Zhao Wang

Familial hemophagocytic lymphohistiocytosis (FHL) is the prototypical genetic form of hemophagocytic lymphohistiocytosis (HLH), a potentially fatal hyperinflammatory condition. Limited awareness of HLH with isolated central nervous system (CNS) involvement often leads to underdiagnosis or diagnostic delay. Here, we report a 13-year-old girl with FHL type 3 (FHL3) presenting with isolated CNS involvement who subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT). This case expands the clinical spectrum of FHL3 and highlights that isolated neurological symptoms may be the initial or sole manifestation of FHL, even without systemic signs. Allogeneic HSCT remains the only definitive therapy for FHL. The patient received a conditioning regimen comprising thiotepa, etoposide, busulfan, cyclophosphamide, and antithymocyte globulin (TT/VP16/BU/CY/ATG). The graft consisted of 20.4 × 10⁸/kg mononuclear cells and 4.71 × 10⁶/kg CD34 + cells. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A (CsA), mycophenolate mofetil (MMF), and methotrexate (MTX). Neutrophil engraftment (absolute neutrophil count ≥ 0.5 × 10⁹/L) occurred on day + 13, and platelet engraftment (≥ 20 × 10⁹/L) on day + 19. The patient did not develop GVHD and achieved full, stable donor chimerism with successful engraftment and minimal toxicity. Neurological remission was observed following transplantation. At the last follow-up on day 679, the patient remained alive without neurological relapse or systemic HLH. In conclusion, this patient achieved long-term CNS remission and correction of the underlying molecular defect following allogeneic HSCT with a TT/VP16/BU/CY/ATG conditioning regimen.

Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) typically have a poor prognosis. In preclinical studies, lenalidomide and a Bruton tyrosine kinase (BTK) inhibitor demonstrated synergistic antitumor effects. Zanubrutinib, a next-generation BTK inhibitor, has greater selectivity to minimize off-target binding. BGB-3111-110 was a phase 1 multicenter dose-escalation/-expansion study. Patients with R/R DLBCL received zanubrutinib 160 mg twice daily plus lenalidomide (15, 20, or 25 mg once daily) until progression or unacceptable toxicity. Primary end points were safety, recommended phase 2 dose (RP2D), and overall response rate (ORR; Lugano 2014 criteria). Sixty-six patients were enrolled and treated. Patients had a median of 2 previous therapies, 83% had stage III/IV disease, and ∼67% had non–geminal center B-cell–like or activated B-cell–like DLBCL. No dose-limiting toxicities occurred; the lenalidomide RP2D was 25 mg once daily when combined with zanubrutinib 160 mg twice daily. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 74%; the most common (>20%) grade ≥3 TEAEs were decreased neutrophil count (58%) and decreased white blood cell count (29%). TEAEs led to 7 treatment discontinuations (11%) and 2 deaths (3%). At the RP2D, ORR and complete response rate were 58% and 42%, respectively; median time to response was 2.8 months. Median duration of response was 14.9 months. Median progression-free survival was 5.5 months (95% confidence interval [CI], 2.9-11.1); the 12-month event-free rate was 34% (95% CI, 21-48). Zanubrutinib plus lenalidomide demonstrated acceptable tolerability and antitumor activity in patients with R/R DLBCL. This trial was registered at www.clinicaltrials.gov as NCT04436107.

We aimed to evaluate the clinical value of splenectomy as a treatment for Chronic active Epstein-Barr virus disease (CAEBVD). We retrospectively reviewed the clinical data from clinical records of patients received splenectomy in our institution from October 1, 2014, to October 1, 2024. The splenectomy cohort (n = 16) was matched to non-splenectomy controls (n = 32) at a 1:2 ratio using propensity scores derived from gender, age, baseline EBV-DNA copies, whether with HLH, and whether received Allo-HSCT. A total of 48 CAEBVD patients were enrolled in this study. Splenectomy cannot minimize the EBV-DNA copies in peripheral blood. The median OS of patients who received splenectomy was 86 months, while that of patients without splenectomy was 23 months. There was no statistically significant difference between the two groups (P = 0.189). When patients experienced recurrence-related death, no significant difference in survival time was observed between the two groups (P = 0.607). In the CAEBVD with HLH subgroup, there was no significant difference in survival times between patients with and without splenectomy (P = 0.423). A total of 18 patients received Allo-HSCT. The time to WBC and PLT engraftment between the non-splenectomy group and splenectomy group showed no significant difference (P = 0.788, P = 0.407). Splenectomy demonstrated no significant benefit in reducing EBV copies and symptom relief, and suggests splenectomy fails to prolong patient survival supporting its limited role in CAEBVD management.

