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Objective To explore the correlation between daunorubicin (DNR) resistance and expression of programmed death receptor ligand 1 (PD-L1) in children with acute myeloid leukemia (AML). Methods Totally 110 bone marrow samples were selected from AML patients admitted to Zhengzhou University Affiliated Children's Hospital from January 2016 to December 2022 as the study group, 50 bone marrow samples from normal bone marrow donors were used as the control group. Human AML cell lines HL60, THP-1, U-937, and Molm-13 were cultured, and the expression of PD-L1 protein was detected by Western blot. LV-PD-L1-shRNA and LV-PD-L1-WT-OE lentiviral vectors were constructed. The effect and mechanism of PD-L1 on DNR resistance in Molm-13 cells were analyzed. Results The expression level of PD-L1 protein was higher than that in control group and the expression level of PD-L1 protein in AMI cell lines was higher than that in healthy bone marrow mononuclear cells (BMMC) (P＜0.05). PD-L1 expression was related to white blood cell count, bone marrow primitive cell ratio, prognostic risk stratification and disease remission after two standard chemotherapy regimens in AML patients (P＜0.05). The overall survival rate of the PD-L1 high expression group was lower than that of the PD-L1 low expression group (P＜0.05). Compared with the LV-PD-L1-WT-OE group, the LV-PD-L1-shRNA group showed a decrease in PD-L1 mRNA expression, cell proliferation activity but an increased apoptosis rate(P＜0.05). LV-PD-L1-shRNA enhanced sensitivity of Molm-13 cells to DNR. TCGA database analysis showed that glucose 6-phosphate dehydrogenase (G6PD) was a potential target gene for PD-L1. Conclusions The high expression of PD-L1 in pediatric AML is related to chemotherapy resistance in children with AML, and DNR resistance might be caused through regulation of G6PD.

Objective To explore the correlation between daunorubicin (DNR) resistance and expression of programmed death receptor ligand 1 (PD-L1) in children with acute myeloid leukemia (AML). Methods Totally 110 bone marrow samples were selected from AML patients admitted to Zhengzhou University Affiliated Children's Hospital from January 2016 to December 2022 as the study group, 50 bone marrow samples from normal bone marrow donors were used as the control group. Human AML cell lines HL60, THP-1, U-937, and Molm-13 were cultured, and the expression of PD-L1 protein was detected by Western blot. LV-PD-L1-shRNA and LV-PD-L1-WT-OE lentiviral vectors were constructed. The effect and mechanism of PD-L1 on DNR resistance in Molm-13 cells were analyzed. Results The expression level of PD-L1 protein was higher than that in control group and the expression level of PD-L1 protein in AMI cell lines was higher than that in healthy bone marrow mononuclear cells (BMMC) (P＜0.05). PD-L1 expression was related to white blood cell count, bone marrow primitive cell ratio, prognostic risk stratification and disease remission after two standard chemotherapy regimens in AML patients (P＜0.05). The overall survival rate of the PD-L1 high expression group was lower than that of the PD-L1 low expression group (P＜0.05). Compared with the LV-PD-L1-WT-OE group, the LV-PD-L1-shRNA group showed a decrease in PD-L1 mRNA expression, cell proliferation activity but an increased apoptosis rate(P＜0.05). LV-PD-L1-shRNA enhanced sensitivity of Molm-13 cells to DNR. TCGA database analysis showed that glucose 6-phosphate dehydrogenase (G6PD) was a potential target gene for PD-L1. Conclusions The high expression of PD-L1 in pediatric AML is related to chemotherapy resistance in children with AML, and DNR resistance might be caused through regulation of G6PD. [ABSTRACT FROM AUTHOR]

A 9-year-old boy diagnosed with acute myeloblastic leukemia and undergoing chemotherapy, was admitted with febrile neutropenia. During his admission, several violaceous plaques appeared on the upper extremities and anterior left hemithorax, which worsened and acquired a necrotic center. We performed a biopsy and histology showed a cutaneous infarction at the dermoepidermal and subcutaneous level. We observed abundant wide hyphae with right-angled branching and a culture isolated Rhizopus oryzae. A plastic surgery consultant performed a surgical debridement of the lesions and treatment was started with intravenous amphotericin B. The patient did well on treatment and after almost a month of hospitalization, he was discharged with oral posaconazole. Mucormycosis is an opportunistic fungal infection associated with immunosuppression, particularly involving prematurity and hematological diseases in the pediatric age group. Multiple lesions, as in our case, are infrequent. The clinical presentation is variable. Direct smear or histological observation is the quickest diagnostic technique whereas culture is the most definitive. The combination of surgical debridement and amphotericin B is the treatment with the highest survival rates. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to present the clinical features and results of treatment of patients diagnosed with refractory or relapsed acute myeloid leukaemia (AML) in Polish Paediatric Leukaemia/Lymphoma Study Group (PPL/LSG) institutions, treated in accordance with the Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012, as their first-line therapy. Material and methods: The outcome data of 10 patients with refractory AML (median age 9.5 years) and 30 with relapsed AML (median age 12 years) were analysed retrospectively. Re-induction was usually based on idarubicin, fludarabine, and cytarabine along with allogeneic haematopoietic stem cell transplant (allo-HSCT) in 5 patients with refractory AML and 7 relapsed AML children. Results: 37.5% (3/8) of refractory AML patients achieved second complete remission second complete remission (CRII). One of ten patients (1/10; 10%) was alive and stayed in complete remission for 34 months after the allo-HSCT. The probability of 3-year event-free survival (pEFS) in this group was 0.125 ±0.11. In the group of relapsed AML patients, the CRII was achieved in 9 patients (34%), and the probability of survival was: pEFS = 0.24 ±0.08; probability overall survival (pOS) = 0.34 ±0.09, with significantly better results achieved in patients who underwent allo-HSCT (pOS = 0.54 ±0.14 vs. 0.08 ±0.08, p < 0.0001). Conclusions: The prognosis of refractory AML and the first AML recurrence in children who were first-line treated in PPL/LSG centres according to Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012 is poor. Failures of re-induction treatment particularly result from difficulties in achieving remission. Allogeneic HSCT improves prognosis in children with refractory and first recurrent AML, under the condition it is performed in complete remission. Novel therapeutic approaches are needed to increase the remission rate and improve the outcomes. [ABSTRACT FROM AUTHOR]

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The results of treatment in children with acute myeloid leukemia (AML) have considerably improved in the past 15 years. Whether cranial irradiation, maintenance therapy, and hematopoietic stem cell transplantation should be used during the first remission remains unclear. This paper presents the histo- ry of development of AML treatment in children, the potentialities of current chemotherapy, and indications for allogenic and autologous hemopoietic stem cell transplantation in accordance with the data obtained by different groups of investigators, including ones from Russia. The Institute of Pediatric Oncology and Hematology (IPOH), Russian Cancer Research Cancer, Russian Academy of Medical Sciences, has developed and introduced an IPOH AML proto- col in 2002. From July 2002 to January 2006, 40 patients were enrolled in this study and stratified into 3 risk groups: 1) a standard risk group (n = 10 — 28.6%)); 2) an intermediate risk group (17 — 48,6%), and 3) a high risk group (n = 8 — 22.9%). Three-year relapse-free survival was 40±12%.

