The emerging role of anti-PD-1 antibody-based regimens in the treatment of extranodal NK/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis

Abstract

Purpose: Anti-PD-1 antibody (anti-PD-1 mAb) showed favorable outcomes in some patients with relapsed/refractory (r/r) extranodal NK/T-cell lymphoma (ENKTL). However, the role of anti-PD-1 antibody in NK/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (NK/T-LAHS) remains unclear. Here, we evaluated the efficacy and toxicity of anti-PD-1 antibody-based treatment in NK/T-LAHS patients.

Methods: The clinical data of 98 patients diagnosed with NK/T-LAHS at Sun Yat-sen University Cancer Center and the First Affiliated Hospital of Guangdong Pharmaceutical University from May 2014 to November 2021 were retrospectively analyzed. All patients received anti-HLH [HLH-2004 (etoposide, dexamethasone, cyclosporine A) or DEP-based (liposomal doxorubicin, etoposide, methylprednisolone)] regimen and sequential anti-ENKTL chemotherapy (ChT) combined with anti-PD-1 antibody or not.

Results: The overall response rate (ORR) of the anti-PD-1 mAb plus ChT regimens was higher than that of the ChT regimens (73.3% vs. 45.5%, P = 0.041). The toxicity of the anti-PD-1 mAb plus ChT regimens was tolerable. Except for higher rate of neutropenia, no significant difference in adverse events (AEs) was observed between the two groups. When the optimal response to anti-ENKTL was achieved, the median EBV DNA levels in patients who received anti-PD-1 mAb plus ChT were significantly lower than patients who received ChT only (878 copies/mL vs. 18,600 copies/mL, P = 0.001). With a median follow-up of 26.6 months (range 0-65.9 months), the median overall survival (mOS) was 3.5 months (95% CI：2.3-4.7 months). Patients treated with anti-PD-1 mAb plus ChT experienced a longer mOS than those who received ChT only [5.2 months (95% CI: 2.5-7.8 months) vs. 1.5 months (95% CI: 0.5-2.6 months), P = 0.002]. Cox multivariate analysis found that anti-PD-1 mAb was an independent prognostic factor for all NK/T-LAHS patients.

Conclusion: In conclusion, anti-PD-1 mAb combined with ChT regimens seemed to be associated with prolonged survival in NK/T-LAHS patients and may represent a potentially promising treatment strategy for this population.

Keywords: Anti-PD-1 antibody; Epstein–Barr virus; Extranodal NK/T-cell lymphoma; Hemophagocytic lymphohistiocytosis.

Fig. 1

Study design flow chart. ENKTL extranodal NK/T-cell lymphoma, NK/T-LAHS extranodal NK/T-cell lymphoma-associated haemophagocytic lymphohistiocytosis, HLH haemophagocytic lymphohistiocytosis, HLH-2004 etoposide, dexamethasone, cyclosporine A, DEP liposomal doxorubicin, etoposide, methylprednisolone, ChT chemotherapy, Anti-PD-1 mAb anti-PD-1 monoclonal antibody

Fig. 2

Response to anti-HLH and anti-ENKTL treatment. A Two-week response to anti-HLH treatment in the HLH-2004 and DEP groups. B Anti-ENKTL treatment in the ChT group and ChT + anti-PD-1 mAb group. ns no significance,   P-value < 0.05 was marked with (*) to show statistically significant

Fig. 3

Circulating EBV DNA levels in the ChT group and the ChT plus anti-PD-1 mAb group. A When HLH was diagnosed. B When the best overall response to anti-ENKTL treatment was achieved. ns no significance, P-value < 0.01 was marked with (**) to show statistically significant

Fig. 4

Kaplan–Meier survival analysis. A Kaplan–Meier survival analysis of 98 NK/T-LAHS patients. B Patients treated with ChT plus anti-PD-1 mAb vs. ChT. C Patients with ECOG PS of 0–1 vs. ECOG PS ≥ 2. D Patients who received pegaspargase vs. patients who did not receive pegaspargase treatment. E Newly diagnosed HLH vs. secondary HLH