Treatment of children with refractory/relapse high risk langerhans cell histiocytosis with the combination of cytarabine, vindesine and prednisone.

BACKGROUND: The patients with multisystem and risk organ involvement Langerhans cell histiocytosis (MS-RO + LCH) have poor prognosis. The patients with MS-LCH who failed front-line therapy have a high mortality rate and the standard salvage treatment has not been established. The combination of cytarabine (Ara-c), vincristine (VCR) and prednisone might be effective for refractory/relapse MS-RO + LCH, with low toxicity. METHODS: We retrospectively analyzed pediatric refractory/relapse MS-RO + LCH patients treated with the low-dose Ara-c (100mg/m2/d×5days) or high-dose Ara-c (500mg/m2/d×5days) combined with vindesine (VDS) and prednisone in a single center. The efficacy, outcomes and adverse events were analyzed. RESULTS: From January 2013 to December 2016, 13 patients receiving the low-dose Ara-c chemotherapy (LAC) and 7 patients receiving the high-dose Ara-c chemotherapy (HAC) were included in the study. 11 (84.6%) of the 13 patients treated with the LAC regimen and 6 (85.7%) of the 7 patients treated with the HAC regimen had response after four courses of the therapy. All patients in the study were alive during follow-up and the 3-year event-free survival rate (EFS) was 53.7% and 85.7% in the LAC and HAC groups. The most frequent adverse event was Grade 1/2 myelosuppression, which was observed in 38.5% (5/13) and 42.9% (3/7) of the patients receiving the LAC and HAC regimen. CONCLUSIONS: A combination of Ara-c, VDS and prednisone was effective and safe for some patients with refractory/relapse MS-RO + LCH. The high-dose Ara-c regimen was associated with a numerically higher EFS rate.

Ruxolitinib-based regimen in children with primary hemophagocytic lymphohistiocytosis.

Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare immune disorder and hematopoietic stem cell transplan- tation (HSCT) is the only potentially curative treatment. Given the high pre-HSCT mortality of pHLH patients reported in the HLH-2004 study (17%), more regimens to effectively control the disease and form a bridge with HSCT are needed. We conducted a retrospective study of pHLH children treated by ruxolitinib (RUX)-based regimen. Generally, patients received RUX until HSCT or unacceptable toxic side-effect. Methylprednisolone and etoposide were added sequentially when the disease was suboptimally controlled. The primary end point was 1-year overall survival. Twenty-one pHLH patients (12 previously treated and 9 previously untreated) were included with a median follow-up of 1.4 years. At last follow-up, 17 (81.0%) patients were alive with a 1-year overall survival of 90.5% (95% confidence interval: 84.1-96.9). Within the first 8 weeks, all patients had an objective response, of which 19 (90.5%) achieved complete response (CR) and two (9.5%) achieved partial response (PR) as a best response. Seventeen (81.0%) patients received HSCT, of which 13 (76.5%) had CR, three (17.6%) had PR and one (5.9%) had disease reactivation at the time of HSCT. Fifteen (88.2) patients were alive post- HSCT. Notably, eight (38.1%) patients received zero doses of etoposide, suggesting the potential of RUX-based regimen to reduce chemotherapy intensity. Patients tolerated RUX-based regimen well and the most frequently observed adverse events were hematologic adverse events. Overall, RUX-based regimen was effective and safe and could be used as a bridge to HSCT for pHLH children.

Subcutaneous panniculitis-like T-cell lymphoma associated with hemophagocytic lymphohistiocytosis: a systematic review of 63 patients reported in the literature.

