Font Size

Childhood Acute Myeloid Leukemia Treatment (Professional) (cont.)

Myelodysplastic Syndromes

The myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS), which represent between 5% and 10% of all myeloid malignancies in children, are a heterogeneous group of disorders with the former usually presenting with cytopenias and the latter with increased peripheral white blood cell (WBC), red blood cell, or platelet counts. MDS is characterized by ineffective hematopoiesis and increased cell death, while MPS is associated with increased progenitor proliferation and survival. Because they both represent disorders of very primitive, multipotential hematopoietic stem cells, curative therapeutic approaches nearly always require allogeneic stem cell transplantation.

Patients usually present with signs of cytopenias, including pallor, infection, or bruising. The bone marrow is usually characterized by hypercellularity and dysplastic changes in myeloid precursors. Clonal evolution eventually can lead to the development of acute myeloid leukemia (AML). The percentage of abnormal blasts is less than 20%. The less common, hypocellular MDS, can be distinguished from aplastic anemia in part by its marked dysplasia, clonal nature, and higher percentage of CD34-positive precursors.[1,2]

Although the etiology of MDS has not been elucidated, clues have begun to be defined. For instance, approximately 20% of malignant myeloid disorders, including MDS, in adults have been shown to have mutations in the TET2 gene.[3] Other genes shown to be mutated in MDS include EZH2, DNMT3A, ASXL1, IDH1/2, RUNX1, ETV6/TEL, and TP53. Most of these genes are key elements of epigenetic regulation of the genome and affect DNA methylation and/or histone modification.[3,4,5] Mutations in proteins involved in RNA splicing have been described in 45% to 85% of MDS.[6] MDS in both adults and children has been shown to have aberrant DNA methylation patterns and approximately one-half of cases are characterized by hypermethylation of the promoters for the CDKN2B and CALC genes, both of which play roles in cell cycle regulation.[7,8] Inherited disorders, such as Fanconi anemia, due to germline mutations in DNA repair genes, or in dyskeratosis congenita, due to mutations in genes regulating telomere length, have significantly increased risk of developing MDS.[9] Additional bone marrow failure syndromes may also evolve into MDS, including those due to mutations in genes encoding ribosome associated proteins, such as Shwachman-Diamond syndrome and Diamond-Blackfan anemia.[9] The 15-year cumulative risk of MDS in patients with severe congenital neutropenia, also know as Kostmann syndrome, which is due to mutations in the gene encoding elastase, has been estimated to be 15% with an annual risk of MDS/AML of 2% to 3%; how mutations affecting this protein as well as what role the chronic exposure of granulocyte-colony stimulating factor (G-CSF) contribute to the development of MDS is unclear.[10,11] Inherited mutations in the RUNX1 or CEPBA genes have also been shown to be associated with familial MDS/AML.[12,13]

The French-American-British (FAB) and World Health Organization (WHO) classification systems of MDS and MPS have been difficult to apply to pediatric patients. Alternative classification systems for children have been proposed, but none have been uniformly adopted, with the exception of the modified WHO system.[14,15,16,17,18] The WHO system [19] has been modified for pediatrics.[17]

Diagnostic Categories for Myelodysplastic and Myeloproliferative Disease in Children

  • Down syndrome disease
    • Transient myeloproliferative disorder.
    • Myeloid leukemia of Down syndrome.
  • Myelodysplastic/myeloproliferative disease
    • Juvenile myelomonocytic leukemia (JMML).
  • Myelodysplastic syndrome
    • Refractory cytopenia (previously called refractory anemia)—peripheral blood blasts <2% and bone marrow blasts <5%.
    • Refractory anemia with excess blasts—peripheral blood blasts 2% to 19% or bone marrow blasts 5% to 19%.
    • Refractory anemia with excess blasts in transformation—peripheral blood or bone marrow blasts 20% to 29%. In the FAB classification, refractory anemia with excess blasts in transformation required evidence of dysplasia, particularly in the red blood cell lineage, and 21% to 30% myeloblasts in the bone marrow; if there was greater than 30% myeloblasts this was considered to be acute myeloid leukemia. In part because of the artificial designation of the percentage of blasts, the WHO classification system now simply considers these patients to have AML and the refractory anemia with excess blasts in transformation subtype has been eliminated.

