The chronic leukemias are a group of malignancies involving the hematopoietic system. Chronic myelogenous leukemia (CML) is a myeloproliferative disease that arises from a clonal process involving an early progenitor hematopoietic stem cell. It also is associated with the Philadelphia chromosome and/or the bcr/abl fusion gene. Chronic myelomonocytic leukemia (CMML) has recently been reclassified by the World Health Organization as a myelodysplastic/myeloproliferative disease.¹ It originates from a clonal hematopoietic stem-cell disorder from which there are dysplastic features in at least one myeloid lineage, <20% blasts in the blood and bone marrow, a persistent monocytosis, and no evidence of the Philadelphia chromosome or the bcr/abl fusion gene. Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder that is characterized by a sustained, mature neutrophilic leukocytosis. There is no monocytosis, eosinophilia, or basophilia, and no associated Philadelphia chromosome or bcr/abl fusion gene. Chronic eosinophilic leukemia (CEL) is another myeloproliferative disease that is similar to hypereosinophilic syndrome but is characterized by a clonal proliferation of eosinophilic precursors with increased blasts.¹ Chronic lymphocytic leukemia (CLL) is a clonal expansion of small, round, and mature-appearing lymphocytes. Hairy cell leukemia (HCL) is a malignancy of small B-lymphoid cells that display surface cytoplasmic "hairy" projections.²

The incidence of CML is approximately 1 per 100,000 population per year. In 2002, it is estimated that there will be 4,400 new cases with 2,000 estimated deaths.³ Most CML cases are identified in the fifth and sixth decades of life, and there is a higher incidence in males. The actual incidence of CMML is difficult to determine since patients have previously been included in other diagnostic categories such as CML and myelodysplastic syndrome. However, it has been estimated to occur annually in 3 per 100,000 individuals over the age of 60 years. The median age at diagnosis is 65 to 75 years, and there has been a higher incidence in males.¹ CNL is rare, with only 33 case reports being identified that appeared to have met the diagnostic criteria.⁴ The mean age at diagnosis is 62.5 years, and there is a 2:1 male:female ratio. CEL is also rare, but the actual incidence is unknown since patients with the disease have often been categorized with those having hypereosinophilic syndrome. The incidence is highest in the fourth decade of life, and the disease more commonly affects males.¹ CLL is the most common form of leukemia in Western countries and is more prevalent with increasing age. Most patients are older than 50 years, and there is a 2:1 male:female ratio.² For patients older than 70 years the incidence is >20 per 100,000 people. In 2002, it is estimated that there will be 7,000 new cases of CLL with 4,500 estimated deaths.³ HCL accounts for about 2% of all leukemias, with an estimated 600 new cases in the United States annually. The median age at diagnosis is 55 years, and there is a 5:1 male:female ratio.²

In chronic leukemias, there is an accumulation of malignant hematopoietic cells in the bone marrow that may ultimately lead to bone marrow failure states. Cytopenias may result in hemorrhage, infection, and organ compromise (eg, congestive heart failure from severe anemia).

CML is characterized by a balanced reciprocal translocation between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11.2)] that occurs in about 90% to 95% of cases. This translocation results in the juxtaposition of the c-abl proto-oncogene from chromosome 9 with a portion of the bcr gene located on chromosome 22 thereby producing a novel bcr/abl fusion gene. The gene product results in an 8.5-kb mRNA transcript that generates a 210-kd bcr/abl fusion protein having abnormal tyrosine kinase activity. Through phosphorylation this enzyme may activate different signal transduction pathways that may result in increased proliferation and decreased apoptosis (programmed cell death) of hematopoietic cells.^1,5

CML is also characterized by three phases that occur during the course of the disease. Initially, there is a chronic phase that may last approximately 2 to 5 years, during which time the disease often is indolent. With progression of the disease there is an accelerated phase that lasts 6 to 18 months, and then ultimately blast crisis develops, which appears similar to an aggressive acute leukemia with a survival of only about 3 to 6 months. The exact molecular mechanism by which CML transforms to more advanced stages of the disease is unknown. However, it is possible that a series of genetic changes is responsible. This would be supported by the finding of additional chromosomal abnormalities that can develop during disease acceleration, known as clonal evolution.^1,5