Secondary Hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening complication mostly occurs in adult patients with rheumatic disease, infection or lymphoma. To adequately steer treatment, clear discrimination of sHLH entities is essential. We aimed to discriminate serum biomarkers which can separate MAS from EBV associated HLH (EBV-HLH) and Lymphoma associated HLH (L-HLH) adequately. Samples from patients aged > 15 diagnosed with sHLH were analyzed using Luminex Multiple Assays (34-plex for pre-2022; 11-plex for post-2022). 209 patients were divided into three cohorts due to change of Luminex kits. Among 86 patients enrolled pre-2021, 45 patients enrolled in 2021–2022, and 78 patients enrolled post-2022. Clinical data and serum biomarkers were analyzed among MAS, EBV-HLH and L-HLH in three cohorts by Kruskal-Wallis Analysis (K-W). The Heatmap and Principal Component Analysis (PCA) were used to describe the distinctive expression of serum biomarkers in MAS, EBV-HLH and L-HLH. Other than the relationship between clinical data and biomarkers was exhibited in the Heatmap according to the Spearman’s Rank Co-efficient. Furthermore Network analysis recognized the prominent biomarker in MAS. The blooding cells disproportion declined in MAS patients relative to EBV-HLH and L-HLH. Other than the level of sCD25 increased higher in EBV-HLH and L-HLH patients than MAS patients. Progressive levels of MIP-1α and IL-10 were elevated in patients with EBV-HLH and L-HLH relative to MAS. PCA and the heatmap of serum biomarkers expressions did not discriminate MAS from EBV-HLH and L-HLH efficiently. Although there was no significant difference in the relationship between clinical data and serum biomarkers, we observed the further positive association between myeloid and lymphoid-derived serum biomarkers in MAS compared with EBV-HLH and L-HLH. Further analysis revealed that IL-17 was as a prominent biomarker in pathology in MAS by Network Analysis. (1) The relationship between myeloid and lymphoid-derived biomarkers was further relevant in MAS than EBV-HLH and L-HLH. (2) The IL-17 released mostly by Th-17 cells was grouped together closely with other inflammatory mediators and we infer that IL-17 may exert an important role in MAS. These findings could guidance the efficacy of drugs targeting key cell and biomarkers specifically associated with MAS.

To summarize the clinical characteristics, treatment outcomes, and prognosis of pregnant patients with hemophagocytic lymphohistiocytosis (HLH), and to evaluate the efficacy of chemotherapy regimens containing etoposide (VP16) in these patients and their impact on survival outcomes. A retrospective analysis was performed on 41 pregnant HLH patients admitted to our hospital between April 2015 and March 2024, focusing on clinical features, treatment strategies, and prognostic factors. Among the 41 cases, 29 developed HLH during pregnancy and 12 postpartum. Etiologies included malignancy-related HLH (5 cases), Epstein-Barr virus (EBV)-related HLH (5 cases), rheumatologic disease-related HLH (2 cases), and pregnancy-related HLH (29 cases, defined as no comorbid HLH-related etiologies except pregnancy). In pregnancy-related HLH patients presenting during gestation, the 2-week overall response rate (ORR) was significantly higher in those receiving VP16-containing induction chemotherapy compared to glucocorticoids-only induction therapy (P = 0.011). Multivariate analysis identified the interval from symptom onset to VP16 initiation as an independent prognostic factor for pregnancy-related HLH (P = 0.025). Survival analysis revealed improved survival in patients who received VP16 within 7 weeks of onset versus those treated after 7 weeks (P = 0.044). HLH in pregnancy progresses rapidly. Early administration of VP16-containing chemotherapy significantly improves ORR and survival outcomes, particularly in pregnancy-related HLH.

