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Second-generation drugs called into first-line therapy for CML
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In 2003, results from the IRIS trial were published in The New England Journal of Medicine. Patients with chronic-phase chronic myelogenous leukemia were randomly assigned to an investigative agent, imatinib, or the mainstay treatment, interferon alfa plus cytarabine. The estimated rate of major cytogenetic response at 18 months was 87.1% in patients who received imatinib vs. 34.7% in those who received interferon alfa plus cytarabine. Imatinib was also better tolerated.
In 2006, with a median follow-up of 60 months, imatinib’s (Gleevec, Novartis) benefit persisted: The estimated rate of complete cytogenetic response was 87% (observed rate, 82%), and the estimated OS was 89%. Even further out, in 2009, 8-year follow-up data were presented at the American Society of Hematology Annual Meeting. The estimated event-free survival was 81%, and the estimated OS was 85%.
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Photo by Alex Rubin, Rubin Photography, Seattle |
Although imatinib was a potent addition to the armamentarium, some patients eventually became resistant to its effects, and some experienced adverse effects that led them to discontinue treatment. More research led to second-generation tyrosine kinase inhibitors that were more potent than imatinib and active against models of imatinib resistance. Dasatinib (Sprycel, Bristol-Myers Squibb) was approved by the FDA in 2006 for patients with CML who were resistant or intolerant to treatment with imatinib, and Nilotinib (Tasigna, Novartis) was approved in 2007.
It seemed as though the treatment paradigm was clear: first-line treatment with imatinib, and then second-line treatment with dasatinib or nilotinib upon resistance or intolerance to imatinib. But then things started to get trickier. In 2010, both dasatinib and nilotinib were approved for first-line CML treatment, leaving many physicians wondering what therapy they should use to start a patient’s CML treatment.
“Many patients have been helped greatly by imatinib, and will continue on this great drug,” said Jorge Cortes, MD, chair of the CML section in the department of leukemia at The University of Texas MD Anderson Cancer Center. “We do have new agents that appear to have some advantages, and we are interested in exploring them. This is not a situation similar to imatinib replacing interferon. We now have three options for patients.”
With the approval of the second-generation drugs for first-line therapy, where does imatinib stand?
“We have the longest follow-up data with imatinib, but the newer agents appear to be superior in terms of achieving cytogenetic and molecular responses,” said Neil Shah, MD, PhD, assistant professor in the department of medicine at the University of California, San Francisco. “There is a fair amount of excitement because as good as imatinib is, the new drugs may prove to be clinically superior.”
The second-generation drugs are more potent at inhibiting BCR-ABL and also are less vulnerable to resistance-conferring mutations. According to Shah, more than 100 BCR-ABL mutations have been identified in imatinib-resistant patients, but it appears as though there are only five or six mutations that are capable of conferring loss of response and resistance to the second-generation drugs.
“Imatinib is a terrific drug, but it’s not a perfect drug,” said Charles Schiffer, MD, professor of medicine and oncology at Wayne State University School of Medicine in Detroit, and a member of the HemOnc Today Editorial Board. “About 60% of patients who start imatinib will be in complete cytogenetic response 5 to 6 years later. So, imatinib still has an important role in CML, but there is room for improvement.”
Nilotinib and dasatinib studies
Two studies published in NEJM in June paved the way for the approval of dasatinib and nilotinib as first-line agents in treating CML.
In the Dasatinib versus Imatinib Study in Treatment-Naive CML Patients (DASISION) trial, 519 patients with newly diagnosed CML in the chronic phase were randomly assigned to receive 100 mg of dasatinib once daily or 400 mg of imatinib once daily. After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was 77% in patients who received dasatinib vs. 66% in patients who received imatinib.
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The rate of major molecular response was 46% for dasatinib and 28% for imatinib. The responses to dasatinib were achieved more rapidly than with imatinib. The safety profiles of the two drugs were similar. Only five patients who received dasatinib progressed to accelerated phase or blast-crisis phase vs. nine patients who received imatinib.
In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients (ENESTnd) trial, 846 patients with newly diagnosed CML in chronic phase were randomly assigned to 300 mg or 400 mg of nilotinib twice daily, or 400 mg of imatinib once daily. At 12 months, the rate of complete cytogenetic response was 78% in patients who received the 400-mg doses of nilotinib, 80% in patients who received the 300-mg doses of nilotinib and 65% for those who received imatinib.
