ALBERT

Description: Background Graft-versus-host disease (GVHD) is a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). Prophylactic in-vivo T-Cell depletion with antithymocyte globulin (ATG) has recently been reported as leading to decreased GVHD rates in matched unrelated and related donor HSCT, without increases in relapse or death. Understanding that higher rates of GVHD are observed with matched unrelated versus matched related donor HSCT, we have always had a local policy to give ATG as part of GVHD prophylaxis in patients undergoing HSCT from an unrelated donor. Here we report and compare clinical outcomes of patients who did and did not receive ATG at our transplant center using a unique, substantially lower ATG dose than previously reported. Methods We conducted a retrospective single-center database study comparing outcomes in 110 matched unrelated donor (MUD; ATG-exposed) and 78 matched related donor (MRD; ATG-unexposed) HSCT patients transplanted for any malignant indication at The Ottawa Hospital from 2009 to 2014. Patients were exposed to a rabbit ATG formulation (Thymoglobulin ®) at 0.5 mg/kg on day -2 and 2.0 mg/kg on day -1 prior to stem cell infusion, to total 2.5 mg/kg. Primary outcomes assessed were incidence of acute and chronic GVHD, defined as new-onset GVHD requiring systemic immunosuppressive therapy at less or more than 100 days post HSCT, respectively. Secondary outcomes included disease relapse and survival. Results At baseline there were no significant differences in median age at transplant, sex, disease indication or risk index, graft source, conditioning regimen and intensity between ATG exposed (MUD) and unexposed (MRD) cohorts. The majority of patients in both cohorts had intermediate or high disease risk index. There were significant baseline differences between the ATG exposed and unexposed cohorts with respect to proportion of 7/8 mismatched unrelated donor transplants (14 v 6% respectively, p = 0.015) and median CD34+ dose (4.9 v 7.6 x 108 cells; p 〈 0.001). No differences were noted in platelet engraftment. ATG exposed patients had significantly shorter time to neutrophil engraftment than the unexposed cohort (16 v 19 days respectively; p=0.007). ATG exposed patients had significantly lower rates of GVHD compared to the unexposed cohort (57 v 79%; p=0.005), with differences noted predominantly in rates of chronic GVHD (18 v 44%, p= 0.009). The proportion of patients off immune suppression one year after HSCT was not significantly different between the cohorts.At median follow-up of 13 (1-73) months for the ATG exposed cohort and 20 (0-69) months for the ATG unexposed cohort, no significant differences in overall survival (median overall survival not met for either cohort), cumulative incidence of relapse (26 v 29%; p=0.73) or relapse-free survival (not met in ATG exposed; 26.2 months in ATG unexposed, p=0.22) were observed between groups (Figure 1). Significant differences were observed with respect to GVHD-Free Relapse-Free Survival (GRFS) between ATG exposed and unexposed cohorts, with a two-year GRFS of 23 v 3% respectively (p = 0.003). There were no significant differences between cohorts in proportion of patients with post HSCT infectious episodes or ICU admissions. Conclusions Here we report significantly lower rates of chronic GVHD and significant improvement in GVHD-free relapse-free survival in our ATG exposed MUD HSCT cohort compared to our ATG unexposed MRD. These findings were observed without differences in relapse or survival outcomes, infectious complications or ICU admissions. While in keeping with other recent reports on ATG use for GVHD prophylaxis, our findings indicate that a lower dose of ATG may be effective in preventing GVHD. Our study suggests that a broader exploration into the optimal dosing of this prophylactic GVHD agent is warranted. Disclosures Bence-Bruckler: Lundbeck: Membership on an entity's Board of Directors or advisory committees. Sabloff:Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Research Funding; Alexion: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding.

