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BackgroundRefractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).MethodsIn phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject's HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted.ResultsT cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses.ConclusionsRecipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.Trial RegistrationNCT00674648; NCT01646645; NCT02136797 (NIH).FundingNIH (P01 CA23766, R21 CA162002 and P30 CA008748); Aubrey Fund; Claire Tow Foundation; Major Family Foundation; \"Rick\" Eisemann Pediatric Research Fund; Banbury Foundation; Edith Robertson Foundation; Larry Smead Foundation.

Relapse and toxicity limit the effectiveness of chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL), yet biomarkers that predict outcomes and toxicity are lacking. We examined radiomic features extracted from pre-CAR-T 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ([ 18 F]FDG PET/CT) scans ( n  = 341) of 180 patients (121 male; median age, 66 years). Three conventional (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], total lesion glycolysis [TLG]) and 116 novel radiomic features were assessed, along with inflammatory markers, toxicities, and outcomes. At both pre-apheresis and pre-infusion time points, conventional PET features of disease correlated with elevated inflammatory markers. At pre-infusion, MTV was associated with grade ≥ 2 cytokine release syndrome (odds ratio [OR] for 100 mL increase: 1.08 [95% confidence interval (CI), 1.01–1.20], P  = 0.031), and SUVmax was associated with failure to achieve complete response (CR) (OR 1.72 [95% CI, 1.24–2.43], P  < 0.001). Higher pre-apheresis and pre-infusion MTV values were associated with shorter progression-free survival (PFS) (HR for 10-unit increase: 1.11 [95% CI, 1.05–1.17], P  < 0.001; 1.04 [95% CI, 1.02–1.07], P  < 0.001) and shorter overall survival (HR for 100-unit increase: 1.14 [95% CI, 1.07–1.21], P  < 0.001; 1.04 [95% CI, 1.02–1.06], P  < 0.001). A combined MTV and LDH measure stratified patients into high and low PFS risk groups. Multiple pre-infusion novel radiomic features were associated with CR. These quantitative conventional [ 18 F]FDG PET/CT features obtained before CAR-T cell infusion, which were correlated with inflammation markers, may provide prognostic biomarkers for CAR-T therapy efficacy and toxicity. The use of conventional and novel radiomic features may thus help identify high-risk patients for earlier interventions.

Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication after allogeneic stem cell transplantation (allo-HCT). However, there is no uniform consensus on the optimal strategy for SOS prevention. Ursodeoxycholic acid is the most used regimen, even though its administration is challenging in recipients unable to tolerate oral medication. Defibrotide was recently studied in a phase 3 trial, but enrollment was stopped early due to futility. Low-dose unfractionated heparin (UFH) is an alternative strategy. However, its efficacy is reputed but unproven increased risk of bleeding has not been fully established. We evaluated 514 adult allo-HCT recipients who received SOS prophylaxis with low-dose UFH. Bleeding complications occurred in 12 patients 2.3% of patients of which only 2 (0.4%) had significant grade 3 bleeding. Only 14 patients were diagnosed with hepatic SOS. Univariate analysis showed that day 100 SOS was higher in recipients of unmodified grafts when compared to CD34+ selected ex vivo T-cell depleted grafts (p ≤ 0.001), and patients with hepatitis B and/or C exposure pre-HCT (p = 0.028). Overall, UFH was well tolerated and associated with a low incidence of subsequent hepatic SOS. Low-dose UFH prophylaxis can be considered in select patients who cannot tolerate oral ursodiol.

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%) for tetanus and poliovirus. Among patients not seroprotected prior to vaccination, vaccine response rates were high for tetanus and polio (100%), moderate for diphtheria (75%) and haemophilus influenzae type b (62%), and lower for pertussis (48%), hepatitis A (43%), hepatitis B (44%), and pneumococcal disease (33%). CD19 CAR T recipients had higher pre-vaccination seroprotection rates than BCMA recipients, but vaccine responses did not differ significantly between groups. Pre-vaccination IgA levels were significantly associated with vaccine response, and absolute B-cell counts trended higher among responders ( p  = 0.054). Our findings highlight the importance of immune reconstitution in vaccine responses post-CAR T.

