OBJECTIVE:The International Federation of Gynecology and Obstetrics 2023 endometrial cancer staging system includes 21 sub-stages and proposes a shift from pure anatomical staging to an approach incorporating histology, grade, lymphovascular invasion, and molecular classification. We sought to evaluate the overall survival prognostic ability of the International Federation of Gynecology and Obstetrics 2023 endometrial cancer staging system compared with the International Federation of Gynecology and Obstetrics 2009 system. METHODS:We collected clinicopathologic characteristics, molecular profiling results, and survival outcomes for all patients with a new diagnosis of endometrial cancer treated at our institution between 2016 and 2020. All cases underwent pathology review by a gynecologic pathologist at our institution. An International Federation of Gynecology and Obstetrics 2009 and 2023 stage was assigned. We applied R2ϵ statistics based on an isotonic proportional hazards model to compare prognostic ability between the 2 staging systems. RESULTS:Of 2067 patients with endometrial cancer, 952 (46%) underwent tumor molecular profiling. When comparing International Federation of Gynecology and Obstetrics 2009 and 2023 staging, 538 (26.0%) patients were upstaged and 100 (4.8%) were downstaged in the 2023 system. Five-year overall survival estimates were similar across most stages between the 2 staging systems, with some exceptions: the International Federation of Gynecology and Obstetrics 2023 IA3 sub-stage demonstrated improved outcomes (100% vs 70.3% for International Federation of Gynecology and Obstetrics 2009 IIIA) and the IICmp53abn group had poorer prognosis (73% vs 86.8% for International Federation of Gynecology and Obstetrics 2009 II). Using isotonic proportional hazards regression models, the 2023 model slightly numerically outperformed the 2009 model for overall survival (R2ϵ 0.546 vs 0.415); however, adjusted 95% confidence intervals were under-developed. CONCLUSIONS:Using a real-world, large, well-annotated cohort of patients with endometrial cancer with expert pathology review, we were able to calculate 5-year progression-free and overall survival rates for each sub-stage. The International Federation of Gynecology and Obstetrics 2023 model demonstrated slightly improved prognostic discrimination compared with the International Federation of Gynecology and Obstetrics 2009 model; however, small patient numbers in each sub-stage and concerns regarding over-fitting limit this analysis.

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.

Bridging therapy (BT) is frequently administered during CD19 CAR T-cell manufacturing for relapsed or refractory large B-cell lymphoma (LBCL), and although disease status at infusion has been associated with outcomes, the prognostic relevance of response to BT, independent of BT modality, has been variably defined in real-world cohorts. To assess the impact of bridging response on clinical outcomes after CD19 CAR T-cell therapy in patients with LBCL, and to determine whether response to BT or BT regimen type are associated with progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. We conducted a retrospective multicenter study of 377 adults with relapsed/refractory LBCL treated with commercial CD19 CAR T-cell products (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel) between 2020 and 2024. BT was administered in 248 patients (66%) during the manufacturing period and categorized by regimen type. Response to BT and CAR T therapy were assessed using Lugano criteria. The primary endpoints were PFS and OS after CAR T infusion. Secondary endpoints included rates of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematologic toxicity. Multivariable Cox regression models adjusted for performance status, lactate dehydrogenase (LDH), CAR T product, and BT category were applied to evaluate associations. Among patients receiving BT, the overall response rate prior to CAR T infusion was 49%, including complete response (CR) in 12%. Patients achieving CR or partial response (PR) to BT had significantly longer PFS and OS compared with those with stable or progressive disease (SD/PD) (median PFS and OS not reached vs shorter durations; P < .01). In multivariable analysis, response to BT remained an independent predictor of both PFS (hazard ratio [HR] for SD/PD versus CR: 2.59, 95% confidence interval [CI] 1.28 to 5.22) and OS (HR: 4.53, 95% CI 1.64 to 12.5), while BT modality itself was not independently associated with survival outcomes. Patients with favorable BT responses demonstrated lower pre-infusion tumor burden and reduced systemic inflammatory markers. Rates of CRS and ICANS did not differ significantly by BT response category. Severe hematologic toxicity was more frequent following intensive chemotherapy-based BT regimens but was not independently associated with long-term outcomes. In this large observational real-world multicenter cohort, response to BT, rather than the specific BT modality, was strongly associated with improved survival outcomes after CD19 CAR T-cell therapy in LBCL. These findings emphasize the prognostic significance of pre-infusion disease control and support treatment strategies focused on achieving effective BT responses while balancing regimen toxicity.

