Chronic Myeloid Leukemia

Chronic Myeloid Leukemia

Michael W.N. Deininger


Chronic myeloid leukemia (CML), although a rare disease, has disproportionately influenced hematology/oncology and modern medicine. Reports of what was probably CML date back to the middle of the 19th century. In 1845, John Hughes Bennett, an Edinburgh pathologist, described a “Case of Hypertrophy of the Spleen and Liver in which Death Took Place from Suppuration of the Blood.”1 It was only a few weeks later when Rudolf Virchow of Berlin reported on a very similar case in an article titled, “Weisses Blut” (white blood).2 It is likely that both patients involved indeed suffered from CML and presented with its most typical clinical features: leukocytosis and splenomegaly. Whereas Bennett believed that the new disease represented an infection, Virchow recognized the neoplastic nature of the process and coined the term “leukemia,” from the Greek words “λευκον αιµα,” which mean “white blood.” The ensuing academic dispute was eventually settled cordially: Virchow acknowledged Bennett’s priority of discovery and Bennett that leukemia is a neoplastic rather than infectious process. Ironically, both were actually preceded by Alfred Donné of Paris, Bennett’s previous mentor, whose description of leukemia in his 1844Cours de Microscopie had lacked sufficient detail and visibility to attract attention.3 The next leap forward came in 1872, when Ernst Neumann established the bone marrow as the origin of leukemia and of blood cells in general.4 The following 100 years saw progress in understanding leukemia, with perhaps the most notable advance being the recognition of myeloid versus lymphoid disease. In 1951, William Dameshek posited that CML belongs to a larger group of related disorders characterized by increased numbers of differentiated blood cells as the result of enhanced proliferation of the bone marrow, which he accordingly named myeloproliferative disorders.5

A fundamental experimental breakthrough by Philadelphia cytogeneticists Peter Nowell and David Hungerford followed in 1960. They observed an abnormally small G-group chromosome in metaphase spreads from several patients with CML.6 This first consistent karyotypic abnormality associated with cancer settled the debate as to whether DNA or proteins transmitted the neoplastic phenotype to the next generation of cells. The discovery team anticipated that this minute chromosome in CML might represent the first in a long list of cancer chromosomes, and thus referred to it as the Ph1 chromosome (now more commonly known as Ph). The presence of Ph in all CML cells was indicative of their clonal origin from a single parental cell. Formal proof for this notion was lacking until Fred Fialkow demonstrated X-chromosome inactivation in CML neutrophils by uniform glucose-6-phosphate dehydrogenase (G6PD) isoenzyme expression.7

In 1973, Janet Rowley recognized that Ph was not just a shortened chromosome 22, but was in fact the product of a reciprocal translocation between chromosomes 9 and 22.8 Over the following 25 years, the molecular anatomy and consequences of t(9;22) were revealed with increasing resolution. Work from several laboratories identified the genes juxtaposed by t(9;22) to form a fusion gene on Ph.9,10 The chromosome 9 partner was found to be ABL1 (formerly ABL), the human homolog of v-abl oncogene of the Abelson murine leukemia virus (A-MuLV).11 On the derivative chromosome 22, ABL1 sequences consistently translocated to the same genetic region, which became known as the “breakpoint cluster region” (BCR), a name that was subsequently used to describe the new gene fused upstream of ABL1. The next critical set of discoveries was that BCR-ABL1, similar to murine v-Abl, is a constitutively active tyrosine kinase and that kinase activity is required for cellular transformation.12 Lastly, retroviral expression of BCR-ABL1 in murine bone marrow cells was found to induce a CML-like disease in mice, another milestone in the history of cancer research.13

Therapy developed slowly. Arsenicals, in use for cancer treatment since ancient times, were the only CML therapy available in the 19th century, usually in the form of Fowler’s solution, which contained potassium arsenite. The German physician Heinrich Lissauer is credited with the first publication on the remarkable efficacy of Fowler’s solution in a patient with leukemia.14 In an 1882 Lancet paper, Conan Doyle, the author of the Sherlock Holmes detective stories, published on a patient with the clinical presentation of CML who achieved a partial response to arsenic.15 In the 1920s, splenic irradiation was used for symptomatic relief and remained the mainstay of therapy for the first half of the 20th century. In 1959, busulfan was introduced as the first drug that reliably controlled white blood cell counts in CML and, 10 years later, hydroxyurea premiered as the first intervention that significantly prolonged survival.16,17 Despite these advances, a cure remained elusive until the late 1970s, when the disappearance of the Ph+ clone in CML patients treated with allogeneic stem cell transplantation was reported.18 In the early 1980s, interferon-α (IFN) became the standard drug therapy. This agent induced complete cytogenetic responses (CCyRs) and long-term survival in 10% to 20% of patients.19

