Childhood Acute Myeloid Leukemia Treatment (PDQ®) 8/12 —Health Professional Version - National Cancer Institute

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

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

Myelodysplastic Syndromes (MDS)

In This Section

• Risk Factors
• Clinical Presentation
• Molecular Abnormalities
• Classification of MDS
• Treatment of Childhood MDS
  • HSCT
  • Other therapies
• Treatment Options Under Clinical Evaluation
• Current Clinical Trials

The myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS) represent between 5% and 10% of all myeloid malignancies in children. They are a heterogeneous group of disorders, with MDS usually presenting with cytopenias and MPS presenting 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 (HSCT).

Risk Factors

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. Genes mutated in dyskeratosis congenital include ACD, CTC1, DKC1, NHP2, NOP10, PARN, RTEL1, TERC, TERT, TINF2, and WRAP53.
• Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and other bone marrow failure syndromes: Resulting from mutations in genes encoding ribosome-associated proteins.[1,2] GATA1 mutations have been linked to Diamond-Blackfan anemia and MDS predisposition.[3]
• 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/acute myeloid leukemia (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.[4]
• Trisomy 21 syndrome: GATA1 mutations are nearly always present in the transient leukemia associated with Trisomy 21 and MDS in Down syndrome children younger than 3 years.[5]
• Congenital amegakaryocytic thrombocytopenia (CAMT): Inherited mutations in the RUNX1 or CEPBA genes are associated with CAMT.[6,7] Mutations in the 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.[8]
• GATA2 mutations: Germline mutations of GATA2 have been reported in patients with MDS/AML in conjunction with monocytopenia, B cell and natural killer cell deficiency, pulmonary alveolar proteinosis, and susceptibility to opportunistic infections.[9,10]
• RUNX1 or CEPBA mutations: Inherited mutations in the RUNX1 or CEPBA genes are associated with familial MDS/AML.[6,7]

A retrospective analysis that used a capture assay to target mutations known to predispose to marrow failure and MDS was performed on genomic DNA from peripheral blood mononuclear cell samples from patients undergoing stem cell transplant for MDS and aplastic anemia. Among the 46 children aged 18 years and younger with MDS, 10 patients (22%) harbored constitutional predisposition genetic mutations (5 GATA2, 1 each of MPL, RTEL1, SBDS, TINF2, and TP53), of which only 2 were suspected before transplant. This is considered a high incidence of genetic mutations compared with only 8% (4 of 64) in patients aged 18 to 40 years.[11]

Clinical Presentation

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 can eventually lead to the development of AML. The percentage of abnormal blasts is less than 20% and lack common AML recurrent cytogenetic abnormalities (t(8;21), inv(16), t(15;17), or KMT2A [MLL] translocations).

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.[12,13]

Molecular Abnormalities

Pediatric myelodysplastic syndromes (MDS) are associated with a distinctive constellation of genetic alterations compared with MDS arising in adults. In adults, MDS often evolves from clonal hematopoiesis and is characterized by mutations in TET2, DNMT3A, and TP53. In contrast, mutations in these genes are rare in pediatric MDS, while mutations in GATA2, SAMD9/SAMD9L, SETBP1, ASXL1, and Ras/MAPK pathway genes are observed in subsets of pediatric MDS cases.[14,15]

A report of the genomic landscape of pediatric MDS described the results of whole-exome sequencing for 32 pediatric primary MDS patients and targeted sequencing for another 14 cases.[14] These 46 cases were equally divided between refractory cytopenia of childhood and MDS with excess blasts (MDS-EB). The results from the report include the following:

• Mutations in Ras/MAPK pathway genes were observed in 43% of primary MDS cases, with mutations most commonly involving PTPN11 and NRAS but with mutations also observed in other pathway members (e.g., BRAF [non–BRAF V600E], CBL, and KRAS). Ras/MAPK mutations were more common in patients with MDS-EB (65%) than in patients with refractory cytopenia of childhood (17%).
• Germline variants in SAMD9 (n = 4) or SAMD9L (n = 4) were observed in 17% of patients with primary MDS, with seven of eight mutations occurring in patients with refractory cytopenia of childhood. These cases all showed loss of material on chromosome 7. Approximately 40% of patients with deletions of part or all of chromosome 7 had germline SAMD9 or SAMD9L variants.
• GATA2 mutations were observed in three cases (7%), and all cases were confirmed or presumed to be germline.
• Deletions involving chromosome 7 were the most common copy number alteration and were observed in 41% of cases. Loss of part or all of chromosome 7 was most commonly observed in SAMD9/SAMD9L cases (100%) and in MDS-EB patients with a Ras/MAPK mutation (71%).
• Other genes that were mutated in more than 1 of the 46 cases studied included SETBP1, ETV6, and TP53.

