[Show abstract][Hide abstract] ABSTRACT: Purpose:
This retrospective cohort study aimed to determine the predictive relevance of clinical characteristics, additional cytogenetic aberrations, and cKIT and RAS mutations, as well as to evaluate whether specific treatment elements were associated with outcomes in pediatric t(8;21)-positive patients with acute myeloid leukemia (AML).
Patients and methods:
Karyotypes of 916 pediatric patients with t(8;21)-AML were reviewed for the presence of additional cytogenetic aberrations, and 228 samples were screened for presence of cKIT and RAS mutations. Multivariable regression models were used to assess the relevance of anthracyclines, cytarabine, and etoposide during induction and overall treatment. End points were the probability of achieving complete remission, cumulative incidence of relapse (CIR), probability of event-free survival, and probability of overall survival.
Of 838 patients included in final analyses, 92% achieved complete remission. The 5-year overall survival, event-free survival, and CIR were 74%, 58%, and 26%, respectively. cKIT mutations and RAS mutations were not significantly associated with outcome. Patients with deletions of chromosome arm 9q [del(9q); n = 104] had a lower probability of complete remission (P = .01). Gain of chromosome 4 (+4; n = 21) was associated with inferior CIR and survival (P < .01). Anthracycline doses greater than 150 mg/m(2) and etoposide doses greater than 500 mg/m(2) in the first induction course and high-dose cytarabine 3 g/m(2) during induction were associated with better outcomes on various end points. Cumulative doses of cytarabine greater than 30 g/m(2) and etoposide greater than 1,500 mg/m(2) were associated with lower CIR rates and better probability of event-free survival.
Pediatric patients with t(8;21)-AML and additional del(9q) or additional +4 might not be considered at good risk. Patients with t(8;21)-AML likely benefit from protocols that have high doses of anthracyclines, etoposide, and cytarabine during induction, as well as from protocols comprising cumulative high doses of cytarabine and etoposide.
Journal of Clinical Oncology 11/2015; DOI:10.1200/JCO.2015.61.1947 · 18.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL.
Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude Children's Research Hospital front-line ALL trials. Patients were included in this study on the basis of their enrolment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterised bioinformatically and correlated with clinical and demographic features in children with ALL.
We identified a novel non-sense ETV6 variant (p.Arg359X) with a high penetrance in an index family. Subsequent targeted sequencing of ETV6 in 4405 childhood ALL cases identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1%). 15 (48%) of 31 ALL-related ETV6 variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukaemia diagnosis than those without (10·2 years [IQR 5·3-13·8] vs 4·7 years [3·0-8·7]; p=0·017). The hyperdiploid leukaemia karyotype was highly over-represented in ALL cases harbouring germline ETV6 risk variants compared with the wild-type group (nine [64%] of 14 cases vs 538 [27%] of 2007 cases; p=0·0050).
Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants are needed.
US National Institutes of Health and American Lebanese Syrian Associated Charities.
The Lancet Oncology 11/2015; DOI:10.1016/S1470-2045(15)00369-1 · 24.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite initial remission, approximately 60-70% of adult and 30% of pediatric patients experience relapse or refractory AML. Studies so far have identified base line gene expression profiles of pathogenic and prognostic significance in AML, however extent of change in gene expression post-initiation of treatment has not been investigated. Exposure of leukemic cells to chemotherapeutic agents such as cytarabine, a mainstay of AML chemotherapy can trigger adaptive response by influencing leukemic cell transcriptome and hence development of resistance or refractory disease. It is however challenging to perform such a study due to lack of availability of specimens post-drug treatment. In this study our primary objective was to identify in vivo cytarabine induced changes in leukemia cell transcriptome and to evaluate their impact on clinical outcome. Our results highlight genes relevant to cytarabine resistance and support the concept of targeting cytarabine-induced genes as a means of improving response.
[Show abstract][Hide abstract] ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2015; DOI:10.1038/leu.2015.171 · 10.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Copy number alterations (CNAs) are a hallmark of pediatric cancer genomes. An increasing number of research groups use multiple platforms and software packages to detect and analyze CNAs. However, different platforms have experimental and analysis-specific biases that may yield different results. We sought to estimate the concordance of CNAs in children with de novo acute myeloid leukemia between two experimental platforms: Affymetrix SNP 6.0 array and Illumina OmniQuad 2.5 BeadChip. Forty-five paired tumor-remission samples were genotyped on both platforms, and CNAs were estimated from total signal intensity and allelic contrast values using the allele-specific copy number analysis of tumors (ASCAT) algorithm. The two platforms were comparable in detection of CNAs, each missing only two segments from a total of 42 CNAs (4.6%). Overall, there was an interplatform agreement of 96% for allele-specific tumor profiles. However, poor quality samples with low signal/noise ratios showed a high rate of false-positive segments independent of the genotyping platform. These results demonstrate that a common analytic pipeline can be utilized for SNP array data from these two platforms. The customized programming template for the preprocessing, data integration, and analysis is publicly available at https://github.com/AplenCHOP/affyLumCNA.
Published by Elsevier Inc.
