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Lymphoma

PD-1 blockade in extranodal NK/T-cell lymphoma: who is in charge?

Leukemia volume 34, pages 3432–3433 (2020)Cite this article

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Combination of radiotherapy and asparaginase-based chemotherapy has drastically improved the survival outcomes for patients of early-stage extranodal NK/T-cell lymphoma (ENKTCL), with 5-year overall survival (OS) rate being 85% [1]. However, patients with advanced or relapsed/refractory ENKTCL fared poorly even in the era of asparaginase [2]. The advent of PD1 blockade provides a new prospect for the treatment of ENKTCL, as several small cohort studies have demonstrated impressive response rates and durable efficacy [3, 4]. A bunch of PD1 antibodies have been approved in treating Hodgkin lymphoma (HL), primary mediastinal large B-cell lymphoma, or ENKTCL, mainly due to high expression of PD-L1 or PD-L2 caused by either genetic alterations at chromosome 9p24.1 (copy gain or amplification of the locus) or Epstein–Barr virus (EBV) infection [5]. Latent membrane protein 1 (LMP1), the oncogenic protein of EBV, could induce PD-L1 expression through activating NF-κB pathway in ENKTCL, and about 80% of patients with ENKTCL had PD-L1 expression in at least 5% of tumor cells [6]. Nevertheless, not all patients with positive expression of PD-L1 eventually benefit from PD1 blockade, and reliable efficacy predictive biomarkers are urgently needed to the implementation of precision medicine in ENKTCL.

In a study recently published in Leukemia, entitled “Whole-genome sequencing identifies Responders to Pembrolizumab in Relapse/Refractory Natural-killer/T Cell Lymphoma” [7], Lim et al. identified structural rearrangements involving PD-L1 gene to be the most powerful predictive biomarker for responders to pembrolizumab. In this study, both genetic profiling and PD-L1 immunohistochemical staining were performed in 19 patients with relapsed/refractory ENKTCL retrospectively. All these patients received pembrolizumab treatment, among whom 47.4% got durable response (36.8% complete response and 10.5% partial response). No association could be found between PD1 blockade efficacy and basic clinical features. Surprisingly, although expression of PD-L1 was positive in nearly all patients (18/19), there was no close correlation between PD-L1 positivity and response to pembrolizumab. Four patients harbored somatic mutations in the 3′-UTR of PD-L1, and all responded to pembrolizumab, resulting in a 100% specificity and 44.4% sensitivity in predicting PD1 blockade efficacy by presence of PD-L1 mutation. Moreover, PD-L1 mutation guided treatment with anti-PD-1 therapy was validated to be feasible in the prospective setting.

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  1. Department of Hematology, Beijing Tongren Hospital, Capital Medical University, 100730, Beijing, China

    Liang Wang & Jing-wen Wang

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Wang, L., Wang, Jw. PD-1 blockade in extranodal NK/T-cell lymphoma: who is in charge?. Leukemia 34, 3432–3433 (2020). https://doi.org/10.1038/s41375-020-01046-8

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