OS for biomarkers, and biomarker panel risk score* Abnormal, N (%) Transplant related mortality Overall Survival Biomarker HR 95% CI P HR 95% CI P Protocol defined CRP >10 mg/L 184 (24) 1.52 1.11 – 2.07 0.008 1.22 0.98 – 1.53 0.072 Ferritin >2500 ng/mL 93 (12) 1.26 0.84 – 1.88 0.27 1.15 0.86 – 1.54 0.35 Albumin < 3.5 g/dL 290 (42) 1.48 1.10 – 2.0 0.010 1.39 1.13 – 1.72 0.002 Optimal threshold, combined model ** CRP >3.67 mg/L 497 (64) 1.56 1.11 – 2.19 0.010 1.24 1.00 – 1.55 0.054 Log(Ferritin), linear n/a 1.20 0.99 – 1.46 0.07 1.20 1.04 – 1.38 0.010 <3.4 g/dL 203 (29.5) 1.58 1.16 – 2.15 0.004 1.37 1.10 – 1.72 0.005 Biomarker Score ** N Low (<1.5) 200 1.0 - - 1.0 Intermediate (1.5-2.0) 331 1.66 1.10-2.49 0.015 1.38 1.06-1.80 0.017 High (>2.0) 159 2.72 1.77-4.19 <0.001 2.01 1.51-2.70 <0.001 * biomarkers adjusted for significant covariates of BMI, disease, mismatch, and CMV serostatus and stratified on conditioning regimen ** combined model includes all biomarkers and HCT-CI Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 739 The combination of a calcineurin inhibitor and methotrexate has been the standard of care in graft-vs.-host disease (GVHD) prophylaxis for over 25 years, with resultant rates of grade II-IV acute GVHD between 30–50%. The mTOR inhibitor, sirolimus, has demonstrated promise in a number of Phase II trials as an immunosuppressant used for GVHD prophylaxis. The BMT CTN, sponsored by the NHLBI and NCI, conducted a multicenter, randomized controlled trial comparing the combination of tacrolimus and sirolimus (Tac/Sir) with tacrolimus and methotrexate (Tac/Mtx) as GVHD prophylaxis after matched, related donor (MRD) hematopoietic stem cell transplantation (HSCT). Methods: Eligible patients were between ages 2 – 60 years, and had acute leukemia in remission, myelodysplasia or chronic myeloid leukemia in chronic or accelerated phase. All had adequate organ function, and a 6/6 HLA-A, B, DRB1 matched sibling donor. 304 patients were randomly assigned to either Tac/Sir (n = 151) or Tac/Mtx (n = 153) as GVHD prophylaxis after TBI-based conditioning and MRD HSCT. An intent-to-treat analysis was performed on the primary endpoint of Grade II-IV GVHD-free survival 114 days from randomization. Ten subjects who received busulfan-based conditioning and were previously reported were excluded from analysis. Three subjects who did not undergo HSCT are included in the primary analysis, but not secondary analyses. Results: Treatment groups were well balanced. The median age of participants was 44 years (range 13 – 59) and 83% had acute leukemia. Neutrophil and platelet engraftment were both faster in the Tac/Sir group (14 vs. 16 days, p < 0.001; 16 vs. 19 days, p = 0.03, respectively), but this did not affect the time to first hospital discharge (20 vs. 21 days, p = 0.37). The incidence of grade II-IV and grade III-IV acute GVHD at 100 days were lower in the Tac/Sir group (26 vs. 34%, p = 0.17; 8 vs. 15%, p = 0.05). Day 100 treatment-related mortality was no different between groups (7 vs. 7%, p = 0.43). The primary endpoint of 114-day acute GVHD-free survival was not statistically different between groups (67 vs. 62%, p = 0.38, Figure). The cumulative incidence of relapse at 2 years from transplantation was not different between groups (27 vs. 30%, p = 0.81). The competing-risk cumulative incidence of chronic GVHD was higher in the Tac/Sir arm (54 vs. 43%, p =0.044). Overall toxicities were not different between groups, with two notable exceptions. The peak and average OMAS oral mucositis scores were lower in the Tac/Sir arm (peak 0.70 vs. 0.96, p < 0.001; average 0.31 vs. 0.47, p < 0.001), however, there was an increased rate of the endothelial injury syndromes, veno-occlusive disease (11 vs. 4%, p = 0.03), and thrombotic microangiopathy (5 vs. 1%, p = 0.05) in the Tac/Sir arm. Causes of death were not different between groups. At 2 years from transplantation, disease-free (DFS) and overall survival (OS) were not different between study arms (DFS 53 vs. 53%, p = 0.76; OS 60 vs. 61%, p = 0.44). Conclusions: No difference in 114-day acute GVHD-free survival was noted between treatment arms. Compared with Tac/Mtx in MRD HSCT, Tac/Sir is associated with more rapid engraftment, less severe acute GVHD and oral mucositis, excess chronic GVHD and endothelial injury syndromes, and similar long-term outcomes. Understanding the trade-offs between regimens, Tac/Sir can be used as an alternative to Tac/Mtx in MRD HSCT. Disclosures: Cutler: Pfizer, inc: Research Funding; Astellas, Inc: Consultancy, Research Funding. Off Label Use: Sirolimus - Prevention of GVHD Tacrolimus - Prevention of GVHD. Waller:Outsuka: Research Funding.