Marginal zone lymphoma (MZL) is a group of indolent B-cell malignancies that have a natural history that follows a remitting and relapsing course. For systemic disease, available first-line therapies include anti-CD20 antibody as monotherapy with or in combination with chemotherapy (chemoimmunotherapy), with second-line options such as covalent (c) Bruton tyrosine kinase inhibitors (BTKi). However, management of relapsed and refractory (R/R) MZL remains a challenge. Pirtobrutinib, a highly selective, non-covalent BTKi has shown promising efficacy and tolerability in patients with poor-prognosis B-cell malignancies following prior therapy, including cBTKi. Here we report the safety and efficacy of pirtobrutinib in patients with MZL from the phase 1/2 BRUIN study. Endpoints included investigator assessed ORR by Lugano 2014 criteria, DOR, PFS, OS, and safety. Among 36 R/R MZL patients (EMZL: n=6; NMZL: n=17; SMZL: n=13), median age was 68 years (range, 22-83) and median prior lines of therapy were 3 (range, 2-10) including anti-CD-20 antibody (100%), chemotherapy (86%) and cBTKi therapy (72%). The ORR was 55.6% (95% confidence interval [CI], 38.1- 72.1) including 3 (8.3%) complete responses and 17 (47.2%) partial responses. Median DOR was 17.8 months (95%CI, 7.4-non-estimable [NE]), and median PFS was 16.6 months (95%CI, 9.0-22.1). With median follow-up of 32.4 months (IQR, 28.0, 41.3), median OS was NE (95%CI, 29.5-NE). The ORR for patients with prior cBTKi therapy was 53.8% (95%CI, 33.4-73.4). Pirtobrutinib was well-tolerated with dose reductions in 4 patients (11.1%) and permanent discontinuation due to TEAEs in 4 (11.1%). Pirtobrutinib showed promising efficacy and safety in patients with heavily pre-treated R/R MZL, including prior cBTKi. NCT03740529

ABSTRACT:Pirtobrutinib, a noncovalent, reversible Bruton tyrosine kinase inhibitor (BTKi), demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), resistant to covalent BTKi (cBTKi). We analyzed genomic correlations with response and resistance to pirtobrutinib in relapsed/refractory (R/R) patients with CLL pretreated with cBTKi enrolled in the phase 1/2 BRUIN trial. DNA sequencing was performed on peripheral blood mononuclear cells at baseline, on treatment, and at progressive disease (PD). Common alterations at baseline included mutations in BTK (43%), TP53 (38%), SF3B1 (25%), NOTCH1 (23%), ATM (19%), XPO1 (11%), PLCG2 (9%), BCL2 (8%), and 17p deletion (28%). Common baseline BTK mutations included C481S (85%), C481R (10%), C481F (6%), and C481Y (4%). At PD, 60 of 88 patients (68%) acquired ≥1 mutation, including 44% with acquired BTK mutations and 24% with other acquired mutations. A total of 55 acquired BTK mutations were detected in 39 patients, including gatekeeper mutations (T474I/F/S/Y/L, 26%), kinase-impaired L528W (16%), C481S/R/Y (5%), V416L (2%), and A428D (1%) and others proximal to the adenosine triphosphate-binding pocket, D539A/G/H (1%) and Y545N (1%). Decrease or complete clearance of BTK C481x was observed at PD in 36 of 43 patients (84%). Using a more sensitive assay, 37% (18/49) of acquired BTK mutations were detected at baseline at low allele frequency. Using a highly sensitive assay at progression, a similar frequency of acquired BTK mutations (39%) was detected, and all patients had detectable acquired mutations. This study highlights the complex clonal dynamics of BTK mutations in patients with R/R CLL undergoing pirtobrutinib treatment, and the extent of resistance without an obvious genomic driver. Trial registration: #NCT03740529 at www.ClinicalTrials.gov.

