Metabolic reprogramming of leukemia cells is important for survival, proliferation, and drug resistance under conditions of metabolic stress in the bone marrow. Deregulation of cellular metabolism, ...leading to development of leukemia, occurs through abnormally high expression of transcription factors such as MYC and Ecotropic Virus Integration site 1 protein homolog (EVI1). Overexpression of EVI1 in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. To identify a metabolic inhibitor for EVI1-induced metabolic reprogramming in MLL-r AML, we used an XFp extracellular flux analyzer to examine metabolic changes during leukemia development in mouse models of AML expressing MLL-AF9 and Evi1 (Evi1/MF9). Oxidative phosphorylation (OXPHOS) in Evi1/MF9 AML cells accelerated prior to activation of glycolysis, with a higher dependency on glutamine as an energy source. Furthermore, EVI1 played a role in glycolysis as well as driving production of metabolites in the tricarboxylic acid cycle. L-asparaginase (L-asp) exacerbated growth inhibition induced by glutamine starvation and suppressed OXPHOS and proliferation of Evi1/MF9 both
and
; high sensitivity to L-asp was caused by low expression of asparagine synthetase (ASNS) and L-asp-induced suppression of glutamine metabolism. In addition, samples from patients with EVI1
MF9 showed low ASNS expression, suggesting that it is a sensitive marker of L-asp treatment. Clarification of metabolic reprogramming in EVI1
leukemia cells may aid development of treatments for EVI1
MF9 refractory leukemia.
Immunophenotyping was performed in 1044 consecutive childhood acute lymphoblastic leukemia (ALL) patients enrolled in the Tokyo Children's Cancer Study Group L04‐16 trial, revealing novel findings ...associated with genetic abnormalities. In addition to TCF3‐PBX1 and MEF2D fusions, the CD10(+) subtype of KMT2A‐MLLT3‐positive ALL frequently exhibited the cytoplasmic‐μ(+) pre‐B ALL immunophenotype. Although ETV6‐RUNX1 was significantly correlated with myeloid antigen expression, more than half of patients expressed neither CD33 nor CD13, while the CD27(+)/CD44(−) immunophenotype was maintained. Expression of CD117 and CD56 in B‐cell precursor‐ALL was limited to certain subtypes including ETV6‐RUNX1 and KMT2A‐MLLT3. Besides BCR‐ABL1, CRLF2, hyperdiploidy, and hypodiploidy, CD66c was also expressed in Ph‐like kinase fusion‐, PAX5 fusion‐, and DUX4 fusion‐positive ALL, but not in MEF2D fusion‐positive ALL, indicating constant selectivity of CD66c expression. In T‐ALL, SIL‐TAL1‐positive patients were likely to exhibit a more mature immunophenotype. Expression of CD21 and CD10 was not rare in T‐ALL, while lack of CD28 was an additional feature of early T‐cell precursor‐ALL. Considering the immunophenotype as a prognostic maker, MEF2D fusion‐positive ALL with CD5 expression may be associated with a poorer prognosis in comparison with those lacking CD5 expression. In cases with characteristic marker expression, the presence of certain fusion transcripts could be predicted accurately.
Acute lymphoblastic leukemia (ALL) in infants accounts for less than 5% of pediatric ALL and is biologically and clinically unique. Approximately 70% to 80% of cases present as an aggressive leukemia ...with
KMT2A
gene rearrangement (KMT2A-r), which is one of the most difficult-to-cure forms of pediatric leukemia. Owing to continuing global efforts through multicenter clinical trials since the mid-1990s, a standard of care for infant KMT2A-r ALL, including minimal residual disease-based risk stratifications, “hybrid chemotherapy” incorporating myeloid leukemia-like drugs (e.g., cytarabine) into the ALL chemotherapy backbone, and selective use of allogeneic hematopoietic stem cell transplantation, has now been established. However, there are still many concerns regarding treatment of infants with KMT2A-r ALL, including insufficient efficacy of the current standard therapies, limited pharmacokinetic/pharmacodynamic data on drugs in infants, and management of both acute and late toxicities. Refinements in risk stratification based on leukemia biology, as well as the introduction of emerging novel immunotherapies and molecular-targeted drugs to contemporary therapy, through international collaboration would provide key solutions for further improvement in outcomes.
To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated ...our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.
► CBFA2T3-GLIS2 is a recurrent fusion gene in pediatric AMKL ► CBFA2T3-GLIS2 AMKL has a distinct expression profile and an inferior outcome ► CBFA2T3-GLIS2 induces BMP signaling and enhanced self-renewal of progenitor cells
Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 ...translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23- or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (± 5%), with large differences across subgroups (11% ± 5% to 92% ± 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio HR = 0.1, P = .004); t(6;11)(q27;q23) (HR = 2.2, P < .001); t(10;11)(p12;q23) (HR = 1.5, P = .005); and t(10;11)(p11.2;q23) (HR = 2.5, P = .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis.
