scholarly journals Advances in the First Line Treatment of Pediatric Acute Myeloid Leukemia in the Polish Pediatric Leukemia and Lymphoma Study Group from 1983 to 2019

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4536
Author(s):  
Małgorzata Czogała ◽  
Walentyna Balwierz ◽  
Katarzyna Pawińska-Wąsikowska ◽  
Teofila Książek ◽  
Karolina Bukowska-Strakova ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Pediatric Leukemia ◽  
Free Survival ◽  
Pediatric Acute Myeloid Leukemia ◽  
Genetic Abnormalities ◽  
Therapeutic Protocols ◽  
Pediatric Aml ◽  
Lymphoma Study Group ◽  
Acute Myeloid

Background: From 1983, standardized therapeutic protocols for pediatric acute myeloid leukemia (AML) based on the BFM group experience were introduced in Poland. We retrospectively analyzed the results of pediatric AML treatment in Poland from 1983 to 2019 (excluding promyelocytic, therapy-related, biphenotypic, and Down syndrome AML). Methods: The study included 899 children suffering from AML treated with the following: AML-PPPLBC 83 (1983–1993, n = 187), AML-PPGLBC 94 (1994–1997, n = 74), AML-PPGLBC 98 (1998–2004, n = 151), AML-BFM 2004 Interim (2004–2015, n = 356), and AML-BFM 2012 (2015–2019, n = 131). Results: The probability of three-year overall survival was 0.34 ± 0.03, 0.37 ± 0.05, 0.54 ± 0.04, 0.67 ± 0.03, and 0.75 ± 0.05; event-free survival was 0.31 ± 0.03, 0.34 ± 0.05, 0.44 ± 0.04, 0.53 ± 0.03, and 0.67 ± 0.05; and relapse-free survival was 0.52 ± 0.03, 0.65 ± 0.05, 0.58 ± 0.04, 0.66 ± 0.03, and 0.78 ± 0.05, respectively, in the subsequent periods. A systematic reduction of early deaths and deaths in remission was achieved, while the percentage of relapses decreased only in the last therapeutic period. Surprisingly good results were obtained in the group of patients treated with AML-BFM 2012 with unfavorable genetic abnormalities like KMT2A-MLLT10/t(10;11)(p12;q23) and DEK-NUP214/t(6;9)(p23;q24), while unsatisfactory outcomes were found in the patients with FLT3-ITD. Conclusions: The use of standardized, systematically modified therapeutic protocols, with the successive consideration of genetic prognostic factors, and advances in supportive care led to a significant improvement in AML treatment outcomes over the last 40 years.

Detection of Novel Pathogenic Gene Rearrangements in Pediatric Acute Myeloid Leukemia By RNA Sequencing

