PURPOSE: Homoharringtonine (HHT) is commonly used for the treatment of Chinese adult AML, and all-trans retinoic acid (ATRA) has been verified in acute promyelocytic leukemia (APL). However, the efficacy and safety of HHT-based induction therapy have not been confirmed for childhood AML, and ATRA-based treatment has not been evaluated among patients with non-APL AML. PATIENTS AND METHODS: This open-label, multicenter, randomized Chinese Children's Leukemia Group-AML 2015 study was performed across 35 centers in China. Patients with newly diagnosed childhood AML were first randomly assigned to receive an HHT-based (H arm) or etoposide-based (E arm) induction regimen and then randomly allocated to receive cytarabine-based (AC arm) or ATRA-based (AT arm) maintenance therapy. The primary end points were the complete remission (CR) rate after induction therapy, and the secondary end points were the overall survival (OS) and event-free survival (EFS) at 3 years. RESULTS: We enrolled 1,258 patients, of whom 1,253 were included in the intent-to-treat analysis. The overall CR rate was significantly higher in the H arm than in the E arm (79.9% v 73.9%, P = .014). According to the intention-to-treat analysis, the 3-year OS was 69.2% (95% CI, 65.1 to 72.9) in the H arm and 62.8% (95% CI, 58.7 to 66.6) in the E arm ( P = .025); the 3-year EFS was 61.1% (95% CI, 56.8 to 65.0) in the H arm and 53.4% (95% CI, 49.2 to 57.3) in the E arm ( P = .022). Among the per-protocol population, who received maintenance therapy, the 3-year EFS did not differ significantly across the four arms (H + AT arm: 70.7%, 95% CI, 61.1 to 78.3; H + AC arm: 74.8%, 95% CI, 67.0 to 81.0, P = .933; E + AC arm: 72.9%, 95% CI, 65.1 to 79.2, P = .789; E + AT arm: 66.2%, 95% CI, 56.8 to 74.0, P = .336). CONCLUSION: HHT is an alternative combination regimen for childhood AML. The effects of ATRA-based maintenance are comparable with those of cytarabine-based maintenance therapy.

B cell expansion with NF-κB and T cell anergy (BENTA) is a rare primary immunodeficiency disorder caused by gain-of-function (GOF) mutations in the CARD11 gene. Affected patients present with persistent B cell lymphocytosis in early childhood paired with lymphadenopathy and splenomegaly. Until now only six activating mutations from 14 patients have been reported in CARD11. Here we report a patient from China with polyclonal B cell lymphocytosis and frequent infections in early life. A heterozygous mutation (c.377G>A, G126D) in exon 5 of CARD11 gene (NM_032415) was identified by whole exome sequencing. In vitro functional studies showed that the G126D mutation is associated with increased expression of CARD11 and NF-κB activation in Hela cells. Flow cytometry analysis indicated NK cell activity and CD107a degranulation of the patient were decreased. RNA sequencing analysis showed that a number of genes in NF-κB pathway increased while those involved in NK cell activity and degranulation were down-regulated. In summary, our work identified a de novo germline GOF mutation in CARD11 with functional evidence of BENTA.

CBFA2T3-GLIS2 is the most frequent chimeric oncogene identified to date in non–Down syndrome acute megakaryocytic leukemia (AMKL), which is associated with extremely poor clinical outcome. The presence of this fusion gene is associated with resistance to high-intensity chemotherapy, including hematopoietic stem cell transplantation (HSCT), and a high cumulative incidence of relapse frequency. The clinical features and clinical effects of China Children’s Leukemia Group–acute myeloid leukemia (AML) 2015/2019 regimens and haploidentical HSCT (haplo-HSCT) for treatment of 6 children harboring the CBFA2T3-GLIS2 fusion gene between January 2019 and December 2021 were retrospectively analyzed. The 6 patients included 4 boys and 2 girls with a median disease-onset age of 19.5 months (range: 6–67 mo) who were diagnosed with AMKL. Flow cytometry demonstrated CD41a, CD42b, and CD56 expression and lack of HLA-DR expression in all 6 patients. All the children were negative for common leukemia fusion genes by reverse transcription polymerase chain reaction, but positive for the CBFA2T3-GLIS2 fusion gene by next-generation sequencing and RNA sequencing. All patients received chemotherapy according to China Children’s Leukemia Group–AML 2015/2019 regimens, and 4 achieved complete remission. Four children underwent haplo-HSCT with posttransplant cyclophosphamide-based conditioning; 3 had minimal residual disease negative (minimal residual disease <0.1%) confirmed by flow cytometry at the end of the follow-up, with the remaining patient experiencing relapse at 12 months after transplantation. Transcriptome RNA sequencing is required for the detection of the CBFA2T3-GLIS2 fusion gene and for proper risk-based allocation of pediatric patients with AML in future clinical strategies. Haplo-HSCT with posttransplant cyclophosphamide–based conditioning may improve survival in children with AMKL harboring the fusion gene.

