Chronic myeloid disorders: Classification and treatment overview

Seminars in

HEMATOLOGY Vol 38, No 1, Suppl2,

January 2001

Chronic Myeloid Disorders: Classification and Treatment Overview Ayah

Teffek

Chronic myeloid disorders (CMD) are collectively characterized by monoclonal myeloproliferation that involves multiple lineages, retains a variable degree of cellular maturation, and has the potential to undergo clonal evolution. However, monoclonal hematopoiesis is neither essential nor specific to CMD. Morphologic and cytogenetic characteristics allow a working classification of these disorders that is clinically useful. There are four major divisions: chronic myeloid leukemia (CML), which is easily identified by the presence of the Philadelphia chromosome (or its molecular equivalent); the myelodysplastic syndromes (MDS), which are characterized by trilineage dysplasia; chronic myeloprollferative diseases (CMPD), which include essential thrombocythemia, polycythemia Vera, and agnogenic myeloid metaplasia (AMM); and atypical CMD, which includes chronic neutrophilic leukemia, chronic eosinophilic leukemla, mast cell disease, and myeloid processes that display overlapping features of MDS and CMPD (hybrid CMD). In CMPD, a diagnosis of polycythemia vera requlres evidence of an erythropoietin-independent increase in red blood cell mass: the diagnosis of both AMM and essential thrombocythemia requires the exclusion of reactive causes of bone marrow flbrosis and thrombocytosis, respectively. In addition, the Philadelphia chromosome, increased red blood cell mass, and dyserythropoiesis should also be absent. Semin Hematol38(suppl2):1-4. Copyright 0 2001 by W.B. Saunders Company.

HRONIC MYELOID DISORDERS (CMD) can be operationally divided into four categories: (1) chronic myeloid leukemia (CML); (2) myelodysplastic syndromes (MDS); (3) atypical CMD; and (4) chronic myeloproliferative diseases(CMPD).

C

Chronic

Myeloid

Leukemia

CML is a clonal disorder resulting from a malignant transformation of a pluripotent, hematopoietic stem cell. l A t(9;22)(q34;ql1.2> chromosomal translocation is associated with CML. The translocation occurs in a breakpoint cluster region (bcr) region of chromosome 22 and in the region of chromosome 9 where the Seminars

c-a61 oncogene resides. Since the chimeric gene is active, the defect can be identified at the DNA, RNA, and protein levels.2 The transformed hematopoietic stem cell of CML gives rise to an expanding pool of committed progenitor cells of granulocytic and other myeloid lineages. CML is readily responsive to chemo-

in Hematology,

From

the Division

of Hematology,

Mayo

Clinic,

Rochester,

MN. Address reprint requests to Ayalew Teffeeri, MD, Associate Profesor of Medicine, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 5J905. Copyright 0 2001 by W.B. Saunders Company 0037-1963/01/3801-2001$35.00/O doi:10.1053/shem.2001.23036

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therapy. With further mutations, however, it progresses into an accelerated phase, which becomes increasingly resistant to chemotherapy and steadily worsens in untreated individuals. Following a diagnosis of CML, the patient is usually treated with allogeneic hematopoietic stem cell transplantation or drug therapy. The decision for one or the other treatment depends on several factors, including patient age, availability of suitable stem cell donors, disease stage, and patient preference. Currently used agents for drug therapy include interferon alfa (IFN-a), hydroxyurea, and busulfan. Treatment with IFN-a has been shown to provide a survival advantage over that of hydroxyurea or busulfan.3 The latter agents are currently considered palliative and do not alter the natural history of the disease. Approximately 20% of patients with CML enjoy prolonged survival as a result of major karyotypic remission. The addition of cytosine arabinoside (Ara-C) may enhance the survival benefit associated with IFN-a treatment,* making the choice between allogeneic hematopoietic stem cell transplantation and IFN-a treatment difficult. However, the recent introduction of STI-57 1, a welltolerated oral agent with specific abl kinase inhibitory properties, may substantially change current treatment strategy in CML.5

Myelodysplastic

Syndrome

Trilineage dyshematopoiesischaracterizes MDS6 Similar to CML, MDS is a clonal stem cell disorder.’ An international prognostic scoring system based on bone marrow myeloblast percentage, number of cytopenias, and cytogenetic findings separates good-risk (median survival, 5.7 years) from intermediate- or poor-risk (median survival, 0.4 years) patients.* More than 70% of patients with MDS are above age 60 years. As a result, treatment in MDS is often palliative and younger patients are offered allogeneic hematopoietic stem cell transplantation in the presence of suitable stem cell donors.9

Atypical Atypical currently

Chronic Myeloid Disorders

CMD includes all CMD that are not classifiable as CML, MDS, or

Tefferi

CMPD. Differentiation of MDS and CMPD can be difficult in the presence of associated bone marrow fibrosis or prominent myeloproliferative features.‘0 Such casesare currently referred to as hybrid, mixed, or overlap CMD. A monoclonal process that may affect multiple lineage has been demonstrated in two other atypical CMD, chronic eosinophilic leukemiai and systemic mast cell disease.12This, however, does not exclude the possibility that some patients with the clinical phenotype of chronic eosinophilic leukemia or systemic mast cell disease may have a cytokine-driven polyclonal process.