Specific genetic defects have not been identified for the other leukemias classified as chronic myeloproliferative diseases. CMML is suspected to originate from an abnormal hematopoietic stem cell. This disease arises because of dysregulation of myeloid proliferation, maturation, and cell survival. This may result in dysplastic hematopoiesis and cytopenias as well as organ compromise from leukemic infiltration. Abnormalities in the Ras signalling pathway may also be involved in this process.¹

CNL may arise from a granulocytic-committed progenitor.⁶ Cytogenetic and molecular studies have demonstrated the clonal nature of the disease; however, most reports have found that patients have normal cytogenetics.⁴ Patients eventually develop either progressive neutrophilia or blastic transformation.⁶

CEL may arise from either a multipotent, pluripotent, or eosinophil-committed progenitor cell.¹ The disease is also characterized by a chronic phase that may progress to blast crisis. Organ damage may result from leukemic tissue infiltration as well as from eosinophilic cytokine and enzyme release (eg, major basic protein, eosinophil cationic protein).⁷

In CLL there is an accumulation of the neoplastic lymphocytes without increased proliferation that results from abnormalities in apoptosis. The bcl-2 proto-oncogene produces the Bcl-2 protein that inhibits apoptotic cell death. This protein is overexpressed in most cases of CLL.⁸ The neoplastic cells in turn have prolonged survival that allows them to increase in the peripheral blood, bone marrow, and other lymphoid tissues. Patients subsequently may develop cytopenias as a result of progressive bone marrow involvement or from autoimmune abnormalities. This, as well as hypogammaglobulinemia and T-cell dysfunction, may allow bacterial, fungal, and viral infections to occur. CLL patients may also develop either transformation to a large cell lymphoma (Richter's syndrome) or prolymphocytic leukemia.²

Although the etiology of CLL is unknown, chromosomal abnormalities are present in approximately 80% of cases. Most common are deletions of chromosomes 13q14 and 11q22-23 as well as trisomy 12.²

HCL is postulated to originate from a peripheral B cell, but the stage of its development after leaving the germinal center is unknown. The leukemia cells release tumor necrosis factor, which may inhibit hematopoiesis and result in cytopenias.⁹ HCL also expresses CD25 (IL-2 receptor), which may contribute to the proliferation of the disease.²

Many patients with chronic leukemias are asymptomatic and their disease is only identified by finding an abnormality during routine laboratory testing. These patients may develop constitutional symptoms such as fatigue, anorexia, weight loss, sweats, and fever. With progressive bone marrow involvement and the development of cytopenias, various infections can occur as well as hemorrhage, anemia-related symptoms (eg, dyspnea, lightheadedness, and fatigue), and easy bruising with petechiae and purpura.

Hepatosplenomegaly and lymphadenopathy may be present, and result in a sensation of abdominal fullness along with discomfort and early satiety. Although lymphadenopathy is uncommon in chronic-phase CML, it may develop with more advanced stages of the disease. Some patients with chronic leukemia may present with hyperleukocytosis that can result in marked splenomegaly. In patients with CML, priapism may also develop.

In CEL, other symptoms related to organ infiltration can occur. Cardiac involvement is the most common, with possible necrosis, endomyocardial fibrosis, congestive heart failure, valvular regurgitation, mural thrombosis, and thromboembolic events. In addition, neurologic (eg, cognitive dysfunction, peripheral neuropathy), pulmonary (eg, cough), cutaneous (eg, angioedema, papules, nodules, urticaria), gastrointestinal, ocular, rheumatologic, and renal involvement may develop.⁷

The initial evaluation of chronic leukemias should include an analysis of the bone marrow and/or peripheral blood with morphologic review by an experienced hematopathologist; immunophenotyping; chromosomal analysis; and appropriate molecular studies. In certain cases, a similar pathologic evaluation may be performed on an excised lymph node, spleen, or other tissue biopsy specimens (eg, endomyocardial biopsy for CEL).

The diagnosis of CML may be established on morphologic review and by demonstrating the presence of the Philadelphia chromosome [t(9;22)] or the bcr/abl fusion gene. In chronic-phase CML, the peripheral blood shows a neutrophilic leukocytosis, with a left shift revealing immature granulocytic forms. Other findings include a blast count of <10%, basophilia, eosinophilia, thrombocytosis, and anemia. The bone marrow findings include myeloid hyperplasia with immature forms, <10% blasts, and no dysplasia; mild to moderate myelofibrosis may be present.¹ Table 1 shows diagnostic criteria for accelerated and blast phase CML. Figure 1A displays some morphologic findings in chronic phase CML.