To review and summarize the clinical features, treatment strategies, and prognosis of subcutaneous panniculitis-like T-cell lymphoma complicated with hemophagocytic lymphohistiocytosis (SPTCL-HLH). We searched the Web of Science, Embase, Cochrane Library, and PubMed databases. The keywords were subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis or hemophagocytic syndrome. The patients were divided into a mutated group and a wild-type group based on the existence of HAVCR2 gene mutation. A total of 45 reports, including 63 patients with SPTCL-HLH, were included in the systematic review. Twelve patients detected gene mutations, including 11 with the HAVCR2 gene mutation and 1 with the STXBP2 gene mutation. Thirty-one patients were tested for autoantibodies. Compared with the wild-type group, patients in the mutated group were younger (p = 0.017), and the autoantibody-positive rate was higher (p = 0.006). The main treatment target of 17 patients was to control HLH, yielding an ORR of 88.2%. Two cases relapsed, and both were treated with corticosteroid monotherapy. The corticosteroid monotherapy experienced a higher recurrence rate than the corticosteroids plus other immunoregulatory agents therapy (66.7 vs. 0.0%, p = 0.029). Eighteen patients received initial anthracycline-based chemotherapy, and 50.0% reached remission. The ORR of initial chemotherapy aiming at controlling HLH was higher than those of anthracycline-based chemotherapy (p = 0.015). The ORR was higher in patients initially controlled for HLH versus chemotherapy without HLH control first (90.5 vs. 61.5%, p = 0.024). Interestingly, one patient with juvenile idiopathic arthritis developed SPTCL-HLH during tocilizumab therapy, discontinuing tocilizumab led to a remission of the disease spontaneously. Sixteen patients received stem cell transplantation (SCT). Fifteen patients, including 5 with relapsed/refractory SPTCL-HLH, responded well and survived after receiving SCT. One case who received a sibling-identical SCT relapsed. Further analysis revealed a homozygous HAVCR2 mutation with the donor. The 2-year overall survival (OS) was 91.0% ± 4.4%. There was a significant difference in the OS among patients of different age groups, and patients aged 40-60 had the lowest 2-year OS (66.7% ± 19.2%). Patients with HAVCR2 gene mutations are younger and more likely to be misdiagnosed with autoimmune diseases. Initial treatment of corticosteroids plus immunoregulatory agents attaches great significance to avoiding too aggressive therapies. Intensive anthracycline-based chemotherapy such as CHOP or CHOP-like regimens can also induce long-term remission for aggressive disease. SCT is still a reliable strategy currently. In addition, a watch and wait approach is recommended in patients with mild SPTCL-HLH caused by drugs. The occurrence of HLH does not necessarily mean a more rapidly progressive disease and worse prognosis in patients with SPTCL, but older patients with SPTCL-HLH may be associated with a lower survival rate.

Clinical characteristics of peripheral lymphocyte subtypes in chronic active Epstein-Barr virus infection.

PURPOSE: To analyze the clinical characteristics of peripheral Epstein-Barr virus(EBV)-infected lymphocyte subtypes in children with chronic active EBV infection(CAEBV). METHODS: The levels of peripheral EBV infection of CD4 + T cells, CD8 + T cells, and CD56 + NK cells were determined by flow cytometry and qPCR in patients with CAEBV from July 2017 to July 2022. RESULTS: A total of 112 children with CAEBV were evaluated in the study. Of them, CD4 + type, CD8 + type, and CD56 + type were defined in 44, 21, and 47 patients, respectively. Patients with CD8 + T-cell type had a significantly higher frequency of rash, while hepatomegaly was more common in patients with CD4 + T-cell type. Generally, patients with CD8 + T-cell type had the lowest overall survival(OS) rate(P = 0.017). As for treatment, patients treated with chemotherapy and hematopoietic stem cell transplantation had a better prognosis(P = 0.001). In multivariate analysis, rash, HLH, CD8 + T-cell type, and no decrease of plasma EBV-DNA after treatment were indicated as independent factors of poor prognosis(P = 0.002, 0.024, 0.022, and 0.012, respectively). CONCLUSION: In children with CAEBV, the rash was more frequent in patients with CD8 + T-cell type, whereas patients with CD4 + T-cell type were more likely to develop hepatomegaly. Patients with CD8 + T-cell type had a poor prognosis despite receiving chemotherapy or further HSCT.

Cladribine and cytarabine in children refractory high risk multisystem Langerhans cell histiocytosis.

