Collaborative Efforts Driving Progress in Pediatric Acute Myeloid Leukemia

C Michel Zwaan, Edward A Kolb, Dirk Reinhardt, Jonas Abrahamsson, Souichi Adachi, Richard Aplenc, Eveline S J M De Bont, Barbara De Moerloose, Michael Dworzak, Brenda E S Gibson, Henrik Hasle, Guy Leverger, Franco Locatelli, Christine Ragu, Raul C Ribeiro, Carmelo Rizzari, Jeffrey E Rubnitz, Owen P Smith, Lillian Sung, Daisuke Tomizawa, Marry M van den Heuvel-Eibrink, Ursula Creutzig, Gertjan J L Kaspers, C Michel Zwaan, Edward A Kolb, Dirk Reinhardt, Jonas Abrahamsson, Souichi Adachi, Richard Aplenc, Eveline S J M De Bont, Barbara De Moerloose, Michael Dworzak, Brenda E S Gibson, Henrik Hasle, Guy Leverger, Franco Locatelli, Christine Ragu, Raul C Ribeiro, Carmelo Rizzari, Jeffrey E Rubnitz, Owen P Smith, Lillian Sung, Daisuke Tomizawa, Marry M van den Heuvel-Eibrink, Ursula Creutzig, Gertjan J L Kaspers

Abstract

Diagnosis, treatment, response monitoring, and outcome of pediatric acute myeloid leukemia (AML) have made enormous progress during the past decades. Because AML is a rare type of childhood cancer, with an incidence of approximately seven occurrences per 1 million children annually, national and international collaborative efforts have evolved. This overview describes these efforts and includes a summary of the history and contributions of each of the main collaborative pediatric AML groups worldwide. The focus is on translational and clinical research, which includes past, current, and future clinical trials. Separate sections concern acute promyelocytic leukemia, myeloid leukemia of Down syndrome, and relapsed AML. A plethora of novel antileukemic agents that have emerged, including new classes of drugs, are summarized as well. Finally, an important aspect of the treatment of pediatric AML--supportive care--and late effects are discussed. The future is bright, with a wide range of emerging innovative therapies and with more and more international collaboration that ultimately aim to cure all children with AML, with fewer adverse effects and without late effects.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.
Fig 1.
(A) Distribution of genetic abnormalities in pediatric acute myeloid leukemia (AML). Collaborating type I and type II mutations in pediatric AML. The circos plot depicts the frequency of the type II mutations and co-occurrence of type I mutations in patients with de novo pediatric AML. The length of the arch corresponds with the frequency of the type II mutation, and the width of the ribbon corresponds with the percentage of patients who have a specific type I mutation or combination of type I mutations. (B) Overview of co-occurring mutations in pediatric cytogenetically normal (CN) AML (N = 53). Each column represents a single occurrence. A colored field means that the occurrence is positive for a mutation or translocation in the corresponding gene(s). A white field indicates that the occurrence tested negative for a mutation or translocation in the corresponding gene(s). A gray field indicates an occurrence that could not be tested for mutations in the corresponding gene. dm, double mutations; ITD, internal tandem duplication; PTD, partial tandem duplication; sm, small mutations.

References

    1. Creutzig U, Van Den Heuvel-Eibrink MM, Gibson B, et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: Recommendations from an international expert panel. Blood. 2012;120:3167–3205.
    1. Kaspers GJL. Pediatric acute myeloid leukemia. Expert Rev Anticancer Ther. 2012;12:405–413.
    1. Pui C-H, Carroll WL, Meshinchi S, et al. Biology, risk stratification, and therapy of pediatric acute leukemias: An update. J Clin Oncol. 2011;29:551–565.
    1. Abrahamsson J, Forestier E, Heldrup J, et al. Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate. J Clin Oncol. 2011;29:310–315.
    1. Cooper TM, Franklin J, Gerbing RB, et al. AAML03P1, a pilot study of the safety of gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed childhood acute myeloid leukemia: A report from the Children's Oncology Group. Cancer. 2012;118:761–769.
    1. Creutzig U, Zimmermann M, Bourquin JP, et al. Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: Results from study AML-BFM 2004. Blood. 2013;122:37–43.
    1. Dluzniewska A, Balwierz W, Armata J, et al. Twenty years of Polish experience with three consecutive protocols for treatment of childhood acute myelogenous leukemia. Leukemia. 2005;19:2117–2124.