IntroductionAcute leukemia accounts for more than 30% of all pediatric cancer cases, and of these, 15–20% are acute myeloid leukemia (AML). Children who super from AML are more likely to develop infections due to the humoral and cellular immune deficits generated by the disease and its treatment. The incidence of fungal infections is underestimated; reports show that up to 75% of fungal infections go undiagnosed until autopsy. In only 30 years, the incidence of invasive candidiasis has increased by 40-fold. Thus, the high morbidity and mortality associated with fungal infections in hematological patients make it necessary to adopt preventive measures.MethodsThis work aimed to retrospectively identify pediatric patients with acute myeloid leukemia and invasive fungal diseases (IFDs) in a Latin American tertiary care hospital. A retrospective analysis of 36 clinical records of pediatric patients diagnosed with AML from 2007 to 2017 was carried out.ResultsOne hundred and twenty-nine hospitalizations were associated with infectious events. Thirteen patients in our study presented 15 infectious events associated with IFDs (11.6%). Two patients died because of complications related to IFDs (15.3%). The most frequent IFD type was aspergillosis, which was observed in 7 cases, followed by Candidemia, which was observed in 4 cases. The most frequent clinical manifestations were fever and respiratory distress.DiscussionMortality due to IFD can be prevented with effective pharmacotherapy. An appropriate antifungal prophylaxis strategy still needs to be developed through larger prospective studies in Latin America.

Acute myeloid leukemia (AML) is the second most common leukemia among children. Although significant progress in AML therapy has been achieved, treatment failure is still associated with poor prognosis, emphasizing the need for novel, innovative therapeutic approaches. To address this major obstacle, extensive knowledge about leukemogenesis and the complex interplay between leukemic cells and their microenvironment is required. The tremendous role of this bone marrow microenvironment in providing a supportive and protective shelter for leukemic cells, leading to disease development, progression, and relapse, has been emphasized by recent research. It has been revealed that the interplay between leukemic cells and surrounding cellular as well as non-cellular components is critical in the process of leukemogenesis. In this review, we provide a comprehensive overview of recently gained knowledge about the importance of the microenvironment in AML whilst focusing on promising future therapeutic targets. In this context, we describe ongoing clinical trials and future challenges for the development of targeted therapies for AML. [ABSTRACT FROM AUTHOR]

Improvement in outcomes of children with acute myeloid leukemia (AML) is attributed to several refinements in clinical management. We evaluated treatment outcomes of Taiwanese pediatric AML patients in the past 20 years. Overall, 860 de novo AML patients aged 0–18 years and registered in the Childhood Cancer Foundation of R.O.C during January 1996–December 2019 were included. Survival analysis was performed to identify factors that improved treatment outcomes. Regardless of treatment modalities used, patients during 2008–2019 had better 5-year event-free survival (EFS) and overall survival (OS) rates than patients during 1996–2007. For patients received the TPOG-AML-97A treatment, only 5-year OS rates were significantly different between patients diagnosed before and after 2008. Patients with RUNX1–RUNX1T1 had similar relapse-free survival rates, but 5-year OS rates were better during 2008–2019. However, the survival of patients who received hematopoietic stem-cell transplantations (HSCT) did not differ significantly before and after 2008. For patients without relapse, the 5-year OS improved during 2008–2019. Non-relapse mortality decreased annually, and cumulative relapse rates were similar. In conclusion, 5-year EFS and OS rates improved during 2008–2019, though intensities of chemotherapy treatments were similar before and after 2008. Non-relapse mortality decreased gradually. Further treatment strategies including more intensive chemotherapy, novel agents' use, identification of high-risk patients using genotyping and minimal residual disease, early intervention of HSCT, and antibiotic prophylaxis can be considered for future clinical protocol designs in Taiwan. [ABSTRACT FROM AUTHOR]

Objective: This study aims to describe the epidemiological characteristics and survival rates of children with acute myeloid leukemia treated in hospitals in southern Brazil and compare them with international data. Methods: A multicenter cohort study was conducted with retrospective data collection of all new patients with acute myeloid leukemia under 18 treated at five referral centers in pediatric hematology-oncology in southern Brazil between January 2005 and December 2015. Results: Of the 149 patients with acute myeloid leukemia, 63.0% (n = 94) were male. The median age at diagnosis was 10.5 years (range 0-18 years) and 40.3% (n = 60) had a white blood cell count below 50,000/mm2. The most common Franco-American-British (FAB) subtype was M3 (n = 43, 28.9%). Nine (6.0%) patients had central nervous system disease. In M3 patients, overall survival (OS) was 69.2% and 3-year event-free survival was 67.7%; in non-M3 patients, these rates were 45.3% and 36.7%, respectively. In non-M3 patients, OS was significantly different between transplanted (61.8%) and non-transplanted (38.2%) patients (p = 0.031). Conclusions: These results show a higher prevalence of the Franco-American-British M3 subtype than that reported in the international literature, as well as a decreased OS compared with that of developed countries. Further multicenter Brazilian studies with a larger sample size are encouraged to better understand the characteristics of acute myeloid leukemia, and to improve the treatment and prognosis in this population. [ABSTRACT FROM AUTHOR]

OBJECTIVES Treatment outcome in children with acute myeloid leukemia (AML) has improved in the developed world but remains poor in developing countries. We assessed the role of etoposide in induction chemotherapy in pediatric AML. METHODS This analysis retrospectively compared 2 induction chemotherapy regimens consisting of daunorubicin and cytarabine with etoposide (ADE) and without etoposide (AD). All newly diagnosed cases of AML younger than 18 years from January 1, 2012, onwards who completed their treatment before January 31, 2019, were included. Data of 186 cases, including 117 males (62.9%) and 69 females (37.1%), were analyzed. Demographic, initial presentation blood counts, and AML subtypes were almost identical in both groups. RESULTS Complete remission rates were almost identical for the ADE versus the AD group (78.8% vs 80.0%, p = 0.980). Treatment-related mortality was higher, albeit not significantly, in the ADE (25 of 105; 23.8%) versus the AD (16 of 81; 19.8%) group (p = 0.508). Overall survival was 32 of 105 (30.5%) in the ADE and 43 of 81 (53.1%) in the AD group (p = 0.079), and disease-free survival was 29 of 105 (27.6%) and 39 of 81 (48.1%) in ADE and AD groups (p = 0.056), respectively. CONCLUSIONS Etoposide in induction treatment of pediatric AML is associated with increased episodes of bacterial and fungal infections and high treatment-related mortality. Moreover, it does not offer any survival benefit. In low- and middle-income countries like Pakistan, it should not be used in the induction treatment protocol. [ABSTRACT FROM AUTHOR]

