Center For International Blood And Marrow Transplant Research Research Articles

Advances in Transplantation for Lymphomas Resulting from CIBMTR Lymphoma Working Committee's Research Portfolio: A Five-Year Report (2013-2018).

The Center for International Blood and Marrow Transplant Research (CIBMTR) is a research collaboration between the National Marrow Donor Program (NMDP)/Be The Match and the Medical College of Wisconsin (MCW). The CIBMTR collaborates with the global scientific community to advance hematopoietic cell transplantation (HCT) and cellular therapy worldwide to increase survival and enrich quality of life for patients. The observation research program within CIBMTR is organized into 15 working committees. This review is aiming to highlight the observational research studies published by the CIBMTR Lymphoma Working committee over the last five years (2013-18) and to summarize how these studies have impacted the field by helping inform clinical practice in scenarios where prospective data from high quality randomized trials were not available or where owing to the rarity of a particular transplant indication such data were unlikely to be generated, outside the setting of a large observational research database. The salient findings reviewed include; (a) studies supporting role of autologous HCT in diffuse large B-cell lymphoma (DLBCL) patients with sensitive relapse of disease within one year of diagnosis, (b) role of autologous HCT vs allogeneic HCT in follicular lymphoma patients with early therapy failure, (c) prognostic scoring system development for classical Hodgkin lymphoma and DLBCL patients with prior autograft failure, (d) defining the role of alternative donor transplantation in lymphomas, (e) evaluating appropriate conditioning regimens for HCT in lymphoma, and (f) outcomes of HCT in rare lymphoid malignancies.

Outcomes of Medicare-age eligible NHL patients receiving RIC allogeneic transplantation: a CIBMTR analysis

AbstractThe application of allogeneic hematopoietic cell transplantation (allo-HCT) in non-Hodgkin lymphoma (NHL) patients ≥65 years in the United States is limited by lack of Medicare coverage for this indication. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report allo-HCT outcomes of NHL patients aged ≥65 years (older cohort; n = 446) compared with a cohort of younger NHL patients aged 55-64 years (n = 1183). We identified 1629 NHL patients undergoing a first reduced-intensity conditioning (RIC) or nonmyeloablative conditioning allo-HCT from 2008 to 2015 in the United States. Cord blood or haploidentical transplants were excluded. The median age was 68 years (range 65-77) for the older cohort vs 60 years (range 55-64) in the younger cohort. The 4-year adjusted probabilities of nonrelapse mortality (NRM), relapse/progression (R/P), progression-free survival (PFS), and overall survival (OS) of the younger and older groups were 24% vs 30% (P = .03), 41% vs 42% (P = .82), 37% vs 31% (P = .03), and 51% vs 46% (P = .07), respectively. Using multivariate analysis, compared with the younger group, the older cohort was associated with increased NRM, but there was no difference between the 2 cohorts in terms of R/P, PFS, or OS. The most common cause of death was disease relapse in both groups. In NHL patients eligible for allo-HCT, there was no difference in OS between the 2 cohorts. Age alone should not determine allo-HCT eligibility in NHL, and Medicare should expand allo-HCT coverage to older adults.

108 - Improved Mortality Prognostication for Critically Ill Pediatric Hematopoietic Cell Transplant Patients: Results From a Virtual Pediatric Systems (VPS) and Center for International Blood and Marrow Transplant Research (CIBMTR) Database Merger

108 - Improved Mortality Prognostication for Critically Ill Pediatric Hematopoietic Cell Transplant Patients: Results From a Virtual Pediatric Systems (VPS) and Center for International Blood and Marrow Transplant Research (CIBMTR) Database Merger

Autologous Transplantation in Follicular Lymphoma with Early Therapy Failure: A National LymphoCare Study and Center for International Blood and Marrow Transplant Research Analysis

Patients with follicular lymphoma (FL) experiencing early therapy failure (ETF) within 2 years of frontline chemoimmunotherapy have poor overall survival (OS). We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National LymphoCare Study (NLCS) to determine whether autologous hematopoietic cell transplant (autoHCT) can improve outcomes in this high-risk FL subgroup. ETF was defined as failure to achieve at least partial response after frontline chemoimmunotherapy or lymphoma progression within 2 years of frontline chemoimmunotherapy. We identified 2 groups: the non-autoHCT cohort (patients from the NLCS with ETF not undergoing autoHCT) and the autoHCT cohort (CIBMTR patients with ETF undergoing autoHCT). All patients received rituximab-based chemotherapy as frontline treatment; 174 non-autoHCT patients and 175 autoHCT patients were identified and analyzed. There was no difference in 5-year OS between the 2 groups (60% versus 67%, respectively; P = .16). A planned subgroup analysis showed that patients with ETF receiving autoHCT soon after treatment failure (≤1 year of ETF; n = 123) had higher 5-year OS than those without autoHCT (73% versus 60%, P = .05). On multivariate analysis, early use of autoHCT was associated with significantly reduced mortality (hazard ratio, .63; 95% confidence interval, .42 to .94; P = .02). Patients with FL experiencing ETF after frontline chemoimmunotherapy lack optimal therapy. We demonstrate improved OS when receiving autoHCT within 1 year of treatment failure. Results from this unique collaboration between the NLCS and CIBMTR support consideration of early consolidation with autoHCT in select FL patients experiencing ETF.

Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms' tumor: a CIBMTR retrospective analysis.

Despite the dramatic improvement in the overall survival for patients diagnosed with Wilms’ tumor (WT), the outcomes for those that experience relapse have remained disappointing. We describe the outcomes of 253 patients with relapsed WT who received high-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplant (HCT) between 1990 and 2013, and reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR). The 5-year estimates for event free survival (EFS) and overall survival (OS) were 36% (95% CI; 29 – 43%) and 45% (95% CI; 38 – 51%) respectively. Relapse of primary disease was the cause of death in 81% of the population. EFS, OS, relapse and transplant-related mortality (TRM) showed no significant differences when broken down by disease status at transplant, time from diagnosis to transplant, year of transplant or conditioning regimen. Our data suggest that HDT followed by autologous HCT for relapsed WT is well tolerated and outcomes are similar to those reported in the literature. Since attempts to conduct a randomized trial comparing maintenance chemotherapy with consolidation versus high-dose chemotherapy followed by stem cell transplant have failed, one should balance the potential benefits with the yet unknown long-term risks. Since disease recurrence continues to be the most common cause of death, future research should focus on the development of consolidation therapies for those patients achieving complete response to therapy.

Haploidentical Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome

This study aimed to validate the capability of the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic scoring system to predict outcomes of patients with myelodysplastic syndromes (MDS) who had undergone HLA-haploidentical related donor hematopoietic stem cell transplantation (haplo-HSCT). We also propose and validate a more suitable prognostic scoring system. A total of 157 patients with MDS who underwent haplo-HSCT were enrolled. The CIBMTR prognostic scoring system could predict the 2-year clinical outcomes, but failed to predict the 100-day clinical outcomes after haplo-HSCT. Our multivariable model identified 2 independent predictors of overall survival: age and monosomal karyotype (MK). Weighted scores of 5, 3, and 2 were assigned to age ≥50 years, age 30 to 49 years, and MK, respectively, and a 2-category system was created: low (score ≤3) and high (score >3). Our refined prognostic scoring system can predict both the 100-day and 2-year clinical outcomes after haplo-HSCT. Our findings indicate that the CIBMTR prognostic scoring system is predictive of the outcomes of patients with MDS following haplo-HSCT, and that older patients with MDS and/or patients with MK should be closely monitored after haplo-HSCT.

Centralized patient‐reported outcome data collection in transplantation is feasible and clinically meaningful

Allogeneic hematopoietic cell transplantation (HCT) cures many patients, but often with the risk of late effects and impaired quality of life. The value of quantifying patient-reported outcomes (PROs) is increasingly being recognized, but the routine collection of PROs is uncommon. This study evaluated the feasibility of prospective PRO collection by an outcome registry at multiple time points from unselected HCT patients undergoing transplantation at centers contributing clinical data to the Center for International Blood and Marrow Transplant Research (CIBMTR), and then it correlated the PRO data with clinical and demographic data. The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), 36-Item Short Form Health Survey (SF-36), and Pediatric Quality of Life Inventory measures were administered before HCT, on day 100, and at 6 and 12 months. Patients were recruited by the transplant center, but posttransplant PRO collection was managed centrally by the CIBMTR. There were 580 eligible patients, and 390 (67%) enrolled. Feasibility was shown by high time-specific retention rates (176 of 238 at 1 year or 74%) and participant satisfaction. Factors associated with higher response rates were an age > 50 years (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.03-2.41; P = .0355), white race (OR, 4.61; 95% CI, 2.66-7.99; P < .0001), and being married (OR, 2.28; 95% CI, 1.42-3.65; P = .0006) for adults and a higher family income for children (OR, 4.99; 95% CI, 2.12-11.75; P = .0002). Importantly, pre-HCT PRO scores independently predicted survival after adjustments for patient-, disease-, and transplant-related factors. The adjusted probabilities of 1-year survival were 56%, 67%, 75%, and 76% by increasing quartiles of the pre-HCT FACT-BMT score and 58%, 72%, 62%, and 82% by increasing quartiles of the pre-HCT SF-36 physical component score. A hybrid model of local consent for centralized PRO collection is feasible, and pretransplant PROs provide critical prognostic information for HCT outcomes. Cancer 2017;123:4687-4700. © 2017 American Cancer Society.

