Definition

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 (Ph) chromosome, bcr/abl fusion gene, or both. Chronic myelomonocytic leukemia (CMML) has recently been reclassified by the World Health Organization as a myelodysplastic-myeloproliferative disease. It originates from a clonal hematopoietic stem cell disorder in which there are dysplastic features in at least one myeloid lineage, less than 20% blasts in the blood and bone marrow, a persistent monocytosis, and no evidence of Ph chromosome or the bcr/abl fusion gene. Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder characterized by a sustained, mature neutrophilic leukocytosis. There is no monocytosis, eosinophilia, or basophilia and no associated Ph or bcr/abl fusion gene. Chronic eosinophilic leukemia (CEL) is another myeloproliferative disease similar to hypereosinophilic syndrome but that is characterized by a clonal proliferation of eosinophilic precursors with increased blasts. 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.

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Incidence

The incidence of CML is approximately 1 per 100,000 population per year. In 2006, it was estimated that there would be 4,500 new cases, with 600 estimated deaths. 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 because patients were previously 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 older than 60 years. The median age at diagnosis is 65 to 75 years, and there has been a higher incidence in men. CNL is rare, with only 33 case reports being identified that appeared to have met the diagnostic criteria. The mean age at diagnosis is 62.5 years, and there is a 2 : 1 male-to-female ratio. CEL is also rare, but the actual incidence is unknown, because 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 men. 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-to-female ratio. For patients older than 70 years, the incidence is more than 20 per 100,000 population. In 2006, it was estimated that there would be approximately 10,000 new cases of CLL, with approximately 4,700 estimated deaths. 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-to-female ratio.

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Pathophysiology and natural history

In chronic leukemias, there is an accumulation of malignant hematopoietic cells in the bone marrow that ultimately may lead to bone marrow failure states. Cytopenias may result in hemorrhage, infection, and organ compromise (e.g., 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.

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 is often indolent. With progression of the disease, there is an accelerated phase that lasts 6 to 18 months and ultimately blast crisis develops, which appears similar to that of 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, which would be supported by the finding of additional chromosomal abnormalities that can develop during disease acceleration, known as clonal evolution.

CMML is suspected to originate from an abnormal hematopoietic stem cell. This disease arises because of dysregulation of myeloid proliferation, maturation, and cell survival. It may result in dysplastic hematopoiesis and cytopenias as well as organ compromise from leukemic infiltration. Abnormalities in the Ras signaling pathway may also be involved in this process. In addition, a single recurrent somatic activating mutation (JAK2V617F) in the Janus kinase 2 (JAK2) tyrosine kinase has been noted in 8% to 13% of cases.

CNL may arise from a granulocyte-committed progenitor. Cytogenetic and molecular studies have demonstrated the clonal nature of the disease; however, most reports have found that patients have normal cytogenetics. Patients eventually develop either progressive neutrophilia or blastic transformation. Somatic mutation in the JH2 autoinhibitory domain of the JAK2 tyrosine kinase has only infrequently been observed in CNL.

CEL may arise from a multipotent, pluripotent, or eosinophil-committed progenitor cell. 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 (e.g., major basic protein, eosinophil cationic protein). An interstitial deletion resulting in the FIP1L1-PDGFRa fusion protein, with constitutive tyrosine kinase activity, has been identified in hematopoietic cells of these patients.

In CLL, there is an accumulation of neoplastic lymphocytes, without the 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. The neoplastic cells, in turn, have prolonged survival, which 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 autoimmune abnormalities. This, as well as hypogammaglobulinemia and T cell dysfunction, may allow bacterial, fungal, and viral infections to occur. CLL may also transform to large cell lymphoma (Richter's syndrome) or prolymphocytic leukemia.

Although the cause 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. More recent investigation has suggested that the predominant alterations in the neoplastic cell's genome involve transcriptional and post-transcriptional deregulations of a novel class of genes known as micro-RNAs (miRNAs). In particular, for B cell CLL, the miRNA genes miR-15a and miR-16-1, located at 13q14.3, are often deleted, downregulated, or both. These miRNAs allow induction of apoptosis by negatively regulating bcl-2. In addition, normal B cells may be distinguished from B cell CLL by miRNA expression profiles, which have also been associated with other prognostic factors in CLL.

HCL has been postulated to originate from a peripheral B cell, but the stage of its development after leaving the germinal center has not been delineated. The leukemia cells release tumor necrosis factor, which may inhibit hematopoiesis and result in cytopenias. More recently, gene expression profiling has demonstrated a distinct homogeneous pattern that differs from those of other B cell non-Hodgkin's lymphomas. These analyses have suggested that HCL cells may be derived from memory B cells. In comparison with memory cells, HCL cells have demonstrated a notable conservation in proliferation, apoptosis, and DNA metabolism programs while having altered gene expression that might affect cell adhesion and response to chemokines. HCL also expresses CD25 (interleukin-2 [IL-2] receptor), which may contribute to the proliferation of the disease.

