Marrow Transplant Clinical Trials Network Research Articles

Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and High-Dose Rituximab for Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma: A Phase Two Multicenter Trial from the Blood and Marrow Transplant Clinical Trials Network

Allogeneic (allo) hematopoietic cell transplantation (HCT) can induce long-term remissions in chemosensitive relapsed follicular lymphoma (FL). The Blood and Marrow Transplant Clinical Trials Network conducted a multicenter phase 2 trial to examine the efficacy of alloHCT using reduced-intensity conditioning with rituximab (RTX) in multiply relapsed, chemosensitive FL. The primary endpoint was 2-year progression-free survival (PFS). The conditioning regimen consisted of fludarabine, cyclophosphamide, and high-dose RTX (FCR), in which 3 of the 4 doses of RTX were administered at a dose of 1 gm/m2. Graft-versus-host disease (GVHD) prophylaxis was with tacrolimus and methotrexate. Sixty-five patients were enrolled and 62 were evaluable. Median age was 55 years (range, 29 to 74). This group was heavily pretreated: 77% had received ≥ 3 prior regimens, 32% had received ≥ 5 prior regimens, and 11% had received prior autologous HCT. Donors were HLA-matched siblings (n = 33) or HLA-matched unrelated adults (n = 29). No graft failures occurred. The overall response rate after HCT was 94% with 90% in complete remission (CR), including 24 patients not in CR before alloHCT. With a median follow-up of 47 months (range, 30 to 73), 3-year PFS and overall survival rates were 71% (95% confidence interval, 58% to 81%) and 82% (95% confidence interval, 70% to 90%), respectively. Three-year cumulative incidences of relapse/progression and nonrelapse mortality were 13% and 16%, respectively. Two-year cumulative incidences of grades 2 to 4 and grades 3 or 4 acute GVHD were 27% and 10%, respectively, and extensive chronic GVHD incidence was 55%. Serum RTX concentrations peaked at day +28 and remained detectable as late as 1 year in 59% of patients with available data. In conclusion, alloHCT with FCR conditioning confers high CR rates, a low incidence of relapse/progression, and excellent survival probabilities in heavily pretreated FL patients.

Recovery of Unrelated Donors of Peripheral Blood Stem Cells versus Recovery of Unrelated Donors of Bone Marrow: A Prespecified Analysis from the Phase III Blood and Marrow Transplant Clinical Trials Network Protocol 0201

We report a comparison of time to recovery, side effects, and change in blood counts from baseline to after donation from unrelated donors who participated in the Blood and Marrow Transplant Clinical Trials Network phase III randomized, multicenter trial (0201) in which donor-recipient pairs were randomized to either peripheral blood stem cell (PBSC) or bone marrow (BM) donation. Of the entire cohort, 262 donated PBSC and 264 donated BM; 372 (71%) donors were from domestic and 154 (29%) were from international centers (145 German and 9 Canadian). PBSC donors recovered in less time, with a median time to recovery of 1 week compared with 2.3 weeks for BM donors. The number of donors reporting full recovery was significantly greater for donors of PBSC than of BM at 1, 2, and 3 weeks and 3 months after donation. Multivariate analysis showed that PBSC donors were more likely to recover at any time after donation compared with BM donors (hazard ratio, 2.08; 95% confidence interval [CI], 1.73 to 2.50; P < .001). Other characteristics that significantly increased the likelihood of complete recovery were being an international donor and donation in more recent years. Donors of BM were more likely to report grades 2 to 4 skeletal pain, body symptoms, and fatigue at 1 week after donation. In logistic regression analysis of domestic donors only in which toxicities at peri-collection time points (day 5 filgrastim for PBSC donors and day 2 after collection of BM donors) could be analyzed, no variable was significantly associated with grades 2 to 4 skeletal pain, including product donated (BM versus PBSC; odds ratio, 1.13; 95% CI, .74 to 1.74; P = .556). Blood counts were affected by product donated, with greater mean change from baseline to after donation for white blood cells, neutrophils, mononuclear cells, and platelets in PBSC donors whereas BM donors experienced a greater mean change in hemoglobin. This analysis provided an enhanced understanding of donor events as product donated was independent of physician bias or donor preference.

Prednisone (PDN)/Sirolimus (SRL) Compared to PDN/SRL/Calcineurin Inhibitor (CNI) as Treatment for Chronic Graft-Versus-Host-Disease (cGVHD): A Randomized Phase II Study from the Blood and Marrow Transplant Clinical Trials Network

Prednisone (PDN)/Sirolimus (SRL) Compared to PDN/SRL/Calcineurin Inhibitor (CNI) as Treatment for Chronic Graft-Versus-Host-Disease (cGVHD): A Randomized Phase II Study from the Blood and Marrow Transplant Clinical Trials Network

Angiogenic Factors, Inflammation, and Outcomes in Myeloablative Allogeneic Hematopoietic Cell Transplantation: A Biomarker Analysis of Gvhd Prophylaxis in Blood and Marrow Transplant Clinical Trials Network Protocol (BMT CTN) 0402

