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Study of Ruxolitinib as a front-line therapy for pediatric HLH
inflammation was relieved in all well-responsive patients, with IFN-γ decreasing rapidly to normal levels at 2 weeks (Figure 2D). Cytopenia and coagulopathy progressively improved in all responding patients with blood transfu- sion support weaned off within 1 week. Platelet counts, in particular, increased to the normal range quickly within 1 week. Neutrophil count improvement varied, but all reached 1×109/L at 2 weeks and 2×109/L at 4 weeks. Hemoglobin and fibrinogen concentrations improved with slightly slower kinetics (Figure 2E and H). Triglyceride was not improved immediately with a rapid phase of improvement 1 week after starting RUX in most individuals (Figure 2I). Hepatic dysfunction resolved with- in 2 weeks (Figure 2J).
In addition, EBV DNA load decreased dramatically in all EBV-HLH patients (Figure 4). Among them, EBV infections were resolved in six of eight patients 1-2 weeks after RUX treatment, with cell-free (plasma) EBV DNA becoming undetectable and having no recurrence after stopping treat- ment until the data cutoff (June 7, 2020) except in patient 8 (CAEBV). The median time that plasma EBV DNA was maintained negative in these patients was approximately 8.7 (range, 0.5-12.0) months. Meanwhile, EBV DNA in whole blood also fell rapidly from very high levels (105-107 copies/mL) to modest levels (103-104 copies/mL), and fluctu- ated at these modest levels during follow-up.
Side effects
Treatment was well tolerated, with no toxicities leading to dose-reductions or interruptions of RUX observed. All possible adverse events are reported in Table 3. Although RUX has been reported to have a risk of thrombocytopenia or anemia in other settings, these side effects were not observed in our study. Cytopenia is a major clinical feature of HLH. However, patients who achieved a response to RUX had neutrophil counts, platelet counts and hemoglo- bin concentrations that improved gradually compared to pretreatment levels. No unusual infections were noted. Renal function was analyzed by creatinine clearance, and cardiac function tested by myocardial enzyme spectrum and ultrasound cardiogram was normal during the clinical course. Three individuals had moderately elevated ALT at 60 days after treatment, which may not have been due to RUX, as they had been off the drug for approximately 1 month. Two patients hadtwo or more grade 1-2 gastroin-
testinal adverse events (nausea, gastritis, decreased appetite) and were resolved soon by supportive therapies. In addition, three patients showed mild oral ulcers, sweat- ing or constipation, and recovered without special treat- ment.
Discussion
HLH is a disorder characterized by high inflammatory cytokine production induced by excessive immune activa- tion. Recently, cytokine-targeted approaches have been suggested as possible treatment options, such as ema- palumab.8, 22, 23 Rather than targeting a single cytokine, RUX can blunt numerous cytokines via inhibition of the JAK 1/2- STAT1 pathway, which makes its clinical use for HLH more rational.11-13 Currently, RUX is often recommended for refractory/relapsed HLH as a salvage treatment regimen; however, its use as a first-line agent is still based on only a small number of case reports, clinician experience or small clinical studies (clinicaltrials gov. Identifier: NCT02400463). To date, the optimal duration of RUX therapy, the utility of concurrent corticosteroids, and the effect of disease etiolo- gy or risk stratification on treatment response remain uncertain.
In this study, we explored the efficacy and safety of RUX monotherapy instead of chemotherapy for secondary HLH in children. RUX has been used for myelofibrosis,24 poly- cythemia,25 and graft-versus-host disease (GvHD)26, 27 and is generally dosed between 5 mg and 25 mg twice daily, demonstrating good clinical benefits and tolerance. In addi- tion, in patients with relapsed or refractory myeloprolifera- tive neoplasms especially those with JAK2 or CSF3R muta- tions, the RUX dose can be increased to 50-200 mg twice a day, and is reasonably tolerated overall.28, 29 The pediatric dosing of RUX in HLH is unestablished. The dose in this study (2.5-10 mg) was modified with reference to the lower dose used for GvHD in children,30 which, similar to HLH, is characterized by the production of high levels of proinflammatory cytokines. In order to eliminate the prob- able interference of corticosteroid use, we enrolled newly diagnosed patients who had not undergone previous corti- costeroid treatment or who had used but discontinued cor- ticosteroids at least 3 days before trial screening due to a lack of response.
AB
Figure 4. Eppstein-Barr virus DNA levels in the whole blood and plasma after treatment with ruxolitinib. Reported Eppstein-Barr virus (EBV) DNA values are limited to 500 copies/L by the clinical laboratory. The dotted line on the x-axis of each graph indicate the start of RUX treatment.
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