Anti-CD19 chimeric antigen receptor T-cells therapy (CAR-T) is effective in secondary cns lymphoma (SCNSL) refractory to high-dose methotrexate (HDMTX)-based chemotherapy
Abstract
Abstract Introduction: Secondary involvement of the CNS is a direful complication of large B cell lymphomas (LBCL), which can occur at diagnosis or relapse. Treatment of SCNSL differs from systemic lymphomas and is based on high dose chemotherapy (CHT) with drugs that penetrate the blood-brain barrier, HDMTX in particular, followed by autologous stem cell transplantation (ASCT). However, 60% of pts is refractory to or relapses after this treatment, 2/3 of relapsed pts do not receive further salvage therapy, and responses are anecdotal. CAR-T is an effective salvage treatment for LBCL whereas experience in SCNSL is limited to a few registry studies, where response to prior lines and the number of SCNSL pts who result unsuitable candidates for CAR-T is roughly reported. Herein we report selection and management of consecutive pts with SCNSL referred to 3 Italian CAR-T-cell centres, providing more detailed information for pts who actually received CAR-T. Methods: SCNSL pts were evaluated for CAR-T eligibility between 07/22 and 03/25. Selected pts were offered a holding therapy according to extension of disease and prior treatments. Pts in CNS remission after holding were evaluated for CAR-T eligibility by a multidisciplinary team of experts. Eligible candidates underwent lymphocytoapheresis (Flu-Cy) and bridging therapy until commercial CAR-T infusion. Results: 23 pts were referred to holding: 6 partial-brain irradiation, 4 intrathecal CHT, 2 polatuzumab vedotin, 5 ibrutinib, 1 HD-ifosfamide-based CHT, 2 MATRix regimen, 1 thiotepa-based ASCT, combinations of these strategies in 2. 7 pts experienced progressive disease after holding, were deemed not eligible for CAR-T and died within one month. The other 16 achieved a remission of CNS disease and were eligible for CAR-T. All pts had ECOG 0-1, and all but one were refractory to prior HDMTX. Only one pt experienced G3-4 CRS, all CRS cases were successfully treated with tocilizumab and steroids, anakinra was used in 2 cases. ICANS were treated with steroids, plus anakinra in 2 cases. G≥3 ICANS occurs in two pts: one required pre-emptive ICU admission but resolved after 3 days, while the second pt had G1 CRS, developed refractory epilepticus status, and died 18 days after CAR-T infusion. Although recommended washout period was respected, the latter event could be explained by multiple intrathecal CHT instillations performed before CAR-T. Four pts had ≥1 cytopenia at 3 months. At a median follow up of 8 months (IQR: 3-12), 12/16 infused pts remain relapse-free; 3 had a systemic relapse, while none experienced CNS recurrence. Conclusion: Varied presentation and high aggressivity of SCNSL impede the use of a uniform treatment for these pts. SCNSL refractory to HDMTX-based polyCHT can benefit significantly from a tailored multimodal holding based on the pt's history and extension of disease. Only pts with good PS and responsive to holding therapy should be offered CAR-T to avoid superfluous toxicity.
Article Details
Authors (38)
Piera Angelillo
10IRCCS San Raffaele Scientific Institute, Milan, Italy
Edoardo Campodonico
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Teresa Calimeri
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Alice Di Rocco
6Division of Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
Alessia Castellino
20Division of Hematology - AO S. Croce e Carle, Cuneo and Laboratory of Blood Tumor Immunology, Molecular Biotechnology Center “Guido Tarone”, University of Torino, Cuneo, Italy
Andrea Ferrario
4ASST Sette Laghi Ospedale di Circolo, UOC Ematologia, Varese, Italy
Melania Celli
5Ospedale Infermi, UO Ematologia, Rimini, Italy
Andrea Assanelli
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Lorenzo Lazzari
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Maria Teresa Lupo Stanghellini
IRCCS San Raffaele Scientific Institute, Italy
Jacopo Peccatori
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Livia Donzelli
2Università Sapienza Roma, Hematology, Department of Translational and Precision Medicine, Rome, Italy
Claudia Castellino
3Division of Hematology, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
Angela Genchi
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Nicoletta Anzalone
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Paolo Vezzulli
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Federico Fallanca
4IRCCS San Raffaele Scientific Institute, Milan, Italy
Francesco Ancona
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Alessandro Bruno
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Giulio Cassanello
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Milena Coppola
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Federico Erbella
1IRCCS San Raffaele Scientific Institute, Strategic Program on Lymphomas, Milano, Italy
Paolo Fiore
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Elena Flospergher
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Camilla Gariazzo
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Filippo Magri
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Fabrizio Marino
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Sarah Marktel
Sara Mastaglio
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Giovanni Matassa
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Raffaella Milani
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Rosamaria Nitti
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Madddalena Noviello
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Alessia Orsini
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Fanny Palumbo
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Annalisa Ruggeri
8San Raffaele Scientific Institute, Milan, Italy
Fabio Ciceri
Vita-Salute San Raffaele University, Milan
Andrés José María Ferreri
19IUniversity Vita-Salute San Raffaele, Milano, Italy Strategic Program on Lymphomas, IRCCS San Raffaele Scientific Institute, Milano, Italy, Milan, Italy