Background: Clonal hematopoiesis (CH) is associated an increased risk of hematologic malignancy and numerous other adverse events. While there are no established therapeutic approaches to treat CH, clinical trials are underway, many of which use targeted therapeutic approaches for specific CH genes or genetic pathways. Since CH screening is generally not part of routine clinical testing, the identification of CH-positive individuals is a challenge to recruitment. While age is the most important risk factor for CH, CH is also known to be associated with other demographic and clinical risk factors. Blood count and blood parameters are also known to be influenced by CH with gene-specific patterns. Here we sought to understand whether commonly available clinical predictors and blood counts could be used to develop a gene-specific CH risk prediction tool with the goal of facilitating CH research screening strategies. Methods: We constructed a prediction model for CH across three cohorts of participants using LASSO regression. Clinical predictors included clinical/demographic characteristics (smoking history, gender, race) and blood count parameters. The UK Biobank served as the development cohort, consisting of 452,547 participants. We used two separate cohorts for validation, The All of Us (AoU) Research database, consisting of 143,850 participants, and MSK-IMPACT cohort, including 8,150 patients with non-hematologic cancers. We compared models with age alone to models including blood count and other clinical/demographic parameters. The predictive performance was determined based on 2 criteria: discrimination by calculating the area under the curve (AUC) receiver operating characteristic (ROC) and calibration by calculating the calibration slope (slope of 1 indicates perfect calibration) and the intercept. Results: A total of 604,547 participants were included in the study. We observed strong associations between clinical features and gene-specific CH including platelet count with DNMT3A and JAK2, neutrophil count and IDH1/2 mutations, and a strong association between spliceosome CH and age. Overall our model showed excellent discrimination (AUC>0.8) for risk JAK2, ASXL1, PPM1D, SF3B1, SRF2, U2AF1 and modest discrimination (AUC>0.7) for DNMT3A, IDH1/2, TP53 and TET2. Compared to a model with age alone, the addition of blood count and clinical parameters improved the model's performance most notably for JAK2 (AUC = 0.72 vs 0.82) and IDH1/2 (AUC = 0.75 vs 0.78). The calibration slopes for gene-specific models ranged from 0.35-1.65 and were highest for JAK2 (slope=0.9; intercept=0.02 ) and TP53 (slope=0.89; intercept=-0.02) . To better determine how our risk prediction model could be used to inform CH screening strategies, we determined the number of patients that would be required to screen using our CH risk prediction model and the number needed to sequence to identify 100 CH positive individuals across 10 CH genes. Application of our risk prediction model to identify individuals at high risk of CH for screening reduced the number of samples needed to sequence by 4-19 fold. Conclusion: We developed and validated a model for gene-specific CH prediction using blood count parameters and demographic factors with strong discriminative performance. These findings highlight the potential of commonly available clinical data to improve CH prediction, aiding in efficient identification of individuals with CH to facilitate clinical trial design.

