The most obvious characteristic of CML is the proliferation of white blood cells (WBC) in the blood stream, so doctors throughout history have focused their attention on reducing those high WBC numbers. This key idea has undergone an evolution over the years, and a revolution over the past decade.
In the 19th century, a popular remedy for CML was Dr. Fowler’s Solution, developed by Dr. Thomas Fowler (also the inventor of a calculator made out of wood). The Solution was a radical one – to poison WBCs with arsenic (Cutler and colleagues. Am J Med Sci 1978;75:74). This approach would remain a mainstay of therapy up until World War II. The other key therapy was radiation therapy following the discovery of X-rays in 1895, and the realization of how toxic this radiation was to dividing cells (Forkner and colleagues. JAMA 1931;97:3; Stephens & Lawrence. Ann Intern Med 1936;9:1488).
The next technology used in CML was borrowed from wartime. Mustard gas had been used to devastating effect in World War I and it was later found that this lethal gas suppressed the ability of bone marrow to produce blood cells. So various mustard gas derivatives were tried in CML. These chemicals were later found to be alkylating agents, which means they cause DNA damage to dividing cells. In the 1950s, one of these alkylating agents – busulfan – became the standard of treatment for CML (Haddow & Timmis. Lancet 1953;264:207-208). This drug is still used in some centres to reduce the number of WBCs when a person is first diagnosed.
Two other drugs developed during this period are also in use today. The first is hydroxyurea, an antimetabolite that was first tested a half-century ago (Thurman and colleagues. Cancer Chemother Rep 1963;29:103-107). A decade later, another anti-metabolite, cytarabine (Ara-C, Cytosar), was shown to inhibit rapidly dividing cells (Baccarani and colleagues. Scan J Haematol 1976;16:335-352).
Ara-C was originally developed to treat viral infections. It was used as an anticancer drug in part because of the long-suspected connection between viruses and cancers. This idea hasn’t really panned out for the most part; an important exception is human papillomavirus, which causes cervical cancer. But in the 1980s, there was a great deal of effort in developing treatments that targeted viruses that were believed to be involved in various diseases.
To achieve this “biological warfare” approach, recombinant DNA technology was needed. This technology splices a gene (such as one involved in interferon production) into a rapidly dividing cell (such as a bacterium), thereby turning the cell into a mini manufacturing plant. As this technology became more widely available in the 1980s, it was soon possible to synthesize interferons, which are the body’s own anti-viral substances. One of the first interferon studies showed that this biological agent was quite effective in CML (Talpaz and colleagues. Blood 1983;62:689-692). Subsequent studies confirmed this finding, and interferon-alfa became the cornerstone of CML treatment for the next two decades.
Evolution to Revolution
While most CML treatments addressed the effects of CML (i.e. WBC numbers), interferon-alfa provided a bridge to the future because it actually treated the underlying cause of disease. Early studies showed that it suppressed cells with the Philadelphia chromosome, which is the genetic defect found in most people with CML (Talpaz and colleagues. Br J Haematol 1985;60:619-624).
The discovery of the Philadelphia chromosome in 1960, and its specific characterization a decade later, provided researchers with a target for treatment (Nowell & Hungerford. J Natl Cancer Inst 1960;25:85-109; Rowley JD. N Engl J Med 1973;289:220-221). But it would take many years before anyone could find a way to hit the target more effectively.
In the 1980s, one researcher investigating interferons turned his attention to proteins that signalled to cells to start proliferating (Lydon and colleagues. Oncogene Res 1990;5:161-173). One such signalling molecule was tyrosine kinase. After sorting through thousands of chemicals, one called CGP57148B was found to inhibit the signalling defect that causes uncontrolled WBC proliferation in CML. This substance, later renamed Signal Transduction Inhibitor (STI571), would become Gleevec (imatinib), the first TKI (tyrosine kinase inhibitor).
The initial large-scale trial of Gleevec showed that it was superior to the standard treatment of interferon-alfa/cytarabine (O’Brien and colleagues. N Engl J Med 2003;348:994-1004). This landmark study also proved an important principle: that therapies could selectively target the underlying defect in CML. More importantly, it showed that this approach was the most effective way of controlling CML. This key principle and this approach are now the cornerstones of CML therapy. And the revolution in CML treatment that began with imatinib continues today with the next-generation siblings of the original “ib” drug: the TKIs Sprycel (dasatinib), Tasigna (nilotinib), Bosulif (bosutinib) and Iclusig (ponatinib).