Treatment with a 19-28z chimeric antigen receptor (CAR) T-cell (CAR-T) therapy after high-dose chemotherapy followed by autologous stem cell transplantation for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) resulted in a high incidence of severe neurotoxicity, according to a small study published in Blood.
However, the same study showed that patients with increased effector immunophenotypes (CD4+ and CD8+) trended toward better progression-free survival (PFS) after transplant. Despite this trend, the authors concluded that “[t]here was no association between CAR T cell peak expansion, persistence, or cytokine changes and PFS.”
The study included 15 patients with chemosensitive, poor-risk, relapsed or refractory DLBCL defined by positive FDG-PET after salvage therapy and/or bone marrow involvement. All patients underwent BEAM conditioned transplant followed by 19-28z CAR-T therapy infusion on days 2 and 3. This treatment is a second-generation CD19 CAR-T cell therapy that incorporates the signaling domain of the T cell CD3ζ chain and costimulatory CD28 domain.
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Median patient age was 61 years. Dose-limiting toxicities occurred at the 2 dose levels examined.
Ten out of 15 patients had treatment-induced neurotoxicity and/or cytokine release syndrome (CRS), which occurred at a median time to onset of 5 days. Of the 10 patients who had severe neurotoxicity, 6 also had grade 2 through grade 4 CRS at a median of 2.5 days. Nine of these patients received tocilizumab; 1 was observed. All neurotoxicity and CRS eventually resolved in these patients.
Neurotoxicity was significantly associated with greater CAR-T cell persistence (P =.05), but not peak CAR-T cell expansion.
The 2-year PFS was 30%. Two of the patients who had disease progression tested negative for CD19 on repeat biopsy.
Patients given decreased naive-like (CD45RA+CCR7+) CD4+ and CD8+ CAR-T cells had significantly better PFS (P =.02 and P =.04, respectively).
“While the long-term durability of this therapy was seen in only a few subjects, the high-risk characteristics of this relatively small phase 1 study population limits efficacy determination,” the researchers wrote. Nonetheless, “Phenotype selection and/or multiple infusions may be the focus of the next clinical trial.”
Reference
Sauter CS, Senechal B, Rivière I, et al. CD19 CAR T cells following autologous transplantation in poor risk relapsed and refractory B cell non-Hodgkin lymphoma [published online July 1, 2019]. Blood. doi: 10.1182/blood.2018883421
