We report a T cell lymphoma (TCL) occurring 3 months after anti-CD19 chimeric antigen receptor (CAR) T cell immunotherapy for non-Hodgkin B cell lymphoma. The TCL was diagnosed from a thoracic lymph ...node upon surgery for lung cancer. The TCL exhibited CD8
cytotoxic phenotype and a JAK3 variant, while the CAR transgene was very low. The T cell clone was identified at low levels in the blood before CAR T infusion and in lung cancer. To assess the overall risk of secondary primary malignancy after commercial CAR T (CD19, BCMA), we analyzed 449 patients treated at the University of Pennsylvania. At a median follow-up of 10.3 months, 16 patients (3.6%) had a secondary primary malignancy. The median onset time was 26.4 and 9.7 months for solid and hematological malignancies, respectively. The projected 5-year cumulative incidence is 15.2% for solid and 2.3% for hematological malignancies. Overall, one case of TCL was observed, suggesting a low risk of TCL after CAR T.
Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and ...axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. However, bendamustine as lymphodepletion prior to lisocabtagene maraleucel (liso-cel), a 4-1BB co-stimulated, fixed CD4:CD8 ratio anti-CD19 CART product, has not been described yet. Thus, we studied a cohort of sequentially-treated patients with large B-cell lymphomas who received bendamustine lymphodepletion before liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (n = 31). Patients were evaluated for toxicities and responses. Of note, 7 patients (22.6%) would have dnot met the inclusion criteria for the registrational liso-cel clinical trials, mostly due to older age. Overall and complete response rates were 76.9% and 73.1%, respectively. At a median follow-up of 6.3 months, the 6-month progression-free and overall survival were 59.9% and 91.1%, respectively. Rates of cytokine-release syndrome (CRS) and neurotoxicity (ICANS) of any grade were 9.7% and 9.7%, respectively, with no grade ≥ 3 events. No infections were reported during the first 30 days following liso-cel infusion. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.
Abstract Patients with B-cell lymphomas have altered cellular components of vaccine responses due to malignancy and therapy, and the optimal timing of vaccination relative to therapy remains unknown. ...Severe acute respiratory syndrome coronavirus 2 vaccines created an opportunity for new insights in vaccine timing because patients were challenged with a novel antigen across multiple phases of treatment. We studied serologic messenger RNA vaccine response in retrospective and prospective cohorts with lymphoma and chronic lymphocytic leukemia, paired with clinical and research immune parameters. Reduced serologic response was observed more frequently during active treatment, but nonresponse was also common within observation and posttreatment groups. Total immunoglobulin A and immunoglobulin M correlated with successful vaccine response. In individuals treated with anti-CD19–directed chimeric antigen receptor–modified T cells, nonresponse was associated with reduced B and T follicular helper cells. Predictors of vaccine response varied by disease and therapeutic group, and therefore further studies of immune health during and after cancer therapies are needed to individualize vaccine timing.
•Bendamustine lymphodepletion before axicabtagene ciloleucel is effective and associated with reduced toxicity than Flu/Cy.•Bendamustine lymphodepletion induces a lower increase of inflammatory ...cytokines associated with the pathogenesis of CRS and neurotoxicity.
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Lymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell (CART) immunotherapies. In this study, we compared the safety and efficacy of bendamustine (Benda) to standard fludarabine/cyclophosphamide (Flu/Cy) LD before CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) for patients with large B-cell lymphoma (LBCL) and follicular lymphoma (FL). We analyzed 59 patients diagnosed with LBCL (n = 48) and FL (n = 11) consecutively treated with axi-cel at the University of Pennsylvania. We also analyzed serum samples for cytokine levels and metabolomic changes before and after LD. Flu/Cy and Benda demonstrated similar efficacy, with complete remission rates of 51.4% and 50.0% (P = .981), respectively, and similar progression-free and overall survivals. Any-grade cytokine-release syndrome occurred in 91.9% of patients receiving Flu/Cy vs 72.7% of patients receiving Benda (P = .048); any-grade neurotoxicity after Flu/Cy occurred in 45.9% of patients and after Benda in 18.2% of patients (P = .031). In addition, Flu/Cy was associated with a higher incidence of grade ≥3 neutropenia (100% vs 54.5%; P < .001), infections (78.4% vs 27.3%; P < .001), and neutropenic fever (78.4% vs 13.6%; P < .001). These results were confirmed both in patients with LBCL and those with FL. Mechanistically, patients with Flu/Cy had a greater increase in inflammatory cytokines associated with neurotoxicity and reduced levels of metabolites critical for redox balance and biosynthesis. This study suggests that Benda LD may be a safe alternative to Flu/Cy for CD28-based CART CD19-directed immunotherapy with similar efficacy and reduced toxicities. Benda is associated with reduced levels of inflammatory cytokines and increased anabolic metabolites.