The refractory cytopenia subtype represents approximately 50% of all childhood cases of MDS. The presence of an isolated monosomy 7 is the most common cytogenetic abnormality, although it does not appear to portend a poor prognosis compared with its presence in overt AML. However, the presence of monosomy 7 in combination with other cytogenetic abnormalities is associated with a poor prognosis.[20,21] The relatively common abnormalities of -Y, 20q- and 5q- in adults with MDS are rare in childhood MDS. The presence of cytogenetic abnormalities found in AML defines disease that should be treated as AML and not MDS.[22] The International Prognostic Scoring System can help to distinguish low-risk from high-risk MDS, although its utility in children with MDS is more limited than in adults, in part because children often have more high-risk characteristics compared with adults, especially in terms of cytopenias.[22,23] Nevertheless, the median survival for children with high-risk MDS remains substantially better than adults.[24]

The optimal therapy for childhood MDS has not been established. A key issue in thinking about therapy for pediatric patients with MDS is that these disorders usually involve a primitive hematopoietic stem cell. Thus, allogeneic hematopoietic stem cell transplantation (HSCT) is considered to be the optimal approach to treatment for pediatric patients with advanced MDS. Unresolved issues include determining the best transplant preparative regimen and source of donor cells.[25,26] However, some data are important to consider when making decisions. For example, disease-free survival has been estimated to be between 50% to 70% for pediatric patients with advanced MDS using myeloablative transplant preparative regimens.[27,28,29,30,31] While using nonmyeloablative preparative transplant regimens are being tested in patients with MDS and AML, such regimens are still investigational for children with these disorders, but may be reasonable in the setting of a clinical trial or when a patient's organ function is compromised in such a way that they would not tolerate a myeloablative regimen.[32,33,34]

The question of whether chemotherapy should be used in high-risk MDS has been examined. The Children's Cancer Group 2891 trial accrued patients between 1989 and 1995, including children with MDS.[27] There were 77 patients with refractory anemia (n = 2), refractory anemia with excess blasts (n = 33), refractory anemia with excess blasts in transformation (n = 26), or AML with antecedent MDS (n = 16) who were enrolled and randomly assigned to standard or intensively timed induction. Subsequently, patients were allocated to allogeneic HSCT if there was a suitable family donor, or randomly assigned to autologous HSCT or chemotherapy. Patients with refractory anemia/refractory anemia with excess blasts had a poor remission rate (45%), and those with refractory anemia with excess blasts in transformation (69%) or AML with history of MDS (81%) had similar remission rates compared with de novo AML (77%). Six-year survival was poor for those with refractory anemia/refractory anemia with excess blasts (28%) and refractory anemia with excess blasts in transformation (30%). Patients with AML and antecedent MDS had a similar outcome to those with de novo AML (50% survival compared with 45%). Allogeneic HSCT appeared to improve survival at a marginal level of significance (P = .08). Based on analysis of these data and the literature, the authors concluded that children with a history of MDS who present with AML and many of those with refractory anemia with excess blasts in transformation do as well with AML therapy at diagnosis as children with AML. An exception to this conclusion is children with AML with a precedent MDS and monosomy 7; these patients have a very poor prognosis and are usually treated with some type of allogeneic HSCT. An analysis of 37 children with MDS treated on Berlin-Frankfurt-Munster AML protocols 83, 87, and 93 confirmed the induction response of 74% for patients with refractory anemia with excess blasts in transformation and suggested that transplantation was beneficial.[35] Another study by the same group showed that with current approaches to HSCT, survival occurred in more than 60% of children with advanced MDS, and outcomes for patients receiving unrelated donor cells were similar to those for patients who received matched-family donor (MFD) cells.[36]