Introduction Anti-CD19 chimeric antigen receptor T-cell therapy (CART) is an effective treatment for relapsed or refractory (R/R) large B-cell lymphoma (LBCL), with three FDA-approved constructs: axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are acute toxicities that most often occur within 7 days of CART infusion. Based on pivotal trials demonstrating a low incidence of these toxicities beyond 14 days, the FDA revised CART monitoring guidelines in June 2025, reducing the required monitoring period from 4 weeks to 2 weeks post CART infusion. Objectives We conducted a real-world analysis of patients treated with anti-CD19 CART for R/R LBCL with the primary objective of examining the incidence of late-onset CRS and ICANS (occurring > 14 days post CART infusion) among the 3 FDA-approved CART constructs and secondary objective of describing the severity and management, including readmission rates, for these toxicities. Methods Patients aged >18yrs treated with CART for R/R LBCL were identified across 15 academic institutions from 2016-2025. Wilcoxon rank-sum, Kruskal-Wallis, Fisher's exact, & pooled t-test were utilized (p<.05) to determine the statistical significance of differences between variables. Results Among 925 patients treated with anti-CD19 CART, 25 (2.7%) developed acute toxicities >14 days post-infusion (Table 1). There was no difference in patient or disease characteristics between patients who developed CRS/ICANS ≤ 14 days post CART infusion vs > 14 post CART (Table 2). There was no significant difference in the incidence or severity of late-onset CRS or ICANS among the different CART constructs (Table 1). One patient received CART as outpatient and required admission on Day 2 for CRS, which resolved by Day 6, and was readmitted on Day 34 for ICANS. 22 of the 25 patients had available readmission data, 15 of whom experienced these late-onset toxicities after discharge for initial hospitalization for CART, necessitating subsequent readmission. Management of late onset toxicities is outlined in Table 1. Conclusion This is the largest real-world study to date examining late-onset CRS and ICANS associated with FDA-approved anti-CD19 CART. Results demonstrate a low risk of these toxicities occurring more than 14 days post-infusion across all constructs. These findings support the FDA's June 2025 label updates, reducing required monitoring for patients treated with these therapies.

ABSTRACT:Chimeric antigen receptor T-cell (CART) therapy has transformed the management of relapsed and refractory large B-cell lymphoma (LBCL), but real-world outcomes data is needed to confirm the benefits seen in clinical trial settings. We performed a multicenter retrospective analysis evaluating CART therapy outcomes according to line of therapy, specifically second line (2L) vs third line (3L) vs fourth line (4L) and beyond (4L+). We included patients who received CD19-directed CART therapy for de novo diffuse LBCL or transformed follicular lymphoma. Overall (N = 466), 21% (n = 98) of patients received CART as 2L, 41% (n = 192) as 3L, and 38% (n = 176) as 4L+. Median follow-up from CART infusion was 35 months. Overall response rate and complete response rate were similar for 2L vs 3L vs 4L+. From CART infusion, median progression-free survival (mPFS) and median overall survival (mOS) were similar for 2L vs 3L, but shorter in patients receiving CART as 4L+ (mPFS, 11.6 vs 12.7 vs 5.7 months, P< .001; mOS, not reached vs 69.4 vs 21.9 months, P< .001). In patients with double-hit or triple-hit lymphoma (DHL/THL), receiving CART in 2L vs 3L significantly improved 3-year OS (63% [2L] vs 32% [3L], P = .01). Patients with disease that required bridging therapy were also at increased risk of progression or death. Overall, our findings inform real-world practice wherein CART therapy as 2L vs 3L yields similar survival outcomes in unselected patients. However, patients specifically with DHL/THL should be considered for CART therapy in the 2L outside of the primary refractory disease (PRD) or early relapsed setting.

CD20.CD19-targeted chimeric antigen receptor modified T-cell immunotherapy (CAR T-cell therapy) is an experimental CAR with increasing use for the treatment of lymphoid malignancies. Although acute neuropsychiatric toxicities are well described following CAR T-cell therapies, late-onset persistent neuropsychiatric symptoms, including mania and psychosis, are poorly characterized, and their underlying mechanisms are unknown. Here, we present two cases of new-onset mania and psychosis in the months following dual targeted CD20.CD19 CAR T-cell therapy, contributing significantly to the literature wherein no cases of such have been reported. We discuss the published literature on chronic neuropsychiatric symptoms following CAR T-cell therapy as well as potential neurobiological mechanisms for these effects. Finally, we discuss therapeutic considerations including the potential role of second-generation antipsychotics, such as olanzapine, which may be effective in the treatment of late-onset and persistent neuropsychiatric symptoms, including psychosis, following CAR-T cell treatment.

