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Background Aplastic anaemia has diverse aetiologies. Distinguishing between these is, in part, testable by analyzing results of haematopoietic cells transplants between genetically-identical twins one of whom has aplastic anaemia. Objective Describe outcomes of genetically-identical twin transplants for aplastic anaemia with and without pretransplant conditioning. Methods We interrogated data from an observational database of 59 consecutive recipients of genetically-identical twin transplants for aplastic anaemia reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) 2000-2019. Results 38 subjects were male. Median age was 18 years (Interquartile Range [IQR], 11-32 years). Median interval from diagnosis to transplant was 2 months (IQR 1-3 months). 11 subjects received a 1st transplant without pretransplant conditioning. 2 of recovered normal bone marrow function. The other 9 received a 2nd transplant with pretransplant conditioning 7 of whom recovered. 48 subjects received pretransplant conditioning before a 1st or 2nd transplant all of whom recovered. Conclusion Only some genetically-identical twins with aplastic anaemia recover normal bone marrow function after a 1st haematopoietic cell transplant without pretransplant conditioning whereas most subjects recover when a transplant is preceded by pretransplant conditioning. These data are consistent with an immune-mediated aetiology of aplastic anaemia in most cases.

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival. RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P

Background The association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes. Methods This study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014-2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied. Results The median age was 55 years (range, 18-83 years). The median PCS was -0.21 (range, -1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was -0.13 (range, -1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00-1.08; P = .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00-1.08; P = .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02-1.15; P = .0004). CCS was not significantly associated with survival, relapse, or NRM. Conclusions Patients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.

We report the outcomes of hematopoietic stem cell transplantation (HSCT) for 52 patients with Shwachman-Diamond syndrome (SDS) who underwent transplantation between 2000 and 2017. The median age at transplantation was 11 years, and the median duration of follow-up was 60 months. The indication for HSCT was bone marrow failure (BMF; cytopenia or aplastic anemia) in 39 patients and myelodysplasia (MDS)/acute myelogenous leukemia (AML) in 13 patients. The donor type was an HLA-matched sibling for 18 patients, an HLA-matched or mismatched relative for 6 patients, and an HLA-matched or mismatched unrelated donor for 28 patients. Preparative regimens for BMF were myeloablative in 13 patients and reduced intensity in 26. At the time of this report, 29 of the 39 patients with BMF were alive, and the 5-year overall survival was 72% (95% confidence interval, 57% to 86%). Graft failure and graft-versus-host disease were the predominant causes of death. Preparative regimens for patients with MDS/AML were myeloablative in 8 and reduced intensity in 5. At the time of this report, only 2 of 13 patients were alive (15%), with relapse the predominant cause of death. Survival after transplantation for SDS-related BMF is better compared with historical reports, but strategies are needed to overcome graft failure and graft-versus-host disease. For SDS- related MDS or AML, transplantation does not extend survival. Rigorous surveillance and novel treatments for leukemia are urgently needed.

With the COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplantation conditioning. The effect on transplantation outcomes in nonmalignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the United States during 2013 to 2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received noncryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (hazard ratio [HR], 2.26; 95% confidence interval, 1.17 to 4.35; P = .01) and of 1-year overall mortality (HR, 3.13; 95% CI, 1.60 to 6.11; P = .0008) after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% (95% CI, 60% to 84%) in the cryopreserved graft group and 91% (95% CI, 86% to 94%) in the noncryopreserved graft group. These data support the use of noncryopreserved grafts whenever possible in patients with severe aplastic anemia.

Allogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.

PURPOSE Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD. METHODS ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days). RESULTS In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) ( P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients. CONCLUSION Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.

BackgroundAllogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.ObjectiveThe effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders.MethodsWe studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models.ResultsFour regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P< .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P< .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P= .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P= .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P< .001).ConclusionsGiven the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, inherited bone marrow failure syndrome. Hematopoietic stem cell transplantation (HSCT) is considered a curative treatment option, but existing descriptions of patient and transplant characteristics and outcomes after related and unrelated donor HSCT are sparse. We describe outcomes after HSCT for congenital amegakaryocytic thrombocytopenia (CAMT; n = 86) from 2000 to 2018. We conducted an analysis of data collected by the Center for International Blood and Marrow Transplant Research on patients with CAMT receiving therapeutic allogeneic HSCT. The predominant donor type was HLA-matched or mismatched unrelated donors (n = 58, 67%). The remaining included HLA-matched sibling (n = 23, 27%) and HLA-mismatched relative (n = 5, 6%). The predominant graft types were bone marrow (n = 53, 62%) and cord blood (n = 25, 29%). The median age at transplantation was 3 years, with 82 of 86 patients being transplanted aged ≤10 years. The 5-year graft failure-free and overall survival were 83% (95% confidence interval [CI], 74-90) and 86% (95% CI, 78-93), respectively. An examination for risk factors confirmed mortality was higher after HLA-mismatched relative and mismatched unrelated donor HSCT compared to HLA-matched sibling and matched unrelated donor HSCT (hazard ratio 3.52, P = .04; 75% versus 93%). The 1-year incidence of graft failure was 19% after HLA-mismatched HSCT (n = 32) compared to 7% after HLA-matched HSCT (n = 54, P = .15). Day-100 grade II-IV acute graft-versus-host disease was 13%, 26%, and 30% after HLA-matched sibling, HLA-matched and mismatched unrelated donor HSCT. The 5-year incidence of chronic graft-versus-host disease was 33% with 24 of 28 patients having received grafts from HLA-matched (n = 13) and mismatched unrelated (n = 11) donors. Although HLA-matched donors are preferred, HLA-mismatched donors also extend survival for CAMT.

We conducted a phase 2 study in which patients undergoing allogeneic hematopoietic stem cell transplantation received tocilizumab in addition to standard immune suppression with tacrolimus and methotrexate for graft-versus-host disease prophylaxis. Thirty-five patients were enrolled between January 2015 and June 2016. The median age of the cohort was 66 (range: 22-76). All patients received busulfan-based conditioning, and were transplanted with human leukocyte antigen-matched related or matched unrelated bone marrow or peripheral stem cell grafts. The cumulative incidences of grades II-IV and III-IV acute graft-versus-host disease were 14% (95% CI 5-30) and 3% (95% CI 0-11) at day 100, and 17% (95% CI 7-31) and 6% (95% CI 1-16) at day 180, respectively. Notably, there were no cases of graft-versus-host disease of the lower gastrointestinal tract within the first 100 days. A comparison to 130 matched controls who only received tacrolimus and methotrexate demonstrated a lower cumulative incidence of grades II-IV acute graft-versus-host disease (17% versus 45%, P=0.003) and a significant increase in grades II-IV acute graft-versus-host disease-free survival at six months (69% versus 42%, P=0.001) with tocilizumab, tacrolimus and methotrexate, which was the primary endpoint of the study. Immune reconstitution was preserved in patients treated with tocilizumab, tacrolimus and methotrexate, as T-cell and B-cell subsets recovered to near normal levels by 6-12 months post-transplantation. We conclude that tocilizumab has promising activity in preventing acute graft-versus-host disease, particularly in the lower gastrointestinal tract, and warrants examination in a randomized setting.