CAR T-cell therapy has transformed relapsed/refractory large B-cell lymphoma (LBCL) treatment, yet durable remissions remain challenging. In this retrospective multicenter study, 479 LBCL patients treated with commercial CD19 CAR-T products, axicabtagene ciloleucel (axi-cel, n = 262), tisagenlecleucel (tisa-cel, n = 131), and lisocabtagene maraleucel (liso-cel, n = 86), were evaluated using serial landmark analyses, with median follow-ups of 23, 34, and 16 months, respectively. Progression-free survival (PFS) was assessed at Day 28 and at 3, 6, 12, 18 and 24 months post-infusion to determine when relapse risk declines and sustained disease-free remission is achieved. Patients who attained a complete response (CR) at early time points had significantly improved PFS. In multivariable analyses, elevated pre-lymphodepletion lactate dehydrogenase (LDH) levels were independently associated with inferior PFS across several landmarks (HR 2.67, P < .001 at Day 28; HR 1.83, P = .044 at 3 months; HR 2.19, P = .016 at 6 months) and showed consistent association with inferior overall survival (OS) at these same time points. Cumulative relapse and non-relapse mortality (NRM) estimates supported the prognostic value of sustained CR. This landmark-based analysis advances understanding of durable remission kinetics following CAR T-cell therapy, indicating a trend toward cure, though longer follow-up is needed to confirm durable remission.

The American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system standardized the classification of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR) T-cell therapy. However, the prognostic relevance of CRS and ICANS, as well as immune effector cell-associated hematological toxicity (ICAHT), remains incompletely defined. In this multicenter retrospective study, adult patients with mature B-cell malignancies treated with CD19-directed CAR-T therapy between 2016 and 2024 at three academic centers were included. CRS and ICANS were graded according to ASTCT criteria, and early ICAHT according to EHA/EBMT consensus definitions. The primary endpoint was non-relapse mortality (NRM); secondary endpoints included overall survival (OS) and progression-free survival (PFS). Outcomes were evaluated using day 30 landmark analyses with multivariable models stratified by center and adjusted for clinically relevant covariates; a complementary sensitivity analysis modeled CRS as a time-dependent covariate for NRM in the full cohort from day 0. Among 560 patients, axi-cel was the most frequently used product (48%), followed by tisa-cel (25%), liso-cel (23%) and brexu-cel (4%). With a median follow-up of 23.9 months, the 2-year cumulative incidence of NRM for the full cohort was 7.2%, with 2-year OS and PFS of 57% and 41%, respectively. Overall, 140 patients (25%) and 61 (11%) developed grade 2 and grade 3 to 4 CRS, respectively; 40 (7%) and 74 (13%) developed grade 2 and grade 3 to 4 ICANS, respectively; and 151 (30%) and 144 (29%) developed grade 2 and grade 3 to 4 early ICAHT, respectively. In a day +30 landmark analysis adjusted for baseline covariates, CRS and early ICAHT severity was not independently associated with NRM, OS, or PFS. In contrast, grade ≥3 ICANS was independently associated with increased NRM (HR: 2.46, 95% CI, 1.00 to 6.04) and inferior OS (HR: 1.79, 95% CI, 1.14 to 2.81), but not with PFS. In the sensitivity analysis, grade 3 to 4 CRS was associated with NRM in univariable but not in multivariable analysis. In this real-world cohort of patients treated with CD19 CAR-T cells, we found that high grade ICANS retained independent prognostic significance for outcomes beyond day 30, whereas CRS and early ICAHT did not; however, severe CRS may still contribute to early treatment-related mortality. These findings support the clinical utility of modern grading systems for outcome interpretation and emphasize neurotoxicity as a priority for preventive interventions after CD19 CAR-T therapy.