Angiogenic Factors, Inflammation, and Outcomes in Myeloablative Allogeneic Hematopoietic Cell Transplantation: A Biomarker Analysis of Gvhd Prophylaxis in Blood and Marrow Transplant Clinical Trials Network Protocol (BMT CTN) 0402

Results of the Blood and Marrow Transplant Clinical Trials Network Study BMT CTN 0601: Scurt - a Multicenter Phase II Trial of Unrelated Donor Reduced Intensity Bone Marrow Transplantation (BMT) for Children with Severe Sickle Cell Disease

Results of the Blood and Marrow Transplant Clinical Trials Network Study BMT CTN 0601: Scurt - a Multicenter Phase II Trial of Unrelated Donor Reduced Intensity Bone Marrow Transplantation (BMT) for Children with Severe Sickle Cell Disease

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

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

Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and High-Dose Rituximab for Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma: A Phase Two Multicenter Trial from the Blood and Marrow Transplant Clinical Trials Network

Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and High-Dose Rituximab for Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma: A Phase Two Multicenter Trial from the Blood and Marrow Transplant Clinical Trials Network

A Multicenter Phase II Trial of Unrelated Donor Reduced Intensity Bone Marrow Transplantation for Children with Severe Sickle Cell Disease (SCURT): Results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0601) Study

▪Background:Children with severe sickle cell disease (SCD) experience organ damage, poor quality of life, and a risk of premature mortality. Allogeneic bone marrow transplantation (BMT) halts disease progression when stable donor erythropoiesis is established. Myeloablative conditioning (MAC) followed by HLA matched sibling donor BMT is effective, but most patients with SCD lack a matched sibling donor and long term side effects from MAC (e.g., infertility) can be barriers to patient acceptance of BMT. The SCURT trial was designed as a prospective, multicenter phase II trial to evaluate outcomes after HLA matched unrelated donor (MUD) BMT with reduced intensity conditioning (RIC). We hypothesized that an intensely immunosuppressive RIC regimen would be sufficient for donor engraftment and could limit toxicity. The primary endpoint was one year event free survival (EFS) (alive and disease free) ≥75%. All patients were evaluable for the primary endpoint for the purpose of this report.Methods:Children between 3 and 19.75 years of age who had ≥1of the following complications - stroke, high transcranial doppler velocity, recurrent acute chest syndrome, or significant vaso-occlusive pain crises were eligible. An independent review committee confirmed eligibility. The preparative regimen consisted of alemtuzumab (48 mg) (day-22 to -19), fludarabine (150 mg/m2) (day-8 to -4), and melphalan (140mg/m2) (day-3). Donors and recipients were matched at the HLA allele-level at HLA-A, -B, -C and -DRB1 loci. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus or cyclosporine, methotrexate (7.5 mg/m2)on days +1, +3 and +6, and methylprednisolone (1 mg/kg/day) from day +7, tapered after day +28.Results:Thirty patients were enrolled between 2008 and 2014. One patient was excluded from analysis for a major eligibility violation at the DSMB's recommendation. Twenty-nine patients (16 M, 13F), 5.9-19.3 years old (median 14.0 years) from 19 centers were evaluable with median follow up of 25.2 months (range, 12-61.5 months). All patients recovered neutrophils (median 12 days) and platelets >50x109/L (median 24 days). Graft rejection (GR) in 3 patients (10%) occurred before day +100, and was followed by autologous hematopoietic recovery. No late GR has been observed. The primary endpoint was met with1-year EFS of 76% (Figure 1A). The 1-year probability of overall survival (OS) was 86% (Figure 1B). The cumulative incidence (CINC) of grade II-IV and III-IV acute GVHD at day 180 were 31% and 17% respectively (Figure 2A). The CINC of chronic GVHD at 1-year was 62%. Chronic GVHD was extensive in 38% (Figure 2B). GVHD when present was noted by 12 months post-BMT. There were 7 deaths, all in patients >14 years at time of BMT. One death occurred after a second transplant for graft rejection. The other 6 deaths occurred between 143 and 960 days post BMT, from GVHD. Non-fatal toxicities included posterior reversible encephalopathy syndrome (PRES) associated with hypertension and seizures in 35%. All cases were observed in the first 6 months post-BMT; all patients recovered with no obvious sequelae. No patient developed veno-occlusive disease, idiopathic pneumonia syndrome or cerebral hemorrhage. Infections were common, and occurred in 76% of patients. CMV and EBV reactivation each occurred in 23% of recipients. Surviving patients report performance scores of 100% (n=14), 90% (n=5), and 80% (n=3) at 2 years or at the time of last assessment. At last follow up, 13 patients had successfully discontinued immunosuppressive therapy.Conclusion:In summary, the RIC regimen employed in this trial of MUD BMT in children with severe SCD resulted in low rates of regimen-related organ toxicity (other than a high rate of PRES) and 1-year EFS of 76%, associated with regression of SCD manifestations. . The risk of graft rejection/disease recurrence was similar to that observed after conventional HLA-identical sibling donor BMT. Chronic GVHD occurred in 62% of patients and was the leading cause of toxicity and mortality. Future trials should focus on effective GVHD prophylaxis after URD BMT. Secondary outcome analyses including health-related quality of life and neurocognitive performance are ongoing. [Display omitted] [Display omitted] DisclosuresWalters:ViaCord and AllCells, Inc: Other: Medical director. Levine:Novartis: Consultancy.

