Real-World Practice Patterns of Patient Management in the Peri-CAR T-Cell Therapy Setting for Patients with Mantle Cell Lymphoma: An International Survey on Behalf of the EBMT Lymphoma Working Party

Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a standard approach for patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) after Bruton tyrosine kinase inhibitor (BTKi) failure. Patient selection and management throughout the CAR-T process is challenging in the MCL setting, with a high dropout rate and increased risk of severe adverse events after infusion. Bridging therapy (BT) is required in most patients, but there is a lack of consensus on the optimal strategy. We sought to deliver information on real-world BT approaches, BTKi use and patient management in the peri-CART setting, providing a framework for future consensus guidelines in R/R MCL patients. Methods: An electronic survey was prepared in the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT) and distributed across EBMT centers to gather information on BT approaches which could lead to practical recommendations. This 20-item questionnaire focused on 1) Referral strategies, 2) BTKi and BCL2i washout prior to leukapheresis, 3) Choice of BT regimens after leukapheresis and 4) Patterns of BTKi and BCL2i use through CAR-T infusion. Results: There were 81 survey participants across 14 countries, mainly including CAR-T infusing centers (95%). Most respondents had a consultant (58%) or head of department (26%) profile, with experience in CAR T-cell therapy (64% with >25 infused patients) and, specifically, CAR-T in R/R MCL (92%). The majority considered CAR-T as the best option after BTKi failure (89%) and did not follow any specific guidelines for patient management in this setting (74%). Referral protocols were heterogeneous across non-infusing centers (N=4). Two of them reached out to the infusing site when the patient had progressive disease (PD) after first line, if adverse prognostic factors were present, but awaited PD after second-line BTKi for low-risk patients. The two others discussed the case with their infusing site in case of PD after first-line, or reached out after PD to second-line BTKi. Concerning usage patterns of targeted molecules prior to leukapheresis, 53% of participants employing a BTKi as BT stopped it prior to this procedure for a washout period, though a significant fraction maintained it through cell collection (33%). Similarly, 47% of respondents considered the use of venetoclax as BT prior to leukapheresis (usually in combination with a BTKi). Notably, most (92%) halted the BCL2i for washout prior to apheresis. Nearly all (96%) clinicians took into account the impact of bendamustine on T-cell fitness, avoiding it completely (43%) or limiting its use to first-line (53%). In terms of BT strategies, most centers favored a systemic approach, but up to 32% selected radiotherapy as their BT of choice when the patient was a suitable candidate. A high degree of variability was noted for systemic BT in this setting and up to 68% of respondents declared managing patients differently according to the presence of adverse prognostic factors. For high-risk patients, 47% of participants employed a chemotherapy-backbone (with [71%] or without [29%] associated targeted agents), while 36% combined venetoclax with a BTKi, and 26% favored pirtobrutinib in monotherapy. The preferred chemotherapy regimens included R-BAC (35%), R-GEMOX (31%) and cyclophosphamide-based (12%). Alternative regimens, such as R-Lenalidomide, Bortezomib or Temsirolimus, were rarely selected. In patients without high-risk features, there was a lower use of chemotherapy (37% vs 47%) and a venetoclax/BTKi combination (20% vs 36%) as BT after apheresis. Conversely, there was a higher use of ongoing single-agent ibrutinib (38% vs 7%) and a similar rate of pirtobrutinib monotherapy (23% vs 26%). Regarding the use of BTKi/BCL2i after infusion, most clinicians recommended stopping the BTKi prior to lymphodepleting chemotherapy (LDC) or CAR-T-cell infusion (69% and 17%, respectively), while a minority maintained it after infusion (14%). A similar approach was adopted with venetoclax, where a clear majority of participants stopped it prior to LDC (90%); only 1 respondent maintained it after infusion. Conclusion: These findings confirm the current heterogeneity of MCL patient management strategies prior to CAR T-cell therapy and highlight the need to develop consensus guidelines harmonizing the role of BTKi and other targeted molecules across leukapheresis, bridging and infusion.