scholarly journals Pediatric Acute Megakaryoblastic Leukemia without Down Syndrome: A Retrospective Study by the International Berlin-Frankfurt-Munster Study Group (I-BFMSG)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3670-3670
Author(s):  
Hiroto Inaba ◽  
Yinmei Zhou ◽  
Oussama Abla ◽  
Souichi Adachi ◽  
Anne Auvrignon ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Retrospective Study ◽  
Large Scale ◽  
Conflicts Of Interest ◽  
Central Nervous System Involvement ◽  
Acute Megakaryoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Megakaryoblastic Leukemia ◽  
Group I ◽  
Significant Difference

Abstract Acute megakaryoblastic leukemia (AMKL) comprises up to 10% of childhood acute myeloid leukemia (AML) cases. However, no large-scale studies have comprehensively evaluated the clinical characteristics and outcomes of patients with AMKL. We performed a large-scale international retrospective study of pediatric patients (diagnosed at age ≤18 years) with de novoAMKL without Down syndrome treated from 1989 to 2009. The study included 490 patients with AMKL, which comprises 7.9% of the pediatric AML patients treated by 19 members of the I-BFMSG. At diagnosis, the median age of patients was 1.5 years (range, 0.0–16.5 years), median white blood cell count was 12.0×109/L (range, 0.6–188.0×109/L), 23 (4.7%) patients showed central nervous system involvement, and both sexes were equally represented. Complete remission (CR) was achieved in 417 (85.1%) patients, and 5-year event-free (EFS) and overall survival (OS) rates were 43.7%±2.7% and 49.0%±2.7%, respectively. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in 206 (42.0%) patients. The 5-year disease-free survival and OS rates for patients who received allo-HSCT in first CR (n=112, 56.3%±5.2%, and 57.7%±5.2%, respectively) and for those who did not receive transplantation in first CR (n=298, 50.2%±3.6% and 55.2%±3.5%) were not significantly different (P=0.12 and P=0.57). Complete cytogenetic data were available for 372 (75.9%) patients: diploid (n=49, 13.2%), hypodiploid (n=18, 4.8%), pseudodiploid (n=119, 32.0%), 47–50 chromosomes (n=142, 38.2%), and >50 chromosomes (n=44, 11.8%). Chromosome gain occurred in 195 (52.4%) patients: +21 was the most common (n=106, 28.5%), followed by +19 (n=93, 25.0%), and +8 (n=77, 20.7%). Losses occurred in 65 cases (17.5%), in the decreasing order of –7 (n=13, 3.5%), –9 (n=9, 2.4%), –13, and –15 (n=7 each, 1.9%). Structural chromosomal aberrations were observed in 278 (74.7%) patients, most commonly t(1;22) (n=51, 13.7%) and 11q23 rearrangements (n=38, 10.2%) with t(9;11) in 21 patients. Other abnormalities included 7p (n=43, 11.6%) and 13q (n=31, 8.3%; 16 with deletions) breakpoints. Patients with t(1;22) were significantly younger at diagnosis (P<0.001; median 0.6 years, range 0.0–6.3 years) and more often female (P=0.05; 64.7%) while those with –7 were significantly older (P=0.006; median 4.2 years, range 0.4–15.0 years) than those with other cytogenetic subgroups. Multiple regression analysis for EFS and OS with clinical and cytogenetic features showed that treatment period (1989–1999 vs. 2000–2009), normal cytogenetics, –7, t(9;11), 13q-, and –15 were associated with significantly worse outcomes than those for other subgroups, whereas abnormalities in 7p were associated with better outcomes (Table). Patients with –13 and 9p abnormalities other than t(9;11) had a poorer EFS and OS, respectively. Patients with +21 or t(1;22) did not show a significant difference in survival rates. This international study on the largest cohort of AMKL patients analyzed to date shows heterogeneity in cytogenetic findings and identifies some subgroups with a particularly dismal outcome. The advent of newer methods to evaluate genetic lesions can help identify therapeutic targets for improving the outcome in this subgroup of patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Intensification of Early-Phase Therapy to Diminish the Prognostic Effect of Myeloid Antigen Expression in Infants with KMT2A-Rearranged Acute Lymphoblastic Leukemia: A Report from the JPLSG MLL-10 Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2384-2384
Author(s):  
Yuki Arakawa ◽  
Takashi Ishihara ◽  
Takako Miyamura ◽  
Takao Deguchi ◽  
Masashi Sanada ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Early Phase ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Age Distribution ◽  
Central Nervous System Involvement ◽  
High Dose ◽  
Pediatric Leukemia ◽  
Hematopoietic Stem ◽  
Significant Difference