Results of a Phase III Randomized, Multi-Center Study of Allogeneic Stem Cell Transplantation after High Versus Reduced Intensity Conditioning in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901

Although reduced intensity conditioning (RIC) has a lower toxicity profile and lower treatment related mortality (TRM), retrospective analyses have shown higher relapse rates and similar overall survival (OS) when compared to myeloablative (MAC) regimens in patients with myeloid malignancies. The BMT CTN performed a phase III randomized trial to compare outcomes by conditioning intensity in patients with MDS (N=54) or AML (N=218) (18-65 years, HCT-specific comorbidity index score ≤ 4) who had < 5% marrow myeloblasts by morphology at time of pre-transplant assessment. The primary endpoint of the study was 18 month post-randomization overall survival (OS). Secondary endpoints included: relapse free survival (RFS), relapse rates, TRM, graft-versus-host disease (GVHD), and quality of life (QOL). The RIC regimens were fludarabine (120-180 mg/m2) with busulfan (≤ 8 mg/kg oral or IV equivalent) (Flu/Bu, N=110) or melphalan (< 150 mg/m2) (FM, N=27). The MAC regimens were busulfan (16 mg/kg oral or 12.8 mg/kg IV) with cyclophosphamide (120 mg/kg) (Bu/Cy, N=40); or fludarabine (120-180 mg/m2) (Bu/Flu, N=87); or, cyclophosphamide (120 mg/kg) and total body irradiation (1200-1420cGy) (CyTBI, N=8). The planned enrollment was 356 patients; however, accrual was stopped early due to a presumed benefit of MAC as assessed by an independent DSMB safety review. Among 272 patients enrolled, 135 received MAC and 137 received RIC regimens. Seven enrolled patients did not receive a transplant (RIC N=4, MAC N=3) mainly due to relapse. Most (80.3%) patients randomized to RIC received a busulfan-based regimen. At 18 months, OS for patients on the RIC arm was 67.7% (95%CI 59.1-74.8%) versus 77.4% (95%CI 69.3-83.6%) on the MAC arm, based on intention-to-treat analysis. Although survival was higher with MAC, the difference was not statistically significant (difference of 9.7%, 95% CI -0.9-20.3%, p=0.07). Grade II-IV acute GVHD through 100 days was 31.6% on the RIC arm versus 44.7% on the MAC arm, p=0.024. TRM on the RIC arm was 4.4% (95%CI 1.8-8.9%) versus 15.8% (95%CI 10.2-22.6%) on the MAC arm, p=0.02. Relapse on the RIC arm was 48.3% (95%CI 39.6-56.4%) versus 13.5% (95%CI 8.3-19.9%) on the MAC arm, p<0.01. RFS for patients on the RIC arm was 47.3% (95%CI 38.7-55.4%) versus 67.7% (95%CI 59.0-74.9%) on the MAC arm and the difference was statistically significant (difference of 20.4%, 95%CI 8.8-31.9%, p<0.01). Among patients randomized to RIC, 44 died; relapse was the primary cause of death (86.4%). Among patients randomized to MAC, 31 died; GVHD was the primary cause of death (51.6%) followed by relapse (32.2%). QOL was assessed as a secondary endpoint in this trial using FACT and SF36 tools. Better QOL was observed at day 100 and one year with RIC, particularly regarding physical components with fewer differences in mental and social components.This trial confirms that RIC results in higher relapse rates and lower TRM compared to MAC, with a statistically significant advantage in RFS for patients receiving MAC. The appropriate choice of conditioning intensity remains challenging with a necessity to balance the risk of relapse with TRM in individual patients; however the data from this trial support MAC as the standard of care for patients able to receive it. For patients who are not candidates for MAC, novel regimens, which incorporate enhanced anti-leukemia activity without increasing toxicity, are needed. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Patient‐reported physical functioning predicts the success of hematopoietic cell transplantation (BMT CTN 0902)

