INCIDENCE, MITIGATION, AND MANAGEMENT OF NEUROLOGIC ADVERSE EVENTS IN THE PHASE 2 CARTITUDE-2 STUDY OF CILTACABTAGENE AUTOLEUCEL IN PATIENTS WITH MULTIPLE MYELOMA
Author(s): ,
Hermann Einsele
Affiliations:
Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II,Würzburg,Germany
,
Samir Parekh
Affiliations:
Mount Sinai Medical Center,New York,United States
,
Deepu Madduri
Affiliations:
Mount Sinai Medical Center,New York,United States
,
Bianca Santomasso
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Jaime Gállego Pérez-Larraya
Affiliations:
Clínica Universidad de Navarra,Pamplona,Spain
,
Niels van de Donk
Affiliations:
Department of Hematology,Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam,Amsterdam,Netherlands
,
Bertrand Arnulf
Affiliations:
Saint-Louis University Hospital AP-HP,Paris,France
,
Maria-Victoria Mateos
Affiliations:
Institute of Cancer Molecular and Cellular Biology, University Hospital of Salamanca,Salamanca,Spain
,
Kevin De Braganca
Affiliations:
Janssen R&D,Raritan,United States
,
Helen Varsos
Affiliations:
Janssen R&D,Raritan,United States
,
Marlene Carrasco-Alfonso
Affiliations:
Legend Biotech USA, Inc.,Piscataway,United States
,
Muhammad Akram
Affiliations:
Legend Biotech USA, Inc.,Piscataway,United States
,
Nikoletta Lendvai
Affiliations:
Janssen R&D,Raritan,United States
,
Carolyn Jackson
Affiliations:
Janssen R&D,Raritan,United States
,
Yunsi Olyslager
Affiliations:
Janssen R&D,Beerse,Belgium
,
Enrique Zudaire
Affiliations:
Janssen R&D,Spring House,United States
,
Claire Li
Affiliations:
Janssen R&D,Spring House,United States
,
Dong Geng
Affiliations:
Legend Biotech USA, Inc.,Piscataway,United States
,
Andrzej Jakubowiak
Affiliations:
University of Chicago,Chicago,United States
Adam Cohen
Affiliations:
Abramson Cancer Center, University of Pennsylvania,Philadelphia,United States
EHA Library. Einsele H. 06/09/21; 324726; EP1003
Hermann Einsele
Hermann Einsele
Contributions
Abstract
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP1003

Type: E-Poster Presentation

Session title: Myeloma and other monoclonal gammopathies - Clinical

Background
Ciltacabtagene autoleucel (Cilta-cel or JNJ-68284528) is a chimeric antigen receptor T (CAR-T) cell therapy with two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies designed to confer high avidity binding. In the phase 2, multicohort, open-label CARTITUDE-2 (NCT04133636) study, the efficacy and safety of cilta-cel in patients with multiple myeloma (MM) were assessed in various clinical settings.

Aims
To describe the mitigation and management strategies implemented in order to identify and reduce the risk for neurologic adverse events (AEs) in Cohort A patients (progressive MM after 1−3 prior lines of therapy).

Methods
Eligible patients (≥18 years of age) had MM per International Myeloma Working Group criteria, measurable disease, Eastern Cooperative Oncology Group performance status ≤1, progressive MM after 1−3 prior lines of therapy (including a proteasome inhibitor and immunomodulatory drug), and were lenalidomide refractory (no prior BCMA-targeting agent). All patients provided informed consent prior to enrollment in the study. Patients received cilta-cel (0.75×106 [range: 0.5–1.0×106] CAR+ viable T cells/kg) as a single infusion 5–7 days after start of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 daily for 3 days). Monitoring and mitigation strategies for neurologic AEs included providing more effective bridging therapy to reduce tumor burden prior to lymphodepletion, frequent assessment of CAR-T-related immune effector cell­-associated neurotoxicity syndrome (ICANS) using the immune effector cell-associated encephalopathy tool, regular handwriting assessments to detect micrographia, and neuroimaging (brain MRI) and EEG for patients with prior neurologic disease. Management strategies included evaluation of infectious and paraneoplastic etiologies upon observation of ICANS ≥ grade 1, administration of tocilizumab (if concurrent cytokine release syndrome [CRS], all grade of ICANS) and/or dexamethasone (grade 2/3) or methylprednisolone (grade 4). ICANS and CRS were graded by American Society for Transplantation and Cellular Therapy criteria; neurotoxicities not classified as ICANS were graded per Common Terminology Criteria for Adverse Events version 5.0.