In 1992, Alexander Levitzki proposed inhibiting ABL1 with small molecules called tyrphostins as a potentially useful approach to treat leukemias driven by ABL1 oncogenes.20 At about the same time, Alois Matter, Jürg Zimmermann, and Nick Lydon at Ciba-Geigy had synthesized a compound called GCP57148B,21 now known as imatinib, that inhibited ABL1 and a restricted set of other tyrosine kinases at submicromolar concentrations. Clinical trials led by Brian Druker from Oregon Health & Science University, very much in the face of skepticism by the manufacturer, rapidly established imatinib’s unprecedented activity in patients with CML and revolutionized CML therapy.22,23,24 Dasatinib and nilotinib, tyrosine kinase inhibitors (TKIs) with increased activity against BCR-ABL1, were initially developed to overcome imatinib resistance, but have since gained approval for frontline therapy.25,26 However, once CML has progressed beyond the chronic phase, allogeneic stem cell transplant is still the recommendation for all eligible patients. There is compelling evidence that CML stem cells are not dependent on BCR-ABL1 kinase activity, implying that treatment must continue indefinitely in order to prevent recurrence of active leukemia. Current research efforts focus on improving the poor prognosis of advanced CML, controlling TKI resistance, and developing strategies to eradicate CML stem cells.



With an annual incidence of 1.3 to 1.6/105 population, CML accounts for 15% to 20% of cases of leukemia in adults. Males are more commonly affected, but there is no geographic, ethnic, or familial predisposition. The only well-established risk factor is exposure to ionizing radiation, evident by the increased CML incidence in survivors of the atomic bomb explosions in Japan; patients who were treated with radiotherapy or exposed to thorotrast, an α-emitting contrast medium used in the 1930s,145, 146 and 147 have an increased CML risk as well. From 2004 to 2009, the median age at diagnosis in the United States was 64 years.148 The prevalence of CML is increasing due to reduced mortality.149 For the United States, estimates
are 70,000 in 2010, 144,000 in 2030, and 181,000 in 2050, when prevalence will approach a plateau.150

Clinical Presentation

Disease Phases

CML evolves in stages termed chronic phase (CML-CP), accelerated phase (CML-AP), and blastic phase (CML-BP). In the Western world, most patients present in CML-CP, whereas more advanced disease at diagnosis is common in developing countries. CML-CP is characterized by left-shifted granulocytosis with maintained terminal differentiation, frequently accompanied by basophilia and sometimes eosinophilia. Thrombocytosis and mild anemia are also common. Dysplasia is not a feature of CML and raises the question of alternative diagnoses, such as atypical CML.152 Bone marrow aspirate and histology are hypercellular for age, but demonstrate complete cellular maturation (Fig. 81.4A). A fairly typical finding is micromegakaryocytes, which are small monolobated megakaryocytes. Mild reticulin fibrosis may be present, but severe reticulin fibrosis is uncommon and may be associated with poorer outcomes.153 Without effective therapy, CML-CP inexorably progresses to CML-BP, which can exhibit a pre-B-lymphoid (25%), myeloid (70%), or indeterminate (5%) phenotype (Fig. 81.4B).154 CML-BP can develop rapidly or over a period of time through the intermediary stage of CML-AP. A variety of clinical and laboratory features has been used to define CML-AP, making comparison of results between different studies difficult. Today, the criteria used in the clinical trials leading to approval of imatinib are widely accepted (Table 81.1).155 The exception is clonal cytogenetic evolution, i.e., the presence of additional cytogenetic abnormalities in the Ph+ cell clone (CCA/Ph+). Although there is agreement that CCA/Ph+ on treatment is diagnostic of CML-AP and therapy failure,156 this is not universally accepted for newly diagnosed patients. Recent studies showed that these patients have inferior outcomes even in the absence of any other features of CML-AP, raising the question of whether the criteria should be changed.157 A blast count of ≥30% in the blood or bone marrow or extramedullary blastic leukemic infiltrates (chloroma) in tissues other than liver or spleen define CML-BP. Gene expression profiling has revealed that CML-AP and CML-BP are closely related to each other, suggesting that CML is a two-phase rather than a threephase disease.158 In the future, molecular markers and response to treatment may replace conventional diagnostic criteria used to define the phases of CML.159

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Oct 21, 2016 | Posted by in HEMATOLOGY | Comments Off on Chronic Myeloid Leukemia

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