Childhood Acute Myeloid Leukemia Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence.[2] This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life.

Primary care physicians.
Pediatric surgical subspecialists.
Radiation oncologists.
Pediatric medical oncologists/hematologists.
Rehabilitation specialists.
Pediatric nurse specialists.
Social workers.

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics.[3] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

References

Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
Wolfson J, Sun CL, Wyatt L, et al.: Adolescents and Young Adults with Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia: Impact of Care at Specialized Cancer Centers on Survival Outcome. Cancer Epidemiol Biomarkers Prev 26 (3): 312-320, 2017. [PUBMED Abstract]
Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]

Survivorship and Adverse Late Sequelae

While the issues of long-term complications of cancer and its treatment cross many disease categories, several important issues related to the treatment of myeloid malignancies are worth emphasizing. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Selected studies of the late effects of AML therapy in adult survivors who were not treated with hematopoietic stem cell transplant (HSCT) include the following:

Cardiac.
1. The Children’s Cancer Survivor Study examined 272 survivors of childhood acute myeloid leukemia (AML) who did not undergo a HSCT.[1]
  - This study identified second malignancies (cumulative incidence, 1.7%) and cardiac toxic effects (cumulative incidence, 4.7%) as significant long-term risks.
  - Cardiomyopathy has been reported in 4.3% of survivors of AML based on Berlin-Frankfurt-Münster studies. Of these, 2.5% showed clinical symptoms.[2]
2. A retrospective study of cardiac function of children treated with United Kingdom Medical Research Council–based regimens at a median of 13 months after treatment reported a mean detrimental change in left ventricular stroke volume of 8.4% compared with baseline values.[3]
3. For pediatric patients, the risk of developing early toxicity was 13.7%, and the risk of developing late cardiac toxic effects (defined as 1 year after completing first-line therapy) was 17.4%. Early cardiac toxic effects was a significant predictor of late cardiac toxic effects and the development of clinical cardiomyopathy requiring long-term therapy.[4]
4. Retrospective analysis of a single study suggests cardiac risk may be increased in children with Down syndrome,[5] but prospective studies are required to confirm this finding.
Psychosocial.
1. A Nordic Society for Pediatric Hematology and Oncology retrospective trial of children with AML treated with chemotherapy only at a median follow-up of 11 years, based on self-reported uses of health care services, demonstrated similar health care usage and marital status as their siblings.[6]
2. A population-based study of survivors of childhood AML who had not undergone an HSCT reported equivalent rates of educational achievement, employment, and marital status compared with siblings. AML survivors were, however, significantly more likely to be receiving prescription drugs, especially for asthma, than were siblings (23% vs. 9%; P = .03). Chronic fatigue has also been demonstrated to be a significantly more likely adverse late effect in survivors of childhood AML than in survivors of other malignancies.[7]

Renal, gastrointestinal, and hepatic late adverse effects have been reported to be rare for children undergoing chemotherapy only for treatment of AML.[8]

Selected studies of the late effects of AML therapy in adult survivors who were treated with HSCT include the following:

In a review from one institution, the highest frequency of adverse long-term sequelae for children treated for AML included the following incidence rates: growth abnormalities (51%), neurocognitive abnormalities (30%), transfusion-acquired hepatitis (28%), infertility (25%), endocrinopathies (16%), restrictive lung disease (20%), chronic graft-versus-host disease (20%), secondary malignancies (14%), and cataracts (12%).[9]
- Most of these adverse sequelae are the consequence of myeloablative, allogeneic HSCT. Although cardiac abnormalities were reported in 8% of patients, this is an issue that may be particularly relevant with the current use of increased anthracyclines in clinical trials for children with newly diagnosed AML.
Another study examined outcomes for children younger than 3 years with AML or acute lymphoblastic leukemia (ALL) who underwent HSCT.[10]
- The toxicities reported include growth hormone deficiency (59%), dyslipidemias (59%), hypothyroidism (35%), osteochondromas (24%), and decreased bone mineral density (24%).
- Two of the 33 patients developed secondary malignancies
- Survivors had average intelligence but frequent attention-deficit problems and fine-movement abnormalities, compared with population controls.
In contrast, The Bone Marrow Transplant Survivor Study compared childhood AML or ALL survivors with siblings using a self-reporting questionnaire.[11] The median follow-up was 8.4 years, and 86% of patients received total-body irradiation (TBI) as part of their preparative transplant regimen.
- Survivors of leukemia who received an HSCT had significantly higher frequencies of several adverse effects, including diabetes, hypothyroidism, osteoporosis, cataracts, osteonecrosis, exercise-induced shortness of breath, neurosensory impairments, and problems with balance, tremor, and weakness than did siblings.
- The overall assessment of health was significantly decreased in survivors compared with siblings (odds ratio, 2.2; P = .03).
- Significant differences were not observed between regimens using TBI compared with chemotherapy only, which mostly included busulfan.
- The outcomes were similar for patients with AML and ALL, suggesting that the primary cause underlying the adverse late effects was undergoing an HSCT.
A Children's Oncology Group (COG) study using a health-related, quality-of-life comparison reported an overall 21% of 5-year survivors having a severe or life-threatening chronic health condition; when compared by type of treatment, this percentage was 16% for the chemotherapy-only treated group, 21% for the autologous HSCT treated group, and 33% for those who received an allogeneic HSCT.[12]

New therapeutic approaches to reduce long-term adverse sequelae are needed, especially for reducing the late sequelae associated with myeloablative HSCT.

