Background ACCESS (NCT04904588), a multi-center phase II trial, was designed to assess safety and efficacy of HLA-mismatched unrelated donor (MMUD) peripheral blood allografts in adult patients with high-risk hematologic malignancies receiving myeloablative (MAC) or non-myeloablative/reduced-intensity conditioning (NMA/RIC) and standard-dose post-transplantation cyclophosphamide (SD PTCy) as graft-versus-host disease (GvHD) prophylaxis. One-year overall survival (75%) was similar irrespective of conditioning intensity and degree of donor HLA MM (Al Malki et al., JCO 2025). However, 56% MAC and 64% RIC adult recipients experienced at least one Common Terminology Criteria for Adverse Events (CTCAE) grade (Gr) ≥2 infection within the first 100 days of transplant (D100). Herein, we describe infection burden in ACCESS patients within one year after transplant. Methods CTCAE Gr≥2 infections were analyzed by time after transplant (Days 0-30, 31-100, 101-180, 181-365), conditioning intensity, degree of donor HLA MM (HLA 7/8 vs. <7/8), pathogen type, and post-MMUD HCT outcomes (Gr2-4 acute GvHD, moderate/severe chronic GvHD, and American Society for Transplantation and Cellular Therapy (ASTCT) Gr≥2 cytokine release syndrome. Infection density was calculated as number of infections per 100 days at risk for enrolled patients. Infection data were summarized with standard descriptive statistics. Infection density with 95% confidence intervals (CI) were estimated using Poisson regression models; p<0.05 was considered statistically significant. Results Median (range) ages for 268 patients receiving MAC (n=75) and RIC/NMA (n=193) were 49.8 (20.4-65.6) and 64.4 (24.3-77.9) years, respectively. CTCAE Gr≥2 infections occurred in 183 (69%) patients: 49 (65%) MAC and 134 (69%) RIC/NMA recipients. Days 0-30 infection densities for Gr2-5 and Gr3-5 infections were higher relative to infection densities at other post-transplant periods and irrespective of conditioning intensity (Fig. 1A) and degree of donor HLA MM (Fig. 1B). When comparing infection densities by conditioning intensity, patients receiving RIC/NMA had higher infection densities at Days 31-180 for Gr3-5 infections (Fig. 1A). When comparing infection densities by degree of donor HLA MM, significant differences were noted only at Days 181-365 in the RIC stratum (Fig. 1B). Similar distribution of pathogen types by conditioning intensity were noted early (Fig. 1C) and late (Fig. 1D) post-transplant, with predominantly gram-positive bacteria and non-respiratory viruses, respectively. Finally, pathogen type frequencies by clinical outcomes were indistinct (Fig. 1E). Conclusion In the MMUD PBSC transplant setting, SD PTCy associates with significant infection burden. These findings provide insights into potential interventions to prevent infection or augment immune response after MMUD transplant.

Abstract: Despite a recent increase in therapeutic options, patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) eventually require novel therapies. We conducted a phase 1 trial of blinatumomab and lenalidomide in R/R B-NHL. Three dose levels representing 2 schedules were explored. The primary end points were adverse events (AEs) and determining the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Thirty-five patients were enrolled, and 34 patients initiated treatment with a median number of prior regimens of 3 (range, 2-8). There were no dose-limiting toxicities (DLTs) in the first 2 dose levels. Dose level 3, 20 mg of lenalidomide daily on days 1 to 21 and days 29 to 49 of a 56-day induction cycle plus blinatumomab 9 μg/d continuous IV infusion (CIVI) on days 1 to 7, 28 μg/d CIVI on days 8 to 14, and 112 μg/d CIVI on days 15 to 56 was determined to be the MTD/RP2D. The most common grade ≥2 AE was neurotoxicity in 11 of 34 patients (32%), with 4 of 16 patients (25%) at the RP2D. At the RP2D, there was 1 DLT, a patient with grade 2 tremor and word-finding difficulty. For all patients completing induction, the overall response rate was 80% (95% confidence interval, 56-94) with a complete response rate of 70%, and 8 of 34 patients (24%) had durable remissions lasting >2 years. GranB+ CD56bright CD16dim CD11b+ natural killer cells and memory regulatory T cells in the peripheral blood at baseline were predictive of response. Concomitant administration of lenalidomide appeared to reduce blinatumomab-mediated T-cell exhaustion. In conclusion, encouraging activity was seen with blinatumomab and lenalidomide in heavily pretreated R/R B-NHL (NCI Protocol no. 9924).

