By Annette M. Boyle
PORTLAND, OR — Not long ago, less than a third of chronic myeloid leukemia (CML) patients survived five years and gastrointestinal stromal tumor (GIST) patients had an even shorter life expectancy, according to the National Cancer Institute. Now significant numbers of patients with these cancers live for another 10 years after diagnosis.
What changed? Several recent studies, including some involving VA research, highlight the improved survival rates in multiple cancers since the development of imatinib kicked off the race to develop personalized, non-toxic therapies. Imatinib, a selective tyrosine kinase inhibitor that is administered orally, dramatically improved survival rates for both gastrointestinal stromal tumor (GIST) and (CML).
Before imatinib, “patients with advanced GISTs faced a life expectancy of 18 months,” said Michael Heinrich, MD, a researcher with Portland Veterans Affairs Health Care System and professor of medicine at the Oregon Health & Science University School of Medicine. “Now we’ve learned that some might live a decade or longer.”
GISTs are soft-tissue sarcomas that can occur anywhere in the gastrointestinal tract. About 6,000 new cases are diagnosed annually nationwide.
The long-term study appeared in the February issue of JAMA Oncology. Researchers followed 695 adults with advanced, inoperable gastrointestinal stromal tumors who were enrolled in a phase III study that started in 2000. A previous report on the study, published in 2008, confirmed imatinib’s effectiveness and recommended treatment with 400 mg daily dose. The initial study had randomized patients to receive either 400 mg per day or 800 mg daily, which was continued until progression or unacceptable toxic effects occurred.1
Of the initial participants, 189 survived for at least eight years and researchers estimated 10-year survival rates of 23% and progression-free survival rates of 7%. About equal numbers of the long-term survivors received 400 mg per day (95) or 800 mg per day (94) of imatinib.
“This is a really exciting finding,” said Heinrich, who was lead author of the study. Not only are more patients living longer, “we’ve come to understand which class of patients benefit the most.”
DNA analysis showed that patients with KIT exon 11-mutant tumors had the best survival rates, compared to those with KIT exon-9 mutation or no KIT mutations or mutations in the platelet-derived growth factor receptor gene (PDGFRA). Up to 88% of GISTs have KIT mutations.
“Our findings also highlight the importance of banked biospecimens to drive new scientific findings, and how tumor mutation testing can optimize treatment for cancer patients,” Heinrich noted.
The initial study of imatinib in CML, the International Randomized Study of Interferon and STI571 (IRIS), enrolled 1,106 previously untreated patients at 177 centers in 16 countries and randomly assigned them to treatment with imatinib or interferon alfa plus cytarabine. About 5,000 patients develop CML each year, according to the National Cancer Institute.
At 18 months, the trial showed that imatinib achieved complete cytogenetic repose in 76.2% of patients, while only 14.5% of patients who responded to the then standard treatment with interferon alfa plus cytarabine. Because of these outstanding results, patients randomly assigned to the interferon combination were permitted to switch to imatinib therapy, which 363 (65.5%) did. The median duration of first-line therapy with interferon alfa plus cytarabine was 0.8 years; for imatinib it was 8.9 years.2
The update to the study recently published in the New England Journal of Medicine reports that, at 10 years, the estimated overall survival rate of patients receiving first-line imatinib therapy was 83.3%, of which 47% continued to receive study treatment and 17.4% were still alive but no longer received study treatment. Of the remainder in the intention-to-treat population, 20.1% had unknown survival status and 15.6% had died. Notably, 39% to 45% of patients who achieved deep molecular response to imatinib and stopped therapy remained in treatment-free remission for at least three years.
In the imatinib group in the intention-to-treat population, 7% had progression to blast crisis or accelerated phase while on treatment. The researchers estimated that the event-free survival rate at 10 years was 79.6% in this group. Of the patients assigned to the imatinib arm, 48.3% completed treatment and 82.8% had a complete cytogenetic response.
While a direct comparison of the two arms of the original study is not possible because of the high rate of crossover, the researchers noted that 50% of patients in the trial who were randomized to the interferon alpha combination treatment initially had died after five or six years. During the study, 12.8% progressed to accelerated phase or blast crisis. The estimated event-free survival rate for this group of patients at 10 years was 56.6%.
A similar, large, long-term study of veterans with CML who filled a prescription for the tyrosine kinase inhibitors (TKI) imatinib, nilotinib or dasatinib between 2001 and 2010 also showed good results, though not quite as strong as those seen in the clinical trial.
The retrospective study, published in Pharmacotherapy in March, evaluated the treatment and outcomes of 2,873 VHA beneficiaries who received first-line treatment with a TKI. Of those, 20.4% switched to a second-line TKI and 8.5% switched to a third-line TKI during the period studied. First-line treatment persistence declined steadily from 75% in year one, to 65% in year two, and 55% in year three of treatment. The five-year survival rate for first-line treatment was 62%.3
Eugene Kreys, PharmD, PhD, lead author of that study, noted to U.S. Medicine that the population he and his colleagues studied “is made up of entirely of veterans of which 97% were male and median age of 68 years as compared to a little over half of the sample being male with a median age of about 50 years of age in the clinical trial. These differences alone would not explain dissimilarities in persistence; however, when comparing the two studies one should keep in mind that we are looking at somewhat different populations.”
“Most importantly,” he added, “our study was an retrospective observational study using a VA database evaluating patients in a naturalistic setting as compared to a clinical trial in NEJM article. There are inherit differences between these two trial designs and clinical trials nearly always result in increased adherence and persistence relative to studies evaluating patients in a naturalistic setting.”
- Heinrich M, Rankin C, Blanke CD, Demetri GD, Borden EC, Ryan CW, von Mehren M, Blackstein ME, Priebat DA, Tap WD, Maki RG, Corless CL, Fletcher JA, Owzar K, Crowley JJ, Benjamin RS, Baker LH. Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033. JAMA Oncol. Published online 2017 Feb 9.
- Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, et al. Long-term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med 2017;376:917-927.
- Kreys ED, Frei CR, Villarreal SM, Bollinger MJ, Jones X, Koeller JM. Evaluation of Long-Term Chronic Myeloid Leukemia Treatment Practices with Tyrosine Kinase Inhibitors in a National Cohort of Veterans. Pharmacotherapy. 2017 Mar;37(3):278-286.