A better angel of our nature: Hanna Michel "Jean" Khoury, MD (April 24, 1967-May 22, 2017).

A better angel of our nature: Hanna Michel "Jean" Khoury, MD (April 24, 1967-May 22, 2017).

Current Use of and Trends in Hematopoietic Cell Transplantation in the United States.

Hematopoietic cell transplantation (HCT) is a well-established treatment to control and/or cure many malignant and nonmalignant diseases involving the hematopoietic system and some solid tumors. We report information about HCT procedures performed in the United States in 2018 and analyze trends and outcomes of HCT as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Overall, compared with 2017, the number of allogeneic HCTs performed in the United States increased by 1%, and the number of autologous HCTs decreased by 5%. Key findings are fewer autologous HCTs performed for non-Hodgkin lymphoma and increasing numbers of haploidentical HCTs, nearly all of which use post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis. There is a continuing increase in HCT in adults age >70 years, particularly for acute myelogenous leukemia and myelodysplastic syndromes. Survival rates by disease, disease stage, donor type, and age are presented. This report, prepared annually by the CIBMTR, provides a snapshot of current transplant activity in the United States.

Autologous (auto) versus matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic (allo) hematopoietic cell transplantation (HCT) in follicular lymphoma (FL) patients (pts) with early chemoimmunotherapy failure (ECF): A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis.

7508 Background: Contrary to most FL, high-risk FL pts with ECF (i.e. relapse within 2 yrs of frontline chemoimmunotherapy) have a 5 yr OS of only 50%. (Casulo, JCO 2015). We used the CIBMTR database to compare autoHCT versus either MSD or MUD alloHCT as the first transplant approach in FL pts with ECF. Methods: Adult FL pts (age ≥18) undergoing autoHCT or alloHCT between 2002-2014 and receiving first line rituximab-based chemoimmunotherapies with evidence of ECF (defined as disease relapse or progression within 2 yrs of treatment initiation) were included. The primary endpoint was OS; secondary endpoints were progression-free survival (PFS), relapse and non-relapse mortality (NRM). Results: 440 pts had ECF (auto = 240, MSD = 105, MUD = 95) (Table 1). The 5 yr adjusted probabilities (AjP) of NRM were significantly lower with autoHCT (5%), versus MSD (17%) or MUD (33%) HCT (p&lt;0.0001). 5 yr AjP of relapse were significantly lower with MSD (31%) or MUD HCT (23%), versus autoHCT (58%; p&lt;0.0001). AjP of 5 yr PFS following auto, MSD and MUD HCT were 38%, 52% and 43% (p=.006) respectively. The AjP of 5 yr OS was significantly higher following autoHCT (70%) or MSD HCT (73%) versus MUD HCT (49%; p=0.004). Conclusions: AutoHCT for FL pts with ECF has low NRM and 5 yr OS rates (70%) that are provocatively higher than historical data (~50%). MSD HCT had the lowest relapse rate with similar survival. A prospective trial confirming the role of HCT in ECF FL is warranted. [Table: see text]

Risk Factors for Subsequent Central Nervous System Tumors in Pediatric Allogeneic Hematopoietic Cell Transplant: A Study from the Center for International Blood and Marrow Transplant Research (CIBMTR)

Survivors of hematopoietic cell transplantation (HCT) are at risk of subsequent solid tumors, including central nervous system (CNS) tumors. The risk of CNS tumors after HCT in pediatric HCT recipients is not known. We evaluated the incidence and risk factors for CNS tumors in pediatric recipients of allogeneic HCT reported to the Center for International Blood and Marrow Transplant Research between 1976 and 2008. A case control design was used. There were no CNS tumors in the nonmalignant cohort (n = 4543) or in those undergoing HCT for solid tumors (n = 26). There were 59 CNS tumors in 8720 patients transplanted for hematologic malignancies. In comparison with the general population, pediatric HCT recipients with hematologic malignancies had a 33 times higher than expected rate of CNS tumors (95% confidence interval, 22.98 to 45.77; P < .0001). The cumulative incidence of subsequent CNS tumors was 1.29% (95% confidence interval .87 to 1.87) at 20 years after HCT. Significant risk factors in the entire cohort were having an unrelated donor (HR, 3.35; P = .0002) and CNS disease before HCT for both acute lymphoblastic leukemia (HR, 8.21; P = .0003) and acute myeloid leukemia (HR, 6.21; P = .0174). Analysis of the matched cohort showed having an unrelated donor transplant (HR, 4.79; P = .0037), CNS disease before HCT (HR, 7.67; P = .0064), and radiotherapy exposure before conditioning (HR, 3.7; P = .0234) to be significant risk factors. Chronic graft-versus-host disease was associated with a lower risk (HR, .29; P = .0143). Survivors of HCT for nonmalignant diseases did not show an increased incidence of CNS tumors, whereas survivors of hematologic malignancies have a markedly increased incidence of CNS tumors that warrants lifelong surveillance.