    1. Entz-Werle N, Suciu S, van der Werfften BJ, et al. Results of 58872 and 58921 trials in acute myeloblastic leukemia and relative value of chemotherapy vs allogeneic bone marrow transplantation in first complete remission: The EORTC Children Leukemia Group report. Leukemia. 2005;19:2072–2081.
    1. Gamis AS, Alonzo TA, Meshinchi S, et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: Results from the randomized phase III Children's Oncology Group Trial AAML0531. J Clin Oncol. 2014;32:3021–3032.
    1. Gibson BES, Webb DKH, Howman AJ, et al. Results of a randomized trial in children with acute myeloid leukemia: Medical Research Council AML12 trial. Br J Haematol. 2011;155:366–376.
    1. Pession A, Masetti R, Rizzari C, et al. Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia. Blood. 2013;122:170–178.
    1. Rubnitz JE, Inaba H, Dahl G, et al. Minimal residual disease-directed therapy for childhood acute myeloid leukemia: Results of the AML02 multicentre trial. Lancet Oncol. 2010;11:543–552.
    1. Tomizawa D, Tawa A, Watanabe T, et al. Appropriate dose reduction in induction therapy is essential for the treatment of infants with acute myeloid leukemia: A report from the Japanese pediatric leukemia/lymphoma study group. Int J Hematol. 2013;98:578–588.
    1. Tomizawa D, Tawa A, Watanabe T, et al. Excess treatment reduction including anthracyclines results in higher incidence of relapse in core binding factor acute myeloid leukemia in children. Leukemia. 2013;27:2413–2416.
    1. Tsukimoto I, Tawa A, Horibe K, et al. Risk-stratified therapy and the intensive use of cytarabine improves the outcome in childhood acute myeloid leukemia: The AML99 trial from the Japanese childhood AML cooperative study group. J Clin Oncol. 2009;27:4007–4013.
    1. Hasle H, Abrahamsson J, Forestier E, et al. Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: Results from NOPHO-AML 2004. Blood. 2012;120:978–984.
    1. Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. Science. 2013;339:1546–1558.
    1. Kelly LM, Gilliland DG. Genetics of myeloid leukemias. Annu Rev Genomics Hum Genet. 2002;3:179–198.
    1. Hollink IHIM, Zwaan CM, Zimmermann M, et al. Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML. Leukemia. 2009;23:262–270.
    1. Brown P, Mcintyre E, Rau R, et al. The incidence and clinical significance of nucleophosmin mutations in childhood AML. Hematology. 2008:979–985.
    1. Ho PA, Alonzo TA, Gerbing RB, et al. Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): A report from the Children's Oncology Group. Blood. 2009;113:6558–6566.
    1. Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, et al. Characterization of CEBPA mutations and promoter hypermethylation in pediatric acute myeloid leukemia. Haematologica. 2011;96:384–392.
    1. Matsuo H, Kajihara M, Tomizawa D, et al. Prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group. Blood Cancer J. 2014;4:e226.
    1. Mrózek K, Bloomfield CD. Chromosome aberrations, gene mutations, and expression changes, and prognosis in adult acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2006:169–177.
    1. Zwaan CM, Meshinchi S, Radich JP, et al. FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: Prognostic significance and relation to cellular drug resistance. Blood. 2003;102:2387–2394.
    1. Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. 2006;108:3654–3661.
    1. Cloos J, Goemans BF, Hess CJ, et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia. 2006;20:1217–1220.
    1. Bachas C, Schuurhuis GJ, Hollink IHIM, et al. High-frequency type I/II mutational shifts between diagnosis and relapse are associated with outcome in pediatric AML: Implications for personalized medicine. Blood. 2010;116:2752–2758.
    1. Smith CC, Wang Q, Chin C, et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukemia. Nature. 2012;485:260–263.
    1. Meshinchi S, Stirewalt DL, Alonzo Ta, et al. Structural and numerical variation of FLT3/ITD in pediatric AML: Brief report. Blood. 2012:4930–4933.
    1. Balgobind BV, Raimondi SC, Harbott J, et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: Results of an international retrospective study. Cancer. 2009;114:2489–2496.
    1. Meyer C, Hofmann J, Burmeister T, et al. The MLL recombinome of acute leukemias in 2013. Leukemia. 2013;27:2165–2176.
    1. Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, et al. NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. 2011;118:3645–3656.
    1. Ostronoff F, Othus M, Gerbing RB, et al. NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: A COG and SWOG report. Blood. 2015;124:2400–2408.
