Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by immune dysregulation and hyperinflammation. It is associated with low incidence and high mortality. Therapeutic options for HLH are limited, underscoring the necessity for novel treatment strategies. Patients with HLH frequently have elevated serum levels of soluble IL-2-receptor (sIL-2R, or sCD25), which is a diagnostic criterion and is associated with a poor prognosis. Activated T cells also express CD25, which is the target of humanized anti-CD25 monoclonal antibody (mAb). Anti-CD25 mAb demonstrates established efficacy in treating multiple sclerosis and preventing post-transplant rejection, with a favorable toxicity profile.

This trial evaluated the efficacy and safety of anti-CD25 mAb (Daclizumab) in patients with HLH who had not responded to previous dexamethasone-based therapy. Patients were excluded if they had HLH attributed solely to transient infection, confirmed autoimmune disease, or malignancy diagnosed pathologically before enrollment, as these conditions require primary treatment directed at the underlying cause. Patients received anti-CD25 mAb at a fixed dose of 25 mg each time. In the absence of HLH improvement after one week of anti-CD25 mAb therapy, the single dose would be increased to 50 mg. The first three doses were administered weekly, with three subsequent doses given every other week. Salvage therapies were initiated immediately upon documented disease progression at any point during treatment. For recurrent HLH with severe genetic defects, hematopoietic stem cell transplantation (HSCT) should be prepared in parallel. After enrollment, dexamethasone was maintained at 10 mg/m² and subsequently tapered, while any preexisting cytotoxic agents or biologics had to be discontinued. The primary efficacy endpoint was the overall response at the end of treatment (week 9). Based on previous literature, the target sample size is 20. This trial has been approved by the ethics committee and conducted with patient informed consent.

At the cutoff date of July 1, 2025, a total of 17 adult HLH patients were enrolled: 8 cases associated with systemic autoinflammatory disorders, 2 cases associated with chronic activated viral infection, 2 cases of primary HLH, and 5 cases associated with unknown etiology (3 occult lymphomas diagnosed within 1–4 months post-enrollment). The cohort comprised 10 females and 7 males, with a median age of 48 years (range, 16 to 75 years). Neurological involvement of HLH was documented in one patient with primary HLH (pHLH). The overall response rate (ORR, without salvage therapies) at week 9 was 88.2% (15/17), with 35.3% (6/17) achieving complete response (CR), 47.0% (8/17) achieving partial response (PR), and 5.9% (1/17) showing HLH improvement. The non-response (NR) rate was 11.8% (2/17), with one case attributed to chronic active Epstein-Barr virus infection (CAEBV) and the other to occult lymphoma. The median time to fever resolution following anti-CD25 mAb initiation was 3 days (range, 1 to 8 days). After a median follow-up of 326 days, three patients died. One death resulted from non-relapse mortality post-transplant, one was related to HLH recurrence and rapid progression, and one was caused by severe pulmonary infection before HSCT. Six patients presented with acute bacterial and/or fungal infections at study entry. During daclizumab treatment, new infections were not reported. All infections resolved except in one patient who presented with severe pulmonary infection upon enrollment. Although HLH achieved PR after treatment, the patient's condition deteriorated secondary to progressive invasive pulmonary fungal infection, resulting in death. No other adverse events of grade 3 or higher were reported.

Anti-CD25 mAb is an effective targeted therapeutic strategy for adult patients with HLH. It had low toxicity and was well tolerated. This novel treatment is promising and merits further investigation in a larger cohort.

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2025
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