200 - Analysis of Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) in Mismatched Unrelated Donor Hematopoietic Stem Cell Transplants (HCT): A Center for International Blood and Marrow Transplant Research (CIBMTR) Cohort Study

200 - Analysis of Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) in Mismatched Unrelated Donor Hematopoietic Stem Cell Transplants (HCT): A Center for International Blood and Marrow Transplant Research (CIBMTR) Cohort Study

489 - Implementation of a Program Assessment Across a Network of 7 HCT Programs to Assess Risks Associated with Clinical Outcome Based on the 2015 Center for International Blood and Marrow Transplant Research (CIBMTR) Transplant Center-Specific Survival Report

489 - Implementation of a Program Assessment Across a Network of 7 HCT Programs to Assess Risks Associated with Clinical Outcome Based on the 2015 Center for International Blood and Marrow Transplant Research (CIBMTR) Transplant Center-Specific Survival Report

117 - Development of Forms for a Tutorial of Transplant Essential Data (TED) as Facilitator to Understand and Learn About Data Entry in CIBMTR (Center for International Blood and Marrow Transplant Research) to Brazilian Centers

117 - Development of Forms for a Tutorial of Transplant Essential Data (TED) as Facilitator to Understand and Learn About Data Entry in CIBMTR (Center for International Blood and Marrow Transplant Research) to Brazilian Centers

Incidence and Outcomes of Cytomegalovirus (CMV) Infection among Hematopoietic Stem Cell Transplant (HSCT) Recipients

BackgroundOutcomes of CMV infection among HSCT recipients likely vary by patient population and treatment modality. However, data on these outcomes have been reported by relatively few centers.MethodsThis was a retrospective cohort study of allogenic HSCT recipients age ≥18 years at Oregon Health and Science University Hospital (OHSU) between 2010–2015. During the study period, OHSU standard practice was to preemptively treat CMV-viremic patients (quantitative PCR assay ≥ 200 copies/mL or consecutive PCR assays <200 copies/mL) with first-line valganciclovir or ganciclovir and second line foscarnet if there were contraindications to first-line agents. Study data were collected from an electronic health record repository and local Center for International Blood and Marrow Transplant Research (CIBMTR) database. Primary outcomes were clinical manifestations of CMV disease, death, and cause of death within 1 year of transplant.ResultsAmong 409 HSCT recipients, mean age was 53 (standard deviation: 13) years and 41% were female. 192 (47%) patients had CMV viremia and the median (interquartile range) time to CMV reactivation was 42 (31–53) days (Figure 1). Patients with acute myeloid leukemia were significantly less likely to have CMV reactivation (39% vs. 55%, P < 0.01) and those with myelodysplastic syndromes had a non-significantly higher risk (24% vs. 17%, P = 0.06). 4 (1%) patients had a documented clinical manifestation of CMV disease (3 pneumonia and 1 pancreatitis). One-year mortality was 36% (148/409); there was no significant difference in mortality (37.5% vs. 35.0%, P = 0.60) or cause of death (P = 0.30) between patients with and without CMV reactivation (Figure 2). The most frequent causes of death among CMV viremic patients were recurrent/persistent disease (35%), acute graft vs. host disease (GVHD) (22%), infection (19%), and chronic GVHD (11%). CMV was documented as the primary cause of death for 2 patients.ConclusionNearly half of HSCT recipients had CMV reactivation and more than a third died within one year of transplant. However, incidence of CMV disease was rare and reactivation was not associated with increased mortality. Further study is needed to identify risk factors for CMV reactivation, infection and mortality in this population.Disclosures J. P. Furuno, Merck & Co.: Consultant and Grant Investigator, Consulting fee, Research grant and Speaker honorarium. L. Strasfeld, Merck: Independent Contractor, Salary. J. C. McGregor, Merck & Co.: Grant Investigator, Research grant

Inferior Access to Allogeneic Transplant in Disadvantaged Populations: A CIBMTR Analysis

