Northside Hospital

Abstract Prolonged cytopenias requiring transfusion and growth factor support are a known complication of allogeneic hematopoietic stem cell transplantation (allo HCT). There is heterogeneity in studies characterizing poor graft function (PGF) due to lack of consensus on a clinical definition. The American Society for Transplant and Cellular Therapy (ASTCT) defined PGF as frequent dependence on blood and/or platelet transfusions and/or growth factor support in the absence of other explanations and in the presence of adequate donor myeloid and lymphoid chimerism. While this definition seeks to bring homogeneity in clinical practice, there is still a knowledge gap in terms of predictors for PGF, its impact on transplant outcomes and management of this complication. Furthermore, there are few studies characterizing PGF in the context of PTCy-based GVHD prophylaxis. To this end, we performed a retrospective single institution analysis of 239 consecutive patients with acute leukemia or myelodysplastic syndromes (MDS), undergoing a first PTCy-based allo HCT between 2016 and 2024. We defined PGF as ≥2 cytopenic lineages (ANC <500 or need for growth factor support, platelets <20,000 or requiring platelet transfusions to maintain a higher platelet threshold, or transfusion dependent anemia defined as ≥2 RBC units in 1 month) for at least 2 weeks from day +28 until day +100, in the presence of >95% donor chimerism and in the absence of relapse or severe GVHD. The median age was 58 (range 19-80) with a diagnosis of AML, MDS or ALL in 48%, 29% and 24% respectively. A haploidentical donor was used in 79%, PBSC was the stem cell source in 98%, and myeloablative conditioning was used is 36%. PGF was identified in 115 (48%) patients. Patients who had PGF were more likely to be CMV positive, ABO incompatible, had microangiopathic hemolytic anemia (MAHA), acute GVHD, or had been treated with ruxolitinib or sirolimus. In multivariable analysis (MVA), ABO incompatibility (OR 2.15, p=0.01), use of sirolimus (OR 3.5, p=0.005), presence of MAHA (OR 5.52, p=0.014), or acute GVHD (grade 2, OR 2.0, p=0.029; or grade 3-4, OR 8.24, p<0.001) were predictors for PGF. Patients with or without PGF had comparable transplant outcomes including overall and disease-free survival, as well as chronic GVHD incidence. Unexpectedly, patients with PGF had a significantly lower cumulative incidence of relapse (p=0.012), however this effect was balanced by higher NRM (p=0.001). In MVA, controlled for age, DRI, acute GVHD, CMV reactivation, and year of transplant, PGF retained a significant association with lower relapse risk (HR 0.37, 95% CI 0.21-0.67, p<0.001) and higher NRM (HR of 4.14, 95% CI 1.36-12.6, p=0.013). In conclusion, PGF is a common problem after PTCy-based allo HCT, occurring in almost half of patients. Predictors of PGF include baseline factors such as ABO incompatibility and early post-transplant factors such as use of sirolimus or the development of MAHA or acute GVHD. Although PGF significantly increased the risk of NRM, it had no impact on survival due to a corresponding decrease in relapse incidence. The positive effect of PGF on relapse reduction, which is independent of disease-related factors or the development of CMV reactivation or GVHD, deserves further study to understand the basis of this finding.

ABSTRACT:Brexucabtagene autoleucel (brexu-cel) produces high rates of measurable residual disease-negative (MRD-) complete response (CR) in adult patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); however, subsequent relapses remain frequent. It is unclear whether maintenance with tyrosine kinase inhibitors (TKIs) can enhance remission durability. We evaluated outcomes among adult patients with relapsed/refractory Ph+ ALL who received commercial brexu-cel and achieved MRD- CR across 19 US institutions. Considering TKI maintenance as a time-varying covariate, we analyzed outcomes based on receipt of subsequent TKI maintenance vs no maintenance. Patients receiving consolidative transplantation or non-TKI maintenance were excluded. Fifty-one patients were included: 20 received TKI maintenance, and 31 received no maintenance. The use of TKI maintenance was associated with a significantly lower 1-year cumulative incidence of relapse (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.02-0.88; P = .037), which translated into improved progression-free survival (PFS; HR, 0.19; 95% CI, 0.04-0.85; P = .029) and a trend toward improved overall survival (HR, 0.34; 95% CI, 0.07-1.62; P = .18). There was no difference in nonrelapse mortality (HR, 0.83; 95% CI, 0.12-5.87; P = .85). This real-world analysis supports the administration of TKI maintenance in Ph+ ALL after achievement of MRD- CR with brexu-cel as a strategy to improve PFS after chimeric antigen receptor T-cell therapy.

