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Page 10 of 14 Fujimoto et al. J Cancer Metastasis Treat 2021;7:66 https://dx.doi.org/10.20517/2394-4722.2021.157

[77]
relapsed or refractory ENKL patients showed superior ORR and CR rates of 58% and 44%, respectively .
Further analyses are warranted to identify the best combination therapy for ENKL patients.

Several novel targeted agents other than PD-1/PD-L1 antibodies have also been evaluated for their efficacy
against ENKL. The clinical efficacy of an anti-CD30 antibody-drug conjugate (brentuximab vedotin) has
been reported in two CD30-positive ENKL cases [80,81] . A phase II study for relapsed or refractory CD30-
positive non-Hodgkin lymphoma, including seven ENKL patients, showed an ORR of 29% and CR rate of
15% . An anti-CD38 antibody (daratumumab) was also reported to have durable efficacy in a CD38-
[82]
positive ENKL case . A phase II study of daratumumab monotherapy conducted for 32 relapsed or
[83]
refractory ENKL patients yielded the ORR of 25% and CR rate of 0% with a median PFS of 55 days .
[84]
Further, the HDAC inhibitor chidamide, which was developed as an oral therapeutic in China, was
evaluated in a multicenter, pivotal phase II study of 79 patients with relapsed or refractory T/NK-cell
lymphoma, including ENKL patients (20%). The ORR and CR rate of ENKL patients treated with
[85]
chidamide were 19% and 6%, respectively . In general, ENKL is strongly associated with type II EBV
latency, in which latent membrane protein 1 (LMP1) and latent membrane protein 2 (LMP2) are
expressed . The durable efficacy of autologous LMP1/2-specific cytotoxic T cells (CTLs) has been
[86]
demonstrated for relapsed or refractory ENKL patients . LMP1/2-specific CTLs were also used as a
[87]
consolidative therapy for high-risk ENKL patients with a complete response after induction therapy or stem
cell transplantation [87,88] . In addition, based on the findings that activation of the JAK-STAT pathway,
particularly associated with STAT3 and STAT5B mutations, is observed in ENKL tumor cells [89-91] , the
[94]
efficacy of a JAK3-selective inhibitor (PRN371) [92,93] and a STAT3 inhibitor (Stattic) was reported in JAK3-
mutated cell lines and a xenograft model and STAT3-mutated cell lines, respectively. Moreover, a pan-JAK
inhibitor (CP-690550) reduced cell viability with increased apoptosis in both JAK3-mutated and wild-type
ENKL cell lines . The clinical efficacies of these agents have not been well studied, and further evaluations
[93]
are needed.

There are no studies evaluating the efficacy of novel targeted agents for ANKL patients. High sensitivities to
[95]
a BCL2 inhibitor and a JAK2 inhibitor in vitro were reported . As described previously, because the
expression of PD-L1 is high in ANKL, PD-1/PD-L1 antibodies are also promising therapeutic agents for
ANKL patients with failed L-asp-containing regimen treatment, and further analysis is warranted.

CONCLUSION
The prognosis of patients with disseminated NK/T cell lymphoma is markedly improving. Recent advances
contribute to the improvement, but there remains room for further remedy, particularly for patients with
relapsed or refractory NK/T cell lymphoma. Developing novel agents is thus warranted.

DECLARATIONS
Authors’ contributions
Wrote the manuscript: Fujimoto A
Revised the manuscript: Suzuki R

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.