The Unfolding Story of Imatinib Mesylate for Chronic Myeloid Leukemia

OncologyONCOLOGY Vol 21 No 6
Volume 21
Issue 6

The development of imatinib mesylate (Gleevec), a tyrosine kinase inhibitor targeted against the causative Bcr-Abl protein in chronic myeloid leukemia (CML), has resulted in hematologic and cytogenetic remissions in all phases of CML. Following imatinib treatment, more than 90% of patients obtain complete hematologic response, and 70% to 80% achieve a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging, exhibiting a major change in the natural history of the disease. The understanding of at least some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that may overcome this resistance. Combination strategies are currently being investigated in preliminary clinical studies and may prove to be useful. Overall, there are an increasing number of treatment options now available for patients with CML.

Just 9 years after the first clinical use of STI571, now known as imatinib mesylate (Gleevec), there can be very few hematologists anywhere in the world unaware of its dramatic contribution to the management of chronic myeloid leukemia (CML). Jabbour and colleagues have written a comprehensive and readable review of the drug's preeminent place in the management of CML today. They predict that if the incidence of the disease does not change while survival for those with the disease is prolonged as much as current projections suggest, its prevalence will increase substantially in coming years.

If a once rare disease becomes more common, it thereby becomes a much more attractive target for the various pharmaceutical companies with new tyrosine kinase inhibitors on the drawing board or in the pipeline. There is no doubt that the advent of this new drug has redirected research efforts in academic institutions and in the pharmaceutical industry. The long-held dream that a small inhibitory molecule could offer major clinical benefit is now a reality and hopefully a model for future achievements.

Unanswered Questions

For previously untreated patients with CML in chronic phase, the drug induces a high level of complete hematologic responses and an almost equally high level of complete cytogenetic responses. This convincingly proves what many had suspected for years-that newly diagnosed patients have, for the most part, a full or near-full complement of residual normal hematopoietic stem cells, which can emerge and regenerate normal hematopoiesis if given the chance. This raises two obvious and important questions: How does the Philadelphia chromosome-positive clone suppress normal hematopoiesis, and what is the real basis for the selectivity of tyrosine kinase inhibitors? The last question can be rephrased as: Why does inhibiting the Bcr-Abl oncoprotein lead to cell death when inhibiting normal Abl seems to have so few adverse effects? How is it that the leukemia cell has become so irreversibly addicted to Bcr-Abl? These questions cannot yet be answered.

Residual Disease

Jabbour and colleagues address the issue of whether one can safely stop imatinib and conclude that in most cases one cannot. Given the fact that the majority of patients do have measurable residual disease even after taking imatinib for 5 years, and given that stopping treatment is usually associated with relapse (although at a variable rate), this does seem to be the correct conclusion. There are, however, tantalizing cases in which patients who have been in molecular remission for more than 2 years and then stopped imatinib showed no evidence of relapse during the subsequent follow-up. Could it be that occasional patients really are cured by long-term imatinib? If so, such patients seem to be rare.

Alternatively, these patients may merely be artifacts of the imperfect methodology we currently have for measuring low levels of residual disease. What is really needed is a very sensitive DNA-based polymerase chain reaction (PCR), which might enable us to study the kinetics of leukemia stem cells, some of which are indubitably quiescent and some of which could theoretically be transcriptionally silent and thus invisible to a standard reverse-transcriptase PCR.[1]

Drug Toxicity?

Jabbour and colleagues have documented the relative freedom from toxicity of this remarkable new agent. They do however mention the provocative work of Kerkela and colleagues,[2] who reported details of 10 patients who developed cardiac failure after taking imatinib for a relatively short time. The authors of this paper carried out very elegant studies with a murine model system, from which they concluded that imatinib damaged mitochondria in murine cardiomyocytes and suggested that the same mechanism might operate in man. In practice, the clinical data in the Kerkela paper are rather unconvincing, and a number of subsequent clinical studies on large numbers of patients provide no support for the notion that imatinib at currently used dosages damages cardiac function in man.[3,4] However, very occasional cases of cerebral haemorrhage are attributable to imatinib,[5] and rare examples of second malignancies that might or might not have been "caused" by imatinib have been reported.[6] These would be worth mentioning in a review that rightly focuses on the very positive contribution of this new agent.

Imatinib Resistance

Much attention has been devoted in the past 5 years to the observation that some patients who develop resistance to imatinib have subclones with BCR-ABL kinase domain mutations that impede imatinib binding. In most cases these mutant subclones probably existed at very low levels before treatment initiation and were selected by the administration of imatinib. This, of course, cannot be the whole story. Mutations are rare in chronic phase patients with primary resistance, and in many cases of secondary resistance, imatinib still seems to be effective in suppressing the kinase activity of Bcr-Abl, at least as judged by the in vitro CRKL phosphorylation assay.

We certainly need a much better understanding of drug kinetics and metabolism. Jabbour and colleagues mention that increased drug efflux but impaired cellular uptake mediated, for example, by low levels of hOCT1[7] could be just as important in dictating variable responses to imatinib. Ultimately, gene-expression profiling could prove valuable in predicting response to imatinib and characterizing causes of resistance.[8,9]

Future Directions

What then of the future? Will all new chronic phase patients continue to get imatinib as first-line therapy, or will one of the newer tyrosine kinase inhibitors take over? It is going to be difficult to show that dasatinib (Sprycel) or nilotinib (Tasigna) is equal to or conceivably better than imatinib. Nevertheless, the target now must be to devise a therapy that will induce high degrees of disease reduction for all patients and hopefully permit therapy to be discontinued safely after some months or years, as is possible for childhood acute lymphocytic leukemia. This dream suggests the need to explore various new options, such as two or three tyrosine kinase inhibitors in combination, tyrosine kinase inhibitors combined with other molecular-targeting agents such as farnesyl transferase inhibitors or histone deacetylase inhibitors, or tyrosine kinase inhibitors in conjunction with effective immunotherapy. We have seen amazing progress in recent years, but there is still much to be done.

-John Goldman, DM

Financial Disclosure: Dr. Goldman is a member of the speakers bureau for Novartis and has received honoraria from Bristol-Myers Squibb.


1. Goldman JM, Gordon MY: Why do stem CML cells survive allogeneic stem cell transplantation or imatinib? Does it really matter? Leuk Lymphoma 47:1-8, 2006.

2. Kerkela R, Grazette L, Yacobi R, et al: Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908-916, 2006.

3. Hatfield A, Owen S, Pilot PR: In reply to 'Cardiotoxicity of the cancer therapeutic agent imatinib mesylate'. Nat Med 13:13, 2007.

4. Atallah E, Kantarjian H, Cortes J: In reply to 'Cardiotoxicity of the cancer therapeutic agent imatinib mesylate'. Nat Med 13:14, 2007.

5. Ebonether M, Stentoft J, Ford J, et al: Cerebral edema as a possible complication of treatment with imatinib. Lancet 359:1751-1752, 2002.

6. Kovitz C, Kantarjian H, Garcia-Manero G, et al: Myelodysplastic syndromes and acute leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia. Blood 108:2811-2813, 2006.

7. Thomas J, Wang L, Clark RE, et al: Active transport of imatinib into and out of cells: implications for drug resistance. Blood 104:3739-3745, 2004.

8. Yong ASM, Szydlo RM, Goldman JM, et al: Molecular profiling of CD34+ cells identifies low expression of CD7 along with high expression of proteinase 3 and elastase as predictors of longer survival in patients with CML. Blood 107:205-212, 2006.

9. Radich J, Dai HD, Mao M, et al: Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Nat Acad Sci USA 103:2794-2799, 2006.

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