Treatment Options for Extranodal Natural Killer/T-Cell Lymphoma

A phase II study included 28 patients with newly diagnosed stage IV or relapsed or refractory ENKL. Patients received steroids, methotrexate, ifosfamide, [L-]asparaginase, and etoposide (SMILE).[9] Despite no head-to-head studies, this regimen is used more often in clinical practice, in patients with advanced-stage disease, or in combination with radiation therapy for patients with localized disease. Other asparaginase-based regimens which have been studied include gemcitabine, oxaliplatin, and pegaspargase (P-GEMOX);[10] gemcitabine, etoposide, pegaspargase, and dexamethasone (GELAD);[11] and dexamethasone, cisplatin, gemcitabine, and pegaspargase (DDGP).[12]For patients who may not tolerate or who have reactions to asparaginase, a nonasparaginase regimen may be given with concurrent radiation therapy.[13][Level of evidence C3]

A phase II study included 28 patients with newly diagnosed stage IV or relapsed or refractory ENKL. Patients received steroids, methotrexate, ifosfamide, [L-]asparaginase, and etoposide (SMILE).[9] Despite no head-to-head studies, this regimen is used more often in clinical practice, in patients with advanced-stage disease, or in combination with radiation therapy for patients with localized disease. Other asparaginase-based regimens which have been studied include gemcitabine, oxaliplatin, and pegaspargase (P-GEMOX);[10] gemcitabine, etoposide, pegaspargase, and dexamethasone (GELAD);[11] and dexamethasone, cisplatin, gemcitabine, and pegaspargase (DDGP).[12]For patients who may not tolerate or who have reactions to asparaginase, a nonasparaginase regimen may be given with concurrent radiation therapy.[13][Level of evidence C3]

The overall response rate after two cycles was 79% (95% confidence interval [CI], 65%–89%), and the complete response rate was 45%. The 1-year overall survival (OS) rate was 55% (95% CI, 38%–69%).

A phase II study included 28 patients with newly diagnosed stage IV or relapsed or refractory ENKL. Patients received steroids, methotrexate, ifosfamide, [L-]asparaginase, and etoposide (SMILE).[9] Despite no head-to-head studies, this regimen is used more often in clinical practice, in patients with advanced-stage disease, or in combination with radiation therapy for patients with localized disease. Other asparaginase-based regimens which have been studied include gemcitabine, oxaliplatin, and pegaspargase (P-GEMOX);[10] gemcitabine, etoposide, pegaspargase, and dexamethasone (GELAD);[11] and dexamethasone, cisplatin, gemcitabine, and pegaspargase (DDGP).[12]For patients who may not tolerate or who have reactions to asparaginase, a nonasparaginase regimen may be given with concurrent radiation therapy.[13][Level of evidence C3]

Grade 4 neutropenia was observed in 92% of patients, and grade 3 or 4 infections were seen in 61% of patients.[9]

A phase II study included 28 patients with newly diagnosed stage IV or relapsed or refractory ENKL. Patients received steroids, methotrexate, ifosfamide, [L-]asparaginase, and etoposide (SMILE).[9] Despite no head-to-head studies, this regimen is used more often in clinical practice, in patients with advanced-stage disease, or in combination with radiation therapy for patients with localized disease. Other asparaginase-based regimens which have been studied include gemcitabine, oxaliplatin, and pegaspargase (P-GEMOX);[10] gemcitabine, etoposide, pegaspargase, and dexamethasone (GELAD);[11] and dexamethasone, cisplatin, gemcitabine, and pegaspargase (DDGP).[12]For patients who may not tolerate or who have reactions to asparaginase, a nonasparaginase regimen may be given with concurrent radiation therapy.[13][Level of evidence C3]

A modification to the SMILE regimen (mSMILE) incorporating pegylated asparaginase has demonstrated reduced toxicity.[10]

A retrospective study (NCT02733458) included 35 patients with newly diagnosed stage III to IV, relapsed, or refractory ENKL. Patients received P-GEMOX.[10]

A retrospective study (NCT02733458) included 35 patients with newly diagnosed stage III to IV, relapsed, or refractory ENKL. Patients received P-GEMOX.[10]

The overall response rate was 80.0%, and the complete response rate was 51.4%. The 3-year progression-free survival (PFS) rate was 38.6%, and the 3-year OS rate was 64.7%.[10][Level of evidence C3]

A prospective multicenter study (NCT02733458) included 52 patients with newly diagnosed stage IE/IIE ENKL who received two cycles of GELAD followed by intensity-modulated radiotherapy (50–56 Gy in 25–58 fractions) and two additional courses of GELAD.[11]

