Treatments for children and adolescents with AML

Hyery Kim, Hyery Kim

Abstract

In recent decades, survival rates for childhood acute myeloid leukemia have remarkably improved, owing to chemotherapy intensification, allogeneic hematopoietic stem cell transplantation, and improved supportive care. Furthermore, treatment protocols have evolved and are currently better matched to prognostic factors and treatment responses. Recently, new molecular prognostic factors were discovered via leukemia genomic studies. Moreover, new tumor subtypes with independent gene expression profiles have been characterized. To broaden the therapeutic options for patients with poor prognoses, therapies that target specific candidate mutations are being identified. Additionally, new drugs are undergoing clinical trials, and immunotherapy is attracting significant interest as a treatment option for recurrent or refractory childhood acute myeloid leukemia.

Keywords: Acute myeloid leukemia; Adolescents; Childhood; Prognosis; Survival; Treatment.

Conflict of interest statement

Authors’ Disclosures of Potential Conflicts of Interest

No potential conflicts of interest relevant to this article were reported.

References

    1. Rubnitz JE. How I treat pediatric acute myeloid leukemia. Blood. 2012;119:5980–8. doi: 10.1182/blood-2012-02-392506.
    1. Kaspers GJ, Creutzig U. Pediatric acute myeloid leukemia: international progress and future directions. Leukemia. 2005;19:2025–9. doi: 10.1038/sj.leu.2403958.
    1. Gibson BE, Wheatley K, Hann IM, et al. Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia. 2005;19:2130–8. doi: 10.1038/sj.leu.2403924.
    1. Rasche M, Zimmermann M, Borschel L, et al. Successes and challenges in the treatment of pediatric acute myeloid leukemia: a retrospective analysis of the AML-BFM trials from 1987 to 2012. Leukemia. 2018;32:2167–77. doi: 10.1038/s41375-018-0071-7.
    1. Rubnitz JE, Inaba H, Dahl G, et al. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol. 2010;11:543–52. doi: 10.1016/S1470-2045(10)70090-5.
    1. Arber DA. The 2016 WHO classification of acute myeloid leukemia: what the practicing clinician needs to know. Semin Hematol. 2019;56:90–5. doi: 10.1053/j.seminhematol.2018.08.002.
    1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405. doi: 10.1182/blood-2016-03-643544.
    1. Davila J, Slotkin E, Renaud T. Relapsed and refractory pediatric acute myeloid leukemia: current and emerging treatments. Paediatr Drugs. 2014;16:151–68. doi: 10.1007/s40272-013-0048-y.
    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;32:3021–32. doi: 10.1200/JCO.2014.55.3628.
    1. Nagarajan R, Gerbing R, Alonzo T, et al. Quality of life in pediatric acute myeloid leukemia: report from the Children's Oncology Group. Cancer Med. 2019;8:4454–64. doi: 10.1002/cam4.2337.
    1. Hann IM, Stevens RF, Goldstone AH, et al. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Blood. 1997;89:2311–8. doi: 10.1182/blood.V89.7.2311.
    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;31:3360–8. doi: 10.1200/JCO.2012.47.4874.
    1. Creutzig U, Ritter J, Zimmermann M, et al. Improved treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine and mitoxantrone: results of Study Acute Myeloid Leukemia-Berlin-Frankfurt-Munster 93. J Clin Oncol. 2001;19:2705–13. doi: 10.1200/JCO.2001.19.10.2705.
    1. Creutzig U, Ritter J, Zimmermann M, et al. Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group. Leukemia. 2001;15:348–54. doi: 10.1038/sj.leu.2402046.
    1. Gibson BE, Webb DK, Howman AJ, et al. Results of a randomized trial in children with acute myeloid leukaemia: medical research council AML12 trial. Br J Haematol. 2011;155:366–76. doi: 10.1111/j.1365-2141.2011.08851.x.
