Aggressive natural killer cell leukemia therapy in the L-asparaginase era: why are we failing?

Purpose: Aggressive natural killer cell leukemia (ANKL) is a rare malignancy with poor prognosis and unclear treatment strategies. Given the poor prognosis and lack of a standardized treatment for ANKL, this study aimed to evaluate the clinical outcomes of L-asparaginase (L-ASNase)-based chemotherapy and hematopoietic stem cell transplantation (HCT). Methods: This retrospective study analyzed 51 patients with ANKL (2000–2023) to assess the clinical outcomes and efficacy of L-ASNase-based chemotherapy. Results: Among the study patients, 18 (36.7%) had poor performance status (ECOG-PS ≥ 3) and 7 (13.7%) died before initiating chemotherapy. Of the 44 treated patients, 30 (58.9%) received L-ASNase-based regimens, showing higher response rates (46.7% vs. 21.4%) and a slightly longer median duration of response (4.5 vs 4.2 months) than non-L-ASNase regimens. Complete administration of L-ASNase in the first cycle improved response rates (p = 0.019), but poor performance led to premature discontinuation (p = 0.011). Among the responders, those who subsequently underwent HCT demonstrated prolonged survival compared to those who did not. Median progression-free survival and overall survival were 0.8 and 1.6 months, respectively. Conclusion: HCT was associated with improved survival, particularly among patients who responded to initial therapy. However, given the high frequency of poor performance status at diagnosis, a stepwise approach, including early supportive care, careful chemotherapy administration, and timely HCT, is crucial for optimizing ANKL outcomes.