Juvenile myelomonocytic leukaemia (JMML) is an aggressive clonal haematopoietic disorder that presents in early childhood. It is classified by the World Health Organization (WHO) as an overlap myeloproliferative or myelodysplastic disorder. The pathogenesis of JMML has been well-explained at the molecular level using clear diagnostic criteria. There is limited literature on JMML in the context of HIV infection. The only curative modality for the majority of patients with JMML is allogeneic haematopoietic stem cell transplant (HSCT). The role of other chemotherapeutic approaches is to ameliorate the disease but they are no substitute for allogeneic HSCT. We report a case of a 59-month-old child with vertically transmitted HIVinfection who was referred to the authors' institution for further management. [ABSTRACT FROM AUTHOR]

Pediatric acute myeloid leukemia (AML) is a rare disease that affects 65 to 85 children under 15 years of age in France each year. The cytogenetic and molecular characteristics allow to differentiate AML into three risk groups: "favorable", "intermediate" and "adverse", which are integrated into the therapeutic decision. Treatment is based on 4 to 5 cycles of multidrug therapy, sometimes combined with hematopoietic stem cells transplant for patients at "adverse" risk or patients with high residual disease. The risk of relapse is currently around 40%, with a 4-year survival rate over 70%. Recent introduction of gemtuzumab ozogamicine immunotherapy aims to reduce the risk of relapse. The research, illustrated by the CONECTAML project, will provide a better understanding of the biology of pediatric AML whose objective is to identify new therapeutic targets. [ABSTRACT FROM AUTHOR]

Antibiotics are frequently administered for prophylaxis of fever in neutropenic children with cancer. This strategy is mainly derived from adults' data, and various pediatric studies evidenced the effectiveness of antibiotics (eg, fluoroquinolones) in the prevention of febrile neutropenia. However, only two pediatric randomized, double‐blind, placebo‐controlled trials have been performed, with a total of 262 leukemic children enrolled, and no other one was ever powered for analyzing effectiveness over other infectious complications. In an era of increasing antibiotic resistance, the widespread use of antibiotic prophylaxis in neutropenic leukemic children needs to be strongly supported. [ABSTRACT FROM AUTHOR]

Background: It is questionable whether enrollment on clinical trials offers any survival advantage at the population level over standard-of-care treatment. The objectives of this study were to describe the impact of trial enrollment on event-free survival and overall survival in pediatric acute myeloid leukemia (AML) using the Cancer in Young People in Canada (CYP-C) database.Methods: Children were included if they had had AML newly diagnosed between ages birth and 14 years from 2001 to 2012. CYP-C is a national pediatric cancer population-based database that includes all cases of pediatric cancer diagnosed and treated at 1 of the 17 tertiary pediatric oncology centers in Canada. Univariate and Cox proportional hazards models were used to evaluate the impact of initial trial enrollment on survival.Results: In total, 397 eligible children with AML were included in the analysis, of whom 94 (23.7%) were enrolled on a clinical trial at initial diagnosis. The most common reason for non-enrollment was that no trial was available. The event-free survival rate at 5 years was 57.8% ± 5.2% for those enrolled versus 54.8% ± 2.9% for those not enrolled (P = .75). The overall survival rate at 5 years was 70.1% ± 4.9% for those enrolled versus 66.3% ± 2.8% for those not enrolled (P = .58). Enrollment on a trial was not associated with improved event-free or overall survival in multiple regression analyses.Conclusions: Enrollment on a clinical trial was not associated with improved survival for children with AML in a population-based cohort. Rationale for trial enrollment should not include the likelihood of benefit compared with non-enrollment. [ABSTRACT FROM AUTHOR]

The article discusses a study focusing on children with acute myeloid leukaemia (AML) and the use of a three-miRNA-based expression signature during diagnosis to predict a relapse. Topics discussed include the identification of differentially expressed (DE) miRNAs in several patients and chemotherapy treatment; the risk of disease recurrence among t(8;21) RUNX1/RUNX1T1 patients; and the overexpression of HSPA5 mediated resistance to cytarabine-induced apoptosis.

To study the prognostic relevance of rare genetic aberrations in acute myeloid leukemia (AML), such as t(16;21), international collaboration is required. Two different types of t(16;21) translocations can be distinguished: t(16;21)(p11;q22), resulting in the FUS-ERG fusion gene; and t(16;21)(q24;q22), resulting in RUNX1-core binding factor (CBFA2T3). We collected data on clinical and biological characteristics of 54 pediatric AML cases with t(16;21) rearrangements from 14 international collaborative study groups participating in the international Berlin-Frankfurt-Münster (I-BFM) AML study group. The AML-BFM cohort diagnosed between 1997 and 2013 was used as a reference cohort. RUNX1-CBFA2T3 (n = 23) had significantly lower median white blood cell count (12.5 3 109/L, P = .03) compared with the reference cohort. FUS-ERG rearranged AML (n = 31) had no predominant French-American- British (FAB) type, whereas 76% of RUNX1-CBFA2T3 had an M1/M2 FAB type (M1, M2), significantly different from the reference cohort (P = .004). Four-year event-free survival (EFS) of patients with FUS-ERG was 7% (standard error [SE] = 5%), significantly lower compared with the reference cohort (51%, SE = 1%, P < .001). Four-year EFS of RUNX1-CBFA2T3 was 77% (SE = 8%, P = .06), significantly higher compared with the reference cohort. Cumulative incidence of relapse was 74% (SE = 8%) in FUS- ERG, 0% (SE = 0%) in RUNX1-CBFA2T3, compared with 32% (SE = 1%) in the reference cohort (P < .001). Multivariate analysis identified both FUS-ERG and RUNX1-CBFA2T3 as independent risk factors with hazard ratios of 1.9 (P < .0001 ) and 0.3 (P = .025), respectively. These results describe 2 clinically relevant distinct subtypes of pediatric AML. Similarly to other core-binding factor AMLs, patients with RUNX1-CBFA2T3 rearranged AML may benefit from stratification in the standard risk treatment, whereas patients with FUS-ERG rearranged AML should be considered high-risk. [ABSTRACT FROM AUTHOR]

Abstract: We compared transplant outcomes between donor types and stem cell sources for childhood acute myeloid leukemia (AML). The medical records of children with AML in the Yeungnam region of Korea from January 2000 to June 2017 were reviewed. In all, 76 children with AML (male‐to‐female ratio = 46:30) received allogenic hematopoietic stem cell transplantation (allo‐HSCT). In total, 29 patients received HSCT from either a matched‐related donor or a mismatched‐related donor, 32 patients received an unrelated donor, and 15 patients received umbilical cord blood. In term of stem cell sources, bone marrow was used in 15 patients and peripheral blood in 46 patients. For all HSCT cases, the 5‐year overall survival (OS) was 73.1% (95% CI: 62.7‐83.5) and the 5‐year event‐free survival (EFS) was 66.1% (95% CI: 54.5‐77.7). There was no statistical difference in 5‐year OS according to the donor types or stem cell sources (P = .869 and P = .911). There was no statistical difference in 5‐year EFS between donor types or stem cell sources (P = .526 and P = .478). For all HSCT cases, the 5‐year relapse rate was 16.1% (95% CI: 7.3‐24.9) and the 5‐year non‐relapse mortality (NRM) was 13.3% (95% CI: 5.1‐21.5). There was no statistical difference in the 5‐year relapse rate according to the donor types or stem cell sources (P = .971 and P = .965). There was no statistical difference in the 5‐year NRM between donor types or stem cell sources (P = .461 and P = .470). [ABSTRACT FROM AUTHOR]