There is no uniform regimen for refractory Langerhans cell histiocytosis (LCH). We retrospectively described patients with refractory multisystem and risk organ involvement LCH treated with the low-dose (Ara-c, 100 mg/m2/d × 5day; 2-CDA, 5 mg/m2/d × 5day) chemotherapy (LDC) and the intermediate-dose (Ara-c, 500 mg/m2/d × 5day; 2-CDA, 9 mg/m2/d × 5day) chemotherapy (IDC). 26 patients and 10 patients receiving the LDC and IDC regimen from January 2013 to December 2016 were included in the study. The overall response rate exhibited no significant difference between the LDC and IDC groups after four courses (76.9% vs 90%, P = 0.375) and eight courses (80.8% vs 100%, P = 0.135) of treatment. No statistical differences in the overall survival rate were observed between the two groups, but 5-year event-free survival rate of patients in the IDC group was higher than that in the LDC group at the median follow-up of 6.16 and 5.07 years (88.9% vs 52.9%, P = 0.033). The patients in the IDC group had more severe myelosuppression than those in the LDC group (grade 3/4 myelosuppression, 80% vs 19.2%, P = 0.001). The intermediate-dose regimen of 2CDA and Ara-c had a higher event-free survival rate and a similar overall survival rate compared with the low-dose regimen.

Efficacy of ruxolitinib for HAVCR2 mutation-associated hemophagocytic lymphohistiocytosis and panniculitis manifestations in children.

Frequent germline mutations of HAVCR2, recently identified in subcutaneous panniculitis-like T-cell lymphoma (SPTCL), are associated with an increased risk of hemophagocytic lymphohistiocytosis (HLH). However, SPTCL-HLH represents a challenge because of the difficulties in treatment with poor survival. Its malignant nature, specifically harbouring HAVCR2 mutations, has also been questioned. To better understand its pathology and treatment, we analysed the clinical data of six patients diagnosed at our centre. The median age at onset was 10.5 years (range, 0.8-12.4). Five patients presented with skin lesions of subcutaneous nodules/plaques and/or ulceration. All patients developed HLH; notably, one infant only had HLH without skin involvement. Histopathologically, only two patients were diagnosed with SPTCL and three were reported as panniculitis with no sufficient evidence of lymphoma. Genetically, germline homozygous mutation of HAVCR2 (p.Y82C) was identified in all patients, with a median diagnosis time of 4.6 months. All patients initially received corticosteroids, immunosuppressants or chemotherapy, achieving unfavourable responses. Strikingly, they responded well to ruxolitinib targeting inflammatory cytokines, allowing rapid disease resolution and/or long-term maintenance of remission. The excellent efficacy of ruxolitinib highlights this disease as an inflammatory condition instead of neoplastic nature and indicates novel agents targeting key inflammatory pathways as an encouraging approach for this disease entity.

Serum cytokine pattern in children with hemophagocytic lymphohistiocytosis.

This study aimed to compare the serum levels of 34 cytokines of children with hemophagocytic lymphohistiocytosis (HLH) and explored the specific cytokine pattern of HLH subtypes and the relationship between cytokine levels and prognosis. This retrospective study assessed the clinical data and cytokine levels of newly diagnosed children with HLH in Beijing Children's Hospital, Capital Medical University, from January 2017 to December 2021. A total of 101 children were enrolled in the study. The levels of IFN-γ and IL-18 increased in more than 90% of patients, and MIP-1α, SDF-1α, IP-10, IL-6, IL-8, IL-10, IL-1 RA, and TNF-α increased at different levels in more than 50% of patients. The levels of IL-10 in EBV-HLH increased significantly, followed by IFN-γ and IL-18, while IL-10 and IFN-γ in CAEBV-HLH had a slight increase. Except for IL-10, the levels of IL-6, Eotaxin, IL-13, IL-18, IFN-γ, and MIP-1ß in Rh-HLH increased significantly. F-HLH had significantly high IL-10 levels and a slight increase in IL-13. We showed that various cytokines could assist in differentiating HLH subtypes with ROC curve analysis. When IL-10/IL-6 was 1.37, the sensitivity and specificity of diagnosing EBV-HLH were higher than 80% (AUC = 0.837, p < 0.001). The effect of cytokine ratio on classifying HLH subtypes (17/22, 77.3%) was more significant than the single cytokine (5/22, 22.7%). The 3-year overall survival (OS) rate of children with F-HLH was the lowest during the follow-up. The 3-year OS of patients with EBV-HLH and CAEBV-HLH was significantly higher than that with F-HLH (88.1% ± 5.0% vs. 94.1% ± 5.7% vs. 57.1% ± 14.6%, p = 0.017). Cox proportional hazards model revealed that elevated GM-CSF and MCP-1, as well as CNS involvement, were independent risk factors for poor outcomes for patients with HLH. Various cytokines play important roles in HLH. Different subtypes of HLH have their specific cytokines pattern, and the ratio of cytokines may be more significant in differentiating HLH subtypes than the single one. Elevated GM-CSF and MCP-1 could be useful biomarkers for a poor prognosis for patients with HLH.