    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. doi: 10.1182/blood-2013-02-484097.
    1. Getz KD, Alonzo TA, Sung L, et al. Four versus five chemotherapy courses in patients with low risk acute myeloid leukemia: a Children's Oncology Group report. J Clin Oncol. 2017;35(Suppl 15):10515. doi: 10.1200/JCO.2017.35.15_suppl.10515.
    1. Aplenc R, Alonzo TA, Gerbing RB, et al. Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: a report from the Children's Oncology Group. J Clin Oncol. 2008;26:2390–3295. doi: 10.1200/JCO.2007.13.0096.
    1. Jen EY, Ko CW, Lee JE, et al. FDA approval: gemtuzumab ozogamicin for the treatment of adults with newly diagnosed CD33-positive acute myeloid leukemia. Clin Cancer Res. 2018;24:3242–6. doi: 10.1158/1078-0432.CCR-17-3179.
    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;118:761–9. doi: 10.1002/cncr.26190.
    1. Woods WG, Neudorf S, Gold S, et al. A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood. 2001;97:56–62. doi: 10.1182/blood.V97.1.56.
    1. Ravindranath Y, Yeager AM, Chang MN, et al. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group. N Engl J Med. 1996;334:1428–34. doi: 10.1056/NEJM199605303342203.
    1. Horan JT, Alonzo TA, Lyman GH, et al. Impact of disease risk on efficacy of matched related bone marrow transplantation for pediatric acute myeloid leukemia: the Children's Oncology Group. J Clin Oncol. 2008;26:5797–801. doi: 10.1200/JCO.2007.13.5244.
    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;27:4007–13. doi: 10.1200/JCO.2008.18.7948.
    1. Niewerth D, Creutzig U, Bierings MB, Kaspers GJ. A review on allogeneic stem cell transplantation for newly diagnosed pediatric acute myeloid leukemia. Blood. 2010;116:2205–14. doi: 10.1182/blood-2010-01-261800.
    1. Bitan M, He W, Zhang MJ, et al. Transplantation for children with acute myeloid leukemia: a comparison of outcomes with reduced intensity and myeloablative regimens. Blood. 2014;123:1615–20. doi: 10.1182/blood-2013-10-535716.
    1. Harris AC, Boelens JJ, Ahn KW, et al. Comparison of outcomes for myeloablative conditioning regimens combining busulfan with either cyclophosphamide or fludarabine in children. Blood (ASH Annual Meeting Abstracts) 2016;128(Suppl 22):664. doi: 10.1182/blood.V128.22.664.664.
    1. Weisser M, Kern W, Rauhut S, et al. Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia. 2005;19:1416–23. doi: 10.1038/sj.leu.2403809.
    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;120:1581–8. doi: 10.1182/blood-2012-02-408336.
    1. Viehmann S, Teigler-Schlegel A, Bruch J, Langebrake C, Reinhardt D, Harbott J. Monitoring of minimal residual disease (MRD) by real-time quantitative reverse transcription PCR (RQ-RT-PCR) in childhood acute myeloid leukemia with AML1/ETO rearrangement. Leukemia. 2003;17:1130–6. doi: 10.1038/sj.leu.2402959.
    1. Yin JA, O'Brien MA, Hills RK, Daly SB, Wheatley K, Burnett AK. Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial. Blood. 2012;120:2826–35. doi: 10.1182/blood-2012-06-435669.
    1. Gaballa S, Saliba R, Oran B, et al. Relapse risk and survival in patients with FLT3 mutated acute myeloid leukemia undergoing stem cell transplantation. Am J Hematol. 2017;92:331–7. doi: 10.1002/ajh.24632.
    1. Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374:422–33. doi: 10.1056/NEJMoa1507471.
    1. Zhao X, Wang Z, Ruan G, et al. Impact of pre-transplantation minimal residual disease determined by multiparameter flow cytometry on the outcome of AML patients with FLT3-ITD after allogeneic stem cell transplantation. Ann Hematol. 2018;97:967–75. doi: 10.1007/s00277-018-3265-1.
