Discussion
neutropenia, toxicity, malignancy, thrombocytopenia, dose-limiting, anemia, HLH
NEUTROPENIA, THROMBOCYTOPENIA, DISEASE, ANEMIA, MYELOFIBROSIS, ADVERSE EFFECTS, REMISSION
This study represents the first extensive investigation of the application of escalated doses of ruxolitinib for treating HLH. In this study, we observed that dose-escalating ruxolitinib demonstrated a significant impact in achieving improved remission among refractory HLH patients, with manageable adverse effects. Four of the eight patients achieved a sustained complete response with resolution of all features of the disease without relapse during the follow-up period. Remarkably, no serious drug-related severe adverse effects attributed to dose escalation were observed in any of the 8 patients. Two patients who failed to respond to dose-escalating ruxolitinib treatment also achieved remission after the addition of rather low-dose etoposide chemotherapy.The therapeutic efficacy of ruxolitinib in HLH has been demonstrated in various ways (The heterogeneity of clinical efficacy of escalating doses of ruxolitinib needs to be noted. Obviously, not all refractory HLH patients respond well to dose-escalated ruxolitinib. Initiating jakinib therapy late in the disease process may not be sufficient to induce disease remission or to prevent life-threatening immune dysregulation (Interestingly, we observed that patients who did not respond to escalating-dose of ruxolitinib suffered significant higher sCD25 levels before treatment. When using 10,000pg/ml as the cutoff value, sCD25 can serve as an effective predictor for the therapeutic outcome of escalated-dose ruxolitinib. More notably, the sCD25 levels of patient 7 and 8 were significantly higher than 10,000pg/ml, and remission was successfully achieved by adding a relatively low dose of etoposide to the escalated-dose ruxolitinib treatment. These findings suggest that the levels of sCD25 may serve as an indicator for early consideration of chemotherapy during treatment: when sCD25 levels are below 10,000 pg/ml, escalating the dose of monotherapy with ruxolitinib can provide more effective remission of HLH; when sCD25 levels are above 10,000, chemotherapy drugs such as etoposide should be considered in addition to higher doses of ruxolitinib. Moreover, under conditions of high-dose ruxolitinib, chemotherapy drugs often require only a smaller dose to achieve the desired therapeutic effect. However, since sCD25 is known to be more elevated/predictive of diagnosis of malignancy, the observed difference in sCD25 levels may simply reflect the distinction between non-malignant and malignant conditions. To validate our conclusion, further investigation with a non-malignancy group is necessary. A prospective clinical trial (NCT04551131) is investigating the combination of ruxolitinib at a dose of 25 mg/mThe increase in the dose of ruxolitinib, while improving the therapeutic effect, also brought concerns about safety. The main adverse effects of ruxolitinib are hematological toxicity, including neutropenia, thrombocytopenia and anemia. In the study of myelofibrosis, thrombocytopenia was identified as the dose-limiting toxic effect, and 25 mg twice daily and 100 mg once daily were identified as the maximum tolerated doses (