Overexpression of cathepsin L (CTSL), an endolysosomal cysteine protease, is associated with inferior survival of patients with various human malignancies. We evaluated the expression/activity of CTSL in peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) of 103 pediatric acute myeloid leukemia (AML) patients to assess its prognostic significance in this malignancy. Thirty-five healthy siblings of patients served as controls. Our results revealed significantly higher CTSL activity (p < .0001), protein (p < .05), and mRNA levels (p < .01) in both PBMCs and BMMCs of patients as compared with controls. BMMCs displayed higher activity of CTSL than PBMCs (p < .01). A dramatic reduction in CTSL activity was recorded after chemotherapy in a significant proportion (74%) of patients (p < .0001). By multivariate analysis, CTSL in BMMCs emerged as a strong independent prognostic marker for overall survival (OS) (p = .004). Thus, our results suggest the potential utility of CTSL in predicting the outcome of pediatric AML. [ABSTRACT FROM AUTHOR]

The prognostic significance of the ETV6/RUNX1-fusion and of the accompanying aberrations is disputable; whether co-existing sub-clones are responsible for delayed MRD-clearance and thus, moderate outcome, remains to be clarified. We studied, in a paediatric cohort of 119 B-ALLs, the relation between the ETV6/RUNX1 aberration and the co-existing subclones with (a) presenting clinical/biological features, (b) early response to treatment(MRD) and (c) long-term outcome over a 12-year period. Patients were homogeneously treated according to BFM-based-protocols. 27/119 patients (22.7%) were ETV6/RUNX1-positive; 19/27 (70.4%) harbored additional genetic abnormalities while 9/19 (33.3%) presented with clonal heterogeneity. The most common abnormalities were del12p13 (37%), 3-6×21q22 (22.2%), del9p21 (18.5%) and 2-3xETV6/RUNX1 (18.5%). MRD d15 -positivity (≥10 −3 ) was detected in 44% of the cohort; the corresponding MRD among patients carrying subclones rises to 88.9%. Common features of all relapses were sub-clonal diversity, FCM-MRD d15 -positivity and additional del(9p21) while there were no censored relapses among ETV6/RUNX1-positive patients with sole translocation and absence of additional aberrations, within a median follow-up time of 90 months. In our study, the presence of clonal heterogeneity and impaired FCM-MRD clearance among ETV6/RUNX1-positive patients, ultimately influenced prognosis. Longer follow-up is needed in order to further validate these initial results. [ABSTRACT FROM AUTHOR]

Adolescents and young adults (AYAs) form a unique group of patients with newly diagnosed acute myeloid leukemia (AML). They differ in terms of disease biology, psychosocial challenges, survival, and in other important respects from children as well as from middle-aged and older adults. AYAs may be treated using pediatric protocols developed in trials composed primarily of younger patients, or using adult protocols developed in trials composed primarily of older patients. After reviewing the distinguishing characteristics of AYAs with AML, we compare and contrast the chemotherapy approaches and argue that neither the pediatric nor adult approaches may be ideally suited for AYAs and the development of AYA-specific approaches merits further consideration. We finish by putting forth ideas for future research to optimize chemotherapy treatment of AYAs with AML. [ABSTRACT FROM AUTHOR]

Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)- type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19+ leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19+ ALAL. AMLtype treatment is preferred in a minority of ALAL cases with CD19- and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial. [ABSTRACT FROM AUTHOR]

There is a desperate need for new and effective therapeutic approaches to acute myeloid leukemia (AML) in both children and adults. Epigenetic aberrations are common in adult AML, and many novel epigenetic compounds that may improve patient outcomes are in clinical development. Mutations in epigenetic regulators occur less frequently in AML in children than in adults. Investigating the potential benefits of epigenetic therapy in pediatric AML is an important issue and is discussed in this review. [ABSTRACT FROM AUTHOR]

Objective: To analyze the cytogenetic abnormalities of a large cohort of consecutive pediatric Acute Myeloid Leukemia (AML) patients, treated on a uniform protocol.Design: Review of case records.Setting: Pediatric Cancer Center of tertiary care hospital between June 2003 and June 2016.Participants: 617 consecutive de novo pediatric AML patients were screened and 472 patients were found eligible. Eligibility criteria included non M3 patients, successful cytogenetic profile and availability of complete recordsMain outcome measure: Cytogenetic profile.Results: Gum-hypertropy, chloromas and rate of complete remission were significantly different between European Leukemia Network classification (ELN) cytogenetic risk groups (P<0.01). t (8;21) (141, 29.8%), loss of Y chromosome (61,12.9%) and trisomy 8 (39, 8.3%) were the most common abnormalities. Among the chromosomal gains, trisomy 8 and trisomy 21 (both P<0.01) were significantly different among the three ELN risk groups. Among the chromosome losses, monosomy 5, 7 (both P<0.01) and 9 (P=0.03), loss of X and loss of Y (both P<0.01) were statistically different amongst three cytogenetic risk groups. Event-free survival (P<0.01) and overall survival (P<0.01) were found to be significantly different among the three risk groups.Conclusions: The higher frequency of t (8; 21) and its association with chloroma in Indian pediatric patients is different from other studies around the world. [ABSTRACT FROM AUTHOR]

The prevalence and clinical relevance of KIT mutations in childhood core-binding factor (CBF) acute myeloid leukemia (AML) have not been well characterized. In this study, a total of 212 children with de novo AML were enrolled from a Chinese population and 50 (23.5%) of the patients were deemed CBF-AML. KIT mutations were identified in 30% of the CBF-AML cohort. The KIT mutations were clustered in exon 17 and exon 8, and KIT mutations in exons 8 and 17 were correlated with a shorter overall survival (OS) (5-year OS: 30.0 ± 14.5% vs. 73.0 ± 8.5%, p = .007) and event-free survival (EFS) (5-year EFS: 30.0 ± 14.5% vs. 73.0 ± 8.5%, p = .003). Multivariate analysis revealed KIT mutations as an independent risk factor in CBF-AML. Our results suggest that KIT mutations are a molecular marker for an inferior prognosis in pediatric CBF-AML. [ABSTRACT FROM AUTHOR]