Cancer Genetics 05/2015; 208(7-8). DOI:10.1016/j.cancergen.2015.04.010 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification.
Patients and methods:
Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children’s Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three).
There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v. 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P.04) but not OS (3 years: 69.4% v. 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v. 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v. 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v. 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v. 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07).
GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.
[Show abstract][Hide abstract] ABSTRACT: Despite remarkable advances in the genomic characterization of adult melanoma, the molecular pathogenesis of pediatric melanoma remains largely unknown. We analyzed 15 conventional melanomas (CM), 3 melanomas arising in congenital nevi (CNM), and 5 spitzoid melanomas (SM), using various platforms, including whole genome or exome sequencing, molecular inversion probe assay, and/or targeted sequencing. CM demonstrated a high burden of somatic single nucleotide variations (SNV), with each case containing a TERT promoter (TERT-p) mutation, 13/15 containing an activating BRAF V600 mutation, and >80% of the identified SNV consistent with UV damage. By contrast, the 3 CNM contained an activating NRAS Q61 mutation and no TERT-p mutations. SM were characterized by chromosomal rearrangements resulting in activated kinase signaling in 40%, and an absence of TERT-p mutations except for the one SM that succumbed to hematogenous metastasis. We conclude that pediatric CM has a very similar UV-induced mutational spectrum to that found in the adult counterpart, emphasizing the need to promote sun protection practices in early life and to improve access to therapeutic agents being explored in adults in young patients. By contrast, the pathogenesis of CNM appears to be distinct. TERT-p mutations may identify the rare subset of spitzoid melanocytic lesions prone to disseminate.
[Show abstract][Hide abstract] ABSTRACT: Rhabdoid tumors (RT) are highly aggressive malignant neoplasms of early childhood that arise in the kidney, brain, and extrarenal sites. The disease is genetically defined by biallelic disruption of the SMARCB1/INI1/SNF5 tumor suppressor gene, a core component of the ATP-dependent chromatin remodeling SWI/SNF complex. The molecular changes leading to SMARCB1 alterations in RT are heterogeneous, including germline or constitutional inactivating mutations, partial or total gene deletions, copy number neutral loss of heterozygosity, and less commonly reciprocal translocations. We report a novel three-way chromosomal rearrangement, identified by conventional cytogenetic and sequential fluorescence in situ hybridization studies, as the underlying molecular mechanism of the loss of SMARCB1 in an extrarenal RT. This case highlights the heterogeneity of genetic events that may lead to loss of SMARCB1 and the development of RT.
Cancer Genetics 08/2014; 207(9). DOI:10.1016/j.cancergen.2014.08.002 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: NUP98/NSD1 has recently been reported in association with poor outcome in acute myeloid leukemia (AML). Previous studies also observed a high-overlap between NUP98/NSD1 and FLT3/ITD, raising the question as to whether the reported poor outcome is due to NUP98/NSD1, or caused by the co-occurrence of these two genetic lesions. We aimed to determine the prognostic significance of NUP98/NSD1 in the context of FLT3/ITD AML. A total of 1421 patients enrolled in five consecutive COG/CCG and SWOG trials were evaluated. NUP98/NSD1 was found in 15% of FLT3/ITD and 7% of cytogenetically normal (CN-) AML. Those with dual FLT3/ITD and NUP98/NSD1 (82% of NUP98/NSD1 patients) had a complete remission (CR) rate of 27% versus 69% in FLT3/ITD without NUP98/NSD1 (P<0.001). The corresponding 3-year OS was 31% versus 48% (P=0.011), respectively. In CN-AML, patients with concomitant NUP98/NSD1 and FLT3/ITD had worse outcome than those harboring NUP98/NSD1 only. In multivariate analysis accounting for other known prognostic factors, the dual NUP98/NSD1 and FLT3/ITD remained an independent predictor of poor outcome and NUP98/NSD1 without FLT3/ITD lost its prognostic significance. Our study demonstrates for the first time that it is the interaction between NUP98/NSD1 and FLT3/ITD that determines the poor outcome of patients with NUP98/NSD1 disease.
[Show abstract][Hide abstract] ABSTRACT: Minimal residual disease (MRD) is a strong prognostic factor in children and adolescents with acute myeloid leukaemia (AML) but nearly one-quarter of patients who achieve MRD-negative status still relapse. The adverse prognostic factors among MRD-negative patients remain unknown. We analysed the AML02 study cohort to identify demographic and genetic prognostic factors. Among the presenting features, certain 11q23 abnormalities, such as t(6;11) and t(10;11), acute megakaryoblastic leukaemia without the t(1;22), and age ≥10 years were associated with inferior outcome in patients who had MRD-negative status after either remission induction I or II. By contrast, those with rearrangement of CBF genes had superior outcome. Our study identifies patient populations for whom close post-remission MRD monitoring to detect and treat emerging relapse and adjustment in treatment intensity might be indicated.
