Cecilia Carpio

The impact of fludarabine pharmacokinetics (PK) on chimeric antigen receptor (CAR) T-cell outcomes is not fully elucidated. We hypothesized that, in relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients, measured fludarabine exposure during lymphodepletion would correlate with CAR T-cell results. We conducted a prospective, single-center study including R/R LBCL patients treated with commercial, CD19-targeted CAR T-cell products. Up to seven plasma samples per patient were collected at predefined intervals during lymphodepletion. Fludarabine exposure (area under the curve, AUC) was estimated using a population PK model. An iterative cubic spline approach identified optimal AUC exposure ranges specific to each CAR-T product. The primary endpoint was progression-free survival (PFS). Among 54 patients with a median follow-up of 24.5 months, the median fludarabine AUC was 18.12 mg*h/L (IQR 14.56-20.55). Optimal exposure windows were 17.5-21.5 mg*h/L for axicabtagene ciloleucel (axi-cel) and 14.0-18.0 mg*h/L for tisagenlecleucel (tisa-cel), with 24 patients (44%) inside these ranges. Median PFS after CAR-T infusion was not reached vs 13.3 months in the optimal vs other cohort (p=0.03). In the multivariable analysis, optimal exposure remained independently associated with improved PFS (p=0.03), together with axi-cel treatment (p=0.03). CAR T-cell expansion and rates of any grade CRS, ICANS and hematotoxicity were similar between groups. In conclusion, prospective measurement of fludarabine exposure identified an optimal AUC window associated with prolonged PFS in R/R LBCL patients receiving CAR T-cell therapy. These findings support the integration of PK-guided fludarabine dosing to enhance therapeutic outcomes.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (B-ALL), with high remission rates across various CAR T-cell constructs. However, the durability of these responses remains a major challenge, with many patients experiencing relapse after an initial remission. This systematic review and meta-analysis aimed to compare the efficacy and safety of different CAR T-cell constructs across 40 clinical trials, including a total of 1540 R/R B-ALL patients. We assessed the impact of patient demographics, prior treatment exposure, and construct characteristics on treatment outcomes. The pooled complete remission rate (CRR) was 83.4% (I² = 49%), with a minimal residual disease-negative complete remission (MRDneg-CR/CRi) rate of 92.7% (I² = 48%). 4-1BB co-stimulatory domain constructs showed higher MRDneg-CR/CRi rates compared with CD28 (94.0% vs. 84.4%p = 0.048) and a lower incidence of immune effector cell-associated neurotoxicity syndrome. Additionally, CAR T-cell products targeting CD19 or CD19/CD22 patients presented higher MRDneg-CR/CRi rates than those targeting CD22 alone. In conclusion, our findings suggest that 4-1BB-based CAR T-cell therapy targeting CD19 offers the best efficacy and safety profile in R/R B-ALL.

Purpose: The microbiota is recognized as an important contributor to the efficacy of immunotherapies. The aim of this study is to analyze the role of gut microbiota and related metabolites in the response of chimeric antigen receptor (CAR) T cells for non-Hodgkin lymphoma. Experimental Design: Stool, serum, and clinical data were collected from 84 patients with non-Hodgkin lymphoma from four hospitals before CD19 CAR T-cell treatment. The microbiota was characterized through 16S rRNA gene sequencing, and serum short-chain fatty acids (SCFA) were measured using mass spectrometry. CAR T cells were exposed to butyrate; their in vitro cytotoxicity was determined, and molecular mechanisms were characterized by flow cytometry and RNA sequencing and then assessed in an in vivo model. Results: As we confirmed the negative impact of antibiotics on the response, we delved into the mechanisms involved. We showed that they reduce microbiota diversity and that their composition correlates with the response. We identified SCFA-producing bacterial groups, including Prevotella, Ruminococcus, and Butyricicoccus, as having a relatively higher abundance in the microbiota of patients who responded to CAR T cells. Analysis of butyrate levels revealed a positive correlation with survival, potentially representing a novel biomarker of response. Finally, we found that stimulation of CAR T cells with butyrate induced phenotypic and transcriptomic changes associated with enhanced antitumor efficacy. Conclusions: Our results support the relationship between microbiota and CAR T-cell therapy major outcomes. Analysis of microbiota led to the identification of SCFAs, especially butyrate, as a prognostic factor, and also provides the basis for considering them as chemical modifiers of CAR T cells to improve their efficacy.