Congenital leukemia is an uncommon myeloproliferative disorder usually diagnosed in the first month of life. Newborns with Down syndrome have an increased susceptibility to acute megakaryoblastic leukemia. We report a case of a newborn with Down syndrome diagnosed with acute myeloid leukemia. The diagnosis was established by clinical and hematological work-up. [ABSTRACT FROM AUTHOR]

Abstract: In Mexico, due to the high rates of diabetes, overweight, and obesity, there has also been noted an increased newborn weight, which may be contributing to the elevated incidence rate of childhood acute leukemia (AL). We conducted a case–control study in public hospitals of Mexico City aimed to know whether a greater weight at birth is associated with a higher risk of developing leukemia. We included incident cases with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) diagnosed between 2010 and 2015. Controls were frequency‐matched to the cases by age, sex, and health institution. Logistic regression analysis was performed adjusting risks by child's sex, overcrowding index, birth order, and mother's age at the time of pregnancy. Adjusted odds ratios (aORs) and 95% confidence intervals were calculated. A total of 1455 cases and 1455 controls were included. An evident association between ALL and child's birthweight ≥2500 g was found (aOR 2.06; 95% CI: 1.59, 2.66) and also, in those with birthweight ≥3500 g (aOR 1.19; 95% CI: 1.00, 1.41). In AML patients with birthweight ≥2500 g and ≥3500 g, an aOR of 1.77 (95% CI: 1.07, 2.94) and 1.42 (95% CI: 1.03–1.95) was observed, respectively. No association was noticed with either type of AL and a birthweight ≥4000 g. To sum up, we found a moderate association between not having a low birthweight and an increased risk of acute leukemias. Birthweight ≥3500 g was also a risk factor for both types of leukemia. This suggests that a greater birthweight may increase the risk of acute leukemias in Mexican children. [ABSTRACT FROM AUTHOR]

Genomic alterations underlying chemotherapy resistance remains poorly characterized in pediatric acute myeloid leukemia (AML). In this study, we used whole exome sequencing to identify gene mutations associated with chemo-resistance in 44 pediatric AML patients. We identified previously unreported mutations involving epigenetic regulators such as KDM5C , SRIT6 , CHD4 , and PRPF6 in pediatric AML patients. Despite low prevalence in general pediatric AML, mutations involving epigenetic regulators including splicing factors, were collectively enriched as a group in primary chemo-resistance AML patients. In addition, clonal evolution analysis of secondary chemo-resistance AML patients reveals dominant clone at diagnosis could survive several course of intensified chemotherapy. And gain of new mutations in genes such as MVP , TCF3 , SS18 , and BCL10 , may contribute to chemo-resistance at relapse. These results provide novel insights into the genetic basis of treatment failure in pediatric AML. [ABSTRACT FROM AUTHOR]

The article discusses a study on paediatric leukemia and lymphoma. Topics include CD38, a non-lineage-restricted cell surface protein that is strongly expressed on plasma cells (PC) and in PC neoplasms, the presence of CD38 expression in acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma, and the diagnosis of paediatric leukaemia and lymphoma.

BACKGROUND: MicroRNA-195 acts as a tumor suppressor in a variety of cancers. However, its clinical significance in pediatric acute myeloid leukemia (AML) remains largely undefined. OBJECTIVE: To investigate the diagnostic and prognostic relevance of miR-195 in this malignancy. METHODS: Expression levels of miR-195 in peripheral blood and bone marrow samples of patients with pediatric AML and normal controls were detected by real-time quantitative PCR. Then, receiver-operating characteristic (ROC) curve analysis, Kaplan-Meier method, and Cox regression analysis were performed to evaluate the diagnostic and prognostic relevance of serum miR-195 in pediatric AML. RESULTS: Compared to normal controls, the expression levels of miR-195 in both bone marrow and patients' sera were significantly decreased (both P < 0.001). In addition, serum miR-195 had an optimal diagnostic cut-off point (2.09) for pediatric AML with sensitivity of 68.87% and specificity of 96.23%. The area under the ROC curve (AUC) based on serum miR-195 was 0.910. Moreover, patients with low serum miR-195 level more often had French-American-British classification subtype M7 (P = 0.02), unfavorable karyotypes (P = 0.01), and shorter relapse-free and overall survivals (both P = 0.001) than those with high serum miR-195 level. Furthermore, the multivariate analysis identified serum miR-195 level as an independent prognostic factor for both relapse-free and overall survivals. CONCLUSION: The findings of this study suggest that the aberrant expression of miR-195 may play crucial roles in the development and progression of pediatric AML patients. Serum miR-195 may serve as a promising marker for monitoring the occurrence of this disease and predicting the clinical outcome of patients. [ABSTRACT FROM AUTHOR]

CNS-directed therapies for the treatment of leukemia can adversely affect the acquisition of new skills, such as reading/writing and math. Two years after the end of treatments, children show gross and fine motor skill delays that may persist even when patients are considered healed. The goal of the present study was to assess motor skills difficulties in pre-school children with leukemia one year after treatment. Particular attention has been paid to those patients who had undergone Hematopoietic Stem Cell Transplantation (HSCT) and to the relationship between motor delays and age bands. Participants were 60 children (median age of 5; inter quartile range: 3.07–5.76), including 31 females and 29 males, 91.7% of them were affected by acute lymphoblastic leukemia (ALL), and 8.3% by acute myeloid leukemia (AML). Five children had undergone HCST. Parents were interviewed by Vineland Adaptive Behavior Scales (VABS) on children’s motor skills and filled in the Italian Temperament Questionnaire (QUIT). VABS’s total scores were converted into equivalent mental age scores (EMA). A score difference of at least three months between current age and equivalent mental age was considered a developmental delay. Non-parametric analyses were run to understand if HSCT treatment and a specific age band influence children’s motor skills. Significant delays were found in global motor skills (56.7%) as well as in fine and gross motor domains. Mann Whitney U tests showed that children with HSCT were reported to have lower gross motor mean ranks (U = 62; p = 0.004; Mean rank = 15.40) than peers without HSCT (Mean rank = 31.87) and lower mean rank values on motor temperament scale (U = 9; p = 0.003; HSCT Mean rank = 4.75 versus no HSCT Mean rank = 27.81). Kruskal Wallis’ tests identified the high risk treatment showing that HSCT experience negatively impacted the motor skills and temperamental motor activity of pre-school children one year after the diagnosis of leukemia. [ABSTRACT FROM AUTHOR]

