Our Health Library information does not replace the advice of a doctor. Please be advised that this information is made available to assist our patients to learn more about their health. Our providers may not see and/or treat all topics found herein. This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER. Myeloid leukemias that arise in children with Down syndrome, particularly in patients younger than 4 years, are a distinct subset of acute myeloid leukemia (AML) characterized by the co-existence of trisomy 21 and GATA1 variants within the leukemic blasts that are often, but not always, megakaryoblastic. This distinct leukemia is further subdivided into two types:[1] It is important to recognize the possibility of these versions in both children with Down syndrome phenotypes and in those who have mosaic trisomy 21, which can be solely present in the leukemic blasts. If possible, newborns with apparent AML should not begin therapy until genetic testing results have been returned.[2] In older children with megakaryocytic AML, it is important to rule out the presence of co-existing trisomy 21 and GATA1 variants. These children may be successfully treated with the lower-intensity chemotherapy regimens that are used for children with myeloid leukemia associated with Down syndrome.[3] References: Cancer in children and adolescents is rare, although the overall incidence 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: For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care. The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[3] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress 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: Incidence Approximately 10% of neonates with Down syndrome develop TAM (also termed transient myeloproliferative disorder [TMD]).[1] This disorder mimics congenital AML but typically improves spontaneously within the first 3 months of life (median, 49 days). However, TAM has been reported to remit as late as 20 months.[2] The late remissions likely reflect a persistent hepatomegaly from TAM-associated hepatic fibrosis rather than active disease.[3] Clinical Presentation and Risk Groups Although TAM is usually a self-resolving condition, it can be associated with significant morbidity and may be fatal in 10% to 17% of affected infants.[2,3,4,5,6] When TAM is detected, it is either in a proliferative, worsening phase or it has already converted to a resolving, improving phase. Observation over time is needed to determine which phase is present. Infants with progressive organomegaly, visceral effusions, preterm delivery (less than 37 weeks of gestation), bleeding diatheses, failure of spontaneous remission, laboratory evidence of progressive liver dysfunction (elevated direct bilirubin), renal failure, and very high white blood cell (WBC) count are at particularly high risk of early mortality.[3,4,6] In one report, death occurred in 21% of these patients with high-risk TAM, although only 10% were attributable to TAM. The remaining deaths were caused by coexisting conditions known to be more prominent in neonates with Down syndrome.[3] The following three risk groups have been identified on the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms:[3] Molecular Features Genomics of TAM TAM blasts most commonly have megakaryoblastic differentiation characteristics and distinctive variants involving the GATA1 gene in the presence of trisomy 21.[7,8] TAM may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may predict an increased risk of developing subsequent AML.[4] GATA1 variants are present in most, if not all, children with Down syndrome who have either transient abnormal myelopoiesis (TAM) or acute megakaryoblastic leukemia (AMKL).[7,9,10,11] GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells. X-linked GATA1 variants result in the absence of the full-length GATA1 protein, leaving only the normally minor variant, a truncated GATA1s transcription factor that has decreased activity.[7,8] This confers increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly explaining the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.[12] Approximately 20% of infants with TAM and Down syndrome eventually develop AML. Most of these cases are diagnosed within the first 3 years of life.[4,8] Treatment of TAM While observation is appropriate for most infants with TAM, therapeutic intervention is warranted in patients with apparent severe hydrops or organ failure. Because TAM eventually spontaneously remits, treatment is short in duration and primarily aimed at the reduction of leukemic burden and resolution of immediate symptoms. Several treatment approaches have been used, including the following: Risk Factors for the Development of AML After Resolution of TAM Subsequent development of myeloid leukemia of Down syndrome (MLDS) is seen in 10% to 30% of children with TAM. It has been reported at a mean age of 16 months (range, 1–30 months).[2,3,14] While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk of developing subsequent MLDS.[4] An additional risk factor reported in two studies is the late resolution of TAM, measured by either time to complete resolution of signs of TAM (defined as resolution beyond the median, 47 days from diagnosis) or by persistence of minimal residual disease (MRD) in the peripheral blood at week 12 of follow-up.[3]; [13][Level of evidence B4] The use of cytarabine for TAM symptoms or persistent MRD in TAM has failed to show a reduction in later MLDS, as reported in large observational cohort studies.[3,6] In a prospective single-arm trial designed to assess whether cytarabine treatment for TAM could prevent the development of later MLDS, no benefit was found when compared with historical controls (19% ± 4% vs. 22% ± 4%, respectively; P = .88).[13][Level of evidence B4] References: General Information Children with Down syndrome have a 10-fold to 45-fold increased risk of leukemia when compared with children without Down syndrome.