The rate of major molecular response was 44% for those who received the 300-mg doses of nilotinib, 43% for those who received the 400-mg doses of nilotinib and 22% for those who received imatinib. Patients who received either dose of nilotinib had a significant improvement in time to progression to accelerated or blast-crisis phase. Gastrointestinal and fluid-retention events were more common with imatinib, but dermatologic events and headache were more common with nilotinib.
“For newly diagnosed patients, the data are pretty compelling that there is an advantage to starting on dasatinib or nilotinib,” said Michael Mauro, MD, associate professor in the Center for Hematologic Malignancies at the Oregon Health & Sciences University Knight Cancer Institute. “They show a PFS advantage, a response advantage and no real penalty regarding toxicities.”
Front-line therapy
So far, the dasatinib and nilotinib trials have not demonstrated a difference in OS, as the follow-up time is short. But the trials have definitely shown an advantage in efficacy and with faster responses.
“One of the potential advantages of imatinib is that it has a longer track record to determine long-term issues of the drug,” said Jerald Radich, MD, member of the Fred Hutchinson Cancer Research Center and professor in the division of oncology at the University of Washington School of Medicine in Seattle. “Physicians have more experience using it than they do the newer drugs, and I suspect there will be a transition period for them to get used to using these drugs that do not have the long track records that imatinib does.”
All three of the drugs are viable front-line treatment options, as they are all approved by the FDA for this particular indication. Physicians must face the challenging decision of which treatment to choose for their patients.
“A patient’s comorbidities and simplicity of treatment regimen may be important in helping physicians and patients choose a preferred initial treatment for patients with chronic phase CML. If, for any reason, patients encounter difficulty with the first agent, they can easily be switched to an alternative choice,” Shah said.
Some suggest making the decision based on disease factors. For example, if patients have a high Sokal risk score, and thus a higher risk of resistance and progression or high white blood cell counts, initiating treatment with nilotinib or dasatinib could be an advantage, Radich said.
“In low risk patients, we would have the discussion to determine if they want a second-line agent upfront, or whether they want to go with imatinib, which has a longer track record,” Radich said. “You can certainly start a patient on imatinib and switch the patient to dasatinib or nilotinib if they don’t reach the treatment milestone with imatinib.”
It may be ideal to include the patient in the decision-making process, by informing them of the good and bad qualities of all drugs.
“I present patients with the long-term data about imatinib and also discuss the recent data on nilotinib and dasatinib and discuss the advantages of all the drugs,” Mauro said. “The patient’s medical history may suggest that one drug would be better tolerated than the others, so if that’s the case, I offer my own advice, based on the medical history.”
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Cytogenetic vs. molecular response
“We know a number of things from the original IRIS trial and from a number of other trials,” Schiffer said. “In people who achieve a complete cytogenetic response, which is a fairly standard measurement, and sustain that response for several years, the rate of relapse is very low. We also know that people who rapidly achieve a major molecular response also have a low rate of relapse.”
The problem with molecular response is that, in the United States, the measurement of molecular response is not standardized, Schiffer said. There is, therefore, confusion and difficulty in measuring major molecular response.
In a study presented at the 2010 ASH Annual Meeting, researchers from Germany found that patients who rapidly reached a major molecular response had a significantly higher PFS and OS.
“What these researchers emphasized less is that if you rapidly achieve a complete cytogenetic response, the same thing is true,” Schiffer said.
Complete cytogenetic response remains the gold standard of treatment. According to Cortes, research has shown that patients who achieve a complete cytogenetic response live longer, whereas a molecular response has not been shown to improve survival.
“Patients who do not show a complete molecular response should not be considered a treatment failure,” Cortes said. “None of the criteria consider a lack of molecular response a failure.”
According to Radich, once a complete cytogenetic response is reached, the next optimal goal is a deeper molecular response. There are studies ongoing to determine whether people with a sustained complete molecular response can eventually go off the drugs and stay in remission after discontinuing therapy.
“Cytogenetic response is the first important milestone you have to reach, and this is the gold standard of treatment,” Radich said. “After that, molecular response may be helpful in predicting future risk of progression or relapse, or identify cases that eventually my be able to discontinue therapy.”
Interferon alfa
Before imatinib, the only effective medical therapy available for patients with CML was interferon alfa, which when combined with cytarabine, was able to achieve cytogenetic and molecular responses in a small group of patients. But the cost was substantial toxicities.
But interferon is trying to make a comeback. A recent study published in NEJM has shown that when added to imatinib, pegylated interferon alfa-2a improved the molecular response rate in patients with CML.