Chronic

Myeloproliferative Diseases

The CMPD include agnogenic myeloid metaplasia (AMM), essential thrombocythemia, and polycythemia Vera. Patients with essential thrombocythemia or polycythemia vera may sometimes develop clinical and laboratory features similar to those seen in AMM. These conditions are referred to as post-thrombocythemic myeloid metaplasia (PTMM) and postpolycythemic myeloid metaplasia (PPMM). The term “myelofibrosis with myeloid metaplasia” (MMM) refers to AMM, PTMM, and PPMM.i3

Agnogenic Myeloid Metaplasia AMM is characterized by marked splenomegaly from extramedullary hematopoiesis, anemia from ineffective erythropoiesis, and profound constitutional symptoms that are prognostically detrimentali? Among the CMPD, AMM has the worst prognosis, with an estimated median survival of 5 years. Adverse prognostic features in AMM include anemia and granulocyte immaturity in the peripheral blood. Current treatment in AMM is largely palliative. The only treatment modality with a curative potential is allogeneic hematopoietic stem cell transplantation, but its application is limited to young patients with poor prognostic factors becauseof an associated increased risk of treatment-related mortality.14 Palliative therapy in AMM includes the use of androgen preparations and corticosteroids for anemia,i5-i7 hydroxyurea for control of myelo-

3

Chronic Myeloid Disorders

proliferation,1s and splenectomy in advanced cases.l9 In addition, recent studies suggest that autologous hematopoietic stem cell transplantation may have a palliative role and result in improvement of anemia and regression of bone marrow fibrosis in some patients with MMM.‘O Most recently, we have demonstrated a markedly increased bone marrow angiogenesis in MMM2i and also found interesting biologic activity using an antiangiogenic agent, thalidomide.22 Additional studies are needed before the role of thalidomide treatment or autologous stem cell transplantation in the treatment of MMM is defined.

Essential Thrombocythemia Essential thrombocythemia is currently defined as a chronic nonreactive thrombocythemic state that is not classifiable as another CMD.23 Recent studies have suggested pathogenetic heterogeneity manifested by variable clonal involvement of myeloid cells2* as well as megakaryocyte and platelet expression of the thrombopoietin receptor (c-M~l).~~,*~ The clinical relevance of these variations is currently being studied. At present, management of patients with essential thrombocythemia depends on the presence or absence of a thrombotic history and advanced age. In low- or intermediate-risk disease (age < 60 years and no history of thrombosis), patients may be followed without a specific therapeutic intervention.27,28 This is most relevant to patients who are either pregnant or are of child-bearing age.27 In high-risk patients (age I 60 years or the presence of thrombosis history), the use of either hydroxyurea or anagrelide to control the platelet count to below 400 X lO’/L may minimize the risk of recurrent thrombosis.3°,3i These agents are sometimes utilized in intermediate-risk patients with extreme thrombocytosis to reduce the risk of hemorrhage.32,3j Most patients with essential thrombocythemia may enjoy a normal life expectancy while 5% to 10% may experience transformation into PTMM or acute leukemia.28,34

Polycythemia Vera Polycythemia vera is the subject of this supplement presented by a very distinguished group

of experts in the field of CMPD. Polycythemia vera is a hematologic stem cell disease often characterized by a clonal increase in red blood cells, granulocytes, and platelets. Lineage heterogeneity in clonal involvement has been demonstrated.35 The incidence of polycythemia vera may be as high as 2.3 per 100,000 and there is a slight male preporlderance.36 Clinical features include splenomegaly, aquagenic pruritus, increased risk of thrombohemorrhagic complications, and ultimate transformation into PPMM and acute leukemia..37 The early and revised diagnostic criteria for polycythemia vera will be discussed by Thomas C. Pearson of St Thomas’ Hospital in London, UK. Josef Prchal from the Baylor College of Medicine in Houston will discuss pathogenetic mechanisms in polycythemia Vera. Lawrence A. Solberg Jr of the Mayo Clinic in Jacksonville, FL, will discuss regulatory mechanisms in normal and disturbed hematopoiesis. Harriet S. Gilbert of Mount Sinal Medical Center in New York, one of the original members of the Polycythemia Vera Study Group (PVSG), will close the symposium by discussing current management.

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