[1] However, the ratio of acute lymphoblastic leukemia to acute myeloid leukemia (AML) is typical for childhood acute leukemia. The exception is during the first 3 years of life, when AML, particularly the megakaryoblastic subtype, predominates and exhibits a distinctive biology characterized by GATA1 variants and increased sensitivity to cytarabine.[2,3,4,5,6,7] Importantly, these risks appear to be similar whether a child has phenotypic characteristics of Down syndrome or whether a child has only genetic bone marrow mosaicism.[8] Prognosis of Children With MLDS Outcome is generally favorable for children with Down syndrome who develop AML. This is called myeloid leukemia of Down syndrome (MLDS) in the World Health Organization (WHO) classification.[9,10,11] For more information, see the sections on General Information About Childhood Myeloid Malignancies and World Health Organization (WHO) Classification System for Childhood AML in Childhood Acute Myeloid Leukemia Treatment. Prognostic factors for children with MLDS include the following: Approximately 29% to 47% of patients with Down syndrome present with myelodysplastic neoplasms (MDS) (<20% blasts) but their outcomes are similar to those with AML.[10,11,13] Treatment of Newly Diagnosed Childhood MLDS Appropriate therapy for younger children (aged ≤4 years) with MLDS is less intensive than current standard childhood AML therapy. Hematopoietic stem cell transplant is not indicated in first remission.[4,9,10,11,12,13,14,18,19] Treatment options for newly diagnosed children with MLDS include the following: Evidence (chemotherapy): The following two prognostic factors were identified:[13] Children with mosaicism for trisomy 21 are treated similarly to those children with clinically evident Down syndrome.[8,10,20] Children with MLDS who are older than 4 years have a significantly worse prognosis.[14] Although an optimal treatment for these children has not been defined, they are usually treated with AML regimens designed for children without Down syndrome. Treatment options under clinical evaluation Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website. Treatment of Relapsed or Refractory Childhood MLDS A small number of trials address outcomes in children with MLDS who relapse after initial therapy or who have refractory MLDS. In three prospective trials of children with newly diagnosed MLDS, outcomes were poor for those who relapsed (4 of 11, 2 of 9, and 2 of 12 patients who relapsed survived).[9,13,16] Thus, these children are treated similarly to children without Down syndrome, with an intensive reinduction chemotherapy regimen. If a remission is achieved, therapy is followed by an allogeneic hematopoietic stem cell transplant (HSCT). Treatment options for children with refractory or relapsed MLDS include the following: Evidence (treatment of children with refractory or relapsed MLDS): Four analyses have specifically examined children with relapsed or refractory MLDS.[21,22,23,24] References: 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. Myeloid Leukemia of Down Syndrome (MLDS) Added text to state that in the Children's Oncology Group AAML1531 trial for children with newly diagnosed MLDS, removing the high-dose cytarabine cycle in those with standard-risk MLDS was unsuccessful. The interim analysis found that patients who did not receive high-dose cytarabine had a lower 2-year event-free survival (EFS) rate of 85.6%, compared with the 2-year EFS rate of 93.5% for patients in the AAML0431 trial. Added text to state that four analyses have specifically examined children with relapsed or refractory MLDS (cited Raghuram et al. as reference 24). Added text about the results of a large study that retrospectively evaluated children with MLDS to determine their outcomes and prognostic factors for survival after relapse or refractory disease. 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® Cancer Information for Health Professionals pages. Purpose of This Summary This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood myeloid proliferations associated with Down syndrome. It is intended as a resource to inform and assist clinicians in the care of their 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: 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 Myeloid Proliferations Associated With Down Syndrome Treatment are: 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 PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]." The preferred citation for this PDQ summary is: PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Myeloid Proliferations Associated With Down Syndrome Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq/myeloid-proliferations-down-syndrome-treatment-pdq. Accessed <MM/DD/YYYY>. Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images. 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. Contact Us More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us. Last Revised: 2024-06-14 This information does not replace the advice of a doctor. Ignite Healthwise, LLC disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use and Privacy Policy. Learn how we develop our content. Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Ignite Healthwise, LLC.Topic Contents
Childhood Myeloid Proliferations Associated With Down Syndrome Treatment (PDQ®): Treatment - Health Professional Information [NCI]
General Information About Childhood Myeloid Proliferations Associated With Down Syndrome
Special Considerations for the Treatment of Children With Cancer
Transient Abnormal Myelopoiesis (TAM) Associated With Down Syndrome
Myeloid Leukemia of Down Syndrome (MLDS)
Latest Updates to This Summary (06 / 14 / 2024)
About This PDQ Summary
Our Health Library information does not replace the advice of a doctor. Please be advised that this information is made available to assist our patients to learn more about their health. Our providers may not see and/or treat all topics found herein.Childhood Myeloid Proliferations Associated With Down Syndrome Treatment (PDQ®): Treatment - Health Professional Information [NCI]