Background Access to allogeneic hematopoietic cell transplantation (HCT) remains limited for patients of non-European ancestry due to donor unavailability. While 7/8 mismatched unrelated donors (MMUD) provide acceptable outcomes, HCT with ≥2 allele mismatches (<7/8) have historically yielded poor survival and prohibitive toxicity. Post-transplant cyclophosphamide (PTCy) has significantly improved outcomes after MMUD HCT, but the prognostic effect of increasing HLA disparity in this setting is unclear. Methods The prospective ACCESS trial (NCT04904588) evaluated PTCy-based GVHD prophylaxis in adults receiving 4–7/8 HLA-mismatched peripheral blood stem cells (PBSC) from donors ≤35 years old after myeloablative (MAC) or reduced-intensity/non-myeloablative (RIC/NMA) conditioning. Primary endpoint was 1-year overall survival (OS). Secondary endpoints included graft failure, non-relapse mortality (NRM), relapse, acute and chronic GVHD, and GVHD-free relapse-free survival (GRFS). Results Among 268 adults, 85 received <7/8 and 183 received 7/8 MMUD PBSC grafts. The <7/8 cohort (median age 57, range 24–78; 49% male) was racially diverse, with the majority (61%) identifying as racial/ethnic groups other than non-Hispanic White, and included 6/8 (82%), 5/8 (14%), and 4/8 (4%) matches. Conditioning intensity in this group was MAC (n=23) and RIC/NMA (n=62). Diagnoses included AML (55%), MDS (15%), lymphoma (14%) and ALL (11%). Most received fludarabine/melphalan (44%) or myeloablative busulfan/fludarabine (21%); the median CD34+ cell dose was 5.5 × 10^6/kg, and 75% of grafts were cryopreserved. The 7/8 group (median age 63, range 20–79; 52% male) had similar disease distribution, conditioning intensity [MAC (n=52), RIC/NMA (n=131)], and infused cell dose. In this cohort, 61% of grafts were cryopreserved, and nearly half (45%) identified as racial/ethnic groups other than non-Hispanic White.At 1 year, OS was 86% (95% CI, 76–92) for <7/8 vs 79% (72–84) for 7/8. Relapse was 23% (14–33) vs 17% (12–23); NRM 8% (4–16) vs 14% (9–19); and GRFS 55% (43–65) vs 51% (44–58) in <7/8 and 7/8, respectively. At 6 months, grade II–IV acute GVHD occurred in 34% (24–44) vs 39% (32–46), and grade III–IV in 7% (3–14) vs 8% (5–13) in <7/8 and 7/8, respectively. At 1 year, moderate/severe chronic GVHD was 8% (3–15) vs 11% (7–16). Primary graft failure occurred only after RIC/NMA: 8% (3–18) with <7/8 vs 3% (1–8) with 7/8.In <7/8 recipients, 1-year OS was 91% with MAC and 84% with RIC/NMA; relapse 32% vs 20%; GRFS 53% vs 55%; and NRM 9% vs 8%, respectively. Conclusions PTCy-based GVHD prophylaxis results in excellent outcomes following <7/8 MMUD HCT, with OS >80% and low NRM and GVHD, comparable to 7/8. Extending donor criteria to 4–6/8 mismatches should broaden equitable donor access while permitting optimization of non-HLA factors.

Importance:Allogeneic hematopoietic cell transplant (HCT) is curative for hematologic cancers, yet access remains inequitable for racially and ethnically underrepresented and socioeconomically disadvantaged populations, making the goal of having a suitable donor for every patient who needs a transplant challenging. The ACCESS trial broadened access by enrolling patients without matched donors, who instead received an HCT from a mismatched unrelated donor. Objective:To compare baseline characteristics of ACCESS trial participants with participants enrolled in a similar clinical trial and a patient-reported outcome (PRO) protocol cohort. Design, Setting, and Participants:This cross-sectional study included adult participants (aged ≥18 years) from 3 cohorts-the ACCESS trial (2021-2024), BMT CTN 1703 trial (2019-2021), and Center for International Blood and Marrow Transplant Research (CIBMTR) PRO Protocol observational study (2020-2025)-who completed a baseline PRO survey. The ACCESS and PRO Protocol cohorts were stratified by conditioning intensity (myeloablative [MAC] vs reduced-intensity and nonmyeloablative [RIC/NMA]); all BMT CTN 1703 participants received RIC/NMA. Exposure:Hematopoietic cell transplant. Main Outcomes and Measures:Racial and ethnic diversity, insurance type, education, and income were compared among cohorts using counts and percentages, and socioeconomic and structural disadvantage were measured using the Social Vulnerability Index and Comprehensive Score for Financial Toxicity-Functional Assessment of Chronic Illness Therapy. Results:Baseline surveys were completed by 208 participants in the ACCESS trial (median [range] age at transplant, 62.3 [20.4-78.9] years; 108 male [51.9%]), 122 participants in the PRO Protocol study (median [range] age at transplant, 63.9 [21.1-78.0] years; 67 male [54.9%]), and 342 participants in the BMT CTN 1703 trial (median [range] age at transplant, 66.9 [20.7-78.6] years; 218 male [63.7%]). Participants in ACCESS were more racially and ethnically diverse, with 15 (7.2%), 25 (12.1%), 46 (22.2%), 110 (53.1%), and 11 (5.3%) of Asian, Black or African American, Hispanic or Latino, White, and other race and ethnicity, respectively, compared with 4 (3.3%), 2 (1.6%), 8 (6.6%) 104 (85.2%), and 4 (3.3%), respectively, in the PRO Protocol and 10 (3.0%), 0, 16 (4.8%), 302 (91.0%), and 4 (1.2%), respectively, in the BMT CTN 1703 trial. Participants in ACCESS were more likely to have Medicaid (36 [18.1%]) vs PRO Protocol (8 [6.7%]) and BMT CTN 1703 (16 [5.1%]) participants and reported lower education (some college or an associate's degree: 103 [49.5%] vs 73 [59.8%] in the PRO Protocol; postcollege education: 34 [17.3%] vs 35 [29.2%] in the PRO Protocol) and household income (<$40 000 annually: 25 [24.0%] vs 8 [11.6%] in the PRO Protocol and 7 [38.9%] in the BMT CTN 1703 trial). Median Social Vulnerability Index scores were highest among participants in the ACCESS MAC group (median [range], 0.72 [0.01-0.97] vs 0.61 [0.16-0.78] in the PRO Protocol MAC group), and 16 participants [27.6%] in the ACCESS MAC group reported moderate to severe financial toxicity. The ACCESS participants lived closer to transplant centers, especially in the RIC/NMA group (median [IQR], 28 [14-75] miles vs 47 [16-96] miles for BMT CTN 1703 participants and 49 [21-104] miles for PRO Protocol participants). Conclusions and Relevance:This cross-sectional study of clinical trial participants and a clinical cohort found that the ACCESS trial enrolled a more racially and ethnically diverse and socioeconomically disadvantaged population. Trial designs that broaden eligibility could expand access to HCT, highlighting the need for systemic interventions to ensure equity.