Abstract Background KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) is a rare and dismal disease in infants. Despite restriction of the indication of allogeneic hematopoietic stem cell transplantation to the high-risk group (patients aged &lt;180 days with KMT2A-r ALL or central nervous system involvement), adoption of an Interfant-06-based induction therapy with stricter age-related dosing followed by COG AALL0631-based post-remission chemotherapy with additional administration of high-dose cytarabine in the early intensification phase led to rapid clearance of minimal residual disease (MRD) in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) MLL-10 trial. The MLL-10 trial demonstrated an improved outcome of 66.2% in 3-year event-free survival (EFS) among infants with KMT2A-r ALL (Tomizawa D. Blood 2021). As the Interfant-06 study showed an association between the expression levels of myeloid markers (MM) and poor MRD clearance at end of induction (EOI) and a high relapse rate (Stutterheim J, J Clin Oncol.2021), we analyzed the significance of MM expression in the MLL-10 cohort and its association with prognosis. Methods We analyzed and compared the MM expression (defined as at least one positive marker [with a positive blast subset ≥ 10%] among CD117, CD13, CD33, and CD65/CD15) by using flow cytometry (FCM) in infants with KMT2A-r ALL who were registered in the JPLSG MLL-10 trial. We also compared the results of immunoglobulin/T-cell receptor (Ig/TCR) gene-based polymerase chain reaction (PCR)-MRD analyses or 4-color FCM-MRD assay between the MM-positive and MM-negative groups at EOI and end of early consolidation. The Ig/TCR-MRD results were classified as negative if &lt;5 × 10 −4 and positive if ≥5 × 10 −4, while the FCM-MRD results were classified as negative if &lt;0.01% and positive if ≥0.01%. We prioritized PCR-MRD and used FCM-MRD when we could not make a primer for PCR-MRD. The presence of MRD was not used as a basis for choosing the appropriate therapy. Results and Discussion Among the patients with KMT2A-rALL, 74 were included in this study, excluding one who was not evaluated with FCM at diagnosis. Of these patients, 42 were MM-positive and 32 were MM-negative. The 3-year EFS rates of the MM-positive and MM-negative patients were 62.3% (95% confidence interval [CI], 45.5-75.3) and 70.0% (95% CI, 50.3-83.1), respectively (p = 0.61). Their 3-year overall survival rates were 80.6% (95% CI, 65.0-89.8) and 87.5% (95% CI, 70.0-95.1), respectively (p = 0.74). The numbers of MM-positive and MM-negative patients according to age group are summarized in Table 1, and the difference in age distribution between the two groups was not significant. The MRD statuses of the patients at EOI in the two groups are also summarized in Table 1. No significant difference in MRD clearance was found between the MM-positive and MM-negative groups. Conclusion In this study, we found no significant difference in survival rate between the MM-positive and MM-negative groups. The MM expression was not a prognostic marker in the infants with KMT2A-r ALL in the MLL-10 cohort. We believe that rapid MRD clearance in the early phase of treatment with enhanced chemotherapy would have the greatest contribution to the improvement of prognosis. In this study, the MM-positive patients from the MLL-10 cohort might have benefited from early-phase treatment intensification in terms of MRD clearance. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Epigenetically Enhanced MED12L in ETO2-GLIS2 Positive Pediatric Acute Megakaryoblastic Leukemia Is Associated with Resistance to the CDK8 Inhibitors

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2208-2208
Author(s):  
Samrat Roy Choudhury ◽  
Jordan T Bird ◽  
Stephanie Byrum ◽  
Dane Jester ◽  
Troy Davidson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Cell Viability ◽  
Conflicts Of Interest ◽  
Target Cells ◽  
Acute Megakaryoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Histone Marks ◽  
Megakaryoblastic Leukemia ◽  
Chip Sequencing