    1. de Rooij JD, Hollink IH, Arentsen-Peters ST, et al. NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern. Leukemia. 2013;27:2280–2288.
    1. Reinhardt D, Diekamp S, Langebrake C, et al. Acute megakaryoblastic leukemia in children and adolescents, excluding Down's syndrome: Improved outcome with intensified induction treatment. Leukemia. 2005;19:1495–1496.
    1. O'Brien MM, Cao X, Pounds S, et al. Prognostic features in acute megakaryoblastic leukemia in children without Down syndrome: A report from the AML02 multicenter trial and the Children's Oncology Group Study POG 9421. Leukemia. 2012:731–734.
    1. Masetti R, Pigazzi M, Togni M, et al. CBFA2T3-GLIS2 fusion transcript is a novel common feature in pediatric, cytogenetically normal AML, not restricted to FAB M7 subtype. Blood. 2013;121:3469–3472.
    1. Gruber TA, Gedman AL, Zhang J, et al. An inv(16)(p13.3q24.3) –encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell. 2012;22:683–697.
    1. Von Bergh ARM, Van Drunen E, Van Wering ER, et al. High incidence of t(7;12)(q36;p13) in infant AML but not in infant ALL, with a dismal outcome and ectopic expression of HLXB9. Genes Chromosomes Cancer. 2006;45:731–739.
    1. Sandahl JD, Coenen EA, Forestier E, et al. T(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: An international study of 62 patients. Haematologica. 2014;99:865–872.
    1. Tarlock K, Alonzo TA, Moraleda PP, et al. Acute myeloid leukemia (AML) with t(6;9)(p23;q34) is associated with poor outcome in childhood AML regardless of FLT3-ITD status: A report from the Children's Oncology Group. Br J Haematol. 2014;166:254–259.
    1. Coenen EA, Zwaan CM, Reinhardt D, et al. Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: A collaborative study by the International Berlin-Frankfurt-Munster AML study group. Blood. 2013;122:2704–2713.
    1. Linch DC, Hills RK, Burnett AK, et al. Impact of FLT3 ITD mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia Impact of FLT3 ITD mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. Blood. 2014;124:273–276.
    1. Walter RB, Othus M, Burnett AK, et al. Resistance prediction in AML: Analysis of 4,601 patients from MRC/NCRI, HOVON/SAKK, SWOG, and MD Anderson Cancer Center. Leukemia. 2015;29:312–320.
    1. Pratcorona M, Brunet S, Nomdedéu J, et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: Relevance to post-remission therapy. Blood. 2013;121:2734–2738.
    1. Hollink IH, Van den Heuvel-Eibrink MM, Zimmermann M, et al. Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia. Blood. 2009;113:5951–5960.
    1. Ho PA, Alonzo TA, Gerbing RB, et al. Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): A report from the Children's Oncology Group. Blood. 2010;116:702–710.
    1. Balgobind BV, Lugthart S, Hollink IH, et al. EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia. Leukemia. 2010;24:942–949.
    1. Ho PA, Alonzo TA, Gerbing RB, et al. High EVI1 Expression is associated with MLL rearrangements and predicts decreased survival in pediatric acute myeloid leukemia: A report from the Children's Oncology Group. Br J Haematol. 2013;162:670–677.
    1. Matsuo H, Kajihara M, Tomizawa D, et al. EVI1 overexpression is a poor prognostic factor in pediatric patients with mixed lineage leukemia-AF9 rearranged acute myeloid leukemia. Haematologica. 2014;99:e225–e227.
    1. Hasle H, Alonzo TA, Auvrignon A, et al. Monosomy 7 and deletion 7q in children and adolescents with acute myeloid leukemia: An international retrospective study. Blood. 2007;109:4641–4647.
    1. Balgobind BV, Hollink IH, Arentsen-Peters ST, et al. Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia. Haematologica. 2011;96:1478–1487.
    1. Berman JN, Gerbing RB, Alonzo TA, et al. Prevalence and clinical implications of NRAS mutations in childhood AML: A report from the Children's Oncology Group. Leukemia. 2011;25:1039–1042.
    1. Meshinchi S, Stirewalt D. Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood. 2003;102:1474–1479.
    1. Burgess MR, Hwang E, Firestone AJ, et al. Preclinical efficacy of MEK inhibition in Nras-mutant AML. Blood. 2014;124:3947–3955.
