Fretham, Caitrin

SummaryTransplant‐associated thrombotic microangiopathy (TA‐TMA) is a complication of allogeneic transplantation (allo‐HCT). The incidence and risk factors associated with TA‐TMA are not well known. A retrospective analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) was conducted including patients receiving allo‐HCT between 2008 and 2016, with the primary objective of evaluating the incidence of TA‐TMA. Secondary objectives included identification of risk factors associated with TA‐TMA, and the impact of TA‐TMA on overall survival and the need for renal replacement therapy (RRT). Among 23,665 allo‐HCT recipients, the 3‐year cumulative incidence of TA‐TMA was 3%. Variables independently‐associated with increased incidence of TA‐TMA included female sex, prior autologous transplant, primary disease (acute lymphoblastic leukaemia and severe aplastic anaemia), donor type (mismatched or unrelated donor), conditioning intensity (myeloablative), GVHD prophylaxis (sirolimus + calcineurin inhibitor), pre‐transplant kidney dysfunction and acute GVHD (time‐varying effect). TA‐TMA was associated with higher mortality (HR = 3·1, 95% Confidence Interval [CI] = 2·8–16·3) and RRT requirement (HR = 7·1, 95% CI = 5·7–311·6). This study provides epidemiologic data on TA‐TMA and its impact on transplant outcomes. Increased awareness of the risk factors will enable providers to be vigilant of this uncommon but serious transplant complication. The results will also provide benchmarking for future study designs and comparisons.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only potentially curative therapy in eligible patients with myelodysplastic syndromes (MDS). Reduced-intensity conditioning (RIC) regimens that have been developed to extend HSCT to older patients resulted in encouraging outcomes. However, several retrospective studies have raised concerns about disease control when RIC is used in MDS and the ideal conditioning regimen has not yet been found. In this study, we aimed to compare two most commonly used RIC regimens; intravenous use of fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel). Study population: Through the CIBMTR, after excluding patients with ex-vivo T cell depletion, we identified 1045 MDS patients aged ≥ 60 years and underwent first HSCT with matched related or matched (8/8) unrelated donor (MRD and MUD) using RIC between 2007-2016. RIC was defined via CIBMTR criteria as a regimen that incorporated an IV busulfan (BU) total dose ≤ 7.2 mg/kg or low-dose melphalan (MEL) total dose ≤ 150 mg/m2. By that, we identified 697 MDS patients who received FluBu (BU 6.4 mg/kg: 87%, BU 3.2 mg/kg: 13%) and 448 receiving FluMel (MEL 140 mg/m2: 80%, MEL 100 mg/m2: 20%). Results: The two groups, FluBu and FluMel, were comparable for disease and transplant related characteristics except the more frequent use of ATG or Campath in FluBu group (39% vs. 31%). The median age was 67 in both groups, and 26% and 19% of FluBu and FluMel groups were aged ³70, respectively. Hematopoietic comorbidity index (HCT-CI) was ³3 in 61% and 59% of FluBu and FluMel groups and MDS risk score by CIBMTR at HCT was high/very high in 34% in both groups. FluMel was associated with a reduced relapse incidence (RI) after HSCT compared with FluBu as presented in Table 1 and Table 2. Adjusted RI at 1-year was 43% with FluBu and 25% with FluMel (p=<0.0001). On the other hand, transplant related mortality (TRM) was higher with FluMel compared with FluBu (27% vs. 15%, p=<0.0001). The difference persisted at 2- and 3-years after HSCT as presented in the figure. Since the magnitude of improvement in RI was greater with FluMel than the improvement in TRM with FluBu, disease-free survival (DFS) was improved at 1-year and beyond with FluMel compared with FluBu (48% vs. 41% at 1-year, p=0.030, and 38% vs 28% at 3-years, p=0.0030). These outcome differences remained significant when sensitivity analyses were performed excluding patients who received RIC with either BU 3.2 mg/kg or Mel 100 mg/m2. FluMel, did not lead to higher incidence of severe grade 3-4 aGvHD (HR=1.2, 95%CI, 0.9-1.6, p=0.3) or chronic GvHD (HR=0.9, 95%CI=0.7-1.06, p=0.2). However, grade 2-4 aGVHD was observed more often with FluMel than FluBu (HR=1.3, 95%CI, 1.1-1.6, p=0.006). This led to inferior outcomes of GRFS within the first 2 months with FluMel (HR=1.9, HR=1.4-2.6, p<0.001) but superior outcomes of GRFS beyond 2 months with FluMel compared with FluBu (HR=0.7, 95%CI=0.6-0.8, p<0.001). Conclusion: Our results suggest that between the two most commonly used RIC regimens in older MDS patients, FluMel was associated with superior DFS and overall survival compared with FluBu due to reduced RI despite higher TRM. Disclosures Oran: AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Nakamura:Kirin Kyowa: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Celgene: Other: support for an academic seminar in a university in Japan; Merck: Membership on an entity's Board of Directors or advisory committees. Scott:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Speakers Bureau. Popat:Jazz: Consultancy; Incyte: Research Funding; Bayer: Research Funding.

