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Study of Ruxolitinib as a front-line therapy for pediatric HLH
diagnosis was 11.5 (range, 4-92) days. From onset to diag- nosis, except for patient 3 who did not receive any treat- ment, the patients had been typically treated with antibi- otics, ganciclovir or intravenous immunoglobulin (Ig). Five subjects had been given corticosteroids for 2-4 days, but all discontinued use before they were referred to our hospital due to a lack of response. Whole-exome sequencing (WES) was performed for all patients and their parents, and no pathogenic gene mutation associated with primary HLH was found. No patient had central nervous system (CNS) involvement at enrollment. All subjects had negative evalu- ations for malignant tumors after bone marrow or cervical lymph node biopsy. The primary disease could not be determined in two of the 12 HLH patients; in the other ten patients, eight cases were EBV-HLH, and two cases were AID-HLH. In the EBV-HLH subgroup, two patients experi- enced their first exposure to EBV, five involved EBV reacti- vation, and one case was clearly identified as chronic active EBV (CAEBV). We classified the patients according to our stratification criteria with four patients at low risk and eight at high risk.
Efficacy of ruxolitinib treatment
Table 2 shows the response outcomes in detail. Among the entire cohort, eight of 12 patients completed the 28-day treatment protocol and achieved CR, but one relapsed at the time of the fourth scheduled response assessment (day 28), and was refractory to alternative HLH-1994 regimen and finally died. Four of 12 patients discontinued the thera- py after 3-7 days of treatment and were adjusted to the HLH-1994 regimen for the following reasons: two subjects had no response to RUX and progressively deteriorated; one subject had a partial response for the first 7 days of ther- apy but progressed soon; one achieved obvious HLH improvement over the first 5 days of treatment; however, the patient remained critically ill and developed potential CNS involvement with drowsiness, although his brain MRI and cerebrospinal fluid (CSF) exam showed no abnormali- ties. According to the above, for the primary endpoint, the best OR rate to RUX at the end of treatment protocol was 83.4% (ten of 12 patients) , with 66.7% (eight of 12 patients) in CR, 8.3% (one of 12 patients) in PR, and 8.3% (one of 12 patients) in HLH improvement. Among the patients who achieved CR, 87.5% (seven of eight patients) maintained CR condition for >6 months. For the eight patients with EBV-HLH, the overall response was 100%, with 75% (six of eight patients) in CR and 25% (two of eight patients) in PR; however, 16.7% (one of six patients) relapsed after CR. Two AID-HLH patients had quite differ- ent responses, with one showing reversal of HLH abnor- malities soon and the other showing no improvement, as did the two patients of unknown etiology. All patients who had no response or discontinued RUX responded well to the subsequent HLH-1994 regimen, achieved CR and remained off therapy except one (AID-HLH) still in treat- ment maintenance until data cutoff.
The EFS time was calculated from the date of RUX ther- apy. All patients were followed up until death or June 7, 2020 (time of data cutoff), whichever occurred first, with a median follow-up of 8.2 (range, 7.1-12.0) months. A total of five of 12 patients had an event, and the expected 6-month EFS rate was 58.3%±14.2% (Figure 1). Patients in the high- risk group showed a tendency towards a worse EFS rate than those in the low-risk group, but there was no statisti- cal significance in this small-scale analysis (50.0±17.7% vs.
Table 3. Adverse events observed in this study.
patient
Patient 1
Patient2 Patient 3 Patient 4 Patient 5 Patient 6
Dose (twice daily)
10 mg
10mg 5mg 2.5 mg 10 mg 10 mg
Ruxolitinib treatment days
28
28 28 28 28 28
Possible adverse event (Grade*)
oral ulcer (1)
- Sweating (1) Elevated ALT (1) Elevated ALT (1)
Nausea (2) Gastritis (1) Elevated ALT (1)
Event led to discontinuation
–
– – – –
–
–
–
Patient7 5mg
Patient 8 10 mg
28 -
28 Nausea (1)
Decreased appetite (2) Patient9 5mg 5 - –
Patient10
Patient 11
Patient12
5mg 3 - –
5 mg 7 Constipation (1) –
5mg 3 - –
*Graded according to National Cancer Institute Adverse Event Common Toxicity Criteria ver- sion 3.0. No serious adverse events occurred, including cytopenia, secondary infections, acute liver failure, acute heart failure and acute renal failure. ALT: alanine aminotransferase.
75.0±21.7%, P=0.556) (Online Supplementary Figure S1 in the Online Supplementary Appendix).
Changes in evaluation indicators before and after ruxolitinib therapy
We analyzed 12 HLH-associated symptoms and labora- tory parameters before, and 1, 2, 4 and 8 weeks after RUX treatment. Some indicators, such as temperature and rou- tine blood, were tested every day within the first treatment week as much as possible. Rapid resolution of various indi- cators was observed with continued therapy. At day 14, a complete recovery in almost all parameters was achieved in eight patients with good response (Figure 2), whereas patients with no response or progress had a persistent abnormality in many indicators (Online Supplementary Figure S2). No relationship was found between patient character- istics at diagnosis and the treatment response (Online Supplementary Table 1). We further analyzed the data before and 1 week after RUX treatment in the CR and non-CR groups respectively. There was a significant difference between the two groups in the improvement of tempera- ture, soluble CD25, ferritin, IFN-γ and neutrophil counts, suggesting that these parameters were important indicators for evaluating the treatment response of RUX in the early phase (Figure 3). Other key cytokines, including IL-6, IL-10, TNF-a and IL-18, showed a similar trend to IFN-γ (Online Supplementary Figure S3).
In detail, within hours of receiving the first dose of RUX, ten of 12 patients became afebrile; however, for the patients who did not respond well to RUX, the antipyretic effect was not sustainable, and the fever recurred within 48-72 hours (Figure 2A; Online Supplementary Figure S2A). Dramatic improvements in soluble CD25 and serum ferritin were observed, falling rapidly to normal levels within approximately 1-2 weeks (Figure 2B and C); in contrast, for patients (patient 10 and 12) who were nonresponsive to RUX, soluble CD25 and serum ferritin increased to high levels (Online Supplementary Figure S2B and C). We also monitored the level of IFN-γ, a key cytokine in HLH. High
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