    1. Kampen KR, Ter Elst A, Mahmud H, et al. Insights in dynamic kinome reprogramming as a consequence of MEK inhibition in MLL-rearranged AML. Leukemia. 2013;28:589–599.
    1. Meshinchi S, Thomson B, Finn LS, et al. Comparison of multidimensional flow cytometry with standard morphology for evaluation of early marrow response in pediatric acute lymphoblastic leukemia. J Pediatr Hematol. 2001;23:585–590.
    1. van der Velden VH, van der Sluijs-Geling A, Gibson BE, et al. Clinical significance of flowcytometric minimal residual disease detection in pediatric acute myeloid leukemia patients treated according to the DCOG ANLL97/MRC AML12 protocol. Leukemia. 2010;24:1599–1606.
    1. Sievers EL, Lange BJ, Alonzo TA, et al. Immunophenotypic evidence of leukemia after induction therapy predicts relapse: Results from a prospective Children's Cancer Group study of 252 patients with acute myeloid leukemia. Blood. 2003;101:3398–3406.
    1. Loken MR, Alonzo TA, Pardo L, et al. Residual disease detected by multidimensional flow cytometry signifies high relapse risk in patients with de novo acute myeloid leukemia: A report from Children's Oncology Group. Blood. 2012;120:1581–1588.
    1. Inaba H, Coustan-Smith E, Cao X, et al. Comparative analysis of different approaches to measure treatment response in acute myeloid leukemia. J Clin Oncol. 2012;30:3625–3632.
    1. Ommen HB, Schnittger S, Jovanovic JV, et al. Strikingly different molecular relapse kinetics in NPM1c, PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 acute myeloid leukemias. Blood. 2010;115:198–205.
    1. Creutzig U, Zimmermann M, Ritter J, et al. Treatment strategies and long-term results in pediatric patients treated in four consecutive AML-BFM trials. Leukemia. 2005;19:2030–2042.
    1. Mandelli F, Vignetti M, Suciu S, et al. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: The EORTC and GIMEMA groups study AML-10. J Clin Oncol. 2009;27:5397–5403.
    1. Löwenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361:1235–1248.
    1. Lee JH, Joo YD, Kim H, et al. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood. 2011;118:3832–3841.
    1. Armenian SH, Hudson MM, Mulder RL, et al. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: A report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 2015;16:e123–e136.
    1. Burnett AK, Russell NH, Hills RK, et al. Optimization of chemotherapy for younger patients with acute myeloid leukemia: Results of the medical research council AML15 trial. J Clin Oncol. 2013;31:3360–3368.
    1. Bishop JF. Approaches to induction therapy with adult acute myeloid leukemia. Acta Haematol. 1998;99:133–137.
    1. Weick BJK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: A Southwest Oncology Group study. Blood. 1996;88:2841–2851.
    1. Ravindranath Y, Chang M, Steuber CP, et al. Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): A review of four consecutive childhood AML trials conducted between 1981 and 2000. Leukemia. 2005;19:2101–2116.
    1. Creutzig U, Zimmermann M, Bourquin JP, et al. Second induction with high-dose cytarabine and mitoxantrone: Different impact on pediatric AML patients with t(8;21) and with inv(16) Blood. 2011;118:5409–5415.
    1. Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: Results of the MRC AML15 Trial. J Clin Oncol. 2011;29:369–377.
    1. Burnett AK, Russell NH, Hills RK, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012;30:3924–3931.
    1. Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): A randomized, open-label, phase 3 study. Lancet. 2012;379:1508–1516.
    1. Tomizawa D, Tabuchi K, Kinoshita A, et al. Repetitive cycles of high-dose cytarabine are effective for childhood acute myeloid leukemia: long-term outcome of the children with AML Treated on two consecutive trials of Tokyo Children's Cancer Study Group. Pediatr Blood Cancer. 2007;49:127–132.
    1. Harrison CJ, Hills RK, Moorman AV, et al. Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment Trials AML 10 and 12. J Clin Oncol. 2010;28:2674–2681.
    1. Perel Y, Auvrignon a, Leblanc T, et al. Treatment of childhood acute myeloblastic leukemia: Dose intensification improves outcome and maintenance therapy is of no benefit—Multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group. Leukemia. 2005;19:2082–2089.