Important resources for details on follow-up and risks for survivors of cancer have been developed, including the COG’s Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers and the National Comprehensive Cancer Network's Guidelines for Acute Myeloid Leukemia . Furthermore, having access to past medical history that can be shared with subsequent medical providers has become increasingly recognized as important for cancer survivors.

References

Mulrooney DA, Dover DC, Li S, et al.: Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: a report from the Childhood Cancer Survivor Study. Cancer 112 (9): 2071-9, 2008. [PUBMED Abstract]
Creutzig U, Diekamp S, Zimmermann M, et al.: Longitudinal evaluation of early and late anthracycline cardiotoxicity in children with AML. Pediatr Blood Cancer 48 (7): 651-62, 2007. [PUBMED Abstract]
Orgel E, Zung L, Ji L, et al.: Early cardiac outcomes following contemporary treatment for childhood acute myeloid leukemia: a North American perspective. Pediatr Blood Cancer 60 (9): 1528-33, 2013. [PUBMED Abstract]
Temming P, Qureshi A, Hardt J, et al.: Prevalence and predictors of anthracycline cardiotoxicity in children treated for acute myeloid leukaemia: retrospective cohort study in a single centre in the United Kingdom. Pediatr Blood Cancer 56 (4): 625-30, 2011. [PUBMED Abstract]
O'Brien MM, Taub JW, Chang MN, et al.: Cardiomyopathy in children with Down syndrome treated for acute myeloid leukemia: a report from the Children's Oncology Group Study POG 9421. J Clin Oncol 26 (3): 414-20, 2008. [PUBMED Abstract]
Molgaard-Hansen L, Glosli H, Jahnukainen K, et al.: Quality of health in survivors of childhood acute myeloid leukemia treated with chemotherapy only: a NOPHO-AML study. Pediatr Blood Cancer 57 (7): 1222-9, 2011. [PUBMED Abstract]
Jóhannsdóttir IM, Hjermstad MJ, Moum T, et al.: Increased prevalence of chronic fatigue among survivors of childhood cancers: a population-based study. Pediatr Blood Cancer 58 (3): 415-20, 2012. [PUBMED Abstract]
Skou AS, Glosli H, Jahnukainen K, et al.: Renal, gastrointestinal, and hepatic late effects in survivors of childhood acute myeloid leukemia treated with chemotherapy only--a NOPHO-AML study. Pediatr Blood Cancer 61 (9): 1638-43, 2014. [PUBMED Abstract]
Leung W, Hudson MM, Strickland DK, et al.: Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 18 (18): 3273-9, 2000. [PUBMED Abstract]
Perkins JL, Kunin-Batson AS, Youngren NM, et al.: Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age. Pediatr Blood Cancer 49 (7): 958-63, 2007. [PUBMED Abstract]
Baker KS, Ness KK, Weisdorf D, et al.: Late effects in survivors of acute leukemia treated with hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Leukemia 24 (12): 2039-47, 2010. [PUBMED Abstract]
Schultz KA, Chen L, Chen Z, et al.: Health conditions and quality of life in survivors of childhood acute myeloid leukemia comparing post remission chemotherapy to BMT: a report from the children's oncology group. Pediatr Blood Cancer 61 (4): 729-36, 2014. [PUBMED Abstract]

Changes to This Summary (04/12/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Classification of Pediatric Myeloid Malignancies

The WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes subsection was extensively revised.

Histochemical, Immunophenotypic, and Molecular Evaluation for Childhood Acute Myeloid Leukemia (AML)

Revised text to state that comprehensive molecular profiling of pediatric and adult AML has shown that AML is a disease demonstrating both commonalities and differences across the age spectrum.

Added text about the genomic differences between pediatric and adult AML.

Added text about RUNX1 mutations in AML patients, including the results of a study of children with AML and RUNX1 mutations (cited Yamato et al. as reference 153).

Treatment of Childhood AML

Added text about the results of the prospective COG ACCL0934 trial for children with acute leukemia receiving intensive chemotherapy who were randomly assigned to receive levofloxacin or no prophylactic antibiotic during the period of neutropenia in one to two cycles of chemotherapy (cited Alexander et al. and Taplitz et al. as references 39 and 40, respectively).

Added Cardiac monitoring as a new subsection.

Myelodysplastic Syndromes (MDS)

The Molecular Abnormalities subsection was extensively revised.

Juvenile Myelomonocytic Leukemia (JMML)

Revised text to state that although mutations among five genes are generally mutually exclusive, 4% to 17% of cases have mutations in two of these Ras pathway genes, a finding that is associated with poorer prognosis (cited Murakami et al. as reference 19).

Added text to state that the presence of mutations beyond disease-defining Ras pathway mutations is associated with an inferior prognosis.

Added text about a report that described the genomic landscape of JMML and found that 16 of 150 patients lacked canonical Ras pathway mutations.

Added text to state that a study observed that approximately 60% of patients had one or more additional mutations beyond their disease-defining Ras pathway mutation. These patients had an inferior overall survival (OS) compared with patients who had no additional mutations. Also added text to state that a third study observed a trend for an inferior OS for patients with two or more mutations compared with patients with zero or one mutation.

Added text about Ras pathway double mutations, including the outcome results of two studies that identified Ras pathway double mutations in patients with JMML.

Added text about DNA methylation profiling, including the results of two studies that investigated the methylation statuses in cohorts of patients with JMML (cited Stieglitz et al. as reference 25).

Added text to state that a study also observed a subset of JMML patients with elevated LIN28B expression and identified LIN28B as the gene for which expression was most strongly associated with hypermethylation status.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute myeloid leukemia and other myeloid malignancies. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment are:

Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
Michael A. Pulsipher, MD (Children's Hospital Los Angeles)
Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389454]

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Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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