Introduction Chimeric antigen receptor (CAR) T-cell therapy has transformed care for large B-cell lymphoma (LBCL) but is limited by cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS). First-line management is high-dose corticosteroids (CS). For CS-refractory ICANS, the optimal treatment approach is unknown. Anakinra use is limited by cost, infections, and morbidity. Alternatively, intrathecal (IT) therapy (steroids +/- chemotherapy) targets the cerebrospinal fluid (CSF) and may limit systemic toxicity, but large datasets are lacking. We report an updated analysis of ICANS management approaches, including IT therapy, in patients (pts) with LBCL. Methods We conducted a multicenter retrospective study of adults with LBCL treated with CD19-directed CAR-T who developed ICANS. Descriptive statistics summarized baseline features; nonparametric tests assessed skewed variables; chi-square compared categorical variables. PFS and OS by Kaplan-Meier; subgroups were compared by log-rank. Results We identified 331 pts with ICANS; 54% (n=178) had grade 3-4. Median age was 65 (23-91); 63% were male. Axi-cel was the most frequently administered CAR-T product (75%, n=248). CRS occurred in 94% (n=312) of pts; 84% (n=263) received tocilizumab. ICANS developed a median of 5 days post-CAR-T (range, 0-24). 98% (n=323) of pts received CS, 28% (n=91) received anakinra, and 25% (n=83) received IT therapy.Among IT-treated pts, 63% (n=52) received early IT (<5 days from ICANS onset) and 37% (n=31) late IT (>5 days). IT regimens included hydrocortisone (HC) alone in 7% (n=6) or HC plus methotrexate, cytarabine, or both in the remainder. Early IT pts were more likely to have grade 3-4 ICANS (81% vs 49%, p=0.001) and to receive anakinra (42% vs 25%, p=0.01). Overall response to CAR T was similar (71% vs 69%).In terms of safety, IT therapy was not associated with increased risk of CNS relapse or infectious complications. By contrast, anakinra recipients had higher infection rates (56% vs 36%, p<0.001) and more ICU admissions (73% vs 29%, p<0.001).PFS did not differ between early IT and systemic-only/late IT overall (p=0.16) or within grade 3-4 ICANS (p=0.84). OS was shorter for grade 3-4 vs grade 1-2 ICANS (14mo vs NR, p<0.01). In grade 3-4 ICANS, anakinra exposure was associated with lower median OS (7.6 vs 20 months, p=0.015). Conclusions These data reinforce poor survival in grade 3-4 ICANS. The benefit of anakinra remains uncertain, as its use was associated with higher infection rates and worse OS in high-grade ICANS. IT therapy was well tolerated and had a more favorable safety profile than anakinra; however, clear efficacy signals were difficult to confirm due to confounding factors and preferential IT use in higher-grade, sicker patients. Future prospective studies are indicated to better delineate the treatment of choice in CS-refractory ICANS.

Introduction Allogeneic hematopoietic stem-cell transplant (allo-HSCT) is a potentially curative therapy for hematologic malignancies; however, it carries substantial risks. Most notably, graft-versus-host disease (GVHD) is the second leading cause of mortality after transplant. Given the significant impact of GVHD in patients undergoing allo-HSCT, research is ongoing to identify optimal prophylactic regimens to reduce its incidence.The BMT CTN 1703 trial (Bolaños-Meade, et. al 2023) compared methotrexate plus a calcineurin inhibitor to a novel regimen consisting of post-transplant cyclophosphamide (PT-Cy), tacrolimus, and mycophenolate mofetil (MMF). The PT-Cy based regimen demonstrated significantly higher GVHD-free, relapse-free survival at one year. Based on these results, Froedtert & the Medical College of Wisconsin (MCW) adopted PT-Cy with tacrolimus and MMF as the standard GVHD prophylactic regimen post allo-HSCT in October 2024.However, use of tacrolimus presents unique challenges due to its narrow therapeutic index and variable pharmacokinetics. Supratherapeutic levels can occur and are associated with nephrotoxicity and neurotoxicity, potentially resulting in patient harm. Oral versus intravenous bioavailability, body mass index (BMI) related variability, and drug-drug interactions (notably with posaconazole) further complicate dosing. In an attempt to optimize tacrolimus levels, Froedtert & MCW has implemented oral initiation of tacrolimus for reduced intensity conditioning (RIC) regimens, along with dose adjustments in patients with a BMI >25 kg/m2. Objectives To identify clinical and demographic factors that influence tacrolimus exposure, with the goal of refining individualized dosing to balance efficacy with toxicity. Methods This is a single center, retrospective, observational study designed to quantify and characterize the rates of therapeutic, subtherapeutic, and supratherapeutic tacrolimus levels in post allo-HSCT patients at Froedtert & MCW. Beginning February 2025, allo-HSCT patient charts will undergo automated data extraction to generate monthly reports for review. Predetermined data collected for each patient includes BMI, antifungal prophylaxis utilized, and initial and peak levels of serum creatinine, liver function tests, and tacrolimus levels. Descriptive statistics will be applied to identify potential trends in the collected data. Patients with tacrolimus levels >15 ng/mL will be flagged for additional review, including assessment of concomitant nephrotoxic agents given within 72 hours of supratherapeutic trough levels, oral intake, and incidence of tacrolimus-related toxicity, to better characterize contributing factors leading to supratherapeutic levels. Results Data trends will be analyzed and presented for patients receiving Pt-Cy and oral tacrolimus from January through December 2025.

