Bendamustine and the combination of fludarabine/cyclophosphamide are fully authorized chemotherapy agents in Switzerland for lymphoma treatment and currently used in routine clinical practice as lymphodepletion strategy before CAR-T immunotherapy, as supported by retrospective studies and clinical experience across multiple centers. None of the drugs described in this protocol are being used at unapproved doses, or in an investigational formulation. Both lymphodepletion regimens have a known safety profile and the risks and burdens imposed on participants do not exceed those encountered in routine CAR-T therapy management, as all procedures (including monitoring, supportive care, and follow-up assessments) align with standard clinical practice. Based on these assumptions, this protocol is designed to investigate the use of bendamustine as an alternative lymphodepletion therapy (which is a part of CAR-T immunotherapy protocol).
Diagnosis of large B-cell lymphoma (LBCL) with at least one line of previous treatment and indication for commercial CAR-T cell therapy as determined by the treating physician. This includes: Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS) and all specific DLBCL subtypes, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, transformed follicular lymphoma, and other transformed indolent B-cell lymphomas (including transformed marginal zone lymphoma and Richter's transformation). Patients with primary or secondary central nervous system (CNS) involvement are eligible.
Planned treatment with commercially available CAR-T cell product
Age ≥18 years
Ability to provide written informed consent
Administration of any other experimental drug within 5 half-lives or ≤ 4 weeks prior to lymphodepletion therapy starts.
Bendamustine 3 months before leukapheresis. After leukapheresis, bendamustine use is allowed as bridging therapy according to physician decision.
Previous administration of anti-CD19 CAR-T products within the last 12 months from lymphodepletion therapy start.
Known history of hypersensitivity to the active substance or any of the excipients found in the composition of bendamustine, fludarabine, or cyclophosphamide.
Parallel
bendamustine hydrochloride
Drug* Dose: 90 mg/m² body surface area * Route: Intravenous infusion * Administration: Infused over 30-60 minutes in 500 mL normal saline or 5% dextrose * Pre-medication: Standard institutional protocols for bendamustine administration (typically antiemetics)
Cyclophosphamide
Drug* Administration: Intravenous infusion per institutional protocols and product guidelines. * Dose: according to the specification described in the prescription information sheet of the CAR-T product used.
Fludarabine
Drug* Administration: Intravenous infusion per institutional protocols and product guidelines. * Dose: according to the specification described in the prescription information sheet of the CAR-T product used.
Incidence of the following side effect occurring within 4 weeks (28 days) from the CAR-T infusion: Occurrence of grade ≥3 cytokine release syndrome (CRS)
Primary Outcome measure consists of 3 side effects: Incidence of at least one of the following side effects occurring within 4 weeks (28 days) from the CAR-T infusion: • Occurrence of grade ≥3 cytokine release syndrome (CRS) • Febrile neutropenia • Grade ≥3 Immune effector Cell-Associated Neurotoxicit. All infections, including those that result in febrile neutropenia, and the CRS and ICANS will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 6.0. Febrile neutropenia is defined as absolute neutrophil count \<1000/mm³ with fever ≥38.3°C (single measurement) or ≥38.0°C sustained for \>1 hour. Participants who remain free of any of the above listed symptoms at least 28 days from the CAR-T cell infusion AND did not stop the trial treatment will be counted as a success for this endpoint, otherwise they will be counted as a failure for the primary endpoint.
Incidence of the following side effect occurring within 4 weeks (28 days) from the CAR-T infusion: Febrile neutropenia
Primary Outcome measure consists of 3 side effects: Incidence of at least one of the following side effects occurring within 4 weeks (28 days) from the CAR-T infusion: • Occurrence of grade ≥3 cytokine release syndrome (CRS) • Febrile neutropenia • Grade ≥3 Immune effector Cell-Associated Neurotoxicit. All infections, including those that result in febrile neutropenia, and the CRS and ICANS will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 6.0. Febrile neutropenia is defined as absolute neutrophil count \<1000/mm³ with fever ≥38.3°C (single measurement) or ≥38.0°C sustained for \>1 hour. Participants who remain free of any of the above listed symptoms at least 28 days from the CAR-T cell infusion AND did not stop the trial treatment will be counted as a success for this endpoint, otherwise they will be counted as a failure for the primary endpoint.
Incidence of the following side effect occurring within 4 weeks (28 days) from the CAR-T infusion: Grade ≥3 Immune effector Cell-Associated Neurotoxicit
All infections, including those that result in febrile neutropenia, and the CRS and ICANS will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 6.0. Febrile neutropenia is defined as absolute neutrophil count \<1000/mm³ with fever ≥38.3°C (single measurement) or ≥38.0°C sustained for \>1 hour. Participants who remain free of any of the above listed symptoms at least 28 days from the CAR-T cell infusion AND did not stop the trial treatment will be counted as a success for this endpoint, otherwise they will be counted as a failure for the primary endpoint.
Best lymphoma response at 3 months post-CAR-T infusion
Best lymphoma response at 3 months is defined as the best response assessment in the following descending order: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or not evaluable (NE), measured as indicated on local guidelines (e.g., Lugano 2014 classification) based on PET/CT imaging. Any assessment up to week 15 (inclusive) will be considered for determining the best response.
Progression-free survival (PFS)
PFS is defined as time from CAR-T infusion to lymphoma progression or death from any cause. Participants not experiencing an event, including participants receiving a subsequent anti-lymphoma therapy without documented disease progression or relapse, will be censored at the last time they were known to be without progression (i.e. last date of tumor assessment without progression) and before the start of a new anti-lymphoma treatment, if any.
Overall survival (OS)
Time from CAR-T infusion to death from any cause. Participants not experiencing an event will be censored at the last date they were known to be alive.
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