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Background: Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen., Methods: In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy., Results: The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72-98) and 88% (95% CI: 67-96); ≥ CR2 were 81% (95% CI: 61-92) and 68% (95% CI: 47-82) and refractory disease were 32% (95% CI: 11-54) and 20% (95% CI: 6-40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64-87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/μL and 140/μL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035)., Conclusion: The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611)., (© 2024. The Author(s).)

Purpose: High hyperdiploidy, the largest and favorable subtype of childhood ALL, exhibits significant biological and prognostic heterogeneity. However, factors contributing to the varied treatment response and the optimal definition of hyperdiploidy remain uncertain., Methods: We analyzed outcomes of patients treated on two consecutive frontline ALL protocols, using six different definitions of hyperdiploidy: chromosome number 51-67 (Chr51-67); DNA index (DI; DI1.16-1.6); United Kingdom ALL study group low-risk hyperdiploid, either trisomy of chromosomes 17 and 18 or +17 or +18 in the absence of +5 and +20; single trisomy of chromosome 18; double trisomy of chromosomes 4 and 10; and triple trisomy (TT) of chromosomes 4, 10, and 17. Additionally, we characterized ALL ex vivo pharmacotypes across eight main cytotoxic drugs., Results: Among 1,096 patients analyzed, 915 had B-ALL and 634 had pharmacotyping performed. In univariate analysis, TT emerged as the most favorable criterion for event-free survival (EFS; 10-year EFS, 97.3% v 86.8%; P = .0003) and cumulative incidence of relapse (CIR; 10-year CIR, 1.4% v 8.8%; P = .002) compared with the remaining B-ALL. In multivariable analysis, accounting for patient numbers using the akaike information criterion (AIC), DI1.16-1.6 was the most favorable criterion, exhibiting the best AIC for both EFS (hazard ratio [HR], 0.45; 95% CI, 0.23 to 0.88) and CIR (HR, 0.45; 95% CI, 0.21 to 0.99). Hyperdiploidy and subgroups with favorable prognoses exhibited notable sensitivities to asparaginase and mercaptopurine. Specifically, asparaginase sensitivity was associated with trisomy of chromosomes 16 and 17, whereas mercaptopurine sensitivity was linked to gains of chromosomes 14 and 17., Conclusion: Among different definitions of hyperdiploid ALL, DI is optimal based on independent prognostic impact and also the large proportion of low-risk patients identified. Hyperdiploid ALL exhibited particular sensitivities to asparaginase and mercaptopurine, with chromosome-specific associations.

Introduction: Tumor lysis syndrome (TLS) is often diagnosed in children with hematological malignancies and can be life threatening due to metabolic disturbances. Continuous renal replacement therapy (CKRT) can reverse these disturbances relatively quickly when conventional medical management fails. Our objective was to investigate the benefit of CKRT in the management of TLS in children admitted to the intensive care unit with hematologic malignancies. In addition, we sought to assess risk factors for acute kidney injury (AKI) in the setting of TLS., Methods: Retrospective review of all children admitted to the intensive care unit with TLS who received CKRT from January 2012 to August 2022., Results: Among 222 children hospitalized with TLS from January 2012 to August 2022, 20 (9%) underwent CKRT to manage TLS in the intensive care unit. The patients' median age was 13 years (range 3-17 y), and most were males (18/20). T-cell acute lymphoblastic leukemia was the most common diagnosis (n=10), followed by acute myeloid leukemia (n=4), Burkitt lymphoma (n=4), and B-cell acute lymphoblastic leukemia (n=2). Five patients required mechanical ventilation, and 2 required vasopressors. The most common indication for CKRT was hyperphosphatemia, followed by, hyperuricemia, and hyperkalemia. All metabolic abnormalities corrected within 12 h of initiation of CKRT. CKRT courses were brief, with a median duration of 2 days (range 1-7 days). Having higher serum phosphorus levels 12 h preceding CKRT was significantly associated with severe acute kidney injury (AKI). The median phosphorus level was 6.4 mg/dL in children with no/mild AKI and 10.5 mg/dL in children with severe AKI (p=0.0375). Serum uric acid levels before CKRT were not associated with AKI. All children survived to hospital discharge, and the one-year survival rate was 90%., Conclusion: CKRT is safe in children with hematologic malignancies with severe TLS and reverses metabolic derangements within 6-12 h. Most patients had AKI at the initiation of CKRT but did not require long-term kidney replacement therapy. Hyperphosphatemia before initiation of CKRT is associated with higher risk of AKI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Anderson, Shoulders, James, Ashcraft, Cheng, Ribeiro and Elbahlawan.)

The general amino acid control (GAAC) enables yeast cells to overcome amino acid deprivation by activation of the alpha subunit of translation initiation factor 2 (eIF2alpha) kinase GCN2 and consequent induction of GCN4, a transcriptional activator of amino acid biosynthetic genes. Binding of GCN2 to GCN1 is required for stimulation of GCN2 kinase activity by uncharged tRNA in starved cells. Here we show that YIH1, when overexpressed, dampens the GAAC response (Gcn- phenotype) by suppressing eIF2alpha phosphorylation by GCN2. The overexpressed YIH1 binds GCN1 and reduces GCN1-GCN2 complex formation, and, consistent with this, the Gcn- phenotype produced by YIH1 overexpression is suppressed by GCN2 overexpression. YIH1 interacts with the same GCN1 fragment that binds GCN2, and this YIH1-GCN1 interaction requires Arg-2259 in GCN1 in vitro and in full-length GCN1 in vivo, as found for GCN2-GCN1 interaction. However, deletion of YIH1 does not increase eIF2alpha phosphorylation or derepress the GAAC, suggesting that YIH1 at native levels is not a general inhibitor of GCN2 activity. We discovered that YIH1 normally resides in a complex with monomeric actin, rather than GCN1, and that a genetic reduction in actin levels decreases the GAAC response. This Gcn- phenotype was partially suppressed by deletion of YIH1, consistent with YIH1-mediated inhibition of GCN2 in actin-deficient cells. We suggest that YIH1 resides in a YIH1-actin complex and may be released for inhibition of GCN2 and stimulation of protein synthesis under specialized conditions or in a restricted cellular compartment in which YIH1 is displaced from monomeric actin.