Marrow Transplant Clinical Trials Network Research Articles

Umbilical Cord Blood Transplantation in Children with Acute Leukemia: Impact of Conditioning on Transplantation Outcomes

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501) randomized children with hematologic malignancies to transplantation with 1 or 2 cord blood units (UCB) between 2006 and 2012. While the trial concluded that survival was similar regardless of number of units infused, survival was better than previously reported. This prompted a comparison of survival of trial versus nontrial patients to determine the generalizability of trial results and whether survival was better because of the trial treatment regimen. During the trial period, 396 recipients of a single UCB unit met trial eligibility but were not enrolled. Trial patients (n = 100) received total body irradiation (TBI) 1320 cGy, cyclophosphamide 120 mg/kg, and fludarabine 75 mg/m2 (TCF). Nontrial patients either received the same regimen (n = 62; nontrial TCF) or alternative regimens (n = 334; nontrial regimens). Five-year survival between trial and nontrial patients conditioned with TCF was similar (70% versus 62%). However, 5-year survival was significantly lower with nontrial TBI-containing (47%; hazard ratio [HR], 1.97; P = .001) and chemotherapy-only regimens (49%; HR, 1.87; P = .007). The results of BMT CTN 0501 appear generalizable to the population of trial-eligible patients. The survival difference between the trial-specified regimen and other regimens indicate the importance of conditioning regimen for UCB transplantation.

Low EGF in myeloablative allotransplantation: association with severe acute GvHD in BMT CTN 0402.

Epidermal growth factor (EGF) is a recently described biomarker of acute GvHD (aGvHD). Whether low plasma EGF prior to hematopoietic cell transplantation (HCT) predisposes to the development of aGvHD, or whether EGF levels fall because of severe aGvHD, is unknown. To evaluate this, we tested plasma samples collected at pre-HCT baseline, day +28 and day +100 during the course of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402. We found that baseline EGF plasma concentrations were three-fold lower in HCT recipients compared to donors (24.3 vs 76.0 pg/mL, P<0.01). Ninety-one patients (43%) had a markedly low plasma EGF at pre-HCT baseline, defined as <2.7 pg/mL-an optimal cutpoint associated with development of grade III-IV aGvHD. Patients with these low EGF levels at pre-HCT baseline had a 2.9-fold increased risk of grade III-IV aGvHD by day +100. Patients with low EGF at day +28 after HCT had an increased risk of death (relative risk 2.3, P=0.02) by 1 year due to transplant-related toxicities, especially aGvHD. Our results suggest that very low plasma EGF early in the HCT process may predispose patients to an increased risk of death, potentially due to epithelial damage and limited repair capacity.

Allogeneic hematopoietic cell transplant (alloHCT) for hematologic malignancies in human immunodeficiency virus infected (HIV) patients (pts): Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0903)/AIDS Malignancy Consortium (AMC-080) trial.

7006 Background: AlloHCT has been regarded as risky in HIV pts, with concern about fatal infection. We set out to assess feasibility and safety of alloHCT in this first prospective multicenter trial. Methods: The primary endpoint was 100-day non-relapse mortality (NRM). Pts had drug-susceptible HIV; age ≥ 15 yr; adequate organ function; acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL), high risk myelodysplastic syndrome (MDS), or Hodgkin (HL) or non-Hodgkin lymphoma (NHL) beyond first CR; an 8/8 HLA-matched related or at least a 7/8 unrelated donor. Pts received myeloablative (MA) or reduced intensity (RI) regimens. HIV outgrowth assays (VOA) were performed with resting CD4+T-cells in pts who had clinically undetectable HIV plasma RNA at 1 yr. Results: Between 5/2012 and 12/2015, 17 pts underwent alloHCT. Pts were: male (17); white (11), African American (3), Other/Unknown (3); median age 47 yrs (25-64). Associated malignancies were AML (9), ALL (2), MDS (2), HL (1), NHL (3). Median CD4 was 224 (55-833). Conditioning was MA (8) and RI (9). At 100 days there was no NRM, 13 pts were in CR, 4 pts had relapsed/progressive disease; and 8 pts achieved complete chimerism. The cumulative incidence of Grades (Gr) II-IV acute Graft vs Host Disease (GvHD) was 41 % (95%CI: 18 %, 64%). At 6 mo, OS was 82 % (95% confidence interval [CI]: 55%, 94%); 9 pts achieved complete chimerism. At 1 year, OS was 57 % (CI: 31%, 77 %); 8 deaths were from relapsed/progressive disease (5), acute GvHD (1), adult respiratory distress syndrome (1) and liver failure (1). Infections were reported in 11 pts (3 Gr 2, 8 Gr 3). Infectious HIV was detected by VOA in 2 of 3 pts who were mixed chimeras but 0 of 2 who were 100% donor. Median follow up of survivors is 24 mo (7 to 27 ). Conclusions: HIV pts with heme malignancies underwent MA or RI alloHCT without any100-day NRM and there were no infectious deaths at 1 year. AlloHCT should be considered the standard of care for HIV pts who meet usual eligibility criteria. Clinical trial information: NCT01410344.