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2575-2575
Author(s):  
Norio Shiba ◽  
Kenichi Yoshida ◽  
Yuichi Shiraishi ◽  
Yusuke Hara ◽  
Genki Yamato ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Rna Sequencing ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Gene Rearrangements ◽  
Pediatric Leukemia ◽  
Pediatric Acute Myeloid Leukemia ◽  
Recurrent Mutations ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Background Pediatric acute myeloid leukemia (AML) comprises approximately 20% of pediatric leukemia cases. AML is a major therapeutic challenge in pediatric oncology, and the current overall survival rate is <70%. The pathogenesis of AML is heterogeneous, and causes include various chromosomal aberrations, gene mutations/epigenetic modifications, and deregulated/overregulated gene expression, resulting in increased proliferation and decreased hematopoietic progenitor cell differentiation. Recurrent chromosomal structural aberrations such as t(8;21), inv(16), and MLL -rearrangements are well established as diagnostic and prognostic markers in AML. Furthermore, recurrent mutations in FLT3, KIT, and RAS have been reported in both adult and pediatric AML. Recently, massively parallel sequencing has facilitated the discovery of recurrent mutations in DNMT3A, TET2, and IDH, which are clinically useful for predicting the prognosis. However, these mutations are rare in pediatric AML, thereby suggesting that other genetic alterations may exist in pediatric AML. In addition, recent studies have reported that the NUP98-NSD1 fusion is an adverse AML prognostic marker and that PRDM16 (also termed MEL1) is a representative gene that is overexpressed in patients who have the NUP98-NSD1 fusion. PRDM16 overexpression occurs in nearly a quarter of pediatric AML patients who are NUP98-NSD1 negative, and this overexpression is increased in specimens with other high-risk lesions (e.g., FLT3-ITD, NUP98-NSD1,and MLL-PTD). Patients and Methods To obtain a complete overview of gene rearrangements and other genetic lesions, we performed RNA sequencing of samples from 47 de novo pediatric AML patients using Illumina HiSeq 2000, including 39 patients with normal karyotypes and 6 patients with Trisomy 8. Among these 47 patients, 35 patients overexpressed PRDM16, which was strongly associated with a poor prognosis in our previous studies. As a control, we selected 12 patients with low PRDM16 expression levels. All patients were enrolled and treated as part of the AML-05 study conducted by the Japan Pediatric Leukemia/Lymphoma Study Group. We determined the known gene mutations present in these patients using the RNA sequencing data. Results Approximately 300 candidate gene rearrangements were identified in 46/47 samples, including 26 in-frame and 78 out-of-frame gene rearrangements. Several recurrent gene rearrangements identified in this study involved previously reported targets in AML, such as FUS-ERG, NUP98-NSD1,and MLL-MLLT3. However, several novel gene rearrangements were identified in the current study, including HOXA10-HOXA-AS3, PRDM16-XXX, CUL1-YYY, and DAZAP1-ZZZ. At present, we are validating these novel gene rearrangements using Sanger sequencing. Known gene alterations, such as FLT3-ITD, MLL-PTD, and mutations of RAS, KIT, CEBPA, WT1, and NPM1 genes, were detected by RNA sequencing. Conclusion In the present study, RNA sequencing was employed to elucidate the complexity of gene rearrangements/mutations in pediatric AML genomes. Our results indicate that a subset of pediatric AML represents a discrete entity that can be discriminated from adult AML in terms of the spectrum of gene rearrangements/mutations. We identified at least one potential gene rearrangement or driver mutation in nearly all AML samples, including various novel fusion genes. Thus, our results suggest that gene rearrangements and mutations play essential roles in pediatric AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals An Immune Checkpoint-Related Gene Signature for Predicting Survival of Pediatric Acute Myeloid Leukemia

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Feng Jiang ◽  
Xin-Yu Wang ◽  
Ming-Yan Wang ◽  
Yan Mao ◽  
Xiao-Lin Miao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Immune Checkpoint ◽  
Myeloid Leukemia ◽  
Immune Cell ◽  
Cox Regression ◽  
Secondary Data ◽  
Gene Signature ◽  
Pediatric Acute Myeloid Leukemia ◽  
Pediatric Aml ◽  
Acute Myeloid

Objective. The aim of this research was to create a new genetic signature of immune checkpoint-associated genes as a prognostic method for pediatric acute myeloid leukemia (AML). Methods. Transcriptome profiles and clinical follow-up details were obtained in Therapeutically Applicable Research to Generate Effective Treatments (TARGET), a database of pediatric tumors. Secondary data was collected from the Gene Expression Omnibus (GEO) to test the observations. In univariate Cox regression and multivariate Cox regression studies, the expression of immune checkpoint-related genes was studied. A three-mRNA signature was developed for predicting pediatric AML patient survival. Furthermore, the GEO cohort was used to confirm the reliability. A bioinformatics method was utilized to identify the diagnostic and prognostic value. Results. A three-gene (STAT1, BATF, EML4) signature was developed to identify patients into two danger categories depending on their OS. A multivariate regression study showed that the immune checkpoint-related signature (STAT1, BATF, EML4) was an independent indicator of pediatric AML. By immune cell subtypes analyses, the signature was correlated with multiple subtypes of immune cells. Conclusion. In summary, our three-gene signature can be a useful tool to predict the OS in AML patients.

scholarly journals MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia

2017 ◽  
Vol 35 (35) ◽  
pp. 3964-3977 ◽  
Author(s):  
Emilia L. Lim ◽  
Diane L. Trinh ◽  
Rhonda E. Ries ◽  
Jim Wang ◽  
Robert B. Gerbing ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Oxidative Phosphorylation ◽  
Treatment Failure ◽  
Myeloid Leukemia ◽  
Outcome Prediction ◽  
Classification Scheme ◽  
Event Free Survival ◽  
Free Survival ◽  
Pediatric Aml ◽  
Acute Myeloid

