- Summary of Myelodysplastic Syndromes
- Symptoms and Signs of Myelodysplastic Syndromes
- Laboratory Features of Myelodysplastic Syndromes
- Specific Myelodysplastic Syndromes
- Clonal (Refractory) Sideroblastic Anemia
- Therapy-Related Myelodysplastic Syndromes
- Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndromes
Van Den Berge and colleagues are credited with the description of this syndrome in 1974.197 Patients with the 5q– syndrome have clonal anemia and dysmorphic cells in the marrow containing, as the sole cytogenetic abnormality, a deletion in the long arm of chromosome 5 (5q).198–200 The anemia, observed most frequently in older women, is associated with marked dyserythropoiesis, erythroid multinuclearity, and hypolobulated and frequently small (“dwarf”) megakaryocytes (Fig. 88–3). Neutropenia and thrombocytopenia are highly uncommon. The syndrome occurs infrequently in children
The somatic mutation in this syndrome resides in a very primitive multipotential cell, which has been defined as a myeloid progenitor in some studies201,202 and as a lymphohematopoietic progenitor in other studies.203,204 Patients with this disorder have a risk of developing AML (approximately 10%) that is similar to the risk of patients with clonal anemia and marrow cells without 5q–. Patients in whom 5q– is a single abnormality by FISH and whose blood and marrow correspond to the morphologic criteria for the 5q– syndrome have a median survival of approximately 7 years.205 Patients who appear to have a solitary 5q– by standard cytogenetics but who have other abnormalities when studied by FISH have a median survival of less than 3 years. With the application of FISH, complex abnormalities involving 5q– are unlikely to represent the classic syndrome with its very favorable prognosis. The less-morbid course of the classic 5q– syndrome is associated with a lower degree of pathologic apoptosis.206
Deletion of 5q– may be a feature of other clonal cytopenias, oligoblastic myelogenous leukemia, or AML. In these situations, two of the classic features of the 5q– syndrome often are absent: macrocytic red cells and normal or elevated platelet count. Blast cells are evident in the oligoblastic leukemias, and basophilia and eosinophilia have been found in more than half of patients.207 The 5q– cytogenetic finding still confers a somewhat better prognosis in these atypical situations if the marrow blast percentage is less than 10. In some cases, the 5q deletion may be a translocation or insertion as judged by FISH. Cells in cases of T- or B-cell acute lymphoblastic leukemia also have contained a 5q– abnormality.200
Extensive studies of the deleted region of the long arm of chromosome 5 have demonstrated a common deleted region and the spectrum of genes that reside in that region and may be involved in the initiation of this clonal syndrome. In the 5q– syndrome, the deletion is at q13-q31, whereas in other MDS with a 5q–, the region involved is 5q22 to q33.208 The studies of the deleted regions of chromosome 5q– in cases with the syndrome have resulted in discrepant findings regarding (1) the size of the common deleted region, (2) the proximal and distal breakpoints on the long arm of chromosome 5 involved, (3) the candidate genes that might represent the tumor suppressor genes lost on 5q–, and, more specifically, (4) the gene or genes required to transform a multipotential hematopoietic cell into the cell that sustains the clone, causing the 5q– syndrome.209 Using short hairpin RNA functional screens of normal CD34+ cells, the inhibition of RPS14 simulates a syndrome akin to that of 5q– with decreased erythropoiesis and increased megakaryocytopoiesis.210 The loss of this gene, part of the ribosomal protein complex, could lead to dysregulation of messenger RNA translation and disturb hematopoiesis and result in oncogenesis.211 An RNA processing defect has been observed in CD34+ cells from patients with the 5q– syndrome.212 Other genes, such as EGR1, CTNNA1 (-catenin), and NPM1 have been examined for a role in the pathogenesis of the 5q– syndrome.213 Mutations have not been found on the normal homologous region of chromosome 5, and an epigenetic change such as hypermethylation of the allelic gene likely accounts for the loss of tumor suppressor activity. Alternatively, haploinsufficiency may induce the dysregulation of ribosomal protein apparently associated with this syndrome.
Lenalidomide, a thalidomide analogue, induces improvement in approximately 85 percent of patients with the classical 5q– syndrome.214–216 One approach is to administer 10 mg/day until improvement or toxicity requiring cessation. The improvement ranges from complete remission with disappearance of abnormal cytogenetics and normalization of blood counts to improvement in blood hemoglobin and loss of transfusion requirement to a maintenance of the low hemoglobin at a level sufficient to markedly decrease the frequency of transfusion. Some patients derive no benefit. The response may occur as soon as 1 week, but on average in about 5 weeks, and may take as long as 7 weeks to occur. In many cases, these patients had been unresponsive to prior erythropoietin treatment. Neutropenia and thrombocytopenia can be adverse effects of lenalidomide. The results are less favorable if additional cytogenetic abnormalities accompany the 5q– change.