Understanding the earliest drivers of cancer formation can lead to less toxic and more effective treatments.
It transformed the outlook for people diagnosed with chronic myeloid leukemia. A disease with a three- to five-year life expectancy became, for most patients, a chronic, long-term condition managed with a daily pill.
And this week, researchers published the outcomes of people treated for more than 10 years with the drug imatinib (Gleevec), ushered from lab to clinical success by Brian Druker, M.D., director of the OHSU Knight Cancer Institute. The findings stand as a testament to the idea that understanding the earliest drivers of cancer formation can lead to less toxic and more effective treatments.
Estimated overall survival at 10 years was 83 percent among patients receiving first-line imatinib treatment, Druker and co-authors reported in the New England Journal of Medicine. Many of the recorded deaths of people in the imatinib group were unrelated to CML. Among 134 patients with cytogenetic assessments at 10 years, 92 percent had a complete cytogenetic response, that is, they had no measurable sign of the chromosome alteration that causes CML.
No surprising toxic effects emerged with long-term use. A total of 51 of 551 patients (9 percent) receiving first-line therapy with imatinib had a serious adverse event. The frequency of adverse events was highest during the first year of treatment and declined over time.
Among the patients in the clinical trial who had been randomly assigned to receive interferon alfa plus cytarabine, nearly two-thirds crossed over to imatinib, typically because of disease progression, lack or loss of response, or unacceptable side effects from the older treatment. The high rate of crossover makes it impossible to compare overall survival directly, but the available data indicate a 26 percent lower risk of death with first-line imatinib therapy than with interferon alfa plus cytarabine, Druker and co-authors said.
Life expectancy in patients with chronic myeloid leukemia has climbed to a level almost equal to that of the general population.
Imatinib is a tyrosine kinase inhibitor that specifically targets a mutant protein, BCR-ABL1, that is a driver of malignant transformation in CML. Second- and third-generation TKIs have continued to improve outcomes by providing effective therapy when CML develops resistance to imatinib. With the advent of these drugs, life expectancy in patients with chronic myeloid leukemia climbed to a level almost equal to that of the general population.
Imatinib treatment has also allowed for the successful stopping of therapy in a subset of patients who achieve deep remission. Druker and co-authors estimated that approximately 10 percent of imatinib-treated patients might be able to achieve a stable treatment-free remission. They said second-generation agents may enable an even larger proportion of patients to be eligible to attempt treatment-free remission.
Other cancers haven’t been as amenable to the targeted therapy approach because the genetic alterations driving them are more complex than the BCR-ABL1 mutation that underlies CML. Solid tumors, for instance, tend to quickly develop resistance to targeted therapies by diverting to alternative metabolic and signaling pathways.
Nevertheless, the imatinib experience has “fundamentally altered the field of oncology,” in the words of Dan L. Longo, M.D., a deputy editor of the New England Journal of Medicine. While none of the new targeted therapies appears to cure a majority of patients, and many hurdles remain, he said, “The future of oncology is more hopeful now.”
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Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia by Andreas Hochhaus, Brian J. Druker and others, NEJM (March 9, 2017)
Imatinib Changed Everything by Dan L. Longo, NEJM (March 9, 2017)
Life Expectancy of Patients With Chronic Myeloid Leukemia Approaches the Life Expectancy of the General Population, by Hannah Bower, Magnus Björkholm, Paul W. Dickman, Martin Höglund, Paul C. Lambert and Therese M.-L. Andersson, Journal of Clinical Oncology, June 20, 2016.