Diagnostic criteria for CMML, CNL, and CEL are listed in Tables 2, 3, and 4, respectively.¹ Figures 1B, 1C, and 1D demonstrates the characteristic morphology of these chronic leukemias.

The National Cancer Institute-sponsored Working Group revised guidelines for CLL diagnosis¹⁰ require an absolute lymphocytosis with >5 x 10⁹/L mature-appearing lymphocytes with <55% atypical cells or prolymphocytes. The bone marrow should demonstrate >30% lymphocytic involvement of all nucleated cells. However, a bone marrow analysis is not necessary to establish the diagnosis because of the routine use of peripheral blood flow cytometric analysis (for immunophenotyping). Phenotypic features consistent with B-cell CLL include: (1) the majority of the lymphocytes expressing B-cell markers (CD19, CD20, CD23) with CD5 but without other pan-T-cell markers; (2) monoclonality of the B cells with either kappa or lambda light chain restriction; and (3) low-density surface immunoglobulin.¹⁰ Morphologic findings of CLL are shown in Figure 1E.

HCL may be diagnosed upon finding hairy cells on morphologic review of the peripheral blood (Figure 1F). The cells are medium-sized lymphoid cells with abundant cytoplasm that extends circumferentially as "hairy" projections. The cells are tartrate-resistant acid phosphatase-positive, and immunophenotyping demonstrates the expression of CD19, CD20, CD22, CD25, CD11c, and CD103.

The goals of therapy for an individual patient with chronic leukemia should be determined before formulating a treatment plan. These goals range from cure, to improved survival and quality of life, to disease palliation and comfort measures.

The principal goal in treating CML is to eliminate the clone of cells that have the Philadelphia chromosome or the bcr/abl fusion gene. Hydroxyurea has been a standard therapy for chronic-phase disease, and it can achieve hematologic remissions as well as decrease splenomegaly. However, this form of therapy does not result in cytogenetic remissions. Subsequently, in the early 1980s, therapy with interferon-α was demonstrated to not only achieve hematologic remissions in most patients, but also to result in cytogenetic remissions in up to 35% of patients. These patients also had a survival advantage over those treated with hydroxyurea. However, intolerable symptoms from interferon, such as a flu-like syndrome, anorexia, and depression have prevented continuation of the agent in some patients. More recently, a specific bcr/abl tyrosine kinase inhibitor, STI571, or imatinib, has been developed. This agent has demonstrated substantial hematologic and major cytogenetic responses in patients with chronic-phase CML who were refractory to interferon-α as well as in patients with accelerated phase or blast crisis.¹¹ Further follow-up is necessary to assess the durability of these responses, and clinical trials combining STI571 with other agents are currently in progress. Allogeneic hematopoietic stem-cell transplantation is a standard therapy for CML with curative potential. However, this therapy is limited to younger patients with HLA-matched donors, and significant transplant-related morbidity and mortality risks remain. Autologous hematopoietic stem-cell transplants have been performed for chronic-phase CML patients with substantially less transplant-related mortality risks than with an allogeneic approach. However, most of these patients develop recurrent disease because the graft-versus-leukemia effect that may be achieved after allogeneic transplantation is absent.¹² Further evidence of a graft-versus-leukemia effect in the allogeneic setting comes from the observation that durable remissions can be achieved with donor leukocyte infusions in patients who relapse after allogeneic transplantation.¹³

CMML has previously been classified with and treated as a myelodysplastic syndrome. Therapeutic approaches have included best-supportive care measures such as antibiotics and blood product transfusion support. Other treatments have consisted of growth factors (granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and erythropoietin); amifostine; immunosuppressive therapy (eg, antithymocyte globulin, cyclosporine); hypomethylating agents (eg, azacytidine, decitabine); low-intensity chemotherapy (eg, hydroxyurea); high-intensity chemotherapy (eg, topotecan); and allogeneic hematopoietic stem-cell transplantation.¹⁴