IntroductionThe complex dynamics of chimeric antigen receptor T-cell (CAR-T cell) cytotoxicity and proliferation are potential factors that influence the clinical response to CAR-T therapy. The patient-specific functionality of CAR-T products play a role in these dynamics. CAR-T products comprise phenotypically and functionally distinct populations of cells that impact therapy response in different ways. We hypothesized that product-specific parameters exist that predict individual patient responses to therapy and that these can be elucidated by simulating the interactions of CAR-T products and tumor cells using an in vitro assay-based model.MethodsWe use an ordinary differential equation (ODE)-based pharmacokinetic (PK) and pharmacodynamic (PD) model to characterize key CAR-T cell functional parameters. Parameters for the model developed using our method are product-specific and derived from in vitro assays performed on individual patient CAR-T products from clinical trial NCT04186520.ResultsOur results demonstrate that while considerable variability is present in in vitro cytotoxicity kinetics and subsequently estimated model parameters between each product, these differences do not predict early (28 days) or late responses (90 days) after treatment across the total cohort of patients investigated. However, we show that differences in an estimated model parameter for increased CAR-T cell responsiveness to tumor cytotoxicity are correlated with durable therapy responses (no relapse through 180 days). Additionally, in a cohort of diffuse large B-cell lymphoma (DLBCL) patients, we demonstrate that a model parameter estimating cooperativity between CAR-T cells is also correlated with durable therapy responses and that may be related to differences in CD4:CD8 ratios in the CAR-T cell product.ConclusionsOverall, our work demonstrates that while pre-treatment CAR-T cell functional parameters vary on a patient and product basis, these parameters do not predict initial therapeutic responses. We find that initial therapeutic responses are possible across a range of initial product kinetic parameters. However, we observed that their potentially exist unique kinetic properties associated with the initial product that is predictive of disease relapse.

Introduction Pure Red Cell Aplasia (PRCA), a significant complication of major ABO mismatched allogenic hematopoietic cell transplant (alloHCT), is mediated by anti-donor isohemagglutinins. Presence of recipient anti-A hemagglutinin, use of reduced-intensity conditioning (RIC) regimens, cyclosporine use, sibling donors, and absence of acute graft versus host disease (aGVHD) are risk factors for PRCA. Widespread adoption of post-transplant cyclophosphamide (PtCy) for GVHD prophylaxis (ppx) has resulted in significant reduction in GVHD risk. However, the impact of PtCy-based ppx on the risk of PRCA among major ABO mismatched alloHCT recipients relative to traditional tacrolimus (Tac)/methotrexate (MTX)-based ppx is not known. Methods In this retrospective study, adult hematological malignancy patients (pts) undergoing a major ABO mismatched alloHCT with either PtCy-based or Tac/MTX-based GVHD ppx (1/2019 and 12/2024) were included. Data collected included demographics, transplant- and GVHD-related variables, PRCA related data, disease relapse, and survival data. The cumulative incidence (CI) of PRCA was estimated with disease progression and death as competing events. Kaplan-Meier estimators with log-rank test were used for progression-free survival (PFS) and overall survival (OS). Results A total of 139 pts were included. Table 1 summarizes baseline characteristics. Eleven pts developed PRCA. The 6-month CI of PRCA following PtCy and Tac/MTX was 7.1% (95%CL: 2.3,16) and 8.4% (95%CL: 3.7, 16%, p=0.8), respectively. Median time to PRCA diagnosis was 44 (31-147) days from alloHCT. 57 pts developed any grade aGVHD with a 6-month CI of 40% (95%CL: 32, 48). None of the pts developed PRCA after aGVHD onset (HR 0.00, 95%CL: 0, 0.57, p=0.012). 6-month CI of PRCA was higher following RIC with fludarabine/busulfan (14%, 95%CL: 6.7, 23) as compared to other regimens (p=0.019). There was also a trend towards higher CI of PRCA among recipients with blood group A (11%) or AB (10%) donors as compared to group B (0%) donors (p=0.09). PRCA resolved in 7 pts with a median of 174 (35 – 365) days.Among patients surviving 6-months post alloHCT (landmark analysis), the 12-month PFS for patients with or without PRCA was 44% (95%CL: 17-100) and 96% (95%CL: 92-100), respectively (p<0.001). Similarly, 12-month OS in similar order was 45% (95%CL: 20-100) and 90% (95%CL: 84-96%)(p=0.005), respectively (Figure 1). Development of PRCA was associated with significantly increased hazard of PFS event (HR 2.61, 95%CL: 1.23, 5.55, p=0.013) as well as death (HR 2.9, 95%CL: 1.29, 6.51, p=0.01). Conclusions Our study did not show an increased risk of PRCA with PtCy when compared with Tac/MTX but demonstrated a significant correlation with absence of aGVHD. Keeping limitations of a retrospective analysis in mind, we report a significant negative impact of PRCA development on PFS and OS post alloHCT.

