Published: September 2014
The chronic leukemias are a group of malignancies involving the hematopoietic system. Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm that arises from a clonal process involving an early progenitor hematopoietic stem cell. It also is associated with the BCR-ABL1 fusion gene localized to the Philadelphia (Ph) chromosome. Chronic myelomonocytic leukemia (CMML) has been reclassified by the World Health Organization (WHO) as a myelodysplastic/myeloproliferative neoplasm. It originates from a clonal hematopoietic malignancy 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, no rearrangement of PDGFRA or PDGFRB, and no evidence of Ph chromosome or the BCR-ABL1 fusion gene. Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder characterized by a sustained, mature neutrophilic leukocytosis. There is no associated Ph chromosome or BCR-ABL1 fusion gene. Chronic eosinophilic leukemia (CEL) is another myeloproliferative neoplasm that is characterized by a clonal proliferation of eosinophilic precursors with increased blasts. Chronic lymphocytic leukemia (CLL) is a neoplasm comprised of small, round to slightly irregular B lymphocytes. Hairy cell leukemia (HCL) is a malignancy of small mature B lymphoid cells that display surface cytoplasmic “hairy” projections.
The age-adjusted incidence rate of CML is approximately 1.6 per 100,000 population per year. Most CML cases are identified after age 45, and there is a higher incidence in men. In the United States, approximately 1,100 new cases of CMML are diagnosed each year with a higher incidence in men and greater than 90% of patients are older than 60 years of age. CNL is rare, with only about 150 cases reported in the literature. The mean age at diagnosis is 62.5 years, and the incidence is comparable between males and females. CEL, not otherwise specified (NOS), is also rare, but the actual incidence is unknown, because patients with the disease have often been categorized with those having idiopathic hypereosinophilic syndrome. The incidence is highest in the 4th 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 higher incidence in men. In 2012, it is estimated that there will be 16,060 new cases of CLL, with 4,580 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 50 years, and there is a 5:1 male-to-female ratio.
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-ABL1 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 prior to the availability of tyrosine kinase inhibitor (TKI) therapy lasted 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. Other somatic mutations that have been identified have included those involving CBL, RUNX1, TET2, ASXL1, IDH and DNMT3A.
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 (NOS) 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). Some patients have been found to have an associated FIP1L1-PDGFRA fusion gene.
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 increase patient's risk for bacterial, fungal, and viral infections. 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. Approximately 40% to 50% of CLL have unmutated immunoglobulin heavy chain variable region genes (IGVH). 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. 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 receptor), which may contribute to the proliferation of the disease.
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.
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). Boxes 1 - 4 shows the World Health Organization diagnostic criteria for four different types of chronic leukemia.
|Box 1: WHO Diagnostic Criteria for Accelerated and Blast Phase Chronic Myelogenous Leukemias|
|Persistent or increasing WBC (>10 x 109/L and/or persistent or increasing splenomegaly unresponsive to therapy|
|Persistent thrombocytosis (>1,000 x 109/L uncontrolled by therapy|
|Persistent thrombocytopenia (<100 x 109/L) unrelated to treatment|
|Clonal cytogenetic evolution occurring after the initial diagnostic karyotype|
|≥20% peripheral blood blasophils|
|10%-19% myeloblasts in the peripheral blood or bone marrow|
|Blasts comprising ≥20% of the peripheral blood WBCs or of the nucleated cells of the bone marrow|
|Extramedullary blast proliferation|
* Requires one or more of the criteria listed. WBCs, white blood cells. Reproduced, with the permission of the publisher, from Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: World Health Organization; 2008:33-34.
|Box 2: WHO Diagnostic Criteria for Chronic Myelomonocytic Leukemia|
|Persistent monocytosis (>1 x 10 9/L in the peripheral blood|
|No Philadelphia chromosome or BCR-ABL1 fusion gene|
|No rearrangement of PDGFRA or PDGFRB (should be excluded in cases with eosinophilia)|
|<20% blasts and promonocytes in the peripheral blood and bone marrow|
Dysplasia in one or more myeloid lineages. If myelodysplasia is absent or minimal, the diagnosis of chronic myelomonocytic leukemia may still be made if the other requirements are met, and:
Reproduced, with the permission of the publisher, from Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: World Health Organization; 2008:76.
|Box 3: WHO Diagnostic Criteria for Chronic Neutrophilic Leukemia|
Peripheral blood leukocytosis ≥25 x 109/L
Hypercellular bone marrow
No identifiable cause for physiologic neutrophilia or, if present, demonstration of clonality or myeloid cells by cytogenetic or molecular studies
|No Philadelphia chromosome or BCR/ABL1 fusion gene.|
|No rearrangement of PDGFRA, PDGFRB or FGFR1|
|No evidence of polycythemia vera, primary myelofibrosis or essential thrombocythemia|
No evidence of a myelodysplastic syndrome or a myelodysplastic/myeloproliferative neoplasm
Reproduced, with the permission of the publisher, from Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: World Health Organization; 2008:39.