In hematopoietic cell transplantation (HCT), current risk adjustment strategies are based on clinical and disease-related variables. Although patient-reported outcomes (PROs) predict mortality in multiple cancers, they have been less well studied within HCT. Improvements in risk adjustment strategies in HCT would inform patient selection, patient counseling, and quality reporting. The objective of the current study was to determine whether pre-HCT PROs, in particular physical health, predict survival among patients undergoing autologous or allogeneic transplantation. In this secondary analysis, the authors studied pre-HCT PROs that were reported by 336 allogeneic and 310 autologous HCT recipients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902 protocol, a study with broad representation of patients who underwent transplantation in the United States. Among allogeneic HCT recipients, the pre-HCT Medical Outcomes Study Short Form-36 Health Survey (SF-36) physical component summary (PCS) scale independently predicted overall mortality (hazards ratio, 1.40 per 10-point decrease; P<.001) and performed at least as well as currently used, non-PRO risk indices. Survival probability estimates at 1 year for the first, second, third, and fourth quartiles of the baseline PCS were 50%, 65%, 75%, and 83%, respectively. Early post-HCT decreases in PCS were associated with higher overall and treatment-related mortality. When adjusted for patient variables included in the US Stem Cell Therapeutic Outcomes Database model for transplant center-specific reporting, the SF-36 PCS retained independent prognostic value. PROs have the potential to improve prognostication in HCT. The authors recommend the routine collection of PROs before HCT, and consideration of the incorporation of PROs into risk adjustment for quality reporting.

Infections after Transplantation of Bone Marrow or Peripheral Blood Stem Cells from Unrelated Donors.

Infection is a major complication of hematopoietic cell transplantation. Prolonged neutropenia and graft-versus-host disease are the 2 major complications with an associated risk for infection, and these complications differ according to the graft source. A phase 3, multicenter, randomized trial (Blood and Marrow Transplant Clinical Trials Network [BMT CTN] 0201) of transplantation of bone marrow (BM) versus peripheral blood stem cells (PBSC) from unrelated donors showed no significant differences in 2-year survival between these graft sources. In an effort to provide data regarding whether BM or PBSC could be used as a preferential graft source for transplantation, we report a detailed analysis of the infectious complications for 2years after transplantation from the BMT CTN 0201 trial. A total of 499 patients in this study had full audits of infection data. A total of 1347 infection episodes of moderate or greater severity were documented in 384 (77%) patients; 201 of 249 (81%) of the evaluable patients had received a BM graft and 183 of 250 (73%) had received a PBSC graft. Of 1347 infection episodes, 373 were severe and 123 were life-threatening and/or fatal; 710 (53%) of these episodes occurred on the BM arm and 637 (47%) on the PBSC arm, resulting in a 2-year cumulative incidence 84.7% (95% confidence interval [CI], 79.6 to 89.8) for BM versus 79.7% (95% CI, 73.9 to 85.5) for PBSC, P=.013. The majority of these episodes, 810 (60%), were due to bacteria, with a 2-year cumulative incidence of 72.1% and 62.9% in BM versus PBSC recipients, respectively (P= .003). The cumulative incidence of bloodstream bacterial infections during the first 100days was 44.8% (95% CI, 38.5 to 51.1) for BM versus 35.0% (95% CI, 28.9 to 41.1) for PBSC (P= .027). The total infection density (number of infection events/100 patient days at risk) was .67 for BM and .60 for PBSC. The overall infection density for bacterial infections was .4 in both arms; for viral infections, it was .2in both arms; and for fungal/parasitic infections, it was .04 and .05 for BM and PBSC, respectively. The cumulative incidence of infection before engraftment was 47.9% (95% CI, 41.5 to 53.9) for BM versus 32.8% (95% CI, 27.1 to 38.7) for PBSC (P= .002), possibly related to quicker neutrophil engraftment using PBSC.Infections remain frequent after unrelated donor hematopoietic cell transplantation, particularly after BM grafts.

Making strides and meeting challenges in pediatric allogeneic hematopoietic cell transplantation clinical trials in the United States: Past, present and future

Over the past 20years, the field of pediatric allogeneic hematopoietic cell transplantation has made ground-breaking strides in the successful treatment of patients with both malignant and non-malignant diseases. As the field advances, so does the need for high-quality studies including randomized controlled trials, aimed at answering clinically important questions about optimizing care and outcomes of children undergoing alloHCT. In an effort to actively address emerging clinical questions, three main cooperative groups in the U.S. have joined forces to develop and implement multiple clinical trials for pediatric alloHCT patients. These groups include the Blood and Marrow Transplant Clinical Trials Network, the Children's Oncology Group and the Pediatric Blood and Marrow Transplant Consortium. Though the field of stem cell transplantation continues to advance, conducting clinical trials in the pediatric population is a unique challenge and as a result, optimal outcomes have yet to be reached in this population. Because of the limited number of pediatric transplant patients at each institution in the U.S., trials aimed at answering important clinical questions still struggle to accrue acceptable numbers of patients in an appropriate amount of time and thus gathering statistically useful data has posed a challenge for the field. In an effort to mitigate some of the challenges associated with obtaining statistically and clinically meaningful information about pediatric alloHCT, the implementation of new cooperative group trials is active and ongoing.

