DDGP Versus SMILE: Comparing Regimens for Extranodal Natural Killer T-Cell Lymphoma

In patients with extranodal natural killer T-cell lymphoma (ENKTL), treatment with the chemotherapy regimen of dexamethasone, cisplatin, gemcitabine, and pegasparaginase (DDGP) improved survival compared with those treated with dexamethasone, methotrexate, ifosfamide, asparaginase, and etoposide (SMILE), according to a study presented by Mingzhi Zhang, MD, PhD, from the First Affiliated Hospital of Zhengzhou University in China, at the 2019 ASH Annual Meeting. DDGP-treated patients also had lower rates of grade 3/4 adverse events.

“A subtype of highly aggressive mature T/NK-cell lymphomas, [ENKTL] is characterized by Epstein-Barr virus infection and varying degrees of systemic inflammation,” Dr. Zhang explained. While it is rare in Western countries, it is rather common in Asia, with a higher incidence among men than women. “Patients with advanced stage III or IV ENKTL have a poor survival and low response to conventional CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]–like chemotherapy, with a 5-year overall survival rate of 30 to 50%.” In earlier research, the SMILE chemotherapy regimen was efficacious in ENKTL, but its toxicity profile limited its clinical use.

In this prospective, randomized, multicenter, open-label trial, Dr. Zhang and researchers evaluated the safety and efficacy of the DDGP regimen, compared with SMILE, in patients with newly diagnosed stage III/IV ENKTL.

The study included 87 patients treated at one of nine centers in China between January 2011 and February 2019. Participants were between the ages of 14 and 70 and had an Eastern Cooperative Oncology Group ECOG performance status of 0 to 2.

Patients were randomized to receive DDGP or SMILE in the following schedules, for up to six 21-day cycles or until disease progression, unacceptable toxicity, or patient refusal:

  • DDGP: cisplatin 20 mg/m2 on days 1-4, dexamethasone 15 mg/m2 on days 1-5, gemcitabine 800 mg/m2 on days 1 and 8, and pegasparaginase 2,500 IU/m2 on day 1
  • SMILE: methotrexate 2 g/m2 on day 1, dexamethasone 40 mg/m2 on days 2-4, ifosfamide 1,500 mg/m2 on days 2-4, L-asparaginase 6,000 U/m2 on days 3-9, and etoposide 100 mg/m2 on days 2-4

Dr. Zhang presented safety and efficacy results for 80 patients who were included in the intention-to-treat population, 40 in the DDGP group and 40 in the SMILE group. After a median follow-up of 41.5 months (range not provided), the median progression-free survival (PFS; primary endpoint) and overall survival (OS; co-secondary endpoint) for patients treated with SMILE was 6.8 months and 75.2 months, respectively. In the DDGP-treated group, median PFS and OS were not reached (p=0.0041 for PFS; p=0.02 for OS).

This also translated to higher 3-year PFS rates and 5-year OS rates in the DDGP group:

  • 3-year PFS: 57% with DDGP vs. 42% with SMILE (p=0.004)
  • 5-year OS: 74% vs. 52% (p=0.02)

While there were no differences in the complete response rates between the two arms (68% vs. 48%; p=0.011), the overall response rate (co-secondary endpoint) was significantly higher in the DDGP group (90% vs. 60%; p=0.002).

As the researchers hypothesized, treatment with DDGP was associated with less toxicity. Patients in the SMILE cohort experienced more frequent grade 3/4 hematologic adverse events (AEs), including leukopenia (34 vs. 25; p=0.022) and neutropenia (34 vs. 26; p=0.015), as well as non-hematologic AEs, including elevated transaminase (5 vs. 0; p=0.027), mucositis (3 vs. 0; p<0.001), and allergic reaction (3 vs. 0; p=0.024).

Notably, there were more treatment-related deaths in the SMILE group (18%) compared with the DDGP group (10%). In the SMILE cohort, deaths were mainly related to infection and hemorrhage due to bone marrow suppression.

Together, the results suggest that DDGP prolonged survival and reduced toxicity; however, the results are limited by the relatively small patient population.

The study authors report no relevant conflicts of interest.


Wang X, Zhang L, Liu X, et al. Efficacy and survival in newly diagnosed advanced extranodal natural killer/T-cell lymphoma: a randomized, controlled, multicenter and open-labeled study with DDGP regimen versus SMILE regimen. Abstract #463. Presented at the 2019 American Society of Hematology Annual Meeting, December 8, 2019; Orlando, FL.