MYELODYSPLASTIC SYNDROMES - THE PEDIATRIC POINT-OF-VIEW

Myelodysplastic syndromes (MDS) are clonal disorders of the multipoten t hematopoietic stem cell characterized by ineffective hematopoiesis a nd associated with marrow hypercellularity, increased intramedullary c ell death and peripheral cytopenians of varying severity. Patients wit h myelodysplasia have a propensity (20% to 30% of cases) to undergo tr ansformation into acute myeloid leukemia (AML), and a large body of ev idence indicates that MDS represent steps in the multiphasic evolution of AML. Progression of the disease is characterized by expansion of t he abnormal done and inhibition of normal hematopoiesis leading to det erioration of the blood cell count and/or development of AMI,. MDS are relatively unusual in childhood, representing only 3% of pediatric he matological malignancies, although it has been reported that up to 17% of pediatric AML cases may have a previous myelodysplastic phase The first systematic attempt at morphological classification of MDS was pr ovided by the French-American-British (FAB) group. However, the FAB cl assification of MDS is only partially applicable in children. Some var iants are extremely rare or absent (refractory anemia with ring sidero blasts and chronic myelomonocytic leukemia), and other peculiar pediat ric disorders, represented by juvenile chronic myelogenous leukemia (J CML) and the monosomy 7 syndrome, are not included. Moreover, since th ere is a partial overlap between pediatric MDS and myeloproliferative disorders and the variants occurring in young children have rather spe cific features, some confusion still surrounds the nosographical defin ition of childhood MDS, so that none of the proposed classifications a re widely accepted and used. Characteristically, some genetic conditio ns such as Fanconi's anemia, Shwachman's and Down's syndromes predispo se to the development of MDS in childhood. The most common variants of childhood MDS are represented by JCML and the monosomy 7 syndrome, bo th disorders typically occurring in young children JCML is characteriz ed by a spontaneous growth of granulocyte-macrophage progenitors that show a striking hypersensitivity to granulocyte-macrophage colony-stim ulating factor. Clinical presentation resembles that of some myeloprol iferative disorders, with massive organomegaly usually not observed in the classically reported variants of MDS. Clinical features of the mo nosomy 7 syndrome resemble those observed in JCML and a differential d iagnosis between these two entities relies upon the higher percentage of fetal hemoglobin, the more pronounced decrease in platelet count an d, in some cases, the lack of the peculiar cytogenetic abnormality in the latter. With the number of children being cured of cancer constant ly rising, a significant increase in secondary or chemotherapy-related myelodysplasia is being observed and these disorders represent a form idable challenge for pediatric hematologists due to their poor respons e to chemotherapy. As a matter of fact, owing to their biological hete rogeneity and aggressive clinical course in childhood, ah MDS variants pose serious difficulties for successful management. If a compatible donor is available, allogeneic bone marrow transplantation (BMT) becom es the treatment of choice and should be performed during the early st ages of the disease. Supportive therapy, differentiative treatments an d low-dose chemotherapy, while valuable alternative therapeutic option s in adults, have limited application in pediatric patients. The role of intensive chemotherapy and autologous BMT has not yet been dearly d efined, and the use of hematopoietic growth factors does not seem to h ave a significant influence on the natural history of the disease. In the future, new insights into the events leading to progressive geneti c changes in the clonal population and into the molecular basis of the se genetic lesions could result in interesting new therapeutic approac hes directed either at the oncogenes involved in the pathogenesis of t he disease, or at the cytokines and/or their receptors causing the abn ormal differentiation and proliferation of the myelodysplastic clone.