Post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis is associated with reduced chronic GVHD (cGVHD) incidence. However, differences in cGVHD presentation, treatment burden, and survival outcomes between PTCy and non-PTCy prophylaxis remain less well characterized, especially outside of haploidentical donor setting.We conducted a single-center retrospective study of 1,534 consecutive matched related or matched/mismatched unrelated donor transplants: 477 received PTCy-based prophylaxis and 1,057 received non-PTCy prophylaxis. PTCy regimens included PTCy/tacrolimus (TAC)/mycophenolate mofetil (MMF) (61%), PTCy/sirolimus (SIR)/MMF (26%), PTCy/SIR (12%), and other (1%). Non-PTCy regimens included TAC/SIR (72%), TAC/methotrexate (MTX) (26%), TAC/MMF (1%), and other (<1%).The 4-year cumulative incidence of cGVHD was significantly lower in the PTCy group (35% vs. 58%, p<0.001), as was moderate/severe cGVHD (17% vs. 46%, p<0.001). Among patients who developed cGVHD (PTCy: n=163; non-PTCy: n=656), those in the PTCy group had less organ involvement (lower % with ocular, joint, liver, oral, pulmonary, skin, and cutaneous sclerosis: all p<0.01), lower organ severity scores (in eye, liver, skin: all p<0.05), and reduced overall NIH moderate/severe disease burden (p<0.01).Despite these favorable features, survival from cGVHD onset was borderline inferior in the PTCy group (p=0.059), with higher non-relapse mortality (NRM) at 24 months (22% vs. 13%, p=0.014). Cause of death distributions were overall comparable between major categories such as GVHD (6% vs. 7%), organ failure (20% vs. 17%), infection (14% vs. 18%), relapse (35% vs. 32%), and other (24% vs. 26%). PTCy-associated cGVHD had higher infectious complications (increased infection density within 100 days of cGVHD onset), despite less immunosuppressive therapy exposure and higher rates of complete immune suppression discontinuation (42% vs. 15%, p<0.001).Although PTCy-based prophylaxis results in lower cGVHD incidence and severity, outcome following cGVHD onset remains suboptimal, driven by increased NRM and infectious complications. These findings warrant multi-center validation and highlight the need for strategies to improve outcomes in cGVHD following PTCy.

Chimeric antigen receptor (CAR) T-cell therapy, including axicabtagene ciloleucel (axi-cel), is efficacious for older patients. However, patients aged 65 + are at risk for more severe neurotoxicity after infusion than younger patients, and post-infusion cognitive outcomes in older patients are unknown. This study assessed changes in objective neurocognitive performance in patients age 65 + compared to those younger than 65 in the first year after axi-cel and examined clinical factors influencing these changes. In patients with large B-cell lymphoma, neuropsychological assessments were conducted prior to initiation of axi-cel and at 30, 90, and 360 days after infusion. Mixed effects models were used to investigate age differences in changes in overall cognition (e.g., total neuropsychological performance [TNP]) and specific domains (i.e., attention, executive function, verbal ability, immediate and delayed memory, and visuospatial abilities). Among 155 participants (63

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.

