Annalisa Paviglianiti and Alberto Mussetti, Haematology Department, Institut Català d'Oncologia (ICO), Barcelona, Spain, comment on the publication entitled "Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial" published in Blood.
Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial
Matthew J Frigault et al.
Blood. 2022 Apr 14;139(15):2306-2315. doi: 10.1182/blood.2021014738.
Three anti-CD19 chimeric antigen receptor T cells (CARTs) products have gained FDA approval in relapsed/refractory large B cell lymphomas. They are based on phase 2 clinical studies that precluded the inclusion of primary central nervous system lymphoma (PCNSL) patients due to potentially increased neurological toxicity (ICANS). Therefore, little is known about anti-CD19 CARTs safety and toxicities in this setting of patients. In this paper, the authors conducted a phase 1/2 clinical trial (NCT02445248) including 12 adult patients with progressive or relapsed PCNSL who received tisagenlecleucel. With a median follow-up of 12.2 months, no treatment related deaths were observed. Grade 1 cytokine release syndrome was observed in 7/12 patients while 6/12 patients experienced ICANS, being of grade ≤2 in 5/6 patients. These findings highly support the safety and tolerability of tisagenlecleucel in patients with PCNSL. The authors reported a high overall response rate with 7/12 patients achieving a response, including a complete response in 6/12. A sustained remission of initial response was observed in 3 of them. Furthermore, expansion of anti-CD19 CARTs was observed in peripheral blood in all but 1 patient with a confirmed cerebrospinal fluid trafficking demonstrated by levels of chimeric antigen receptor transgene RNA. These data demonstrate an acceptable safety profile of tisagenlecleucel in PNCSL with significant efficacy confirmed by peripheral expansion and central nervous system trafficking in the absence of systemic disease.
The importance of this paper relies on the proof-of-concept that anti-CD19 CARTs (tisacel in this case) may represent a potential curative therapy for patients with relapsed/refractory PCNSL. Despite the low number of patients, efficacy and safety results are promising. Anti-CD19 CARTs seems to be a curative option for such patients and their approval should be pursued for this very specific type of lymphoma. In fact, other therapies such as BTK-inhibitors or checkpoint inhibitors do have only a palliative potential. (1,2)This study opens newer questions in the field. Should these anti-CD19 CARTs be combined with other drugs such as ibrutinib which showed to be effective against PCNSL and synergic with anti-CD19 CARTs?(3). Should such therapies be tested also during first-line of therapies as it was done for aggressive B cell lymphomas?(4) As long as these therapies will not be approved, hematologists should be aware that anti-CD19 CARTs could represent a potential curative option for patients with PCNSL and clinical trials using such a therapeutic strategy represent an urgent clinical need.
1. Nayak L, Iwamoto FM, LaCasce A, Mukundan S, Roemer MGM, Chapuy B, et al. PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood. 2017 Jun 8;129(23):3071–3.
2. Soussain C, Choquet S, Blonski M, Leclercq D, Houillier C, Rezai K, et al. Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II ‘proof-of-concept’ iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) network. European Journal of Cancer. 2019 Aug;117:121–30.
3. Gauthier J, Hirayama AV, Purushe J, Hay KA, Lymp J, Li DH, et al. Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure. Blood. 2020 May 7;135(19):1650–60.
4. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat Rev Clin Oncol. 2018 Jan;15(1):47–62.