In the study, 636 patients with untreated chronic-phase CML were randomly assigned to imatinib 400 mg daily, imatinib 400 mg daily; with cytarabine; imatinib 400 mg daily with pegylated interferon alfa-2a; or imatinib 600 mg daily. They measured molecular and cytogenetic responses, time to treatment failure, OS, event-free survival and adverse events.
There was no difference in the rates of cytogenetic response among the four groups. The molecular response rate for the pegylated interferon alfa-2a plus imatinib group was 30% vs. 14% for the imatinib 400 mg daily group. But during the first year, 45% of patients receiving the pegylated interferon alfa-2a discontinued treatment, mainly due to adverse events. There were also more adverse events overall in the group that received pegylated interferon alfa-2a. There was no benefit in event-free survival or OS.
“Two additional studies have shown no benefit of adding interferon alfa to imatinib, so this evidence should be considered, at best, inconclusive or questionable,” Cortes said. “Interferon may have a role, but we have to find the right place for it. It is more likely to be used at the end of treatment, if patients still have residual disease after treatment with a tyrosine kinase inhibitor, to see if that will help the patient move to a complete response. But at the moment, there is no evidence of a benefit, and it is still clearly an experimental approach.”
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The studies of interferon continue. Some studies may be designed to test the imatinib/interferon combination against the second-generation drugs nilotinib and dasatinib. Some experts said the monotherapy will prevail and spare patients from the adverse effects associated with interferon.
“I am hopeful that the second-generation drugs are able to achieve a response that is equivalent or superior to that of the imatinib and interferon combination,” Shah said. “There are studies ongoing now that are combining the second-generation drugs with interferon. It will be several years before we can learn whether this would add anything substantial to monotherapy with a second-generation drug, but this is an area of significant ongoing research.”
Drugs in investigation
At the 2010 ASH Annual Meeting, data were presented on a new TKI, bosutinib (Pfizer), both in the third-line setting and the first-line setting.
In an open-label, phase 1/2 study, the safety and efficacy of bosutinib as a third-line treatment in CML was assessed. The study included 28 patients with CML who were resistant to nilotinib and 86 patients who were resistant or intolerant to dasatinib. All had failed initial treatment with imatinib. The patients received a starting does of 500 mg of bosutinib.
At week 24, 26% of the patients had achieved a major cytogenetic response and 13% had a complete cytogenetic response. The cumulative response rates were 34% for a major cytogenetic response and 22% for a complete cytogenetic response. Most patients (81%) who achieved a major cytogenetic response retained their response after a median duration of 23 months.
In a phase 3 study, 502 newly diagnosed patients were randomly assigned to bosutinib 500 mg/day or imatinib 400 mg/day. At week 48, 71.5% of the patients were in complete cytogenetic response and 74.8% of patients were in complete hematological response. The rates of complete cytogenetic response rates were similar between the two groups, but the median time to complete cytogenetic response was shorter in the bosutinib group. More patients in the bosutinib group discontinued treatment because of adverse effects.
Resistance to mutation
Bosutinib, along with imatinib, dasatinib and nilotinib, has one critical weakness: It is ineffective against the T315I mutation. But for patients with this particular mutation, there may be a new treatment option in the future. The drug ponatinib (Ariad Pharmaceuticals) is currently in phase 2 trials.
Data from a phase 1 trial of ponatinib were also presented at the 2010 ASH Annual Meeting. Sixty-seven patients were enrolled in this trial: 95% of these patients had failed treatment with two tyrosine kinase inhibitors, and 64% of these patients had failed treatment with three tyrosine kinase inhibitors. Patients were treated at doses up to 60 mg. Of the 30 patients with CML in the chronic phase, 94% had a complete hematologic response and 63% had a major cytogenetic response.
“An agent to overcome the T315I mutation would represent a quantum leap in the management of patients with chronic phase CML, following the quantum leaps that imatinib and the second-generation tyrosine kinase inhibitors have made in the past decade,” Shah said.
Another agent of interest is DCC-2036 (Deciphera Pharmaceuticals). This drug binds to and inhibits the BCR-ABL in a different manner than the approved tyrosine kinase inhibitors. According to Shah, the hope is that this agent will also be less vulnerable to the resistance-conferring mutations, such as T315I. The agent is currently in a phase 1 trial. – by Emily Shafer
Disclosures: Dr. Cortes is a consultant for Ariad, Novartis and Bristol-Myers Squibb, and receives research funding from Novartis, Bristol-Myers Squibb, Pfizer and Ariad. Dr. Mauro receives research funding from Bristol-Myers Squibb, Novartis and Ariad. Dr. Radich is a consultant for Novartis, Bristol-Myers Squibb, and Pfizer, and receives research funding from Novartis. Dr. Schiffer is a consultant for Bristol-Myers Squibb, Novartis and Pfizer, and receives research funding from Bristol-Myers Squibb, Novartis and Ariad. Dr. Shah has served as a consultant for Bristol-Myers Squibb, Novartis and Ariad.