Abstract Introduction. ETO2-GLIS2 (aka CBFA2T3-GLIS2) is the most common (30%) alteration in pediatric de novo acute megakaryoblastic leukemia (AMKL). These patients have poor response to induction therapy, a high incidence of relapse (~90%), and dismal 5-year survival rates (&lt;20%). Previous studies suggest that ETO2-GLIS2 induces leukemia through abnormal enhancer formation as a single oncogenic "hit". Because ETO2-GLIS2 expression induces formation of leukemia-specific neo-superenhancer (SE) elements, we hypothesize that mediator (MED) proteins are involved in linking neo-SE elements to distal gene expression, and thus could be a therapeutic target. Here, we analyzed expression of MED-family genes in ETO2-GLIS2 positive AMKL patients in combination with enhancer-histone marks, and evaluated impact of MED-kinase inhibition with selective CDK8 inhibitors (CDKi) against cell viability. Methods. To address our hypothesis, we analyzed published RNA sequencing dataset (Smith et al. 2020) for human MED-genes expression from a pan-pediatric AML cohort (N=1476). The cohort consisted of subgroups expressing fusions of ETO2-GLIS2 (N=40), CBFB-MYH11 (N=174), DEK-NUP214 (N=49), KMT2A-ELL (N=50), KMT2A-MLLT10 (N=86), KMT2A-MLLT3 (N=114), KMT2A-MLLT4 (N=49), NUP98-NSD1 (N=107), RUNX1-RUNX1T1 (N=210) and no detectable fusions (N=526), compared to normal bone marrow (NBM) samples (N=71). Enrichment of histone marks overlapping MED-genes was analyzed from published chromatin immunoprecipitation (ChIP) sequencing in ETO2-GLIS2 positive M-07e AMKL line (Thirant et al. 2017). We tested efficacy of CDK8 inhibition with BI-1347 and CCT251545 against M-07e cells to determine their activity in the context of marked MED12L overexpression. Results. We examined expression of 29 MED-genes comprising the 4 major (head, middle, tail, and kinase) MED-modules. MED gene expression was variable across AML subtypes and NBM. However, MED genes were more commonly over-expressed in the ETO2-GLIS2 group, in particular MED 17, MED1, MED10, MED27, and MED12L (paralog of MED12) were upregulated in the subgroup. Most notably, we noted exceptional upregulation of MED12L (FC 4.9, log2), compared to NBM (Figure 1). Because MED12/12L plays an intrinsic biological role in establishing oncogenic enhancer-expression loops in hematopoietic stem or leukemic cells, we investigated the overlap of enhancer bound histones such as H3K27ac and H3K4me1 to MED12L in M-07e cells, compared to umbilical cord blood-derived normal megakaryoblasts (MK) (S004BT; Blueprint epigenome database). We found enrichment of H3K4me1 at MED12L transcription start site (TSS) and upstream promoter both in MK and M-07e cells. In addition, we observed a large region of H3K27ac enrichment spanning 89 Kb (16 kb upstream and 73 kb downstream) across MED12L TSS in M-07e cells, suggesting neo-enhancer activity at this locus. Considering the dependency of MED12 on CDK8 for MED-kinase activities (Klatt et al. 2020), we treated M-07e cells with CDK8i(s), to test our hypothesis if perturbation of epigenetically enhanced MED12L expression can impact leukemic growth. However, we observed a poor correlation between M-07e cell viability and IC 50 of BI-1347 (IC 50: 0.87 µM, R 2: 0.36) or CCT251545 (IC 50: 0.4 µM, R 2: 0.48). In contrast, ETO2-GLIS2 negative MV4-11 AML cells were susceptible to both BI-1347 (IC 50: 0.44 µM, R 2: 0.88) and CCT251545 (IC 50: 0.12 µM, R 2: 0.87). Given the inefficacy of CDK8i against M-07e, and cooperativity of bromodomain extra-terminal (BET)-BRD4 and MED12/12L in forming enhancer complexes, we tested possible inhibitory impact of BRD4 inhibitor JQ1 on MED12L expression and leukemic growth in target cells. We observed effective reduction in M-07e cell viability (IC 50:0.3 µM, R 2: 0.93) with concomitant reduction not only in BRD4 protein-expression, but diminished MED12L protein expression at IC 50 and higher doses of JQ1. Conclusion. Our findings revealed that MED12L is highly overexpressed and overlapped with strong neo-enhancer chromatin-marks in ETO2-GLIS2 positive cells, while maintaining resistance to CDK8i. Future studies will contribute to deeper insights into the preferential recruitment and role of MED12L in ETO2-GLIS2 bound enhancers and potential mechanisms of resistance to CDK8 inhibition in the disease. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Outcome and Prognostic Features in Pediatric Acute Megakaryoblastic Leukemia Without Down Syndrome

