Paulson, Kristjan

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.

Abstract Introduction: Allogeneic stem cell transplant is an intensive procedure, offered in a limited number of medical centres. We sought to describe how sociodemographic variables impacted access to transplant across the United States, and if disadvantaged populations had inferior access to transplant. Methods: Data from the Surveillance, Epidemiology and End Results Program (SEER) and the Center for International Blood and Marrow Transplant Research (CIBMTR) was integrated to determine the rate of unrelated donor transplantation between 2000 and 2010 in each of the 612 counties included in the SEER registry. Patients under the age of 65 with AML, ALL, and MDS were included, and the analysis was restricted to unrelated donors due to limited availability of ZIP code in CIBMTR data. New incident cases were determined from SEER, and the number of transplants was determined from CIBMTR. The transplant rate was calculated (transplants performed divided by incident cases) for each county. County attributes (percent minority, rural/urban status, percentage below the poverty line, and median family size) were obtained from US Census data. Poisson regression was used to describe how county attributes impacted transplant rates. Transplant rates were calculated separately for AML, White residents, and pediatric ALL. Results: 3147 patients were identified in the CIBMTR dataset that met inclusion criteria. The estimated ZIP code completeness was 75%. There were 30,468 new incident diagnoses of ALL, AML, and MDS. For AML, patients from rural areas (less than 20,000 residents) and patients from areas with higher poverty levels had lower transplant rates (Table 1). Minority status and family size did not impact transplant rate. In regression models, higher levels of poverty remained associated with lower transplant rates, while rurality did not (Table 2). The results were similar among White residents. In contrast, in pediatric ALL, no county attributes (poverty, rurality, percent minority, and family size) were significantly associated with a difference in transplant rate (Table 1). However, numbers of transplants were smaller, limiting power. Discussion: Patients with AML from disadvantaged areas had lower rates of unrelated donor transplant. While patients from disadvantaged areas were also more likely to be non-White, and non-White Americans are less likely to have an available unrelated donor, this difference was also seen in White Americans from disadvantaged areas. This suggests the lower transplant rate is due impaired access to transplant. Poverty rate was the most important predictor of transplant rate. The results of this study suggest that improving access to transplant in disadvantaged populations should be a priority for health care administrators. Based on these results, approximately 2500 Americans do not undergo allogeneic transplant annually due to inferior access associated with higher poverty rates. Table 1 Univariate Analysis Table 1. Univariate Analysis Table 2 Acute Myeloid Leukemia, Regression Model * Metropolitan = county > 50,000 people, micropolitan = county > 20,000, rural county < 20,000. Table 2. Acute Myeloid Leukemia, Regression Model. / * Metropolitan = county > 50,000 people, micropolitan = county > 20,000, rural county < 20,000. Disclosures Hahn: Novartis: Equity Ownership; NIH: Research Funding.

Abstract 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. Figure 1: Adjusted overall survival in BMT CTN 0201 trial participants and non-participants Figure 1:. Adjusted overall survival in BMT CTN 0201 trial participants and non-participants Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.