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, 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 hematopoietic 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. Other genes shown to be mutated in MDS include EZH2, DNMT3A, ASXL1, IDH1/2, RUNX1, ETV6-TEL, GATA2, DKC1, LIG4, and TP53. Most of these genes are key elements of epigenetic regulation of the genome and affect DNA methylation and/or histone modification.[3,5,6] Mutations in proteins involved in RNA splicing have been described in 45% to 85% of MDS and appear to occur early in the course of the disease. 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.[8,9]
Patients with the following germline mutations or inherited disorders have a significantly increased risk of developing MDS:
- Fanconi anemia: Caused by germline mutations in DNA repair genes.
- Dyskeratosis congenita: Resulting from mutations in genes regulating telomere length.
- Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and other bone marrow failure syndromes: Resulting from to mutations in genes encoding ribosome-associated proteins.[10,11] GATA1 mutations have been linked to Diamond-Blackfan anemia and MDS predisposition.
- Severe congenital neutropenia: Caused by mutations in the gene encoding elastase. The 15-year cumulative risk of MDS in patients with severe congenital neutropenia, also known as Kostmann syndrome, has been estimated to be 15%, with an annual risk of MDS/AML of 2% to 3%. It is unclear how mutations affecting this protein and how the chronic exposure of granulocyte colony-stimulating factor (G-CSF) contribute to the development of MDS.
- Trisomy 21 syndrome: GATA1 mutations are nearly always present in the transient leukemia associated with Trisomy 21.
- Congenital amegakaryocytic thrombocytopenia (CAMT): Inherited mutations in the RUNX1 or CEPBA genes are associated with CAMT.[15,16] Mutations in in c-MPL gene are the underlying genetic cause of CAMT; there is a less than 10% risk of developing MDS/AML in patients with CAMT.
- GATA2 mutations: Germline mutations of GATA2 have been reported in patients with MDS/AML in conjunction with monocytopenia, B and NK deficiency, pulmonary alveolar proteinosis, and susceptibility to opportunistic infections.[18,19]
- RUNX1 or CEPBA mutations: Inherited mutations in the RUNX1 or CEPBA genes are associated with familial MDS/AML.[15,16]
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 2008 WHO classification system.[20-24] The WHO system  has been modified for pediatrics. Refer to Table 3 and Table 4 for the WHO classification schema and diagnostic criteria.
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.[26,27] 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.
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 as many characteristics differ between children and adults.[28,29] The median survival for children with high-risk MDS remains substantially better than adults and the presence of monosomy 7 in children has not had the same adverse prognostic impact as in adults with MDS.
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 MDS. Unresolved issues include determining the best transplant preparative regimen and source of donor cells.[31,32] However, some data are important to consider when making decisions. For example, survival as high as 80% has been reported for patients with early-stage MDS proceeding to transplant within a few months of diagnosis. Further, early transplant and not receiving pretransplant chemotherapy have been associated with improved survival in children with MDS.[Level of evidence: 3iiA] Disease-free survival (DFS) has been estimated to be between 50% to 70% for pediatric patients with advanced MDS using myeloablative transplant preparative regimens.[34-38] 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.[39-41]; [Level of evidence: 3iiiA]
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. 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-Münster 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. 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.
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 WHO classification has now omitted the category of refractory anemia with excess blasts in transformation, concluding that this entity was essentially AML. The optimal therapy for patients with refractory anemia/refractory anemia with excess blasts without an HLA-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 transplantation, 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 symptomatic cytopenias.[35,38] The 8-year DFS for children with various stages of MDS transplanted with either HLA matched or mismatched unrelated donor transplants has been reported to be 65% and 40%, respectively.[Level of evidence: 3iiiDii] A 3-year DFS of 50% was reported with the use of unrelated cord blood donor transplants for children with MDS, when the transplants were done after 2001.[Level of evidence: 3iiiDiii]
Because MDS in children is often associated with inherited predisposition syndromes, reports of transplantation in small numbers of patients have been documented. For example, in patients with Fanconi anemia and AML or advanced MDS, the 5-year overall survival (OS) has been reported to be 33% to 55%.[46,47][Level of evidence: 3iiiA] Second transplants have also been used in pediatric patients with MDS/MPD who relapse or suffer graft failure. The 3-year OS was 33% for those retransplanted for relapse and 57% for those transplanted for initial graft failure.[Level of evidence: 3iiiA]
For patients with clinically significant cytopenias, supportive care, including transfusions and prophylactic antibiotics, can be considered. In addition, the use of hematopoietic growth factors can improve the hematopoietic status, but there remains some concern that such treatment could accelerate conversion to AML. Steroid therapy has also been used, including glucocorticoids and androgens, with mixed results. Treatments directed toward scavenging free oxygen radicals with amifostine [51,52] or the use of differentiation-promoting retinoids, DNA methylation inhibitors (e.g., azacytidine and decitabine), and histone deacetylase inhibitors, have all shown some response, but no definitive trials in children with MDS have been reported. Azacytidine has been by the U.S. Food and Drug Administration (FDA) approved for the treatment of MDS in adults based on randomized studies. 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, especially those with thrombocytosis, and is now FDA-approved for use in this group. Immunosuppression with antithymocyte globulin and/or cyclosporine has also been reported.[55,56]
Treatment Options Under Clinical Evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
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.
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