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

[54]
patients after the first cycle and eventually observed in all patients . Therefore, AspaMetDex should only
be used in a relapsed or refractory setting of the disease. Only a prospective clinical trial comparing the
efficacy of DDGP (DEX, CDDP, gemcitabine, and peg-asparaginase) and SMILE has been reported from
[55]
China, but the results cannot be evaluated owing to the poor study design . The authors included a larger
proportion of stage III ENKL patients than that found in the historical data (usually less than 20% of
advanced-stage ENKL), and the methods and patient selection criteria described were different from the
registered data on ClinicalTrials.gov (NCT01501149). Therefore, we conclude that the recommended
standard treatment for advanced-stage ENKL is still the SMILE regimen .
[42]
Hematopoietic stem cell transplantation for ENKL
Hematopoietic stem cell transplantation (HSCT) is recommended for relapsed or refractory limited-stage
ENKL, in which a complete response (CR) is not achieved after the first-line treatment, as well as for
advanced-stage ENKL. The advantage of upfront HSCT has not been established in limited-stage ENKL
patients or ENKL patients with favorable risk factors who achieved first CR after induction therapy . In
[56]
contrast, the results of a SMILE phase 2 study suggest that the OS of patients with advanced-stage, relapsed,
[42]
or refractory ENKL is better in the HSCT group than in the non-HSCT group . Therefore, HSCT remains
the mainstay for advanced-stage ENKL in the first CR or partial response (PR). Although autologous HSCT
and allogeneic HSCT have not been compared, generally, autologous HSCT is recommended for relapsed
limited-stage ENKL patients with chemo-sensitivity or advanced-stage ENKL patients who achieve first CR
or PR after L-asp-containing chemotherapy, and allogeneic HSCT is recommended for the remaining
patients . Recently, the efficacy of four cycles of VIDL followed by up-front autologous HSCT in newly
[57]
[58]
diagnosed advanced-stage ENKL patients was reported in Korea . Seventeen of 24 patients prospectively
included in this phase 2 study, who achieved CR or PR after four cycles of VIDL, finally proceeded with
upfront autologous HSCT. The median duration of the response was 15.2 months. However, nine patients
(53%) relapsed after HSCT and four (24%) of the nine relapsed in the central nervous system (CNS).
Therefore, we have to pay attention to CNS relapse in ENKL patients who received HSCT. Further, these
results suggest that advanced-stage ENKL patients, especially those with risk factors for CNS involvement,
should be treated with intermediate-dose MTX-containing chemotherapy, including SMILE, and upfront
[59]
HSCT . The durable efficacy of allogeneic HSCT for ENKL was reported from the Center for International
Blood and Marrow Transplant Research (CIBMTR) with a three-year OS of 34% and no relapse after two
[60]
years from HSCT treatment .

ANKL
A standard treatment for ANKL has not been established, and there are no prospective clinical trials for
ANKL patients due to its rarity. The anthracycline-containing regimen is not effective for ANKL, with a
median OS of 2-3 months . SMILE therapy is recommended as a first-line treatment for ANKL, as for
[5]
advanced-stage ENKL, although the reported evidence is limited. In a small-scale retrospective study, the
ORR of SMILE therapy in 13 patients with ANKL was 38% . Since ANKL progresses rapidly, most patients
[61]
have B symptoms, liver dysfunction, and a poor general condition at diagnosis [5,12] . The dose of anti-cancer
agents in SMILE can be reduced for such comorbid patients. Another alternative is an L-asp monotherapy
followed by SMILE therapy after an improvement in organ function or the general condition. One case
report showed the successful treatment with L-asp monotherapy as a first-line therapy for ANKL with
severe liver dysfunction at diagnosis . In that case, SMILE was supplemented after the improvement of
[62]
liver function with L-asp monotherapy.

Hematopoietic stem cell transplantation for ANKL
Most ANKL patients who do not receive allogeneic HSCT, even if they achieve CR after induction
chemotherapy, progress to relapse disease and eventually die [5,11,12] . Therefore, allogeneic HSCT is