Introduction: In 2018, the National Heart Lung and Blood Institute (NHLBI) began work on BioData Catalyst, a shared cloud platform where scientists can access and analyze de-identified data from NHLBI-funded projects. Hematopoietic cell transplant for sickle cell disease is potentially curative but is associated with life threatening complications most of which occur within the first or second year after transplantation. In the current era with increasing interest in gene therapy and/or editing to cure sickle cell disease we felt it timely to report on transplant recipients who have survived beyond 2-years after their transplantation. The aim of the current analysis was: 1) estimate the conditional survival rates after hematopoietic cell transplantation stratified by time survived since transplantation, 2) identify risk factors for death beyond 2-years after transplantation and 3) to compare all-cause mortality risks to those of an age, sex, and race-matched general population in the United States. Methods: Permission to access de-identified records of 950 patients with sickle cell disease was granted and data were accessed through a BioData Catalyst PIC-SURE portal (https://picsure.biodatacatalyst.nhlbi.nih.gov). All analyses were performed in this secure cloud environment using the available statistical software package(s). Conditional survival estimates were obtained using the Kaplan-Meier method for the sub-cohort that had survived a given length (x) of time after transplantation. Cox regression models were built to identify risk factors associated with mortality beyond 2 years after transplantation. The standardized relative mortality risk (SMR) or the ratio of observed to expected number of deaths, was used to quantify all-cause mortality risk after transplantation and compared to age and sex-matched general population. Person-years at risk were calculated from an anchor date (i.e., 2-, 5- and 7-years) after transplantation until date of death or last date known alive. The expected number of deaths was calculated using sex and age-specific US mortality rates. The equality of SMRs was tested and two-sided 95% confidence intervals (CI) were calculated. The incidence of graft failure was calculated using the cumulative incidence estimator to accommodate competing risks. Results: Patients were transplanted at 94 transplant centers in the United States between 2000 and 2017 with 70% of transplants after 2010. The median follow-up of the cohort was 5 years (range 2 - 20 years). Three hundred patients (32%) were observed for more than 7 years. The median age at transplantation was 11 years and 8% (n=78) were older than 30 years. The predominant donor was an HLA-matched sibling (66%), the predominant graft was bone marrow (70%), and about half the cohort received myeloablative conditioning. The 10-year probability of survival in 2- and 5-year survivors was 96% (95% CI 94-98) and 98% (95% CI 96-99), respectively (Figure 1). The 12-year probability of survival in 7-year survivors was 97% (95% CI 92-99). Risk factors for late death included older age and alternative donors (Table 1). Every 10-year increment in patient age was associated with a 75% increase-risk of mortality. The risk of death is 3.5 times higher after alternative donor (mismatched relative, HLA-matched and mismatched unrelated donor) compared to HLA-matched siblings. Amongst the alternative donors, mortality risks were not different. Compared to an age-, sex- and race-matched US population, the risk for late death was higher in transplant survivors but diminished over time (Table 2). Graft failure (beyond 2-years after transplantation) remains an obstacle; 4% (95% CI 3 - 6) after HLA-matched sibling and 12% (95% CI 8 - 18), (HR 2.59, p Conclusion: Durable survival is likely in the majority of 2-year survivors. The expected risk for death receded over time but the risk for late death is not negligible even as late as 7-years after transplantation underscoring the need for continued surveillance. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Inborn errors of immunity such as hemophagocytic lymphohistiocytosis (HLH) and chronic granulomatous disease (CGD) are characterized by hyperinflammation. Hematopoietic cell transplantation (HCT) in the setting of hyperinflammation leads to high morbidity and mortality. Consequently, there is increasing use of less intense conditioning regimens, which can increase risk of mixed chimerism or graft failure. We sought to study the effect of common regimens on outcomes after HCT using data reported to the Center for International Blood and Marrow Transplant Research. Methods : 365 patients aged Results : Patient demographics were similar across the three treatment groups. Patients with HLH were more likely to receive the Flu/Mel regimen. Although unrelated donor HCTs were predominant across the treatment groups, cord blood graft was more common in the Bu/Cy group. Conditioning regimens changed over the study period with most Flu/Mel/TT and Flu/Bu regimens used after 2010. Consequently, outcomes were censored 2-years post-HCT to account for differences in follow-up. The day-100 incidence of VOD was higher with Bu/Cy (18%) compared to Flu/Mel (4%) and Flu/Mel/TT or Flu/Bu (7%) regimens (p Conclusion : The data does not support the use of a reduced intensity Flu/Mel regimen for hyperinflammatory inborn errors of immunity. Although we did not observe differences in event-free survival between Bu/Cy and Flu/Mel/TT or Flu/Bu regimens, lower incidences of VOD and bacterial infections favor Flu/Mel/TT or Flu/Bu regimens. Disclosures Pulsipher: Bellicum: Honoraria; Jasper: Honoraria; Novartis: Honoraria; Miltenyi: Honoraria, Research Funding; Mesoblast: Honoraria; Adaptive: Research Funding. Stenger:ISCT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding.

