In 1845, Edinburgh pathologist John Hughes Bennett reported a “Case of Hypertrophy of the Spleen and Liver in which Death Took Place from Suppuration of the Blood” in the Edinburgh Medical Journal. Only a few weeks later, Rudolf Virchow in Berlin published a very similar case. Although one cannot know for sure, these two patients probably represent the first descriptions of the disease that later became known as chronic myeloid leukemia (CML). While Bennet thought that the patient had an infection, Virchow suspected a neoplastic disorder that he soon called white blood disease or leukemia. A dispute about the priority of the discovery arose, but was eventually settled cordially, when Virchow acknowledged Bennet’s priority and even wrote a letter to support his promotion. In 1872, Ernst Neumann observed that leukemia cells originated in the bone marrow. The next decades saw the differentiation into myeloid versus lymphoid and acute versus chronic leukemias.
A real quantum leap, however, was the discovery by Philadelphia cytogeneticists Peter Nowel and David Hungerford of an abnormally small G-group chromosome that we now call the Philadelphia chromosome (Ph). This was a seminal step, as it unequivocally proved that cancer was a problem of DNA. Thirteen years later Janet Rowley recognized that Ph was the product of a reciprocal translocation between chromosomes 9 and 22. In the 1980s, the translocation partners were identified as BCR and ABL, followed by the discovery that unregulated tyrosine kinase activity is critical to BCR-ABL’s ability to transform cells. A faithful murine disease model was established in 1990.
Therapy developed slowly. In 1865, Heinrich Lissauer described the use of arsenic in two patients with leukemia, nothing too novel in view of the fact that the use of arsenic for cancer therapy had been described in the Indian Ramayana more than 2000 years earlier. In the 1920s, splenic irradiation was introduced for symptomatic relief. Effective control of blood counts became feasible with busulfan (1959), followed 10 years later when the better-tolerated hydroxyurea became available, probably the first intervention with a (modest) prolongation of survival. A breakthrough was achieved in the mid-1970s when the Seattle group reported the disappearance of the Ph chromosome in CML patients who underwent allotransplant, the first cures of CML. Soon later, interferon-α was found to induce durable complete cytogenetic responses and long-term survival, although in only a small fraction of patients. In 1992, Alexander Levitzki proposed the use of ABL inhibitors to treat leukemias driven by ABL oncogenes. At about the same time, scientists at Ciba-Geigy had synthesized a potent inhibitor of ABL that was termed GCP57148B and is now known as imatinib. Clinical trials initiated by Brian Druker, much against the skepticism of the manufacturer, rapidly established the compound’s activity in patients with CML and revolutionized CML therapy.
In 2008, the majority of patients diagnosed with chronic phase CML can expect to have durable responses with good quality of life. For that 20% to 30% who fail imatinib, second-line inhibitors are an effective salvage strategy. However, once the disease has progressed beyond the chronic phase, allotransplant is still the recommended treatment for all eligible patients. Unfortunately, evidence is accumulating that residual leukemia may persist even in the best responders and that therapies directed at the BCR-ABL tyrosine kinase are not curative since they fail to eradicate the CML stem cells. Thus, the CML saga continues, and much work remains to be done.
See the related ASH 50th Anniversary Review articles under the ACUTE AND CHRONIC LEUKEMIAS section of the publication ASH 50th Anniversary Reviews: A Salute to the American Society of Hematology.