191 - Development and management of a multi-center, center-specific cellular therapy manufacturing approach: The experience of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol #1401

191 - Development and management of a multi-center, center-specific cellular therapy manufacturing approach: The experience of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol #1401

74 - Follistatin and Endoglin: Potential Biomarkers of Endothelial Damage and Non-Relapse Mortality after Myeloablative Allogeneic Hematopoietic Cell Transplantation in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402

74 - Follistatin and Endoglin: Potential Biomarkers of Endothelial Damage and Non-Relapse Mortality after Myeloablative Allogeneic Hematopoietic Cell Transplantation in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402

54 - Understanding Physicians' Perspectives About Translating Research Into Clinical Practice: Example of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0201 Results

54 - Understanding Physicians' Perspectives About Translating Research Into Clinical Practice: Example of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0201 Results

Pretransplantation Exercise and Hematopoietic Cell Transplantation Survival: A Secondary Analysis of Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0902)

Pretransplantation Exercise and Hematopoietic Cell Transplantation Survival: A Secondary Analysis of Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0902)

Follistatin and Endoglin: Potential Biomarkers of Endothelial Damage and Non-Relapse Mortality after Myeloablative Allogeneic Hematopoietic Cell Transplantation in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402

Introduction:Inflammation and angiogenesis are linked biologic processes influencing the onset and recovery of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT). In aGVHD, angiogenic factors (AF) contributing to tissue healing/repair (e.g. epidermal growth factor [EGF]) versus AF associated with tissue damage/inflammation (e.g. follistatin [FS]) exist in a dysregulated balance. Whether these AF are associated with, or predictive of, non-relapse mortality (NRM) in the absence of aGVHD, is not understood. Given that regimen-related tissue injury plays a role in NRM, we hypothesized that elevated levels of inflammation-associated AF early after HCT would be associated with NRM even in patients without aGVHD.Methods:We studied plasma samples from patients enrolled on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) aGVHD prophylaxis study 0402, a randomized trial of tacrolimus/methotrexate vs tacrolimus/sirolimus after matched sibling peripheral blood stem cell transplantation with myeloablative conditioning. Levels of AF (angiopoietin-2 [Ang2], EGF, FS, vascular endothelial growth factor [VEGF]-A and -B, endoglin [sEng], placental growth factor [PlGF], and soluble VEGF receptor [sVEGFR]-1 and -2) were quantified by MILLIPLEX magnetic bead panels.We analyzed factors associated with NRM in univariate analysis and used multivariate analysis to develop composite AF scores to predict NRM. In calculating the composite scores, we extrapolated the individual probabilities of NRM based upon regression models, and sorted the individual probabilities into 3 composite scores based on: 1) estimated probability of NRM <10%, 2) probability of NRM between 10-19%, 3) probability of NRM >20%.Results:221 patients from BMT CTN 0402 had pre-transplant plasma samples and samples at day +28 available for analysis. Univariate analysis showed associations of raw levels of Ang2, FS, sEng, and sVEGFR1 on day +28 with NRM. Of these, only higher levels of log-transformed FS (p=0.01) and of sEng (p=0.04) showed a correlation with NRM; these two AF were selected for the final model. In multivariate analysis, patients with the highest levels of day +28 FS and sEng (score 3, n=32, Figure) had a 4.6-fold higher relative risk (RR) of NRM (95% confidence interval 1.7-12.3, p<0.01, Table). The prognostic value of the composite score was stronger than either individual factor alone (RR log[FS]=2.1, p=0.03, and RR log[sEng]=2.3, p=0.07). Grade III-IV aGVHD and patient age>50 years were also independently associated with 1-year NRM. There was no effect of patient gender, disease status, CMV serostatus, or type of GVHD prophylaxis (tacrolimus/methotrexate versus tacrolimus/sirolimus) on NRM. There was no significant effect of the composite score, grade III-IV aGVHD, or age on the competing risk of relapse. FS and sEng measured before HCT were not associated with 1-year NRM (p=0.91 and p=0.62, respectively). There was only a weak correlation between the day 0 and day 28 FS and sEng (Spearman’s rho 0.36 and 0.38, respectively). Among the 221 cohort patients, there were 25 deaths due to NRM, including 5 deaths occurring prior to day 56. Death was more likely to be from organ toxicity in patients with composite score 3 (5/9, 56%) vs those with a composite score of 1 (1/8, 12%) or 2 (3/8, 37%).Conclusions:A composite score using day 28 plasma levels of FS and sEng predicts the risk of 1-year NRM after HCT, providing further evidence that endothelial dysfunction is a relevant biological problem in HCT. Pre-HCT measurements of FS and sEng were not associated with NRM, suggesting that elevations in these factors may reflect susceptibility to regimen-related toxicity. We have previously shown that elevated levels of FS and sEng at the onset of aGVHD are associated with poor survival. Here, we show that these factors are predictive of NRM independent of aGVHD. Follistatin modulates inflammatory responses following tissue injury via interaction with the transforming growth factor β superfamily and may reflect endothelial cell damage. sEng is upregulated in proliferating endothelial cells, in inflammation and tissue ischemia, and can influence leukocyte adhesion and endothelial transmigration. Measurement of these predictive AF may highlight prospective opportunities to intervene and prevent subsequent complications thereby limiting NRM after allogeneic HCT. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison of Autologous Hematopoietic Cell Transplant (autoHCT), Bortezomib, Lenalidomide (Len) and Dexamethasone (RVD) Consolidation with Len Maintenance (ACM), Tandem Autohct with Len Maintenance (TAM) and Autohct with Len Maintenance (AM) for up-Front Treatment of Patients with Multiple Myeloma (MM): Primary Results from the Randomized Phase III Trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 -

