Comparison of Clinical Characteristics and Prognosis between Aggressive NK-Cell Leukemia and Advanced-Stage Extranodal NK/T-Cell Lymphoma

Introduction: Natural killer (NK)-cell neoplasms are rare hematological malignancies, including two major subtypes: aggressive NK-cell leukemia (ANKL) and extranodal NK/T-cell lymphoma, nasal type (ENKL). ANKL and ENKL share several characteristics, such as a strong association with Epstein-Barr virus (EBV) and a high prevalence in East Asia and Latin America. Because NK cells express multi-drug resistance (MDR)-associated P-glycoprotein/ABCB1 on their surface, anthracycline-containing chemotherapies, such as CHOP, are less effective for patients with both subtypes. The prognosis was not significantly different between ANKL and ENKL stage IV in the previous era (Suzuki R, et al. Ann Oncol. 2010: 21; 1032-40.). However, subsequently, effective chemotherapies consisting of non-MDR-associated anti-cancer agents, such as SMILE, have been developed for ENKL patients. In the present study, to explore clinical differences between ANKL and advanced-stage ENKL, comparisons of patient characteristics and prognosis of the two subtypes were conducted using recent data of patients, including those treated with novel treatment strategies. Methods: Data of 224 patients, including 108 ANKL patients diagnosed between 2000 and 2021 from ANKL22 study (UMIN 000046096) and 116 advanced-stage ENKL patients diagnosed between 2014 and 2021 from NKEA-Next project (UMIN 000046300), were analyzed. Diagnosis was made by considering the distribution of the disease, clinical course and EBV status, based on the World Health Organization classification. Results: The median age was 49 years in ANKL patients and 60 years in ENKL patients (P < 0.001). Among 116 ENKL patients, 5 were stage III and 111 were stage IV. There was no sex predilection observed in either group. B symptoms were more frequently observed in ANKL patients (86% vs. 53%; P < 0.001), along with poorer performance status (PS) at diagnosis (ECOG PS 2-4: 46% vs. 34%; P = 0.04). In terms of the site of involvement, the common extranodal sites were bone marrow (100%), spleen (84%), liver (70%), and peripheral blood (57%) for ANKL, and nasal cavity (56%), bone/bone marrow (45%), and skin (42%) for ENKL. The frequency of lymph node involvement was similar between both subtypes (40% for ANKL and 36% for ENKL). Pancytopenia, particularly thrombocytopenia, was more prevalent in ANKL patients than in ENKL patients (median platelet count, 4.6×104/μL vs. 19.5×104/μL; P < 0.001). Soluble IL-2 receptor level was significantly higher in ANKL patients than in ENKL patients (median, 8,274 U/dL vs. 1,408U/dL; P < 0.001). Among patients tested for EBV DNA positivity in peripheral blood, approximately 90% were detectable in both groups (89% for ANKL and 92% for ENKL; P = 0.51). Overall survival (OS) was significantly worse for ANKL than advanced-stage ENKL, with a 2-year OS of 18.3% and 37.7%, respectively (P < 0.001). This difference persisted when comparing ANKL and ENKL stage IV (2-year OS: 35.6% for ENKL stage IV; P < 0.001). Moreover, the prognosis for ANKL was significantly worse than that for ENKL with bone/bone marrow involvement (2-year OS: 18.3% vs. 37.9%; P = 0.003). Regarding first-line treatment, SMILE chemotherapy was the most commonly used for both subtypes (42% for ANKL and 55% for ENKL). The 2-year OS of patients treated with SMILE was 22.8% for ANKL and 57.1% for ENKL, respectively (P < 0.001). Fifty-two ANKL patients (48%) underwent hematopoietic stem cell transplantation (HSCT) (allogeneic HSCT 49, autologous HSCT 3), and 45 ENKL patients (39%) underwent HSCT (allogeneic HSCT 26, autologous HSCT 19). The prognosis of ANKL patients who underwent HSCT was significantly worse than that of ENKL patients who underwent HSCT (2-year OS: 36.3% vs. 63.7%; P = 0.008), but significantly better than that of ENKL patients who did not undergo HSCT (2-year OS: 18.0%; P = 0.03). Among patients undergoing allogeneic HSCT, ANKL patients who underwent allogeneic HSCT had worse OS than ENKL patients who underwent allogeneic HSCT (2-year OS: 36.4% vs. 55.2%; P = 0.06). Conclusion: The present study demonstrated differences in clinical characteristics and prognosis between ANKL and advanced-stage ENKL patients. Despite being younger, ANKL patients have a worse prognosis and require more effective treatments, including allogeneic HSCT. Further studies are warranted to elucidate the differences between these diseases.