Introduction: Allogeneic stem cell transplant is an intensive procedure, offered in a limited number of medical centres. We sought to describe how sociodemographic variables impacted access to transplant across the United States, and if disadvantaged populations had inferior access to transplant.Methods: Data from the Surveillance, Epidemiology and End Results Program (SEER) and the Center for International Blood and Marrow Transplant Research (CIBMTR) was integrated to determine the rate of unrelated donor transplantation between 2000 and 2010 in each of the 612 counties included in the SEER registry. Patients under the age of 65 with AML, ALL, and MDS were included, and the analysis was restricted to unrelated donors due to limited availability of ZIP code in CIBMTR data. New incident cases were determined from SEER, and the number of transplants was determined from CIBMTR. The transplant rate was calculated (transplants performed divided by incident cases) for each county. County attributes (percent minority, rural/urban status, percentage below the poverty line, and median family size) were obtained from US Census data. Poisson regression was used to describe how county attributes impacted transplant rates. Transplant rates were calculated separately for AML, White residents, and pediatric ALL.Results: 3147 patients were identified in the CIBMTR dataset that met inclusion criteria. The estimated ZIP code completeness was 75%. There were 30,468 new incident diagnoses of ALL, AML, and MDS.For AML, patients from rural areas (less than 20,000 residents) and patients from areas with higher poverty levels had lower transplant rates (Table 1). Minority status and family size did not impact transplant rate. In regression models, higher levels of poverty remained associated with lower transplant rates, while rurality did not (Table 2). The results were similar among White residents. In contrast, in pediatric ALL, no county attributes (poverty, rurality, percent minority, and family size) were significantly associated with a difference in transplant rate (Table 1). However, numbers of transplants were smaller, limiting power.Discussion: Patients with AML from disadvantaged areas had lower rates of unrelated donor transplant. While patients from disadvantaged areas were also more likely to be non-White, and non-White Americans are less likely to have an available unrelated donor, this difference was also seen in White Americans from disadvantaged areas. This suggests the lower transplant rate is due impaired access to transplant. Poverty rate was the most important predictor of transplant rate. The results of this study suggest that improving access to transplant in disadvantaged populations should be a priority for health care administrators. Based on these results, approximately 2500 Americans do not undergo allogeneic transplant annually due to inferior access associated with higher poverty rates. [Display omitted] [Display omitted] DisclosuresHahn:Novartis: Equity Ownership; NIH: Research Funding.

Role of Donor Source on Clinical Outcomes and Inpatient Resource Utilization for Hematopoietic Cell Transplantation in Children with Acute Leukemia

Acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) are the two most common childhood leukemias. Novel drug therapies and allogeneic hematopoietic cell transplant (alloHCT) have improved ALL and AML treatment outcomes over the past two decades. However, alloHCT may be associated with significant morbidity and mortality that results in increased healthcare utilization. To date, no multi-center comparative effectiveness studies have been performed specifically evaluating alloHCT in children with ALL or AML. This study uses a novel methodology to investigate the hypothesis that matched sibling donor (MSD) alloHCT has significantly lower healthcare utilization compared to unrelated donor (URD) and that among URD, umbilical cord blood transplants (CBT) will have higher initial utilization but lower long-term utilization.Clinical and transplant outcomes data from the Center for International Blood and Marrow Transplant Research (CIBMTR) database were merged with inpatient resource utilization and standardized cost data from the Pediatric Health Information System (PHIS) database using a probabilistic merge methodology. This merged dataset contained U.S. patients age 1-21 years who received alloHCT for ALL or AML from 2004-2013 with comprehensive CIBMTR data at a PHIS reporting hospital. The primary outcomes of overall survival (OS), leukemia free survival (LFS), and inpatient resource utilization were evaluated using Kaplan-Meier analysis, Cox proportional hazards, and unadjusted Poisson regression analysis. Cost and resource comparisons for all donor types were made through day+100 and focused on URD only comparisons up to 2-year follow-up. Donor procurement costs were not directly included in this analysis.A total of 797 patients (54% of CIBMTR eligible patients and 89% of CIBMTR patients at PHIS centers) were successfully identified in both CIBMTR and PHIS; 433 had ALL and had 364 AML. LFS for ALL at 3 years was 68% for MSD, 53% for MUD, and 53% for CBT. The LFS in ALL was significantly impacted by donor type, age, disease status, and CMV (Table). The associated total costs were significantly higher for well-matched unrelated bone marrow (MUD) vs MSD at 100d ($246,149 vs $147,547, p<0.01), but CBT costs were not significantly higher compared to MUD at 100d ($275,673 vs $246,149, p=0.09). When median total costs per day were compared across donor source, findings were similar with well- MUD was significantly higher than MSD at 100d ($3,388/d vs $2,511/d, p=0.012), and no significant difference between CBT and MUD ($3,881/d vs $3,388/d, p=0.53). The corresponding average length of stay (ALOS) was 35 days for MUD, 34 days MSD, and 53 days CBT. Among URD alloHCT, median CBT costs per day were not significantly higher compared to MUD at 2yrs ($2,472/d vs $2,294/d, p=0.49).AlloHCT for AML had a 3-yr LFS of 56% for MSD, 46% for MUD, and 41% for CBT. LFS were significantly different by disease status and performance status (Table). The associated total costs were significantly higher for MUD at 100d than MSD ($259,293 vs $143,870, p<0.001), but CBT costs were not significantly higher compared to MUD at 100d ($301,160 vs $259,293, p=0.055). Comparisons of median total costs per day were similar, MUD vs MSD at 100d was significantly higher ($3,627/d vs $2,478/d, p<0.01), but CBT costs were not significantly higher compared to MUD at 100d ($3,891/d vs $3,627/d, p=0.95). The corresponding ALOS was 38 days for MUD, 35 days MSD, and 66 days CBT. Among URD alloHCT, median CBT costs per day were not significantly higher compared to MUD at 2yrs ($3,232/d vs $3,102/d, p=0.49).This study recapitulates previously published outcomes of alloHCT for acute leukemia AND adds key findings on the impact of alloHCT on inpatient resource utilization and costs. Specifically, MSD and MUD alloHCT provide similar survival outcomes; however, MSD alloHCT has a significant advantage in cost and resource utilization for both ALL and AML. Among URD transplants, CBT does not show any substantial survival or resource utilization advantage over MUD. Ongoing research will need to be performed to determine if the difference among URD alloHCT becomes significant with a larger sample size and/or beyond the 2 years following alloHCT. [Display omitted] DisclosuresPulsipher:Novartis: Consultancy, Other: Study Steering Committee; Jazz Pharmaceutical: Consultancy; Medac: Other: Housing support for conference; Chimerix: Consultancy. Hahn:Novartis: Equity Ownership; NIH: Research Funding.