Human leukocyte antigen (HLA)-mismatched unrelated donor (MMUD) hematopoietic cell transplantation (HCT) has emerged as an effective therapy for adult patients with hematologic malignancies. The MMUD ACCESS Trial (NCT04904588), which incorporated post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GvHD) prophylaxis, demonstrated combined overall survival of 81% in enrolled patients, 59% who were ethnically diverse. Given PTCy is also associated with significant bacterial and viral infections, we defined infection burden in the full adult cohort (N=268) using infections graded according to an international standard (CTCAE, Common Terminology Criteria for Adverse Events, version 5.0). Infection density (number of infections per 100 days at risk), cumulative incidence of infection, and frequency of pathogen types were categorized by post-HCT time, conditioning intensity, level of donor HLA mismatch, and presence of acute GvHD. Of 465 recorded CTCAE grade 2-5 infections recorded in 183 (68%) adults, 176 (38%) infections were significant or life-threatening and most infections (296, 64%) occurred within the first 100 days. Infection density at Days 0-30 was significantly higher than at other times and was similar by conditioning and level of HLA mismatch as were pathogen types and isolates. Multivariable analysis showed that acute GvHD is significantly associated with infection. Lastly, 21 (7.8%) patients died from infection. Results show significant infection burden using standard dose PTCy in the MMUD HCT setting, irrespective of conditioning and level of donor HLA mismatch, and will serve as a benchmark for trials investigating reducing infection burden following MMUD HCT.

Abstract Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), especially those progressing after Bruton tyrosine kinase (BTK) inhibitor and/or chimeric antigen receptor (CAR) T-cell therapy and those with high-risk features, have poor outcomes. The bispecific antibody, mosunetuzumab, combined with the antibody-drug conjugate (ADC), polatuzumab vedotin (Mosun-Pola), targets CD20 and CD79b via independent cell-killing mechanisms. In this multicenter phase 2 study, patients with MCL who had received ≥2 previous lines of therapy, including a BTK inhibitor, were enrolled. Patients received outpatient fixed-duration mosunetuzumab subcutaneously (17 cycles), with cycle 1 step-up dosing to mitigate cytokine release syndrome (CRS), and polatuzumab vedotin (1.8 mg/kg IV) for 6 cycles. The primary end point was centrally assessed best objective response rate. A total of 42 patients with a median of 3 previous therapies were enrolled; 26% had previous CAR T-cell therapy. A number of patients had MCL with high-risk features (Ki-67 of ≥50%, 67%; blastoid/pleomorphic morphology, 38%; TP53 aberration, 48%). Objective response occurred in 88.1% of evaluable patients (95% confidence interval [CI], 74.4-96.0) and complete response in 78.6% (95% CI, 63.2-89.7). With a median follow-up of 15.9 months, median progression-free survival was 18.6 months (95% CI, 13.9 to not estimable). Consistent efficacy was observed in high-risk subgroups. CRS occurred in 42.9% of patients and was limited to grade 1/2 events. Mosun-Pola achieved high complete remission rates while maintaining a manageable safety profile in patients with R/R MCL exhibiting high-risk features. This is, to our knowledge, the first bispecific-ADC combination therapy study in MCL. This trial was registered at www.clinicaltrials.gov as #NCT03671018.

