Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma

Abstract

Advanced natural killer/T cell lymphoma (NKTL) has demonstrated poor prognosis with currently available therapies. Here, we report the efficacy of anti-programmed death 1 (PD-1) antibody with the P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) regimen in advanced NKTL. Nine patients underwent six 21-day cycles of anti-PD-1 antibody (day 1), pegaspargase 2000 U/m² (day 1), gemcitabine 1 g/m² (days 1 and 8) and oxaliplatin 130 mg/m² (day 1), followed by anti-PD-1 antibody maintenance every 3 weeks. Programmed death-ligand 1 (PD-L1) expression and genetic alterations were determined in paraffin-embedded pretreatment tissue samples using immunohistochemistry and next-generation sequencing (NGS) analysis. Responses were assessed using ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) and computed tomography or magnetic resonance imaging. Eight patients exhibited significant responses, comprising of seven complete remissions and one partial remission (overall response rate: 88.9%). After a median follow-up of 10.6 months, 6/9 patients (66.7%) remained in complete remission. The most common grade 3/4 adverse events were anemia (33.3%), neutropenia (33.3%), and thrombocytopenia (33.3%); all of which were manageable and resolved. Immunochemotherapy produced a high response rate in patients with positive PD-L1 expression (5/6, 83.3%). NGS analysis suggested that STAT3/JAK3/PD-L1 alterations and ARID1A mutation were associated with immunochemotherapy efficacy. Mutation in DDX3X and alteration in epigenetic modifiers of KMT2D, TET2, and BCORL1 might indicate a poor response to immunochemotherapy. In conclusion, the anti-PD-1 antibody plus P-GEMOX regimen demonstrated promising efficacy in advanced NKTL. PD-L1 expression combined with specific genetic alterations could be used as potential biomarkers to predict therapeutic responses to immunochemotherapy.

Fig. 1

Changes in circulating EBV DNA during immunochemotherapy. a The EBV DNA in case 2 increased from 2220 to 28,100 copies/mL after 3 cycles of immunochemotherapy, and then became normal after salvage therapy of modified SMILE. b–f The EBV DNA in cases 3, 4, 5, 6, and 7 became normal after 1 or 2 cycles of immunochemotherapy. g The EBV DNA in case 8 increased from 2350 to 27,000 copies/mL after immunochemotherapy, and became normal after salvage therapy of etoposide, pegaspargase, and liposome doxorubicin. h The EBV DNA in case 9 decreased after the first cycle of immunochemotherapy, and then increased. EBV DNA then fell to 0 copies/mL after salvage therapy of modified SMILE

Fig. 2

Imaging results of three representative patients. a–f PET/CT results of case 1. Baseline PET/CT showed multiple lymph nodes involvement (a, b). After the sixth cycle of conventional chemotherapy, there were persistent FDG-avid lesions by PET/CT scan (c, d). After 2 cycles of immunochemotherapy, no FDG-avid lesions were observed and CR was confirmed (e, f). g–j PET/CT and MRI results of case 3. Baseline PET/CT and MRI examination showed neoplastic metabolic lesions invading the nasal cavities and sinuses, with MRI-proved lymphomatous infiltration in the sternal manubrium (g, h). After 4 cycles of immunochemotherapy, no FDG-avid lesions were found in a follow-up PET/CT scan, and the manubrium sternum lesions completely disappeared; demonstrating CR (i, j). k, l PET/CT results of case 6. Baseline PET/CT scan of case 6, presenting no nasal disease but systemic tumor invasion of the skin and lymph nodes (k). After 6 cycles of immunochemotherapy, all original skin lesions resolved, and no FDG-avid lesions were seen in the PET/CT scan, which indicated a response of CR (l)

Fig. 3

Immunohistochemistry (IHC) and hematoxylin/eosin (HE) staining of tumor specimens from seven NKTL patients. The expression of PD-L1, CD3, CD4, CD8, CD56, and Epstein–Barr virus-encoded RNA (EBER) in the clinical samples was analyzed by IHC staining (original magnification ×400). Due to limited tissue slides available for immunostaining, some of the specimens were only stained for the selected markers as indicated. PD-L1 was negative for case 9. EBER was positive in all seven cases. The expression of PD-L1 was only stained for cases 2 and 8

Fig. 4

Heatmap for altered genes in the seven NKTL patients