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.
