Pegasparaginase-Based Chemotherapy Yields Promising Preliminary Results in Extranodal Natural Killer/T-Cell Lymphoma

Dexamethasone, Cisplatin, gemcitabine, and pegaspargase resulted in improved preliminary outcomes vs dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide for patients with newly diagnosed locally advanced stage III or IV extranodal natural killer/ T-cell lymphoma.

Dexamethasone, cisplatin, gemcitabine, and pegaspargase (DDGP) compared with the SMILE regimen of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide, demonstrated promising preliminary results in patients with newly diagnosed locally advanced stage III or IV extranodal natural killer/ T-cell lymphoma (ENKL), according to results from a phase 4 trial (NCT01501149), published in JAMA Oncology.

Median progression-free survival (PFS) was not reached in the DDGP group and was 6.8 months in the SMILE group after a median follow-up of 41.5 months (HR, 0.42; 95% CI, 0.23-0.77; P = .004). Additionally, the median overall survival (OS) was not reached in the DDGP group vs 75.2 months in the SMILE group (HR, 0.41; 95% CI, 0.19-0.89; P = .02). At 3 years, the PFS rate was 56.6% vs 41.8% and the 5-year OS rate was 74.3% vs 51.7% in the DDGP and SMILE groups, respectively. The overall response rate was 90.0% in the DDGP group and 60.0% in the SMILE group (P = .002).

“This randomized clinical trial showed that when compared with the SMILE regimen, the DDGP regimen provided a safer and more effective strategy for patients with advanced-stage (III/IV) ENKL. However, a larger number of patients and more detailed data, such as genetic and molecular analyses, are needed to determine subsets of patients who are more suitable for these treatments in the future,” the study investigators wrote.

A total of 87 patients enrolled and were randomly assigned to either the DDGP group (n = 43) or the SMILE (n = 44) group. Two patients withdrew from the study because of researchers’ decision, and 5 refused or withdrew for multiple reasons before the trial began. Patients received an average of 5.75 cycles of chemotherapy in the DDGP group vs 4.68 in the SMILE group.

In the DDGP group, patients were treated with 20 mg/m2 of cisplatin intravenously on days 1 to 4; 15 mg/m2 of dexamethasone intravenously on days 1 to 5; 800 mg/m2 of intravenous gemcitabine on days 1 and 8; and 2500 IU/m2 of intramuscular pegaspargase on day 1. In the SMILE group, patients received 40 mg of intravenous dexamethasone on days 2 to 4; 2 g/m2 of intravenous methotrexate on day 1; 1.5 g/m2 of intravenous ifosfamide on days 2 to 4; 6000 U/m2 of L-asparaginase on days 3 to 9; and 100 mg/m2 of intravenous etoposide.

Eighty-eight percent of patients in the DDGP group completed 6 cycles of therapy , with 4 patients discontinuing treatment because of disease progression and 1 for family reasons. Of those in the SMILE group, 65% completed 6 cycles of treatment with 7 patients discontinuing due to disease progression, 6 due to adverse effects, and 1 due to hemophagocytic syndrome.

Common grade 3 and 4 hematologic adverse effects (AEs) in the SMILE group vs the DDGP group included leukopenia (85.0% vs 62.5%) and neutropenia (85.0% vs 65.0%), respectively. Additionally, patients in the SMILE group had higher rates non-hematologic AEs such as elevated transaminase, mucositis, and allergy compared with the DDGP group. Treatment-related deaths were reported in 17.5% of those in the SMILE group and were caused by infection (n = 6) and hemorrhage (n = 1). In the DDGP group, the incidence of death was 2.5% with 1 patient having cerebral hemorrhage, and 1 patient in the SMILE group having treatment-related grade 3/4 heart failure.


Wang X, Zhang L, Liu X, et al. Efficacy and safety of a pegasparaginase-based chemotherapy regimen vs an L-asparaginase-based chemotherapy regimen for newly diagnosed advanced extranodal natural killer/T-cell lymphoma: a randomized clinical trial. JAMA Oncol. Published Online June 16, 2022. doi:10.1001/jamaoncol.2022.1968