Concerns of increased toxicity when dosing obese patients undergoing autologous hematopoietic cell transplantation have historically led to dose-adjustments. We retrospectively compared outcomes of 239 adult patients with lymphoma between 3 groups: nonobese patients, obese patients dosed on adjusted body weight, and obese patients dosed on total body weight. We found dosing obese patient on adjusted body weight resulted in poorer transplant outcomes. Toxicities were similar across all dosing strategies. Hematopoietic cell transplantation requires higher doses of chemotherapy, and practices of adjusting the weight because of concerns of organ toxicity are common. This retrospective analysis of 239 adult recipients of autologous hematopoietic cell transplantation for lymphoma assessed the effect of obesity on transplantation outcomes. Background: Prior data evaluating the impact of obesity in autologous hematopoietic cell transplantation (AHCT) for lymphomas have provided differing results when assessing overall (OS) and progression-free survival (PFS). Impact on survival outcomes have been described, but direct comparison of discrete toxicities is lacking. Patients and methods: We retrospectively compared outcomes with patients divided between 3 groups: nonobese patients (n = 129), obese patients dosed on adjusted body weight (AdjBW) (n = 32), and obese patients dosed on total body weight (TBW) (n = 78). Results: In multivariate analysis of OS with the nonobese group as the comparator, outcomes trended worse in obese patients dosed on AdjBW (HR 1.22, 95% CI 0.52-2.85) but were improved in obese patients dosed on TBW (HR 0.19, 95% CI 0.04-0.85, P = .012). PFS of obese patients dosed on AdjBW vs. the nonobese group was comparable (HR 1.19, 95% CI 0.63-2.24), but improved in obese patients dosed on TBW (HR 0.45, 95% CI 0.23-0.89, P = .021). Notably, no differences were noted between groups in gastrointestinal, infectious, renal, or hepatic toxicities. Conclusion: In summary, our data suggest that recipients of AHCT for lymphoma should be dosed on TBW to maximize curative outcomes with no apparent increase in toxicities.

Recurrent mosaic somatic mutations in circulating leukocytes can be frequently found in the aging population. These mutations frequently arise in epigenetic modifier genes like TET2. In the absence of signs of hematologic malignancies this condition is termed clonal hematopoiesis (CH). Although CH has been associated with increased incidence and adverse outcomes in patients with solid tumors, the disease-specific effects and mechanisms by which CH alters solid tumor biology have not been delineated. To develop insights into the interplay between mutant CH clones and epithelial tumor cells we analyzed a cohort of over forty-seven thousand patients who underwent paired blood and tumor sequencing. After correcting for age, sex, ancestry, stage, smoking, and previous treatment history, we identify unique patterns of poor survival associated with specific CH genotypes and solid tumor histologies. Given that the detection of tumor-infiltrating TET2-CH clones is especially associated with poorer outcomes in thyroid cancer patients (HR 2.18, 95%CI 1.18-4.05, p=0.013), we focused on studying the role of CH in thyroid cancer biology. Compared to other CH alleles, TET2-mutant CH is enriched in the tumor microenvironment (TME) across solid tumors and is associated with adverse prognosis specifically in Anaplastic thyroid cancer (ATC) patients. ATC is a clinically aggressive malignancy with a dismal prognosis. Combined BRAF/MEK inhibition offers significant therapeutic benefit in patients with BRAFV600E-mutant ATCs. However, relapses are common and overall survival remains poor. A hallmark of ATC is significant infiltration with myeloid cells, particularly macrophages. ATCs are most common in the aging population, which also has an increased incidence of TET2-mutant CH. These mutant macrophages have been shown to accelerate CH-associated pathophysiology including atherosclerosis. However, the clinical and mechanistic contribution of TET2-mutant clones to the prognosis and/or treatment response in solid tumors has not been elucidated. Using subclonal murine models of Tet2-mutant CH we confirm that mutant macrophages selectively infiltrate mouse BrafV600E-mutant ATC models (58% higher enrichment of Tet2-/- cells in the TME compared to the WT counterparts) and confer resistance to BRAF/MEK inhibition (68-days median survival compared to no mortality after 147 days). Using single-cell CITEseq, we identify that the overexpression of Tgfβ-family ligands by CH macrophages is the driver of this resistance. Importantly, inhibition of Tgfβ signaling or the depletion of mutant-macrophages completely restored the sensitivity to MAPK pathway inhibition. In summary, this work identified a novel actionable resistance mechanism mediated by a clonally driven process within the tumor-immune microenvironment. Pablo Sanchez Vela, Vera Tiedje, Julie L. Yang, Brian R. Untch, Laura Boucai, Aaron J. Stonestrom, Alberto Bueno Costa, Sebastià Franch Expósito, Sebastià Franch Expósito, Avi Srivastava, Marina Kerpelev, Jillian Greenberg, Matthew Wereski, Amanda Kulick, Kevin Chen, Tianyue Qin, Soo-Yeon Im, Anthony R. Martinez Benitez, Raquel Pluvinet, Merve Sahin, Kamal Menghrajani, Gnana P. Krishnamoorthy, Elisa de Stanchina, Ahmet Zehir, Rahul Satija, Jeffrey Knauf, Robert L. Bowman, Manel Esteller, Sean Devlin, Michael F. Berger, Richard P. Koche, Ross L. Levine, James A. Fagin. TET2-mutant clonal hematopoiesis enrichment in the tumor microenvironment is an actionable driver of treatment resistance in solid tumors: Thyroid cancer as a paradigm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2552.