Systemic juvenile xanthogranuloma: A systematic review.

OBJECTIVE: To perform a systematic review to investigate the available literature regarding systemic juvenile xanthogranuloma (SJXG) and report the population characteristics, clinical manifestation, therapy, and outcome. REVIEW METHODS: A search of PubMed, Embase, and Cochrane Library for all articles published between 1981 and 2022 was performed with variations and combinations of the following search terms: extracutaneous, visceral, systemic, and juvenile xanthogranuloma (JXG). Data extracted included demographics, organ involvement, treatment, outcome, and permanent sequelae. RESULTS: A total of 103 articles encompassing 159 patients met the inclusion criteria. The median onset age was 9 months, with a male predominance (61%). The distribution of major involved organs varied by age, and younger onset age was associated with more organ involvement. The most commonly involved site was the central nervous system (CNS) (40.9%), followed by the liver (31.4%), the lung (18.9%), and the eye (18.2%). At the termination of follow-up, 93 patients (58.5%) were alive with no disease, 56 (35.2%) were alive with disease, and 10 (6.3%) were dead of disease. There was a significant difference in outcome between patients with and without spleen involvement (p = .0003), and patients with spleen involvement suffered a higher risk of death. Permanent sequelae mainly comprised CNS symptoms and ocular manifestations. CONCLUSIONS: SJXG can involve varying numbers and combinations of extracutaneous sites. There is no standard therapy for SJXG and clinicians should choose individualized therapy modalities.

Microplastics in plateau agricultural areas: Spatial changes reveal their source and distribution characteristics.

The Huangshui catchment on the northeastern Qinghai-Tibet Plateau (QTP) was selected as the study area to investigate the abundance, distribution characteristics, and influencing factors of microplastics (MPs) in surface agricultural soils (0-20 cm). The MP levels ranged from 6 to 444 items/kg, with an average of 86 items/kg. The relative abundance of small-sized MPs (<2 mm) was higher than that of large-sized MPs (2-5 mm). Polyethylene was the most common, and residual mulching film in farmland was the main source of MPs. The spatial distribution characteristics of MPs were analyzed through inverse distance weight interpolation, and MP abundance in agricultural soils in neighboring urban areas was significantly higher than that in other areas. Further analysis found that population density was significantly positively correlated with MP abundance (R2 = 0.9090, p < 0.01), indicating that human activities play a key role in MP pollution even in remote areas. In addition, the effects of irrigation, land use type, and soil physicochemical properties on the abundance of MPs were analyzed. Atmospheric transport and irrigation with surface water contribute to soil MP pollution. The direct effects of soil properties on MP abundance are still largely unclear, requiring further studies.

First-in-human application of double-stranded RNA bacteriophage in the treatment of pulmonary Pseudomonas aeruginosa infection.