Therapy for CNL and CEL has included agents such as hydroxyurea, busulfan, 6-thioguanine, and interferon. Although these agents have been able to control disease burden and reduce splenomegaly, they have not been curative treatment. However, allogeneic stem-cell transplantation may potentially cure some patients who are appropriate candidates for this aggressive approach.^4,6,7

Often patients with CLL require no treatment initially. Therapy is indicated for patients who develop systemic symptoms (eg, extreme fatigue, fevers, night sweats, weight loss); worsening anemia or thrombocytopenia from either progressive bone marrow involvement or an autoimmune etiology (not responsive to corticosteroids); massive or progressive splenomegaly/lymphadenopathy; or a rapid lymphocyte doubling time (<6 months).¹⁰ Therapeutic agents have included chlorambucil (with or without corticosteroids); cyclophosphamide, vincristine, and prednisone (CVP); and purine analogues (eg; fludarabine, cladribine). When compared with chlorambucil, fludarabine has demonstrated an improved disease-free survival but no improvement in overall survival. Rituximab and alemtuzumab (monoclonal antibodies directed against CD20 and CD52, respectively) have demonstrated significant single-agent activity in CLL and are currently being evaluated in combination trials with other agents.¹⁵ For selected patients, both autologous and allogeneic hematopoietic stem-cell transplants may also be considered, including nonmyeloablative approaches with reduced-intensity conditioning regimens.¹⁶

Therapy for HCL previously had been indicated for patients who developed severe infections or cytopenias as well as for patients with symptomatic splenomegaly. Initial therapeutic approaches consisted of splenectomy, and later interferon-α. Subsequently, pentostatin and cladribine were found to be highly effective with most patients achieving durable, long-term remissions.¹⁷ Therefore, treatment with these agents is often administered earlier before patients become symptomatic.

Patients with chronic-phase CML usually have a longer survival than those with the more advanced phases of the disease. However, prognostic systems have been proposed to help better predict outcomes. Initially, prior to the use of interferon, Sokal et al found age, spleen size, platelet count, and the percentage of myeloblasts to be independent prognostic factors.¹⁸ With the use of a Cox model, patients were then categorized into either high-, intermediate-, or low-risk groups with median survivals of 34, 44, and 57 months, respectively. A subsequent system was developed for patients previously treated with interferon and found that the percentage of basophils and eosinophils were other prognostic factors in addition to those from the Sokal scoring system.¹⁹ Respective median survivals for the high-, intermediate-, and low-risk groups were 42, 65, and 98 months. One other risk assessment system has been developed for patients prior to allogeneic stem cell transplantation.²⁰ Risk factors have included stage of the disease, histocompatibility, age, interval from diagnosis to transplant, and the sex of the donor and the recipient. Five-year survivals incrementally increased from 18% to 72%, while transplant-related mortality incrementally decreased from 73% to 20% for high-risk to low-risk-score patients, respectively.

For CMML, median survivals have often ranged from 20 to 40 months. This disease had been included in the International Prognostic Scoring System for myelodysplastic syndromes.²¹ Independent risk factors identified were the percentage of bone marrow blasts, cytogenetic abnormalities, and the number of cytopenias. After generating a risk score based upon the number of these factors that were present, patients were categorized into either low-, first intermediate-, second intermediate-, or high-risk groups with median survivals of 5.7, 3.5, 1.2, and 0.4 years, respectively.

CNL is a slowly progressive disease with survivals reported from 6 months to 20 years. Death may occur as a result of progressive, refractory neutrophilia or from transformation to acute leukemia.^1,4,6 CEL may also have a variable survival, ranging from months to more than 20 years. The findings of marked splenomegaly, increasing blasts, dysplasia in other myeloid lineages, and severe visceral disease are poor prognostic factors.^1,7

Although CLL is considered an indolent disease, standard therapeutic approaches have not been curative. The Rai clinical staging system groups patients into five stages: (0) lymphocytosis only; (1) lymphadenopathy; (2) hepatosplenomegaly; (3) anemia; and (4) thrombocytopenia.²² Median survivals were 12+, 8.5, 6, 1.5, and 1.5 years, respectively. Other unfavorable prognostic factors include a rapid lymphocyte doubling time (<12 months) and CD38 expression.^2,10

HCL patients who are untreated have a median survival of approximately 5 years. However, therapy with cladribine or pentostatin has achieved 10-year overall survivals of 80% to 90%.¹⁷

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