The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.

Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities-some defined principally by genetic features-that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.

Myelodysplastic (preleukemia) syndromes: the bone marrow factory failure problem.

The myelodysplastic syndromes are a group of hematologic disorders that adversely affect the levels of hemoglobin, platelets, erythrocytes, and leukocytes. Although the cause of this syndrome is unknown, new diagnostic techniques have facilitated identification and classification of these diseases into five categories: refractory anemia (refractory cytopenia), refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. Cytogenetic abnormalities may be present in more than 55% of the patients. Symptomatic patients should be assessed relative to life-threatening versus non-life-threatening cytopenias and age. Management consists of primarily supportive measures, although certain approaches that are currently being used or under investigation, such as concomitant administration of erythropoietin and other growth factors, show promise for the future.

Haematological features of primary myelodysplastic syndromes (PMDS) at initial presentation: a study of 118 cases.

The haematological features of 118 cases of primary myelodysplastic syndromes (PMDS) were reviewed to see how these could be related and classified according to the recent FAB proposals. A majority of the cases were elderly who presented with a macrocytic or normocytic anaemia and reticulocytopenia. Cases of acquired idiopathic sideroblastic anaemia (AISA) usually had normal leucocyte and platelet counts, erythroid hyperplasia, marked dyserythropoiesis and more than 20% ringed sideroblasts. Cases of refractory anaemia with excess of blasts (RAEB) had frequent neutropenia and thrombopenia usually with prominent dysgranulopoiesis and dysthrombopoiesis. Refractory anaemia or refractory cytopenia appeared morphologically to be a heterogeneous group. Leukaemic transformation did not occur in any of these 16 cases of AISA whereas six of the 34 cases of RAEB transformed into acute leukaemia. It appears that the cases of PMDS present with well defined haematological features which permit recognition of different groups; these latter groups appear to be morphologically and prognostically distinct.

Clinical-cytogenetic correlations in myelodysplasia (preleukemia).

Cytogenetic studies detected abnormalities in 107 (43%) of the 247 patients in this series. Some degree of overt clinical progression occurred in 55 patients (22%), this being 29% of those patients with cytogenetic abnormalities and 17% of those with normal chromosomes. The presence and complexity of a clonal cytogenetic abnormality correlated with shorter survival. In each clone category of a complexity classification (simple, complex, very complex), patients with some normal cells appeared to have better survival than those with none. In multiple regression analyses, the prognostic value of chromosomes was independent of (and second in importance to) the FAB type of myelodysplastic syndrome (MDS) whichever chromosome classification was used. Patients with refractory anemia (RA) had the lowest incidence of chromosome abnormalities and no cases were found to have only abnormal cells (AA). A greater proportion of patients with refractory anemia with an excess of blasts (RAEB) and RAEB in transformation (RAEB-t) had clonal abnormalities. Morphology alone is not at present able to distinguish between RA or refractory anemia with ringed sideroblasts and similar disorders that may not be MDS in the strict sense. Demonstration of a clonal cytogenetic abnormality remains a positive indication of the presence of the neoplastic nature of the disease.

The myelodysplastic syndromes.

The myelodysplastic syndromes are a heterogenous group of disorders characterized by abnormalities in the maturation and differentiation of hematopoietic cells. A single diagnostic test is not available but laboratory and clinical features are often characteristic. The French-American-British Co-operative Group has classified these disorders into five subgroups. Despite distinctive morphologic features, this classification identifies only two major prognostic groups. The natural history is variable with some patients rapidly developing acute leukemia, others experiencing complications of pancytopenia in the absence of acute leukemia, while others have minimal symptoms and prolonged survivals. A number of therapeutic modalities have been used including hematinics, steroids, retinoids, low-dose chemotherapy, aggressive chemotherapy, and bone marrow transplantation. Supportive care is the mainstay of treatment for most patients.

[Prognostic factors in myelodysplastic syndromes: analysis of 72 cases]. / Prognostische Faktoren bei myelodysplastischen syndromen (MDS): eine Analyse von 72 Fällen.