British Journal of Haematology 08/2014; 168(1). DOI:10.1111/bjh.13107 · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
BCR-ABL1–like acute lymphoblastic leukemia (ALL) is a recently identified B-cell ALL (B-ALL)subtype with poor outcome that exhibits a gene expression profile similar to BCR-ABL1-positive ALL but lacks the BCR-ABL1 fusion protein. We examined the outcome of children with BCR-ABL1–like ALL treated with risk-directed therapy based on minimal residual disease (MRD) levels during remission induction.
Patients and methods:
Among 422 patients with B-ALL enrolled onto the Total Therapy XV study between 2000 and 2007, 344 had adequate samples for gene expression profiling. Next-generation sequencing and/or analysis of genes known to be altered in B-ALL were performed in patients with BCR-ABL1–likeALL who had available material. Outcome was compared between patients with and those without BCR-ABL1–like ALL.
Forty (11.6%) of the 344 patients had BCR-ABL1–like ALL. They were significantly more likely to be male, have Down syndrome, and have higher MRD levels on day 19 and at the end of induction than did other patients with B-ALL. Among 25 patients comprehensively studied for genetic abnormalities, 11 harbored a genomic rearrangement of CRLF2, six had fusion transcripts responsive to ABL tyrosine kinase inhibitors or JAK inhibitors, and seven had mutations involving the Ras signaling pathway. There were no significant differences in event-free survival (90.0% +/- 4.7% [SE] v. 88.4% +/- .9% at 5 years; P = .41or in overall survival (92.5% +/- 4.2% v. 95.1% +/- 1.3% at 5 years; P = .41) between patients with and without BCR-ABL1–like ALL.
Patients who have BCR-ABL1–like ALL with poor initial treatment response can be salvaged with MRD-based risk-directed therapy and may benefit from identification of kinase-activating lesions for targeted therapies.
[Show abstract][Hide abstract] ABSTRACT: With improved contemporary therapy, we re-assess long-term outcome in patients completing treatment for childhood acute lymphoblastic leukemia to determine when cure can be declared with a high degree of confidence. In 6 successive clinical trials between 1984 and 2007, 1291(84.5%) patients completed all therapy in continuous complete remission. The post-therapy cumulative risk of relapse or development of a second neoplasm and the event-free survival rate and overall survival were analyzed according to the presenting features and the three treatment periods defined by relative outcome. Over the three treatment periods, there has been progressive increase in the rate of event-free survival (65.2% vs 74.8% vs 85.1% [P<0.001]) and overall survival (76.5% vs 81.1% vs 91.7% [P<0.001]) at 10 years. The most important predictor of outcome after completion of therapy was the type of treatment. In the most recent treatment period, which omitted the use of prophylactic cranial irradiation, the post-treatment cumulative risk of relapse was 6.4%, death in remission 1.5%, and development of a second neoplasm 2.3% at 10 years, with all relapses except one occurring within 4 years off therapy. None of the 106 patients with the t(9;22)/BCR-ABL1, t(1;19)/TCF3-PBX1 or t(4;11)/MLL-AFF1 had relapsed after 2 years from completion of therapy. These findings demonstrate that with contemporary effective therapy that excludes cranial irradiation, approximately 6% of children with acute lymphoblastic leukemia may relapse after completion of treatment, and those who remain in remission at 4 years post-treatment may be considered cured (i.e., less than 1% chance of relapse).Leukemia accepted article preview online, 30 April 2014; doi:10.1038/leu.2014.142.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2014; 28(12). DOI:10.1038/leu.2014.142 · 10.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is a rare subtype associated with FLT3-internal tandem duplication (ITD) and poor outcomes. The clinical outcomes of paediatric patients with t(6;9) with and without FLT3-ITD treated on six consecutive cooperative trails were evaluated. In contrast to patients without t(6;9), those with t(6;9) had a significantly lower complete remission rate, higher relapse rate (RR), and poor overall survival (OS). Within t(6;9) patients, those with and without FLT3-ITD had an OS of 40% and 27% respectively (P > 0·9), demonstrating that t(6;9) is a high-risk cytogenetic feature in paediatric AML and its clinical impact is independent of the presence of FLT3-ITD.
British Journal of Haematology 03/2014; 166(2). DOI:10.1111/bjh.12852 · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Deregulated cytokine signaling is a characteristic feature of acute myeloid leukemia (AML), and expression signatures of cytokines and chemokines have been identified as significant prognostic factor in this disease. Given this aberrant signaling, we hypothesized that expression of Suppressor of Cytokine Signaling-2 (SOCS2), a negative regulator of cytokine signaling, might be altered in AML and could provide predictive information. Among 188 participants of the Children's Oncology Group AAML03P1 trial, SOCS2 mRNA levels varied >6,000-fold. Higher (>median) SOCS2 expression was associated with inferior overall (60±10% vs. 75±9%, p=0.026) and event-free (44±10% vs. 59±10%, p=0.031) survival. However, these differences were accounted for by higher prevalence of high-risk and lower prevalence of low-risk disease among patients with higher SOCS2 expression, limiting the clinical utility of SOCS2 as predictive marker. It remains untested whether high SOCS2 expression identifies a subset of leukemias with deregulated cytokine signaling that could be amenable to therapeutic intervention.