Background: Len maintenance after autoHCT has improved progression-free (PFS) and overall survival (OS). However, the role of additional interventions after autoHCT such as tandem autoHCT or triple therapy consolidation remains to be determined.Methods: This is a phase III clinical trial (NCT#01109004) of transplant-eligible patients (pts) with symptomatic MM <71 years of age within 12 months of initiating therapy and without prior progression who were randomly assigned 1:1:1 to receive melphalan 200mg/m2 autoHCT and 4 cycles of RVD consolidation (lenalidomide 15mg daily days 1-14, dexamethasone 40mg day 1,8 and 15, and bortezomib 1.3mg/m2 days 1,4,8 and 11 every 21 days) (ACM), versus tandem melphalan 200mg/m2 autoHCT (TAM) or versus a single autoHCT (AM). Randomization was stratified by disease risk (cytogenetic abnormalities - del13q by karyotype, del17q, t(4;14), t(14;16), t(14;20) and hypodyploid; or high beta-2 microglobulin) and center. All arms included Len maintenance (at maximum tolerated dose of 5 to 15 mg orally daily until progression) with dose modifications for toxicities. All patients were reviewed centrally for eligibility, response and progression. The primary objective was to compare 38-month PFS of the three arms. The events for PFS included progression, non-protocol anti-myeloma therapy, or death. Comparisons between treatment groups were based on pairwise log-rank tests stratified on disease risk, with significance levels adjusted for the 3 pairwise comparisons and for interim analyses. In calculating the cumulative incidence of progression, the events were progression or non-protocol anti-myeloma therapy, and death was a competing risk.Results: From June 2010 to November 2013, 758 pts (ACM, N=254; TAM, N=247; AM, N=257) aged 20-70 years (median 57y) were enrolled. Of those enrolled, 24% were classified as high risk. Non-compliance rates following the first autoHCT were 12%, 32% and 5% for ACM, TAM and AM, respectively. Median available follow up from randomization was 38 months. Follow-up is continuing through January 2017. 38-month estimated probabilities for PFS were 57% (95% CI: 50-63%), 56% (95% CI: 49-63%) and 52% (95% CI: 45-59%) for ACM, TAM and AM, respectively (ACM vs TAM p=0.75, ACM vs AM p=0.21, TAM vs AM p=0.37). Corresponding probabilities of OS were 86% (95% CI: 80-90%), 82% (95%CI: 76-87%) and 83% (95% CI: 78-88%). Median OS has not been reached. Cumulative incidences of disease progression at 38 months were 42% (95% CI: 36-48%), 42% (95% CI: 35-48%) and 47% (95% CI: 40-54%) for the ACM, TAM and AM arms, respectively. There were 39 cases of second primary malignancy (SPM) reported in 36 participants and the cumulative incidences for first SPM were 6.0% (95% CI: 3.4-9.6%), 5.9% (95% CI: 3.3-9.6%) and 4.0% (95% CI: 1.9-7.2%) for the ACM, TAM, and AM, respectively.Conclusions: The primary results of the largest randomized US transplant trial in MM demonstrated comparable PFS and OS. The addition of RVD consolidation or a second auto-HCT was not superior to a single auto HCT followed by Len maintenance in the upfront treatment of MM. A long term follow-up trial to track outcomes in these patients is ongoing. DisclosuresStadtmauer:Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy. Pasquini:Atara: Other: travel reimbursement for a meeting; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees. Efebera:Millennium/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria. Ganguly:Onyx: Speakers Bureau; Seattle Genetics: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Giralt:Celgene: Consultancy; Millenium/Takeda: Consultancy. Hari:Celgene: Consultancy; Millennium/Takeda: Consultancy. McCarthy:Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Millennium/Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; The Binding Site: Consultancy, Honoraria. Qazilbash:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Shah:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Membership on an entity's Board of Directors or advisory committees. Vesole:Takeda: Speakers Bureau; Celgene: Speakers Bureau. Vij:Millennium/Takeda: Consultancy; Celgene: Consultancy. Vogl:Celgene: Consultancy; Millennium/Takeda: Consultancy, Research Funding. Somlo:PUMA: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Millennium/Takeda: Speakers Bureau; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Krishnan:Celgene: Consultancy, Speakers Bureau; Millennium/Takeda: Consultancy, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau.

Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation (HCT): A Single Center Analysis of 613 Adult HCT Recipients Using a Modified Composite Endpoint

Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation (HCT): A single Center Analysis of 613 Adult HCT Recipients Using a Modified Composite EndpointIntroductionThe success of allogeneic HCT is based on long term survival, free of relapse or morbidity as commonly encountered when patients develop graft versus host disease (GVHD). The Bone marrow transplant clinical trials network (BMTCTN) recently incorporated a composite endpoint to determine success rate in ongoing clinical trials. The new composite endpoint of GVHD free, relapse free survival (GRFS) includes the factors of acute GVHD grade 3-4, relapse, death and chronic GVHD requiring systemic immunosuppression. As the decision to start patients on immunosuppression for chronic GVHD can be subjective and physician dependent, we elected to assess the success of allogeneic HCT using a more objective endpoint m-GRFS where the clinically significant negative events are acute GVHD grade 3-4, moderate-severe chronic GVHD, disease relapse and Death at 1 and 2-year post HCT.MethodsSix hundreds and thirteen patients who underwent a first allogeneic HCT after a HLA-identical sibling (MRD, n=212), 10/10 matched unrelated donor (MUD, n=251) or T-replete haploidentical donor with post-transplant cyclophosphamide (HIDT, n=150) were included in this analysis. Patient, Disease and Transplant related variables were prospectively documented and obtained from our institutional database. The Kruksall-Wallis test was used to compare continuous variables and the Chi-squared test for categorical variables. OS, DFS and m-GRFS were estimated by the Kaplan-Meier (K-M) method. Log-log transformed confidence intervals for OS, DFS and GRFS were calculated. Comparison of m-GRFS between demographic subgroups and between clinical subgroups were evaluated using the log-rank test for the entire study period and using the Wald test for a select time point. Competing risks analysis was performed to disentangle the components of GRFS. Grade III/IV acute GVHD, mod-severe chronic GVHD, relapse and death were considered as competing risks and cumulative incidences of these endpoints were calculated. Patients were considered to have met the endpoint once any of the components occurred. Cox regression analysis was conducted to examine the impact of donor, demographic and clinical factors on the primary endpoint of modified GRFS. The proportional hazards assumption was checked by temporarily including and testing time-dependent variables and the variables in the final model passed the proportionality test. The adjusted GRFS for one characteristic was calculated as the average survival of the whole sample, assuming that everyone in the sample had this characteristic.ResultsThe median follow-up was 50.2 months. Patients characteristics were as follows: median age 53 years (18-77), male 56%, reduced intensity/non-ablative 49%, AML 37%, ALL 13%, MDS/MPD 24%, bone marrow graft 19%, HCT-comorbidity index >=3 in 39%, and high/very high DRI 34%. The unadjusted Kaplan-Meier estimates for 1- and 2-year m-GRFS were 36% (95%CI 32%-40%) and 28% (95%CI 25%-32%). The 2-year m-GRFS for MRD recipients was 30% (24-36%), MUD 24% (19-30%) and HIDT 33% (26-41%). The most common event at 2 years post HCT was chronic GVHD (39%) followed by relapse (31%), acute GVHD 3-4(20%) and death (10%). After adjusting for age, gender, diagnosis, conditioning intensity, donor type, cell source, HCT-CI, DRI , donor-recipient gender mismatch and year of transplant, the multivariate cox model on m-GRFS showed donor type, DRI risk , donor recipient sex mismatch and year of transplant to be significant predictors of m-GRFS (table 1). Patients who received a MUD had worse GRFS compared to MRD (HR 1.39, p=0.003) whereas HIDT had similar GRFS to MRD (HR 1.10, p=0.43). HIDT had better GRFS than MUD (HR 0.79, p=0.046). The adjusted 1- and 2- year m-GRFS showed donor type (MUD vs MRD), DRI, donor-recipient sex mismatch and transplant year to be associated with worse GRFS (table 2).Conclusionsm-GRFS is a useful measure of transplant success. It appears to be significantly impacted by several modifiable factors including donor type, donor-recipient sex match and also by DRI. Adjusting donor choice and early referral of patients for transplant evaluation to improve DRI can potentially overcome the negative impact of these factors. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Umbilical Cord Blood (UCB) Transplantation in Children with Acute Leukemia: Impact of Conditioning Regimen on Transplant Outcomes