BACKGROUND:This study presents patient-reported outcomes (PROs) from the phase 1/2 BRUIN (NCT03740529) trial of pirtobrutinib monotherapy for the treatment of B-cell malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). METHODS:PROs were collected at each cycle using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and item library (IL) sets for CLL/SLL- and MCL-related symptoms and an Expanded Fatigue measure. Prespecified analyses included descriptive change from baseline, time to worsening (TTW) using Kaplan-Meier method, and longitudinal analyses using a mixed model for repeated measures. RESULTS:A total of 263 patients with CLL/SLL and 124 with non-blastoid MCL who received pirtobrutinib monotherapy after prior BTKi were included in the final PRO analysis. The proportion of patients with CLL/SLL who improved or remained stable from baseline through Cycle 31 remained above 80% for physical function (PF), CLL/SLL-related symptoms, fatigue, and global health status/quality of life (GHS/QoL). The proportion of patients with MCL who improved or remained stable through Cycle 20 remained above 70% for PF, MCL-related symptoms, fatigue, and GHS/QoL. Median TTW was not reached in either CLL or MCL. Longitudinal analyses for PF, CLL/SLL-related symptoms, fatigue, and GHS/QoL consistently met statistically significant and clinically-meaningful improvement from baseline for CLL. PRO assessments remained stable over time for MCL. CONCLUSIONS:The final analysis from the BRUIN trial demonstrates stability in PROs throughout the duration of treatment with pirtobrutinib. Most patients with CLL/SLL and MCL reported stable or improved outcomes throughout the study.

Regulators worldwide are increasingly evaluating how decentralized and point-of-care (POC) manufacturing models can be integrated into existing frameworks for cell and gene therapies, including chimeric antigen receptor T-cell (CAR-T) therapies. These models challenge traditional centralized production by distributing manufacturing across several clinical or academic sites, requiring new approaches to ensure product consistency, traceability, and Good Manufacturing Practice (GMP) compliance. Across jurisdictions, regulators are converging on several common themes. First, decentralization must operate under a unified quality management system with clearly defined oversight, typically anchored by a central “control” or coordinating site responsible for governance, batch oversight, and harmonized procedures. Second, comparability across sites is critical, necessitating standardized processes, validated technologies, and robust data systems to support real-time quality monitoring. Third, regulators emphasize that decentralized models do not reduce GMP requirements; rather, they require additional structures to ensure alignment across distributed facilities. Many authorities are exploring mechanisms to clarify roles and responsibilities within POC networks, including oversight, documentation standards, and expectations for training, inspection, and data integrity. Some regulators are also assessing how existing pathways such as hospital exemptions, accelerated approval mechanisms, or special designations, could support early clinical use while maintaining rigorous safety and quality controls. In parallel, discussion papers, stakeholder consultations, and emerging guidance reflect a shared interest in addressing technological advances such as automated, closed-system manufacturing. In this article, we review and discuss work being done in this regard across Europe, Canada, and the United States.