Background:Severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain frequent, life-threatening complications of CD19 chimeric antigen receptor (CAR) T-cell therapy and constrain its safety, scalability, and outpatient adoption. Existing predictive models lack sufficient external validation for routine clinical use, and pre-infusion biomarkers that capture host susceptibility before infusion are urgently needed. Methods:We applied unbiased mass-spectrometry-based proteomics to pre-infusion biofluids from 98 prospectively-followed adults with relapsed/refractory (r/r) lymphoma at two academic centers (MD Anderson Cancer Center, n = 39, plasma; Moffitt Cancer Center, n = 59, serum). Logistic regression with backward feature selection on the MD Anderson cohort yielded panels for severe (Grade ≥ 2) CRS and ICANS that were locked and tested without refitting on the Moffitt cohort. Patients were stratified into low-, intermediate-, and high-risk tertiles. Ingenuity Pathway Analysis defined upstream regulators and canonical pathways. The 17 CRS-associated and 21 ICANS-associated consensus proteins were classified into mechanistic themes for biological interpretation. Results:A 5-marker CRS panel (SCRIB, MYL6, MTHFD1L, HSP90B1, MMP2) achieved AUCs of 0.85 (95% CI 0.72-0.98) and 0.76 (0.63-0.89) in the discovery and validation cohorts, respectively. An expanded 8-marker ICANS panel (the CRS panel plus SPOCK2, SLC3A2, CD84) achieved AUCs of 0.91 (0.81-1.00) and 0.67 (0.51-0.84). In the combined dataset, high-risk-tertile patients were 13.84-fold (95% CI 4.21-56.26) and 8.59-fold (2.87-29.09) more likely to develop Grade ≥ 2 CRS and ICANS, respectively. Pathway analysis converged on AKT-driven inflammation and endothelial activation. Functional clustering of the consensus proteins partitioned into mechanistically coherent themes consistent with a dual-anatomy model: severe CRS reflected peripheral macrophage priming and endothelial activation with surplus complement amplification (HSP90B1▴, CSF1▴, MMP2▴, HEG1▴, C3▴) and endotheliopathic coagulation (PROC▾, F7▾), whereas severe ICANS reflected cerebrovascular junction and basement-membrane stripping (CDH5▾, ITGB1▾, FN1▾, brain-enriched SPOCK2▾), hepatic synthetic suppression (TTR▾, APOA2▾, IGFBP3▾), compromised plasma antioxidant capacity (GPX3▾, PON1▾), and inflammasome dis-restraint via DPP9▾. PGLYRP2 and SCRIB depletion were shared by both signatures and identified a common upstream priming substrate. Conclusions:Externally validated, pre-infusion proteomic panels predict severe CRS and ICANS following CAR T-cell therapy and define a coherent pre-infusion endothelial-immune priming axis (HSP90B1, MMP2, AKT) with mechanistically interpretable, druggable nodes. The dual-anatomy framework distinguishes peripheral CRS-biased from cerebrovascular ICANS-biased phenotypes downstream of a shared microbiome-host barrier priming substrate, providing a foundation for biomarker-guided risk stratification and cluster-matched prophylactic intervention to enhance the safety and outpatient feasibility of CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape across several hematologic malignancies. However, variability in biomarker assays, timing, and interpretation across clinical centers hampers the comparability of results, limits translational insight, and constrains evidence-based decision-making. As immune effector cells expand into emergent platforms and new indications, standardized biomarker frameworks are increasingly critical for optimizing patient outcomes and prospectively advancing the field. These expert panel recommendations, developed by the American Society for Transplantation and Cellular Therapy Committee on Cellular Therapy, aim to harmonize biomarker testing practices in CAR T-cell therapy. It provides evidence-based recommendations on the selection, timing, and clinical application of laboratory-based, cytokine, and CAR T-cell monitoring assays to inform toxicity management, guide treatment decisions, and support future research. A multidisciplinary expert panel reviewed current literature, clinical practices, and available evidence on biomarker use in CAR T-cell recipients. Through iterative consensus, the group established recommendations for routine laboratory assessments, cytokine profiling, and CAR T-cell pharmacokinetic monitoring. Biomarkers were stratified by clinical utility into "must-have," "can-have," and "nice-to-have" tiers based on clinical relevance, reproducibility, intent, and biological significance. The panel recommends comprehensive baseline laboratory testing-including metabolic panels, complete blood counts, inflammatory markers, and disease-specific biomarkers-prior to lymphodepletion. Serial measurements of inflammatory markers and targeted cytokines (eg, interleukin (IL)-6, interferon gamma, tumor necrosis factor alpha, chemokine C-X-C motif 9 (CXCL9)) are advised during acute toxicity phases. CAR T-cell monitoring by flow cytometry or ddPCR should occur at defined intervals to assess expansion, persistence, and therapeutic response. Both cytokines and CAR-T kinetics carry great promise as potential dynamic predictors of toxicity or nonresponse. Harmonized timing, fold-change calculations, and standardized reporting are critical for enabling cross-study comparability and advancing biomarker-driven care. Standardized biomarker testing is essential to improve patient outcomes, enable precision toxicity management, and accelerates CAR T-cell therapy innovation. These American Society for Transplantation and Cellular Therapy consensus recommendations provide a practical framework for clinical implementation and future research, bridging routine practice with next-generation biomarker-driven strategies.