In the ELM-2 study (NCT03888105) of patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) (n = 141), odronextamab 160 mg weekly (after step-up dosing) significantly improved Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Lymphoma Subscale (LymS, least squares mean [95% confidence interval], 3.02 [1.76, 4.27]), FACT-General (FACT-G, 2.85 [0.81, 4.90]), Trial Outcome Index (TOI, 4.56 [2.18, 6.94]), and Total Score (5.64 [2.64, 8.64]); as well as European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) global health status/quality of life scale (GHS/QoL, 4.04 [1.23, 6.84]) and EQ-5D-3L visual analog scale (VAS, 3.59 [0.79, 6.39]) for overall health status. The least squares mean improvement in FACT LymS was clinically meaningful and patients were more likely to report clinically meaningful improvement or maintenance than clinically meaningful worsening overall for every scale. These improvements in patient-reported outcomes support the feasibility of odronextamab monotherapy regimen as a potential treatment option in r/r DLBCL.

Despite advances in vaccination and the use of antiviral treatments, patients with hematologic malignancies, including B-cell lymphoproliferative disorders, are particularly vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The recent introduction of bispecific antibodies (BsAbs) in the treatment algorithm of relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL) has raised concerns regarding their impact on COVID-19 outcomes. This study aimed to evaluate the impact of SARS-CoV-2 infection on treatment outcomes in patients receiving BsAbs. We assessed the severity of COVID-19 and SARS-CoV-2 serostatus, with antibody titers measured before, during, and after BsAbs administration. A total of 109 patients with B-NHL treated with BsAbs from March 2020 to January 2023 were included. SARS-CoV-2 infection was observed in 56 patients (51%), with 36% experiencing prolonged viral shedding, causing therapy delays in 78% of patients and permanent discontinuations in 19%. Regarding COVID-19 severity, 36% of patients presented moderate, 20% severe, and 12% critical disease. Seven patients (13%) died owing to COVID-19 pneumonia. Similar to observations with anti-CD20 monoclonal antibodies, BsAbs were associated with negative antispike serostatus for at least 6 months after treatment completion. Importantly, this lack of seroconversion was linked with severe disease and increased mortality. These findings underscore important considerations for the management of patients receiving BsAbs.

Summary: Classical Hodgkin lymphoma (cHL) has high curability following initial standard treatments. A less favourable outcome is observed in patients aged ≥60 (poorer tolerability and efficacy). Low‐intensity chemotherapies are currently employed for this group of patients, although there is still a need for improvement. This phase Ib/II multicentre, single‐arm study evaluated the safety and efficacy of the combination of brentuximab vedotin with cyclophosphamide, prednisolone, procarbazine, etoposide, mitoxantrone (BrEPEM) in older untreated patients with cHL. Forty patients were enrolled (6 phase Ib; 34 phase II). Median age was 73 years (range: 67–88), 93% stage III/IV and median Cumulative Illness Rating Scale–Geriatric (CIRS‐G) was 5 (range: 1–28). The median follow‐up was 43.2 months. The most common adverse events were haematological toxicities (neutropenia G ≥3: 32%). During treatment, five patients died from infections. Per protocol/intention‐to‐treat analysis showed an overall response of 93%/63% and a complete response of 89%/60% respectively. Median progression‐free survival (PFS) and overall survival (OS) were 14.3 months (95% confidence interval [CI] = 11.5–not reached [NR]) and NR (95% CI = 29.5–NR) respectively. Estimated 2‐year PFS and OS were 44% (95% CI = 31–62) and 69% (95% CI = 56–85) respectively. BrEPEM is an alternative option for older untreated cHL patients, albeit not exempt from toxicity. Studies directed to better patient selection are needed to improve survival and mitigate toxicities.

Torque Teno Virus (TTV) is a single-stranded circular DNA virus which has been identified as a surrogate marker of immune competence in transplantation. In this study we investigated the dynamics of plasma TTV DNAemia in 79 adult patients undergoing chimeric antigen receptor T-cell (CAR-T) therapy for relapsed or refractory large B-cell lymphoma, also evaluating the impact of TTV on immunotoxicities, response and survival outcomes. After lymphodepleting therapy, TTV DNA load was found to decrease slightly until reaching nadir around day 10, after which it increased steadily until reaching maximum load around day 90. TTV DNA load < 4.05 log10 copies/ml at immune effector cell-associated neurotoxicity syndrome (ICANS) onset identified patients at risk of progressing to severe forms of ICANS (OR 16.68, P = 0.048). Finally, patients who experienced falling or stable TTV DNA load between lymphodepletion and CAR-T infusion had better progression-free survival than those with ascending TTV DNA load (HR 0.31, P = 0.006). These findings suggest that TTV monitoring could serve as a surrogate marker of immune competence, enabling predictions of CAR-T efficacy and toxicity. This could pave the way for the development of TTV-guided therapeutic strategies that modulate clinical patient management based on plasma TTV load, similar to suggested strategies in solid organ transplant recipients.

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 freque... Plain language summary Lymphoma is an aggressive blood cell cancer. A treatment called chimeric antigen receptor (CAR) T-cell therapy has recently been developed for patients with lymphoma and othe...

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.