Patients with B-cell lymphomas have altered cellular components of vaccine responses due to malignancy and therapy, and the optimal timing of vaccination relative to therapy remains unknown. ...SARS-CoV-2 vaccines created an opportunity for new insights in vaccine timing because patients were challenged with a novel antigen across multiple phases of treatment. We studied serologic mRNA vaccine response in retrospective and prospective cohorts with lymphoma and CLL, paired with clinical and research immune parameters. Reduced serologic response was observed more frequently during active therapies, but non-response was also common within observation and post-treatment groups. Total IgA and IgM correlated with successful vaccine response. In individuals treated with CART-19, non-response was associated with reduced B and T follicular helper cells. Predictors of vaccine response varied by disease and therapeutic group, and therefore further studies of immune health during and after cancer therapies are needed to allow individualized vaccine timing.
Abstract 4204
Most patients with asymptomatic advanced-stage low grade follicular lymphoma (FL) are managed by a ”watch and wait” strategy until they develop disease related symptoms or significant ...progression in tumor volume. The median time to first treatment (TFT) has been reported to be about 30 months from initial diagnosis (Ardeshna et al., Lancet 2003; 362: 516–22). Various prognostic factors such as FLIPI have been developed to estimate progression free survival and overall survival, but predictors for TFT from diagnosis have not been well defined in this population. The optimal frequency of follow-up and surveillance imaging remains unclear.
We reviewed our institutional database of FL patients who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) or FDG-PET imaging at diagnosis or as part of follow-up imaging during the ”watch and wait” period. Only patients with FL with low grade histologies (grade 1 or 2) on tissue biopsy who were untreated prior to FDG-PET imaging and with a minimum of 6 months of follow-up after the imaging were included in the analysis. SUVmax was defined as the highest lesional SUV on each scan and was determined by a nuclear medicine physician. ROC curve analysis was used to identify SUVmax cutoff values which would best predict short (≤ 6 months) vs. long (> 6 months) TFT with clinically relevant sensitivity and specificity for a training set of patients. The SUVmax cutoff value was then tested in another set of patients for the ability to categorize patients by TFT ≤ 6 months vs. > 6 months from imaging. Comparison between the two groups was performed using the Fisher’s exact test. STATA 10.1 software was utilized for data analysis.
78 FL patients followed in our institution from 2001 until 2011 were included in the study. In the training set of 27 patients (median age 52 years, range 19–67), the ROC curve analysis revealed that an SUVmax cutoff at 10 could distinguish between those with TFT ≤ 6 months vs. > 6 months. When applied to the test set of 51 patients (median age 53, range 18–82), an SUVmax ≥ 10 was able to predict short TFT correctly in 14 out of 16 patients who required treatment ≤ 6 months from the FDG-PET or FDG-PET/CT scan (positive predictive value of 88%). SUVmax ≥ 10 had a high specificity in the test set (90%), but limited sensitivity (47%). A Fisher’s exact test (two sided) confirmed that the association between SUVmax ≥ 10 and short vs. long TFT groups was statistically significant (p=0.006).
SUVmax ≥ 10 on FDG-PET or FDG-PET/CT imaging in patients with low grade FL can be used to identify those who will have a short TFT. An SUVmax cutoff at 10 could be an important factor in determining the frequency of clinical and imaging follow-up in asymptomatic, advanced-stage low grade FL patients who are managed by a ”watch and wait” strategy.
No relevant conflicts of interest to declare.
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