Hematopoietic cell transplant (HCT) is a potentially curative treatment modality for patients with hematologic malignancies, but it can be associated with significant financial burden and toxicity due to increased medical expenditures (ie, prescription drugs). Prophylactic anti-infective medications are an essential component of allogeneic hematopoietic cell transplantation (allo-HCT) and help mitigate early post-transplant complications. Although these prophylactic anti-infective medications are essential, insurance barriers (ie, prior authorizations, denials, and high out-of-pocket costs) limit access for many patients and may result in reduced access to allo-HCT. The objective of this study was to evaluate the degree and severity of insurance barriers in a large cohort of allo-HCT recipients to characterize the patient populations and transplant types experiencing these barriers. Medical records of patients who received high-cost medications (mold-active triazoles and letermovir [LTV]) during their first allo-HCT (1/1/20 - 5/1/22) were evaluated for insurance type, ancestry/ethnicity, and stem cell source. Pharmacy records were used to analyze insurance barriers in the first 100 d post-transplant. Patients were categorized as having Minimal to None, Moderate, or Extensive barriers. In the azole (n = 287, voriconazole n = 162, posaconazole n = 64, isavuconazole n = 61) and LTV (n = 191) groups, the median age was 61 (range 19 to 81) and 61 years (range 22 to 81), respectively, with 44% female overall. In the azole group, 60% of patients had Minimal to None, 23% had Moderate, and 17% had Extensive barriers, while in the LTV group, 39% had Minimal to None, 28% had Moderate, and 33% had Extensive barriers. Seventy percent of patients had private insurance. The proportion of private vs. governmental insurance was equal in each barrier category in the azole group; however, among patients receiving LTV, those with government insurance were more likely to fall into the Extensive barrier category. Extensive insurance barriers impacted 17% (49/287) of patients prescribed high-cost azoles. Among these patients, 31% had projected costs exceeding $1000, 78% required financial assistance (20% copay assistance card, 12% drug manufacturer assistance, 62% internal financial assistance), and 80% required more than 60 min of PharmD time to coordinate financial resources to make care affordable, compared to just 1% of patients with minimal/no barriers. Among patients prescribed LTV, one-third (63/191, 33%) faced extensive insurance barriers with 57% of these patients having projected costs exceeding $1000, 98% required financial assistance (34% copay assistance card, 45% manufacturer assistance, 21% internal financial assistance), and 68% required more than 60 min of PharmD time, compared to 8% of patients with minimal/no barriers. For both the azole and LTV groups, by univariable analysis, insurance type, ancestry/ethnicity, and stem cell source were not statistically significantly associated with having moderate or extensive barriers. Approximately half of the cohort required additional financial resources to ensure access to essential post-allo-HCT azoles and LTV. Neither insurance type nor transplant characteristics predicted the level of barrier, suggesting that all patients should be assessed for financial toxicity. Pharmacists play an integral role in overcoming the insurance barriers for these high-cost medications, and work is ongoing to expand our understanding of the financial issues impacting our patients.