In 2019, the American Society for Transplantation and Cellular Therapy (ASTCT) developed consensus definitions and grading criteria for the common immune effector cell (IEC)-associated toxicities of cytokine release syndrome (CRS) and IEC-associated neurotoxicity syndrome (ICANS). These grading scales were widely adopted by clinicians, investigators, and sponsors, allowing a clearer understanding of outcomes across clinical trials and a uniform basis to inform treatment algorithms. Since then, other IEC class effects, such as IEC-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) and non-ICANS attributable neurotoxicity, have been recognized. ASTCT convened experts for 2 tasks. First, to consider updating the previously published ASTCT grading criteria for CRS, ICANS, and IEC-HS. Second, to consider existing definitions and grading criteria, and/or create consensus criteria for emerging toxicities, including immune effector cell-associated hematotoxicity; non-ICANS neurological toxicities such as parkinsonism, cranial nerve palsies, and polyneuropathies; IEC-associated enterocolitis; tumor inflammation-associated neurotoxicity; and on-target, off-tumor toxicities. These updated consensus toxicity definitions and grading criteria can facilitate comparisons of toxicities of IEC and T-cell engager therapy across clinical trials and in real-world settings, as well as aid clinicians in better characterizing the severity of toxicity that can ultimately be tied to management guidelines.

ABSTRACT:The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T-cell (CAR-T) therapy is not well established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017 to 2020 were selected from the Center for International Blood and Marrow Transplant Research registry. Patients were randomly assigned to training or validation cohorts. Comorbidities given weighted scores comprised the CT-CI, which was then validated for overall survival (OS) prognostication. A total of 1916 patients from 97 medical centers were included, with a median age of 64 years (19-91 years). About 70% of patients had comorbidities, such as cardiac disease (12%); diabetes (14%); hepatic dysfunction (mild, 8%; moderate to severe, 2%); psychiatric disturbance (18%); and pulmonary dysfunction (moderate, 15%; severe, 12%). The CT-CI was calculated, stratified patients in 3 categories, and was associated with increased mortality. Patients with higher CT-CI scores had worse OS (CT-CI 1: hazard ratio [HR], 1.37 [95% confidence interval [CI], 1.16-1.62; P < .001]; CT-CI 2: HR, 1.49 [95% CI, 1.17-1.89; P = .001]; CT-CI ≥ 3: HR, 2.55 [95% CI, 1.90-3.42; P< .001]). Higher CT-CI scores predicted treatment-related mortality and relapse. There was no correlation between the CT-CI score and CAR-T-related toxicities. The novel CT-CI score stratifies the effect of patient comorbidities on survival after CAR-T therapy and can be used for clinical decision-making and treatment selection in high-risk populations. However, comorbidities and fear of increased toxicity should not preclude patients from this effective therapy.

Chronic GVHD is less frequent after post-transplant cyclophosphamide (PTCy)–based prophylaxis, but its clinical characteristics and outcomes compared with chronic GVHD following non-PTCy approaches remain understudied. We addressed this through a single-center retrospective study of 1,534 consecutive adult transplants (PTCy: n = 477; non-PTCy: n = 1,057) using matched related or matched/mismatched unrelated donors. The cumulative incidence of NIH moderate/severe chronic GVHD was significantly lower after PTCy (17% v 46%; P < .001). Among chronic GVHD-affected patients (PTCy: n = 163; non-PTCy: n = 656), chronic GVHD after PTCy involved fewer organ sites, had lower severity scores, and less NIH moderate/severe disease overall. However, this profile did not translate into improved survival. Univariate analysis demonstrated higher non-relapse mortality (24-month NRM: 22% v 13%; P = .014) for the PTCy group, while on multivariate analysis NRM was associated with increased age, NIH overall moderate/severe chronic GVHD severity, prior grade III/IV acute GVHD, reduced platelet count and increased bilirubin. Chronic GVHD after PTCy was associated with increased infectious complications despite reduced immunosuppressive (IS) therapy and higher rates of complete IS discontinuation. Overall, PTCy-based prophylaxis was associated with a lower incidence and severity of chronic GVHD, and after adjustment for established prognostic factors, mortality following chronic GVHD diagnosis was comparable to that observed after non-PTCy prophylaxis approaches. Multicenter validation of these findings and novel strategies to mitigate non-relapse mortality in chronic GVHD are warranted.

