Background Aggressive natural killer cell leukemia (ANKL) is a rare and fulminant hematologic malignancy characterized by a median overall survival of less than two months, even with intensive chemotherapy. Patients typically present acutely with fever, constitutional symptoms, hepatosplenomegaly, and hemophagocytic lymphohistiocytosis (HLH). Recent studies have identified recurrent genomic alterations involving genes in the JAK/STAT signaling pathway in ANKL. In addition, our previous work has demonstrated that the JAK inhibitor ruxolitinib is effective and well tolerated in patients with secondary HLH. These findings provide a strong rationale for combining ruxolitinib with P-Gemox (pegaspargase, gemcitabine, and oxaliplatin) to improve outcomes in ANKL. Based on this rationale, we conducted a pilot trial of this combination regimen in adult patients with ANKL (chictr.org.cn identifier: ChiCTR2400086092).

Methods

Adult patients (18–80 years) with newly diagnosed ANKL were enrolled. Key exclusion criteria included severe mental illness, HIV infection, severe renal dysfunction, severe cirrhosis, and active malignancies other than ANKL. All enrolled patients received up to six cycles of combination therapy every three weeks, consisting of ruxolitinib 10 mg orally twice daily on days 1–21; pegaspargase 2500 IU/m² on day 2; gemcitabine 1000 mg/m² on days 1 and 8; and oxaliplatin 100 mg/m² on day 1. Patients achieving complete remission (CR) or partial remission (PR) with available donors proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT) as soon as feasible.

Results

From October 18, 2024 to July 18, 2025, seven patients with newly diagnosed ANKL were enrolled in this study. The median age was 32 years (range, 26–54), and six patients were female. At diagnosis, six patients (85.7%) presented with HLH, and all patients were Epstein-Barr virus (EBV) positive. Therapeutic responses were evaluable in six patients, as the assessment of the last patient is pending. After one cycle of therapy, the overall response rate (ORR) was 83.3% (5/6), including 4 patients (66.6%) with CR, 1 patient (16.7%) with PR, and 1 patient (16.7%) with no response (NR). After two cycles, the ORR remained 83.3% (5/6), with all five responders achieving CR. One non-responder died on day 25 due to rapid disease progression. Another patient died on day 86 from H1N1 influenza and disease progression secondary to treatment delay. Four patients (66.6%) who achieved CR underwent allo-HSCT and remained alive at last follow-up, with the longest survival reaching 9.0 months.

Conclusions

In this study, the combination of ruxolitinib and P-Gemox demonstrated encouraging efficacy in newly diagnosed adult patients with ANKL. This regimen appears to be an effective and well-tolerated induction strategy while bridging to allo-HSCT. These preliminary findings warrant further evaluation in larger, prospective studies.

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2025
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