In a secondary analysis from the BMT CTN 1702 trial, we report on donor search and selection strategies according to baseline recipient search prognosis (SP). A total of 1751 patients in 3 SP groups-very likely, 958; less likely, 517; very unlikely, 276- were analyzed. The target time to HCT was most often 6 to 12 weeks (SP P = nonsignificant) and was associated with acute myelogenous leukemia remission status (P < .01). The baseline preferred alternative donor (across all SP groups was most commonly a haploidentical (haplo) donor (62.2% overall), whereas the use of mismatched unrelated donors (MMUDs) increased over time during the study period. Those in the less/very unlikely groups prioritized more alternative donor types at baseline and had more priority ranking changes (SP P < .01). While a comparable number of donors were typed (all SP: median, 3 donors; median time, 1.1 months), less/very unlikely SP had greater use of alternative donors (SP P < .01). Reasons for nonselection of typed donors varied by SP group. For less/very unlikely SP, the rates of HLA mismatching and donor-specific antibodies were higher, while for very likely SP, the use of other preferred donors was more common. Of 1751, 65% reached HCT: 94% of the very likely had an 8/8 matched unrelated donor (MUD) and 91% of the very unlikely had an alternative donor (haplo, 61%; MMUD, 22%; umbilical cord blood, 8%). HCT occurred within the initial desired timeline in 38% of all subjects. HCT delays occurred in 29%, mostly for disease or patient health overall, and of these 52% reached HCT after delay. In this prospective, multicenter evaluation of donor search and selection practices, we demonstrate that patients with poor likelihood of 8/8 MUD matching can reach HCT at comparable rates and with similar effort (time spent typing, number of donors typed) using an early alternative donor-centered strategy. Uniformly across SP groups, the target time to HCT is not commonly reached and is disrupted mostly by disease/patient health delays and not by donor unavailability.

BMT CTN 1506 ("MORPHO") was a phase 3 study of post-hematopoietic cell transplantation (HCT) maintenance with gilteritinib versus placebo for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) in first remission. Subgroup analysis indicated a significant benefit of post-HCT gilteritinib for participants in North America, but no benefit for those in Europe or Asia. We conducted a post-hoc analysis of the data focusing on days from AML diagnosis to HCT, pre-HCT FLT3 inhibitor use, and FLT3-ITD measurable residual disease (MRD). Participants transplanted < 120 days from AML diagnosis and/or those treated with FLT3 inhibition pre-HCT were more likely to have improved survival from post-HCT gilteritinib. Pre-HCT MRD levels were higher (P = 0.001) in participants transplanted within 120 days from diagnosis and in those treated with a FLT3 inhibitor pre-HCT and transplanted within 120 days (P = 0.008). Pre-HCT MRD was dependent on both FLT3 inhibitor use and time to HCT, as participants treated with successive courses of chemotherapy + FLT3 inhibition had successively lower MRD by the time of HCT. Time from AML diagnosis to HCT and pre-HCT FLT3 inhibitor use both appeared to impact MRD levels immediately prior to HCT, and geographic differences in these two practice patterns likely accounted for the observed regional differences in benefit from post-HCT gilteritinib. Increasing the number of courses of treatment pre-HCT may lower MRD sufficiently to eliminate the need for post-HCT inhibition, but with a presumed risk of some patients experiencing early progression. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

PURPOSE:The US radiation oncology workforce comprises diverse physician populations working in varied geographic and clinical settings. Data related to concerns of specific non-mutually exclusive groups, including academically affiliated community providers (AACPs), private practitioners (PPs), physician-scientists (PSs), and rural providers (RPs) are sparse. The ASTRO Workforce Committee utilized the 2025 Member Survey to characterize these cohorts and identify their unique professional challenges. METHODS AND MATERIALS:The 2025 ASTRO Member Survey included targeted questions for specific physician populations regarding practice roles, effort distribution (clinical, administrative, academic), funding, and their "top three" profession concerns. Responses were cross-referenced with demographic data from the survey for further context. Descriptive analysis was employed to summarize the qualitative and quantitative trends across subgroups. RESULTS:From 875 total responses, 433 members answered some workforce-related questions, including 100 AACP, 162 PP, 92 PS, and 68 RP radiation oncologists. AACPs reported a median clinical effort of 80%. AACP concerns included: time/funding for academics (41%), increasing administrative burdens (37%), decreasing reimbursement/increasing expenses (27%), staffing challenges (21%), and academic medical center support for research/clinic (14%). PPs and RPs reported a median clinical effort of 80% with 20% effort on administration/nonclinical work. PP concerns included: administrative and regulatory burdens (56%), decreased relative reimbursement (47%), challenges recruiting/maintaining staffing (21%), and maintaining/replacing equipment (14%). PSs reported median clinical effort of 60%, with 20% for basic/translational. Consistent PS concerns focused on the unstable research funding climate (85%) and decreased protected time (48%), followed by challenges recruiting staff/trainees (12%). Representing subsets of the other 3 groups, RP concerns included barriers to timely specialty care, declining reimbursement, and poor payor mix, along with administrative/clinical burdens. CONCLUSIONS:Although administrative burden, staffing challenges, and reimbursement volatility were universal concerns across the US radiation oncology workforce, each physician subgroup faced specific pressures. AACPs and PPs struggle with the friction between clinical volume and nonclinical work. PSs are primarily threatened by funding and time constraints. RPs are additionally challenged by barriers to timely and optimal care. These findings provide a roadmap for ASTRO and practice leaders to develop targeted advocacy and support strategies to sustain a diverse and healthy workforce.