Abstract Anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy is a promising option for relapsed or refractory lymphoma patients, yet our mechanistic understanding of response heterogeneity remains incomplete. Using retrospective longitudinal data from 21 patients treated with axicabtagene ciloleucel (including CAR T counts, absolute lymphocyte counts, tumor burden, and survival), we developed a computational modeling approach to distinguish between two expansion mechanisms: homeostasis- and antigen-driven. For each patient, we trained and compared three-compartment models to describe the dynamics of normal T-, CAR T-, and tumor cells. Comparisons revealed two distinct patient groups: patients who can be exclusively characterized by homeostatic proliferation as the CAR T expansion mechanism (homeostatic expanders, 10/21) and those of mixed type (mixed homeostatic/antigen-driven expanders, 11/21). These groups were distinguished by differences in the relationship between baseline metabolic tumor volume (taken one to two weeks before CAR T) and the inferred tumor burden at dosing. Notably, homeostatic expanders demonstrated significantly better overall survival (60% vs. 10% beyond day 180, p = 0.011), with 6 of 7 patients in this group achieving long-term responses. Our findings highlight how the ability of CAR T-cells to function in a homeostatic reconstitution context and the ability to quantify tumor burden at CAR T dosing influence the predictability of long-term responses. Our personalized mathematical modeling approach provides novel insights into optimizing CAR T-cell therapy and understanding the dynamics of cellular immunotherapy. Importantly, the absence of antigen-driven expansion increases the negative impact of high tumor burden at the time of infusion. Citation Format: Philipp Martin Altrock, Álvaro Martinez-Rubio, María Rosa, Arne Traulsen, Michael D. Jain, Frederick L. Locke. Modeling the role of homeostatic T-cell reconstitution in durable response to CAR T-cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6834.