Results
As of 15 Jan 2021 (median follow-up: 5.8 months [range: 2.5–9.8 months]), 20 patients in Cohort A received cilta-cel. The median age was 60 years (range: 38–75) and 65% of patients were male. Neurotoxicities occurred in 4 patients (20%). Three patients had ICANS (grade 1/2); the median time to onset of symptoms was 8 days (range: 7–11), and the median duration was 2 days (range: 1–2). Two of the 3 patients received supportive measures to treat ICANS, including levetiracetam and steroids; all 3 had concurrent CRS and all recovered. One patient developed isolated grade 2 facial paralysis on Day 29 after cilta-cel infusion and recovered 51 days after the onset of event following treatment with dexamethasone for 28 days. No movement or neurocognitive disorders were reported.

Conclusion
Neurologic AEs were generally manageable in patients with MM following treatment with cilta-cel. With a median follow-up of 5.8 months, there were no movement or neurocognitive disorders in patients with progressive MM who had received 1−3 prior lines of therapy (Cohort A). These results suggest that early detection and management of neurologic AEs can lead to better treatment outcomes.

Keyword(s): B-cell maturation antigen, CAR-T, Multiple myeloma, Safety

Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP1003

Type: E-Poster Presentation

Session title: Myeloma and other monoclonal gammopathies - Clinical

Background
Ciltacabtagene autoleucel (Cilta-cel or JNJ-68284528) is a chimeric antigen receptor T (CAR-T) cell therapy with two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies designed to confer high avidity binding. In the phase 2, multicohort, open-label CARTITUDE-2 (NCT04133636) study, the efficacy and safety of cilta-cel in patients with multiple myeloma (MM) were assessed in various clinical settings.

Aims
To describe the mitigation and management strategies implemented in order to identify and reduce the risk for neurologic adverse events (AEs) in Cohort A patients (progressive MM after 1−3 prior lines of therapy).

Methods
Eligible patients (≥18 years of age) had MM per International Myeloma Working Group criteria, measurable disease, Eastern Cooperative Oncology Group performance status ≤1, progressive MM after 1−3 prior lines of therapy (including a proteasome inhibitor and immunomodulatory drug), and were lenalidomide refractory (no prior BCMA-targeting agent). All patients provided informed consent prior to enrollment in the study. Patients received cilta-cel (0.75×106 [range: 0.5–1.0×106] CAR+ viable T cells/kg) as a single infusion 5–7 days after start of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 daily for 3 days). Monitoring and mitigation strategies for neurologic AEs included providing more effective bridging therapy to reduce tumor burden prior to lymphodepletion, frequent assessment of CAR-T-related immune effector cell­-associated neurotoxicity syndrome (ICANS) using the immune effector cell-associated encephalopathy tool, regular handwriting assessments to detect micrographia, and neuroimaging (brain MRI) and EEG for patients with prior neurologic disease. Management strategies included evaluation of infectious and paraneoplastic etiologies upon observation of ICANS ≥ grade 1, administration of tocilizumab (if concurrent cytokine release syndrome [CRS], all grade of ICANS) and/or dexamethasone (grade 2/3) or methylprednisolone (grade 4). ICANS and CRS were graded by American Society for Transplantation and Cellular Therapy criteria; neurotoxicities not classified as ICANS were graded per Common Terminology Criteria for Adverse Events version 5.0.

Results
As of 15 Jan 2021 (median follow-up: 5.8 months [range: 2.5–9.8 months]), 20 patients in Cohort A received cilta-cel. The median age was 60 years (range: 38–75) and 65% of patients were male. Neurotoxicities occurred in 4 patients (20%). Three patients had ICANS (grade 1/2); the median time to onset of symptoms was 8 days (range: 7–11), and the median duration was 2 days (range: 1–2). Two of the 3 patients received supportive measures to treat ICANS, including levetiracetam and steroids; all 3 had concurrent CRS and all recovered. One patient developed isolated grade 2 facial paralysis on Day 29 after cilta-cel infusion and recovered 51 days after the onset of event following treatment with dexamethasone for 28 days. No movement or neurocognitive disorders were reported.

Conclusion
Neurologic AEs were generally manageable in patients with MM following treatment with cilta-cel. With a median follow-up of 5.8 months, there were no movement or neurocognitive disorders in patients with progressive MM who had received 1−3 prior lines of therapy (Cohort A). These results suggest that early detection and management of neurologic AEs can lead to better treatment outcomes.

Keyword(s): B-cell maturation antigen, CAR-T, Multiple myeloma, Safety

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