Comparison of Characteristics and Outcomes of Trial Participants and Nonparticipants: Example of Blood and Marrow Transplant Clinical Trials Network 0201 Trial

Controversy surrounds the question of whether clinical trial participants have better outcomes than comparable patients who are not treated on a trial. We explored this question using a recent large, randomized, multicenter study comparing peripheral blood (PB) with bone marrow transplantation from unrelated donors, conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). We compared characteristics and outcomes of study participants (n = 494) and nonparticipants (n = 1384) who appeared eligible and received similar treatment without enrolling on the BMT CTN trial at participating centers during the study time period. Data were obtained from the Center for International Blood and Marrow Transplant Research. Outcomes were compared between the 2 groups using Cox proportional hazards regression models. No significant differences in age, sex, disease distribution, race/ethnicity, HLA matching, comorbidities, and interval from diagnosis to hematopoietic cell transplantation were seen between the participants and nonparticipants. Nonparticipants were more likely to have lower performance status, lower risk disease, and older donors, and to receive myeloablative conditioning and antithymocyte globulin. Nonparticipants were also more likely to receive PB grafts, the intervention tested in the trial (66% versus 50%, P < .001). Overall survival, transplantation-related mortality, and incidences of acute or chronic graft-versus-host disease were comparable between the 2 groups though relapse was higher (hazard ratio, 1.22; 95% confidence interval, 1.02 to 1.46; P = .028) in nonparticipants. Despite differences in certain baseline characteristics, survival was comparable between study participants and nonparticipants. The results of the BMT CTN trial appear generalizable to the population of trial-eligible patients.

Wanted: Prospective Studies of Alternative Donors

Wanted: Prospective Studies of Alternative Donors

Circulating Angiogenic Factors Associated with Response and Survival in Patients with Acute Graft-versus-Host Disease: Results from Blood and Marrow Transplant Clinical Trials Network 0302 and 0802

Circulating angiogenic factors (AF) reflect tissue healing capacity, although some AF can also contribute to inflammation and are indicative of endothelial dysfunction. The AF milieu in acute graft-versus-host disease (aGVHD) has not been broadly characterized. We hypothesized that patients with abundant AF involved in repair/regeneration versus those mediating damage/inflammation would have improved outcomes. Circulating AF known predominantly for repair/regeneration (epidermal growth factor [EGF], fibroblast growth factor-1 and -2, heparin binding–EGF–like growth factor, and vascular endothelial growth factor-A [VEGF-A], -C, and -D) and for damage/inflammation (angiopoietin-2, endothelin-1, soluble endoglin [sEng], follistatin [FS], leptin, and placental growth factor [PlGF]) were measured in a discovery set of hematopoietic cell recipients with grade III and IV aGVHD and compared with controls, then validated in 2 aGVHD cohorts enrolled in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials 0302 (n = 105, serum) and 0802 (n = 158, plasma) versus controls without aGVHD (n = 53, serum). Levels of EGF and VEGF-A were lower than in controls at the onset of aGVHD in both trials and higher with complete response to first-line aGVHD therapy in CTN 0802. FS and PlGF were elevated in aGVHD measured in either serum or plasma. At day 28 after initial aGVHD therapy, elevated FS was an independent negative prognostic factor for survival in both cohorts (hazard ratio, 9.3 in CTN 0302; 2.8 in CTN 0802). These data suggest that circulating AF are associated with clinical outcomes after aGVHD and, thus, may contribute to both pathogenesis and recovery.

Comparison of Characteristics and Outcomes of Trial Participants and Nonparticipants: Example of Blood and Marrow Transplant Clinical Trials Network 0201 Trial

Comparison of Characteristics and Outcomes of Trial Participants and Nonparticipants: Example of Blood and Marrow Transplant Clinical Trials Network 0201 Trial

Do Hematopoietic Cell Transplant Patients Treated on a Clinical Trial Do Better? Comparison of Characteristics and Outcomes of Patients Enrolled Versus Not Enrolled on Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) 0201 Trial