    1. Kaspers G. How I treat pediatric relapsed acute myeloid leuaemia. Br J Haematol. 2014;166:636–645.
    1. Lange, Beverly J, Yang RK, Gan J, et al. Soluble Interleukin-2 receptor a activation in a Children's Oncology Group randomized trial of interleukin-2 therapy for pediatric acute myeloid leukemia. Pediatr Blood Cancer. 2011;57:398–405.
    1. Kaspers GJL, Zimmermann M, Reinhardt D, et al. Improved outcome in pediatric relapsed acute myeloid leukemia: Results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013;31:599–607.
    1. Pui C-H, Schrappe M, Ribeiro RC, et al. Childhood and adolescent lymphoid and myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2004:118–145.
    1. Kaspers GJ, Creutzig U. Pediatric acute myeloid leukemia: International progress and future directions. Leukemia. 2005;19:2025–2029.
    1. Abbott BL, Rubnitz JE, Tong X, et al. Clinical significance of central nervous system involvement at diagnosis of pediatric acute myeloid leukemia: A single institution's experience. Leukemia. 2003;17:2090–2096.
    1. Pui CH, Howard SC. Current management and challenges of malignant disease in the CNS in pediatric leukemia. Lancet Oncol. 2008;9:257–268.
    1. Creutzig U, Reinhardt D. Current controversies: Which patients with acute myeloid leukaemia should receive a bone marrow transplantation? A European view. Br J Haematol. 2002;118:365–377.
    1. Chen AR, Alonzo TA, Woods WG, et al. Current controversies: Which patients with acute myeloid leukemia should receive a bone marrow transplantation? An American view. Br J Haematol. 2002;118:378–384.
    1. Bleakley M, Lau L, Shaw PJ, et al. Acute myeloid leukemia bone marrow transplantation for pediatric AML in first remission: A systematic review and meta-analysis. Bone Marrow Transplant. 2002;29:843–852.
    1. Niewerth D, Creutzig U, Bierings MB, et al. A review on allogeneic stem cell transplantation for newly diagnosed pediatric acute myeloid leukemia. Blood. 2010;116:2205–2214.
    1. Hasle H. A critical review of which children with acute myeloid leukemia need stem cell procedures. Br J Haematol. 2014;166:23–33.
    1. Leung W, Pui CH, Coustan-Smith E, et al. Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia. Blood. 2012;120:468–472.
    1. Goemans BF, Tamminga RY, Corbijn CM, et al. Outcome for children with relapsed acute myeloid leukemia in the Netherlands following initial treatment between 1980 and 1998: Survival after chemotherapy only? Haematologica. 2008;93:1418–1420.
    1. Beier R, Albert MH, Bader P, et al. Allo-SCT using BU, CY, and melphalan for children with AML in second CR. Bone Marrow Transplant. 2012:651–656.
    1. Testi AM, Biondi A, Lo Coco F, et al. GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood. 2005;106:447–453.
    1. Gregory J, Kim H, Alonzo T, et al. Treatment of children with acute promyelocytic leukemia: Results of the first North American Intergroup Trial INT0129. Pediatr Blood Cancer. 2009;53:1005–1010.
    1. Soignet SL, Maslak P, Wang Z-G, et al. Complete remission after treatment of acute promyelocytic leukemia. N Engl J Med. 1998;339:1341–1348.
    1. Mathews V, George B, Chendamarai E, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: Long-term follow-up data. J Clin Oncol. 2010;28:3866–3871.
    1. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–121.
    1. Zwaan CM, Reinhardt D, Hitzler J, et al. Acute leukemias in children with Down syndrome. Hematol Oncol Clin North Am. 2010;24:19–34.
    1. Sorrell AD, Alonzo TA, Hilden JM, et al. Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on Children's Oncology Group trial A2971: A report from the Children's Oncology Group. Cancer. 2012;118:4806–4814.
    1. Kudo K, Kojima S, Tabuchi K, et al. Prospective study of a pirarubicin, intermediate-dose cytarabine, and etoposide regimen in children with Down syndrome and acute myeloid leukemia: The Japanese childhood AML cooperative study group. J Clin Oncol. 2007;25:5442–5447.
    1. Creutzig U, Reinhardt D, Diekamp S, et al. AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia. 2005;19:1355–1360.
    1. Taga T, Saito AM, Kudo K, et al. Clinical characteristics and outcome of refractory/relapsed myeloid leukemia in children with Down syndrome. Blood. 2012;120:1810–1815.