Trends in Pre- and Post-Transplant Therapies Prior to First Autologous Hematopoietic Cell Transplantation Among Patients with Multiple Myeloma in the United States, 2004-2014

Background: Novel therapies and novel treatment paradigms such as post-transplant consolidation and/or maintenance therapies within the last decade have led to remarkable improvement in the survival of multiple myeloma (MM), the second most common hematologic malignancy seen in adults. Upfront autologous hematopoietic cell transplantation (AHCT) remains the standard of care in transplant-eligible patients. We analyzed trends in pre- and post-transplant therapies among patients undergoing AHCT for MM in the United States (US) using the Center for International Blood and Marrow Transplant Research (CIBMTR) database.Methods: All first AHCT in the US (n=37705) using high dose melphalan for MM reported to the CIBMTR between 2004 and 2014 were included and a representative subset (n=5077) were included in subanalyses. During this period, the CIBMTR captured 60-80% of AHCT activity for MM in the US. Demographic, disease-related and treatment-related data were analyzed for trends. Data on use of individual chemotherapies for induction and post-transplant consolidation/maintenance were obtained (thalidomide, T; lenalidomide, R; bortezomib, V; cyclophosphamide, C; dexamethasone, D). Post-transplant therapies were available in the 2008-2014 cohort. Kaplan-Meier method was used to conduct survival analysis; PFS and OS analysis were compared 2004/05, 2006/07, 2008/09, 2010/11 and 2012/13 so that at least 3 years of actual follow up was available for all patients.Results: The baseline demographic data for the 5077 patients (2004/05, N =1062, 2006/07, N=972, 2008/09, N=1156, 2010/11, N=566, 2012/14, N=1321) showed a median (range) age was 59 (20-82) years, with 58% males, 23% African Americans, 42% KPS <90%. International Staging System, ISS stage III was seen in 33%. 76% of patients underwent first AHCT in <12 months from diagnosis. 88% had chemosensitive disease (i.e. pre-AHCT response partial response or better), 85% of patients had melphalan dose 200 mg/m2. 27% had AHCT in <6 months of diagnosis, 49% 6-12 months, 14% 12-24 months and 9% >24 months. The median follow up of survivors was 68 months (1-135). Figure 1A shows the various induction regimen trends over the period. RVD is the most frequent pre-transplant induction regimen and used in 44% of induction regimens since 2010, followed by VD, CVD and RD. Planned post-transplant treatments (consolidation or maintenance) at day 100 were more frequent after 2010 (Figure 1B) with R being the most frequent maintenance agent. The frequency of maintenance utilization did not go up significantly from 2010 to 2014, and 51% of patients received post-transplant therapies during this period. Among the patients who died, myeloma remained the most common cause of death: 2004-2005, 70%; 2006-2007, 74%; 2008-2009, 76%; 2010-2011, 79% and 2012-2014, 75%. Survival data showed improvement in PFS over the study period with 3-year median PFS improving from 29 (26-32) months in 2004/05 to 32 (29-35) months in 2006/07 to 38 (35-41) months in 2008/09 to 52 (48-56) months in 2010/11 to 56 (50-61) months in 2012/13 (p-value <0.001) (Figure 2). Similarly, 3 year median OS also showed improvement in successive time periods; 74 (72-77) months in 2004/05 to 77 (74-79) months in 2006/07, 77 (74-79) months in 2008/09, 78 (74-81) months in 2010/11 to 83 (79-87) months in 2012/13 (p-value <0.001) (Figure 3).Conclusions: This analysis shows that outcomes of upfront AHCT recipients for MM have improved in the last 10 years at a steady pace with a substantial improvement in the most recent cohort (Fig 3). RVD is currently the most common pre-transplant induction regimen since 2010. Approximately half of patients are placed on maintenance treatment after AHCT, with R as the most frequently used maintenance agent. Despite these impressive gains in the field, progression of MM remains the most frequent cause of death. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Genetic Alterations Predict Outcomes in Patients with Myelodysplastic Syndrome Receiving Allogeneic Hematopoietic Stem Cell Transplantation

