Autologous CD19-directed CAR-T cells(University of Sao Paulo)

Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited.

We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period.

Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1–2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3–4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1–0.7; P = .010).

CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted.

The utility of CD19-targeted chimeric antigen receptor T-cell (CAR-T cell) therapy in the management of refractory/relapsed B-cell malignancies has increased tremendously in recent times. In addition to cytokine release syndrome (CRS), neurotoxicity, and infections, CAR-T cell patients develop cytopenias, with about 15% of the patients continuing to have severe cytopenias up to three months after treatment. Retrospective reviews have reported the development of myelodysplastic syndrome (MDS) in patients undergoing CAR-T cell therapy. Here, we describe four cases of MDS and/or clonal cytopenias of undetermined significance (CCUS), developing after CAR-T cell therapy. A retrospective review of four patients with relapsed/refractory B-cell lymphomas treated with CD19-directed autologous CAR-T cell was conducted at our institution. The median age was 72.5 years (range 63-76). Three of the four patients had double-hit diffuse large B-cell lymphoma (DLBCL). The median number of lines of therapy before CAR-T cell was three. Only one patient had a prior autologous stem cell transplant (ASCT). The median time to diagnosis of MDS/CCUS from CAR-T cell therapy was three months. Two cases of CCUS diagnosed were at one- and two-month post-CAR-T cell, and two cases of MDS were diagnosed at 10 and 26 months. None of the patients had dysplastic clones before the initiation of CAR-T cell therapy. Only one patient was found to have CCUS-developed CRS post-CAR-T cell requiring treatment with tocilizumab and steroids. Three patients showed complete response, with one showing a very good partial response. All the patients were in remission with no additional therapies post-CAR-T cell. One patient died secondary to COVID-19-related complications. Four patients with prolonged cytopenias were found to have either MDS or CCUS after CAR-T cell therapy. Two CCUS cases underwent bone marrow evaluation early in the course of cytopenias and may develop into MDS, acute myeloid leukemia (AML), or myeloproliferative neoplasm over time. Our retrospective case series review, compared to previous studies, constitutes of patients with no prior clonal hematopoiesis-related cytogenetic abnormalities, fewer lines of therapy, and only one patient with previous hematopoietic stem cell transplantation (HSCT). Based on the upcoming data and our review, a bone marrow biopsy with next-generation sequencing (NGS) is imperative in patients with prolonged cytopenias after CAR-T cell therapy. A diagnosis of CCUS/MDS in these cases can help guide treatment.