Purpose Children with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction. Patients and Methods To identify miRNA biomarkers that are associated with treatment failure, we performed a comprehensive sequence-based characterization of the pediatric AML miRNA landscape. miRNA sequencing was performed on 1,362 samples—1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples—127 primary and 37 relapse samples—were analyzed by using RNA sequencing. Results By using penalized lasso Cox proportional hazards regression, we identified 36 miRNAs the expression levels at diagnosis of which were highly associated with event-free survival. Combined expression of the 36 miRNAs was used to create a novel miRNA-based risk classification scheme (AMLmiR36). This new miRNA-based risk classifier identifies those patients who are at high risk (hazard ratio, 2.830; P ≤ .001) or low risk (hazard ratio, 0.323; P ≤ .001) of experiencing treatment failure, independent of conventional karyotype or mutation status. The performance of AMLmiR36 was independently assessed by using 878 patients from two different clinical trials (AAML0531 and AAML1031). Our analysis also revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples, and several candidate targets of miR-106a-5p were involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells. Conclusion To assess the utility of miRNAs for outcome prediction in patients with pediatric AML, we designed and validated a miRNA-based risk classification scheme. We also hypothesized that the abundant expression of miR-106a could increase treatment resistance via modulation of genes that are involved in oxidative phosphorylation.

Acute Differentiated Dendritic Cell Leukemia: A New Form of Pediatric Acute Myeloid Leukemia (AML) with MLL Translocations.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3263-3263
Author(s):  
Luca Lo Nigro ◽  
Laura Sainati ◽  
Anna Leszl ◽  
Elena Mirabile ◽  
Monica Spinelli ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Myeloid Leukemia ◽  
Fusion Transcript ◽  
Fish Analysis ◽  
Rt Pcr ◽  
Pediatric Acute Myeloid Leukemia ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Background: Myelomonocytic precursors from acute or chronic leukemias can differentiate to dendritic cells in vitro, but leukemias with a dendritic cell immunophenotype are rare, have been reported mainly in adults, and their molecular pathogenesis is unknown. Dendritic cells are classified as Langherans, myeloid and lymphoid/plasmacytoid cells, but leukemias arising from dendritic cells are unclassified in the FAB system. We identified a new entity of pediatric acute myeloid leukemia (AML) presenting with morphologic and immunophenotypic features of mature dendritic cells, which is characterized by MLL gene translocation. Methods and Results: Standard methods were used to characterize the morphology, immunophenotype, karyotype and MLL translocations in 3 cases of pediatric AML. The patients included two boys and one girl diagnosed with AML between 1–6 years old. Their clinical histories and findings included fever, pallor, abdominal and joint pain, adenopathy, hepatosplenomegaly, normal WBC counts but anemia and thrombocytopenia. and no evidence of CNS disease. The bone marrow aspirates were hypocellular and replaced completely by large blasts with irregular nuclei, slightly basophilic cytoplasm, and prominent cytoplasmic projections. There were no cytoplasmatic granules or phagocytosis. Myeloperoxidase and alpha napthyl esterase reactions were negative, excluding FAB M5 AML, and the morphology was not consistent with any standard FAB morphologic diagnosis. The leukemic blasts in all three cases were CD83+, CD86+, CD116+, consistent with differentiated myeloid dendritic cells, and did not express CD34, CD56 or CD117. MLL translocations were identified in all 3 cases. In the first case FISH analysis showed t(10;11)(p12;q23) and RT-PCR identified and a ‘5-MLL-AF10-3’ fusion transcript. In the second case FISH analysis showed t(9;11)(p22;q23) and RT-PCR identified and a ‘5-MLL-AF9-3’ fusion transcript. In the remaining case, the MLL gene rearrangement was identified by Southern blot analysis and RT-PCR showed an MLL-AF9 fusion transcript. The fusion transcripts in all 3 cases were in-frame. Remission induction was achieved with intensive chemotherapy, and all three patients have remained in durable remission for 30–60 months after hematopoietic stem cell transplantation. Conclusions. We have characterized a new pediatric AML entity with features of mature dendritic cells, MLL translocation and an apparently favorable prognosis. The in-frame MLL fusion transcripts suggest that chimeric MLL oncoproteins underlie its pathogenesis. The partner genes in all 3 cases were known partner genes of MLL that encode transcription factors. This study increases the spectrum of leukemias with MLL translocations. Comprehensive morphological, immunophenotypic, cytogenetic and molecular analyses are critical for this diagnosis, and will reveal its frequency and spectrum as additional cases are uncovered.