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501; NCT00412360) randomized children with hematologic malignancy to one or two cord blood unit transplantation between December 2006 and February 2012. While the trial concluded that survival was similar regardless of number of units infused, results were generally better than those previously reported after single UCB transplant. The apparently improved survival in recipients of BMT CTN 0501 compared to prior studies in children transplanted with a single UCB unit prompted a comparison of trial versus non-trial treatment outcomes to determine 1) the generalizability of trial results and 2) whether survival was better for patients treated with the trial regimen. Using data reported to the Center for International Blood and Marrow Transplant Research during the trial period, 396 recipients of one UCB unit transplant met the broad eligibility criteria for BMT CTN 0501 (i.e. aged 1- 21 years, high-risk acute leukemia, performance score ≥70). Trial and non-trial patients were comparable in their HCT-CI score. Trial patients (n=100) received total body irradiation (TBI) 1320 cGy, cyclophosphamide 120 mg/kg, and fludarabine 75 mg/m2 (TCF). Non-trial patients either received the same regimen as in the trial (N=62; non-trial TCF) or an alternative regimen (N=334; non-trial non-TCF regimen). Excluded were 13 patients on BMT CTN 0501 randomized to receive a single UCB unit for malignant diseases other than acute leukemia. Patient and disease characteristics of those treated on BMT CTN 0501 and others were similar except that those who received non-trial TCF regimen were more likely to report performance scores of 80 or 70 (24% versus 11%, p=0.04) and transplanted in relapse (18% vs. 5%, p=0.02) and those that received non-TCF regimens were more likely to 1-10 years of age (76% versus 53%, p<0.0001). Sixty-three percent of non-trial non-TCF regimens included TBI (≥1000 cGy) and the predominant non-TBI regimen was busulfan and cyclophosphamide. All patients received a calcineurin inhibitor for graft-versus-host disease (GVHD) prophylaxis. Donor-recipient HLA-match, median infused total nucleated cells and median follow up times were similar across the groups. Three-year survival rates were similar between patients receiving TCF regimen either on (A) or off trial (B), Figure1A, p=0.83. Similarly, there were no differences in hematopoietic recovery, relapse or non-relapse mortality between trial and non-trial TCF. However, compared to TCF on trial (A), overall survival rates were significantly lower with non-TCF non-TBI (C) and TBI (D) containing regimens after adjusting for age, CMV serostatus, disease and disease status; Figure 1B, 68% versus 55% (p=0.001) and 68% versus 50% (p=0.04), respectively. Results of multivariate analysis are shown in Table 1. Compared to patients treated on trial (TCF regimen; 20% at 3-years) relapse rates were higher with non-TCF non-TBI (42%, p=0.003) but not TBI-containing regimens (25%, p=0.38) after adjusting for age, disease, disease status and CMV seropositivity. Among non-TCF patients, relapse risk was higher for non-TBI compared to TBI-containing regimens (hazard ratio [HR] 1.61, p=0.02) but not mortality risk (HR 0.93, p=0.74). Cytogenetic risk features were not associated with relapse or survival. There were no differences in hematopoietic recovery, acute and chronic GVHD. The results of BMT CTN 0501 appear generalizable to the population of trial eligible patients. The survival differences between the trial specified and other conditioning regimens support use of the TCF regimen to improve survival. It also indicates the importance of conditioning regimen for outcome and may serve as a stimulus to design trials to identify the optimal regimen for children with acute leukemia undergoing UCB transplantation. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long-Term Follow up of Patients with HIV-Associated Non-Hodgkin Lymphoma (NHL) after Autologous Stem Cell Transplantation (ASCT)