The role of extranodal (EN) sites as potential sanctuary regions resistant to CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy in large B-cell lymphoma (LBCL) remains unclear. To investigate this, we retrospectively analyzed 283 adults treated with commercial CD19 CAR-T therapy, assessing 958 PET-CT scans across four time points: pre-apheresis, pre-lymphodepletion, best response, and relapse. EN involvement prior to CAR-T therapy was common (76%). Outcomes for patients with exclusive EN disease were similar to those with nodal (ND) disease alone; however, patients with concomitant EN and ND disease (EN + ND) had lower complete response rates and shorter progression-free survival. Site-specific outcomes varied: lungs/pleura/pericardium and gastrointestinal/peritoneum involvement had the lowest local response rates (48% and 51%, respectively). Notably, the risk of same-site relapse was highest in the lungs/pleura/pericardium (hazard ratio [HR] 7.8) and gastrointestinal/peritoneum (HR 5.97). Among patients relapsing after CAR-T, two-year overall survival rates from time of relapse were significantly lower in those with EN relapse (23% for exclusive EN; 25% for EN + ND) compared to exclusive ND relapse (64%; p  = 0.008). These findings underscore the high prevalence of EN disease in CAR-T recipients and its site-specific impact on outcomes, highlighting the need for organ-targeted strategies to enhance treatment efficacy. Differential site-specific response and relapse/progression risk according to pre-CAR-T therapy anatomical site involvement in Large B-cell Lymphoma. Risk of site-specific relapse or progression was not evaluable for CNS/orbital/cranial sinuses, adrenal/genitourinary, hepatobiliary/pancreas, and spleen due to insufficient number of events.

Corticosteroids are commonly used to manage cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) following chimeric antigen receptor (CAR) T‐cell therapy, and yet, their dose‐specific impact on outcomes remains uncertain. We retrospectively evaluated 276 adults with large B‐cell lymphoma (LBCL) treated with CD19‐directed CAR‐T therapy (axi‐cel, tisa‐cel, or liso‐cel) between 2016 and 2023 at a single institution. Cumulative corticosteroid dose was defined as the total dose administered within 21 days of infusion. Corticosteroids were administered to 105 patients (38%), initiated at a median of 5 days post‐infusion (interquartile range [IQR] 3–7) for CRS (38%), ICANS (15%), or both (47%). Use was more frequent with axi‐cel (P < 0.001), although the cumulative dose and duration were similar across products. To assess the impact of corticosteroid exposure, we carried out a 21‐day landmark analysis. Corticosteroid exposure, modeled as a time‐dependent covariate, was not significantly associated with infection risk, non‐relapse mortality, or inferior overall survival (OS) or progression‐free survival (PFS). However, in a landmark analysis, patients receiving above‐median cumulative corticosteroid doses had a significantly higher risk of infection compared to those receiving below‐median corticosteroid doses or no corticosteroids (P = 0.042). In a landmark multivariable analysis, corticosteroid cumulative dose was associated with increased late hematologic toxicity (adjusted hazard ratio [HR] 1.02, 95% CI 1.02–1.03). Finally, in a sensitivity analysis excluding patients with Grade ≥4 CRS/ICANS, corticosteroid cumulative dose remained unassociated with OS or relapse, but was linked to shorter PFS (adjusted HR 1.04, 95% CI 1.01–1.06). These findings support the safe yet judicious use of corticosteroids to manage CAR‐T toxicities in LBCL.