For more information:
- Cortes J. #210. Presented at: 52nd ASH Annual Meeting; Dec. 4-7, 2010; Orlando, Fla.
- Deininger M. Blood. 2009;114:Abstract 1126.
- Druker BJ. New Engl J Med. 2006;355:2408-2017.
- Gambacorti-Passerini C. #208. Presented at: 52nd ASH Annual Meeting; Dec. 4-7, 2010; Orlando, Fla.
- Kantarjian H. N Engl J Med. 2010;362:2260-2270.
- Khoury HJ. #892. Presented at: 52nd ASH Annual Meeting; Dec. 4-7, 2010; Orlando, Fla.
- Müller MC. #669. Presented at: 52nd ASH Annual Meeting; Dec. 4-7, 2010; Orlando, Fla.
- O’Brien SG. New Engl J Med. 2003;348:994-1004.
- Preudhomme C. N Engl J Med. 2010;363:2511-2521.
- Saglio G. N Engl J Med. 2010;362:2251-2259.
What role does imatinib play in CML after the approval of dasatinib and nilotinib for newly diagnosed CML?
Imatinib is still being used extensively. The key question is should we replace all the treatment for newly diagnosed CML with dasatinib and nilotinib, or should some patients continue to receive imatinib? Many patients still respond very well to imatinib, and there is no reason to rush and give all the patients the second-line drugs, especially since the follow-up on the ENESTnd and the DASISION studies are fairly short.
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One approach that can be taken is that low-risk patients, according to Sokal score, should start on imatinib, whereas intermediate- and high-risk patients would benefit from going right away to the second-line drugs. Then, for the low-risk patients, who account for 55% to 60% of the patients, if the response is suboptimal by 3 months, then it would be time to switch to a second-line drug. The result would be that 60% to 70% of patients would be on second-line drug, but there are patients who will still remain on imatinib.
I don’t see reason to completely replace imatinib completely with the second-line drugs. To a large extent, I follow this model I just described. I prefer to start with imatinib, but I take into consideration a lot of variables, such as performance status, age and medical history. There are a lot of variables that influence my decision. Older patients, for example, I would not put on nilotinib. If a patient has heart disease, I would not go with imatinib. With three available drugs, it is important to try to calculate the best option for the patients.
Moshe Talpaz, MD, is the Alexander J. Trotman Professor and director of Hematologic Malignancies at the University of Michigan. Disclosure: Dr. Talpaz is on the speakers’ bureau for Novartis, is on the advisory board for Novartis and Bristol-Myers Squibb, and receives research funding from Novartis, Bristol-Myers Squibb, Ariad and Deciphera.
The treatment paradigm for front-line treatment is changing to a more aggressive approach using second-line therapies such as dasatinib and nilotinib. There are two trials that have looked at this question, and both met their primary endpoints. One was a comparison of nilotinib with imatinib that showed a higher rate of major molecular response related to nilotinib.
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Another trial was a comparison of dasatinib with imatinib, and in that trial dasatinib was superior in terms of complete cytogenetic response at 12 months. It has also been hinted that PFS may be improved with second-line agents, especially in the nilotinib trial. So the treatment paradigm is starting to shift. If you go by these randomized trials, the second-line agents have shown advantages, particularly with nilotinib. As such, we have to accept that this evidence is paradigm-changing.
So should every newly diagnosed patient be treated with one of the second-line inhibitors? We should not try to give dogmatic answers to this question. There can be circumstances where one may select imatinib — for example, in low-risk patients — and many physicians may decide to use the compound that they know better and that has substantial long-term follow-up. Another issue is that some patients might have a high co-pay that would result in higher costs with the second-line agents, which are about 50% more expensive than imatinib. Of course, the ultimate question will be whether overall survival is superior and whether more patients will be able to maintain responses without continued therapy. Nonetheless, the frontline paradigm has started to change.
Michael Deininger, MD, PhD, is the M. Wintrobe Professor of medicine and chief of the division of hematology and hematologic malignancies at the University of Utah School of Medicine. Disclosure: Dr. Deininger is a consultant for Novartis, Bristol-Myers Squibb and Ariad, and receives research funding from Celgene, Genzyme, Bristol-Myers Squibb and Ariad.