Background: The association of clinical trial participation with outcomes in cancer patients is controversial, with some studies reporting better outcomes for trial participants while others do not. It is possible that the difference in outcomes is due to differences in baseline characteristics of participants and non-participants. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0201 trial was a large randomized, multi-center study comparing peripheral blood (PB) with bone marrow (BM) for hematopoietic cell transplantation (HCT) from HLA-matched or 1 allele mismatched unrelated donors (URD) in patients with acute leukemia, chronic myeloid leukemia and myelodysplastic syndromes. The trial reported no significant survival differences between PB and BM; there was decreased risk of graft failure but increased risk of chronic graft-versus-host disease (GVHD) with PB grafts (Anasetti et al NEJM 2012).Methods: We compared characteristics of BMT CTN 0201 study participants (n=494) with HCT recipients who did not participate on the trial (n=1384) but were potentially eligible by virtue of known characteristics. These patients received similar conditioning and GVHD prophylaxis as trial participants at 38 United States trial centers during the study time-period. Centers that had no eligible non-trial participants were excluded. Outcomes between patients on and off trial were compared using Cox proportional hazards regression models. Data were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) that collects patient data on all trial and non-trial allogeneic HCT recipients through its registry function.Results: Approximately 29% [494/1878] of apparently eligible patients were randomized and analyzed as part of the trial. There were no significant differences between study participants and non-participants in age or sex distribution, disease types, HLA or sex matching, comorbidities, or interval from diagnosis to HCT. Higher proportions of non-participants were Hispanic, had a lower performance status and lower disease risk, and received myeloablative conditioning and antithymocyte globulin (ATG) or Campath than the study participants. PB was used more commonly as the graft source in the non-participants as compared to the study participants (65% vs. 50%, p<0.001). In multivariate models, overall mortality (HR 1.09, 95% CI 0.95-1.25, p=0.22), transplant-related mortality (HR 1.08, 95% CI 0.89-1.32, p=0.42) and risks of acute grade II-IV (HR 0.96, 95% CI 0.82-1.12, p=0.57) and chronic GVHD (HR 1.06, 95% CI 0.92-1.23, p=0.41) were comparable between study non-participants and participants. Non-participants were at higher risk for relapse than participants (HR 1.24, 95%CI 1.04-1.49, p=0.02) in the multivariate analysis adjusted for disease risk and other clinical variables. Center effect was examined and was not found to be significant (p=0.10). There was no significant interaction between graft source and trial participation (P=0.22) and the risk of mortality was comparable for BM (HR 0.99, 95% CI 0.80-1.22, p=0.90) and PB recipients (HR 1.17, 95% CI 0.97-1.41, p=0.09) whether on trial or off trial. (Figure)Conclusion: Approximately 29% of patients who appeared eligible and were treated with conditioning and GVHD prophylaxis regimens allowed on the trial were enrolled. Despite some differences in clinical characteristics, most of the outcomes of non-trial participants were comparable to trial participants, suggesting that there is no definitive evidence that the outcomes of patients in a clinical trial are superior to those of the non-participants treated in a similar fashion. The comparable outcomes also indicate that the results of this trial were not seriously affected by selection bias and are therefore representative of the larger population. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Autologous Hematopoietic Stem Cell Transplantation (AHCT) in Patients with Chemotherapy-Sensitive, Relapsed/Refractory (CSRR) Human Immunodeficiency Virus (HIV)-Associated Lymphoma (HAL): Results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0803)/AIDS Malignancy Consortium (AMC-071) Trial

▪Background: HIV infection is associated with increased risk of non-Hodgkin (NHL) and Hodgkin lymphoma (HL). Historically HIV-infected patients had inferior outcomes and increased treatment-related morbidity and mortality over uninfected patients. Highly active antiretroviral therapy (HAART) improved the prognosis for patients with HAL and permitted treatment identical to that in uninfected patients. The role of AHCT in HIV-infected patients, however, remains under investigation. This BMT CTN 0803/ AMC-071 trial, sponsored by the National Heart, Lung and Blood Institute and National Cancer Institute, was designed to prospectively assess overall survival (OS) after AHCT in patients with CSRR HAL.Methods: Patients with treatable HIV-1 infection, age > 15 years, adequate organ function and CSRR aggressive NHL or HL were included. Mobilization and collection followed institutional guidelines. Patients underwent AHCT using the BEAM regimen [carmustine 300 mg/m2 (day -6), etoposide 100 mg/m2 twice daily (days -5 to -2), cytarabine 100 mg/m2 (days -5 to -2), melphalan 140 mg/m2 (day -1)]. Patients received AHCT on day 0 and standard supportive care through discharge. HAART was withheld during the preparative regimen and until therapy-related GI toxicity resolved. The primary trial objective was estimation of one-year OS. Secondary objectives included lymphoma response post-transplant, progression-free survival (PFS), transplant-related mortality (TRM), infection-related complications and recovery of hematological function (RHF) post-AHCT. RHF was defined as ANC > 1500/µl, untransfused hemoglobin > 10 gm/dL and platelet > 200,000/µl. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.Results: Between July 2010 and May 2013, 43 patients were enrolled; 3 progressed prior to AHCT and were excluded from analysis. Forty patients underwent AHCT (5 female, 35 male). Median age was 46.9 years (range, 22.5-62.2). Lymphoma subtypes included diffuse large B-cell lymphoma (40%), plasmablastic lymphoma (5%), Burkitt/Burkitt-like lymphoma (17.5%) and HL (37.5%). All patients received < 2 salvage regimens. Prior to transplant, 30 patients (75%) were in complete remission (CR), 8 (20%) were in partial remission (PR) and 2 (5%) had relapsed/progressive disease (RPD). Pre-HCT HIV viral load (VL) was undetectable in 31 patients (77.5%) and detectable in 9 (22.5%) with a median VL of 84 copies/mL (interquartile range [IQR], 58-234). Median CD4 count was 250.5/µL (range 39-797, IQR 175-307). All 40 patients completed BEAM and underwent HCT. At day 100 post-HCT, 39 patients were assessed for disease response (1 inevaluable due to early death): 36 (92.3%) were in CR, one (2.6%) in PR and two (5.1%) had RPD. By one-year post-HCT, 5 patients died (3 from recurrent/persistent disease, 1 from organ failure [cardiac arrest] and 1 from invasive fungal infection). Cumulative incidence of TRM was 5.2% (95% confidence interval [CI]: 0.9%-15.7%). With a median follow-up of 24 months post-AHCT, estimated probability of one-year OS was 86.6% (95% CI: 70.8%-94.2%) (Figure 1). By one-year, 5 patients relapsed post-HCT, 3 of whom subsequently died. The cumulative incidence of relapse/progression at one-year post-HCT was 12.5% (95% CI: 4.5%-24.8%). Estimated probability of one-year PFS was 82.3% (95% CI: 66.3%-91.1%) (Figure 2). Within one-year of HCT, 13 patients experienced grade 3 and 2 patients grade 4 toxicities (1 patient with mucositis and 1 patient with dyspnea/hypoxia/ cardiac arrhythmia/hypotension). Seventeen patients (42.5%) developed a total of 42 episodes of infection within one-year post-HCT, including 9 with an infection severity grade of severe. Median time to neutrophil engraftment (> 500/µl) was 11 days (range, 9-32).Median time to platelet transfusion-independent engraftment >20,000/µl was 18 days (range, 9-176); 1 patient died prior to platelet recovery. Eleven (28.9%) of 38 evaluable patients and 24 (75%) of 32 evaluable patients achieved RHF by 100 days and 1-year post-HCT, respectively.Discussion: Patients with HAL may successfully undergo AHCT with favorable outcomes. AHCT should be considered the standard of care for patients with relapsed/refractory HAL who meet standard eligibility criteria. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Use of Recombinant Thrombomodulin for Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation Ameliorate Disease Severity