▪Background: Allogeneic hematopoietic stem cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndrome (MDS). However, mortality after HCT for MDS is high, with deaths attributable to both relapsed disease and transplant-related complications. The genetic lesions that drive MDS pathogenesis have the potential to predict the outcome of patients following HCT.Methods: We performed targeted sequencing of 127 genes on pre-HCT blood samples from 1514 patients who received allogeneic HCT for MDS between 2005 and 2014. All MDS patients enrolled in the Center for International Blood and Marrow Transplant Research (CIBMTR) Repository were considered for inclusion. Patients were excluded only if blasts were >/= 20% or if they had diagnosis of CMML or MDS/MPN overlap. The median age of patients was 59 years (range 0.4 - 77 years), including 241 (16%) < 40 years of age. Donors were 8/8 HLA-matched unrelated donors (n = 862, 57%), HLA-identical siblings (n = 181, 12%), < 8/8 HLA-matched unrelated donors (n = 296, 20%), or umbilical cord blood (n = 174, 11%).Results:TP53 mutations were independently associated with poor overall survival (HR 1.71, 95% CI 1.45-2.02, p < 0.0001) and a shorter time to relapse (HR 2.34, 1.85-3.00, p < 0.0001). In a multivariable model the adverse prognostic significance of TP53 mutations was independent of recipient age, performance status, hematologic status at time of HCT, bone marrow blast count, and karyotype. RAS pathway mutations were independently associated with a shorter time to relapse (HR 1.73, 1.34-2.23, p < 0.0001) and JAK2 V617F mutations were associated with higher transplant-related mortality (TRM) (HR 2.13, 1.38-3.27, p = 0.0006).Patients with therapy-related MDS (t-MDS) comprised 21% of the cohort (n = 311) and had significantly worse survival than patients with primary MDS (HR 1.4, 1.2-1.6, p = 0.0002). Only TP53 (OR 3.8, p <0.0001) and the p53 regulator PPM1D (OR 4.8, p < 0.0001) were selectively mutated in t-MDS. Overall survival was inferior in t-MDS patients with TP53 mutations (HR 1.7, 1.3-2.3, p = 0.0004), but similar in t-MDS patients without TP53 mutations compared to patients with primary MDS (HR 1.1, 0.9-1.4, p = 0.37).In univariate analysis, young recipient age was powerfully associated with good post-transplant survival. However, we identified a group of adult patients under 40 years old with compound heterozygous mutations in the Shwachman-Diamond Syndrome (SDS)-associated SBDS gene that had remarkably poor prognosis and no long-term survivors (HR 6.0, 1.6-23.0, p = 0.009). All patients with biallelic SBDS mutations had somatic TP53 mutations, suggesting a biological synergy between SBDS and TP53 mutations in clonal MDS transformation of genetically-defined SDS.Finally, we used recursive partitioning to identify 6 distinct MDS subgroups based on the association between clinical and genetic variables and post-HCT survival, then evaluated each subgroup to identify links to relapse or TRM (Figure 1). Consistent with our multivariable model, the presence of TP53 mutations was the most important prognostic variable, with mortality driven by relapse and not influenced by conditioning intensity. In patients age 40 and older without TP53 mutations, two subgroups had poor outcomes: those with RAS pathway mutations, with median OS of 11 months and high risk of relapse (p = 0.001), and those with JAK2 mutations, with median OS of 6 months and high risk of TRM (p < 0.001). Among patients under 40 years old without TP53 mutation, we identified two subgroups based on evaluation of three high-risk clinical features (t-MDS, platelets < 30 x 109/L at HCT, or bone marrow blasts at diagnosis >/= 15%). Patients < 40 years old with at least one high-risk feature had 3 year OS of 49.0%, associated with high TRM (p < 0.001), while those with no high-risk features had 3 year OS of 81.4%.Conclusions: We found that TP53 mutations are the most important predictor of prognosis in allo-HCT for MDS, independent of other clinical and genetic variables, and that the adverse outcome in TP53 mutated MDS is not influenced by conditioning intensity, donor type, or graft source. TP53 mutations account for the characteristically poor outcomes of clinically distinct subgroups, including t-MDS and genetically-defined SDS. We present a multivariable model that identifies 6 distinct MDS subgroups with differential post-HCT survival and differences in relapse and TRM. [Display omitted] DisclosuresLindsley:Takeda Pharmaceuticals: Consultancy; MedImmune: Research Funding. Mar:H3 Biomedicine: Other: Spouse's employment.