A significant issue to consider for these results is that the subtype refractory anemia with excess blasts in transformation is likely to represent patients with overt AML, while refractory anemia and refractory anemia with excess blasts represent MDS. The optimum therapy for patients with refractory anemia/refractory anemia with excess blasts without MFD is unknown. Some of these patients require no therapy for years and have indolent diseases. Because failure rates after HSCT are lower in this group, strong consideration should be given for such treatment, especially when a 5/6 or 6/6 HLA-MFD is available. However, alternative forms of HSCT, utilizing matched unrelated donor cord blood, should be considered when treatment is required, as is usually the case in patients with severe cytopenias.[28,31]

For patients with clinically significant cytopenias, supportive care, including transfusions and prophylactic antibiotics, can be considered, but have not been proven to be curative; however, it is important that supportive care be utilized in these patients awaiting transplant. In addition, the use of hematopoietic growth factors can improve the hematopoietic status, but there is some concern that such treatment could accelerate conversion to AML.[37] Steroid therapy has also been used, including glucocorticoids and androgens, with mixed results.[38] Treatments directed toward scavenging free oxygen radicals with amifostine [39,40] or the use of differentiation-promoting retinoids,[41] DNA methylation inhibitors (e.g., azacytidine and decitabine), and histone deacetylase inhibitors, have all shown some positive responses. Azacytidine has been FDA-approved for the treatment of MDS in adults based on randomized studies.[42] Agents, such as lenalidomide, an analog of thalidomide, have been tested based on findings that demonstrated increased activity in the bone marrow of patients with MDS. Lenalidomide has shown most efficacy in patients with 5q- syndrome and is now FDA-approved for use in this group.[43] Immunosuppression with antithymocyte globulin and/or cyclosporine has also been reported.[43,44]

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted.

  • The use of a variety of inhibitors of DNA methylation and histone deacetylase inhibitors, as well as other therapies designed to induce differentiation, are being studied in both young and older adults with MDS.[45,46,47]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood myelodysplastic syndromes. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