▪Background and Objectives: Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (SCT) is a devastating complication of SCT and lacks optimal managements with a high mortality. Its pathogenesis is not well understood but suggested that endothelial toxicity caused by chemoradiotherapy, infections, immunosuppressive drugs, graft-versus-host-disease (GVHD) and infections have been thought to play important roles. Recently recombinant human soluble thrombomodulin (rTM) was reported to be a safe and efficient treatment of disseminated intravascular coagulation for hematological malignancies. rTM which contains active extracellular domain of thrombomodulin, inactivates coagulation and the thrombin-rTM complexes activates protein C to activated protein C (APC). APC in activates factors Va and VIIIa with protein S, and subsequently lead to further thrombin formation. And, also rTM possesses cytoprotective effects against calcineurin inhibitor induced endothelial cell damage, anti-inflammatory activity such as decrease of high-mobility group box 1 protein, IL-6 and TNF-a. Hence we compared the efficacy of rTM with TMA to other conventional treatments.Patients and Methods: Of 223 patients who had received SCT in our institute from January 2009 to March 2014, 16 patients diagnosed as TMA after allogeneic stem cell transplantation were identified from database. Diagnosis of TMA was based on the Bone Marrow Transplant Clinical Trials Network (BMT-CTN). Patients treated with rTM as a first-line therapy were categorized as rTM group and treated with other therapies as a first-line therapy were as control group.Results: TMA occurrence was total 16 cases (7.2%). rTM group had 9 patients and control group had 7 patients. rTM group had male dominant (M/F 8/1 vs. 1/6) compared to control group. Both group showed similar age, disease distribution (rTM; 2 Leukemia, 5 Lymphoma and 2 ATLL vs. control; 3 Leukemia, 2 CML-BC and 2 ML), disease risk (rTM; 2 standard (1-2 CR or MDS) and 7 high vs. control; 7 high), hematopoietic cell transplantation specific comorbidity index, type of donor source (rTM; 5 related PBSC and 4 unrelated BM vs. control; 4 related PBSC and 3 unrelated BM), HLA compatibility (rTM; 4 haplo-identical donor vs. control; 3 haplo), conditioning regimen (rTM; 8 reduced intensity vs. control; 5 reduced intensity), GVHD prophylaxis (rTM; 5 CyA/Tac and short MTX, 4 Tac/ATGmPSL vs. control; 5 CyA/Tac and short MTX, 2 Tac/ATGmPSL) and year of transplant. Median onset of TMA in rTM group and control group were on day 24.5 (16-274) and day 72 (7-338) (p=0.13) post SCT, respectively. Compared with control group, rTM group revealed significantly superior overall survival after the onset of TMA (Figure1, p=0.043). Seven patients (77.8%) of rTM group recovered from TMA, while no patients recovered in control group. Acute GVHD were occurred in 5 cases of rTM group and in 4 cases of control group (p=0.29). Grade II to IV acute GVHD were occurred in 3 of rTM group and in 4 cases of control groups (Figure 2, P=0.66). Leading causes of death were 4 GVHD of 5 cases in rTM group and 3 TMA of 7 cases in control group. Both group had no lethal hemorrhagic event.Conclusion; The use of rTM in TMA improved overall survival after the onset of TMA in this retrospective small number analysis. rTM reduced TMA mortality but GVHD was still a major cause of death in TMA survivors. Larger prospective studies are warranted to fully evaluate the efficacy of rTM. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Optimized Cyclophosphamide (CY) Dosing in Combination with Fludarabine, TBI and ATG As Conditioning for Unrelated Donor Bone Marrow Transplantation (BMT) in Severe Aplastic Anemia (SAA): A Phase I/II Study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN)

