CML – a short history of treatment since the mid-20th century

The treatment of CML over the last 50 years can be divided into three distinct eras, first cytotoxic drugs, then the choice of allogeneic stem cell transplantation or interferon-alfa (IFN) and most recently the era of tyrosine kinase inhibitors (TKI).

Even purely palliative radiotherapy was rather haphazard and only temporarily effective before the 1950s. In 1953 David Galton, a young clinical investigator working at the Royal Marsden Hospital in London, was given a new alkylating agent recently synthesized by Alexander Haddow, a very talented chemist, who suggested that he test it in variety of malignant conditions. Galton quickly discovered that the drug, then called myleran and subsequently busulfan, was highly effective in reversing the splenomegaly and controlling the leukocyte counts in patients with newly diagnosed CML. In 1968 he published a paper reporting that busulfan-treated patients lived longer than those who received radiotherapy and thereafter busulfan became the standard treatment for CML in the UK. Hydroxyurea gained popularity in the United States. Both drugs were convenient to administer, lacked short-term toxicity, although busulfan regularly rendered women infertile and men azoospermic. In those days the median survival from diagnosis was about 5 years. Galton suspected that though busulphan was a valuable drug in the short term, it might actually be mitogenic and thus hasten the advent of blastic transformation, and this may well have been the case.

Two new approaches were introduced in the early 1980s. Investigators in Seattle had shown that CML patients transplanted with marrow cells collected from their identical twins could expect a number of years without evidence of leukemia detectable in their body. This led investigators on both sides of the Atlantic to explore the possibility that transplants performed with ’stem’ cells from a patient’s HLA-identical sibling might offer benefit for a CML patient who lacked an identical twin. This proved to be the case, though the morbidity and indeed mortality associated with allogeneic stem cell transplants remained a major problem. About this time Moshe Talpaz in Houston pioneered the use of IFN to treat CML. Some of the patients who received this treatment achieved Philadelphia chromosome negativity and a small number of patients who achieved this status did not relapse when the IFN was discontinued. Interferon was associated with modest prolongation of life when compared with the use of hydroxyurea but still in the 1980s treatment for CML patients remained very imperfect.

In the 1990s Brian Druker in conjunction with scientists at Ciba Geigy in Basel started working on the notion that a small molecule that blocked the enzymatic action of the BCR-ABL protein might be clinical value. The culmination of their research was the development of a phenylaminopyrimidine molecule, then called CGP-57148B and now imatinib, that seemed to have selective action against CML cells in the laboratory. It was first used in the clinic in 1998 to treat patients with interferon-resistant CML in chronic phase. Soon thereafter it was used to treat previously untreated CML patient. By 2011 it is clear that 50-60% of patients treated with imatinib for five or more years can expect to have durable complete cytogenetic responses and to remain alive and well for at least 10 years - with the prospect of many more years or even decades without medical problems.

The clinical picture has been further improved by the introduction of more powerful agents that act in a manner similar to imatinib, namely dasatinib, nilotinib and bosutinib, though the last drug is not yet approved for use outside the context of a clinical study.

Viewed over a period of 50 years, the treatment of CML must be regarded as a remarkable success. Many but not all patients diagnosed in chronic phase can today look forward to a normal expectation of life comparable to that of a person without CML.

Perhaps of even greater importance has been the remarkable demonstration that understanding the molecular basis of malignancy can lead to logical or ‘rational’ development of very specific small inhibitory molecules that can lead to control or even in some cases cure various malignant diseases. This seminal observation has led to the revision of research strategies in leukemia and cancer and has unquestionably brought somewhat nearer the day when all malignant diseases can be treated and eradicated with comparative ease.

Profossor John Goldman

Imperial College London