  1. Kasahara S, Hara T, Itoh H, et al.: Hypoplastic myelodysplastic syndromes can be distinguished from acquired aplastic anaemia by bone marrow stem cell expression of the tumour necrosis factor receptor. Br J Haematol 118 (1): 181-8, 2002.
  2. Orazi A: Histopathology in the diagnosis and classification of acute myeloid leukemia, myelodysplastic syndromes, and myelodysplastic/myeloproliferative diseases. Pathobiology 74 (2): 97-114, 2007.
  3. Nikoloski G, Langemeijer SM, Kuiper RP, et al.: Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 42 (8): 665-7, 2010.
  4. Schlegelberger B, Göhring G, Thol F, et al.: Update on cytogenetic and molecular changes in myelodysplastic syndromes. Leuk Lymphoma 53 (4): 525-36, 2012.
  5. Tan PT, Wei AH: The epigenomics revolution in myelodysplasia: a clinico-pathological perspective. Pathology 43 (6): 536-46, 2011.
  6. Yoshida K, Sanada M, Shiraishi Y, et al.: Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478 (7367): 64-9, 2011.
  7. Hasegawa D, Manabe A, Kubota T, et al.: Methylation status of the p15 and p16 genes in paediatric myelodysplastic syndrome and juvenile myelomonocytic leukaemia. Br J Haematol 128 (6): 805-12, 2005.
  8. Vidal DO, Paix„o VA, Brait M, et al.: Aberrant methylation in pediatric myelodysplastic syndrome. Leuk Res 31 (2): 175-81, 2007.
  9. Alter BP, Giri N, Savage SA, et al.: Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br J Haematol 150 (2): 179-88, 2010.
  10. Rosenberg PS, Zeidler C, Bolyard AA, et al.: Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br J Haematol 150 (2): 196-9, 2010.
  11. Rosenberg PS, Huang Y, Alter BP: Individualized risks of first adverse events in patients with Fanconi anemia. Blood 104 (2): 350-5, 2004.
  12. Liew E, Owen C: Familial myelodysplastic syndromes: a review of the literature. Haematologica 96 (10): 1536-42, 2011.
  13. Owen C, Barnett M, Fitzgibbon J: Familial myelodysplasia and acute myeloid leukaemia--a review. Br J Haematol 140 (2): 123-32, 2008.
  14. Occhipinti E, Correa H, Yu L, et al.: Comparison of two new classifications for pediatric myelodysplastic and myeloproliferative disorders. Pediatr Blood Cancer 44 (3): 240-4, 2005.
  15. Niemeyer CM, Baumann I: Myelodysplastic syndrome in children and adolescents. Semin Hematol 45 (1): 60-70, 2008.
  16. Niemeyer CM, Kratz CP: Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia: molecular classification and treatment options. Br J Haematol 140 (6): 610-24, 2008.
  17. Hasle H: Myelodysplastic and myeloproliferative disorders in children. Curr Opin Pediatr 19 (1): 1-8, 2007.
  18. Mandel K, Dror Y, Poon A, et al.: A practical, comprehensive classification for pediatric myelodysplastic syndromes: the CCC system. J Pediatr Hematol Oncol 24 (7): 596-605, 2002.
  19. Nösslinger T, Reisner R, Koller E, et al.: Myelodysplastic syndromes, from French-American-British to World Health Organization: comparison of classifications on 431 unselected patients from a single institution. Blood 98 (10): 2935-41, 2001.
  20. Göhring G, Michalova K, Beverloo HB, et al.: Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome. Blood 116 (19): 3766-9, 2010.
  21. Haase D, Germing U, Schanz J, et al.: New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 110 (13): 4385-95, 2007.
  22. Hasle H, Baumann I, Bergsträsser E, et al.: The International Prognostic Scoring System (IPSS) for childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML). Leukemia 18 (12): 2008-14, 2004.
  23. Cutler CS, Lee SJ, Greenberg P, et al.: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 104 (2): 579-85, 2004.
  24. Hasle H, Niemeyer CM: Advances in the prognostication and management of advanced MDS in children. Br J Haematol 154 (2): 185-95, 2011.
  25. Uberti JP, Agovi MA, Tarima S, et al.: Comparative analysis of BU and CY versus CY and TBI in full intensity unrelated marrow donor transplantation for AML, CML and myelodysplasia. Bone Marrow Transplant 46 (1): 34-43, 2011.
  26. Nemecek ER, Guthrie KA, Sorror ML, et al.: Conditioning with treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies. Biol Blood Marrow Transplant 17 (3): 341-50, 2011.
  27. Woods WG, Barnard DR, Alonzo TA, et al.: Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group. J Clin Oncol 20 (2): 434-40, 2002.