NADH Dehydrogenase Subunit 4 (ND4) Mutations in Pediatric Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1380-1380
Author(s):  
Michael A Morgan ◽  
Birgit Markus ◽  
Malou Hermkens ◽  
Frederik Damm ◽  
Katarina Reinhardt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Nadh Dehydrogenase ◽  
Survival Advantage ◽  
Nadh Dehydrogenase Subunit ◽  
Pediatric Leukemia ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 1380 NADH dehydrogenase subunit 4 (ND4) is encoded by mitochondrial DNA and is an integral component of Complex I, one of the core enzymatic complexes critical for mitochondrial oxidative phosphorylation and regulation of the balance between NADH and NAD+. ND4 mutations have recently been described in adult acute myeloid leukemia (AML). In the current study, we investigated the frequency and prognostic impact of ND4 mutations in 289 pediatric leukemia patients (&lt;= 18 years). Total cellular DNA was isolated from bone marrow or peripheral blood samples at diagnosis (n=289) and at complete remission (n=6) for children treated uniformly within multicenter treatment trials AML-Berlin-Frankfurt-Münster (BFM, n=180) and Dutch Childhood Oncology Group (DCOG, n=109). ND4 mutations were detected by direct sequencing in 13 of 289 (4.5 %) pediatric AML patients. Mutations occurred throughout the ND4 sequence, and included missense mutations (n=10), deletions (n=2) and a nonsense mutation. The most commonly detected mutations were S86N (n=2), delA 11,032–11,038 (n=2), and F50L (n=2). All other mutations were detected in single cases. Four (30.8 %) ND4 mutations were heteroplasmic (i.e. both wild-type and mutated ND4 were detected) and 9 (69.2 %) were homoplasmic (i.e. only mutated ND4 was detected), which is similar to the distribution we previously observed for adult AML patients (37.9% and 62.1%, respectively). Of the 4 heteroplasmic mutations detected in the pediatric AML cohort, 3 are predicted to result in a truncated ND4 protein. The remaining heteroplasmic mutation, which results in an L72P substitution, is predicted to be damaging (PolyPhen2 score = 0.999). Thus all 4 heteroplasmic mutations are expected to interfere with ND4 protein function. In contrast, 3 of the 9 (33.3 %) homoplasmic mutations are within transmembrane regions and only 1 (11.1 %) is predicted to be damaging (S459Y, PolyPhen2 score = 0.906). The 11 predicted transmembrane domains (TMD) of ND4 may be important for mitochondrial proton transport. However, like in adult AML, the presence of ND4 mutations affecting or not affecting a TMD had no impact on pediatric AML patient outcome. Non-tumoral DNA available through samples collected in routine follow-up examinations during complete remission allowed determination of mutation origin (e.g. somatic or germ-line) in 6 cases. Interestingly, the homoplasmic substitutions resulting in F50L, S86N and A131T were each defined to be germline mutations in both adult and pediatric AML samples. The heteroplasmic one base-pair deletion in a stretch of seven adenine residues (11,032–11,038) detected in two pediatric leukemia samples was determined to be somatic in the one case for whom a sample obtained during complete remission was available for analyses. Patient characteristics including age, FAB-subtype, WBC count, cytogenetic subgroup or presence of FLT3-ITD were similar regardless of ND4 mutation status. In accordance with our earlier observations in adult AML, comparison of ND4mutated with ND4wildtype patients demonstrated no significant difference on overall survival (OS, P=.67). In the adult study, a survival advantage was observed for patients with somatic heteroplasmic ND4 mutations. No survival advantage was observed for children with heteroplasmic ND4 mutations, possibly due to limited numbers of ND4mutated patients treated in the BFM and DCOG study groups. Gene expression profiles (GEP) for ND4mutated (n=11) and ND4wild-type (n=188) pediatric AML patients revealed no significant differences. However, 8 probe sets were found to be differentially regulated when GEP for heteroplasmic ND4mutated (n=4) and ND4wildtype (n=187) were compared. Two of these probe sets annotated the SETDB2 (CLLD8, KMT1F) gene, which encodes a histone H3 methyltransferase. Quantitative RT-PCR validated the lower SETDB2 expression as a characteristic of ND4mutated cases (P=.02). SETDB2 contributes to several important cellular functions, including heterochromatin formation, chromatin condensation and transcriptional repression. In summary, ND4 mutations were not predictive for outcome in pediatric AML, but were significantly associated with decreased SETDB2 expression, providing a link between mitochondrial gene mutation and epigenetic control of gene expression. Disclosures: No relevant conflicts of interest to declare.

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