72 patients were diagnosed as suffering from myelodysplastic syndromes (MDS) according to the FAB classification: 16 patients with refractory anaemia (RA), 11 patients with acquired idiopathic sideroblastic anaemia (AISA), 14 patients with refractory anaemia with an excess of blast cells (RAEB), 7 patients with RAEB in transformation (RAEB/t) and 24 patients with chronic myelomonocytic leukaemia (CMML). The duration of the preleukaemic phase was between 2 and 189 months (median: 15 months); RAEB in transformation and CMML showed a median phase of less than 12 months. Transformation into acute leukaemia (AL) occurred in 46 patients (64%). Of the clinical signs only thrombocytopenia was a significant poor prognostic factor (p less than 0.01). Cytogenetic studies were made in 31 patients. 14 had clonal aneuploidy: these patients had a higher risk of AL, but not a significantly shorter preleukaemic phase (p greater than 0.1). Stem cell cultures (CFUc) were carried out in 31 patients. Patients without colony growth or only cluster growth showed a high incidence (10/11 and 8/8) of transformation into AL; preleukaemic phases were significantly shorter than in patients with normal colony growth or cluster + colony growth in all FAB subgroups (p less than 0.001). The bone marrow blast cell count was indirectly proportional to the duration of the preleukaemic phase: thrombocytopenia, cytogenic aberrations and failure of in vitro colony growth are additional poor prognostic factors in MDS.

[Myelodysplastic syndromes: preleukemic syndromes]. / Les syndromes myélodysplasiques: syndromes préleucémiques.

The myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by peripheral blood cytopenias with a hypercellular bone marrow exhibiting dyspoiesis. The predominant in elderly patients are associated with a high risk of progression to acute myelogenous leukemia. The etiology of MDS is unknown in most cases. About 10% of MDSs are secondary. MDS are classified by the French American British (FAB) classification into five subgroups. The incidence of the disorders is difficult to estimate but it seems to be increasing. Clonal cytogenetic aberrations are found in 30 to 50% of de novo MDS. The only currative treatment for MDS is allogeneic bone marrow transplantation.

Preleukemic states. I. Definition and classification. II. Refractory anemia with an excess of myeloblasts in the bone marrow (smoldering acute leukemia).

Approaches to the diagnosis and classification of preleukemic states involving chronic cytopenias are presented and discussed. Diagnosis of these states is facilitated by the identification of anomalies in all the myeloid cell lines (i.e., those derived from the bone marrow). These cellular anomalies may be morphologic, biochemical, or functional in nature or may affect the quantity of cell in each line in the bone marrow and the peripheral blood. Such anomalies may occur alone or may be associated. A tentative classifiction is proposed which is based on one or several of these anomalies. Among the quantitative criteria of classification is a moderate and static excess of myeloblasts and promyelocytes in the bone marrow. Refractory anemia with an excess of myeloblasts (RAEM) in the most frequent of these states. Its main clinical and hematologic features are described. The disease course is quite typical, the mean survival being 20 months; some patients survive for more than 30 months. Acute myeloid leukemia (AML) was the cause of death in less than 28% of cases. Infection in the absence of severe neutropenia was frequent. The relationship between RAEM and AML is disc,ssed, and the individual characteristics of RAEM are emphasized.

[Cytogenetics of preleukemic states]. / Citogenética de los estados preleucémicos.

In about a half of preleukemic states it is possible to find chromosomal aberrations, as three n. degrees 8 chromosomes, a single n. degrees 7 or n. degrees 5 chromosome, or a partial deletion of long arm or n. degrees 5 chromosomes. From a prognostic point of view, the presence of the indicated chromosomal abnormalities show a three times increased risk to suffer leukemia. Several abnormal cell clones may be produced, but generally only one of them has the proliferative capacity to establish an evolutive non-lymphoblastic acute leukemic process.

Myelodysplastic syndromes: a study of 101 cases according to the FAB classification.

