Yingyi He

Background: Patients with anaplastic lymphoma kinase (ALK)-positive malignancies increasingly rely on ALK inhibitors (ALKis) as first-line therapy, yet thromboembolism (TE) across the ALKi family and its impact on patients’ safety remain incompletely characterized, particularly in the real-world populations. Objective: The aim of this study was to evaluate the real-world TE risks associated with ALKis using pharmacovigilance data mining and to identify and characterize the high-risk contributors to TE. Methods: We extracted 52,808 adverse event (AE) reports from the FDA Adverse Event Reporting System (2013–2024), including 17,124 ALKi-treated patients. TE signal strength was calculated via disproportionality analysis and presented by the lower limit of reporting odds ratio (ROR ₀₂₅ ) and information component (IC ₀₂₅ ). Multivariate logistic regression and time-to-onset (TTO) analyses were conducted to characterize the risk factors. Results: Among ALKi users, 251 TE cases were identified. Crizotinib exhibited significant TE safety signals for embolism (ROR ₀₂₅ = 2.66; IC0 ₂₅ = 1.19), pulmonary artery thrombosis (ROR ₀₂₅ = 4.94; IC0 ₂₅ = 1.01), pulmonary thrombosis (ROR ₀₂₅ = 1.29; IC0 ₂₅ = 0.13), and venous thrombosis limb (ROR ₀₂₅ = 1.66; IC0 ₂₅ = 0.08). Older age (OR = 1.006, P = 2.40e-06), male sex (OR = 1.47, P = 2.00e-16), and crizotinib use (OR = 2.79, P = 1.59e-05) independently predicted fatal TE outcomes. Female patients <65 years experienced earlier TE onset (median 14 vs. 44–53 days; P = 0.006). Conclusion: This study validates the elevated TE safety signal strength of crizotinib in the real-world settings, while no disproportionate TE signals were detected for other ALKi in the FAERS database. Clinicians could prioritize agent-specific risks, especially in older male patients and during early treatment phases.

Cancer immunotherapies exhibit impressive efficacy in some cancers but show only limited benefits for refractory hematological malignancies. The complex immune escape mechanisms of hematological cancers remain unclear. Here, we found that P-selectin glycoprotein ligand 1 (PSGL-1) was highly expressed by hematological cancers and negatively correlated with cancer prognosis. PSGL-1 deficiency in tumors suppressed the progression of multiple mouse models of hematological cancer by promoting infiltration of macrophages and their phagocytic activity. Tumor PSGL-1 inhibited the interaction between tumor ICAM-1 and CD11a/CD18 integrin (LFA-1) in macrophages, thereby suppressing prophagocytic signaling downstream of LFA-1. A humanized antibody targeting human PSGL-1 (αhPSGL-1) efficiently triggered macrophage phagocytosis of human hematological malignancies in vitro and slowed cancer progression in vivo. Additionally, PSGL-1 blockade potentiated the efficacy of doxorubicin chemotherapy and anti-CD47 and anti-CD38 antibody therapy. Therefore, PSGL-1 is a previously undescribed phagocytosis checkpoint, and targeting PSGL-1 could be a promising immunotherapy strategy for treating hematological malignancies.

Background: ASXL1 mutation is an independent prognostic factor in adult acute myeloid leukemia (AML), but its effect on the prognosis of pediatric AML is poorly understood.Aims: This study aimed to investigate the clinical characteristics and prognostic factors of ASXL1‐mutant pediatric AML from a large Chinese multicenter cohort.Methods: A total of 584 pediatric patients with newly diagnosed AML from 10 centers in South China were enrolled. The exon 13 of ASXL1 was amplified by polymerase chain reaction (PCR), and then analyzed the mutation status of the locus. (n = 59 for ASXL1‐mut group, n = 487 for ASXL1‐wt group).Results: ASXL1 mutations were found in 10.81% of all patients with AML. A complex karyotype was significantly less common in the ASXL1‐mut AML group than in the ASXL1‐wt group (1.7% vs. 11.9%, p = 0.013). Furthermore, TET2 or TP53 mutations were predominantly found in the ASXL1+ group (p = 0.003 and 0.023, respectively). The 5‐year overall survival (OS) and event‐free survival (EFS) of the total cohort were 76.9% and 69.9%. In ASXL1‐mut AML patients, a white blood cell (WBC) count ≥50 × 10⁹/L had significantly poorer 5‐year OS and EFS than a WBC count 9/L (78.0% vs. 44.6%, p = 0.001; 74.8% vs. 44.6%, p = 0.003, respectively), while receiving hematopoietic stem cell transplantation (HSCT) had a higher 5‐year OS and EFS (84.5% vs. 48.5%, p = 0.024; 79.5% vs. 49.3%, p = 0.047, respectively). In the multivariate Cox regression analysis, patients with high‐risk AML undergoing HSCT tended to have a better 5‐year OS and EFS than those receiving chemotherapy as a consolidation (HR = 0.168 and 0.260, both p < 0.001), and WBC count ≥50 × 10⁹/L or failure to achieve complete response after the first course were independent adverse predictors of OS and EFS (HR = 1.784 and 1.870, p = 0.042 and 0.018; HR = 3.242 and 3.235, both p < 0.001).Conclusion: The C‐HUANA‐AML‐15 protocol is a well‐tolerated and effective in the treatment of pediatric AML. ASXL1 mutation is not an independent adverse prognosis predictor for survival in AML, whereas ASXL1‐mut patients tend to have a poor prognosis if WBC count ≥50 × 10⁹/L, but they can benefit from HSCT.

