Editorial
Targeting the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia
N Engl J Med 2001; 344:1084-1086April 5, 2001DOI: 10.1056/NEJM200104053441409
- Article
Chronic myeloid leukemia (CML) is one of the most remarkable cancers.1,2 It was probably the first type of leukemia to be recognized, in the 1840s, as a distinct entity. A landmark was the discovery of the Philadelphia (Ph) chromosome in 1960.3 This led to the identification in CML cells of the BCR-ABL fusion gene and its corresponding protein, which is now firmly established as the unique cause of the initial, or “chronic,” phase of CML. ABL and BCR, which are located on chromosomes 9 and 22, respectively, are normal genes whose function is still unknown. The ABL gene encodes a tyrosine kinase whose activity is tightly regulated. Both genes are truncated in the formation of the t(9;22) reciprocal translocation that characterizes CML cells, and two fusion genes are generated: BCR-ABL on the derivative 22q– chromosome (the Ph chromosome) and ABL-BCR on chromosome 9q+. The BCR-ABL gene encodes a 210-kd protein with deregulated tyrosine kinase activity. The presence of this protein in the leukemia cells of almost every patient with CML is strong evidence of its pathogenetic role. This notion is further strengthened by the report that insertion of the BCR-ABL gene into murine stem cells induces a leukemia-like disease in mice.4 The two reports by Druker and colleagues in this issue of the Journal, 5,6 which document the clinical efficacy of the BCR-ABL tyrosine kinase inhibitor STI571 in CML, must be accepted as final proof that the BCR-ABL oncoprotein is the unique cause of chronic-phase CML.
Although this much is clear, numerous questions remain. The only factor known to predispose people to CML is ionizing radiation. For most patients, no predisposing factors are identified, and the cause of the chromosomal translocation is obscure. Similarly, we understand little of the mechanisms of the inevitable progression from the chronic phase to the ultimately fatal acute phase or blast crisis. The clinical heterogeneity of the disease also remains unexplained. With standard therapy, the median survival is about 6 years, but some patients die within a year of diagnosis and others survive for 20 or more years. In some patients, the disease starts with an aggressive chronic phase, whereas in others it is indolent. Wherein lies the difference? Not, apparently, in the BCR-ABL oncoprotein, which seems remarkably consistent from patient to patient. Also, does the BCR-ABL tyrosine kinase actually cause CML? Logically, it must activate one or more signal-transduction pathways that lead to the malignant phenotype, but no pathway has been definitely incriminated.7
The treatment of CML evolved slowly at first, but the pace has quickened in the past 20 years. Busulfan yielded to hydroxyurea and hydroxyurea to interferon alfa. Until very recently, all agreed that the best medical treatment for patients with newly diagnosed CML was interferon alfa, either alone or in conjunction with cytarabine. The relatively few young patients who have HLA-matched donors can be offered allogeneic stem-cell transplantation, which is associat-ed with appreciable procedure-related morbidity and mortality but remains the only approach that can unequivocally eradicate the leukemia. Much, however, has now changed with the advent of STI571.
In the early 1990s, knowing that the constitutively activated kinase had a major role in CML, Druker approached scientists at what was then Ciba–Geigy with a proposal to find a small molecule that would inhibit the BCR-ABL tyrosine kinase activity. This collaboration yielded a phenylaminopyrimidine molecule, then called CGP 57148B, which occupies the kinase pocket of the BCR-ABL protein and blocks access to ATP, thereby preventing phosphorylation of any substrate8 (Figure 1Figure 1
Likely Mode of Action of STI571.). Preclinical studies showed that the molecule was highly effective in blocking the tyrosine kinase activity of ABL; the stem-cell factor receptor, c-kit; and the platelet-derived growth factor receptor (PDGFR) but had little effect on other tyrosine kinases. CGP 57148B inhibited proliferation of CML cell lines and clonogenic cells from patients with CML but did not affect equivalent control cells.9 Beginning in 1998, these encouraging results led to clinical studies, from which arose the trials by Druker et al., involving 83 patients with CML in the chronic phase5 and 58 patients with CML in blast crisis or Ph-chromosome–positive acute lymphoblastic leukemia (ALL).6 The reports of these trials document the impressive capacity of the compound, now renamed STI571 (for signal-transduction inhibitor), to reverse very rapidly the clinical and hematologic abnormalities of CML in the chronic phase and, in many cases, to reduce to zero or to low levels the proportion of Ph-chromosome–positive cells in the bone marrow. The toxicity profile seems very mild for a drug with this degree of potency.
STI571 has considerable advantages over interferon alfa. It can be given by mouth, whereas interferon alfa must be injected; hematologic responses are more rapid and probably more frequent; the rate of cytogenetic response is clearly higher than with interferon alfa; and it has fewer adverse effects. However, follow-up of patients given the drug is still very short, and there is no direct evidence that STI571 prolongs life. Important clinical problems could still emerge. These points provide the rationale for the ongoing prospective comparison of STI571 with the combination of interferon alfa plus cytarabine. As the story unfolds, STI571 may well become the single best agent for treating CML. It is expected to be licensed for use in the United States this fall and in other countries soon thereafter.
The mechanism by which chronic-phase CML cells become resistant to conventional cytotoxic drugs, such as hydroxyurea, is unknown. Disease progression probably involves the occurrence of additional molecular changes in the Ph-chromosome–positive clone that block cellular maturation. If this model is valid, it is surprising that STI571 has efficacy in the blast crisis of CML.6 There are two possible explanations: either the BCR-ABL tyrosine kinase is necessary for blastic transformation, or other signal transduction pathways that are activated during blastic transformation can also be inhibited by STI571. The former possibility is supported by the observation that, at least in the laboratory, cell lines resistant to STI571 overexpress BCR-ABL and may show amplification of the fusion gene.10-12
If STI571 inhibits the BCR-ABL kinase so effectively, what is the result of its inhibition of the ABL kinase in normal cells? So far, the effect appears to be minimal. Presumably, the ABL protein, like the product of many other so-called housekeeping genes, is not essential in normal signaling pathways. Does it matter whether STI571 inhibits normal c-kit or PDGFR? Apparently not. We now know that some gastrointestinal stromal tumors have an oncogenic mutation in the proto-oncogene c-kit. Thus, the anti–c-kit effect could be the basis of the clinical efficacy of STI571 in the tumor that responded so impressively, as reported by Joensuu et al. in a case report in this issue of the Journal.13 Will STI571 be useful in the treatment of other cancers? Time will tell, since clinical trials have now started for patients with lung, prostate, and cerebral tumors.
How does one advise a patient with CML today? For a relatively young patient, for whom a cure is the chief objective, hematopoietic stem-cell transplantation must remain a serious option until it becomes clear that STI571 (or the combination of STI571 with other agents) can cure a high proportion of patients or at least prolong life more than interferon alfa. If a cure is less important, especially if the estimated transplant-related mortality exceeds 15 to 20 percent, then initial treatment with STI571 seems logical. The time has not yet come to delay or rule out transplantation in patients with newly diagnosed disease who are candidates for this procedure. If, however, STI571 is shown to reduce progression to blast crisis and to obliterate all molecular evidence of residual leukemia, the role of transplantation in CML will have to be reevaluated.
John M. Goldman, D.M.
Junia V. Melo, M.D., Ph.D.
Imperial College School of Medicine, London W12 0NN, United Kingdom- References
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