Background CD19 CAR T-cell therapy is frequently complicated by cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematotoxicity (ICAHT) which contribute to infections and non-relapse mortality (NRM). Herein, we characterize cytokines and inflammatory markers associated with severe CRS, ICANS, ICAHT and infections in r/r adult B-ALL post CAR T. Methods We retrospectively analyzed 20 adults with r/r B-ALL treated with commercial CD 19 CAR T (16 Brexu-cel; 4 Tisa-cel) between 01/2018 – 04/2025. Cytokines and inflammatory markers were measured at three predefined timepoints. Toxicities were graded as per ASTCT criteria for CRS and ICANS; EHA/EBMT for T- and N-ICAHT and CTCAE v 5.0 for infections. Early events were defined as Day 0-30 and late as Day 31-100 post CAR T (Fig 1 and 2). Associations between log-transformed biomarker levels with severe Gr ≥2 versus non-severe Gr <2 toxicities were tested by logistic regression test. Results Baseline disease characteristics are summarized in Table 1. Most patients were young with 29 years as median age at apheresis (range: 21–71, 25% were ≥50 yrs), heavily pre-treated with 3 median prior lines of therapy (range: 1-10, 40% with ≥3) and received cladribine/cyclophosphamide lymphodepletion (65%).CRS occurred in 95% (Gr ≥2: 45%) with1 Gr 5 event, median onset at Day 5 (range: 0–13) and median duration 4 days (range: 1–12). ICANS in 70% (Gr ≥2 in 50%); median onset at Day 7 and median duration 2 days (range: 1–9). Treatment included steroids (55%), tocilizumab (60%) and anakinra (20%). Early T- ICAHT occurred in 55 % (Gr ≥2: 50%) and N-ICAHT in 80% (Gr ≥2: 40%). Treatment included G-CSF (30%) and platelet transfusion (25%). At Day 30, 7 pts were censored (Fig 1). Late T- ICAHT occurred in 38% and N-ICAHT in 54% (all ≥ Gr 2). Treatment included G-CSF (46%), platelet transfusion (31%) and IVIG (46%). Early infections occurred in 45 % (Gr ≥2: 40% 25% bacterial) with 2 Gr 5 events while late infections were observed in 31% (23% bacterial) (all ≥Gr 2) with 1 Gr 5 event.Severe CRS was associated with high baseline CRP and low albumin; elevated Day 0 and peak IL-6 and CRP; and increased peak LDH, IFN-γ, CXCL10, IL-18, TNF-α and low albumin (all p ≤0.05). Severe ICANS correlated with peak IL-6, LDH, IFN-γ, CXCL10 and low albumin (all p ≤0.05) and trended with baseline and Day 0 IL-6; Day 0 and peak GM-CSF; peak TNF-α. Severe early T-ICAHT, N-ICAHT and early infections trended with high IL-6, high ferritin and low albumin across the three time points. (p∼0.05), while peak IFN-γ and CXCL10 trended with early infections (Fig 3). Conclusions In this pilot analysis, baseline and peri-infusion biomarkers—particularly IL-6, CRP, albumin, CXCL10, and IFN-γ—were associated with severe early ICAHT, early infections, CRS, and ICANS, suggesting shared underlying pro-inflammatory milieu in r/r adult B-ALL CAR T recipients.

Clinical trials and real-world evidence have established the benefit of chimeric antigen receptor (CAR) T-cell therapy to reduce progression of hematologic malignancies and, in some settings, increase overall survival. However, recent studies have highlighted that patients in long-term remission remain at risk of morbidity and nonrelapse mortality, primarily because of infections and subsequent myeloid malignancies. In addition, these patients may also be survivors of chemotherapy, radiation, and/or stem-cell transplant, with broad survivorship needs. Here, we provide a roadmap for the care of patients in long-term remission after CAR-T-cell therapies and discuss avenues for future research.

Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but many patients with large B cell lymphoma (LBCL) experience primary resistance or relapse. To uncover resistance mechanisms, here we examine pre-infusion tumor biopsies and observe that increased immunoregulatory macrophages correlate with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-γ) upregulates inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Proteomic profiling reveals that iNOS-expressing macrophages promote apoptosis and cell cycle arrest while downregulating protein synthesis machinery in CAR T cells. Metabolically, CAR T cells exhibit reduced glycolytic intermediates and altered tricarboxylic acid (TCA) cycle activity. Pharmacological inhibition of iNOS enhances CAR T cell treatment efficacy in vivo. Elevated levels of iNOS+CD14+ monocytes in leukaphereses are associated with non-durable responses to CAR T cells. Targeting iNOS in immunoregulatory macrophages, potentially by modulating CAR T-produced IFN-γ, could improve LBCL outcomes. Tumor associated macrophages can support cancer progression by suppressing T cell effector functions. Here the authors report that induction of iNOS in tumor-associated macrophages by IFN-gamma secreted from CAR T cells contributes to the development of CAR-T resistance in B cell lymphoma.