|Box 4: WHO Diagnostic Criteria for Chronic Eosinophilic Leukemia|
|There is eosinophilia eosinophil count (≥1.5 x 109/L|
There is no Philadelphia chromosome or BCR-ABL1 fusion gene or other myeloproliferative neoplasms (polycythemia vera, essential thromboycythemia, primary myelofibrosis) or MDS/myeloproliferative neoplasm (chronic myelomonocytic leukemia or a chronic myelogenous leukemia)
|There is no t(5;12)(q31-35; p13) or other rearrangement PDGFRB|
There is no FIP1L1-PDGFRA fusion gene or other rearrangement of PDGFRA
|There is no rearrangement PGFR1|
|The blast cell count in the peripheral blood and bone marrow is <20% and there is no inv(16)(p13q22) or t (16;16)(p13;q22) or other feature diagnostic of AML|
|There is a clonal cytogenetic or molecular genetic abnormality, or blast cells are more than 2% in the peripheral blood or more than 5% on the bone marrow.|
|(If the patient has eosinophilia, but these criteria are not met, the diagnosis may be reactive eosinophilia, ideopathic hypereosinophilia or idiopathic syndrome)|
Reproduced, with the permission of the publisher, from Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: World Health Organization; 2008:52.
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-ABL1 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 that is usually less than 2%, 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 through 4 demonstrate the characteristic morphology of CMML, CNL, and CEL.
The International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines require an absolute lymphocytosis with more than 5 × 109/L mature-appearing lymphocytes with clonality confirmed by flow cytometry 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 most lymphocytes expressing B cell markers (CD19, CD20, and CD23) with CD5 but without other pan-T cell markers; monoclonality of B cells with either kappa or lambda light chain restriction; and 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 (Figure 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 Annexin A1, 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 Ph chromosome or BCR-ABL1 fusion gene. Hydroxyurea had 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 flu-like syndrome, anorexia, and depression, had prevented continuation of this agent in some patients. Subsequently, a specific BCR-ABL1 TKI, 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 revealed imatinib to be vastly superior for achievement of complete hematologic, major cytogenetic, and complete cytogenetic responses, as well as for progression-free survival. Subsequent follow-up analyses later reported improved overall survival for patients treated with imatinib. In addition, imatinib dose escalation has also been reported to be beneficial for chronic phase CML patients with suboptimal cytogenetic response or resistance to standard dose imatinib therapy.
More recently, the novel TKIs 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. Subsequently, dasatinib and nilotinib were both found to result in more rapid responses then imatinib with significantly higher rates of complete cytogenetic and major molecular responses in newly-diagnosed chronic phase CML patients. These agents have thus become front-line therapy for newly-diagnosed chronic phase CML. They also are used to treat accelerated and blast phase disease, albeit with lower responses than that achieved for chronic phase CML. Allogeneic hematopoietic progenitor cell (HPC) transplantation is a standard therapy for CML, with curative potential. However, this therapy is limited to patients without prohibitive medical comorbidities and who have a suitable HPC donor. There are significant transplant-related morbidity and mortality risks with this approach. Reduced intensity conditioning allogeneic HPC transplantation has been investigated. This has expanded the potential for transplantation to older patients and those not medically suitable for a myeloablative transplant approach. Patients with a leukemia relapse after HPC transplantation may achieve durable remissions with donor leukocyte infusions. The National Comprehensive Cancer Center (NCCN) clinical practice guidelines for CML can be reviewed at online at www.nccn.org/professionals/physician_gls/f_guidelines.asp#site.
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 HPC transplantation.
Therapy for CNL and CEL (NOS) has included agents such as hydroxyurea, busulfan, 6-thioguanine, prednisone and interferon-α. These agents have been able to control the disease burden and reduce splenomegaly, but they have not been curative. Although imatinib has been effective for patients with myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA and PDGFRB there is extremely limited experience with this agent in patients with CEL (NOS) from which it cannot be recommended. More recently, anti-IL-5 antibody therapy has become available for CEL, NOS. Allogeneic HPC transplantation may potentially cure some CNL and CEL (NOS) 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 (<6 months). Therapeutic agents have included chlorambucil, with or without corticosteroids, cyclophosphamide-vincristine-prednisone, 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 single-agent activity in CLL but subsequently have been administered in combination with other agents (e.g., fludarabine, cyclophosphamide and rituximab). For select patients, allogeneic HPC transplantation may also be considered, commonly with a reduced-intensity conditioning approach.
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. Subsequently, rituximab and the anti-CD22 recombinant immunotoxin BL22 had also been found to be effective therapy for relapsed or refractory HCL.
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 and TKIs, 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 undergoing allogeneic HPC 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. Subsequently, in the era of TKI therapy it had been demonstrated by quantitative real-time polymerase chain reaction assay that patients receiving imatinib who achieved a 3-log reduction in bcr-abl transcript levels by 12 months of therapy had a negligible risk of disease progression during the subsequent 12 months.
For CMML, median survivals have often ranged from 20 to 40 months. An M.D. Anderson prognostic score for CMML had been developed that identified the following factors to be independently associated with inferior survival: hemoglobin <12 g/dL, absolute lymphocyte count >2.5 × 109/L, circulating immature myeloid cells and ≥10% blasts in the bone marrow. Patients could be categorized into low, intermediate grade 1, intermediate grade 2 and high risk groups with median overall survivals of 24, 15, 8 and 5 months, 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 for many patients, standard therapeutic approaches have not been curative. The Rai clinical staging system categorizes 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 (<12 months) and CD38 expression. Genomic aberrations (e.g. 17p deletion associated with a poor prognosis), unmutated IGVH genes (unfavorable risk), as well as serum B2 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%. HCL with an unmutated IGVH gene status or mutation/deletion of TP53 have been associated with response failure to cladribine and rapid disease progression after such therapy.