A double-stranded RNA (dsRNA) phage phiYY is able to kill a pyomelanin-producing Pseudomonas aeruginosa strain, which was isolated from a 40-year-old man with interstitial lung disease (ILD) and chronic lung infection. Phage therapy was used as a last resort for this patient. The three-course nebulized phiYY treatment was used to reduce the bacterial burden and clinical symptoms of the patient. Recurrences of P. aeruginosa infections were observed 1-3 days post phage therapy. The recurrent isolates exhibited distinct antibiotic-susceptibility profiles compared with the original strain yet were still susceptible to phiYY. This assay represents the application of dsRNA phage in the treatment of chronic lung infection, albeit the safety and efficacy of the dsRNA phage require further assessment.

Distribution of pesticide residues in agricultural topsoil of the Huangshui catchment, Qinghai Tibet Plateau.

This study presents monitoring data on the spatial distribution and occurrence of pesticide residues of cultivated soil in the Huangshui catchment in the northeastern part of the Qinghai Tibet Plateau. We also provide factors that influence the distribution of pesticides, such as the properties of pesticides and soil and crop types. A total of 110 soil samples were collected in early April 2021, and 49 pesticides were analyzed. Only 3.6% of the samples contained no pesticide residues (concentrations < limit of quantitation or not detected [ND]), and the total pesticide concentration ranged from ND to 0.925 mg/kg. Most commonly, two to five pesticides were found in the soil samples (> 70.9%), and up to 10 pesticide residues were present in some samples. A total of 85 different pesticide combinations were observed in all the soil samples. Chlorpyrifos and difenoconazole were the dominant compounds. The levels of pesticide residues were mainly driven by their half-life values. Bulk density, along with soil water content and pH, also affected the retention of pesticides in the soil. The crop type played no role in the distribution of pesticides.

Chronic Active Epstein-Barr Virus Infection With Central Nervous System Involvement in Children: A Clinical Study of 22 Cases.

OBJECTIVE: To analyze the clinical features, treatment, and prognosis of chronic active Epstein-Barr virus infection (CAEBV) with central nervous system (CNS) involvement in children. METHODS: Patients with CAEBV admitted to Beijing Children's Hospital, Capital Medical University, were enrolled in this study from January 2017 to December 2020. They were divided into a CNS group and a non-CNS group based on the presence of CNS involvement. RESULTS: Twenty-two patients developed CNS disease, accounting for 23.9% (22/92) of CAEBV patients in the same period. Of these, only 2 of 22 patients presented initially with neurologic symptoms in the CNS group, and they all improved after treatment. Cerebrospinal fluid (CSF) examination demonstrated normal protein concentration and cell number in all patients with CNS involvement. Only 7 patients were positive for CSF EBV-DNA. Twenty-one patients had neuroimaging abnormalities, such as white matter signal abnormalities, encephalography or calcification. In the CNS group, 7 (31.8%) patients died, including 5 who died of active hemophagocytic lymphohistiocytosis, 1 died of unrelated causes, and 1 died of respiratory failure caused by pulmonary lymphoproliferative disease progression after transplantation. The 3-year overall survival was lower in the CNS group than in the non-CNS group (63.6% ± 11.9% versus 86.9% ± 4.1%, P = 0.027). Hemophagocytic lymphohistiocytosis (HLH) is an independent risk factor for CNS involvement in patients with CAEBV (OR = 2.946, 95% CI: 1.042-8.335, P = 0.042). Compared with the non-CNS group, blood EBV-DNA loads and CD4+/CD8+ ratio of T lymphocytes in the CNS group were higher (P < 0.001), while fibrinogen levels and natural killer (NK)-cell activity were lower (P = 0.047). Children with CAEBV were more likely to develop CNS diseases with low NK-cell activity (NK-cell activity < 14.00%, P = 0.023) or high alanine aminotransferase (ALT) levels (ALT levels > 40 U/L, P = 0.032). CONCLUSION: CAEBV with CNS involvement has nonspecific clinical manifestations, laboratory data, neuroimaging but has a worse prognosis. Blood fibrinogen levels and NK-cell activity in CAEBV children with CNS involvement are lower than in those without CNS involvement. In contrast, blood EBV-DNA loads and CD4+/CD8+ ratio of T lymphocytes are higher. Children with CAEBV who presented with HLH, NK-cell activity <14.00%, serum ALT >40 U/L and high-blood EBV-DNA loads are prone to develop CNS diseases.

NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH), particularly primary HLH (pHLH), is a rare, life-threatening disease. Germline genetic deficiency of 12 known HLH genes impairs cytotoxic degranulation in natural killer (NK) cells or cytotoxic T lymphocytes (CTLs) and contributes to pHLH development. However, no pathogenic mutations in these HLH genes are found in nearly 10% of HLH patients, despite a strong suspicion of pHLH, suggesting that the underlying genetic basis of HLH is still unclear. To discover novel susceptibility genes, we first selected 13 children with ppHLH (presumed primary HLH patients in the absence of detectable known HLH gene variants) and their parents for initial screening. Whole-genome sequencing (WGS) in one trio and whole-exome sequencing (WES) in twelve trios revealed that two ppHLH patients carried biallelic NBAS variants, a gene that is involved in Golgi-to-endoplasmic reticulum (ER) retrograde transport upstream of the degranulation pathway. Additionally, two candidate genes, RAB9B and KLC3, showed a direct relationship with known HLH genes in protein-protein interaction (PPI) network analysis. We analyzed NBAS, RAB9B, KLC3 and known HLH genes in an independent validation cohort of 224 pediatric HLH patients. Only biallelic NBAS variants were identified in three patients who harbored no pathogenic variants in any of the known HLH genes. Functionally, impaired NK-cell cytotoxicity and degranulation were revealed in both NBAS biallelic variant patients and in an NBAS-deficient NK-cell line. Knockdown of NBAS in an NK-cell line (IMC-1) using short hairpin RNA (shRNA) resulted in loss of lytic granule polarization and a decreased number of cytotoxic vesicles near the Golgi apparatus. According to our findings, NBAS is the second most frequently mutated gene (2.11%) in our HLH cohort after PRF1. NBAS deficiency may contribute to the development of HLH via a dysregulated lytic vesicle transport pathway.

Development and application of an LC-MS/MS method for pharmacokinetic study of ruxolitinib in children with hemophagocytic lymphohistiocytosis.

Ruxolitinib (RUX), a small molecule inhibitor of JAK1/JAK2, has been identified as the possible novel targeted agent for the treatment of hemophagocytic lymphohistiocytosis (HLH). However, due to the lack of randomized clinical trials (RCTs), it is extremely difficult to determine the effective therapeutic dose for RUX in HLH patients, especially in pediatric patients. At the same time, the clinical response of pediatric patients to RUX varies greatly among individuals according to several case reports. Therefore, it is imperative to investigate the pharmacokinetic and pharmacodynamic characteristics of RUX in HLH children, and this must be based on a satisfactory method to determine the concentration of RUX. Owing to several limits of published analytical methods, herein, we describe a novel liquid chromatography tandem mass spectrometry (LC-MS/MS) method for monitoring RUX in children's plasma samples. The protein precipitation method using methanol was used for sample cleanup. The analytes were separated by gradient elution in which 2.0 mM ammonium acetate in distilled water and acetonitrile were used as mobile phases. In the positive electrospray ionization (ESI+) mode, the m/z 307.1 → 186.0 and 316.1 → 185.9 ion pair transitions of RUX and RUX-d9 were used for the qualitative and quantitative analysis, respectively. The calibration curves of RUX were linear in the concentration range from 0.5 to 400 ng mL-1. The intra- and inter-batch precision, accuracy, recovery, dilution completeness, and stability of this method were all within acceptable standards, and no matrix effects or residues were found. This method was successfully applied to the clinical pharmacokinetic study of RUX in 32 children with HLH. The pharmacokinetic parameters of HLH children after a single dose of RUX and the steady state plasma concentration after multiple administrations were proposed through this method. Most importantly, it was found that the age and serum creatinine (SCr) of children with HLH had a significant and complex impact on the in vivo process of RUX after the single as well as multiple administrations of RUX.

