Dual resistance to asparaginase and PD-1 blockade in extranodal natural killer/T-cell lymphoma: dismal outcomes from a multicenter cohort

Asparaginase-based regimens and anti-PD-1 therapies have significantly improved survival in patients with extranodal natural killer/T-cell lymphoma (ENKTL) and are now increasingly incorporated into earlier treatment lines. However, clinical outcomes for patients with dual resistance to asparaginase and PD-1 inhibitors remain poorly defined. We conducted a multicenter retrospective study of 61 patients with dual resistance from a cohort of 900 ENKTL patients across 12 academic centers in China. Among 61 patients, median overall survival from initial diagnosis (OS-1) was 21.9 months (95% CI: 14.7-43.1). After the onset of dual resistance, the median post-resistance survival (OS-2) was 4.9 months (95% CI: 2.8-9.9). Rechallenge with asparaginase-based regimens or anti-PD-1 agents resulted in only limited benefit, yielding median progression-free survival (PFS) of 3.2 months (95% CI: 1.4-5.0) and 2.7 months (95% CI: 2.1-3.3), respectively. Chidamide-containing regimens were associated with a significantly longer OS-2 compared to regimens without chidamide (HR, 0.46; 95% CI: 0.24-0.88; P = 0.019). Other novel agents, including inhibitors of XPO1, PI3K, and JAK1, along with brentuximab vedotin, did not demonstrate a significant survival benefit in patients with dual-resistant ENKTL. This is the first comprehensive analysis of dual-resistant ENKTL, revealing poor prognosis and suggesting a potential signal of benefit associated with chidamide-containing regimens.