Background: Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases, which has been studied extensively and is approved for myelodysplastic syndrome in adults but with less focus in children. Accordingly, we conducted a phase 1 multicenter, randomized, open-label study to evaluate decitabine pre-treatment before standard induction therapy in children with newly diagnosed AML to assess safety and tolerability and explore a number of biologic endpoints. Results: Twenty-four patients were fully assessable for all study objectives per protocol (10 in Arm A = epigenetic priming induction, 14 in Arm B = standard induction). All patients experienced neutropenia and thrombocytopenia. The most common grade 3 and 4 non-hematologic adverse events observed were gastrointestinal toxicities and hypophosphatemia. Plasma decitabine PK were similar to previously reported adult data. Overall CR/CRi was similar for the two arms. MRD negativity at end-induction was 85% in Arm A versus 67% in Arm B patients. DNA methylation measured in peripheral blood over the course of treatment tracked with blast clearance and matched marrow aspirates at day 0 and day 21. Unlike end-induction marrow analyses, promoter methylation in blood identified an apparent reversal of response in the lone treatment failure, 1 week prior to the patient's marrow aspirate confirming nonresponse. Decitabine-induced effects on end-induction (day 35-43 following initiation of treatment) marrows in Arm A were reflected by changes in DNA methylation in matched paired marrow diagnostic aspirates. Conclusions: This first-in-pediatrics trial demonstrates that decitabine prior to standard combination chemotherapy is feasible and well tolerated in children with newly diagnosed AML. Pre-treatment with decitabine may represent a newer therapeutic option for pediatric AML, especially as it appears to induce important epigenetic alterations. The novel biological correlates studied in this trial offer a clinically relevant window into disease progression and remission. Additional studies are needed to definitively assess whether decitabine can enhance durability responses in children with AML. [ABSTRACT FROM AUTHOR]

Background: Outcomes for children with acute myeloid leukemia (AML) have improved over the past 20 years even though the medications used for induction therapy have not changed.Methods: This study analyzed data from patients with AML who were enrolled in successive protocols (AML97 and AML02) to determine the contributors to the improved outcomes of the latter clinical trial.Results: There were significant improvements in 5-year overall survival (48.9% vs 71.2%; P < .0001) and event-free survival (43.5% vs 61.8%; P = .002) from AML97 to AML02. The 5-year cumulative incidence of early death (ED)/treatment-related mortality (TRM) was reduced for patients treated in AML02 (18.5% vs 7.9%; P = .007). Although the overall incidence of refractory disease (6.5% vs 5.6%; P = .736) and relapse (29.3% vs 21.0%; P = .12) did not differ between the 2 studies, patients with low-risk AML who were treated in AML02 had a reduced incidence of relapse (27.3% vs 8.8%; P = .036).Conclusions: The improved outcomes of the AML02 trial resulted from improved disease control for low-risk patients and overall decreased ED/TRM. These results emphasize the importance of supportive-care measures throughout chemotherapy courses and hematopoietic cell transplantation and the value of treatment intensity for patients with low-risk AML while underscoring the need for novel therapy, rather than increased therapy intensity, for children with high-risk AML. Cancer 2017;123:3791-3798. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia (AML) in early childhood is characterised by a high frequency of recurrent genomic aberrations associated with distinct myeloid subtypes, clinical outcomes and pathogenesis. Genomic instability is the first step of pathogenic mechanism in early childhood AML. A sum of adverse events is necessary to the development of infant AML (i-AML), which includes latency of biochemicalmolecular and cellular effects. Inherited genetic susceptibility associated with exposures to biotransformation substances can modulate the risk of DNA damage and it is a very important piece in the pathogenic puzzle. In this review, we have aimed to explore the chain of events in the time-points of the natural history of i-AML, which includes maternal exposures during pregnancy, the speculations about the formation of somatic mutations during foetal life and the secondary genomic aberrations associated with i-AML. The modulation of risk conferred by xenobiotic metabolism's genes variants is the bottom line of the pathogenic process. Since we have conducted observational and molecular investigations in early childhood leukaemia, the data focused here is based on Brazilian findings with summarised results of our experience with epidemiological and molecular studies in early-age leukaemia. [ABSTRACT FROM AUTHOR]

The reported treatment outcomes of children treated for cancer in Eastern European countries are inferior to those in Northern/Western Europe. We hypothesized that recent survival rates could be comparable to the current standards and performed a population-based analysis of treatment outcome of childhood acute myeloid leukemia (AML) in Lithuania, a small Eastern European country. Children < 18 years old who were treated for AML from 2000 to 2013 were included (n = 54). Estimates of 5-year event-free (EFS5y) and overall survival (OS5y) rates were analyzed. Comparing periods 2000-2006 (n = 32) and 2007-2013 (n = 22), the EFS5y improved from 31 to 63% (p = 0.04), and the OS5y improved from 31 to 72% (p = 0.02) because of reductions in toxicity-related mortality (42 vs. 15%, p = 0.08) and relapse (43 vs. 25%, p = 0.08). The most significant improvement was demonstrated in high-risk patients (OS5y improved from 26 to 75%, p = 0.02) who benefited from hematopoietic stem cell transplantation: the post-transplant EFS5y increased from 13 to 86% (p = 0.01).Conclusions: The current survival rate of Lithuanian children treated for AML was comparable to the expected rate in other parts of Europe. What is Known: • In the last three decades, significant improvement has been achieved in treating childhood cancer, with an overall survival (OS) rate of > 80% in high-income countries. The difference in survival rates between Northern/Western and Eastern European countries as well as between high- and middle-/low-income countries is as much as 20%. Recently, the 5-year event-free survival rate of acute myeloid leukemia (AML) has reached > 60% in high-income countries. The survival rates for myeloproliferative diseases were the lowest in Eastern European countries. • The reported inferior survival rates were calculated based on outcome data of patients treated until 2007. The recent survival rates in Eastern European countries are unknown. What is New: • Being a small Eastern European country, Lithuania has experienced good economic growth during the last decade. We hypothesized that economic growth and gain of experience could result in better survival rates of children treated for cancer in our country in recent years. • A population-based analysis of treatment outcome of childhood AML treated in Lithuania in the recent years was performed for the first time. The survival rates of childhood AML in Lithuania are comparable to those of other high-income countries. Current survival rates of children treated for cancer in Eastern European countries could be comparable to the best current standards contributing to better European survival rates of childhood cancer in general. [ABSTRACT FROM AUTHOR]

Background:Brain and Acute Leukemia Cytoplasmic (BAALC) is a gene which its expression is confined to progenitor cells; therefore, no expression has been illustrated in mature cells of bone marrow or white blood cells (WBC). In addition, high BAALC expression is associated with poor prognosis in Acute Myeloid Leukemia (AML) individuals and is considered as an important risk factor in Cytogenetic Normal Acute Myeloid Leukemia. Materials and Methods: This retrospective study was designed to evaluate prognostic importance of BAALC gene expression in pediatric AML patients. Recently, recognized 114 AML Iranian children with age range of 1-15 years were entered in this study during 2012-2015. Real-Time PCR was applied for BAALC gene. Results: High BAALC gene expression was detected in 47 patients (41.2%) and low expression in 67 patients (58.8%). High BAALC gene expression group (n=47) contained23 males and 24 females. All patients were followed up for 2 years to measure disease prognosis. BAALC expression was a main unfavorable prognostic factor in AML patient's especially normal karyotype. AML cases with high BAALC expression had considerable further cumulative risk after 25 months; it was 39 months in low expressed cases. All of cytogenetic normal acute myeloid leukemias (CN-AML) and high BAALC expressed patients died. High BAALC expression in AML cases was associated with considerable shorter overall survival (OS). Conclusion: According to our findings, BAALC expression is a significance poor prognostic factor in AML patients with normal karyotype. This study suggests new therapeutic strategies to ameliorate the treat rate of AML patients. Further research with longer follow up and larger sample size is required to definite statistical perusals. [ABSTRACT FROM AUTHOR]