A second report described the application of a targeted sequencing panel of 105 genes to 50 pediatric patients with MDS (refractory cytopenia of childhood = 31 and MDS-EB = 19) and was enriched for cases with monosomy 7 (48%).[14,15] SAMD9 and SAMD9L were not included in the gene panel. The second report described the following results:

• Germline GATA2 mutations were observed in 30% of patients, and RUNX1 mutations were observed in 6% of patients.
• Somatic mutations were observed in 34% of patients and were more common in patients with MDS-EB than in patients with refractory cytopenia of childhood (68% vs. 13%).
• The most commonly mutated gene was SETBP1 (18%); less commonly mutated genes included ASXL1, RUNX1, and Ras/MAPK pathway genes (PTPN11, NRAS, KRAS, NF1). Twelve percent of cases showed mutations in Ras/MAPK pathway genes.

Patients with germline GATA2 mutations, in addition to MDS, show a wide range of hematopoietic and immune defects as well as nonhematopoietic manifestations.[16] The former defects include monocytopenia with susceptibility to atypical mycobacterial infection and DCML deficiency (loss of dendritic cells, monocytes, and B and natural killer lymphoid cells). The resulting immunodeficiency leads to increased susceptibility to warts, severe viral infections, mycobacterial infections, fungal infections, and human papillomavirus–related cancers. The nonhematopoietic manifestations include deafness and lymphedema. Germline GATA2 mutations were studied in 426 pediatric patients with primary MDS and 82 cases with secondary MDS who were enrolled in consecutive studies of the European Working Group of MDS in Childhood (EWOG-MDS).[17] The study had the following results:

• Germline GATA2 mutations were identified in 7% of pediatric patients with primary MDS. While the median age of patients presenting with GATA2 mutations was 12.3 years in the EWOG-MDS pediatric population, most cases of germline GATA2-related myeloid neoplasms occur during adulthood.[18]
• GATA2 mutations were more common in patients with MDS-EB (15%) than in patients with refractory cytopenia of childhood (4%).
• Among patients with GATA2 mutations, 46% presented with MDS-EB and 70% showed monosomy 7.
• Familial MDS/AML was identified in 12 of 53 GATA2-mutated patients for whom detailed family histories were available.
• Nonhematologic phenotypes of GATA2 deficiency were present in 51% of GATA2-mutated patients with MDS and included deafness (9%), lymphedema/hydrocele (23%), and immunodeficiency (39%).

SAMD9 and SAMD9L germline mutations are both associated with pediatric MDS cases in which there is an additional loss of all or part of chromosome 7.[19] In 2016, SAMD9 was identified as the cause of the MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy), which is associated with early-onset MDS with monosomy 7.[20] Subsequently, mutations in SAMD9L were identified in patients with ataxia pancytopenia syndrome (ATXPC; OMIM 159550Exit Disclaimer). SAMD9and SAMD9L mutations were also identified as the cause of myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270Exit Disclaimer),[21] a syndrome first identified in phenotypically normal siblings who developed MDS or AML associated with monosomy 7 during childhood.[22]

• Causative mutations in both SAMD9 and SAMD9L are gain-of-function mutations and enhance the growth-suppressing activity of SAMD9/SAMD9L.[20,22]
• Both SAMD9 and SAMD9L are located at chromosome 7q21.2. Cases of MDS in patients with SAMD9 or SAMD9L mutations often show monosomy 7, with the remaining chromosome 7 having wild-type SAMD9/SAMD9L. This results in the loss of the enhanced growth-suppressing activity of the mutated gene.
• Phenotypically normal patients with SAMD9/SAMD9L mutations and monosomy 7 may progress to MDS or AML or, alternatively, may show loss of their monosomy 7 with a return of normal hematopoiesis.[22] The former outcome is associated with the acquisition of mutations in genes associated with MDS/AML (e.g., ETV6 or SETBP1), while the latter is associated with genetic alterations (e.g., revertant mutations or copy-neutral loss of heterozygosity with retention of the wild-type allele) that result in normalization of SAMD9/SAMD9L activity. These observations suggest that monitoring of patients with SAMD9/SAMD9L-related monosomy 7 using clinical sequencing for acquired mutations in genes associated with progression to AML may identify patients at high risk of leukemic transformation who may benefit most from hematopoietic stem cell transplantation.[22]

(Refer to the WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes section of this summary for more information about the WHO classification of MDS.)