Introduction Renal dysfunction is a recognized risk factor for mortality after HCT, as it is included in the comorbidity index (HCT CI). Yet, further understanding on outcomes in patients with different level of renal dysfunction or undergoing hemodialysis (HD) at time of transplant remains scant. This study explores the impact of different levels renal dysfunction on major HCT outcomes in a large population using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods The study population included 8,102 patients age 40 years and older who received HCT for treatment of malignancies from 2008 to 2016, with available pre-transplant creatinine measurement. eGFR, calculated using CKD-EPI (CKD-epidemiology collaboration) method, was used to assigned patients in four categories: eGFR ≥ 90ml/min (eGFR≥ 90, N=4,237, reference), eGFR 60-90ml/min (eGFR 60-90, N=3,158), eGFR 45-59ml/min (eGFR 45-59, N=538) and eGFR <45ml/min(eGFR<45, N=169). A separate cohort of patients on HD at time of HCT (N=46) was analyzed independently. Multivariate analysis models were built for assessment of overall mortality, transplant-related mortality (TRM), disease relapse or progression, graft-versus-host disease (GVHD), hepatic sinusoidal obstructive syndrome (SOS), thrombotic microangiopathy (TMA), idiopathic pneumonia syndrome (IPS) and need of HD post-transplant. Common patient-, disease- and transplant-related covariates were tested on all models and HCT CI was computed without reported renal dysfunction comorbidity to avoid collinearity. Results Patient characteristics are shown in table 1. The groups were comparable on disease risk index, graft and donor source, but patients with eGFR>90 were younger and received myeloablative conditioning more frequently. The cohort of eGFR <45 had a higher proportion of patients with HCT CI ≥3. TRM and overall survival according to eGFR groups are shown in Figure. In the multivariate analysis models eGFR as the main effect was associated with TRM (p<0.0001), overall mortality (p<0.0001), and requirement of HD post HCT (p<0.0001), but not for relapse/progression (p=0.98), GVHD (grades II-IV, p=0.34; III-IV, p=0.70; and chronic, p=0.20), TMA (p=0.46), SOS (p=0.02) or IPS (p=0.06). Compared to eGFR ≥90, the hazard ratio (HR) for TRM for eGFR 60-89 was 1.12 (p=0.07), for eGFR 45-59 was 1.46 (p<0.001) and for eGFR<45 was 1.74 (p=0.004). Corresponding HRs for overall mortality were 1.0 (p=0.9), 1.17 (p=0.03) and 1.63 (p<0.0001), respectively. Similarly, for the need of HD post HCT, HR for eGFR60-89 was 1.29 (p=0.03), eGFR45-59 was 2.45 (p<0.001) and for eGFR<45 was 3.09 (p<0.0001). Only eGFR<45 was associated with higher risk of SOS (HR2.66, p=0.03). Among 46 patients on HD prior to HCT, one-year probability of overall survival was 20% (95% Confidence Interval [CI] 10-32%) and cumulative incidence of TRM at one year was 67% (95% CI, 50-81%). Conclusion These findings indicate that degree of renal dysfunction is an independent predictor of OS, TRM, probability of receiving HD and SOS when adjusted for other risk factors. The impact of eGFR on the need of HD, a complication that increases morbidity post HCT is an important finding. Additionally, the outcomes of a subset of patients on HD at time of transplants are dismal. These results can further assist the prognostic assessment of candidates for an allogeneic HCT. Disclosures Stadtmauer: Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding. Wingard:Ansun: Consultancy; Pluristem: Consultancy; Celgene: Consultancy; Merck: Consultancy; Shire: Consultancy. Ganguly:Seattle Genetics: Speakers Bureau; Daiichi Sankyo: Research Funding; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. Pasquini:Pfizer: Other: Advisory Board; Amgen: Consultancy; Medigene: Consultancy; BMS: Research Funding; Novartis: Research Funding; Kit Pharma: Research Funding.