Description: In 2001, the Docket Report from the Food and Drug Administration expressed concerns regarding the potential of microbially contaminated hematopoietic stem cell products to produce morbidity and mortality in transplant recipients. This concern was the basis for development of regulatory standards for hematopoietic stem cell products. We surveyed a total of 2972 patients at 121 U.S. transplant centers that registered patients with the CIBMTR in the years 2000 and 2001. Information regarding microbial contamination of infused grafts was obtained from 94 transplant centers (80% response rate) for 2312 patients. 52 (2%) of 2286 infused grafts tested were culture positive for bacterial or fungal organisms. The microbial isolates included: coagulase negative staphylococcus (56%), gram negative organisms (15%), coagulase positive staphylococcus (10%), gram positive rods (10%), streptococcus (8%), and fungus (1%). Prophylactic antibiotics targeted at the contaminant were given to 17 of the 52 recipients of contaminated grafts. Antibiotic regimens included vancomycin alone (76%), aminoglycosides and vancomycin (12%), or cephalosporin and vancomycin (12%). 47 (50%) of the centers that participated have existing policies regarding contaminated products. Patients with non-malignant disorders or who received bone marrow were more likely to have a contaminated graft. No differences in age distribution, sex, race, type of transplant (allogeneic vs autologous) and year of transplant were noted between recipients of contaminated and non-contaminated grafts. The unadjusted 100-day survival of persons receiving contaminated grafts was 86% (95% Confidence Interval [CI] 72–93%) versus 81% (95% CI 80–83%) among those receiving non-contaminated grafts, p=0.35. In summary, about 2% of hematopoietic stem cell products infused for allogeneic or autologous transplantations in U.S. centers will test positive for microbial contamination, but such contamination does not increase posttransplant mortality. The absence of significant 100-day mortality among patients infused with contaminated grafts suggests that stringent regulatory policies regarding the use of contaminated hematopoietic cell products may not be indicated.

Description: 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

Description: We describe outcomes after human leukocyte antigen-matched sibling bone marrow transplantation (BMT) for 179 patients with β-thalassemia major. The median age at transplantation was 7 years and the median follow-up was 6 years. The distribution of Pesaro risk class I, II, and III categories was 2%, 42%, and 36%, respectively. The day 30 cumulative incidence of neutrophil recovery and day 100 platelet recovery were 90% and 86%, respectively. Seventeen patients had graft failure, which was fatal in 11. Six of 9 patients with graft failure are alive after a second transplantation. The day 100 probability of acute graft-versus-host disease and 5-year probability of chronic graft-versus-host disease was 38% and 13%, respectively. The 5-year probabilities of overall- and disease-free survival were 91% and 88%, respectively, for patients with Pesaro risk class II, and 64% and 62%, respectively, for Pesaro risk class III. In multivariate analysis, mortality risks were higher in patients 7 years of age and older and those with hepatomegaly before BMT. The leading causes of death were interstitial pneumonitis (n = 7), hemorrhage (n = 8), and veno-occlusive disease (n = 6). Proceeding to BMT in children younger than 7 years before development of end-organ damage, particularly in the liver, should improve results after BMT for β-thalassemia major.

Description: The addition of antithymocyte globulin (ATG) to a regimen of high-dose cyclophosphamide has been advocated to enhance engraftment after allogeneic bone marrow transplantation (BMT) for severe aplastic anemia (SAA). In a prospective clinical trial, 134 patients were randomly assigned to receive cyclophosphamide alone or in combination with ATG. All patients received T-cell–replete bone marrow from an HLA-matched sibling. With a median follow-up of 6 years, the 5-year probabilities of survival were 74% for the cyclophosphamide alone group and 80% for the cyclophosphamide plus ATG group (P = .44). Graft failure and graft-versus-host disease (GVHD) rates were similar in both groups. With the survival rates achieved, this study is not adequately powered to detect significant differences between the 2 treatment groups. In conclusion, the results of allogeneic BMT for SAA have improved over time related to advances in supportive care. The addition of ATG to the preparative regimen did not significantly improve the outcome.