Persistence or recurrence of large B-cell lymphoma after CD19-CAR-T is common, yet data guiding management are limited. We describe outcomes and features following CAR-T treatment failure. Of 305 adults who received CD19-CAR-T, 182 experienced disease recurrence or progression (1-year cumulative incidence 63% [95%CI: 57–69]). Of 52 post-CAR-T biopsies evaluated by flow cytometry, 49 (94%) expressed CD19. Subsequent anti-cancer treatment was administered in 135/182 (74%) patients with CAR-T treatment failure. Median OS from the first post-CAR-T treatment was 8 months (95%CI 5.6–11.0). Polatuzumab-, standard chemotherapy-, and lenalidomide-based treatments were the most common approaches after CAR-T. No complete responses (CRs) were observed with conventional chemotherapy, while CR rates exceeding 30% were seen following polatuzumab- or lenalidomide-based therapies. Factors associated with poor OS among patients treated post-CAR-T were pre-CAR-T bulky disease (HR 2.27 [1.10–4.72]), lack of response to CAR-T (2.33 [1.02–5.29]), age >65 years (HR 2.65 [1.49–4.73]) and elevated LDH at post-CAR-T treatment (HR 2.95 [1.61–5.38]). The presence of ≥2 of these factors was associated with inferior OS compared to ≤1 (56% vs. 19%). In this largest analysis to date of patients who progressed or relapsed after CD19-CAR-T, survival is poor, though novel agents such as polatuzumab and lenalidomide may have hold promise.

BACKGROUNDUnderstanding outcomes and immunologic characteristics of cellular therapy recipients with SARS-CoV-2 is critical to performing these potentially life-saving therapies in the COVID-19 era. In this study of recipients of allogeneic (Allo) and autologous (Auto) hematopoietic cell transplant and CD19-directed chimeric antigen receptor T cell (CAR T) therapy at Memorial Sloan Kettering Cancer Center, we aimed to identify clinical variables associated with COVID-19 severity and assess lymphocyte populations.METHODSWe retrospectively investigated patients diagnosed between March 15, 2020, and May 7, 2020. In a subset of patients, lymphocyte immunophenotyping, quantitative real-time PCR from nasopharyngeal swabs, and SARS-CoV-2 antibody status were available.RESULTSWe identified 77 patients with SARS-CoV-2 who were recipients of cellular therapy (Allo, 35; Auto, 37; CAR T, 5; median time from cellular therapy, 782 days; IQR, 354-1611 days). Overall survival at 30 days was 78%. Clinical variables significantly associated with the composite endpoint of nonrebreather or higher oxygen requirement and death (n events = 25 of 77) included number of comorbidities (HR 5.41, P = 0.004), infiltrates (HR 3.08, P = 0.032), and neutropenia (HR 1.15, P = 0.04). Worsening graft-versus-host disease was not identified among Allo recipients. Immune profiling revealed reductions and rapid recovery in lymphocyte populations across lymphocyte subsets. Antibody responses were seen in a subset of patients.CONCLUSIONIn this series of Allo, Auto, and CAR T recipients, we report overall favorable clinical outcomes for patients with COVID-19 without active malignancy and provide preliminary insights into the lymphocyte populations that are key for the antiviral response and immune reconstitution.FUNDINGNIH grant P01 CA23766 and NIH/National Cancer Institute grant P30 CA008748.

CD19-targeted chimeric antigen receptor (CAR) T cell therapy is an effective treatment for diffuse large B cell lymphoma (DLBCL). In addition to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), B cell aplasia and hypogammaglobulinemia are common toxicities predisposing these patients to infections. We analyzed 60 patients with DLBCL treated with FDA-approved CD19 CAR T cells and report the incidence, risk factors, and management of infections during the first year after treatment. A total of 101 infectious events were observed, including 25 mild, 51 moderate, 23 severe, 1 life-threatening, and 1 fatal infection. Bacteria were the most common causative pathogens. The cumulative incidence of overall, bacterial, severe bacterial, viral, and fungal infection at 1 year were 63.3%, 57.2%, 29.6%, 44.7%, and 4%, respectively. In multivariate analyses, the use of systemic corticosteroids for the management of CRS or ICANS was associated with an increased risk of infections and prolonged admission. Impaired performance status and history of infections within 30 days before CAR T cell therapy was a risk factor for severe bacterial infection. In conclusion, infections were common within the first 60 days after CAR T cell therapy, however, they were not associated with an increased risk of death.