Abstract Background: Despite recent advancements in NHL therapies, many patients experience disease progression or relapse. Agents with novel mechanisms of action and combination strategies are needed to improve clinical outcomes. B-cell lymphoma 6 (BCL6) is a master transcriptional regulator of immune cells, particularly of germinal center B cells, and an established oncogenic driver in NHL. ARV-393 is an oral PROteolysis TArgeting Chimera (PROTAC) BCL6 degrader that binds an E3 ubiquitin ligase and BCL6 to induce ubiquitination of BCL6 and its subsequent proteasomal degradation. ARV-393 monotherapy potently inhibited tumor growth and induced tumor regressions across NHL cell-derived xenograft (CDX) and patient-derived xenograft models, including models of DLBCL, transformed follicular lymphoma, and nodal T-follicular helper cell lymphoma (nTFHL). Furthermore, administration of ARV-393 with a CD20×CD3 bispecific antibody, glofitamab, demonstrated combinatorial antitumor activity in a humanized high-grade B-cell lymphoma CDX model, inducing deeper tumor growth inhibition and increased tumor regressions vs either monotherapy. These preclinical findings demonstrated single-agent ARV-393 antitumor activity across NHL subtypes and suggested mechanistic synergy with glofitamab, supporting clinical investigation of monotherapy in NHL and this chemotherapy-free combination in patients with DLBCL. Methods: This global, multicenter, open-label, first-in-human, phase 1 dose escalation and optimization/expansion study (NCT06393738) is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ARV-393 as monotherapy in relapsed or refractory (R/R) NHL or in combination with glofitamab in R/R DLBCL, with a primary objective of determining provisional doses for further exploration. Patients eligible for ARV-393 monotherapy are adults with confirmed R/R B-cell NHL who previously received ≥2 lines of systemic therapy (including rituximab), or nTFHL who previously received standard of care therapy. Patients eligible for ARV-393 in combination with glofitamab are adults with pathologically confirmed R/R DLBCL, DLBCL not otherwise specified, or large B-cell lymphoma arising from follicular lymphoma who were treated with ≥2 prior lines of systemic therapy. ARV-393 will be administered orally once daily in 28-day cycles alone or in combination with intravenous glofitamab during 21-day cycles. Approximately 255 patients will be enrolled across study cohorts. As of January 2026, enrollment is ongoing. Citation Format: Martin Hutchings, Andrew Zelenetz, Jacob H. Christensen, Almudena Cascales Hernandez, Sarit Assouline, Luis E. Malpica Castillo, Shalin Kothari, Dipenkumar Modi, Miguel A. Canales Albendea, Damian Cubillas, Alejandro M. Garcia-Sancho, Catherine M. Diefenbach, John Kuruvilla, Paolo F. Caimi, Krish Patel, Sean Landrette, Eric Zhi, Yuanyuan Zhang, Roland Meier, Mathew J. Matasar. Phase 1 study of ARV-393, a PROTAC BCL6 degrader, as monotherapy in patients with advanced non-Hodgkin lymphoma (NHL) or combined with glofitamab in patients with diffuse large B-cell lymphoma (DLBCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT268.

Introduction Allogenic hematopoietic stem cell transplantation (AHSCT) for myelofibrosis (MF) patients (pts) can involve several disease-specific challenges, including medical comorbidities resulting from MF, delayed engraftment, and graft-versus-host disease (GVHD). Several strategies exist to minimize these difficulties. The use of post-transplant cyclophosphamide has decreased the incidence of GVHD in HLA-mismatched transplants, but pts with MF were excluded from most GVHD prevention studies. We evaluated outcomes of pts at our center who underwent AHSCT for MF. Objective 1. To evaluate the relationship between pre-transplant variables and outcomes in myelofibrosis patients receiving mismatched donor transplants. Methods The study population included adult pts with diagnosis of primary or secondary MF who underwent AHSCT between 2005 and 2024 at Karmanos Cancer Institute. We assessed associations between six variables (age, conditioning regimen, HLA match status, GVHD prophylaxis, CD 34+ve cell dose and Karnofsky performance status (KPS)) on acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse-free survival (RFS), overall survival (OS), relapse, and non-relapse mortality (NRM). Results We identified 69 pts. 44 pts (63.8%) had fully matched donor (MD) and 25 pts (36.2%) had mismatched donors (MMD). 12 pts (17.4%) received post-transplant cyclophosphamide while 57 pts (82.6%) received a calcineurin inhibitor-based regimen with or without thymoglobulin. With median follow-up of 5.03 years, the median overall survival (OS) was 12.5 years (95% CI 1.7-NE) with OS at 2 years being 59.4% (95% CI 48.6-72.5). The cumulative incidences of grade II-IV and III-IV aGVHD at 100 days were 26.4% (95% CI 16.5-37.3) and 10.3% (95% CI 4.5-18.9), respectively. The cumulative incidence of extensive cGVHD at 1 year was 30.3% (95% CI 19.6-41.7). The cumulative incidences of relapse and NRM at 1 year were 7.4% (95% C1 2.7-15.3) and 28.2% (95% CI, 18.0-39.3), respectively.In multivariable analysis, we observed that:1. Pts with MMD had a significantly higher risk of death compared to those with MD (HR 3.42; 95% CI 1.4-8.34; p=0.007).2. Pts with MMD had a significantly higher risk of death or disease relapse (HR 3.38; 95% CI 1.41-8.09; p=0.006).3. Pts with MMD had a significantly higher risk of NRM compared to those with MD (HR 4.69; 95% CI 1.63-13.49; p = 0.004).4. Pts with KPS<80 had significantly higher risk of developing aGVHD (HR 2.45; 95% CI 1.11-5.42; p=0.027). Conclusions Our analysis shows that pts with MMD had significantly higher risk of death, disease relapse, and NRM than those with MD. In addition, pts with KPS<80 had significantly higher risk of developing aGVHD. With a limited number of pts who received post-transplant cyclophosphamide, we did not observe a significant difference in aGVHD, cGVHD, NRM, relapse, RFS or OS compared to other GVHD prevention strategies.