We studied 1110 children, adolescents and young adults with β thalassemia major transplanted with grafts from HLA-matched relative (n=677; 61%), HLA-mismatched relative (n=78; 7%), HLA-matched unrelated (n=252; 23%) and HLA-mismatched unrelated (n=103; 9%) donors in 2000 - 2016. The median age at transplantation was 6 years (range Disclosures Dvorak: Jazz Pharmaceuticals: Consultancy; Chimerix, Inc.: Membership on an entity's Board of Directors or advisory committees. Shenoy:Novartis, Vertex, Bluebird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees. Walters:Sangamo Therapeutics: Consultancy; bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director.

We report on 499 patients with severe aplastic anemia aged >= 50 years who underwent hematopoietic cell transplantation (HCT) from HLA-matched sibling (n = 275, 55%) or HLA-matched (8/8) unrelated donors (n =187, 37%) between 2005 and 2016. The median age at HCT was 57.8 years; 16% of patients were 65 to 77 years old. Multivariable analysis confirmed higher mortality risks for patients with performance score less than 90% (hazard ratio HR], 1.41; 95% confidence interval [CI], 1.03 to 1.92; P= .03) and after unrelated donor transplantation (HR, 1.47; 95% CI,1 to 2.16; P = .05). The 3-year probabilities of survival for patients with performance scores of 90 to 100 and less than 90 after HLA-matched sibling transplant were 66% (range, 57% to 75%) and 57% (range, 47% to 76%), respectively. The corresponding probabilities after HLA-matched unrelated donor transplantation were 57% (range, 48% to 67%) and 48% (range, 36% to 59%). Age at transplantation was not associated with survival, but grades II to IV acute graft-versus-host disease (GVHD) risks were higher for patients aged 65 years or older (subdistribution HR [sHR], 1.7; 95% confidence interval, 1.07 to 2.72; P= .026). Chronic GVHD was lower with the GVHD prophylaxis regimens calcineurin inhibitor (CNI) + methotrexate (sHR, .52; 95% CI, .33 to .81; P= .004) and CNI alone or with other agents (sHR, .27; 95% CI, .14 to .53; P < .001) compared with CNI + mycophenolate. Although donor availability is modifiable only to a limited extent, choice of GVHD prophylaxis and selection of patients with good performance scores are key for improved outcomes. (C) 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Allogeneic HCT practice patterns for PID changed between 1974–2016. Three-year survival improved to >70% for SCID and non-SCID patients after 1999, and further increased to 94% for SCID patients transplanted 2010–2016 following newborn screening diagnosis.