  28. Parikh SH, Mendizabal A, Martin PL, et al.: Unrelated donor umbilical cord blood transplantation in pediatric myelodysplastic syndrome: a single-center experience. Biol Blood Marrow Transplant 15 (8): 948-55, 2009.
  29. Andolina JR, Kletzel M, Tse WT, et al.: Allogeneic hematopoetic stem cell transplantation in pediatric myelodysplastic syndromes: improved outcomes for de novo disease. Pediatr Transplant 15 (3): 334-43, 2011.
  30. Al-Seraihy A, Ayas M, Al-Nounou R, et al.: Outcome of allogeneic stem cell transplantation with a conditioning regimen of busulfan, cyclophosphamide and low-dose etoposide for children with myelodysplastic syndrome. Hematol Oncol Stem Cell Ther 4 (3): 121-5, 2011.
  31. Woodard P, Carpenter PA, Davies SM, et al.: Unrelated donor bone marrow transplantation for myelodysplastic syndrome in children. Biol Blood Marrow Transplant 17 (5): 723-8, 2011.
  32. Champlin R: Hematopoietic stem cell transplantation for treatment of myleodysplastic syndromes. Biol Blood Marrow Transplant 17 (1 Suppl): S6-8, 2011.
  33. Nelson RP Jr, Yu M, Schwartz JE, et al.: Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia. Bone Marrow Transplant 45 (8): 1300-8, 2010.
  34. Warlick ED: Optimizing stem cell transplantation in myelodysplastic syndromes: unresolved questions. Curr Opin Oncol 22 (2): 150-4, 2010.
  35. Creutzig U, Bender-Götze C, Ritter J, et al.: The role of intensive AML-specific therapy in treatment of children with RAEB and RAEB-t. Leukemia 12 (5): 652-9, 1998.
  36. Strahm B, Nöllke P, Zecca M, et al.: Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome in children: results of the EWOG-MDS 98 study. Leukemia 25 (3): 455-62, 2011.
  37. Zwierzina H, Suciu S, Loeffler-Ragg J, et al.: Low-dose cytosine arabinoside (LD-AraC) vs LD-AraC plus granulocyte/macrophage colony stimulating factor vs LD-AraC plus Interleukin-3 for myelodysplastic syndrome patients with a high risk of developing acute leukemia: final results of a randomized phase III study (06903) of the EORTC Leukemia Cooperative Group. Leukemia 19 (11): 1929-33, 2005.
  38. Chan G, DiVenuti G, Miller K: Danazol for the treatment of thrombocytopenia in patients with myelodysplastic syndrome. Am J Hematol 71 (3): 166-71, 2002.
  39. Mathew P, Gerbing R, Alonzo TA, et al.: A phase II study of amifostine in children with myelodysplastic syndrome: a report from the Children's Oncology Group study (AAML0121). Pediatr Blood Cancer 57 (7): 1230-2, 2011.
  40. Schanz J, Jung H, Wörmann B, et al.: Amifostine has the potential to induce haematologic responses and decelerate disease progression in individual patients with low- and intermediate-1-risk myelodysplastic syndromes. Leuk Res 33 (9): 1183-8, 2009.
  41. Sadek I, Zayed E, Hayne O, et al.: Prolonged complete remission of myelodysplastic syndrome treated with danazol, retinoic acid and low-dose prednisone. Am J Hematol 64 (4): 306-10, 2000.
  42. Silverman LR, Demakos EP, Peterson BL, et al.: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20 (10): 2429-40, 2002.
  43. Yazji S, Giles FJ, Tsimberidou AM, et al.: Antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndromes. Leukemia 17 (11): 2101-6, 2003.
  44. Yoshimi A, Baumann I, Führer M, et al.: Immunosuppressive therapy with anti-thymocyte globulin and cyclosporine A in selected children with hypoplastic refractory cytopenia. Haematologica 92 (3): 397-400, 2007.
  45. Mufti G, List AF, Gore SD, et al.: Myelodysplastic syndrome. Hematology (Am Soc Hematol Educ Program) : 176-99, 2003.
  46. Esteller M: DNA methylation and cancer therapy: new developments and expectations. Curr Opin Oncol 17 (1): 55-60, 2005.
  47. Bhalla K, List A: Histone deacetylase inhibitors in myelodysplastic syndrome. Best Pract Res Clin Haematol 17 (4): 595-611, 2004.
eMedicineHealth Public Information from the National Cancer Institute

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 or call 1-800-4-CANCER

This information is not intended to replace the advice of a doctor. Healthwise disclaims any liability for the decisions you make based on this information.

Some material in CancerNet™ is from copyrighted publications of the respective copyright claimants. Users of CancerNet™ are referred to the publication data appearing in the bibliographic citations, as well as to the copyright notices appearing in the original publication, all of which are hereby incorporated by reference.

Medical Dictionary