Interim PET-CT Scan to Improve Risk Modeling for Patients with Extranodal Natural Killer/T-Cell Lymphoma Treated with Non-Anthracycline Containing L-Asparaginase Based Regimen

Abstract

Background Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare and distinct subtype of non-Hodgkin lymphoma characterized by predominant involvement of the nasal cavity and nasopharynx and the application of L-asparaginase (L-asp) based non-anthracycline containing induction therapy has improved clinical outcomes of the patients. Currently, prognostic index of natural killer lymphoma plus Epstein-Barr virus is widely used to evaluate prognosis of patients with ENKTL. In this study, we evaluated the value of interim fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) for the better prognostication of ENKTL patients. Methods Patients with histologic diagnosis of ENKTL from May 2009 to May 2020 treated with L-asp based non-anthracycline containing induction regimen and who had interim PET-CT analysis at Asan Medical Center, Seoul, Korea were included. Response was assessed using the Deauville 5-point scales (DS). Progression-free survival (PFS) was defined as time from the induction therapy to disease progression or any cause of death, and overall survival (OS) was defined as time from the induction therapy to any cause of death. Survival curves were estimated by Kaplan-Meier method and compared using log-rank test. Key baseline characteristics and candidate prognostic factors including age, Eastern Cooperative Oncology Group performance status, Epstein-Barr virus (EBV) detection from blood at baseline, distant lymph node (LN) involvement, initial stage, location of disease (nasal vs. non-nasal), and serum lactate dehydrogenase level were included in the univariate analysis. In the multivariate analysis, variables exhibiting a potential association with survival (p < 0.05) in the univariate analysis were included. Results A total of 58 patients were included in the analysis. Median age was 55 years (range, 19-80), 34 patients (58.6%) were male, 19 patients (32.8%) had non-nasal disease and 43 patients (74.1%) had stage 4 disease at diagnosis. Among 43 patients with stage 4 disease, 19 patients (44.2%) received VIDL regimen consisting of etoposide, ifosfamide, dexamethasone and L-asp while 23 patients (55.8%) received SMILE regimen consisting of ifosfamide, etoposide, methotrexate, dexamethasone and L-asp as induction treatment. All 15 patients with stage 1 or 2 disease received combined modality treatment with cisplatin-based concurrent chemoradiation and L-asp containing chemotherapy. With median follow-up duration of 52.7 months (95% confidence interval [CI] 37.7-81.3), median PFS and OS were 9.9 months (95% CI 4.8-28.6) and 25.6 months (95% CI 13.3-not applicable), respectively. Thirty-two patients (55.2%) had interim PET-CT DS (iDS) of 4-5. Patients with iDS 4-5 showed significantly worse outcomes in terms of both PFS and OS compared to patients with iDS 1-3 with hazards ratio (HR) of 2.13 (95% CI 1.11-4.06, p = 0.019) and 2.51 (95% CI 1.19-5.33, p = 0.013), respectively. The 2-years PFS rates for patients with iDS 4-5 and iDS 1-3 were 27.3% (95% CI 15.3-44.8) and 49.0% (95% CI 32.9-69.3), respectively. The 2-years OS rates were 35.6% (95% CI 22.1-54.0) and 64.3% (95% CI 48.0-86.2), respectively. In the univariate analysis, age, EBV detection from blood at baseline, initial stage, location of disease (nasal vs. non-nasal), distant LN involvement and iDS showed potential association (p < 0.05) with OS. In multivariate analysis, iDS were independently associated with OS with HR of 3.96 (iDS 4-5 vs. 1-3, 95% CI 1.76-8.94, p < 0.001), along with location of disease with HR of 4.03 (non-nasal vs. nasal, 95% CI 1.83-8.91, p < 0.001). Conclusion The interim PET-CT response based on the DS is useful for predicting OS of patients with ENKTL in the era of non-anthracycline-based L-asp containing induction therapy.