Description: Total body irradiation (TBI)-based conditioning regimens are considered the standard of care for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic cell transplantation (HCT). However, due to concerns regarding acute and long-term toxicities, non-TBI regimens, commonly including busulfan (BU), have been increasingly explored. We performed a retrospective cohort analysis with the hypothesis that there would be equivalence of these two myeloablative approaches by reviewing outcomes for adult patients (pts), aged 18-60 years, undergoing a first, well-matched sibling, related or unrelated donor HCT in CR1 or CR2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 2005-2014. Eight hundred nineteen pts received TBI (63% 9-12 Gy, 37% ≥13 Gy) combined with etoposide (25%) or cyclophosphamide (Cy) (75%) and 299 pts received intravenous BU combined with a second alkylator Cy (15%) or melphalan (Mel) (13%), or a nucleoside analogue fludarabine (Flu) (41%) or clofarabine (Clo)(30%). The majority of the BU-based pts were treated at the Moffitt or MD Anderson Cancer Center. The BU-based regimens were grouped together for analyses since no significant differences in basic outcomes among the different chemotherapy-only regimens were noted. Patients in the BU-containing group were older but had better performance status, took longer to achieve CR1 and longer to receive HCT; more received peripheral blood than marrow grafts, peri-HCT ATG, pre- and post HCT tyrosine kinase inhibitors ( TKI), and were treated more recently than pts in the TBI-based group (Table 1). With median follow-up of 3.6 years for the BU-based group and 5.3 years for the TBI-based group, adjusted 3 year outcomes showed treatment-related mortality (TRM) BU 19% vs. TBI 25% (p=.04); relapse BU 37% vs. TBI 28% (p=.007); disease-free survival (DFS) Bu 45% vs. TBI 48% (p=.35); and overall survival (OS) BU 57% vs. TBI 53% (p=.35) (Figures A-B). Patients in the BU group had significantly more grade II-IV acute GVHD (47% vs. 40%, p=.025), but marginally less chronic GVHD (49% vs. 55% at 3 years, p=.073). In multivariate analysis, the BU group had a significantly higher rate of acute GVHD after day 50 (RR 1.75, 95% CI 1.19-2.58, p=.004), but marginally less chronic GVHD (RR 0.83, 95% CI 0.68-1.01 p=.059) and higher risk of relapse (RR 1.46, 95% CI 1.15-1.85 p=.002) compared with TBI-based regimens. Despite the observed higher risks of acute GVHD and relapse, BU-based conditioning led to similar TRM, OS, and DFS following HCT for ALL. Table 1 Table 1. Figure Figure. Disclosures Ciurea: Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership. Seftel:Otsuka: Research Funding. Pulsipher:Medac: Other: Housing support for conference; Chimerix: Consultancy; Jazz Pharmaceutical: Consultancy; Novartis: Consultancy, Other: Study Steering Committee. Champlin:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

Description: BACKGROUND: Non-secretory myeloma (NSM), where immunofixation fails to detect a monoclonal protein in serum and/or urine, accounts for

Description: Background: Indolent lymphomas are characterized by a chronic relapsing-remitting course. Bendamustine-Rituximab (BR) has been shown to improve overall response rate and progression free survival (PFS) in the upfront treatment of patients with indolent B-cell non-Hodgkin lymphoma (iNHL), as compared with conventional chemoimmunotherapy (Rummel et al., 2013; Flinn et al., 2014). The pan-Canadian Oncology Drug Review has recommended publicly funding BR, but concluded there is substantial uncertainty regarding the regimen's cost-effectiveness. The objective of our study was to assess the cost-effectiveness of BR as compared with Rituximab-Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (RCHOP) as frontline treatment for patients with advanced iNHL from a Canadian perspective. Methods: A Markov model was developed to estimate the costs, life expectancy and quality-adjusted life-years (QALYs) associated with the two regimen options allowing determination of the incremental cost-utility ratio (ICUR). Model parameters were derived from peer-reviewed studies. Key health states included FT (frontline therapy), MR (2-year state of maintenance R), PF1 (1st progression-free state), PD1/2/3 (subsequent progressive disease states requiring salvage), PF2/3/4 (subsequent progression-free states post-salvage), palliation and death. To determine progression after FT, individual data elements were derived from the published literature, and transition probabilities were determined through parametric survival analysis. Age-related mortality was obtained from Statistics Canada. Cost data (in 2016 Canadian dollars) were obtained from current funding arrangements under the New Drug Funding Program of Cancer Care Ontario, the Ontario Health Insurance Plan Schedule of Benefits and Fees, and the published literature. Utility values for health states and utility decrements associated with treatment related adverse events (AEs) were derived from peer-reviewed studies. The analysis was performed from the health care provider perspective, with a lifetime time horizon (equivalent to 24 years) and cycle lengths of 6 months. Patients were treated with a maximum of 3 lines of salvage therapy (3rd salvage permitted in age-appropriate patients achieving at least 1 year remission from 2nd line salvage). In order to address uncertainty of model input variables, a probabilistic analysis in which model inputs were represented by probability distributions was utilized, permitting a Monte Carlo simulation with 5000 replications. Costs and utilities were discounted at a rate of 5% per annum. Subgroup analyses for the following iNHL histologies were performed using individualized parametric survival curves: follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL). Results: The average costs and QALYs for the two treatment strategies were as follows: $116,811 and 5.86 QALYs for RCHOP; $121,364 and 6.38 QALYs for BR. The incremental cost per QALY gained for using BR with respect to RCHOP was $8,812 (Figure 1). Subgroup analyses revealed robust ICUR results: $27,398 (FL), $8,924 (MCL), $10,012 (MZL), $6,565 (LPL). For the commonly accepted willingness to pay threshold (WTP) of $50,000 per QALY, BR was the more cost-effective strategy 92% of the time in the entire cohort (Figure 2). In the subgroup analyses, BR was the more cost-effective strategy 66%, 82%, 64%, 86% of the time in FL, MCL, MZL, LPL respectively. ICUR results were robust to sensitivity analyses of key variables including age at study entry, maximum allowable age for therapy, duration of AEs, probability of death from palliation state and discount rate. Conclusion: Our model suggests that BR is a cost-effective strategy for the frontline treatment of patients with iNHL as compared with RCHOP. The cost-effectiveness of BR may be driven by the upfront PFS advantage despite higher acquisition costs and is consistent in various iNHL histology subgroups. Our analysis supports the use of frontline BR for iNHL in the Canadian setting. Figure 1 Cost-effectiveness acceptability curve Figure 1. Cost-effectiveness acceptability curve Figure 2 Incremental cost-effectiveness of BR relative to RCHOP with WTP threshold of $50,000 per QALY Figure 2. Incremental cost-effectiveness of BR relative to RCHOP with WTP threshold of $50,000 per QALY Disclosures Bence-Bruckler: Lundbeck: Membership on an entity's Board of Directors or advisory committees.