PURPOSE We designed a CD19-targeted chimeric antigen receptor (CAR) comprising a calibrated signaling module, termed 1XX, that differs from that of conventional CD28/CD3ζ and 4-1BB/CD3ζ CARs. Preclinical data demonstrated that 1XX CARs generated potent effector function without undermining T-cell persistence. We hypothesized that 1XX CAR T cells may be effective at low doses and elicit minimal toxicities. METHODS In this first-in-human, phase I, dose escalation and expansion clinical trial, patients with relapsed or refractory large B-cell lymphoma received 19(T2)28z-1XX CAR T cells at four dose levels (DLs), ranging from 25 to 200 × 10 6 . RESULTS Twenty-eight patients underwent apheresis and received CAR T cells. Sixteen and 12 patients were treated in the dose escalation and expansion cohorts, respectively. The overall response rate (ORR) was 82% and complete response (CR) rate was 71% in the entire cohort. The lowest dose of 25 × 10 6 was selected for dose expansion. In 16 patients treated at this DL, 88% achieved ORR and 75% CR. With the median follow‐up of 24 months, the 1-year event-free survival was 61% (95% CI, 45 to 82) and 14 patients remain in continuous CR beyond 12 months. In all cohorts, grade ≥3 cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome rates were low at 4% and 7%, respectively. 1XX CAR T-cell products contain a higher proportion of CD8 T cells with memory features, and CAR T-cell persistence has been detected beyond 1-2 years in patients with ongoing remission. CONCLUSION The calibrated potency of the 1XX CAR affords excellent efficacy at low cell doses with favorable toxicity profiles and may benefit the treatment of other hematologic malignancies, solid tumors, and autoimmunity.

6553 Background: Current guidelines support allogeneic hematopoietic cell transplantation (allo-HCT) in patients with acute leukemia who achieve complete remission (CR) and are at high risk for relapse. Patients with primary refractory disease or those refractory to re-induction therapy after relapse have a poor prognosis without allo-HCT. While several studies have explored the role of allo-HCT in this setting, most have focused on patients receiving myeloablative conditioning (MAC) and have not included contemporary transplant patients or accounted for the impact of molecular genetic risk factors. Consequently, the benefit of allo-HCT in this patient population remains unclear. Methods: This study evaluated the outcomes of patients with acute leukemia from two centers who underwent allo-HCT between 2009 and 2020 while not in CR at the time of transplant, receiving either myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens. Results: Our cohort included 196 patients who underwent transplantation between 2009 and 2020, with the majority (86%) diagnosed with acute myeloid leukemia (AML). At 36 months post-transplant, the probability of overall survival (OS) was 24% (95% CI: 19-31). In multivariable analysis, the presence of circulating blasts, recipient CMV seropositivity, and low pre-transplant albumin levels were associated with reduced OS. The cumulative incidence of relapse was 54% (95% CI: 47-61) at 36 months, with the presence of circulating blasts being significantly associated with an increased incidence of relapse. Among AML patients, the presence of at least one high-risk mutation (TP53, RUNX1, ASXL1, or FLT3-ITD, historically considered high-risk per National Comprehensive Cancer Network [NCCN] criteria version 3.2021) was also associated with an increased incidence of relapse. Conclusions: Allo-HCT provides a durable remission in a select group of patients with relapsed or refractory acute leukemia, with an overall survival of 24% at 36 months. The presence of circulating blasts, CMV seropositivity, and low albumin levels at the time of allo-HCT were associated with increased relapse and inferior OS in this retrospective analysis. The impact of these factors should be further investigated in larger, prospective cohorts to better identify patients with acute leukemia not in CR who would benefit from allo-HSCT.

