Response to comments from Drs. Alter and Rosenberg

Abstract

We thank Drs. Alter and Rosenberg for their comments 1 on our paper 2 . In adults, and more so in children, the classifications of myelodysplastic syndrome (MDS) are still debated, and modifications are periodically proposed. Controversy prevails with regard to whether some MDS groups need to be combined together or further split, and whether some cases should be classified as MDS or acute myeloid leukemia (AML). The inclusion criteria of pediatric MDS vary in different published studies and sometimes are not precisely stated. In particular, there are no "standard definitions" of MDS in inherited bone marrow failure syndromes (IBMFS ). The advantage of the CCC classification is that it was designed to include all categories of MDS (de novo, therapy-related and syndrome-associated). In contrast to the WHO classification, the CCC classification includes the category of refractory cytopenia with ringed sideroblasts since despite its rarity, this cytopathology exists in children as evidenced by this series and other reports in the literature.6 Had we used the pediatric WHO MDS classification we could not have categorized either of our cases of refractory cytopenia with ringed sideroblasts. In addition, the significance of refractory cytopenia with dysplasia has not been systematically and thoroughly studied in IBMFS; therefore, this category was included in our classification while in the WHO classification it was omitted.The first component of the CCC classification refers to the etiology of MDS, which we termed "category". In our classification, the category can be general (e.g. syndromic MDS) or more specific (e.g. Fanconi anemia-associated MDS). We analyzed the differential risk of disease progression and survival among patients with various syndromic diagnoses.We used the diagnostic criteria for MDS published by Hasle and colleagues.4 This also applied to cases with refractory cytopenia. The only exception was a patient with constitutional trisomy 8, who led us to propose expansion of the published criteria. As explained in the Discussion, this patient clearly had MDS, since he had an MDS/AML predisposition syndrome (constitutional trisomy 8), progressive cytopenia and a hypercellular marrow. He had no prominent dysplasia, no ringed sideroblasts, no excess blasts, no cytogenetic abnormalities and no indication of any other dietary, metabolic or infectious etiologies that could account for the blood dyscrasia.With regard to the cases of unclassified IBMFS, we stated in the Online Supplementary Data that patients who fulfilled specific diagnostic criteria for an IBMFS were recruited by hematologists at each center submitting data to the registry.7 Patients were considered to have unclassified IBMFS if they did not fit the clinical, laboratory and genetic diagnostic criteria of known IBMFS.7 The majority of these patients underwent extensive genetic testing, which was negative. Genetic testing was performed at the discretion of the referring physician.As stated in the Methods of our paper, when we compared the ris...