Mario Sánchez-Salinas

PURPOSE Approximately 30%-40% of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) infused with CD19-targeted chimeric antigen receptor (CAR) T cells achieve durable responses. Consensus guidelines suggest avoiding bendamustine before apheresis, but specific data in this setting are lacking. We report distinct outcomes after CAR T-cell therapy according to previous bendamustine exposure. METHODS The study included CAR T-cell recipients from seven European sites. Safety, efficacy, and CAR T-cell expansion kinetics were analyzed according to preapheresis bendamustine exposure. Additional studies on the impact of the washout period and bendamustine dose were performed. Inverse probability treatment weighting (IPTW) and propensity score matching (PSM) analyses were carried out for all efficacy comparisons between bendamustine-exposed and bendamustine-naïve patients. RESULTS The study included 439 patients with R/R LBCL infused with CD19-targeted commercial CAR T cells, of whom 80 had received bendamustine before apheresis. Exposed patients had significantly lower CD3 + cells and platelets at apheresis. These patients had a lower overall response rate (ORR, 53% v 72%; P < .01), a shorter progression-free survival (PFS, 3.1 v 6.2 months; P = .04), and overall survival (OS, 10.3 v 23.5 months; P = .01) in comparison with the bendamustine-naïve group. Following adjustment methods for baseline variables, these differences were mitigated. Focusing on the impact of bendamustine washout before apheresis, those with recent (<9 months) exposure (N = 42) displayed a lower ORR (40% v 72%; P < .01), shorter PFS (1.3 v 6.2 months; P < .01), and OS (4.6 v 23.5 months; P < .01) in comparison with bendamustine-naïve patients. These differences remained significant after IPTW and PSM analysis. Conversely, the cumulative dose of bendamustine before apheresis did not affect CAR-T efficacy outcomes. CONCLUSION Recent bendamustine exposure before apheresis was associated with negative treatment outcomes after CD19-targeted CAR T-cell therapy and should be therefore avoided in CAR T-cell candidates.

Background: Acute kidney injury (AKI) occurs in 30% of patients infused with chimeric antigen receptor (CAR) T-cells. The purpose of this study was to identify risk factors and long-term outcomes after AKI in patients who received CAR T-cell therapy. Methods: Medical records of 115 adult patients with R/R hematological malignancies treated with CD19-targeted CAR T-cells at Vall d'Hebron University Hospital between July 2018 and May 2021. Baseline demographic data including age, gender, ethnicity, body mass index (BMI), and co-morbidities, as well as the type of hematological neoplasia and prior lines of therapy were collected. Laboratory parameters including serum creatinine and whole blood hemoglobin were retrospectively reviewed and values were gathered for days +1, +7, +14, +21, and +28 post-infusion. Results: A total of 24/115 (21%) patients developed AKI related to CAR T-cell therapy; 6/24 with AKI over chronic kidney disease (CKD). Two patients had AKI in the context of lymphodepleting (LD) chemotherapy and the other 22 after CAR T-cell infusion, starting at day+1 in 3 patients, day+7 in 13 patients, day +14 in 1 patient, day+21 in 2 patients, and day+28 in 3 patients. Renal function was recovered in 19/24 (79%) patients within the first month after infusion. Male gender, CKD, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with AKI. Male gender, CKD, ICANS grade ≥3 and CRS grade ≥2 were identified as independent risk factors for AKI on multivariable analysis. In terms of the most frequent CAR T-cell related complications, CRS was observed in 95 (82%) patients and ICANS in 33 (29%) patients. Steroids were required in 34 (30%) patients and tocilizumab in 37 (32%) patients. Six (5%) patients were admitted to the intensive care unit (1 for septic shock, 4 for CRS grade ≥2 associated to ICANS grade ≥2, and 1 for CRS grade ≥3). A total of 5 (4.4%) patients died in the first 30 days after CAR T-cell infusion for reasons other than disease progression, including 4 cases of infectious complications and 1 of heart failure. Conclusion: Our results suggest that AKI is a frequent but mild adverse event, with fast recovery in most patients.

Abstract Chimeric antigen receptor (CAR) T‐cell therapy is a promising treatment option for relapsed or refractory (R/R) large B‐cell lymphoma (LBCL). However, only a subset of patients will present long‐term benefit. In this study, we explored the potential of PET‐based radiomics to predict treatment outcomes with the aim of improving patient selection for CAR T‐cell therapy. We conducted a single‐center study including 93 consecutive R/R LBCL patients who received a CAR T‐cell infusion from 2018 to 2021, split in training set (73 patients) and test set (20 patients). Radiomics features were extracted from baseline PET scans and clinical benefit was defined based on median progression‐free survival (PFS). Cox regression models including the radiomics signature, conventional PET biomarkers and clinical variables were performed for most relevant outcomes. A radiomics signature including 4 PET‐based parameters achieved an AUC = 0.73 for predicting clinical benefit in the test set, outperforming the predictive value of conventional PET biomarkers (total metabolic tumor volume [TMTV]: AUC = 0.66 and maximum standardized uptake value [SUV max ]: AUC = 0.59). A high radiomics score was also associated with longer PFS and OS in the multivariable analysis. In conclusion, the PET‐based radiomics signature predicted efficacy of CAR T‐cell therapy and outperformed conventional PET biomarkers in our cohort of LBCL patients.

Abstract Bridging therapy (BT) after leukapheresis is required in most relapsed/refractory (R/R) large B‐cell lymphoma (LBCL) patients receiving chimeric antigen receptor (CAR) T cells. Bendamustine‐containing regimens are a potential BT option. We aimed to assess if this agent had a negative impact on CAR‐T outcomes when it was administered as BT. We included R/R LBCL patients from six centers who received systemic BT after leukapheresis from February 2019 to September 2022; patients who only received steroids or had pre‐apheresis bendamustine exposure were excluded. Patients were divided into two BT groups, with and without bendamustine. Separate safety and efficacy analyses were carried out for axi‐cel and tisa‐cel. Of 243 patients who received BT, bendamustine (benda) was included in 62 (26%). There was a higher rate of BT progressors in the non‐benda group (62% vs. 45%, p = 0.02). Concerning CAR‐T efficacy, complete responses were comparable for benda versus non‐benda BT cohorts with axi‐cel (70% vs. 53%, p = 0.12) and tisa‐cel (44% vs. 36%, p = 0.70). Also, 12‐month progression‐free and overall survival were not significantly different between BT groups with axi‐cel (56% vs. 43% and 71% vs. 63%) and tisa‐cel (25% vs. 26% and 52% vs. 48%); there were no differences when BT response was considered. CAR T‐cell expansion for each construct was similar between BT groups. Regarding safety, CRS G ≥3 (6% vs. 6%, p = 0.79), ICANS G ≥3 (15% vs. 17%, p = 0.68), severe infections, and neutropenia post‐infusion were comparable among BT regimens. BT with bendamustine‐containing regimens is safe for patients requiring disease control during CAR T‐cell manufacturing.

Chimeric antigen receptor (CAR) T cells targeting CD19 have changed the treatment landscape of patients with relapsed/refractory diffuse large B-cell lymphoma. Infections are one of the most frequent complications after CAR T-cell therapy. Most of these infections are bacterial, although viral infections can also occur in this setting. Adenovirus-induced hemorrhagic cystitis is a rare infectious complication and is usually observed after bone marrow or solid organ transplantation. Herein we report a case of adenovirus-induced hemorrhagic cystitis in a patient experiencing urinary symptoms within the first month after CAR T-cell infusion. Based on our experience and a literature review, we discuss the diagnostic approach and potential treatment options for this infrequent infection after CAR T-cell therapy.