Chimeric antigen receptor (CAR) T-cell therapy has reshaped the treatment paradigm for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, its role in central nervous system lymphoma (CNSL) remains uncertain. We conducted a multicentre, retrospective study on 54 adult R/R CNSL patients treated at four international institutions with commercial (axi-cel, tisa-cel, liso-cel) or a point of care (POC) CD19-CAR T-cell products. At day 100 post CAR-T infusion, 65% of patients attained a complete response as their best response in both systemic and central nervous system compartments. The median progression-free survival (PFS) was 7.5 months, with a 1-year PFS of 35%. The median overall survival (OS) was 19 months, with a 1-year OS of 63%. In multivariable analyses, CAR-T product was significantly associated with PFS ( p  = 0.009) and OS ( p  = 0.013), with patients receiving tisa-cel exhibiting poorer outcomes than axi-cel and patients receiving liso-cel or POC CAR-T product demonstrating better outcomes than axi-cel. Toxicity profiles were consistent with pivotal trials in R/R DLBCL. Grade ≥3 cytokine release syndrome occurred in 11% of patients, while grade ≥3 immune-effector cell-associated neurotoxicity syndrome was observed in 28%. Our study supports the feasibility and safety of anti-CD19 CAR-T therapy in CNSL. The specific CAR-T product infused emerged as a factor influencing outcomes.

This single-center, retrospective study analyzed vaccine responses in patients who received post-Chimeric Antigen Receptor (CAR) T-cell therapy vaccination between 2018 and 2024. Vaccinations were administered according to EBMT/CIBMTR recommendations and pathogen-specific IgG responses to 12 vaccine-preventable infections were assessed. Seroprotection was defined by established cut-offs or a significant fold increase in titers. A total of 73 patients that had not received intravenous immunoglobulins within the eight weeks prior to pre- or post titer were included. The median time to vaccination initiation was 13 months (range 6–66) post-CAR T. Pre and post-vaccination titers were available for 49 patients. Pre-vaccination seroprotection was high (> 85

Double-unit cord blood transplantation (dCBT) has been associated with high rates of progression-free survival (PFS) in adults with hematologic malignancies but also with relatively high rates of acute graft-versus-host disease (aGVHD). We conducted a single-arm, phase 2 clinical trial that investigated the addition of tocilizumab, an interleukin-6 receptor blocker, to cyclosporine-A (CSA) and mycophenolate mofetil (MMF) for aGVHD prophylaxis after intermediate-intensity dCBT. A total of 45 patients (median age, 47 years; range, 27-60 years; 80% acute leukemia; median hematopoietic cell transplant-comorbidity index, 2) were enrolled from March 2018 to March 2021. Transplant outcomes were compared with 39 previous CSA and MMF dCBT controls with similar inclusion criteria. Tocilizumab recipients had less pre-engraftment syndrome (38%; 95% confidence interval [CI], 24-52 vs 72%; 95% CI, 54-84; P < .001) but inferior day 45 neutrophil engraftment (93%; median, 25.5 days vs 97%; median, 22 days; P = .009]. The primary end point of day 100 grade 2 to 4 aGVHD was no different between groups (71%; 95% CI, 55-82 with tocilizumab vs 82%; 95% CI, 65-91; P = .11). However, there was a trend toward a lower day 100 incidence of stage 1 to 4 lower gastrointestinal aGVHD with tocilizumab (16%; 95% CI, 7-28 vs 33%; 95% CI, 19-48; P = .059). There were no significant differences in the 3-year incidences of relapse, transplant-related mortality, PFS, or overall survival between the groups. Tocilizumab recipients exhibited a distinct pattern of gut microbiome disruption. In summary, tocilizumab-based GVHD prophylaxis delayed neutrophil recovery without a significant reduction in aGVHD and had no survival benefit after dCBT. Investigation of alternative strategies to prevent severe aGVHD after dCBT is warranted. This trial was registered at www.clinicaltrials.gov as #NCT03434730.

This cohort study examines barriers to access of CAR T-cell therapy among patients with hematologic cancer referred for this treatment.

SIGNIFICANCE:The acceptance of MRD-negative complete response as an endpoint that is reasonably likely to predict clinical benefit will allow for the design of streamlined clinical trials for accelerated approval, enabling significantly faster patient access to novel therapies. Cooperative efforts were required to obtain and analyze clinical trial data from multiple sponsors and to determine the best approach to analysis with a relatively limited number of available datasets. The process to evaluate MRD as an intermediate endpoint, undertaken jointly by myeloma researchers and industry, with feedback from the FDA, serves as a roadmap for other areas of oncology to develop intermediate endpoints.