Myelodysplastic Syndromes and Myeloproliferative Disorders, The

Clinical Laboratory Science, Fall 2004 by Williams, J Lynne

LEARNING OBJECTIVES:

1. Compare and contrast the FAB and WHO classification systems for the myelodysplastic syndromes (MDS) and the myeloproliferative disorders (MPD).

2. Discuss the rationale for the use of antiangiogenic therapy in MDS.

3. Explain epigenetic alterations of DNA, and the functional role of DNA methyltransferase and histone deacetylase (HDAC) in these changes.

4. Describe the role of molecular assays for PRV-1 and Mpl in the diagnosis of MPD.

5. Discuss the role of neoangiogenesis in idiopathic myelofibrosis.

6. Explain why Imatinib (Gleevec) (the bcr-abl tyrosine kinase inhibitor) is effective in some patients with myelofibrosis.

ABBREVIATIONS: AML = acute myelocytic leukemia; APL = acute promyelocytic leukemia; CML = chronic myelocytic leukemia; CMML = chronic myelomonocytic leukemia; CMPD = chronic myeloproliferative disorders; ET = essential thrombocythemia; FAB = French American British; FDA = Food and Drug Administration; HDAC = histone deacetylase; HDACi = HDAC inhibitor; HSCT = hematopoietic stem cell transplantation; HU = hydroxyurea; IMF = idiopathic myelofibrosis; MDS = myelodysplastic syndromes; PDGF = platelet derived growth factor; PRV-1 = polycythemia rubra vera-1; PV = polycythemia vera; RA = refractory anemia; RARS = refractory anemia with ringed sideroblasts; RCMD = refractory cytopenia with multilineage dysplasia; RAEB = refractory anemia with excess blasts; RCMD-RS = RCMD with ringed sideroblasts; TGF-β = transforming growth factor beta; TNF-α = tumor necrosis factor alpha; TPO = thrombopoietin; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; WHO = World Health Organization.

INDEX TERMS: hematopoietic stem cells; myelodysplastic syndromes; myeloproliferative disorders.

The myelodysplastic syndromes (MDS) and the myeloproliferative disorders (MPD) are a diverse group of hematologie diseases characterized by deregulation of the CD34 hematopoietic stem cell, and with a propensity to transform to acute myeloblastic leukemia (AML). As is true for the acute leukemias, there has been intense interest in determining the molecular mechanisms underlying the cellular deregulation, and the development of more targeted therapies based on unique molecular phenotypes.

In 1997, the Clinical Advisory Committee of the World Health Organization (WHO) published a revised classification of neoplastic diseases of the hematopoietic and lymphoid tissues. This new WHO classification system incorporated morphologic, biologic, and genetic information into a working nomenclature that had clinical relevance, and replaced the previous French-American-British (FAB) classification which was predominantly a morphologic classification system.1 This paper will not attempt a comprehensive discussion of the WHO classification system, but will summarize the significant changes, and then discuss selected aspects of the MDS/MPDs presented at the 45th Annual Meeting of the American Society of Hematology.

The WHO classification of the chronic myeloproliferative diseases lists seven disease entities (Table 1). The major changes from the FAB classification are:

1. Only the Philadelphia chromosome cases (or those with the BCR/ABL fusion gene) are called chronic myelocytic leukemia (CML) by the WHO system. The Phcases, which show myelodysplastic signs, and are known to have significantly worse prognosis, are called atypical CML (aCML), and belong to the newly created myelodysplastic/myeloproliferative group.

2. There are two newly recognized entities which were not included in the FAB classification, chronic neutrophilic leukemia (CNL) and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES).

The WHO classification of the myelodysplastic syndromes incorporates many of the definitions of the FAB system, but updates and refines the definition of some subtypes and thus improves their clinical relevance (Table 2). The WHO classification recognizes eight subtypes, in contrast to the five listed by the FAB system. The major changes include:

1. The definitions of the lower grade diseases, refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS) have been refined, and a new category refractory cytopenia with multilineage dysplasia (RCMD) has been introduced (Table 3). In the WHO classification, RA and RARS are defined as diseases in which dysplasia is morphologically restricted to the erythroid lineage. If there is multilineage dysplasia (10% or more dysplastic cells in two or more of the myeloid lineages) the diagnosis is RCMD. In cases of RCMD with at least 15% ringed sideroblasts, the diagnosis is RCMD-RS.

2. Refractory anemia with excess blasts (RAEB) is divided into two subgroups, RAEB-1 (with 5% to 9% blasts) and RAEB-2 (with 10% to 19% blasts), reflecting a difference in median survival and rate of transformation to acute leukemia for these two groups of patients.

3. The most significant change was the lowering of the blast threshold for the diagnosis of acute myelocytic leukemia from 30% to 20% blasts in the blood or bone marrow. As a result, the FAB category RAEB-T is eliminated from the WHO classification.