A Phase II Prospective Study Evaluating an L-Asparaginase Regimen, Simple, in Newly Diagnosed Extranodal NK/T Cell Lymphoma

Background:

Extranodal NK/T-cell lymphoma (ENKTL) is a rare and aggressive subtype of mature T- and NK-cell lymphoma, characterized by resistance to conventional anthracycline-containing chemotherapy owing to high levels of P-glycoprotein expression in neoplastic cells. Non-anthracycline, non-P-glycoprotein dependent regimens, such as SMILE, have shown remarkable efficacy. However, the SMILE regimen is associated with significant toxicities associated with treatment related mortalities. A regimen that is effective and less toxic is needed, particularly for older patients with poor tolerance to chemotherapy.

Methods:

This prospective phase II study enrolled consecutive patients aged ≥ 16 years with histologically confirmed newly-diagnosed ENKTL from January 2013 to September 2023. Patients were excluded if they had central nervous system involvement or an expected survival of less than 3 months. The trial was approved by institutional ethics committee (ClinicalTrials.gov I.D.: NCT03071822).

The SIMPLE regimen consisted of cisplatin 25 mg/m² on days 1-3, gemcitabine 750 mg/m² on days 1 and 15, ifosfamide 1200 mg/m² on days 2-4, dexamethasone 40 mg on days 2-4, and L-asparaginase 6000 units/m² on even days 8-20. Six cycles of treatment were given at 28-day intervals. For limited-stage disease, involved-field radiotherapy of 50 Gy was administered between cycles 3 and 4 of chemotherapy. Dose reductions of 25% were allowed for patients experiencing prolonged grade 4 hematological toxicities in the prior cycle, and up to 50% for those aged ≥ 65 years.

The primary endpoints were the overall response rate (ORR) and complete response rate (CR) stratified by stage I/II and stage III/IV disease. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and treatment-related toxicities (graded according to CTCAE v5.0). Statistical analyses were performed using IBM SPSS v23.0, with a significance level of p=0.05. Kaplan Meier method was used for survival analysis.

Results:

For the stage I/II disease cohort, 63 patients (male=39; female=24) at a median age of 55(29-85) years were enrolled. Of 62 evaluable patients, the best responses were: partial response (PR; N=4, 6.4%), CR (N=54, 87%), giving an ORR of 93.4%. At a median follow-up of 43 months, the median PFS and OS were not reached. The 3-year PFS and OS were 73.8% and 83%. The prognostic score for NK lymphoma, PINK-E, was significantly associated with PFS (3-year PFS for score 0: 94%; 1: 76.6%; and 2: 36%; p<0.01).

For the stage III/IV cohort, 37 patients (male=16; female=21) at a median age of 60 (16-78) years were enrolled. Of 35 evaluable patients, the ORR was 80% (CR: 65.7%; PR: 14.3%). With a median follow-up of 18 months, the 2-year PFS and OS were 30.5%. and 60.2%. Note that the relatively low 2-year PFS was due to censoring at the time of consolidation with either allogeneic hematopoietic stem cell transplantation (N=5) or anti-PD1 antibodies (N=11).

Hematologic toxicities included neutropenia (99%; grade 3/4: 95%), thrombocytopenia (100%; grade 3/4: 89%), and anemia (100%; grade 3/4: 28%). Important non-hematologic toxicities included mucositis (78%; grade 3/4: 4%) and elevated alanine aminotransferase (71%;grade 3/4: 4%). Anaphylaxis to L-asparaginase was reported in 4% (all grade 3). There was no treatment-related mortality.

Conclusion

The SIMPLE regimen is a highly effective regimen with tolerable toxicity. However, the results for stage III/IV disease require further improvement.