▪Objective: To determine toxicity and efficacy of adding fludarabine (FLU) to a standard preparative regimen of low-dose total body irradiation (TBI), anti-thymocyte globulin (ATG) and CY (Deeg J et al, Blood 108:1485, 2006), with de-escalation of the CY dose.Patients and Methods: Between May 2006 and December 2013, the BMT CTN (sponsored by the NHLBI and NCI) conducted a Phase I/II trial of unrelated donor BMT in SAA (BMT CTN 0301; NCT 00326417). Patients were eligible if they were aged < 65 years, with adequate organ function, and an available unrelated marrow donor matched at 7 or 8 of 8 HLA-A, B, C, and DRB1 loci. The trial accrued 97 patients, although analyses are limited to 96; 1 patient withdrew consent prior to BMT. All patients received TBI 200 cGy (day -1), ATG (either thymoglobulin 3 mg/kg IV or ATGAM 30 mg/kg IV daily x 3, days –4 to –2), FLU (30 mg/m2 IV daily x 4, days –5 to –2). The Phase I portion of the trial tested four CY dose levels: 150 mg/kg (days –4 to –2); 100 mg/kg (days –3 to –2); 50 mg/kg (day –2); and 0 mg/kg. The Phase I design allowed enrollment of up to six patients at each CY dose level unless toxicity or graft failure boundaries were crossed. In the Phase II portion, patients were enrolled onto the optimal CY dose level, using adaptive Bayesian criteria to rank desirability of CY doses based on Day 100 outcomes of engraftment and early death. The primary endpoint of the study was determination of the optimal CY dose based on Day 100 assessments of graft failure (primary: absolute neutrophil count <0.5 x 109/L and secondary: sustained decline in absolute neutrophil count to <0.5 x 109/L), major (grade 3 or higher) regimen-related toxicity (RRT) and early death. Early stopping guidelines were based on a composite endpoint of graft failure and treatment-related mortality through day 100.Results: Twenty-one patients accrued to the Phase I portion of the trial and all CY dose levels were tested. CY dose level 0 mg/kg was closed after 3 of the first 3 patients developed secondary graft failure. The Phase II portion of the trial opened with CY dose level 150 mg/kg. However, this dose level was closed for excess toxicity (7 of 14 patients died; organ failure n=4, ARDS n=2 and infection n=1; Tolar et al, Biol Blood Marrow Transplant, 2012). Patients were subsequently assigned to CY dose level 100 mg/kg (CY DL 100; n=41) or CY dose level 50 mg/kg (CY DL 50; n=38), depending on Bayesian assessment of criteria noted above except that the last 20 patients were preferentially assigned to CY DL 50 to balance accrual to the two dose levels. Approximately half of patients were male and 79% Caucasian. The median age was 20.6 years. The median age for CY DL 50 and DL 100 was 24.5 (0.5-65) and 17.6 (1.9-63) years, respectively. The number of transplants with a mismatched (i.e.7/8) donor was 7 (18%) in the CY DL 50 group and 14 (34%) in the CY DL 100 group. All patients reached their Day 100 endpoint. The cumulative incidence of grade 2-4 acute GVHD was comparable between the two CY dose levels: 24% (DL 50) vs 27% (DL 100). All deaths before Day 100 were due to primary or secondary graft failure (CY DL 50; n=1 and CY DL 100; n=2),. Table 1 shows individual Day 100 outcomes for CY DL 50 and CY DL 100. Median follow up is 15 (3-27) and 24 (12-50) months for CY DL 50 and 100, respectively. All surviving patients on CY dose level 100 mg/kg have achieved a minimum follow up of 12 months, as opposed to only 75% of surviving patients on CY dose level 50 mg/kg.Conclusion: Results of the adaptive Bayesian dose selection suggest that the most desirable CY dose is 50 mg/kg followed by CY dose, 100 mg/kg. However, interpretation of data needs to take into account the potential imbalance of donor-recipient HLA disparity in the CY 50 mg/kg dose level. CY dose 150 mg/kg and 0 mg/kg should be avoided.Table 1Day 100 OutcomeCY DL 50 (n=38)CY DL 100 (n=41)Graft Failure, primary and secondary3 (8%)6 (15%)Survival37 (97%)39 (95%)Major RRT (Grade III or higher)4 (11%)9 (22%) DisclosuresNo relevant conflicts of interest to declare.