We performed a Ph2 trial in adults and children to test abatacept for AGVHD prevention (‘ABA2', Clinicaltrials # NCT01743131), based on our promising preclinical and pilot patient data. ABA2 had 2 cohorts: A) HLA-mismatched (‘7/8', n = 43), a single-arm study with pre-specified CIBMTR matched analysis (vs CNI+MTX or CNI+MTX+ATG). B) HLA-matched (‘8/8', n = 142), randomized double-blind, comparing CNI+MTX+placebo vs CNI+MTX+ABA (‘ABA'). For each ABA arm, patients received 4 doses of 10mg/kg on d -1,5,14,28. ABA2 was designed as a screening Ph2 trial, with relaxed Type 1 error (0.2) and standard Type 2 error (0.2). Power analysis assumed ABA would decrease Gr 3-4 AGVHD from 30%–>10% in 7/8s and from 20%–>10% in 8/8s. Here we report top-line results for the 7/8s (median f/u = 708d, 264-1491) and 8/8s (median f/u = 369d, 180-1175). Reduced Grade 3-4 AGVHD: ABA was associated with decreased d180 Gr 3-4 AGVHD. In 7/8s, Gr 3-4 AGVHD = 2.5% in ABA (1 event/43 patients) vs 31% (CNI+MTX) and 22% (+ATG), 1 sided p = 0.001, 0.005,). In 8/8s, Gr 3-4 AGVHD = 6.85 % (5 events/73 patients) in ABA vs 14.6% (10 events) in placebo, 1 sided p = 0.068). Reduced Grade 2-4 AGVHD in 8/8s: ABA was associated with decreased d180 Gr 2-4 AGVHD. In 7/8s, Gr 2-4 AGVHD = 42% (ABA) vs 54% (CNI+MTX) and 45% (+ATG, 1 sided p = 0.098, 0.25). In 8/8s, Gr 2-4 AGVHD = 44.5% in ABA vs 62.3% in placebo (1 sided p = 0.004). Chronic GVHD: For 7/8s, 1 yr CGVHD = 38.8% (ABA) vs 43.5% (CNI+MTX) and 35.5% (+ATG, p = 0.4, 0.99). For 8/8s, follow up is still too short to adequately evaluate, and adjudication is ongoing. No Increase In Relapse: In 7/8s, relapse = 9.37% at 1 y vs 12.9% in CNI+MTX and 13.6% in +ATG (p = 0.115 and 0.085). In 8/8s, relapse = 13.8% at 1y (ABA) vs 20.5% (placebo, p = 0.7). Remarkably, in 7/8s, where median follow up=708d, there have been no further relapses reported in ABA2, with 9.37% relapse at 2 yr vs 20.63% (CNI+MTX) and 23.4% (ATG), despite matched disease risk. Statistically significant survival advantage in 7/8s: TRM: For 7/8s, 1 yr TRM = 10.5% (ABA) vs 32.7% (CNI+MTX) and 26% (+ATG, p = 0.024, 0.365). For 8/8s, TRM = 7.1% vs 14.6% at 1 yr (p = 0.5). Relapse-Free Survival (RFS): For 7/8s, RFS = 73.7% (ABA) vs 38.7% in CNI+MTX and 48.7% in +ATG (p = 0.001 and 0.027). For 8/8s, RFS = 79.1% for ABA vs 64.9% (placebo, p = 0.38). OS: For 7/8s, OS = 71% (ABA) vs 47.5% (CNI+MTX) and 58% (+ATG, p = 0.01 and 0.145). For 8/8s, OS = 83.2% (ABA) vs 76.6 (placebo, p = 0.32). Our results suggest that short-course (4 doses) ABA can safely prevent AGVHD without compromising relapse. While this was a modestly sized study (7/8s: n = 43, 8/8 n = 142), the comparative event size for 7/8s was high enough that the protective effect of ABA was highly statistically significant. For 8/8s, there was a statistically significant improvement for Gr 2-4 GVHD and a trend toward an advantage for ABA in all other parameters. These results are the first to demonstrate efficacy of in vivo T cell costimulation blockade in preventing AGVHD.

To study family-specific variation in the survival of pink salmon Oncorhynchus gorbuscha, we partitioned family size into four life history divisions: (1) maternal fecundity, (2) deposition of fertilized eggs and egg loss from the redd, (3) freshwater survival (and male potency), and (4) marine survival. We directly measured the variability in fecundity and then measured the family-specific variability of freshwater survival in several Alaskan hatchery populations. Next, we measured freshwater survival in spatially clustered groups of wild pink salmon (not identified to a specific dam or sire) in Prince William Sound, Alaska. Drawing on estimates of the family-specific variation of marine survival in pink salmon from previous studies, we concluded that family-specific egg deposition processes and family-specific variability in the marine environment were the primary sources of the overall variability in pink salmon family size, at least in the populations studied. We hypothesize that the freshwat...