NEW YORK—Even with a 10-year overall survival (OS) rate of 84%-90%, researchers continue to carry out trials on emerging drugs to try and find therapies that provide a better outlook for patients.
According to Susan O’Brien, MD, of MD Anderson Cancer Center in Houston, Texas, who presented at the NCCN 5th Annual Congress on Hematologic Malignancies, even if a better treatment is available, it will be tough to demonstrate survival benefits.
Dr O’Brien listed standard-dose imatinib, high-dose imatinib, imatinib-based combinations, second generation tyrosine kinase inhibitors (TKIs) and stem cell transplant as possible frontline therapies, noting that imatinib-based combinations are only used in clinical trials and second-generation TKIs are not available commercially.
At 8 years of follow-up, data on imatinib shows a survival rate of about 84%-90%, compared to about 50% for stem cell transplant, which continues to decrease over time. Dr O’Brien believes transplant is a viable option for some patients down the line, but at this point in time for chronic stage patients, transplant is not a reasonable option when one compares these two survival curves upfront.
Most recommendations for the use of imatinib come from follow-up on the IRIS trial, Hochhaus et al 2009, said Dr O’Brien. The trial compared patients on imatinib vs interferon (IFN-α) and low-dose Ara-C, and led to the approval of imatinib for frontline therapy.
Follow-up of the IRIS trial continues to be crucial because there are not 20- or 30-year data available. Now is the 8-year data will help physicians treat current patients.
Because imatinib is such a targeted therapy, investigators thought that if patients were on imatinib long enough they would develop a mutation or something that leads to resistance, said Dr O’Brien. And as time went on, they expected to see increasingly more episodes of transformation.
“When rate of transformation came out, people were surprised.... What you see is the opposite. If you see transformation, it happens early on,” she said
This finding led to the hypothesis that in some patients there is a very small resistant clone up front. When these patients are administered imatinib , it allows the resistant clone to emerge and form resistant disease. “There are no standard techniques that will pick up this clone, so there is no reason for testing,” she added.
She also pointed out that there has not been enough follow-up to form criteria for suboptimal response. Suboptimal response at 6 months may be more like failure than suboptimal response at 12 months. Dr O’Brien noted that if the response is not technically a failure, the guidelines say imatinib can be continued. But in fact, she said, many people on the NCCN guidelines committee felt that the imatinib dose should be increased in the case of suboptimal response.
Although imatinib has revolutionized the treatment of CML, the search continues for an even better option.
To this end, investigators have conducted 2 trials comparing imatinib head-to-head with nilotinib (Larson et al, 2010 ASCO abstract) or dasatinib (Kantarjian et al, NEJM 2010) in newly diagnosed patients.
At 12 months, nilotinib 300 mg and 400 mg twice a day produced a greater percentage of major molecular responses (MMR) than imatinib 400 mg once a day (44%, 43% vs 22%, respectively). More patients on either dose of nilotinib experienced complete cytogenetic response (CCyR) than with imatinib at 12 months (80%, 78% vs 65%, respectively) and overall response (85%, 82% vs 74%, respectively).
Dasatinib also proved to be more effective than imatinib. More patients randomized to 100mg of dasatinib once a day experienced CCyr by 12 months than patients randomized to 400mg of imatinib once a day (83% vs 72%) as frontline treatment. Percentages of confirmed CCyR were 77% for desatinib and 66% for imatinib. Also, 1.9% of patients receiving dasatinib progressed to accelerated phase or blast phase, compared to 3.5% of patients receiving imatinib.
Dasatinib and nilotonib both result in lower rates of anemia and neutropenia than imatinib. Imatinib therapy still has the lowest occurrence of thrombocytopenia.
With all these new developments and less than 10 years of data to go on, Dr O’Brien brought up some issues physicians should consider when choosing frontline therapy for CML, including the relevance of short-term endpoints, the difficulty of assessing survival differences among developing therapies, the cost of drugs, and the spectrum of toxicities.