Replication of Candidate SNP Survival Analyses and Gene-Based Tests of Association with Survival Outcomes after an Unrelated Donor Blood or Marrow Transplant: Results from the Discovery-BMT Study

▪Over the past decade, there have been numerous published candidate gene association studies of non-HLA variants, genes and/or pathways in relation to BMT survival outcomes. Most of these studies investigated a small number of candidate single nucleotide polymorphisms (SNPs), chosen based on known gene function, in a limited number of cases without replication. Here we test the association of previously reported SNPs with survival outcomes (overall survival (OS), progression-free survival (PFS), death due to disease (DD) or transplant-related mortality (TRM)) after URD BMT using data from the DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to one-Year mortality after BMT) study which included 2,052 European descent recipient-unrelated donor pairs (Cohort 1) and 763 recipient-unrelated donor pairs (Cohort 1) reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2000-2009 and 2009-2011, respectively. DISCOVeRY-BMT is a Genome Wide Association Study (GWAS) that includes over 9 million typed or imputed SNPs. This represents the largest study to date and is well powered to test both SNP and gene-based association hypotheses.We conducted an extensive literature review of PubMed using MESH terms related to transplant and hematologic disease which yielded 76 candidate gene association studies that investigated a total of 46 genes with any survival outcome. Of the 46 genes, 11 genes (CTLA4, CYP2B6, CYP2C19, GSTM1, GSTT1, IL23R, IL6, MTHFR, NOD2/CARD15, TNFSRF1B, and VDR) were studied in at least 2 publications. A total of 16 SNPs in 8 of these genes reported a significant (P< 0.05) association with at least one survival outcome (OS, PFS, DD or TRM). We tested these 16 SNPs for an association with the survival outcome originally reported in each article (Table 1). All association models included age at BMT, diagnosis (AML, ALL, MDS), disease status at BMT, cell source (blood, bone marrow) and year of BMT. P-values from Cohorts 1 and 2 were combined using a fixed-effects model in METAL software. Since the candidate gene studies have a gene-based hypothesis, we also performed gene-level testing using the VErsatile Gene-Based Association Study (VEGAS2) software to measure the aggregate effect of all available typed and imputed SNPs from our GWAS data in these 8 genes.The candidate gene association studies included heterogeneous patient populations of autologous and/or allogeneic (related or unrelated donors) BMT for a variety of hematologic diseases. Most candidate gene studies performed genotyping on both donors and recipients, and SNPs were tested either independently for donor or recipient genomes, or considering the total number of variant alleles the recipient-donor pair had at a given locus (0-4) (Table 1).The 16 SNPs from the previous candidate gene association studies were not significantly associated at a nominal P<0.05 to either the survival outcome reported in the original published paper, or to any survival outcome (Table 1). Likewise, the VEGAS2 gene-based analysis did not reveal any statistically significant associations for any of the 8 genes at P<0.05. Our study also corroborated prior reports of SNPs and genes that were not associated with survival outcomes.Candidate gene association studies use a priori biological knowledge to select genes that are likely associated with outcome and subsequently SNPs within the gene thought likely to affect function based on knowledge at the time of the investigation. Our findings suggest that neither the genetic variation tested in these candidate genes, nor other individual SNPs in the gene independently or collectively are not associated with survival outcomes in recipients of URD BMT. Our failure to replicate the prior candidate gene studies may be due to these SNPs being dependent on the underlying disease (ie. AML, ALL, etc), the donor relation (related, unrelated, autologous), or that there is no true association of these SNPs with the outcomes studied.#These authors contributed equally [Display omitted] DisclosuresMcCarthy:Gamida Cell: 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; Karyopharm: 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; Janssen: 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; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hahn:Novartis: Equity Ownership; NIH: Research Funding. Sucheston-Campbell:NIH/NCI: Research Funding.