    1. Voso MT, Ottone T, Lavorgna S, et al. MRD in AML: the role of new techniques. Front Oncol. 2019;9:655. doi: 10.3389/fonc.2019.00655.
    1. von Neuhoff C, Reinhardt D, Sander A, et al. Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. J Clin Oncol. 2010;28:2682–9. doi: 10.1200/JCO.2009.25.6321.
    1. Kutny MA, Alonzo TA, Gerbing RB, et al. Arsenic trioxide consolidation allows anthracycline dose reduction for pediatric patients with acute promyelocytic leukemia: report from the Children's Oncology Group phase III historically controlled trial AAML0631. J Clin Oncol. 2017;35:3021–9. doi: 10.1200/JCO.2016.71.6183.
    1. Cortes J, Kantarjian HM, Kadia TM, et al. Value of minimal residual disease (MRD) monitoring using real-time quantitative PCR in patients with acute promyelocytic leukemia (APL) treated with ATRA, ATO, +/- GO. Blood (ASH Annual Meeting Abstracts) 2019;134(Suppl):3851. doi: 10.1182/blood-2019-124599.
    1. Fenaux P, Chastang C, Chevret S, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999;94:1192–200. doi: 10.1182/blood.V94.4.1192.
    1. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116:3751–7. doi: 10.1182/blood-2010-02-269621.
    1. Gamis AS, Alonzo TA, Gerbing RB, et al. Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood. 2011;118:6752–9. quiz 996. doi: 10.1182/blood-2011-04-350017.
    1. Ravindranath Y, Abella E, Krischer JP, et al. Acute myeloid leukemia (AML) in Down's syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498. Blood. 1992;80:2210–4. doi: 10.1182/blood.V80.9.2210.2210.
    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;118:4806–14. doi: 10.1002/cncr.27484.
    1. Taub JW, Berman JN, Hitzler JK, et al. Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial. Blood. 2017;129:3304–13. doi: 10.1182/blood-2017-01-764324.
    1. Hitzler JK, Berman J, Gerbing RB, et al. High-dose cytarabine is indispensable for the survival of children with myeloid leukemia of down syndrome despite negative minimal residual disease post-induction. Blood (ASH Annual Meeting Abstracts) 2019;134(Suppl):118. doi: 10.1182/blood-2019-126723.
    1. Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. 2006;108:3654–61. doi: 10.1182/blood-2006-03-009233.
    1. Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014;124:3441–9. doi: 10.1182/blood-2014-05-578070.
    1. Tarlock K, Alonzo TA, Gerbing RB, et al. Gemtuzumab ozogamicin reduces relapse risk in FLT3/ITD acute myeloid leukemia: a report from the Children's Oncology Group. Clin Cancer Res. 2016;22:1951–7. doi: 10.1158/1078-0432.CCR-15-1349.
    1. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381:1728–40. doi: 10.1056/NEJMoa1902688.
    1. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454–64. doi: 10.1056/NEJMoa1614359.
    1. Webb DK. Management of relapsed acute myeloid leukaemia. Br J Haematol. 1999;106:851–9. doi: 10.1046/j.1365-2141.1999.01629.x.
    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;24:1422–8. doi: 10.1038/leu.2010.127.
    1. Burnett AK, Hills RK, Milligan DW, et al. Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol. 2010;28:586–95. doi: 10.1200/JCO.2009.22.9088.
    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;100:171–9. doi: 10.1007/s12185-014-1616-9.
    1. Kaspers GJ, 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. doi: 10.1200/JCO.2012.43.7384.
    1. Shukla N, Kobos R, Renaud T, Steinherz LJ, Steinherz PG. Phase II trial of clofarabine with topotecan, vinorelbine, and thiotepa in pediatric patients with relapsed or refractory acute leukemia. Pediatr Blood Cancer. 2014;61:431–5. doi: 10.1002/pbc.24789.
    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;120:2482–9. doi: 10.1002/cncr.28674.