ABSTRACT:Posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is now standard for matched unrelated donor (MUD) hematopoietic cell transplantation (HCT). Previous studies comparing MUD and haploidentical donor HCT using PTCy were limited in size and follow-up. We therefore performed a registry-based analysis examining the impact of donor type on HCT with PTCy. Adult patients (n = 5873) receiving MUD (n = 1973) or haploidentical (n = 3900) HCT with PTCy for acute leukemia (74.2%) or myelodysplastic syndrome (MDS; 25.8%) reported to the Center for International Blood and Marrow Transplant Research between 2017 and 2021 were included. Primary end points were 3-year overall survival (OS) and GVHD-free, relapse-free survival (GRFS). Cox regression and sensitivity analyses were performed through adjustment of propensity scores. Haploidentical HCT had worse OS (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.04-1.27; P = .005) and GRFS (HR, 1.19; 95% CI, 1.10-1.29; P < .001) versus MUD HCT. Donor age was the only other donor factor associated with survival. Results were confirmed in sensitivity analysis. When restricted to reduced intensity conditioning or donors <30 years, OS did not differ between groups. Haploidentical HCT was associated with higher primary graft failure (HR, 1.67; P = .002), increased grade 3/4 acute GVHD (HR, 1.28; P = .039), higher moderate/severe chronic GVHD (HR, 1.47; P < .001), and nonrelapse mortality (HR, 1.34; P < .001). Grade 2 to 4 acute GVHD and relapse risk did not differ. This large analysis showed that in adults with acute leukemia or MDS, MUD HCT was associated with improved outcomes versus haploidentical HCT with PTCy-based GVHD prophylaxis.

TPS7103 Background: Despite recent advancements in NHL therapies, many patients experience disease progression or relapse. Agents with novel mechanisms of action and combination strategies are needed to improve clinical outcomes. B-cell lymphoma 6 (BCL6) is a master transcriptional regulator of immune cells, particularly of germinal center B cells, and an established oncogenic driver in NHL. ARV-393 is an oral PROteolysis TArgeting Chimera (PROTAC) BCL6 degrader that binds an E3 ubiquitin ligase and BCL6 to induce ubiquitination of BCL6 and its subsequent proteasomal degradation. ARV-393 monotherapy potently inhibited tumor growth and induced tumor regressions across NHL cell-derived xenograft (CDX) and patient-derived xenograft models, including models of DLBCL, transformed follicular lymphoma, and nodal T-follicular helper cell lymphoma (nTFHL). Furthermore, administration of ARV-393 with a CD20×CD3 bispecific antibody, glofitamab, demonstrated combinatorial antitumor activity in a humanized high-grade B-cell lymphoma CDX model, inducing deeper tumor growth inhibition and increased tumor regressions vs either monotherapy. These preclinical findings demonstrated single-agent ARV-393 antitumor activity across NHL subtypes and suggested mechanistic synergy with glofitamab, supporting clinical investigation of monotherapy in NHL and this chemotherapy-free combination in patients with DLBCL. Methods: This global, multicenter, open-label, first-in-human, phase 1 dose escalation and optimization/expansion study (NCT06393738) is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ARV-393 as monotherapy in relapsed or refractory (R/R) NHL or in combination with glofitamab in R/R DLBCL, with a primary objective of determining provisional doses for further exploration. Patients eligible for ARV-393 monotherapy are adults with confirmed R/R B-cell NHL who previously received ≥2 lines of systemic therapy (including rituximab), or nTFHL who previously received standard of care therapy. Patients eligible for ARV-393 in combination with glofitamab are adults with pathologically confirmed R/R DLBCL, DLBCL not otherwise specified, or large B-cell lymphoma arising from follicular lymphoma who were treated with ≥2 prior lines of systemic therapy. ARV-393 will be administered orally once daily in 28-day cycles alone or in combination with intravenous glofitamab during 21-day cycles. Approximately 255 patients will be enrolled across study cohorts. As of January 2026, enrollment is ongoing. Copyright © 2026 AACR. Originally presented at AACR 2026. Reprinted with permission. Clinical trial information: NCT06393738 .

Posttransplant cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD) improves outcomes in recipients of HLA mismatched unrelated donor (MMUD) allogeneic hematopoietic cell transplantation (allo HCT). Outcomes of MMUD HCT using PTCy in patients requiring reduced intensity or non-myeloablative conditioning (RIC/NMA) are not well described. The Phase II, prospective, ACCESS trial sought to evaluate PTCy-based GVHD prophylaxis in adult recipients of MMUD using peripheral blood stem cell allografts. Here, we report combined results of RIC/NMA recipients treated in the initial study (N = 70) and a planned expansion cohort (N = 123). The number of centers participating in the expansion protocol was 33 compared to 13 in the initial study. Median participant age was 65.0 (range: 22.9-78.9) and the HCT comorbidity index was high-risk (≥ 3) in 65 (33.7%). Donor HLA matching was < 7/8 in 62 (32.1%) participants. One-year survival was 79.6% (95% confidence interval: 73.2-84.7) and was similar between HLA 7/8- and HLA < 7/8-matched donor recipients. Survival was similar between participants in the initial study (78.6%) and the expansion cohort (80.3%) indicating generalizability of this strategy. One-year incidence of severe infection (Grade 3-5) was 39% (32%-46.9%). The 1-year incidence of non-relapse mortality and relapse estimates were 12.5% (8.3%-17.6%) and 17.3% (12.3%-23%), respectively. MMUD with PTCy-based GVHD prophylaxis and RIC/NMA conditioning was safe and effective to facilitate HCT. Outcomes were similar in the expansion cohort that enrolled from a greater number of centers. Post-HCT infections were prevalent.

