Efficacy and Safety of Combined Anti-PD-1, Bortezomib and Pegaspargase Regimen for Newly Diagnosed Early Stage Extranodal NK/T-Cell Lymphoma

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive lymphoma with a poor prognosis. L-asparaginase-based treatment regimens, such as SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide), DDGP (dexamethasone, cisplatin, gemcitabine,and pegaspargase) and P-gemox (gemcitabine, oxaliplatin, and pegaspargase), have shown higher response rate and survival outcomes than traditional anthracycline-containing regimen. However, the safety profile did not seem satisfactory. It is imperative to develop novel approach with low toxicity and high efficiency for ENKTL patients. In this single arm, multi-center pilot study (ChiCTR2200066349), we aimed to observe the efficacy and safety of PPB (anti-PD-1, bortezomib and pegaspargase) regimen in newly diagnosed early stage ENKTL patients. Patients were eligible if they were≤70 years old with newly diagnosed ENKTL in stages I/II and had an Eastern Cooperative Oncology Group performance status of 0 to 2. Treatment included 6 cycles of PPB: intravenous tislelizumab (200mg, d1), subcutaneous bortezomib (1.3mg/m², d1,4,8,11) and intramuscular pegaspargase (2500 IU/m², d1), and repeated every 3 weeks. Additionally, local radiotherapy was performed after two cycles of PPB regimen. We enrolled 7 patients in the preliminary study, with 3 achieving CR and 4 achieving PR, resulting in a CR rate of 42.9% and an ORR of 100% (7/7). In terms of safety, PPB regimen is well tolerated, and the incidence of hematological toxicity (including neutropenia, anemia and thrombocytopenia) is 71.4% (5/7). Most patients (4/7) have only grade 1-2 hematological toxicity, and only one patient experienced grade 3 neutropenia. Three patients showed mild transaminase abnormalities, with no severe hepatic/renal insufficiency or coagulation disorders. Four patients had mild nausea and vomiting, one patient had mild diarrhea. All patients had no cardiac events. In this single arm clinical trial, the PPB regimen showed promising preliminary results with tolerable side effects. A confirmation trial based on larger population is needed in the future.

No relevant conflicts of interest to declare.

NF-kB signaling pathway is involved in the regulation of cell cycle and apoptosis, and targeting the NF-kB pathway may represent a reasonable approach for the treatment of malignant tumors. Studies have reported that abnormal activation of NF-kB signaling pathway in ENKTL. Bortezomib is an FDA-approved proteasome inhibitor for the treatment of multiple myeloma and mantle cell lymphoma. Bortezomib induces apoptosis by inhibiting the NF-kB signaling pathway. Lee et al reported that bortezomib combined with CHOP was used as the first-line treatment for advanced T cell and NK/T cell lymphoma. The CR rate was 61.5% after receiving multiple courses of treatment, indicating that the addition of this inhibitor has improved the efficacy of chemotherapy for lymphoma. The toxicity was tolerable, and the study concluded that this regimen is a recommended first-line treatment for advanced T-cell and ENKTL cell lymphoma.