The survival rate of children with acute lymphoblastic leukemia (ALL) has increased to approximately 90% after substantial progress in risk-oriented treatment strategies. Between 2005 and 2013, the ...Tokyo Children’s Cancer Study Group (TCCSG) conducted a risk-oriented, non-randomized study, L04-16. The principal aim of this study was to assemble background characteristics and treatment outcomes, and gather genetic information on leukemic cells under central diagnosis. This report outlines the background characteristics and treatment outcomes of 1033 children with ALL treated according to a TCCSG platform. The 5-year event-free and overall survival (OS) rates for all children were 78.1 ± 1.3 and 89.6 ± 1.0%, respectively. The OS rate was significantly higher in children with B-cell precursor (BCP)-ALL (91.9 ± 1.0%,
n
= 916) than in those with T-ALL (71.9 ± 4.3%,
n
= 117,
p
< 0.001). In univariate analysis for BCP-ALL, children aged 1–6 years (5y-OS: 94.2 ± 1.0%), with an initial white blood cell count of < 20,000/μL (94.0 ± 1.0%), high hyperdiploidy (95.4 ± 1.6%),
ETV6
-
RUNX1
(97.4 ± 1.2%) or
TCF3
-
PBX1
(96.9 ± 2.1%), and “Day8NoBlasts” (96.4 ± 1.1%) had the best outcomes. Genetic investigation revealed two novel fusion genes within this cohort:
ETV6
-
ZNF385A
and
ZNF362
-
TCF4
. Our study highlighted the clinical aspects of genomic features of ALL in Japanese children. We provide fundamental information for the further molecular investigation of this disease.
Graft-versus-host disease (GVHD) occasionally leads to morbidity and mortality but is thought to reduce the risk of relapses in patients with a hematological malignancy. However, information on the ...effect of GVHD in pediatric leukemia is limited. Using a nationwide registry, we retrospectively analyzed 1526 children who underwent allogeneic stem cell transplantation for leukemia. Grades 0-I acute GVHD were associated with a higher relapse rate at three years after transplantation, at 25.4 and 24.3%, respectively, than grades II, III, or IV acute GVHD at 18.9%, 21.2%, and 2.6%, respectively. In contrast, the overall survival curve of the grades 0 and I GVHD groups (79.0% and 79.5%, respectively) approximated that of the grade II GVHD group (76.3%), and the probability of survival was worst in the severe GVHD groups (66.9% for grade III and 42.5% for grade IV). Chronic GVHD also reduced the relapse risk but conferred no survival advantage. Acute lymphoblastic leukemia was more sensitive to acute GVHD than acute myeloid leukemia (AML) while AML was more sensitive to chronic GVHD. Our study reproduced the preventive effects of GVHD against pediatric leukemia relapses but failed to demonstrate a significant survival advantage.
We retrospectively analyzed nationwide records of 163 Fanconi anemia (FA) patients aplastic anemia (AA),
n
= 118; myelodysplastic syndrome (MDS),
n
= 30; acute leukemia,
n
= 15 who underwent first ...allogeneic hematopoietic stem cell transplantation (HSCT) between 1987 and 2015 in Japan. An alternative donor was used in 119 (73%) patients, and 160 (98%) patients received a non-T-cell-depleted graft. With an 8.7-year median follow-up, 5-year overall survival (OS) was 81%. The 5-year OS was significantly higher in AA patients than in MDS and acute leukemia patients (89%, 71%, and 44%, respectively). In the MDS/leukemia group, factors associated with poor outcome in univariate analysis were older age at HSCT (≥ 18 years), conditioning regimen without anti-thymocyte or lymphocyte globulin, and grade II–IV acute graft-versus-host disease. After 1 year, of 137 survivors, 15 developed subsequent malignancies, of whom 12 were diagnosed with head and neck (HN)/esophageal cancer. An irradiation regimen and older age were associated with the risk of HN/esophageal cancer. Five of seven deaths were attributed to subsequent malignancies more than 5 years after HSCT. On the basis of the risk factors for HSCT in MDS/leukemia patients and subsequent malignancies, a more effective HSCT approach is required.
Background
Therapeutic drug monitoring for busulfan is important to prevent adverse events and improve outcomes in stem cell transplantation. We investigated intravenous busulfan pharmacokinetics and ...evaluated the utility of limited sampling strategy (LSS) as a simple method to estimate the area under the concentration‐time curve (AUC).
Procedure
The study comprised 87 busulfan measurements in 54 children who received intravenous busulfan between August 2015 and May 2020. AUCs were calculated from three to five blood sampling points in each patient, and the correlation between AUC and plasma concentrations (ng/mL) at 1, 2, 3, 4, and 6 h after initiating busulfan infusion (C1, C2, C3, C4, and C6, respectively).
Results
By one‐point sampling strategy, the most relevant predicted AUC was based on C6 (r2 = 0.789; precision, 11.0%) in all patients. The predicted AUC based on C6 was acceptable (r2 = 0.937; precision, 5.9%) for adolescent patients weighing >23 kg, but the correlation was poor in infants and young children weighing ≤ 23 kg (r2 = 0.782; precision, 11.4%). By two‐point sampling strategy, the predicted AUC based on C3 and C6 showed the most relevant concentrations (r2 = 0.943; precision, 6.4%), even in infants and young children, whereas the predicted AUC based on C3 and C6 was acceptable (r2 = 0.963; precision, 5.7%).
Conclusions
The AUC of busulfan can be predicted based on C6 in adolescent patients. However, there was substantial interindividual variation in busulfan pharmacokinetics in infants and young children, in whom two‐point LSS was necessary for accurate AUC prediction.
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