Introduction Despite advances in targeted therapies, patients (pts) with BTK/BCL2 inhibitor (i) exposed relapsed, refractory (R/R) CLL have poor outcomes. While CD19 CAR T-cell therapy (lisocabtagene maraleucel) was approved for CLL pts exposed to BTKi/BCL2i, the complete response (CR) rate was 18% and the median PFS was 11.9 months in the pivotal phase II trial. Given sensitivity of CLL to CD20 targeting agents, we opened a cohort for R/R CLL pts within a larger ongoing trial of lentiviral anti-CD20/anti-CD19 (LV20.19) CAR T cells for R/R B-cell malignancies (NCT04186520). Objectives Determine the safety and efficacy of LV20.19 CAR T cells in R/R CLL Methods We conducted a Phase 1/2 trial of LV20.19 CAR T cells at a fixed dose of 2.5e6 cells/kg in B-cell malignancies. We now report outcomes from the CLL cohort. CAR T cells were manufactured utilizing an adaptive 8/12-day process with the CliniMACS Prodigy® device and lymphodepletion starting during the manufacturing process to facilitate fresh infusion. CLL pts must have had two prior lines of therapy, one required to be a BTKi or BCL2i. Disease response was assessed using Hallek iwCLL criteria. Results Eighteen pts with CLL received LV20.19 CAR T cells; 17 achieved target dose and were deemed evaluable. Ten pts were treated at a dose of 2.5e6 cells/kg; 7 pts were subsequently treated at a lower dose of 1e6 cells/kg due to presence of dose limiting toxicities (DLT). The median age was 65 years (34-75), and the median lines of prior therapy were 3 (range 2-7). All were BTKi/BCL2i exposed with 14 (82%) pts being refractory to both classes.In terms of safety, 16/17 pts had CRS, only 1 pt with Grade 3 CRS. Two (12%) pts at the 2.5e6 cells/kg dose had ICANS; 1 grade 3 and 1 grade 4 ICANS, the latter was found to have CLL in the CSF. Eight (47%) pts developed IEC-HS. Two CLL pts had grade 3 and grade 4 IEC-HS at the 2.5e6 cells/kg dose level. Both met criteria for DLT; one died of fungemia related to immunosuppression. Consequently, the trial was amended for future CLL pts to receive a reduced dose of 1e6 cells/kg. At this lower dose, none of the 7 pts experienced high grade 3-4 CRS, ICANS, or IEC-HS.In terms of clinical response, the best ORR was CR/CRi in 14 (82%) pts. Among 7 pts where ClonoSEQ MRD testing was done; all achieved negativity. The median PFS for all pts was 32 months (Figure 1). The median OS (Figure 2) was not reached with median follow-up of 2 years for surviving pts. There was no difference in best ORR between the two doses. CAR T cell expansion and area under curve (AUC) was similar at both dose levels, p=0.74 (Figure 3). Conclusions Dual targeted LV20.19 CAR T cell therapy resulted in high CR/CRi rate and encouraging PFS compared to currently available single targeted CARs in pts with BTKi/BCL2i exposed CLL. At a lower dose of 1e6 cells/kg, responses were maintained with an improved safety profile. These data suggest dual targeting of CD20 and CD19 may improve CAR-T outcomes in R/R CLL.

Introduction and Objectives Post-transplant cyclophosphamide (PTCy) at 50mg/kg on days (D) +3/+4 represents standard GVHD prophylaxis in adults undergoing reduced intensity conditioning (RIC) allogeneic transplantation (HCT) from an HLA-matched donor. Recently, lower cyclophosphamide doses have been explored to mitigate drug toxicity and improve engraftment kinetics. While toxicity appears lessened, no significant improvement to GVHD control has been identified. As prior studies demonstrated a possible role for ruxolitinib as GVHD prophylaxis, we initiated a Phase II study where older adults undergoing RIC, HLA-matched HCT, receive PTCy at a lower dose, along with ruxolitinib, aiming to mitigate PTCy related toxicities and improve GVHD control. Methods This prospective phase II study (NCT05622318) enrolled adults ≥60 years, with hematologic malignancies, undergoing RIC peripheral blood allogeneic HCT from an HLA-matched donor. GVHD prophylaxis consisted of PTCy, 25mg/kg on D+3/4, tacrolimus (D+5-180), mycophenolate mofetil (MMF) (D+5-35), and ruxolitinib 5mg twice daily (D+28-60– 1 year). Here we report on engraftment kinetics, ruxolitinib compliance through D+100, BMT-CTN grade 2-3 infections by D+100, Grade 2-4 and 3-4 acute GVHD, chronic GVHD requiring IS, relapse, and GRFS. Results 56 pts were enrolled/treated. Median age is 69 years (range 60-78 years), 28 pts had MDS or MPN, 27 pts had AML/ALL. RIC included Flu/Bu (N=41) or Flu/Mel100mg/m2 (N=15). Donors included MUD (N=50) or MRD (N=6). Median f/u of survivors is 267 days (range: 48-367 days). PB chimerisms confirmed donor engraftment in all patients on D+28. Median time to neutrophil and platelet engraftment was 14 days (range: 11-33 days), and 13 days (range: 10-37 days) post-HCT, respectively. Ruxolitinib was initiated at a median 34 days (range: 28-82 days) post-HCT. Ruxolitinib was interrupted in 4 pts (7%) due to ruxolitinib related AEs within the first 100 days. By day 100, the cumulative incidence of grade 2-3 infections was 11%. Incidence of grade 2-4 and 3-4 aGVHD at D180 was 13% and 4%, and incidence of cGVHD requiring IS at 1y was 2%. Incidence of relapse was 11%. Estimated 1y GRFS was 78% (+/-7%). Conclusion In older adults, de-escalated PTCy and ruxolitinib enables rapid and reliable engraftment and low rates of severe infections. Compared to PTCy 50 × 2, we report lower rates of G2-4 acute GVHD, but similar rates of G3+ acute GVHD. This could be explained by delayed initiation of ruxolitinib after D+28. Lower rates of chronic GVHD, and comparable relapse rates overall lead to a very favorable 1 y GRFS in an older population.