Clinical significance of cerebrospinal fluid soluble CD25 in pediatric hemophagocytic lymphohistiocytosis with central nervous system involvement.

OBJECTIVE: To analyze the clinical significance of soluble CD25 (sCD25) levels in cerebrospinal fluid (CSF) in pediatric hemophagocytic lymphohistiocytosis (HLH) with central nervous system (CNS) involvement. METHODS: All patients diagnosed with HLH admitted to Beijing Children's Hospital, Capital Medical University between January 1, 2017 and October 31, 2021 who received a measurement of their HLH-related parameters and CSF sCD25 levels at admission were enrolled in this study. RESULTS: CSF sCD25 levels in patients with primary HLH were higher than those in patients with Epstein-Barr virus infection-associated HLH, and the median level was 444 pg/ml. The difference in CSF sCD25 levels between the non-CNS group and the CNS group was statistically significant (591 [259-33,643] pg/ml vs. 123 (36-437) pg/ml, p < .001). The best cutoff value of CSF sCD25 was 273.5 pg/ml (AUC = 0.987, 95% CI: 0.972-1.000), with sensitivity, specificity, positive predictive values, and negative predictive values of 96.4%, 92.8%, 81.8%, and 98.7%, respectively. CSF sCD25 in the severe CNS involvement group was significantly higher than that in the nonsevere CNS involvement group (p = .014). The 3-year overall survival (OS) of patients with high CSF sCD25 levels was lower than that of patients with low CSF sCD25 levels(71.6% ± 8.1% vs. 93.3% ± 2.9%, hazard ratio [HR] = 3.637, p = .003). CONCLUSION: Increased CSF sCD25 levels in active disease can predict CNS-HLH. Primary HLH has a higher CSF sCD25 level than Epstein-Barr virus infection-associated HLH. Patients who are diagnosed with CNS-HLH with CSF sCD25 levels higher than 273.5 pg/ml are more likely to develop severe CNS involvement, suggesting a poor prognosis.

A study of ruxolitinib response-based stratified treatment for pediatric hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a lethal disorder characterized by hyperinflammation. Recently, ruxolitinib (RUX), targeting key cytokines in HLH, has shown promise for HLH treatment. However, there is a lack of robust clinical trials evaluating its efficacy, especially its utility as a frontline therapy. In this study (www.chictr.org.cn, ChiCTR2000031702), we designed ruxolitinib as a first-line agent for pediatric HLH and stratified the treatment based on its early response. Fifty-two newly diagnosed patients were enrolled. The overall response rate (ORR) of ruxolitinib monotherapy (day 28) was 69.2% (36/52), with 42.3% (22/52) achieving sustained complete remission (CR). All responders achieved their first response to ruxolitinib within 3 days. The response to ruxolitinib was significantly associated with the underlying etiology at enrollment (P = .009). Epstein-Barr virus (EBV)-HLH patients were most sensitive to ruxolitinib, with an ORR of 87.5% (58.3% in CR). After ruxolitinib therapy, 57.7% (30/52) of the patients entered intensive therapy with additional chemotherapy. Among them, 53.3% (16/30) patients achieved CR, and 46.7% (14/30) patients dominated by chronic active EBV infection-associated HLH (CAEBV-HLH) developed refractory HLH by week 8. The median interval to additional treatment since the first ruxolitinib administration was 6 days (range, 3-25 days). Altogether, 73.1% (38/52) of the enrolled patients achieved CR after treatment overall. The 12-month overall survival (OS) for all patients was 86.4% (95% confidence interval [CI], 77.1% to 95.7%). Ruxolitinib had low toxicity and was well tolerated compared with intensive chemotherapy. Our study provides clinical evidence for ruxolitinib as a frontline agent for pediatric HLH. The efficacy was particularly exemplified with stratified regimens based on the early differential response to ruxolitinib. This study was registered in the Chinese Clinical Trials Registry Platform (http://www.chictr.org.cn/) as ChiCTR2000031702.