The myelodysplastic syndromes (MDS) are a group of closely related disorders characterized by chronic cytopenias with cellular marrow, poor prognosis and refractoriness to treatment. We studied 101 consecutive cases of MDS diagnosed over a 7-year period. Peripheral blood (PB) and bone marrow (BM) samples were reviewed and classified according to the proposals of the French-American-British (FAB) cooperative group for MDS. The combined analysis of the initial laboratory features and qualitative haematological abnormalities readily allowed the distinction between the different subgroups. Thirty-two of 79 cases (40.5%) evolved towards other diseases, frequently acute leukaemia (24/79, 30%), or transformed into other MDS (7/79, 9%). In five cases, initially classified as refractory anaemia (RA) or refractory anaemia with ring sideroblasts (RAS), a transitory change to another type of MDS--two chronic myelomonocytic leukaemias (CMML), two refractory anaemias with excess of blasts (RAEB) and one refractory anaemia with excess of blasts 'in transformation' (RAEB-t)--was observed before the evolution towards acute leukaemia. This provides a new link between all these syndromes and increases the number of transitions to other MDS. Overall prognosis was very poor, with differences between subgroups. RA had the best prognosis whereas RAEB-t had the worst one. This study shows that the FAB classification is readily usable and defines well-characterized subgroups of MDS, although there are frequent transitional forms, and as the natural history of the MDS unfolds they may convert into another. The actual poor prognosis and the frequent evolution towards acute leukaemia makes necessary to investigate new methods of treatment for these disorders.

Myelodysplastic syndrome is not merely "preleukemia".

Myelodysplastic syndrome (MDS) is a disease characterized by ineffective hematopoiesis. There are significant biologic and clinical differences between MDS and acute myeloid leukemia (AML). We studied a cohort of 802 patients, 279 (35%) with newly diagnosed MDS and 523 (65%) with newly diagnosed AML, and compared clinical and biologic characteristics of the 2 groups. Complete clinical and cytogenetic data were available on all patients, and a subgroup of patients was studied for apoptosis, angiogenesis, proliferation, and growth factors. Our results demonstrate that MDS is a discrete entity that is different from AML and is characterized primarily by increased apoptosis in early and mature hematopoietic cells. Using cell sorting and loss of heterozygosity, we demonstrate that the leukemic cells from MDS patients are capable of differentiation into mature myeloid cells and monocytes. We also demonstrate that there is a significant overlap between AML and MDS when MDS is defined on the basis of an arbitrary percentage of blasts of 20% or 30%. These data suggest that despite similarities between AML and MDS in their responses to treatment and outcomes, MDS is biologically and clinically different from AML and should not be considered an early phase of AML. The data indicate that MDS must be better defined on the basis of its biology rather than the percentage of blasts; further, the data suggest that there is a need to develop therapeutic approaches that specifically address the biologic abnormalities of MDS.

Modifications in the classification of primary myelodysplastic syndromes: the addition of a scoring system.

A retrospective series of patients with the primary myelodysplastic syndrome has been reviewed and the survival updated. A scoring system is proposed that has advantages in predicting survival outcome. The importance of either dysmegakaryocytopoiesis or dysgranulocytopoiesis is emphasized because of its prognostic impact on leukaemic progression. Over 50 per cent of the patients die from either acute leukaemia or consequences of defective marrow production of granulocytes and platelets. Although only a few cases were included, the RAEB-T group has a very poor outcome and appears much closer to FAB M2 in biologic behaviour than RAEB. Both the criteria for the FAB subtypes and the scoring system can be applied easily in each case of myelodysplasia. Of the 56 patients only 9 were still alive as of April, 1984. Eight of these were in the RA-S and RA categories (or using the scoring system grouping 7 were group 1). All of the 16 patients who progressed to overt AML died within 4 weeks, and none was treated with chemotherapy. Of the remaining 31 patients, half died as a result of infection and/or haemorrhage and the remainder from apparently unrelated causes (cardiovascular, carcinoma, renal failure). These latter deaths are not surprising in light of the median age of 72 years.

Classification of acute leukemia.

The classification of acute leukemia has almost invariably been based on the morphologic diagnosis into two broad categories: acute lymphocytic and acute myeloid leukemia. Despite the wide range of morphologic variation in both groups, strict criteria to define the subgroups have only recently been proposed. The conventional markers for B and T cells are now being applied to leukemic cells as are cytochemistry and electron microscopy, terminal deoxynucleotidyl transferase, serum lysozyme, and surface markers, E-rosettes, membrane immunoglobulin, antinull acute lymphocytic leukemia antiserum, and Fc and C3 receptors. The myelodysplastic syndromes may mimic acute leukemia and it is important that they be identified and treated appropriately. The high incidence with which chronic myelomonocytic leukemia terminates in acute leukemia suggests that it is a preleukemic condition, whereas refractory anemia with excess blasts and acquired idiopathic sideroblastic anemia may have long, drawn-out courses. Only a small population of patients with the latter conditions develop acute leukemia.