Treatment Options Under Clinical Evaluation
Current Clinical Trials

Studies have attempted to retrospectively classify and analyze the outcome of children with myelodysplastic syndromes (MDS).[1,2] This continues to be problematic. The French-American-British (FAB) classification of adult MDS is only partially helpful in the categorization of children with MDS. Children with MDS present with FAB subtypes of refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEB-T). Juvenile myelomonocytic leukemia (JMML) and monosomy 7 will be discussed below. The optimal therapy for childhood MDS is controversial. The Children's Cancer Group 2891 trial accrued patients between 1989 and 1995, including children with MDS.[3] There were 77 patients with RA (2), RAEB (33), RAEB-T (26), or acute myeloid leukemia (AML) with antecedent MDS (16) who were enrolled and randomized to standard or intensively timed induction. Subsequently patients were allocated to allogeneic hematopoietic stem cell transplantation (HSCT) if there was a suitable family donor, or randomized to autologous HSCT or chemotherapy. Patients with RA/RAEB had a poor remission rate (45%), and those with RAEB-T (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 RA/RAEB (28%) and RAEB-T (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 conclude that children with a history of MDS who present with AML (excluding those with monosomy 7) and many of those with RAEB-T do as well with AML therapy at diagnosis as AML patients. For patients who achieve remission and for whom there is no matched-family donor, it is unclear whether aggressive continuation of chemotherapy or alternative donor stem cell transplant is optimum therapy.[3] Children with RA/RAEB as well as patients with AML have a low response rate to AML induction therapy. Because failure rates after HSCT are lower in this group when treated at diagnosis, strong consideration should be given for such treatment, especially when a 5/6 or 6/6 HLA-matched family donor is available. The optimum therapy for patients with RA/RAEB without matched family donors is unknown. Some of these patients require no therapy for years and have indolent diseases. However, alternative forms of HSCT, utilizing matched unrelated donors, or perhaps cord blood, should be considered in an exploratory fashion when treatment is required, usually for severe cytopenia. An analysis of 37 children with MDS treated on AML-BFM 83, 87, and 93 protocols confirmed the induction response of 74% for patients with RAEB-T, and suggested that transplantation was beneficial.[4]

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.

• The use of a variety of inhibitors of DNA methylation and histone deacetylase inhibitors, as well as other therapies designed to induce differentiation, are currently being studied in both young and older adults with MDS.[5-7]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References

1. Passmore SJ, Hann IM, Stiller CA, et al.: Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood 85 (7): 1742-50, 1995.  [PUBMED Abstract]
   
   
2. Luna-Fineman S, Shannon KM, Atwater SK, et al.: Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients. Blood 93 (2): 459-66, 1999.  [PUBMED Abstract]
   
   
3. 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.  [PUBMED Abstract]
   
   
4. 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.  [PUBMED Abstract]
   
   
5. Mufti G, List AF, Gore SD, et al.: Myelodysplastic syndrome. Hematology (Am Soc Hematol Educ Program) : 176-99, 2003.  [PUBMED Abstract]
   
   
6. Esteller M: DNA methylation and cancer therapy: new developments and expectations. Curr Opin Oncol 17 (1): 55-60, 2005.  [PUBMED Abstract]
   
   
7. Bhalla K, List A: Histone deacetylase inhibitors in myelodysplastic syndrome. Best Pract Res Clin Haematol 17 (4): 595-611, 2004.  [PUBMED Abstract]
   
   

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