Mineishi, Shin

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

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.

Abstract Abstract 487FN2 Background: Given the life-threatening nature of severe VOD (sVOD) and multi-organ failure (MOF), DF was made available in the US through a prospective treatment IND protocol (T-IND) to gather additional safety and response data from SCT patients (pts) with sVOD who were not eligible for a pivotal Phase 3 trial. Following completion of this Phase 3 trial, the T-IND protocol has continued and been amended to include pts who would have met eligibility criteria for the completed phase 3 trial, as well as pts with non-severe VOD and non-SCT pts who develop VOD after chemotherapy (chemo). This is the largest prospective evaluation of DF for the treatment of sVOD/MOF post SCT and non-SCT pts to date. Methods: Pts were initially required to have a diagnosis of VOD by Baltimore criteria (total bilirubin > 2.0 mg/dL with > 2 of the following: hepatomegaly, ascites or 5% weight gain) with MOF (either renal and/or pulmonary failure) that followed SCT. Following treatment of 104 pts, an amendment expanded eligibility criteria to include pts with VOD after chemo and pts with non-severe VOD (defined as no MOF). Key exclusion criteria included clinically significant bleeding or >1 pressor to maintain BP. CR was defined as bilirubin < 2 mg/dL + resolution of MOF (if applicable). Mortality was assessed at Day +100 (D+100) in all pts. DF was given at 6.25 mg/kg IV q6h (25 mg/kg/d) with treatment duration recommended for at least 21d. Results: This interim analysis is based on 269 pts enrolled between December 2007 and March 2011 at 67 centers. Nearly all pts (n=251) had undergone SCT (with allogeneic SCT in 225, 90%); 18 developed VOD after chemo alone. Of the 269 cases of VOD, 200 were severe at study entry, with 25% (66/269) of all pts dialysis dependent and 31% (83/269) ventilator dependent. Median age was 16 years (range 0.1 – 70); 55% were male. In the SCT pts, the most common diagnosis was leukemia (29% AML; 22% ALL; CML 3%; 4% other), with conditioning of CY (71%), BU (46%) and TBI (38%) respectively; 18% had undergone multiple SCTs (>1 SCT). Median onset of VOD was 15 d post-SCT. When presenting after chemo alone (n=18), median onset of VOD was 16 d after the first dose, most frequently after CY (61%), cytarabine (44%) and vincristine (39%), and for treatment of leukemia (AML 33%, ALL 33%, other 6%). Overall mean number of days of DF administration in all pts was 22 (range 1–88).Of 269 pts, 32% (85/269) achieved a CR and 50% [ by Kaplan-Meier estimate] survived to D+100. In the subgroup of SCT pts, 31% (78/251) achieved CR and 50% survived to D+100; 134 pts met entry criteria for the original Phase 3 trial and comparison to the Phase 3 historical control showed a statistically improved outcome in CR (30% vs 9%, p=0.0006) and D+100 survival (46% vs 25%; p=0.006). Of 200 pts with sVOD, CR was 28% and D+100 survival was 44%. In the 18 chemo only pts, CR was 39% and D+100 survival was 50%. CR rate and D+100 survival for the 69 pts with non-severe VOD were 42% and 62%, respectively. Delay of >2 d (vs < 2 d) in the start of DF after VOD diagnosis resulted in reduced CR (23% vs 35%, p=0.0339) and survival (37% vs 56%, p=0.01). Children as compared to adults had higher rates in CR (35% vs 29%) and survival (55% vs 43%). Toxicity proved generally manageable: 22% of pts experienced a total of 81 related AEs, primarily consisting of hemorrhage (19%) and hypotension (4%). Hemorrhage included pulmonary bleeding (6%), GI hemorrhage (3%), epistaxis (3%) and hematuria (3%). Similar to the observation of decreased GvHD in other studies, the incidence of all grade GvHD in the allogeneic SCT pts was 8%. Conclusions: In 269 pts with mainly sVOD/MOF, DF therapy achieved significantly improved outcome compared to an untreated historical control. Importantly, CR and survival were improved in pts who were treated within 2d of VOD diagnosis (vs. later) and in pts who had not yet progressed to sVOD. As with prior studies, there was a low incidence of DF-associated toxicities. Interestingly, the incidence of GvHD in allo-SCT pts was low, consistent with the reduction of GvHD seen in the large randomized EBMT pediatric prevention study. These results confirm the findings of previous trials and strongly support early intervention with DF once the diagnosis of VOD is made after SCT, as well as its use in pts who have not progressed to advanced MOF. The use of DF for VOD following intensive chemotherapy without SCT also appears promising, but more research in this patient population is needed. Enrollment to the T-IND study continues. Disclosures: Richardson: Gentium: Membership on an entity's Board of Directors or advisory committees. Arai:Gentium: Research Funding. Symons:Otsuka Pharmaceuticals: Research Funding. Martin:Gentium: Research Funding. Massaro:Gentium: Consultancy. D'Agostino:Gentium: Membership on an entity's Board of Directors or advisory committees. Hannah:Gentium: Consultancy. Tudone:Gentium: Employment. Hume:Gentium: Employment. Iacobelli:Gentium SpA: Employment. Soiffer:Gentium: Honoraria.