BACKGROUND In the adult population with newly diagnosed chronic myeloid leukemia (CML), variant translocations are usually not considered to be impairing the prognosis, whereas some additional cytogenetic abnormalities (ACAs) are associated with a negative impact on survival. Because of the rarity of CML in the pediatric population, such abnormalities have not been investigated in a large group of children with CML. METHODS The prognostic relevance of variant t(9;22) and ACAs at diagnosis was assessed in 301 children with CML in the chronic phase who were enrolled in the International Registry for Chronic Myeloid Leukemia in Children and Adolescents. RESULTS Overall, 19 children (6.3%) presented with additional cytogenetic findings at diagnosis: 5 children (1.7%) had a variant t(9;22) translocation, 13 children (4.3%) had ACAs, and 1 had both. At 3 years, for children with a classic translocation, children with ACAs, and children with a variant t(9;22) translocation who were treated with imatinib as frontline therapy, the probability of progression-free survival (PFS) was 95% (95% confidence interval [CI], 91%-97%), 100%, and 75% (95% CI, 13%-96%), respectively, and the probability of overall survival (OS) was 98% (95% CI, 95%-100%), 100% (95% CI, 43%-98%), and 75% (95% CI, 13%-96%), respectively. No statistical difference was observed between the patients with classic cytogenetic findings and those with additional chromosomal abnormalities in terms of PFS and OS. CONCLUSIONS In contrast to adults with CML, additional chromosomal abnormalities observed at diagnosis do not seem to have a significant prognostic impact. Cancer 2017;123:3609-16. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

MicroRNA (miR)-122 functions as a tumor suppressor in various human cancers. However, its involvement in childhood acute myeloid leukemia (AML) remains unknown. In this study, quantitative real-time PCR assay demonstrated that miR-122 expression in bone marrow specimens from AML children were significantly lower than that in non-malignant controls (P < 0.001). Statistically, AML children with low miR-122 expression more frequently had large white blood cell count (P = 0.022), French-American-British classification subtype M7 (P < 0.001), unfavorable cytogenetics (P = 0.002) and day 7 response to the treatment (P = 0.036), short relapse-free (P = 0.001) and overall (P = 0.008) survivals than those with high expression. Multivariate analysis also determined that miR-122 expression was an independent prognostic factor for both relapse-free and overall survivals. Functionally, the enforced expression of miR-122 in AML cell lines efficiently suppressed cell proliferation and reduced the ratio of S-phase cells in vitro (all P < 0.05). In conclusion, the abnormal expression of miR-122 may be a marker of the aggressive progression in childhood AML. Importantly, its downregulation may serve as a prognostic factor to predict poor outcome. Our study also reveal that miR-122 may function as a tumor suppressor in childhood AML, highlighting a new therapeutic strategy for this malignancy. [ABSTRACT FROM AUTHOR]

Given that 30-40% of children with acute myeloid leukaemia ( AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission ( CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival ( OS5y) was 39 ± 4% for the whole group and 43 ± 4% for the 190 patients given re-induction therapy, of whom 76% received regimens that included fludarabine, cytarabine ( FLA) ± anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology ( NOPHO) upfront blocks and 5% received other regimens. Late relapse ≥1 year from diagnosis, no allogeneic stem cell transplantation ( SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS5y was 61 ± 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML. [ABSTRACT FROM AUTHOR]

Hyperleucocytosis in paediatric acute myeloid leukaemia ( AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0-18 years registered in the Nordic Society of Paediatric Haematology and Oncology ( NOPHO) registry, with special focus on very high white blood cell counts ( WBC >200 × 10/l). Eighty-six patients (10%) had WBC 100-199 × 109/l and 57 (6%) had WBC ≥200 × 109/l. Patients with WBC ≥200 × 109/l had a high frequency of t(9;11) and a paucity of trisomy 8. Due to the high frequency of deaths within the first 2 weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200 × 109/l (39% vs. 61%). Main cause of early death was intracranial haemorrhage and leucostasis. Twenty-six per cent of these patients never started antileukaemic protocol therapy. Leukapheresis or exchange transfusion was used in 24% of patients with hyperleucocytosis without impact on survival. Patients with hyperleucocytosis surviving the first week had identical survival as patients with lower WBC. We conclude that death within the first days after diagnosis is the major challenge in patients with high WBC and advocate rapid initiation of intensive chemotherapy. [ABSTRACT FROM AUTHOR]

Despite the high incidence of Down syndrome (DS) in Arab countires, the incidence and outcomes of myeloid leukemia of DS (ML-DS) have not been studied. We evaluated 206 pediatric acute myeloid leukemia (AML) patients diagnosed between 2005 and 2012 and identified 31 (15%) ML-DS. The incidence of ML-DS was 48 per 100,000 compared to 0.6 per 100,000 for AML in non-DS children. Thus, patients with DS had 80-fold increased risk of ML-DS compared to AML in non-DS children. The median age at diagnosis was 1.8 years, male/female ratio was 1.2, majority (84%) of patients had FAB-M7 subtype, and the cytogenetic abnormalities were normal karyotype (constitutional trisomy 21) in 48%, additional trisomy in 23%, and other aberrations in 29%. Complete remission, cumulative incidences of relapse (CIR), toxic-death, and 5-year event-free survival (EFS) rates were 96.8%, 19.4%, 13.1%, and 67.7 ± 8.4%; respectively. In the present study, multivariate analysis revealed favorable outcome (5-year EFS 86.7 ± 8.8%) for patients with normal karyotype. The incidence and clinical characteristics of ML-DS in Saudi patients were comparable to other reports. However, there is a need to optimize risk stratification and treatment intensity to reduce CIR and toxic death rates to further improve outcomes of patients with ML-DS. [ABSTRACT FROM AUTHOR]

Aberrations in epigenetic modifications contribute to leukemogenesis in childhood acute myeloid leukemia (AML). We combined DNA hypomethylating agent azacitidine with histone deacetylase inhibitor panobinostat in preclinical models of childhood AML. Synergistic cytotoxic effect upon treatment with azacitidine and panobinostat with combination indices <1.0 was observed. Azacitidine and panobinostat increased median survival by 26 and 6 days respectively in MV4;11 xenografted mice. Mice treated with both drugs showed a drastic reduction in leukemic burden leading to complete remission sustained for the duration of the experimental period lasting more than 519 days. Reduced leukemic burden and prolonged survival was also observed in AML-193 xenografted mice treated with azacitidine-panobinostat combination. Differential gene expression profiling was performed on AML cells treated with azacitidine, panobinostat or azacitidine-panobinostat combination. Functional mapping of transcripts uniquely regulated by the azacitidine-panobinostat combination in MV4;11 cells identified p53 as an upstream regulator. A comparison of the uniquely modulated transcripts by azacitidine-panobinostat combination in MV4;11 cells versus AML-193 and THP-1 cells, bearing mutated p53, also revealed p53 as the topmost upstream regulator. Finally, expression of mutant p53 in MV4;11 cells reduced sensitivity to azacitidine-panobinostat combination, suggesting that p53 may be a predictor of response to epigenetic therapy in pediatric AML. [ABSTRACT FROM AUTHOR]