ABSTRACT Background The treatment landscape for relapse/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) has evolved with recent novel agents. With the availability of novel agents that slow disease progression, managing treatment side effects and monitoring response in patients with these hematologic malignancies may present a challenge for healthcare providers. The imperative to engage patients in the management of their condition demands that specialists are knowledgeable about new treatment options and are skilled and confident in educating patients to manage and monitor for potential side effects. Aims This study aimed to establish the current knowledge, skills and confidence levels of oncologists, hematologists and hematologist‐oncologists (ONC/HEM) and identify the challenges they experience when managing and monitoring treatment and engaging patients with CLL or MCL in shared decision‐making. The long‐term aim is to inform evidence‐based continuing medical education to optimize ONC/HEM competencies. Methods and Results This cross‐sectional study employed a quantitative survey, completed by 285 ONC/HEM practicing in academic or community settings in Brazil, France, Germany, the United Kingdom, and the United States. Using 5‐point Likert‐type scales, participants reported their knowledge/skills/confidence levels, and their agreement with selected statements. Sub‐optimal levels of knowledge/skills to identify and manage side effects associated with treatments for CLL or MCL were reported. Challenges with patient risk stratification and engaging patients in shared decision‐making were reported, with a greater proportion reported by those in community settings. Of note, 31% of participants reported sub‐optimal skills identifying patients at higher risk for progression and using stratification to plan and manage treatment, and 58% never/rarely/sometimes considered patients' concerns about treatment safety. Conclusion Continuing medical education activities to improve knowledge of new treatments and associated pathways for patients with CLL or MCL, and to develop skills/confidence to engage in shared decision‐making are recommended. Setting‐specific issues should be integrated into interventions to ensure relevant educational support for the ONC/HEM.

In September 2004, Oprah Winfrey exuberantly shouted, "Everyone gets a CAR!" to the joy and excitement of the audience members at her show. Later, these same audience members learned that the car was a taxable gift resulting in a significant Internal Revenue Service bill, and for some not worth the costs. In this issue of Blood, van Meerten et al1 present data from the ZUMA-2 cohort 3 trial that administered brexucabtagene autoleucel (brexucel), a CD19 chimeric antigen receptor (CAR) T-cell therapy, to patients with relapsed mantle cell lymphoma (MCL) before exposure to Bruton tyrosine kinase (BTK) inhibitors, a class of drugs which is a current standard second-line treatment. The question now is do all patients with MCL need a CAR at first relapse, and what are the possible costs of getting a CAR before BTK?