Description: Background/Objective: Mobilized peripheral blood hematopoietic progenitor cells are the most common stem cell source for autologous hematopoietic stem cell transplantation (auto-HSCT). Successful short-term stem cell engraftment requires collection of at least 2x106 CD34+ cells/kg. The American Society of Bone Marrow Transplantation (ASBMT) recommends a stem cell infusion target of 3-5 x106 cells/kg (Giralt et al. 2014). However, the number of CD34+ cells to reinfuse to ensure long-term engraftment has not been established. Plerixafor, a reversible CXCR4 antagonist, increases CD34+ cell yield at collection even in patients who are predicted poor mobilizers (PPM). Although plerixafor could be used universally for all collections, this may not be the most cost-effective strategy (Veltri et al. 2012). This study sought to determine the minimum number of CD34+ cells/kg required for adequate long-term hematopoiesis, identify factors associated with poor long-term hematopoiesis, and determine if plerixafor mobilization improved long-term peripheral blood counts. Methods: A retrospective chart review was conducted on patients who underwent auto-HSCT between January 2004 and September 2013 at The Ottawa Hospital, for management of hematological malignancies. Peripheral blood cell counts were collected from 1 to 5 years after auto-HSCT, or until disease relapse. Poor long-term hematopoiesis was defined as an ANC

Description: We report the retrospective outcomes of unrelated donor (URD) transplants in 169 patients with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) who received transplants between 1995 and 2004. Median age was 33 years (range, 16-59 years). A total of 50% had a white blood cell count (WBC) more than 30 × 109/L, 18% extramedullary disease, 42% achieved CR more than 8 weeks from diagnosis, 25% had adverse cytogenetics, and 19% had T-cell leukemia. A total of 41% were HLA well-matched, 41% partially matched with their donors, and 18% were HLA-mismatched. At 54-month median follow-up, incidences of acute grade 2-IV, III to IV, and chronic graft-versus-host disease were 50%, 25%, and 43%, respectively. Five-year treatment-related mortality (TRM), relapse, and overall survival were 42%, 20%, and 39%, respectively. In multivariate analyses, TRM was significantly higher with HLA-mismatched donors and T-cell depletion. Relapse risk was higher if the diagnostic WBC was more than 100 × 109/L. Factors associated with poorer survival included WBC more than 100 × 109/L, more than 8 weeks to CR1, cytomegalovirus seropositivity, HLA mismatching, and T-cell depletion. Nearly 40% of adults with ALL in CR1 survive 5 years after URD transplantation. Relapse risks were modest; TRM is the major cause of treatment failure. Selecting closely HLA-matched URD and reducing TRM should improve results.