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Signs and symptoms

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 (e.g., 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 in 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 (e.g., cognitive dysfunction, peripheral neuropathy), pulmonary (e.g., cough), cutaneous (e.g., angioedema, papules, nodules, urticaria), gastrointestinal, ocular, rheumatologic, and renal involvement may develop.

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Diagnosis

The initial evaluation of chronic leukemias should include an analysis of the bone marrow, peripheral blood, or both, 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 specimen (e.g., endomyocardial biopsy for CEL).

The diagnosis of CML may be established on morphologic review and by demonstrating the presence of the Ph 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 less than 10%, basophilia, eosinophilia, thrombocytosis, and anemia. The bone marrow findings include myeloid hyperplasia with immature forms, less than 10% blasts, and no dysplasia; mild to moderate myelofibrosis may be present. Figure 1 illustrates some morphologic findings in chronic phase CML. Figures 2, 3, and 4 demonstrate the characteristic morphology of CMML, CNL, and CEL.

The National Cancer Institute–sponsored Working Group revised guidelines for CLL diagnosis require an absolute lymphocytosis with more than 5 × 10⁹/L mature-appearing lymphocytes and less than 55% atypical cells or prolymphocytes. The bone marrow should demonstrate more than 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 the following: (1) most lymphocytes expressing B cell markers (CD19, CD20, and CD23) with CD5 but without other pan–T cell markers; (2) monoclonality of B cells with either kappa or lambda light chain restriction; and (3) low-density surface immunoglobulin. Morphologic findings of CLL are shown in Figure 5.

HCL may be diagnosed on finding hairy cells on morphologic review of the peripheral blood (Fig. 6). The cells are medium-sized lymphoid cells with abundant cytoplasm that extends circumferentially as “hairy” projections. The cells are tartrate-resistant and acid phosphatase–positive, and immunophenotyping demonstrates the expression of CD19, CD20, CD22, CD25, CD11c, and CD103.

Summary

• Diagnostic criteria for accelerated and blast phase CML, CMML, CNL, and CEL are shown in Table 1 and Boxes 1, 2, and 3, respectively.
• A diagnosis of CLL requires an absolute lymphocytosis with more than 5 × 10⁹/L mature-appearing lymphocytes (with less than 55% atypical cells or prolymphocytes); the diagnosis may be established by peripheral blood flow cytometric analysis, which identifies characteristic immunophenotypic markers.
• HCL may be diagnosed on finding hairy cells on morphologic review of the peripheral blood that are tartrate-resistant and acid phosphatase–positive and have characteristic immunophenotypic markers by flow cytometric analysis.

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Treatment

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 Ph chromosome or 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 alfa was demonstrated not only to 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 flulike syndrome, anorexia, and depression, have prevented continuation of this agent in some patients. Subsequently, a specific bcr/abl tyrosine kinase inhibitor, imatinib (STI571; Gleevec), was developed. This agent has demonstrated substantial hematologic and major cytogenetic responses in patients with chronic phase CML who were refractory to interferon alfa as well as in patients with accelerated phase CML or blast crisis. A randomized clinical trial of imatinib versus interferon and low-dose cytarabine in patients with newly diagnosed chronic phase CML has revealed imatinib to be vastly superior for achievement of complete hematologic, major cytogenetic, and complete cytogenetic responses, as well as for progression-free survival.

More recently, the novel tyrosine kinase inhibitors dasatinib (BMS-354825; Sprycel) and nilotinib (Tasigna; AMN107), have been shown to induce hematologic and cytogenetic responses in patients with CML or Ph+ ALL who cannot tolerate or are resistant to imatinib. 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 human leukocyte antigen (HLA)–matched donors, and there are significant transplant-related morbidity and mortality risks with this approach. Nonmyeloablative or reduced intensity conditioning, allogeneic, hematopoietic stem cell transplantation has recently been investigated. This has expanded the potential for transplantation to older patients and those not medically suitable for a myeloablative transplant. Autologous hematopoietic stem cell transplantation has been performed for chronic phase CML patients, with substantially fewer transplantation-related mortality risks than with an allogeneic approach. However, most of these patients develop recurrent disease because of the lack of a graft-versus-leukemia effect that may be achieved after allogeneic transplantation. 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. The National Comprehensive Cancer Center (NCCN) clinical practice guidelines for CML can be reviewed at online at www.nccn.org/professionals/physician_gls/PDF/cml.pdf.

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 treatment modalities have consisted of growth factors (e.g., granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, erythropoietin), amifostine, immunosuppressive therapy (e.g., antithymocyte globulin, cyclosporine), hypomethylating agents (e.g., azacytidine, decitabine), low-intensity chemotherapy (e.g., hydroxyurea), high-intensity chemotherapy (e.g., topotecan), and allogeneic hematopoietic stem cell transplantation.