Objectives: To investigate the clinical features of thrombotic microangiopathy associated with allogeneic hematopoietic stem cell transplantation in children. Methods: A retrospective analysis of continuous clinical data from HSCT received in the Department of Hematology and Oncology of Wuhan Children's Hospital from August 1, 2016 to December 31, 2021. Results: During this period, 209 patients received allo-HSCT in our department, 20 (9.6%) of whom developed TA-TMA. TA-TMA was diagnosed at a median of 94 (7–289) days post-HSCT. Eleven (55%) patients had early TA-TMA within 100 days post-HSCT, while the other 9 (45%) patients had TA-TMA thereafter. The most common symptom of TA-TMA was ecchymosis (55%), while the main signs were refractory hypertension (90%) and multi-cavity effusion (35%). Five (25%) patients had central nervous system symptoms (convulsions and lethargy). All 20 patients had progressive thrombocytopenia, with 16 patients receiving transfusion of platelets that was ineffective. Ruptured red blood cells were visible in only two patients with peripheral blood smears. Cyclosporine A or Tacrolimus (CNI) dose was reduced once TA-TMA was diagnosed. Nineteen cases were treated with low-molecular-weight heparin, 17 patients received plasma exchange, and 12 patients were treated with rituximab. TA-TMA-related mortality percentage in this study was 45% (9/20). Conclusion: Platelet decline and/or ineffective transfusion post-HSCT should be considered an early indicator of TA-TMA in pediatric patients. TA-TMA in pediatric patients may occur without evidence of peripheral blood schistocytes. Aggressive treatment is required once diagnosis is confirmed, but the long-term prognosis is poor.

Background: Calreticulin (CALR) has been investigated in several malignant diseases and is associated with immune-cell infiltration. However, the prognostic value of CALR in kidney renal clear cell carcinoma (KIRC) is still unknown.Methods: Based on the computational analysis, data from 530 KIRC cases and 72 normal kidney samples from The Cancer Genome Atlas (TGCA-KIRC) database were analyzed in this study. The expression of CALR mRNA in pan-cancer and immune infiltrates was analyzed using the Tumor Immune Estimation Resource (TIMER) database. The CALR protein expression was obtained from the UALCAN and Human Protein Atlas (HPA) databases. Survival, functional, and statistical analyses were conducted using R software.Results: The CALR expression was higher in KIRC cases than in normal kidneys. A high CALR expression was correlated with TNM stage, pathological stage, and histological grade. Kaplan–Meier survival analysis showed that a high CALR expression was associated with poor overall survival, disease-specific survival, and progression-free interval. Gene set enrichment analysis (GSEA) indicated that CALR was enriched in IL-6 and IL-2 signaling, interferon signaling, TNF signaling, inflammatory response, apoptosis, and the p53 pathway. CALR is correlated with immune-infiltrating cells. A significant correlation was observed between CALR expression and immunomodulators.Conclusion: We identified CALR as a prognostic biomarker of KIRC. Meanwhile, the CALR expression associated with immune infiltration indicated that CALR might be a potential immunotherapy target for patients with KIRC.

The unfolded protein response (UPR) plays a pivotal role in the pathogenesis and progression of acute myeloid leukemia (AML). This study aims to investigate the prognostic value of UPR-related genes (URGs) and establish a UPR-related gene signature (URGsig) to enhance prognosis prediction and guide therapeutic decision-making in AML. Gene expression profiles of AML patients were obtained from the GDC and GEO databases. Cox regression and LASSO regression analyses were applied to identify key genes for the construction of URGsig. Comprehensive bioinformatics analyses were conducted to elucidate the biological and clinical implications of URGsig. A nomogram integrating URGs and clinical prognostic features was developed to predict survival probability for AML patients. Additionally, the differential expression of core genes within the URGsig was validated in clinical samples. Notably, two distinct UPR-related subtypes were identified, and they displayed significant heterogeneity in clinical outcomes and tumor microenvironment (TME). The URGsig, comprising six URGs, showed a strong correlation with survival outcomes and exhibited robust predictive capabilities. Importantly, patients categorized into the high-risk subgroup based on URGsig were predicted to show lower chemosensitivity but a better response to immunotherapy. The nomogram performed well in prognosis prediction, with an area under the curve (AUC) of 0.912 for 5-year overall survival. In summary, our findings highlight the URGsig as a promising prognostic biomarker and provide novel insights into the mechanism by which UPR influences the immune landscape of AML. This paradigm may lay a foundation for the development of personalized treatment strategies for AML patients.