Childhood acute myeloid leukemia (AML) is frequently characterized by chromosomal instability. Approximately 50% of patients have disease relapse, and novel prognostic markers are needed to improve risk stratification. We performed genome-wide genotyping in 446 pediatric patients with de novo AML enrolled in Children's Oncology Group (COG) studies AAML0531, AAML03P1, and CCG2961. Affymetrix and Illumina Omni 2.5 platforms were used to evaluate copy-number alterations (CNAs) and determine their associations with treatment outcome. Data from Affymetrix and Illumina studies were jointly analyzed with ASCAT and GISTIC software. An average of 1.14 somatically acquired CNAs per patient were observed. Novel reoccurring altered genomic regions were identified, and the presence of CNAs was found to be associated with decreased 3-year overall survival (OS), event-free survival (EFS), and relapse risk from the end of induction 1 (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.2-2.4; HR, 1.4; 95% CI, 1.0-1.8; and HR, 1.4; 95% CI, 1.0-2.0, respectively). Analyses by risk group demonstrated decreased OS and EFS in the standard-risk group only (HR, 1.9; 95% CI, 1.1-3.3 and HR, 1.7; 95% CI, 1.1-2.6, respectively). Additional studies are required to test the prognostic significance of CNA presence in disease relapse in patients with AML. COG studies AAML0531, AAML03P1, and CCG2961 were registered at www.clinicaltrials.gov as #NCT01407757, #NCT00070174, and [ABSTRACT FROM AUTHOR]

In children with acute myeloid leukaemia ( AML), assessment of initial treatment response is an essential prognostic factor; methods more sensitive than morphology are still under evaluation. We report on the measurement of minimal residual disease ( MRD), by multicolour flow-cytometry in one centralized laboratory, in 142 children with newly diagnosed AML enrolled in the Associazione Italiana di EmatoOncologia Pediatrica- AML 2002/01 trial. At the end of the first induction course, MRD was <0·1% in 69, 0·1-1% in 16 and >1% in 51 patients. The 8-year disease-free survival ( DFS) of 125 children in morphological complete remission and with MRD <0·1%, 0·1-1% and ≥1% was 73·1 ± 5·6%, 37·8 ± 12·1% and 34·1 ± 8·8%, respectively ( P < 0·01). MRD was also available after the second induction course in 92/142 patients. MRD was ≥0·1% at the end of the first induction course in 36 patients; 13 reached an MRD <0·1% after the second one and their DFS was 45·4 ± 16·7% vs. 22·8 ± 8·9% in patients with persisting MRD ≥0·1% ( P = 0·037). Multivariate analysis demonstrated that MRD ≥0·1% after first induction course was, together with a monosomal karyotype, an independent adverse prognostic factor for DFS. Our results show that MRD detected by flow-cytometry after induction therapy predicts outcome in patients with childhood AML and can help stratifying post-remission treatment. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation (HSCT) represents the cornerstone of treatment in pediatric high-risk and relapsed acute myeloid leukemia (AML). The aim of the present study was to compare outcomes of pediatric patients with AML undergoing HSCT using 3 different conditioning regimens: total body irradiation (TBI) and cyclophosphamide (Cy); busulfan (Bu) and Cy; or Bu, Cy, and melphalan (Mel). In this retrospective study, registry data for patients > 2 and <18 years age undergoing matched allogeneic HSCT for AML in first complete remission (CR1) in 204 European Group for Blood and Marrow Transplantation centers between 2000 and 2010 were analyzed. Data were available for 631 patients; 458 patients received stem cells from a matched sibling donor and 173 from a matched unrelated donor. For 440 patients, bone marrow was used as stem cell source, and 191 patients received peripheral blood stem cells. One hundred nine patients received TBICy, 389 received BuCy, and 133 received BuCyMel as their preparatory regimen. Median follow-up was 55 months. Patients receiving BuCyMel showed a lower incidence of relapse at 5 years (14.7% versus 31.5% in BuCy versus 30% in TBICy, P  < .01) and higher overall survival (OS) (76.6% versus 64% versus 64.5%, P  = .04) and leukemia-free survival (LFS) (74.5% versus 58% versus 61.9%, P  < .01), with a comparable nonrelapse mortality (NRM) (10.8% versus 10.5% versus 8.1%, P  = .79). Acute graft-versus-host disease (GVHD) grades III and IV but not chronic GVHD, was higher in patients receiving BuCyMel. Older age at HSCT had an adverse impact on NRM and the use of peripheral blood as stem cell source was associated with increased chronic GVHD and NRM as well as lower LFS and OS. Among pediatric patients receiving HSCT for AML in CR1, the use of BuCyMel conditioning proved superior to TBICy and BuCy in reducing relapse and improving LFS. [ABSTRACT FROM AUTHOR]

The outcome for children with acute myeloid leukemia (AML) has improved significantly over the past 30 years, with complete remission and overall survival rates exceeding 90 and 60%, respectively, in recent clinical trials. However, these improvements have not been achieved by the introduction of new agents. Instead, intensification of standard chemotherapy, more precise risk classification, improvements in supportive care, and the use of minimal residual disease to monitor response to therapy have all contributed to this success. Nevertheless, novel therapies are needed, as the cure rates for many subtypes of childhood AML remain unacceptably low. Here, we briefly review advances in our understanding of the biology and genetics of AML, the results of recent clinical trials, and current recommendations for the treatment of children with AML. [ABSTRACT FROM AUTHOR]

Over the last four decades the survival of paediatric patients with acute myeloid leukaemia has gradually increased to 70% in high-income countries. The therapy is very intensive and associated with many acute and long-term side effects. The early death rate has been reduced to 1-4%. The acute toxicity is a limiting factor for improving survival in low-income countries. Transplant is associated with more endocrinological late effects while cardiotoxicity is more common after relapse. Reducing the physical costs of therapy without jeopardizing survival may be accomplished by optimal supportive care, less cardiotoxic anthracyclines, less consolidation courses and strict indications for stem cell transplantation. Analysing scenarios with different frequency of transplantation in first complete remission show similar overall survival rates, indicating that almost all patients can be spared the procedure in first remission. Reducing relapse risk is an effective way of reducing toxicity and more targeted therapy and improved risk group stratifications are needed. [ABSTRACT FROM AUTHOR]