A prospective multicenter study (NCT02733458) included 52 patients with newly diagnosed stage IE/IIE ENKL who received two cycles of GELAD followed by intensity-modulated radiotherapy (50–56 Gy in 25–58 fractions) and two additional courses of GELAD.[11]

With a median follow-up of 32 months, the estimated 4-year OS rate was 94.2% (95% CI, 83.2%–93.1%), and the 4-year PFS rate was 90.4% (95% CI, 78.4%–95.9%).[11][Level of evidence C3]

A prospective multicenter study (NCT02733458) included 52 patients with newly diagnosed stage IE/IIE ENKL who received two cycles of GELAD followed by intensity-modulated radiotherapy (50–56 Gy in 25–58 fractions) and two additional courses of GELAD.[11]

The overall response rate was 94.2%, and the complete response rate was 92.3%.

A retrospective study included 80 patients with newly diagnosed (n = 48), refractory (n = 23), or first-relapse (n = 9) ENKL. Patients received DDGP.[12]

A retrospective study included 80 patients with newly diagnosed (n = 48), refractory (n = 23), or first-relapse (n = 9) ENKL. Patients received DDGP.[12]

The overall response rate was 91.3% (95% CI, 85.0%–96.3%), and the complete response rate was 60.0% (95% CI, 48.8%–71.3%). The 2-year PFS rate was 81.4% (95% CI, 76.3%–86.5%), and the 2-year OS rate was 87.1% (95% CI, 83.4%–91.4%).[12][Level of evidence C3]

A phase I/II study of 27 patients with newly diagnosed stage IE or contiguous IIE disease studied the nonasparaginase-based regimen DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin). Patients received three cycles of DeVIC at the recommended phase II dosing and concurrent radiotherapy dosed at 50 Gy.[13]

A phase I/II study of 27 patients with newly diagnosed stage IE or contiguous IIE disease studied the nonasparaginase-based regimen DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin). Patients received three cycles of DeVIC at the recommended phase II dosing and concurrent radiotherapy dosed at 50 Gy.[13]

With a median follow-up of 32 months, the 2-year OS rate was 78% (95% CI, 57%–89%). The overall response rate was 81%, and the complete response rate was 77%.[13][Level of evidence C3]

A phase I/II study of 27 patients with newly diagnosed stage IE or contiguous IIE disease studied the nonasparaginase-based regimen DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin). Patients received three cycles of DeVIC at the recommended phase II dosing and concurrent radiotherapy dosed at 50 Gy.[13]

The most common grade 3 or higher nonhematologic toxicity was mucositis related to radiation, which occurred in 30% of patients.

A retrospective review included 1,273 patients with early-stage disease. Patients were stratified into a low-risk group and high-risk group using stage, age, lactate dehydrogenase level, performance status, and primary tumor invasion.

A retrospective review included 1,273 patients with early-stage disease. Patients were stratified into a low-risk group and high-risk group using stage, age, lactate dehydrogenase level, performance status, and primary tumor invasion.

Low-risk patients fared best with radiation therapy alone,[14] while high-risk patients fared best with a strategy of radiation therapy combined with chemotherapy.[15-17][Level of evidence C3]

A retrospective review included 303 previously untreated patients from an international consortium who received nonanthracycline chemotherapy.[18]

A retrospective review included 303 previously untreated patients from an international consortium who received nonanthracycline chemotherapy.[18]

The OS rates were identical (72%−74% at 5 years) for patients with early-stage disease who received either concurrent chemotherapy and radiation therapy or chemotherapy followed by radiation therapy.[18][Level of evidence C3]

In a phase II trial, the anti–PD-L1 antibody avelumab was given to 21 patients with relapsed or refractory disease.[25]

In a phase II trial, the anti–PD-L1 antibody avelumab was given to 21 patients with relapsed or refractory disease.[25]

The complete response rate was 24%, and the overall response rate was 38%. The responses correlated with tumor PD-L1 expression.[25][Level of evidence C3]

Treatment with pembrolizumab, an anti–PD-1 antibody, resulted in similar responses in patients with relapsed or refractory disease.[26][Level of evidence C3]

A single-arm multicenter phase II study (GEMSTONE-201 [NCT03595657]) included 80 patients with relapsed or refractory ENKL. Patients received the anti–PD-L1 monoclonal antibody sugemalimab.

A single-arm multicenter phase II study (GEMSTONE-201 [NCT03595657]) included 80 patients with relapsed or refractory ENKL. Patients received the anti–PD-L1 monoclonal antibody sugemalimab.

The objective response rate was 44.9% (95% CI, 33.6%–56.6%), and the complete response rate was 35.9%. The 12-month duration of response rate was 82.5% (95% CI, 62.0%–92.6%).[27][Level of evidence B3]