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

Often, patients with CLL require no initial treatment. Therapy is indicated for patients who develop systemic symptoms (e.g., extreme fatigue, fevers, night sweats, weight loss), worsening anemia or thrombocytopenia from progressive bone marrow involvement or an autoimmune cause that is not responsive to corticosteroids; massive or progressive splenomegaly or lymphadenopathy, or a rapid lymphocyte doubling time (less than 6 months). Therapeutic agents have included chlorambucil, with or without corticosteroids, cyclophosphamide-vincristine-prednisone (CVP), and purine analogues (e.g., 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. For select patients, both autologous and allogeneic hematopoietic stem cell transplantation may also be considered, including nonmyeloablative approaches with reduced intensity conditioning regimens. The National Comprehensive Cancer Center (NCCN) clinical practice guidelines for CLL can be reviewed at www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.

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 alfa. Subsequently, pentostatin and cladribine were found to be highly effective, with most patients achieving durable long-term remissions. Therefore, treatment with these agents is often administered earlier, before patients become symptomatic. More recently, rituximab and the anti-CD22 recombinant immunotoxin BL22 have also been found to be effective therapy for relapsed or refractory HCL.

Summary

• Although different treatments exist for CML, most patients are now initially managed with imatinib. Allogeneic hematopoietic stem cell transplantation remains a potentially curative treatment approach for suitable patients who do not respond to imatinib and who have HLA-matched donors.
• CMML, CNL, and CEL may be managed with various cytotoxic therapies. However, allogeneic hematopoietic stem cell transplantation may potentially cure some patients who are appropriate candidates.
• Patients with CLL who require treatment may be managed with chemotherapy (e.g., chlorambucil, fludarabine), monoclonal antibodies (e.g., rituximab, alemtuzumab), clinical trials, or hematopoietic stem cell transplantation.
• HCL may be effectively treated initially with a purine analogue (e.g., cladribine, pentostatin), whereas relapsed and refractory disease may be managed well with rituximab or the anti-CD22 recombinant immunotoxin BL22.

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Outcomes

Patients with chronic phase CML usually have a longer survival than those with a more advanced phase of the disease. However, prognostic systems have been proposed to help predict outcomes more effectively. Initially, before the use of interferon, Sokal and colleagues had found age, spleen size, platelet count, and percentage of myeloblasts to be independent prognostic factors. With the use of a Cox model, patients were then categorized into high-, intermediate-, or low-risk groups, with median survivals of 34, 44, and 57 months, respectively. The Hasford system was developed for patients previously treated with interferon; it was found that the percentage of basophils and eosinophils were other prognostic factors in addition to those from the Sokal scoring system. Respective median survivals for the high-, intermediate-, and low-risk groups were 42, 65, and 98 months, respectively. The Gratwohl risk assessment system was developed for patients before allogeneic stem cell transplantation. Risk factors included stage of the disease, histocompatibility, age, interval from diagnosis to transplant, and donor and recipient gender. Five-year survivals incrementally increased from 18% to 72%, whereas transplantation-related mortality incrementally decreased from 73% to 20% for high-risk to low-risk score patients, respectively. More recently, it has been demonstrated by quantitative real-time polymerase chain reaction assay that those patients on imatinib who achieve a 3-log reduction in bcr-abl transcript levels by 12 months of therapy have a negligible risk of disease progression during the subsequent 12 months.

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. Independent risk factors identified were the percentage of bone marrow blasts, cytogenetic abnormalities, and number of cytopenias. After generating a risk score based on the number of these factors that were present, patients were categorized into 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. CEL may also have a variable survival, ranging from months to longer than 20 years. The findings of marked splenomegaly, increasing blasts, dysplasia in other myeloid lineages, and severe visceral disease are poor prognostic factors.

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. Median survivals were 12+, 8.5, 6, 1.5, and 1.5 years, respectively. Other unfavorable prognostic factors include a rapid lymphocyte doubling time (less than 12 months) and CD38 expression. Genomic aberrations, mutated IgVH genes (and its surrogate marker ZAP-70 expression), as well as serum β₂ microglobulin and thymidine kinase, also provide additional prognostic information.

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

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Suggested Readings

• Biology of chronic lymphocytic leukemia. Rev Clin Exp Hematol. 4: 2000; 5-21.
• National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood. 87: 1996; 4990-4997.
• International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 89: 1997; 2079-2088.
• Mature B-cell neoplasms. Jaffe ES, Harris NL , Stein H , Vardiman JW. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissues. 2001; ;Lyon, France. 127-130.
• JAK2 mutation 1849G > T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome–negative CML, and megakaryocytic leukemia. Blood. 106: 2005; 3370-3373.
• Cancer statistics, 2006. CA Cancer J Clin. 56: 2006; 106-130.
• Chronic eosinophilic leukemia and hypereosinophilic syndromes. Proposal for classification, literature review, and report of a case with a unique chromosomal abnormality. Cancer Genet Cytogenet. 107: 1998; 111-117.
• Chronic neutrophilic leukaemia: A distinct clinical entity?. Br J Haematol. 116: 2002; 10-18.
• Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 63: 1984; 789-799.
• Chronic myelomonocytic leukemia. Jaffe ES, Harris NL , Stein H , Vardiman JW. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissues. 2001; ;Lyon, France. 17-31.