Background:The Blood and Marrow Transplant Clinical Trials Network 0803 study confirmed the safety and efficacy of ASCT in HIV-infected patients with lymphoma. Short term toxicity and transplant related mortality was low (5.2%) and engraftment, treatment-related mortality and survival outcomes were not statistically significantly different from that of age and diagnosis matched CIBMTR controls. However, median follow up in that trial was 24 months after ASCT, and the questions of second cancer incidence and other infections in a this population remain (Alvarnas et al, ASH 2014). Herein we report the long term outcomes of ASCT in HIV-infected patients.Methods: Retrospective cohort trial of 52 HIV-infected patients who underwent ASCT for high-risk NHL at City of Hope from January 1, 1998 to December 31, 2011. Two patients were excluded from the analysis due to early post-transplant mortality: one patient died at day 22 due to multiorgan failure, and another died at day 72 due to relapsed lymphoma. Fifty patients with a minimum survival of 100-days post ASCT were evaluated for long-term outcomes. Estimation of event-free survival (EFS) and overall survival (OS) was computed using Kaplan-Meier curves and the cumulative incidence of relapse was estimated with competing risk of mortality.Results: Median follow up was 5.43 years (range 0.30-14.96 years). Median age at the time of transplantation was 45 years (range 26-64 years of age). Prior to transplant, 23 patients (46%) were in complete remission and 27 (54%) were in partial remission. Most patients had aggressive NHL, with diffuse large B-cell lymphoma (48%) and Burkitt lymphoma (24%) being most common histologies. Other subtypes included Burkitt-like (10%), plasmablastic (10%), follicular lymphoma (2%), and T-cell lymphomas (6%). Nine patients relapsed (18%), at a median time of 97 days (range 54-253 days) post ASCT. Fifteen patients (30%) died; 8 out of 15 (53%) died due to relapse. Opportunistic infections (OI) occurred in 8 patients (16%) at a median of 0.68 years (range 0.17-10.82 years). Types of OI included CMV retinitis (1), HSV/Zoster (1), HPV (1), Candida esophagitis (1) and PJP (3). One patient died from OI (PJP). Seven patients (14%) developed a second primary malignancy (SPM) at median time to SPM of 5.63 years (range 1.02-14.35 years). Type of SPM included treatment-related myelodysplastic syndrome (t-MDS) with progression to acute myelogenous leukemia (AML) (2) observed at 3.2 years and 12.6 years, respectively, after ASCT; squamous cell carcinoma of the tongue (1), and skin cancers, including melanoma (1) at 14.3 years post ASCT, basal cell carcinoma (2) at 5.5 and 5.6 years post ASCT, and squamous cell carcinoma in situ (1) at 1.0 year post ASCT. Two patients died from the t-MDS.Conclusions: Thirty-five of 50 patients (70%) were alive at the time of analysis confirming the efficacy of this procedure. EFS/OS at 1 year and 5 years post ASCT was 78% (95% CI:67.3%-90.4%)/82% (95% CI: 71.9%-93.4%) and 71.4% (95% CI:59.8%-85.3%)/73.3% (95% CI: 61.8%-86.9%), respectively. Relapse of NHL tended to occur early post-transplant. Cumulative incidence of relapse was 18% at 1 year post ASCT (95% CI: 8.8%-29.8%). Development of OI was also seen early post-ASCT. While SPM appeared as late as 14.35 years following ASCT, it was no higher than that seen in the non-HIV ASCT setting. This is the largest single institution study reporting long-term follow up of HIV-positive patients post ASCT for NHL and demonstrating that while SPM remain a long term concern neither SPM, OI or HIV infection were major factors in mortality. DisclosuresNo relevant conflicts of interest to declare.

A trial of unrelated donor marrow transplantation for children with severe sickle cell disease

AbstractChildren with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n = 12), transcranial Doppler velocity >200 cm/s (n = 2), ≥3 vaso-occlusive pain crises per year (n = 12), or ≥2 acute chest syndrome episodes (n = 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1- and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of ≥75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. The BMT CTN #0601 trial was registered at www.clinicaltrials.gov as #NCT00745420.

Pretransplantation Exercise and Hematopoietic Cell Transplantation Survival: A Secondary Analysis of Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0902)

Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0902 evaluated whether exercise and stress management training before hematopoietic cell transplantation (HCT) improved physical and mental functioning after HCT. Neither overall survival nor other patient-reported transplantation outcomes were improved by the training intervention. In some animal studies of HCT, moderate-intensity exercise for 8 weeks before HCT has been associated with positive effects on hematopoietic progenitors, resulting in improved donor engraftment and improved survival. Accordingly, we performed a secondary analysis of data from BMT CTN 0902 to determine whether exercise engagement before HCT was associated with engraftment and survival. We found no significant associations between self-reported pre-HCT exercise levels and engraftment or survival. There was also no effect of pretransplantation exercise on either neutrophil or platelet engraftment. These findings do not support the observations in animal models but are limited by several shortcomings that do not refute the hypothesis that exercise before HCT may be beneficial.