Efficacy of CART- cell therapy is often challenged by a spectrum of toxicities that can have adverse patient outcomes. Persistent cytopenia and infectious complications, within the first 100 days after infusion represent a major cause of morbidity, yet their recovery trajectories, and prognostic implications remain poorly defined.We conducted a retrospective analysis of patients (pts) who received CD19- or BCMA-targeted CART-cell therapy for Diffuse large B cell lymphoma (DLBCL) or Multiple Myeloma(MM) at Karmanos Cancer Center between 2016 and 2024. Hematologic parameters were recorded before CAR T cell collection and at 1, 2, 3, 6, and 12-months following CART-cell infusion or until relapse, requiring additional treatment. Cytopenia was graded according to CTCAE v5.0 criteria. Cytopenia was characterized over time both by maximum grade and by trajectory clustering using a k-means-based approach to identify distinct recovery patterns.Our study included 174 adult pts who received CAR T-cell therapy with baseline characteristics are reported in Table 1. Cytokine release syndrome (CRS) was observed in 68% pts: grade 1 in 41%, and grade ≥3 in 4%. ICANS was observed in 28% pts and grade ≥3 ICANS occurred in 11% pts. 82% received CART as inpt, and 34 (24%) of the inpts and 16 (52%) of outpts required readmission. 21 pts required Intensive care unit admission. Infectious complications occurred in 30% within the first 100 days post-infusion. Among these, 25 pts experienced bacterial, 24 pts had documented viral ifns. Several pts experienced multiple concurrent viral ifns. Additionally, one pt developed Pneumocystis jirovecii pneumonia, and 2 pts developed mucormycosis, both of which were fatal. 19 pts required hospitalization due to ifn. Non relapse mortality was attributed to ifn in 12 pts. In Univariable and multivariate analysis, ICANS was identified as a significant predictor of ifn within 100 days (OR = 2.15; 95% CI, 1.06- 4.36, p= 0.033), independent of Pre CART risk factors and Post CART risk factors as reported in Table 2. Also, pts with 3–4 prior lines of therapy had significantly higher odds of neutropenia compared to those with 0–2 prior lines (OR = 2.68, 95% CI 1.14 to 6.73; p = 0.028). Pts clustered into the high anemia and thrombocytopenia grps had higher odds of ifn within 100 days post-CART-cell therapy. At a median follow-up of 6 yrs, 7 pts developed secondary malignancies following CART-cell therapy, including MDS(n=5), AML(n=1), and aplastic anemia (n=1).Our findings suggest that post-CART immune dysregulation, particularly ICANS which is often treated with steroids, increases the risk of developing ifns in the early post-infusion period. Higher grade of anemia and thrombocytopenia is associated with a higher risk of infectious complications. We also observed a few secondary myeloid neoplasms, which could contribute to long-term hematopoietic toxicity in some pts.

ACCESS is a prospective, multicenter phase II trial evaluating peripheral blood stem cell (PBSC) transplantation using 4-7/8 HLA-mismatched unrelated donors (MMUD) with post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate. Adults undergoing first HCT with myeloablative (MAC) or reduced-intensity/nonmyeloablative (RIC/NMA) conditioning were enrolled, with donors aged 18-35 years and matched at 4/8-7/8 HLA loci by high-resolution typing. This expanded analysis includes all enrolled adult PBSC recipients, including the protocol-specified RIC/NMA cohort expansion, to improve precision of outcome estimates and provide descriptive analyses by HLA match level. Among 268 adults, 183 received 7/8 and 85 received <7/8 MMUD grafts; 82.4% of the <7/8 cohort received 6/8 grafts. Median follow-up among survivors was 11.9 months. At 1-year, overall survival was 78.6% (95% CI, 71.9-83.9) in the 7/8 cohort and 85.6% (95% CI, 76.0-91.5) in the <7/8 cohort. One-year relapse, non-relapse mortality, and GVHD-free relapse-free survival were 17.1%, 13.7%, and 51.1% versus 22.8%, 8.4%, and 54.6%, respectively. The cumulative incidence of grade II-IV and grade III-IV acute GVHD by day 100 was 36.6% and 7.7% in the 7/8 cohort versus 28.3% and 5.9% in the <7/8 cohort. Moderate-to-severe chronic GVHD at 1 year was 11.3% versus 7.7%, respectively. Among adult ACCESS recipients treated on a uniform young-donor PBSC/PTCy platform, short-term outcomes with predominantly 6/8 MMUD transplantation were encouraging. Because donor match level was not prospectively assigned and between-group comparisons were exploratory, these findings are descriptive and should not be interpreted as establishing equivalence with 7/8 MMUD transplantation. (Registered as NCT04904588 at CT.gov)