    1. Webb DK, Wheatley K, Harrison G, et al. Outcome for children with relapsed acute myeloid leukemia following initial therapy in the Medical Research Council (MRC) AML 10 trial: MRC Childhood Leukemia Working Party. Leukemia. 1999;13:25–31.
    1. Sander A, Zimmermann M, Dworzak M, et al. Consequent and intensified relapse therapy improved survival in pediatric AML: Results of relapse treatment in 379 patients of three consecutive AML-BFM trials. Leukemia. 2010;24:1422–1428.
    1. Cooper TM, Alonzo TA, Gerbing RB, et al. AAML0523: A report from the Children's Oncology Group on the efficacy of clofarabine in combination with cytarabine in pediatric patients with recurrent acute myeloid leukemia. Cancer. 2014;120:2482–2489.
    1. Horton TM, Perentesis JP, Gamis AS, et al. A Phase 2 study of bortezomib combined with either idarubicin/cytarabine or cytarabine/etoposide in children with relapsed, refractory or secondary acute myeloid leukemia: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2014;61:1754–1760.
    1. Gorman M. Outcome for children treated for relapsed or refractory acute myelogenous leukemia (rAML): A Therapeutic Advances in Childhood Leukemia (TACL) consortium study. Pediatr Blood Cancer. 2010;55:421–429.
    1. Nakayama H, Tabuchi K, Tawa A, et al. Outcome of children with relapsed acute myeloid leukemia following initial therapy under the AML99 protocol. Int J Hematol. 2014;100:171–179.
    1. Creutzig U, Zimmermann M, Dworzak MN, et al. The prognostic significance of early treatment response in pediatric relapsed acute myeloid leukemia: Results of the international study Relapsed AML 2001/01. Haematologica. 2014;99:1472–1478.
    1. Moore AS, Kearns PR, Knapper S, et al. Novel therapies for children with acute myeloid leukemia. Leukemia. 2013;27:1451–1460.
    1. Tasian SK, Pollard JA, Aplenc R. Molecular therapeutic approaches for pediatric acute myeloid leukemia. Front Oncol. 2014;4:55.
    1. Shukla N, Kobos R, Renaud T, et al. Phase II trial of clofarabine with topotecan, vinorelbine, and thiotepa in pediatric patients with relapsed or refractory acute leukemia. Pediatr Blood Cancer. 2014;61:431–435.
    1. Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123:3239–3246.
    1. Lancet JE, Roboz GJ, Cripe LD, et al. A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia. Haematologica. 2014;100:231–237.
    1. Zwaan CM, Reinhardt D, Corbacioglu S, et al. Gemtuzumab ozogamicin: First clinical experiences in children with relapsed/refractory acute myeloid leukemia treated on compassionate-use basis. Blood. 2003;101:3868–3871.
    1. Zwaan CM, Reinhardt D, Zimmerman M, et al. Salvage treatment for children with refractory first or second relapse of acute myeloid leukemia with gemtuzumab ozogamicin: Results of a phase II study. Br J Haematol. 2010;148:768–776.
    1. Laszlo GS, Gudgeon CJ, Harrington KH, et al. Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML. Blood. 2014;123:554–561.
    1. Röllig C, Müller-Tidow C, Hüttmann A, et al. Sorafenib versus placebo in addition to standard therapy in younger patients with newly diagnosed acute myeloid leukemia: Results from 267 patients treated in the randomized placebo-controlled SALSoraml trial. Presented at the American Society of Hematology Annual Meeting; December 6-9, 2014; San Francisco, CA. (abstr 6)
    1. Galanis A, Ma H, Rajkhowa T, et al. Crenolanib is a potent inhibitor of flt3 with activity against resistance-conferring point mutants. Blood. 2014;123:94–100.
    1. Goemans BF, Zwaan CM, Miller M, et al. Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia. 2005;19:1536–1542.
    1. Pollard JA, Alonzo TA, Gerbing RB, et al. Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML. Blood. 2010;115:2372–2379.
    1. Manara E, Bisio V, Masetti R, et al. Core-binding factor acute myeloid leukemia in pediatric patients enrolled in the AIEOP AML 2002/01 trial: Screening and prognostic impact of c-KIT mutations. Leukemia. 2014;28:1132–1134.
    1. Shimada A, Taki T, Tabuchi K. KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): A study of the Japanese Childhood AML Cooperative Study Group. Blood. 2006;107:1806–1809.