Patients in the liso-cel plus ibrutinib cohort of the phase 1/2, open-label TRANSCEND CLL 004 study had relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and received liso-cel (50×106 [dose level (DL)1] or 100×106 [DL2] chimeric antigen receptor-positive T cells) with concurrent ibrutinib from enrollment through 90 days after liso-cel infusion or longer per investigator discretion. Primary end point was complete response/remission (CR)/CR with incomplete marrow recovery (CRi) by investigator assessment. Among 56 patients who received ibrutinib plus liso-cel (DL1, n=5; DL2, n=51), median (range) age was 64.5 years (44‒77), 98% had high-risk cytogenetics, 55% had progression on Bruton tyrosine kinase inhibitor and venetoclax failure, and median (range) number of prior therapies was 5 (1‒13). Median (range) follow-up was 24.8 months (3.1‒51.8). At DL2, CR/CRi rate was 45% (95% confidence interval [CI], 31‒60) and overall response rate was 86% (95% CI, 74‒94). Median (95% CI) duration of response was not reached (NR; 28.7‒NR) for patients with CR/CRi and 41.4 months (23.3‒NR) for all responders. Median (95% CI) progression-free survival was 31.4 months (20.1‒NR). In DL1+DL2, most common grade ≥3 treatment-emergent adverse events (TEAE) were neutropenia (52%) and anemia (41%). Cytokine release syndrome was reported in 80% of patients (grade 3, 4%; no grade 4/5), and neurological events in 41% (grade 3/4, 11%; no grade 5). Ibrutinib-related TEAEs were reported in 68% of patients (grade 3/4, 43%; no grade 5). Liso-cel plus ibrutinib demonstrated notable efficacy in patients with relapsed/refractory CLL/SLL with predictable and manageable safety. Clinicaltrials.gov: NCT03331198; NCT03435796.

We conducted a phase 1-2 study in which patients undergoing allogeneic hematopoietic stem cell transplantation received tildrakizumab in addition to standard immune suppression with tacrolimus and methotrexate for graft versus host disease (GVHD) prophylaxis. Fifty patients were enrolled between March 2020 and June 2023 with a median age of 56 (range 19-64). All patients received myeloablative busulfan-based conditioning and were transplanted with HLA-matched related or unrelated peripheral blood stem cell grafts. Patients were treated with tildrakizumab on an extended subcutaneous administration schedule for five doses which was well tolerated. The cumulative incidences of grades II-IV and III-IV acute graft versus host disease were 14% (95% CI 7-28) and 4% (95% CI 1-16) at day 100, respectively. The incidence of chronic GVHD requiring systemic immune suppression was 52.7% (95% CI 40.4-68.9) at twelve months. The one-year probabilities of overall, disease-free, and GVHD-free relapse-free survival were 80% (95% CI 70-92), 78% (95% CI 67-90), and 19.3% (90% CI 11.8-31.4), respectively. Pharmacokinetic analysis revealed that the half-life of tildrakizumab approximated 28 days without formation of detectable anti-tildrakizumab neutralizing antibodies. Comparative examination of fecal microbial composition in tildrakizumab and a similarly transplanted cohort treated with tocilizumab prophylaxis demonstrated that both cytokine blockade strategies had a low frequency of enterococcal dominance. We conclude that tildrakizumab resulted in a low incidence of acute GVHD and attenuation of microbiome dominance with potentially pathogenic organisms but did not mitigate the emergence of chronic GVHD as administered on this dosing schedule. NCT 04112810

Financial toxicity, the economic burden associated with cancer treatment, is an evolving concern for patients undergoing innovative therapies like chimeric antigen receptor T-cell (CAR T-cell) therapy. The high costs of CAR T-cell therapy pose significant financial challenges, impacting well-being and treatment adherence. This study explores the financial burdens experienced by patients and caregivers across the CAR T-cell treatment course. Seventeen patients receiving CAR T-cell therapy were interviewed at four time points: preinfusion (baseline), D 90, D 180, and 1-yr post-treatment. Semi-structured interviews explored financial experiences, including direct medical costs, insurance coverage, caregiving demands, and ancillary expenses. Interviews were analyzed using thematic analysis to identify key patterns and track how financial concerns changed over time. Six themes emerged: (1) financial strain on caregivers, (2) employment disruptions, (3) healthcare and insurance costs, (4) relocation and travel expenses, (5) long-term financial planning, and (6) financial assistance navigation. Initially, patients were most concerned about treatment access and insurance approval. By D 90, stress shifted to out-of-pocket costs and job-related disruptions. At later time points, patients emphasized sustained financial planning and recovery-related expenses. Patients receiving CAR T-cell therapy face significant and evolving financial burdens. Key stressors include caregiving-related financial strain, insurance complexities, and travel-related expenses. Interventions such as caregiver support, upfront financial counseling, and clearer insurance communication may reduce this burden. Future research should evaluate interventions aimed at alleviating these financial stressors and promoting equitable access to CAR T-cell therapy.