Intraocular Relapse as Initial Manifestation in Pediatric Acute Myeloid Leukemia after Stem Cell Transplant: A Case Report

High FLT3 Transcript Level Is Associated with Unfavorable Prognosis in Pediatric Non-Promyelocytic Acute Myeloid Leukemia.

Hypodiploidy, defined as modal numbers (MNs) 45 or lower, has not been independently investigated in pediatric acute myeloid leukemia (AML) but is a well-described high-risk factor in pediatric acute lymphoblastic leukemia. We aimed to characterize and study the prognostic impact of hypodiploidy in pediatric AML. In this retrospective cohort study, we included children below 18 years of age with de novo AML and a hypodiploid karyotype diagnosed from 2000 to 2015 in 14 childhood AML groups from the International Berlin-Frankfurt-Münster (I-BFM) framework. Exclusion criteria comprised constitutional hypodiploidy, monosomy 7, composite karyotype, and t(8;21) with concurring sex chromosome loss. Hypodiploidy occurred in 81 patients (1.3%) with MNs, 45 (n= 66); 44 (n=10) and 43 (n= 5). The most frequently lost chromosomes were chromosome 9 and sex chromosomes. Five-year event-free survival (EFS) and overall survival (OS) were 34% and 52%, respectively, for the hypodiploid cohort. Children with MN≤44 (n= 15) had inferior EFS (21%) and OS (33%) compared with children with MN= 45 (n= 66; EFS, 37%; OS, 56%). Adjusted hazard ratios (HRs) were 4.9 (P= .001) and 6.1 (P= .003). Monosomal karyotype or monosomy 9 had particular poor OS (43% and 15%, respectively). Allogeneic stem cell transplantation (SCT) in first complete remission (CR1) (n= 18) did not mitigate the unfavorable outcome of hypodiploidy (adjusted HR for OS was 1.5; P= .42). We identified pediatric hypodiploid AML as a rare subgroup with an inferior prognosis even in the patients treated with SCT in CR1.

Mutation Profiling Reveals Novel Epigenetics and Splicing Mutations in Chemorefractory Pediatric AML

Divergent Epigenomes in Pediatric and Adult Acute Myeloid Leukemia Implicate Cell of Origin and Transcriptional Silencing of Immune Responses As Sources of Clinically Relevant Heterogeneity: A Report from the Children's Oncology Group and NCI/COG Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative

BackgroundHuman leukocyte antigen‐identical sibling donor (ISD)‐hematopoietic stem cell transplantation (SCT) is a potentially curative treatment for high‐risk pediatric acute myeloid leukemia (AML). A haploidentical donor (HID) is readily available to almost all children. Previous studies have demonstrated that patients with HID‐SCT had similar outcomes compared to ISD‐SCT for pediatric and adult AML. However, the role of HID‐SCT in high‐risk pediatric AML is unclear.MethodsTo compare the overall survival of high‐risk AML children who underwent either HID‐SCT or ISD‐SCT, we analyzed 179 cases of high‐risk AML patients under 18 years of age treated with either ISD‐SCT (n = 23) or HID‐SCT (n = 156). Granulocyte colony‐stimulating factor plus anti‐thymocyte globulin‐based regimens were used for HID‐SCT. We also analyzed the subgroup data of AML patients at first complete remission (CR1) before SCT with known cytogenetic risk.ResultsThe numbers of adverse cytogenetic risk recipients were 8 (34.8%) and 13 (18.8%) in the ISD‐SCT group and the HID‐SCT group, and the number of patients with disease status beyond CR1 were 6 (26.1%) and 14 (20.3%) in the two groups. The cumulative rates of grades II‐IV acute graft‐versus‐host disease (GVHD) were 13.0% in the ISD‐SCT group and 34.8% in the HID‐SCT group (P = 0.062), with a three‐year cumulative rates of chronic GVHD at 14.1% and 34.9%, respectively (P = 0.091). The relapse rate in the ISD‐SCT group was significantly higher than that in the HID‐SCT group (39.1% vs. 16.4%, P = 0.027); with non‐relapse mortality at 0.0% and 10.6% (P = 0.113), respectively. The three‐year overall survival rates were 73.0% for the ISD‐SCT group and 74.6% for the HID‐SCT group (P = 0.689). In subgroup analysis, the three‐year relapse rate in the ISD‐SCT group was higher than that in the HID‐SCT group (50.0% vs. 9.2%, P = 0.001) and the three‐year DFS in the ISD‐SCT group (50.0%) was lower than that in the HID‐SCT group (81.2%) (P = 0.021).ConclusionsUnmanipulated HID‐SCT achieved DFS and OS outcomes comparable to those of ISD‐SCT for high‐risk pediatric AML patients with potentially higher rate but manageable GVHD.

Overexpression of BRE in Pediatric MLL-Rearranged Acute Myeloid Leukemia Associated with t(9;11)(p22;q23).