    1. Jain N, Curran E, Iyengar NM, et al. Phase 2 study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: A University of Chicago phase 2 consortium trial. Clin Cancer Res. 2014;20:490–498.
    1. Döhner H, Lübbert M, Fiedler W, et al. Randomized, phase 2 trial comparing low-dose cytarabine with or without volasertib in AML patients not suitable for intensive induction therapy. Blood. 2014:1426–1434.
    1. Kantarjian HM, Martinelli G, Jabbour EJ, et al. Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer. 2013;119:2611–2619.
    1. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142–152.
    1. Stumpel D, Schneider P, Seslija L, et al. Connectivity mapping identifies HDAC inhibitors for the treatment of t(4;11)-positive infant acute lymphoblastic leukemia. Leukemia. 2012;26:682–692.
    1. Daigle SR, Olhava EJ, Therkelsen CA, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2014;20:53–65.
    1. Stein EM, Tallman MS. Mixed lineage rearranged leukemia. Curr Opin Hematol. 2015;22:92–96.
    1. Zuber J, Shi J, Wang E, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011;478:524–528.
    1. Mussai F, Egan S, Higginbotham-Jones J, et al. Arginine dependence of acute myeloid leukemia blast proliferation: A novel therapeutic target. Blood. 2015;125:2386–2397.
    1. Lancet JE. A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia. Haematologica. 2015;100:231–237.
    1. Zwaan CM, Rizzari C, Mechinaud F, et al. Dasatinib in children and adolescents with relapsed or refractory leukemia: Results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium. J Clin Oncol. 2013;31:2460–2468.
    1. Slats AM, Egeler RM, van der Does-van den Berg A, et al. Causes of death—other than progressive leukemia—in childhood acute lymphoblastic (ALL) and myeloid leukemia (AML): The Dutch Childhood Oncology Group experience. Leukemia. 2005;19:537–544.
    1. Creutzig U, Zimmermann M, Reinhardt D, et al. Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: Analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98. J Clin Oncol. 2004;22:4384–4393.
    1. Sung L, Aplenc R, Alonzo TA, et al. Effectiveness of supportive care measures to reduce infections in pediatric AML: A report from the Children's Oncology Group. Blood. 2013;121:3573–3577.
    1. Groll AH, Castagnola E, Cesaro S, et al. Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in pediatric patients with cancer or allogeneic hemopoietic stem-cell transplantation. Lancet Oncol. 2014;15:e327–e340.
    1. Van de Wetering MD, van Woensel JB, Lawrie TA. Prophylactic antibiotics for preventing Gram-positive infections associated with long-term central venous catheters in oncology patients. Cochrane Database Syst Rev. 2013;11:1–33.
    1. Alexander S, Nieder M, Zerr DM, et al. Prevention of bacterial infection in pediatric oncology: What do we know, what can we learn? Pediatr Blood Cancer. 2012;59:16–20.
    1. Dvorak CC, Fisher BT, Sung L, et al. Antifungal prophylaxis in pediatric hematology/oncology: New choices and new data. Pediatr Blood Cancer. 2012;59:21–26.
    1. Sung L, Nathan PC, Alibhai SMH, et al. Meta-analysis: Effect of prophylactic hematopoietic colony-stimulating factors on mortality and outcomes of infection. Ann Intern Med. 2007;147:400–411.
    1. Wheatley K, Goldstone AH, Littlewood T, et al. Randomized placebo-controlled trial of granulocyte colony stimulating factor (G-CSF) as supportive care after induction chemotherapy in adult patients with acute myeloid leukaemia: A study of the United Kingdom Medical Research Council Adult Leukemia Working Party. Br J Haematol. 2009;146:54–63.
    1. Ehlers S, Herbst C, Zimmermann M, et al. Granulocyte colony-stimulating factor (G-CSF) treatment of childhood acute myeloid leukemias that overexpress the differentiation-defective G-CSF receptor isoform IV is associated with a higher incidence of relapse. J Clin Oncol. 2010;28:2591–2597.
    1. Oberoi S, Lehrnbecher T, Phillips B, et al. Leukapheresis and low-dose chemotherapy do not reduce early mortality in acute myeloid leukemia hyperleukocytosis: A systematic review and meta-analysis. Leuk Res. 2014;38:460–468.
    1. Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol. 2012;30:4427–4438.
    1. Sung L, Robinson P, Treister N, et al. Guideline for the prevention of oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation. BMJ Support Palliat Care. doi: [epub ahead of print on March 27, 2015]

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