Hemophagocytic lymphohistiocytosis (HLH) has been described as a threshold disease depending on triggering factors and the residual cytotoxic capacity of NK cells. This study aimed to investigate the clinical characteristics of Epstein–Barr virus (EBV)-triggered primary HLH and the prognostic value of EBV-DNA load in EBV-triggered primary HLH cases. We retrospectively analyzed the clinical data of 95 patients with primary HLH treated between January 2013 and January 2024. Based on the peripheral blood EBV status at initial diagnosis, 57 patients were categorized into the EBV-triggered primary HLH group and 38 patients into the non-EBV-triggered primary HLH group. Clinical and functional characteristics, response to treatment, and prognosis were compared between the two groups. Among patients with EBV-triggered primary HLH, the proportion of patients with familial HLH type 2 (FHL2) was significantly lower (P = 0.011), whereas the proportion of patients with X-linked lymphoproliferative disorder (XLP) was higher (P = 0.037). Functional assays showed that in primary HLH patients with gene defects in cytotoxic degranulation, the proportion of EBV-triggered primary HLH patients with reduced NK cell activity and degranulation function was significantly higher (P = 0.026 and P = 0.030). Importantly, multivariate Cox regression analysis identified EBV-DNA > 10,000 copies/mL as an independent risk factor affecting the prognosis of patients with EBV-triggered primary HLH, particularly in non-FHL cases (P = 0.045). EBV-triggered primary HLH is more prevalent in patients with XLP but less frequent in FHL2 patients. High EBV-DNA load is an adverse prognostic factor in EBV-triggered primary HLH patients.

X-linked inhibitor of apoptosis protein (XIAP) deficiency is a congenital immunodeficiency disorder characterized by increased susceptibility to Epstein-Barr virus (EBV) infection and is frequently associated with hemophagocytic lymphohistiocytosis (HLH). To investigate the correlation between EBV and XIAP deficiency-related HLH, including EBV infection status, XIAP genetic mutation sites, and the efficacy of different treatment regimens in patients with EBV-positive XIAP deficiency-related HLH, and to analyse the prognosis of these patients. We retrospectively analysed patients diagnosed with EBV-positive XIAP deficiency-related HLH. Data were collected from August 2017 to August 2024, and 10 patients were included in this study. All patients exhibited an elevated EBV-DNA load. EBV-DNA was detected in both plasma (2/10) and peripheral blood mononuclear cells (10/10), specifically B cells (9/9) and T cells (4/9). Treatment regimens containing rituximab, HLH-2004, and dexamethasone with or without ruxolitinib achieved complete remission. However, only the regimen containing rituximab successfully eradicated EBV from plasma and peripheral blood mononuclear cells in all patients. None of the patients underwent allogeneic haematopoietic stem cell transplantation. No cases of HLH recurrence or EBV reactivation were observed during a median follow-up of 28 months. EBV infection plays a crucial role in triggering HLH in patients with XIAP deficiency. XIAP deficiency-related HLH is frequently associated with EBV infection, which predominantly affects B cells. Treatment regimens containing rituximab can effectively control HLH and eliminate EBV infection. Allogeneic haematopoietic stem cell transplantation may be avoidable in paediatric patients achieving EBV eradication through rituximab-containing regimens.

Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory disorder characterized by excessive cytokine release. More than 30% of HLH cases are refractory to frontline therapy. Unfortunately, there is no universally accepted second-line regimen, and about 30% of patients fail to respond to current salvage treatments. Moreover, evidence guiding alternative therapies and the optimal timing for switching to new treatments in refractory patients is limited. This study retrospectively analyzed the efficacy and safety of the RED regimen (ruxolitinib, emapalumab, and dexamethasone) in 15 refractory HLH patients who had failed at least two previous salvage therapies. Overall, eight (53.3%) patients achieved partial remission, and four of those eight proceeded to hematopoietic stem cell transplantation (HSCT). Notably, pre-RED levels of C-X-C motif chemokine 9 (CXCL9) and interleukin-18 (IL-18) were significantly higher in patients who later responded to RED, suggesting that these biomarkers may predict a better response. We also observed that, for eight partial-remission patients, hemoglobin, fibrinogen, aspartate aminotransferase, calcium, and CXCL9 levels tracked well with early therapeutic responses (one to two weeks). No grade 3 or higher adverse effects were linked to the RED regimen. This comprehensive investigation of the RED approach in HLH, although small in sample size, supports the possibility that RED can serve as an effective and relatively safe salvage therapy for refractory HLH.