Background Renal impairment (RI) is a common comorbidity identified during pre-transplant evaluation and is a well-established risk factor for non-relapse mortality (NRM) after allogenic hematopoietic cell transplantation (HCT). We hereby present HCT renal and survival outcomes in patients (pts) with pre-existing RI comparing commonly used graft-versus-host disease (GVHD) prevention regimens. Methods We analyzed clinical outcomes in 355 pts with pre-existing RI who underwent HCT at our center between 2018 – 2022 (Fig 1). RI was defined as eGFR< 90 ml/min/m2 estimated by the MDRD (Modification of Diet and Renal Disease) equation using creatinine prior to start of the conditioning. RI was graded based on eGFR as grade (G) 1 (60-89), G2 (45-59), G3 (30-44) and G4 (<30). The primary outcome was the development of acute kidney injury (AKI) defined as increase in serum creatinine from day of admission by ≥ 0.3 mg/dl within 48 hours or > 1.5 times within 7 days at any time within 3 months post-HCT. AKI was staged using KDIGO criteria (Kidney Disease Improving Global Outcomes). Secondary outcomes included 1-year NRM, progression-free survival (PFS), and overall survival (OS). Results Baseline characteristics are summarized (Fig 1,2). Most pts had G1 pre-HCT RI (83.7%) while none had G4. At 3 months post-HCT, the cumulative incidence of AKI was 47% (95% CI: 42-52) in all pts (Fig 3,4). Most AKIs were pre-renal (78%), stage I (54%), primarily due to dehydration (38%) followed by medications (20%), 26 pts required temporary while 1 required permanent dialysis. The average peak creatinine was 2.2 mg/dl (range: 1.1 – 11.2) and average lowest eGFR was 33.7 ml/min/m2 (range: 4-63.6). In multivariate analysis, AKI was significantly lower with PTCy/SIR as compared to PTCy/TAC (HR 1.9, 95% CI 1.19- 2.98, p=0.006) and TAC/MTX (HR 2.4, 95% CI 1.46- 4.08, p=<0.001) but not TAC/SIR (HR 1.5, 95% CI 0.97- 2.41, p=0.06). Additionally, pre-HCT RI ≥ G2 (HR 1.5, 95% CI 0.99-2.26, p=0.054) and HCT-CI ≥3 (HR 1.4, 95% CI 1.02-1.88, p=0.04) influenced higher risk of AKI post-HCT.At 1-year post-HCT, NRM was 19% (95% CI: 16- 24), PFS was 63% (95% CI: 58-68) and OS was 74% (95% CI: 70-79) for all pts (Fig 3, 4). In multivariate analysis, GVHD prophylaxis type had no independent impact on these outcomes. NRM was higher with age ≥60 yrs (HR 1.9, 95% CI 1.13- 3.1, p=0.02) and HCT-CI ≥3 (HR 1.7, 95% CI 1.11- 2.54, p=0.02). PFS was negatively affected by recipient CMV seropositivity (HR 1.6, 95% CI 1.05- 2.27, p=0.03) and HCT-CI ≥3 (HR 1.3, 95% CI 1.00- 1.80, p=0.05). OS was significantly worse with age ≥60 yrs (HR 1.6, 95% CI 1.10- 2.32, p=0.01) and HCT-CI ≥3 (HR 1.6, 95% CI 1.14- 2.18, p=0.006). Conclusions Half of the pts with pre-existing RI, particularly those with eGFR <60, are at high risk of developing AKI post-HCT. While immunosuppression can significantly influence the risk of AKI, PTCy/SIR demonstrates a more favorable impact on renal function after HCT.

Chimeric antigen receptor (CAR) T cell therapy is now widely used for the treatment of various haematological malignancies, with emerging applications in solid tumours and autoimmune diseases. Alongside its demonstrated clinical activity, this therapeutic modality has a toxicity profile that differs from those associated with traditional cytotoxic therapies, other immunotherapies, and even other cell therapy approaches such as allogeneic haematopoietic stem cell transplantation. One increasingly recognized yet poorly understood complication is the development of post-CAR T cell therapy lymphoproliferative and lymphomatous disorders, which have a clinical and biological spectrum that remains incompletely characterized. These rare events include both CAR-transgene-positive and transgene-negative lymphomas with variable and sometimes overlapping clinical features. Causal attribution is difficult, given that these proliferations often emerge in the context of clonal haematopoiesis, inflammatory or infectious triggers, immune suppression and/or viral reactivation. In this Review, we synthesize the growing body of evidence on post-CAR T cell therapy lymphoproliferative disorders, drawing on the limited but increasing number of well-characterized cases. We outline the spectrum of lymphoproliferations described so far, highlight recurrent pathological and molecular features, and discuss factors that might promote clonal expansion or transformation, including pre-existing clonal haematopoiesis, dysregulated signalling pathways, inflammatory stimuli and, rarely, CAR-transgene vector integration. A clearer framework for these disorders might improve early recognition, guide diagnostic evaluation, support treatment decision-making, facilitate classification and consensus-building efforts, and inform future mechanistic studies and pharmacovigilance efforts.

