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Although chimeric antigen receptor (CAR) T-cell therapy is improving outcomes of patients with non-Hodgkin lymphoma (NHL), it is not indicated for the use in patients with central nervous system (CNS) involvement. Due to concerns around neurotoxicity associated with the use of these products, CNS involvement was an exclusion criterion in previous clinical studies assessing the efficacy and safety of CAR T-cells.1
Matthew J Frigault from Massachusetts General Hospital, Boston, MA, US, and colleagues recently reported in Blood the results of a retrospective analysis of a small number of patients with high-grade B-cell NHL and secondary CNS involvement, who were treated with commercial tisagenlecleucel (tisa) at the Massachusetts General Hospital.2
Eight patients with CNS involvement received lymphodepleting chemotherapy with cyclophosphamide (250mg/m2) and fludarabine (25mg/m2) 5, 4, and 3 days before single infusion of tisa (0.6–6.0 x 108 cells). Patients received CNS-directed bridging therapy until lymphodepletion. Initial response was assessed 28 days after infusion by the treating physician in collaboration with a neuro-oncology specialist. Cytokine release syndrome (CRS) and neurotoxicity (NT) were evaluated by the treating physician according to the Lee criteria 2014 and CTCAE v5 and then retrospectively compared with the recent ASTCT 2019 guidelines.3,4
ASCT, autologous stem cell transplant; DLBCL, diffuse large B-cell lymphoma; HGBCL, high-grade B-cell lymphoma; PMBCL, primary mediastinal large B-cell lymphoma |
|
Total number of patients |
8 |
---|---|
Median age |
50 years (17–79) |
Sex Female Male |
4 4 |
NHL subtype DLBCL HGBCL PMBCL |
5 2 1 |
Site of CNS involvement at infusion Parenchymal only Leptomeningeal only Both |
3 3 2 |
Systemic disease at baseline Yes No |
2 6 |
Median number of prior therapies |
5 (3–6) |
Number of patients with prior ASCT |
1 |
CSF, cerebral spinal fluid; CR, complete response; D, days following CAR-T infusion; NA, non-applicable; PD, progressive disease; PR, partial response; RT, radiotherapy; *Not evaluable due to disease progression | |||
Max CRS/NT (ASTCT 2019)4 | Response | Follow-up | |
---|---|---|---|
Patient 1 | Grade 1 CRS | PD leading to death | NA |
Patient 2 | None | CR, CSF (-) | Systemic relapse at D90 with CNS (-) RT to focal relapse followed by resolution on D180 without additional CNS directed therapy |
Patient 3 | Grade 1 CRS | PR, CSF (-) | CR at D180 |
Patient 4 | Grade 1 CRS | PD | RT and lenalidomide |
Patient 5 | Grade 1 CRS, NT* | PD leading to death | NA |
Patient 6 | Grade 1 CRS | PD; Prior sitesresolved, new lesion CSF (+) | Ibrutinib maintenance and RT to residual disease |
Patient 7 | Grade 1 CRS | PR | Ongoing response at D90 |
Patient 8 | Grade 1 CRS | CR | Ongoing response at D90 |
This retrospective analysis points to the viability of tisa as a treatment option for patients with secondary CNS. Patients did not experience increased rates of CRS or NT while CNS responses were seen in half of the patients. The data presented in this retrospective study remain preliminary with a short follow-up but may pave the way for longer and larger prospective studies assessing the use of CAR T-cell therapy for the treatment of CNS disease. The authors are planning to explore this further in a pilot study of tisa in primary lymphoma.
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