OR43 Frequency of HLA DPA1 and DPB1 mismatching in a population of 1199 pairs of presumed HLA identical sibling transplant pairs

Aim The ideal graft source for allogeneic hematopoietic stem cell transplantation (HCT) is an HLA-identical matched sibling (MSD). The Blood and Marrow Transplant Clinical Trials Network recommends that family donors be HLA-A and -B typed at intermediate or higher resolution and HLA-DRB1 typed at high resolution by DNA-based methods as a minimum requirement. Where possible, familial haplotypes should be assigned to establish presumptive high-resolution match identity between the donor and recipient (additionally HLA-C and DQB1 may be considered). Extended typing at additional HLA loci including DPB1 is not commonly performed. Results from unrelated donor HCT studies suggest that mismatches at HLA-DPB1 increase the risk of acute graft versus host disease. Due to the genetic distance from the other classical loci crossover events may lead to mismatching at DPB1 in the MSD setting and therefore may ultimately play a role in transplant outcomes. Methods A cohort of 1199 presumed MSD pairs, from 55 centers, collected by the CIBMTR Research Repository from 2007 to 2015 were analyzed. All pairs were reported to the CIBMTR as HLA identical siblings and received a transplant for either AML (44%), ALL (24%), MDS (26%) and 6% other diseases. The median patient age was 52, 59% were male, 86% received PBSC and 14% BM. To determine the crossover frequency the subjects were typed by targeted exon NGS of exons 2 and 3 for both Class I and Class II yielding G group or better results, at HLA-A, B, C, DRB1, DRB3/4/5, DQA1, DQB1, DPA1 and DPB1. Results The majority (97.25%) of MSD pairs were identical at all loci tested. A small subset (2.75%) of the pairs contained a mismatch impacting either DPA1, DPB1 or both. The majority of the 33 mismatches, 26 (78.79%) were DPB1, 6 (18.18%) included both DPA1 and DPB1 and 1 (3.03%) only DPA1. Analysis of the T-cell-epitope groups found that 28% of the DPB1 mismatches were not permissive. All were presumed crossover events, but family typing was not available to confirm. Six (18%) of the DPB1 mismatches included a homozygous recipient with a heterozygous donor suggesting a potential loss of heterozygosity. Conclusion The mismatch frequency at the DP loci in MSD pairs was relatively low at 2.75% and 28% were not TCE permissive. The impact of DP mismatching on MSD HCT outcomes are unclear and warrant further study.

Autologous hematopoietic cell transplantation for HIV-related lymphoma: results of the BMT CTN 0803/AMC 071 trial

AbstractAutologous hematopoietic cell transplant (AHCT) for HIV-infected patients is largely limited to centers with HIV-specific expertise. The Blood and Marrow Transplant Clinical Trials Network 0803/AIDS Malignancy Consortium 071 trial is a multicenter phase 2 study of AHCT for patients with HIV-related lymphoma (HRL). Eligible patients had chemotherapy-sensitive relapsed/persistent HRL, were >15 years of age, and had treatable HIV infection. Patients were prepared using carmustine, etoposide, cytarabine, and melphalan and received consistent management of peritransplant antiretroviral treatment. The primary endpoint was 1-year overall survival. Forty-three patients were enrolled; 40 underwent AHCT. Pretransplant HIV viral load was undetectable (<50 copies/mL) in 32 patients (80%); the median CD4 count was 249/μL (range, 39-797). At a median follow-up of 24.8 months, 1-year and 2-year overall survival probabilities were 87.3% (95% confidence interval [CI], 72.1-94.5) and 82% (95% CI, 65.9-91), respectively. The probability of 2-year progression-free survival was 79.8% (95% CI, 63.7-89.4). One-year transplant-related mortality was 5.2%. Median time to neutrophil and platelet recovery was 11 days and 18 days, respectively. Nine patients experienced a total of 13 unexpected grade 3-5 adverse events posttransplant (10 grade 3 and 3 grade 4 events). Twenty-two patients had at least 1 infectious episode posttransplant. At 1 year post-AHCT, median CD4+ T-cell count was 280.3 (range, 28.8-1148.0); 82.6% had an undetectable HIV viral load. Trial patients were compared with 151 matched Center for International Bone Marrow Transplant Research controls. Outcomes between HIV-infected patients and controls were not statistically significantly different. HRL patients should be considered candidates for AHCT if they meet standard transplant criteria. The trial was registered at www.clinicaltrials.gov as #NCT01141712.