Background CD19 CAR T cells therapy induces high remission in r/r B-ALL but is limited by immune-effector cell–associated hematotoxicity (ICAHT) and infectious complications. While the ALL-Hematotox (ALL-HT) score predicts post-CAR-T neutropenia (Nair et al., Blood 2025, real-world data are limited. We aimed to describe the incidence, timing, and predictors of cytopenias and infections following commercial CD19 CAR T therapy in r/r B-ALL. Methods We retrospectively examined 53 B-ALL patients treated with brexu-cel or tisa-cel (2018–2025). Cytopenia were graded per CTCAE v5.0 at baseline and Days 7/14/30/90. Infections were classified as early (<30 d) or late (31–100 d) and grade ≥3 if requiring IV antibiotics or hospitalization. CRS/ICANS were graded per ASTCT. ALL-HT score was calculated using baseline labs; patients with score >4 was considered high risk . Univariate logistic regression evaluated associations of patient and tumor characteristics with cytopenias and infections. Results Patient and disease characteristics are summarized in Table 1. 46 (87%). Among 53 patients (median age 38 years; 58% male), 46 (87%) reached Day 100 follow-up. Most patients (93%) received brexu-cel. Marrow blast burden at baseline was >50% in 14%. Prior therapies included blinatumomab (57%), inotuzumab (30%), and alloHSCT (23%). 72% were classified as low risk by ALL-HT score. CRS occurred in 92% and ICANS in 55%.The prevalence of cytopenias and infections are summarized in Table 2. High-risk ALL-HT scores were significantly associated with Day 30 neutropenia (p=0.011) and thrombocytopenia (p<0.001). Flu/Cy lymphodepletion correlated with both Day 30 thrombocytopenia (p=0.008) and Day 90 neutropenia (p=0.029).By Day 100, 51% developed at least one infection; 29.8% had ≥G3. Early infections (n=16) were 80% bacterial and 75% ≥G3; late infections (n=17) were 72% bacterial and 41% ≥G3. Infection-related deaths occurred early (n=2) and late (n=1). High-risk ALL-HT scores were associated with early (p=0.004) and late (p=0.029) infections. Additional risk factors for early infections included bridging therapy administration (p=0.012), day 30 IgG<400 mg/dL (p=0.006). Severe late infections were associated with day 90 IgG<400mg/dL (p=0.032), Flu/Cy (p=0.015), and high pre-LD blasts (p=0.020). Conclusion Prolonged cytopenias and infectious complications are frequent after CD19-directed CAR T-cell therapy for r/r B-ALL; nearly one-third experience severe infections with early and late mortality. The ALL-HT score effectively stratifies hematologic and infectious risk. Hypogammaglobulinemia was strongly associated with severe infections, highlighting the need for prospective studies evaluating prophylactic IVIG. Compared to Flu/Cy, cladribine-based lymphodepletion may confer a more favorable cytopenia/infection profile and merits further investigation.

Representativeness of Study Participants

ABSTRACT:Antibiotic (ABX)-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies. In this study, we observed that prior exposure to broad-spectrum ABXs with extended anaerobic coverage such as piperacillin-tazobactam and meropenem was associated with worse anti-CD19 CAR-T therapy survival outcomes in patients with large B-cell lymphoma (N = 422) than other ABX classes. In a discovery subset of these patients (n = 67), we found that the use of these ABXs was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n = 58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery, n = 40; validation, n = 28). These findings were recapitulated in an immune-competent CAR-T mouse model, in which meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-Ts, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy. This trial was registered at www.clinicaltrials.gov as #NCT06218602.