BACKGROUND:Limited data exists comparing the efficacy of novel therapies containing brentuximab vedotin and/or checkpoint inhibitors to standard chemotherapy as treatment for relapsed/refractory classical Hodgkin Lymphoma. METHODS:In this study, we evaluated outcomes of 162 patients receiving second-line therapy, of which 64% (n = 104) were in the chemotherapy cohort and 36% (n = 58) in the novel therapy cohort. RESULTS:Over all responses for novel therapy and chemotherapy cohort were 76% versus 70% (P = .44), and complete response (CR) rates were 57% versus 46% (P = .40). The 2-year EFS rates were 72% versus 60% in novel therapy and chemotherapy cohort, respectively (P = .10). For patients who proceeded to autologous stem cell transplant (ASCT; n = 135), pretransplant CR predicted improved progression-free survival. In patients not proceeding to ASCT, prolonged 2-year EFS (86% vs. 33%, P < .01) was observed in those receiving novel therapy as second-line treatment. CONCLUSIONS:These data suggest improved outcomes in patients who receive novel agents compared to chemotherapy during second-line treatment.

Lymphodepleting chemotherapy (LD) enhances chimeric antigen receptor T cell (CAR-T) expansion, persistence, and clinical activity. Fludarabine-cyclophosphamide is most used, but the benefit of alternative agents is unknown. This study compares fludarabine- versus bendamustine-based LD in the real-world setting prior to CAR-T treatment of relapsed or refractory large cell lymphoma (LBCL). We assessed outcomes of patients with LBCL who received commercial CD19 CAR-T therapies during 2017 to 2023, using data from Center for International Blood and Marrow Transplant Research. Of 5256 patients with LBCL treated with axicabtagene ciloleucel, tisagenlecleucel, or lisocabtagene maraleucel, 92% and 9% received fludarabine and bendamustine LD, respectively. Multivariate analyses showed bendamustine had inferior overall response rate (ORR) (hazard ratio [HR] 0.773, P = .0013), but there was no difference in complete response (HR 0.828, P = .0606). The 1-year and 2-year rates of progression-free survival (PFS) were lower for bendamustine (P = .04), and the 1-year and 2-year rates of overall survival (OS) were similar (P = .65) The bendamustine group had lower rates of toxicities than the fludarabine group, including severe cytokine release syndrome (odds ratio [OR] 0.445, P < .0001), immune effector cell-associated neurotoxicity syndrome (OR 0.432, P < .0001), prolonged cytopenia (OR 0.479, P < .0001) Treatment-related mortality (TRM) was lower in the bendamustine group. In a subset analysis adjusting for distribution of LD regimens, the main conclusions were the same. Regardless of CAR-T products used, compared to patients who received bendamustine, patients who received fludarabine LD had higher ORR and PFS, without significant impact on OS. Bendamustine was associated with a reduced incidence of toxicities and TRM. Providers can consider relevant patient characteristics when choosing LD and the trade-off between efficacy and safety. Bendamustine can be considered an alternative LD prior to CAR-T for LBCL.

ABSTRACT:Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications for 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event, with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. In a multivariable analysis, receipt of ≥3 lines of therapy before tisa-cel (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.13-3.08; P = .015), any-grade cytokine release syndrome (HR, 1.78; 95% CI, 1.17-2.71; P = .007), and lack of neutrophil recovery (HR, 2.63; 95% CI, 1.47-4.69; P = .001) were associated with an increased risk for any infection. Similar associations were observed for bacterial infections, with the addition of younger age as an adverse risk (<6 vs 6-15 years; HR, 2.38; 95% CI, 1.23-4.61; P = .01). Risk factors for viral infections included increasing age (1-year increase; HR, 1.05; 95% CI, 1.01-1.09; P = .016), prior history of any infection (HR, 2.76, 95% CI, 1.40-5.46; P = .004), and prior hematopoietic cell transplant (HR, 2.10; 95% CI, 1.18-3.71; P = .011). D100 infection-related mortality (IRM) rate was low at 0.2% (95% CI, 0.0-0.8). In this multicenter real-world study, we observed a high incidence of infectious complications but a low IRM following tisa-cel for R/R B-ALL.

