Etoposide, dexamethasone, and pegaspargase with sandwiched radiotherapy in early-stage natural killer/T-cell lymphoma: A randomized phase III study.

Methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) with sandwiched radiotherapy is known to be effective for early-stage extranodal natural killer/T-cell lymphoma, nasal type (NKTCL). We explored the efficacy and safety of reduced-intensity, non-intravenous etoposide, dexamethasone, and pegaspargase (ESA) with sandwiched radiotherapy. This multicenter, randomized, phase III trial enrolled patients aged between 14 and 70 years with newly diagnosed early-stage nasal NKTCL from 27 centers in China. Patients were randomly assigned (1:1) to receive ESA (pegaspargase 2,500 IU/m2 intramuscularly on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2-4) or MESA (methotrexate 1 g/m2 intravenously on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2-4, and pegaspargase 2,500 IU/m2 intramuscularly on day 5) regimen (four cycles), combined with sandwiched radiotherapy. The primary endpoint was overall response rate (ORR). The non-inferiority margin was -10.0%. From March 16, 2016, to July 17, 2020, 256 patients underwent randomization, and 248 (ESA [n = 125] or MESA [n = 123]) made up the modified intention-to-treat population. The ORR was 88.8% (95% confidence interval [CI], 81.9-93.7) for ESA with sandwiched radiotherapy and 86.2% (95% CI, 78.8-91.7) for MESA with sandwiched radiotherapy, with an absolute rate difference of 2.6% (95% CI, -5.6-10.9), meeting the non-inferiority criteria. Per-protocol and sensitivity analysis supported this result. Adverse events of grade 3 or higher occurred in 42 (33.6%) patients in the ESA arm and 81 (65.9%) in the MESA arm. ESA with sandwiched radiotherapy is an effective, low toxicity, non-intravenous regimen with an outpatient design, and can be considered as a first-line treatment option in newly diagnosed early-stage nasal NKTCL.