2020 ◽  
Author(s):  
Yu Wang ◽  
Aidong Lu ◽  
Yueping Jia ◽  
Yingxi Zuo ◽  
Jun Wu ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Prognostic Factors ◽  
Induction Therapy ◽  
Residual Disease ◽  
Univariate Analysis ◽  
Poor Response ◽  
Acute Megakaryoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Megakaryoblastic Leukemia ◽  
Prognostic Features

Abstract Background: Acute megakaryoblastic leukemia (AMKL) is a biologically heterogeneous subtype of acute myeloid leukemia (AML) that originates from megakaryocytes. Despite improvements in the accuracy of diagnosing AMKL as well as increased amount of data available on this rare subtype, clear prognostic factors and treatment recommendations remain undefined.Methods: We performed a retrospective study on 40 patients (age ≤18 years) with non–Down syndrome AMKL and assessed the effect of different prognostic factors on the outcomesResults: The complete remission (CR) rate of the patients was 57.9% and 81.1%, respectively, at the end of induction therapy Ⅰ and Ⅱ. The overall survival (OS) and event-free survival (EFS) rate at 2 years was 41±13% and 41±10%, respectively. An analysis of the cytogenetic features showed that patients with +21 or hyperdiploid (＞50 chromosomes) had significantly better OS than those in other cytogenetic subgroups (Plog-rank=0.048 and Plog-rank=0.040, respectively). Besides cytogenetics, an excellent early treatment response (CR and minimal residual disease＜1% after induction therapy Ⅰ) also provided a significant survival benefit in univariate analysis in our study. However, multivariate analysis indicated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) was the only independent prognostic marker (RR=11.192; 95 % CI, 2.045-61.241; P=0.005 for OS and RR=5.400; 95 % CI, 1.635-17.832; P=0.006 for EFS, respectively). Conclusion: AMKL in patients with non-Down syndrome has a poor outcome and allo-HSCT may be a better option for post-remission therapy than conventional chemotherapy especially for those having a poor response to induction therapy.

scholarly journals Acute Megakaryoblastic Leukemia in Childhood: Comparison Between Patients with and without Down Syndrome

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 952-952
Author(s):  
Maria Sara Felice ◽  
Jorge Gabriel Rossi ◽  
Marta Gallego ◽  
Cristina N. Alonso ◽  
Silvia Eandi Eberle ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Total Population ◽  
Conflicts Of Interest ◽  
P Value ◽  
Induction Phase ◽  
Acute Megakaryoblastic Leukemia ◽  
Megakaryoblastic Leukemia ◽  
Frequent Event ◽  
Wbc Count

Abstract Introduction: Acute Megakaryoblastic Leukemia (AMKL) is an unusual AML subtype in childhood, being the most frequent AML in Down syndrome (DS) patients. AMKL corresponds to 19.3% of AML in our Hospital and some special characteristics have been observed. Objective: To analyze characteristics of AMKL and to compare patients with or without DS. Patients and Methods:From January-1990 to June-2014 AMKL was diagnosed in 77 cases: 57 in non-DS and 20 in DS children. Fivecases were secondary leukemias and 3 cases had been previouslytreated with chemotherapy due to wrong diagnosis. One patient was on induction at the time of analysis. These 9 cases were not evaluable for follow-up. Forty-eight non-DS and 20 DS caseswere evaluable. Megakayocyte lineage commitment was confirmed in all cases by fluorescence microscopy. MPO was analyzedboth by flow cytometry and cytochemistry. G-banding and RT-PCR were performed according to standard techniques. Four successive BFM-based protocols were administeredwith schedule modification for DS patients. Results: Mean age was:2 (range: 2 mo-13 y) years of age and mean WBC count was: 27,500 (range: 1,600-250,000)/mm3. No differences were observed in age or hematological findings at diagnosis. Extramedullar compromise was detected in 10 (17.5%) of non-SD cases. Immunophenotype defined ambiguous lineage leukemia in 3 (5.0%) of the non-DS cases, with compromise of T-lineage. Interestingly, in 4 cases the megakaryoblasts also co-expressed MPO.Cytogenetic findings showed hyperdiploidy (n=7), t(1;22)(p13;q23) (n=3), t(16;21)/FUS-ERG (n=2), abnormalities in chromosome 7 (n=5) and complex karyotype (n=9). Complete remission (CR) was achieved in 51 (33 non-DS and 18 DS) (75.0%) of 68 evaluable cases;null-responses observed in7(only non-DS, 10.3%). Early deaths occurred in 10 (14.7%) during induction phase, 2 of them before treatment onset. From the 51 patients who achieved CR, 16 (14 non-DS and 2 DS) presented relapses(p: 0.04) and 9 (6 in non-DS and 3 in DS) died in CR. EFS-probability for the total population was 34 (6)%, for non-DS 21 (6)% and for DS 63 (11)%(p-value: 0.0026). LFS-probability was 45 (7)% for the total population, for non-DS 29 (8)% and for DS 70 (11)% (p-value: 0.0117). Median follow-up: 148 (range: 2-194) months. Conclusions: 1- Extramedullar compromise and T/myeloid mixed lineage or co-expression of MPO were observed only in non-DS AMKL, in 17.5% and 12.0% respectively. 2- Null-response was observed only in non-SD patients. 3- The most frequent event of non-DS was relapse, and toxic deaths in DS. 4- The significantly better outcome of patients with DS was confirmed in our setting. Disclosures No relevant conflicts of interest to declare.

Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome

2017 ◽  
Vol 56 (5) ◽  
pp. 394-404 ◽  
Author(s):  
Yusuke Hara ◽  
Norio Shiba ◽  
Kentaro Ohki ◽  
Ken Tabuchi ◽  
Genki Yamato ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Prognostic Impact ◽  
Acute Megakaryoblastic Leukemia ◽  
Megakaryoblastic Leukemia ◽  
Molecular Profiles

Acute megakaryoblastic leukemia in Down syndrome: orbital infiltration

2000 ◽  
Vol 130 (1) ◽  
pp. 128-130 ◽  
Author(s):  
Jeffrey L Olson ◽  
Michael J May ◽  
Linda Stork ◽  
Nina Kadan ◽  
J.Bronwyn Bateman
Keyword(s):  
Down Syndrome ◽  
Acute Megakaryoblastic Leukemia ◽  
Megakaryoblastic Leukemia

scholarly journals Integrated differential transcriptome maps of Acute Megakaryoblastic Leukemia (AMKL) in children with or without Down Syndrome (DS)

2014 ◽  
Vol 7 (1) ◽  
Author(s):  
Maria Chiara Pelleri ◽  
Allison Piovesan ◽  
Maria Caracausi ◽  
Anna Concetta Berardi ◽  
Lorenza Vitale ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Acute Megakaryoblastic Leukemia ◽  
Megakaryoblastic Leukemia

scholarly journals Foot and ankle deformities in children with Down syndrome

2018 ◽  
Vol 12 (3) ◽  
pp. 218-226 ◽  
Author(s):  
L. R. Perotti ◽  
O. Abousamra ◽  
M. del Pilar Duque Orozco ◽  
K. J. Rogers ◽  
J. P. Sees ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Down Syndrome ◽  
Hallux Valgus ◽  
Body Mass ◽  
Weight Bearing ◽  
Foot And Ankle ◽  
Children With Down Syndrome ◽  
Radiographic Measurements ◽  
Group I ◽  
Significant Difference

Purpose Foot and ankle deformities are common orthopaedic disorders in children with Down syndrome. However, radiographic measurements of the foot and ankle have not been previously reported. The aim of this study is to describe the foot and ankle deformity in children with Down syndrome. Methods Children who had foot and ankle radiographs in the standing weight-bearing position were selected. Three groups of patients were identified. The relationship of radiographic measurements with age, body mass index and pain is discussed. In all, 41 children (79 feet) had foot radiographs and 60 children (117 ankles) had ankle radiographs, with 15 children overlapping between Groups I and II. Results In Group I, hallux valgus deformity was seen before ten years of age and hallux valgus angle increased afterwards. Metatarsus adductus angle showed a significant increase (p = 0.006) with obesity and was higher in patients who had foot pain (p = 0.05). In Group II, none of the ankle measurements showed a significant difference with age or body mass index percentiles. Tibiotalar angle (TTA) and medial distal tibial angle (MDTA) were higher in patients who had ankle pain. In Group III, correlation analysis was performed between the different measurements with the strongest correlations found between TTA and MDTA. Conclusion In children with Down syndrome, radiographic evaluation of the foot and ankle reveals higher prevalence of deformities than clinical examination. However, foot and ankle radiographs are needed only for symptomatic children with pain and gait changes. Level of Evidence Level IV - Prognostic Study

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