    1. Miano M, Pistorio A, Putti MC, et al. Clofarabine, cyclophosphamide and etoposide for the treatment of relapsed or resistant acute leukemia in pediatric patients. Leuk Lymphoma. 2012;53:1693–8. doi: 10.3109/10428194.2012.663915.
    1. Niktoreh N, Lerius B, Zimmermann M, et al. Gemtuzumab ozogamicin in children with relapsed or refractory acute myeloid leukemia: a report by Berlin-Frankfurt-Münster study group. Haematologica. 2019;104:120–7. doi: 10.3324/haematol.2018.191841.
    1. Cooper TM, Absalon M, Alonzo TA, et al. AAML 1421, a phase I/II study of CPX-351 followed by fludarabine, cytarabine, and G-CSF (FLAG) for children with relapsed acute myeloid leukemia (AML): a report from the Children's Oncology Group. J Clin Oncol. 2019;37(Suppl 15):10003. doi: 10.1200/JCO.2019.37.15_suppl.10003.
    1. van Eijkelenburg NKA, Rasche M, Ghazaly E, et al. Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study. Haematologica. 2018;103:1484–92. doi: 10.3324/haematol.2017.187153.
    1. Messinger Y, Boklan J, Goldberg J, et al. Combination of clofarabine, cyclophosphamide, and etoposide for relapsed or refractory childhood and adolescent acute myeloid leukemia. Pediatr Hematol Oncol. 2017;34:187–98. doi: 10.1080/08880018.2017.1360970.
    1. Cooper TM, Sison EAR, Baker SD, et al. A phase 1 study of the CXCR4 antagonist plerixafor in combination with high-dose cytarabine and etoposide in children with relapsed or refractory acute leukemias or myelodysplastic syndrome: a Pediatric Oncology Experimental Therapeutics Investigators' Consortium study (POE 10-03) Pediatr Blood Cancer. 2017;64:e26414. doi: 10.1002/pbc.26414.
    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;61:1754–60. doi: 10.1002/pbc.25117.
    1. Inaba H, Rubnitz JE, Coustan-Smith E, et al. Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia. J Clin Oncol. 2011;29:3293–300. doi: 10.1200/JCO.2011.34.7427.
    1. Inaba H, Stewart CF, Crews KR, et al. Combination of cladribine plus topotecan for recurrent or refractory pediatric acute myeloid leukemia. Cancer. 2010;116:98–105. doi: 10.1002/cncr.24712.
    1. Fassas A, Anagnostopoulos A. The use of liposomal daunorubicin (DaunoXome) in acute myeloid leukemia. Leuk Lymphoma. 2005;46:795–802. doi: 10.1080/10428190500052438.
    1. Hijiya N, Gaynon P, Barry E, et al. A multi-center phase I study of clofarabine, etoposide and cyclophosphamide in combination in pediatric patients with refractory or relapsed acute leukemia. Leukemia. 2009;23:2259–64. doi: 10.1038/leu.2009.185.
    1. Jeha S, Razzouk B, Rytting M, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia. J Clin Oncol. 2009;27:4392–7. doi: 10.1200/JCO.2008.18.8706.
    1. Krauss AC, Gao X, Li L, et al. FDA approval summary: (daunorubicin and cytarabine) liposome for injection for the treatment of adults with high-risk acute myeloid leukemia. Clin Cancer Res. 2019;25:2685–90. doi: 10.1158/1078-0432.CCR-18-2990.
    1. Taylor SM, Jones PA. Multiple new phenotypes induced in 10T1/2 and 3T3 cells treated with 5-azacytidine. Cell. 1979;17:771–9. doi: 10.1016/0092-8674(79)90317-9.
    1. Sun W, Triche T, Jr, Malvar J, et al. A phase 1 study of azacitidine combined with chemotherapy in childhood leukemia: a report from the TACL consortium. Blood. 2018;131:1145–8. doi: 10.1182/blood-2017-09-803809.
    1. Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28:562–9. doi: 10.1200/JCO.2009.23.8329.
    1. Witkowski MT, Lasry A, Carroll WL, Aifantis I. Immune-based therapies in acute leukemia. Trends Cancer. 2019;5:604–18. doi: 10.1016/j.trecan.2019.07.009.

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