TPS7096 Background: N-(4-hydroxyphenyl)retinamide (4-HPR; fenretinide) is a synthetic amide derivative of all-trans retinoic acid. Clinical data from trials of earlier fenretinide formulations indicate that higher plasma levels of fenretinide correlate with improved patient responses. Although fenretinide intravenous emulsion (4-HPR-ILE) increased plasma concentration and yielded complete and partial responses in peripheral T-cell lymphomas, its dose-limiting hypertriglyceridemia mainly related to triglyceride from the soy oil vehicle posed a significant impediment to clinical development (Maurer BJ et al. Clin Cancer Res. 2017). Methods: A new formulation of intravenous fenretinide, designated ST-001 nanoFenretinide, is an innovative dosage form composed of phospholipid nanoparticles in a free-flowing solution (Patent number US 8709379 B2). ST-001 effectively eliminates the risk of vehicle-related hypertriglyceridemia, because it is free of triglycerides. It is also free of adjuvants, non-ionic surfactants, polyoxylated compounds, alkoxylated oils, and animal-derived substances known to cause allergy or hypersensitivity. ST-001 potentially provides a safer form of intravenous fenretinide for achieving therapeutic plasma concentrations. In this Phase 1a/1b clinical trial (NCT04234048), ST-001 is administered via intravenous infusion (IV) to patients with relapsed/refractory T-cell non-Hodgkin’s lymphoma (NHL) following at least one prior treatment, including cutaneous (CTCL) and non-cutaneous T-cell lymphoma subtypes (angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, and follicular T-cell lymphoma). The U.S.-based trial will enroll up to 54 patients across three stages: up to 9 patients (single patient cohorts) for Phase 1a accelerated dose escalation, up to 15 patients (3 patient cohorts) for Phase 1a standard dose escalation and determination of maximum tolerated dose (MTD), and 30 patients for Phase 1b to determine the optimal dose. The primary objectives are to determine the MTD, toxicity profile, adverse events and dose-limiting toxicities (DLTs) based on NCI Common Toxicity Criteria, and anti-tumor activity, when administered over 4 hours daily for 5 consecutive days every 3 weeks, for a maximum of 8 cycles. Secondary objectives include pharmacokinetic profiling and investigating potential mechanisms of action using pharmacodynamic biomarkers. The accelerated stage has completed enrollment, and the standard stage is open for enrollment as of January 2025. This study investigates a novel fenretinide formulation aiming to address treatment challenges in T-cell NHL, with a focus on safety, tolerability, clinical activity, and pharmacology. Clinical trial information: NCT04234048 .

Introduction: Since initial approval in 2017, chimeric antigen receptor T-cell therapy (CAR-T) has transformed outcomes for hematological malignancies. CAR-T has traditionally been administered in the inpatient (inpt) setting, due to the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). As reported by Hansen et al in Cancers, outpatient (outpt) CAR-T administration has been shown to have a favorable safety profile and lower financial toxicity. Many institutions have strict guidelines for selecting outpt treatment candidates, including caregiver support, proximity to the hospital, and infrastructural support within the institution. In this single-center institutional study, we assess the safety and efficacy of outpt CAR-T administration at an urban hospital. Methods: We retrospectively collected data from all patients who received CAR-T therapy from May 2016 to September 2024 at Karmanos Cancer Institute in Detroit, Michigan. Data was stratified by inpt and outpt CAR-T administration. We selected only patients with multiple myeloma (MM) or diffuse large B-cell lymphoma (DLBCL) for this study. Baseline patient characteristics were summarized using counts and percentages for categorical variables, and medians with ranges for continuous variables. Group comparisons based on inpt versus outpt status were performed using the chi-square test or Fisher's exact test for categorical variables, and the Wilcoxon rank-sum test for continuous variables. Overall survival (OS) was defined as the time from CAR-T administration to death from any cause. Relapse-free survival (RFS) was defined as the time from CAR-T administration to documented relapse or death, whichever occurred first. Kaplan–Meier methods were used to estimate survival distributions for OS and RFS. Follow-up time was estimated using the reverse Kaplan–Meier method. Survival distributions were compared using the log-rank test. The proportional hazards assumption was evaluated using Schoenfeld residuals. Where the proportional hazards assumption was held, Cox proportional hazards regression was used to derive hazard ratios. In cases where the assumption was violated, a weighted Cox regression model was applied. Results: During the study period, 174 patients received CAR-T. 143 patients were treated inpt, and 31 patients were treated outpt. Most patients treated in the outpt setting had DLBCL (77.4%, p = 0.027). In the outpt cohort, 14 patients received tisa-cel, 7 patients received ida-cel, 6 patients received liso-cel, and 4 patients received axi-cel. The inpt cohort received cilta-cel, brexu-cel, or other products in addition to the aforementioned therapies. Interestingly, there was not a statistically significant difference in CRS between the inpt (75.68%) and outpt (55.0%) cohorts (p = 0.099). There was no statistically significant difference in incidence of ICANS, infectious complications, or cardiac complications between inpt and outpt cohorts. 35.5% of patients in the outpt cohort required readmission within 100 days. The median duration of hospitalization for readmitted patients in the outpt cohort was 6 days, the median duration of overall hospitalization for the inpt cohort was 11 days, and this was statistically significant (p = 0.008). Incidence of ICU admission was 3.23% and 14.0% in the outpt and inpt cohort respectively, which was not statistically significant (p = 0.21). With median follow up of 2.05 years and 1.77 years, median overall survival (OS) was 2.15 years (95% CI, 1.48 to NR) and 4.24 years (95% CI, 2.17 to NR) for outpt and inpt cohorts respectively, but was not statistically significant. Similarly, relapse free survival (RFS) was not statistically different between the two groups. Additionally, there was not a statistically significant relationship between age, and whether CAR-T was administered inpt or outpt. Conclusions: Outpt infusion of CAR-T cells was safe and post CAR-T cell outcomes did not differ based on inpt vs. outpt infusion. In fact, the readmitted patients in the outpt cohort had a shorter hospital duration compared to patients treated inpatient, which was statistically significant. Outpt infusion of CAR T cells can reduce the burden of hospitalization for these patients.

ABSTRACT:Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 patients (3.2%), respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient days. After a 24-month median follow-up, 1482 patients (44%) had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0). Patients with a Karnofsky performance score of ≤80, infection history before CAR T-cell therapy, axi-cel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell-associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell therapy. Furthermore, results identify patients at a heightened risk of infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.