Background: Though the efficacy of anti C‐type lectin‐like molecule‐1 (CLL1) CAR T‐cells in refractory/relapsed acute myeloid leukemia (R/R‐AML) have been occasionally reported, the influence of co‐stimulatory domain CAR T‐cells is not investigated so far.Method: Seven R/R‐AML children treated with anti‐CLL1 CAR T‐cells were enrolled onto this preliminary comparison study. Among these seven patients, four received CD28/CD27‐based CAR T‐cells therapy, and three received 4‐1BB‐based CAR T‐cells therapy.Result: The overall response rates were 75% and 66.7% in CD28/CD27 and 4‐1BB group respectively. All patients experienced grade 1 to 2 cytokine release syndrome, with only one patient experiencing grade 2 immune effector cell‐associated neurotoxicity syndrome. The maximum CAR T‐cells durations were 156 and 274 days for CD28/CD27 group and 4‐1BB group respectively. The 1‐yr overall survival rate was 57.1%.Conclusions: A preliminary similar efficacy/safety index was observed in anti‐CLL1‐based CAR T‐cells with 4‐1BB or CD28/CD27 co‐stimulatory elements in treating pediatric R/R‐AML.

Approximately one‐third children with anaplastic large cell lymphoma (ALCL) relapse after completion of chemotherapy, particularly for those high‐risk patients. The introduction of novel therapeutic modalities is much needed for these sub‐group patients. Two groups (n = 3, n = 4) of ALCL patients were treated with crizotinib‐ and alectinib‐included ALCL‐99 therapy, respectively, achieving complete remission rates of 66.7% and 100%. Two patients of crizotinib group relapsed, while none relapsed among the alectinib‐treated patients. Adding alectinib instead of crizotinib sufficiently suppressed and maintained the deep NPM‐ALK molecular response. ALK inhibitors were well tolerated with only grade 1 adverse events in both groups. Though a relatively small case number, this study raised the possibility that alectinib‐included therapeutic regimens may benefit the early response, in‐depth molecular remission, and persistent remission to some extent. Further studies are warranted to validate our preliminary findings.

We present the first infantile disseminated Bacillus Calmette-Guérin (BCG) disease case with STAT1 deficiency, which is manifested by multiple Langerhans cell histiocytosis–like osteolytic lesions. The diagnosis of BCG-induced osteomyelitis was not initially considered until the additional biopsy revealing granulomatous inflammation, a key pathological diagnostic component for mycobacterial infection.

The prognosis of patients with T‐cell acute lymphoblastic leukemia (T‐ALL) has been largely lacked behind than that of patients with B‐cell ALL, especially in refractory or relapsed cases. Here, we describe a 4.7‐year‐old male child with TCF‐SPI1‐postitve T‐ALL who developed refractoriness disease after a seven drugs‐conventional therapy. Several studies have suggested the therapeutic potential of dasatinib in refractory T‐ALL. Actually, dasatinib‐included therapy dramatically reduces the leukemic burden and re‐induces this patient into complete remission without systemic adverse events. Although this is a single exceptional case, the translational potential evidence of dasatinib in specific T‐ALL subtype should not be under‐estimated.

Through the advancements in recent decades, childhood acute lymphoblastic leukemia (ALL) is gradually becoming a highly curable disease. However, the truth is there remaining relapse in ∼15% of ALL cases with dismal outcomes. RAS mutations, in particular NRAS mutations, were predominant mutations affecting relapse susceptibility. KRAS mutations targeting has been successfully exploited, while NRAS mutation targeting remains to be explored due to its complicated and compensatory mechanisms. Using targeted sequencing, we profiled RAS mutations in 333 primary and 18 relapsed ALL patients and examined their impact on ALL leukemogenesis, therapeutic potential, and treatment outcome. Cumulative analysis showed that RAS mutations were associated with a higher relapse incidence in children with ALL. In vitro cellular assays revealed that about one-third of the NRAS mutations significantly transformed Ba/F3 cells as measured by IL3-independent growth. Meanwhile, we applied a high-throughput drug screening method to characterize variable mutation-related candidate targeted agents and uncovered that leukemogenic-NRAS mutations might respond to MEK, autophagy, Akt, EGFR signaling, Polo−like Kinase, Src signaling, and TGF−β receptor inhibition depending on the mutation profile.