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 peg-asparaginase (DDGP) improved survival compared with those treated with dexamethasone, methotrexate, ifosfamide, asparaginase, and etoposide (SMILE), according to a study presented by Xinhua Wang, 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.

“ENKTL is rare in Western countries, but rather common in Asia and South America,” Dr. Wang explained. “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 five-year overall survival rate of only 30%.” 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. Wang 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 performance status score 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 peg-asparaginase 2,500 IU/m2 on day 1 (n=40)
  • SMILE: methotrexate 2 g/m2on 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 (n=40)

Dr. Wang presented safety and efficacy results for 80 patients who were included in the intention-to-treat population.

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 6.83 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 three-year PFS rates and five-year OS rates in the DDGP group:

  • 3-year PFS: 56.6% with DDGP vs. 41.8% with SMILE (p=0.004)
  • 5-year OS: 74.3% vs. 51.7% (p=0.02)

While there were no differences in the complete response rates between the two arms (67.5% vs. 47.5%; 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 fewer toxicities. Patients in the SMILE cohort experienced more frequent grade 3/4 hematologic toxicities, including leukopenia (34 vs. 25; p=0.022) and neutropenia (34 vs. 26; p=0.015), as well as non-hematologic toxicities, including elevated transaminase (5 vs. 0; p=0.027), mucositis (3 vs. 0; p<0.001), and allergy (3 vs. 0; p=0.024).

Notably, there were more treatment-related deaths in the SMILE group (17.5%), 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 interests.


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.