Patient-Reported Outcomes and Socioeconomic Status as Predictors of Clinical Outcomes after Hematopoietic Stem Cell Transplantation: A Study from the Blood and Marrow Transplant Clinical Trials Network 0902 Trial

This secondary analysis of a large, multicenter Blood and Marrow Transplant Clinical Trials Network randomized trial assessed whether patient-reported outcomes (PROs) and socioeconomic status (SES) before hematopoietic stem cell transplantation (HCT) are associated with each other and predictive of clinical outcomes, including time to hematopoietic recovery, acute graft-versus-host disease, hospitalization days, and overall survival (OS) among 646 allogeneic and autologous HCT recipients. Pretransplantation Cancer and Treatment Distress (CTXD), Pittsburgh Sleep Quality Index (PSQI), and mental and physical component scores of the Short-Form 36 were correlated with each other and with SES variables. PROs and SES variables were further evaluated as predictors of clinical outcomes, with the PSQI and CTXD evaluated as OS predictors (P < .01 considered significant given multiple testing). Lower attained education was associated with increased distress (P = .002), lower income was related to worse physical functioning (P = .005) and increased distress (P = .008), lack of employment before transplantation was associated with worse physical functioning (P < .01), and unmarried status was associated with worse sleep (P = .003). In this large heterogeneous cohort of HCT recipients, although PROs and SES variables were correlated at baseline, they were not associated with any clinical outcomes. Future research should focus on HCT recipients at greater psychosocial disadvantage.

Trajectories of Quality of Life after Hematopoietic Cell Transplantation: Secondary Analysis of Blood and Marrow Transplant Clinical Trials Network 0902 Data

Quality of life is increasingly recognized as an important secondary endpoint of hematopoietic cell transplantation (HCT). The current study examined the extent to which attrition results in biased estimates of patient quality of life. The study also examined whether patients differ in terms of trajectories of quality of life in the first 6 months after transplantation. A secondary data analysis was conducted of 701 participants who enrolled in the Blood and Marrow Transplantation Clinical Trials Network 0902 trial. Participants completed the Medical Outcomes Study Short Form 36, a measure of quality of life, before undergoing transplantation and again 100 days and 180 days after transplantation. Results indicated that attrition resulted in slightly biased overestimates of quality of life but the amount of overestimation remained stable over time. Patients could be grouped into 3 distinct classes based on physical quality of life: (1) low and stable; (2) average and declining, then stable; and (3) average and stable. Four classes of patients emerged for mental quality of life: (1) low and stable; (2) average, improving, then stable; (3) higher than average (by almost 1 SD) and stable; and (4) average and stable. Taken together, these data provide a more comprehensive understanding of quality of life that can be used to educate HCT recipients and their caregivers.

Practice Patterns and Preferences Among Hematopoietic Cell Transplantation Clinicians

Hematopoietic cell transplantation can cure many high-risk diseases but is associated with complexity, cost, and risk. Several areas in transplantation practice were identified in the 2014 Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium (BMT CTN SOSS) as high priorities for further study. We developed a survey for hematopoietic cell transplantation clinicians to identify current practices in BMT CTN SOSS priority areas and to understand, more generally, the variation in approach to transplantation and estimation of transplantation benefit in current medical practice. Of 1439 transplantation clinicians surveyed, 305 responded (20% response rate). Clinicians were well represented by age, experience, geography, and size of practice. We found that several techniques identified in the BMT CTN SOSS, such as maintenance therapy for acute myeloid leukemia or myelodysplastic syndromes after allogeneic transplantation, were already being utilized in practice on and off study, with higher rates of use in higher-volume centers. There was significant variation among clinicians in use of transplantation technologies and approaches to common transplantation scenarios. Appraisals of risks and benefits of transplantation appeared to converge upon similar estimates despite the presentation of different hypothetical scenarios. These results suggest overall equipoise in several BMT CTN SOSS high-priority areas and support the need for better data to inform clinical practice.

Can we agree on patient-reported outcome measures for assessing hematopoietic cell transplantation patients? A study from the CIBMTR and BMT CTN.

Much research into the impact of hematopoietic cell transplantation (HCT) on recipients' symptoms, functioning and health-related quality of life uses diverse patient-reported outcome (PRO) measures. Robust conclusions regarding PROs in HCT patients are constrained by methodological issues, including the use of multiple different and noncomparable assessment measures. We reviewed 114 publications addressing PROs in HCT patients. Although three multi-item measures were most frequently used (FACT-BMT, n=28; European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30, n=26; and SF-36, n=26), 25 additional measures were used in more than one study. Another 50 measures were used in single studies. Over 50% of studies used more than one measure. We recommend that the field agrees upon a set of measures to address the core domains important to patients, to reduce heterogeneity and allow comparisons across studies and between different populations. Measures should be available in a free and easily accessible manner internationally. We discuss the relative benefits of the National Institutes of Health-supported Patient-Reported Outcomes Measurement Information System (PROMIS) system to achieve these goals. To further address these issues, the Blood and Marrow Transplant Clinical Trials Network has recently created a task force to implement PROMIS measures alongside traditional PRO measures in future clinical trials. Robust comparisons between measures in this setting may allow for the development of a standard for HCT patients.