Classification of MDS

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.[23-27] The WHO system [28] has been modified for pediatrics.[26] Refer to Table 3 and Table 4 for the WHO classification schema and diagnostic criteria. The 2016 revision to the WHO MDS classification did not affect classification in children.[29]

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.[30,31] The relatively common abnormalities of -Y, 20q-, and 5q- in adults with MDS are rare in childhood MDS. The presence of cytogenetic abnormalities that are found in AML defines disease that should be treated as AML and not MDS.[32]

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 because many characteristics differ between children and adults.[33,34] 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 does the presence in adults with MDS.[35]

Treatment of Childhood MDS

Treatment options for children with MDS include the following:

1. HSCT.
2. Other therapies.

HSCT

MDS and associated disorders usually involve a primitive hematopoietic stem cell. Thus, allogeneic HSCT is considered to be the optimal approach to treatment for pediatric patients with MDS. Although matched sibling transplantation is preferred, similar survival has been noted with well-matched, unrelated cord blood and haploidentical approaches.[36-40]

When making treatment decisions, some data should be considered. 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. Additionally, early transplant and not receiving pretransplant chemotherapy have been associated with improved survival in children with MDS.[41][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.[39,42-45] While 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.[46-49]; [50][Level of evidence: 3iiiA]

The question of whether chemotherapy should be used in high-risk MDS has been examined.

Evidence (HSCT):

1. 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.[51]
2. 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.[52]
3. The Children's Cancer Group 2891 trial accrued patients between 1989 and 1995, including children with MDS.[42] 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 either autologous HSCT or chemotherapy.
   • Patients with refractory anemia or 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 or 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 (P = .08).

When analyzing these results, it is important to consider 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 represents MDS. The WHO classification has now omitted the category of refractory anemia with excess blasts in transformation, concluding that this entity was essentially AML.

Because survival after HSCT is improved in children with early forms of MDS (refractory anemia), transplantation before progression to late MDS or AML should be considered. HSCT should especially be considered when transfusions or other treatment are required, as is usually the case in patients with severe symptomatic cytopenias.[39,45] The 8-year disease-free survival (DFS) for children with various stages of MDS has been reported to be 65% for those treated with HLA matched donor transplants and 40% for those treated with mismatched unrelated donor transplants.[45][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 the year 2001.[53][Level of evidence: 3iiiDiii]

Because MDS in children is often associated with inherited predisposition syndromes, reports of transplantation in small numbers of patients with these disorders 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%.[54,55][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 after relapse and 57% for those transplanted after initial graft failure.[56][Level of evidence: 3iiiA]

For patients with clinically significant cytopenias, supportive care that includes transfusions and prophylactic antibiotics are considered standard of care. The use of hematopoietic growth factors can improve the hematopoietic status, but concerns remain that such treatment could accelerate conversion to AML.[57]

Other therapies

Other supportive therapies that have been studied include the following:

• Steroid therapy, including glucocorticoids and androgens, have been tried with mixed results.[58]
• Treatments directed toward scavenging free oxygen radicals with amifostine [59,60] or the use of differentiation-promoting retinoids,[61] 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 approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDS in adults on the basis of randomized studies.[62] (Refer to the Disease-Modifying Agents section in the PDQ summary on Myelodysplastic Syndromes Treatment for more information.)
• 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 the most efficacy in patients with 5q- syndrome, especially those with thrombocytosis, and is now FDA-approved for use in adults with this finding.[63]
• Immunosuppression with antithymocyte globulin and/or cyclosporine has also been reported in adults.[63,64]

Treatment Options Under Clinical Evaluation

The use of a variety of DNA methylation inhibitors and histone deacetylase inhibitors, as well as other therapies designed to induce differentiation, are being studied in both young and older adults with MDS.[65-67]

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, refer to the ClinicalTrials.gov website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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