Rawan G. Faramand

From the 2026 National Summit on Hematologic Cancers

Allogeneic hematopoietic cell transplantation (allo‑HCT) remains a potentially curative therapy for advanced hematologic malignancies through the combined effects of cytotoxic conditioning and graf...

Brexucabtagene-autoleucel (brexu-cel) produces high rates of measurable residual disease-negative (MRD-) complete response (CR) in adults 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 adults with relapsed/refractory Ph+ ALL who received commercial brexu-cel and achieved MRD- CR across 19 U.S. institutions. Considering TKI maintenance as a time-varying covariate, we analyzed outcomes based on receipt of subsequent TKI maintenance versus 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 (HR 0.12; 95% CI, 0.02-0.88; p=0.037) which translated into improved progression-free survival (PFS, HR 0.19; 95% CI, 0.04-0.85; p=0.029) and a trend towards improved overall survival (OS, HR 0.34; 95% CI, 0.07-1.62; p=0.18). There was no difference in non-relapse mortality (NRM, HR 0.83; 95% CI, 0.12-5.87; p=0.85). This real-world analysis supports the administration of TKI maintenance in Ph+ ALL following achievement of MRD- CR with brexu-cel as a strategy to improve PFS following chimeric antigen receptor T cell therapy.

Minor histocompatibility antigen (mHAg)-specific alloreactive donor T cells cause graft vs. host disease (GVHD) in matched related donor allogeneic hematopoietic cell transplantation (HCT). In a phase I trial, we expanded and infused (on day -2) mHAg-specific donor regulatory T cells (Treg) together with sirolimus-based pharmacologic prophylaxis to examine safety and preliminary efficacy of this GVHD prevention approach. We employed a 3+3 phase I design escalating Treg dose in 4 levels: 0.5 x 105/kg, 1 x 105/kg, 2 x 105/kg, and 4 x 105/kg. Dose-limiting toxicity (DLT) included grade 4-5 related infusion reaction, grade 4-5 unexpected organ toxicity, grade III-IV acute GVHD, or treatment-related death. Secondary and exploratory measures examined acute and chronic GVHD, survival outcomes, and Treg clone (TCR-Seq) expansion in culture, and in-vivo longevity and expansion post-HCT. 15 subjects were included (N=3 each per dose levels 1-3, and N=6 in dose level 4). No DLT were observed, and 4 x 105/kg Treg was identified as MTD. Median follow up for survivors was 41.7 months (range 14.5-72.8). The day 100 cumulative incidence of grade II-IV acute GVHD was 13% (95% CI 2-35%). NIH moderate/severe chronic GVHD by 1 year was 6.7% (95% CI 0.36-27%) and by 3 years was 20% (95%CI 4.4-44%). Overall survival was 73% (95% CI 54-100%). Treg clones expanded in culture, and demonstrated post-HCT lineage fidelity, persistence, and in-vivo expansion. This translational trial supports mHAg-specific expanded donor Treg as a novel GVHD prevention strategy, and demonstrates expanded donor Treg clones can persist and expand through one-year post-HCT. NCT01795573

In a real-world analysis of brexucabtagene autoleucel recipients with relapsed/refractory B-cell acute lymphoblastic leukemia (N = 278), lack of response to prior blinatumomab correlates with significantly worse following chimeric antigen receptor T-cell therapy outcomes.

To prevent graft-versus-host disease (GVHD) in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT), a calcineurin inhibitor plus methotrexate is routinely used. Early phase studies suggested improved outcomes with Orca-T, an allogeneic T-cell immunotherapy that uses purified donor regulatory T cells to prevent GVHD with significantly less immunosuppression. This phase 3 trial randomized adult patients (N = 187) with acute leukemias or myelodysplastic syndrome undergoing myeloablative conditioning to receive either Orca-T with tacrolimus or a conventional allograft with tacrolimus and methotrexate (Tac/MTX), using granulocyte colony-stimulating factor–mobilized peripheral blood from HLA-matched donors. The primary end point was survival free from moderate-to-severe chronic GVHD (cGVHD; cGFS). Using a stratified log-rank test, cGFS was significantly higher in the Orca-T arm than in Tac/MTX (hazard ratio, 0.26; 95% confidence interval, 0.14-0.47; P< .001). One-year estimates were as follows: cGFS was 78.0% with Orca-T vs 38.4% with Tac/MTX; cumulative incidence of moderate-to-severe cGVHD was 12.6% with Orca-T and 44.0% with Tac/MTX (Gray test P< .001); overall survival was 93.9% with Orca-T vs 83.1% with Tac/MTX (P = .12); GVHD-free and relapse-free survival was 63.1% and 30.9% in the Orca-T and Tac/MTX arms (P< .001), respectively; nonrelapse mortality (NRM) was 3.4% with Orca-T vs 13.2% with Tac/MTX (P = .03). Orca-T met the primary end point of improved survival free from cGVHD compared with Tac/MTX prophylaxis and should be considered a new therapeutic option with low toxicity for GVHD prophylaxis. Moreover, significantly less toxicity was observed with Orca-T patients, including fewer serious infectious complications and less NRM. This trial was registered at www.clinicaltrials.gov as NCT05316701.

Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.