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Page 8 of 14 Fujimoto et al. J Cancer Metastasis Treat 2021;7:66 https://dx.doi.org/10.20517/2394-4722.2021.157

recommended for all ANKL patients who achieve a response and are eligible for this procedure. The
[63]
effectiveness of allogeneic HSCT for ANKL was first reported in 1996 . Small-scale retrospective studies
showing durable response and long-term survival for ANKL patients who received allogeneic HSCT have
been reported since then [21,64,65] . A retrospective study of 21 ANKL patients who underwent allogeneic HSCT
reported from CIBMTR showed that the two-year OS was 24% and two-year relapse rate was 59%. In this
study, approximately 30% of patients who achieved CR at the time of HSCT had long-term survival,
whereas all who had active disease at the time of HSCT eventually died within one year due to relapse .
[66]
Another retrospective study reported in Korea showed that up-front allogeneic HSCT improves survival
outcomes for ANKL patients . In contrast, in a small-scale retrospective study in Japan, of seven patients
[67]
who underwent allogeneic HSCT and had active disease at the time of HSCT, four achieved CR after HSCT
[12]
and two of these four patients remained disease-free for more than two years . These results suggest that
allogeneic HSCT can provide long-term survival, even in patients with active disease at the time of HSCT.
Recently, the impact of allogeneic HSCT for 59 ANKL patients on survival outcomes was reported in
Japan . The median OS and PFS were 3.9 and 2.6 months, respectively, which are consistent with the
[68]
previous data from CIBMTR. The prognosis of patients who relapsed within one year after HSCT was poor,
with a median OS of only 1.4 months. In contrast, if patients survived more than one year without relapse,
the subsequent five-year OS from one year after allogeneic HSCT was good (85.2%). The prognosis of
patients who achieved CR or PR at the time of HSCT was significantly better than that of patients without a
response, which was also comparable to a previous finding (five-year OS, 40.6% vs. 16.1%, P = 0.046).
Interestingly, 15 of 24 patients with primary induction failure at the time of HSCT achieved CR after
allogeneic HSCT, and the prognosis of the 15 patients (five-year OS, 32.0%) was almost comparable with
that of patients with CR or PR at HSCT (P = 0.95). Therefore, allogeneic HSCT should be considered for all
patients with ANKL to improve survival, even for those without response at HSCT. In addition, we should
try to develop novel treatments that could provide higher responses for ANKL patients, because the efficacy
and response rate of the current treatments are still not satisfactory.

NOVEL AGENTS AND THE POSSIBILITY OF CHEMO-FREE TREATMENTS
The prognosis of patients with ENKL or ANKL refractory to L-asp-based regimens is extremely poor. A
scheme of the associated molecular pathway and the results of clinical trials of promising novel agents for
relapsed or refractory ENKL are shown in Figure 2 and Table 2, respectively. A recent study showed that, in
patients with EBV-associated lymphoma, including ENKL and ANKL, PD-L1 is frequently expressed in
tumor cells owing to PD-L1/PD-L2 genetic alterations mainly in the 3’-untranslated regions (UTR) [69,70] . The
PD-1/PD-L1 antibody, an immune checkpoint inhibitor, is the most promising treatment for these patients.
An excellent response to pembrolizumab at 100 mg (2 mg/kg) once every three weeks in seven patients with
ENKL who relapsed or were refractory to L-asp-containing regimens was reported with the ORR of 100%
and CR rate of 71%, although this study had a patient selection bias . Similarly, a retrospective analysis of
[71]
19 ENKL patients who were treated with pembrolizumab at 3 mg/kg once every three weeks showed that
the ORR and CR rate were 47% and 37%, respectively . Next-generation sequencing analysis of the samples
[72]
of the 19 patients before pembrolizumab initiation in this study revealed that the gene mutation occurred
most frequently in the 3’-UTR of PD-L1 (21%), which was the only therapeutic biomarker significantly
associated with a good response to pembrolizumab. All ENKL patients (n = 4) with a PD-L1 mutation
achieved CR with pembrolizumab and sustained the response for more than 30 months. In contrast, PD-L1
expression, evaluated by immunohistochemistry, was not significantly associated with the response to
pembrolizumab , which was consistent with the results of another study of seven ENKL patients treated
[72]
with pembrolizumab at 100 mg . In this study, the ORR and CR rate were 57% and 29%, respectively .
[73]
[73]
Regarding other immune checkpoint inhibitors, the efficacy of low-dose nivolumab, given at 40 mg every
two weeks, was also reported in a small case series . In addition, sintilimab, a novel PD-1 antibody,
[74]