Deregulation of Splicing in Pediatric Acute Myeloid Stem and Progenitor Cells

Germline Variant Burden Warrants Universal Genetic Testing in Pediatric AML

Integrating Genomics and Functional Phenotypes to Refine Risk Assessment in Acute Myeloid Leukemia across the Age Spectrum: Insights from Singapore

Simple SummaryThe FMS-like tyrosine kinase 3 (FLT3) gene mutated in 10–15% of pediatric acute myeloid leukemia (AML) is associated with an inferior outcome. We retrospectively analyzed the nationwide pediatric AML database from between 2005 and 2022. FLT3-ITD mutation was found in 10.7% of patients. An improvement in the outcome was found in the analyzed period of time. The treatment results in FLT3-ITD--positive patients treated under the AML-BFM 2012 and 2019 protocols were better in comparison to the AML-BFM 2004 protocol and better than previously reported by most authors. However, the outcome in patients with FLT3-ITD compared to children without this mutation was still significantly worse, with higher percentage of non-responders and relapses. It seems that SCT and FLT3 inhibitors have a beneficial impact on the prognosis; however, it should be confirmed in a larger group of patients. This gives hope for the improvement of the treatment results in pediatric AML with FLT3-ITD in the future.Background: The FMS-like tyrosine kinase 3 (FLT3) gene mutated in 10–15% of pediatric acute myeloid leukemia (AML) is associated with an inferior outcome. The aim of the study was to analyze the outcome and characteristics of FLT3-ITD-positive pediatric AML. Methods: We retrospectively analyzed the nationwide pediatric AML database from between 2005 and 2022. FLT3-ITD was found in 54/497 (10.7%) patients with available analysis. Three consecutive treatment protocols were used (AML-BFM 2004 Interim, AML-BFM 2012 Registry, AML-BFM 2019 recommendations). Results: Probabilities of 5-year overall (OS), event-free (EFS) and relapse-free survival were significantly lower in the FLT3-ITD-positive patients compared to FLT3-ITD-negative (0.54 vs. 0.71, p = 0.041; 0.36 vs. 0.59, p = 0.0004; 0.47 vs. 0.70, p = 0.0029, accordingly). An improvement in the outcome was found in the analyzed period of time, with a trend of better survival in patients treated under the AML-BFM 2012 and AML-BFM 2019 protocols compared to the AML-BFM 2004 protocol (5-year EFS 0.52 vs. 0.27, p = 0.069). There was a trend of improved outcomes in patients treated with FLT3 inhibitors (n = 9, 2-year EFS 0.67 vs. 0.33, p = 0.053) and those who received stem cell transplantation (SCT) (n = 26; 5-year EFS 0.70 vs. 0.27, p = 0.059). The co-occurrence of the WT1 mutation had a dismal impact on the prognosis (5-year EFS 0.23 vs. 0.69, p = 0.002), while the NPM1 mutation improved survival (5-year OS 1.0 vs. 0.44, p = 0.036). Conclusions: It seems that SCT and FLT3 inhibitors have a beneficial impact on the prognosis. Additional genetic alterations, like the WT1 and NPM1 mutations, significantly influence the outcome.

GATA2 mutations and overexpression in pediatric acute myeloid leukemia

The role of stem cell transplantation in the treatment of leukemia and myelodysplasia (MDS) in children has changed over the past decade. In pediatric acute lymphoblastic leukemia (ALL), the overall cure-rate is high with conventional chemotherapy. However, selected patients with a high-risk of relapse are often treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission (CR1). Patients with a bone-marrow relapse who attain a second remission frequently receive HSCT. High minimal residual disease (MRD) levels directly prior to HSCT determines the relapse risk. Therefore, MRD positive patients are eligible for more experimental approaches such as intensified or experimental chemotherapy pre-HSCT, as well as immune modulation post-HSCT. In pediatric acute myeloid leukemia (AML) the role of allo-HSCT in CR1 is declining, due to better outcome with modern multi-agent chemotherapy. In relapsed AML patients, allo-HSCT still seems indispensable. Targeted therapy may change the role of HSCT, in particular in chronic myeloid leukemia, where the role of allografting is changing in the imatinib era. In MDS, patients are usually transplanted immediately without prior cytoreduction. New developments in HSCT, such as the role of alternative conditioning regimens, and innovative stem cell sources such as peripheral blood and cord blood, will also be addressed.

Although the expression of both myeloid- and lymphoid-associated cell-surface antigens in acute myeloid leukemia (AML) has been described, the clinical significance of such antigen expression remains unknown in the pediatric population. We sought to define an antibody panel for optimal diagnostic antigenic analysis and to test associations among antigen expression and a number of clinical features at presentation and prognosis in pediatric AML. We reviewed the extensive immunophenotypic analysis performed at the time of diagnosis on 132 assessable patients registered on a single Pediatric Oncology Group AML protocol between 1984 and 1988. Eighty-eight percent of patients were identified by testing for expression of CD33 and CD13. Overall, 61% of patients expressed at least one lymphoid-associated antigen, most commonly CD4, CD7, or CD19. Expression of CD5, CD10, CD20, or CD22, commonly detected in T- or B-lineage pediatric acute lymphoid leukemia (ALL), was uncommon; coexpression of multiple lymphoid-associated antigens was also uncommon. Expression of the monocyte-associated antigen CD14 correlated with French-American-British (FAB) M4 or M5 morphology. Otherwise, no correlation between antigen expression and FAB classification was noted. None of the myeloid, lymphoid, natural-killer (NK), or progenitor-associated antigens were associated with significant differences in the likelihood of remission induction or event-free survival when expressor versus nonexpressor groups were compared. The distribution of cell-surface antigen expression in pediatric acute leukemia usually permitted the discrimination of AML from ALL by using a limited panel of antibodies. Although the expression of lymphoid-associated antigens was common, such expression did not seem to be associated with an adverse prognosis in pediatric AML.

Hypodiploidy in Childhood Acute Myeloid Leukemia: A Retrospective Cohort Study within the International Berlin-Frankfurt-Münster Study Group

EVI1 overexpression is a poor prognostic factor in pediatric patients with mixed lineage leukemia-AF9 rearranged acute myeloid leukemia.