NEW YORK—Despite higher, faster responses with newer second-generation tyrosine kinase inhibitors (TKIs) to treat patients with newly diagnosed chronic- phase chronic myeloid leukemia (CML), most clinicians still prefer frontline treatment with the gold-standard TKI imatinib, according to a survey of participants at this year's Great Debates & Updates in Hematologic Malignancies meeting here.
Over the last decade imatinib has helped thousands of CML patients survive and, basically, has turned a once-fatal disease into a long-term chronic illness.
Two experts from the same New York institution made their cases for whether imatinib should continue to be the first choice for CML patients or if the newer, more potent TKIs are the better choice.
The audience was slightly in favor of imatinib at the outset, and after hearing both arguments, the majority were still in favor of using imatinib.
Imatinib ’Tried and True’
There is a benefit to the “tried and true” treatment of imatinib for newly diagnosed CML patients, said Gail Roboz, MD, Associate Professor of Medicine and Director of the Leukemia Program at Weill Medical College of Cornell University and NewYork-Presbyterian Hospital.
“We are in a happy place as leukemia doctors with our therapeutic armamentarium. We have choices that actually work. The impact of imatinib on CML has been uncontroversial and incontrovertible. Imatinib has stood the test of time. People are living longer. Imatinib leads to excellent overall survival.”
Annual “event” rates show that CML patients who respond to imatinib do well over time, she continued. “Those who are doing well continue to do well. Complete response [CR] and major molecular response [MMR] do matter in CML.” If a patient has a minor response or no cytogenetic response, the patient is not likely to do well. Therefore, it is important to have other therapies available, she said.
The landmark IRIS trial showed that patients who achieved more than a three-log reduction in complete cytogenetic response (CCyR) were on the road to recovery. Clinicians now note therapeutic milestones at three, six, 12, and 18 months to optimize therapy.
“There is still a lot of debate over whether three-month or six-month milestones are more important,” Roboz noted. “Many experts believe six months is reasonable, and even at three months we can discriminate between whether imatinib is or is not working. My impression is that within 12 months we can determine if a patient is on the right track. By then you should be able to figure out which of your patients are doing well on therapy.”
The eight-year update of the IRIS data allowed clinicians to predict what would happen to patients on imatinib. This study measured levels of BCR-ABL transcripts at three and six months in the newly diagnosed imatinib-treated patients. At three months, about one-third of the patients had less than one percent BCR-ABL transcripts, and 97 percent achieved five-year overall survival (OS). At six months, 63 percent had less than one percent BCR-ABL transcripts and had the same five-year OS.
“My impression is we have time to see how well the patient is doing,” she said.
The ENESTnd trial compared nilotinib in 300 and 400 mg doses with imatinib at 400 mg. OS was very good for all three treatment groups, Roboz noted. In a trial comparing dasatinib with imatinib, imatinib had a high rate of overall survival for the majority of patients, and a molecular response was seen within three months of therapy.
“Comparisons of imatinib with second-generation TKIs suggest that many patients have a better result at six months,” she said. “OS improves with a molecular response at three months. The molecular response is deeper on second-generation TKIs, but at three months does that matter?”
In addition, she said, the long-term safety and tolerability of imatinib are well-characterized. Chronic fatigue is the most common long-term side effect with imatinib. Other adverse events include cytopenias, edema (including periorbital edema), gastrointestinal disturbances, musculoskeletal complaints and cramps, and skin complaints, which are mostly Grade 1 or 2, as well as possible effects on bone health and bone density.
In conclusion, Roboz said “there are things that make life easier for both the doctor and the CML patient with imatinib. There are long-term efficacy data, and a clear exit strategy if optimal milestones are not met. We have some information about imatinib in pregnancy. There are no food issues, and more information on drug interactions. Importantly, imatinib is less expensive than second-generation TKIs.”
Her final comment: “Imatinib is an excellent choice for first-line therapy for selected CML patients with chronic phase disease.”
Second-Generation TKIs Preferable
TKIs have made a tremendous difference in patient outcomes in CML, agreed Ellen K. Ritchie, MD, Assistant Director of the Leukemia Program. “In what other disease in hematologic malignancies do we have so many drugs that work? Which one do we want to use? Which is the fairest of them all? Are the newer TKIs really better?”
Ritchie emphasized that no patient should die of CML, and that it was up to the clinician to determine the best strategy to achieve that goal for each patient: “Cancer therapy in general has taught us that using our best therapy first gives us the best long-term outcome. Is CML any different? Shouldn't we use the most potent therapy upfront?”
She also referenced the IRIS eight-year follow-up data, noting that no patient achieved a CCyR by 12 months. “We really want the patient to have the best response possible as early as possible to improve long-term survival,” she said. “The lower the BCR-ABL transcript levels, the better likelihood of survival.”
Current guidelines define response by achievement of CCyR and MMR at specific time points, Ritchie pointed out. “Responses to TKIs predict how well patients will do. A quick response is important for those with disease,” and adding nilotinib and dasatinib lead to faster CCyR and MMR than the standard 400 mg dose of imatinib does.
In a comparison of TKI frontline therapies, the median time to MMR was six months for higher-dose 800 mg imatinib, nilotinib, and dasatinib and nine months for imatinib at 400 mg. The event-free survival rate was better with second-generation TKIs than with imatinib at 800 mg, but OS was the same.
“If OS is the same with them all, why are we having this conversation? Why don't we hedge our bets and just give all CML patients imatinib at higher doses?” she asked. “Should we agree with the Supreme Court in India that ruled that Novartis should not be given to a patent for nilotinib because it did not show ‘enhanced or superior efficacy’ over imatinib and that nilotinib is not demonstrably more effective than its predecessor?”
She did note, however, that there are issues of tolerability and adverse events with the higher dose of imatinib compared with the lower dose. “If we give imatinib 800 mg doses, they are not as well tolerated. as imatinib 400 mg doses.” In the Phase III TOPS trial comparing imatinib 400 mg with 800 mg doses, CCyR and MMR were the same in both arms at 12 months, but there were about twice as many grade 3 or 4 adverse events with the 800 mg dose compared with the 400 mg dose, and a higher rate of dose interruption and discontinuation with the higher dose.
Factors Predicting Response
Some experts believe a single measurement of BCR-ABL transcripts performed at three months is the best way to identify patients destined to do poorly, Ritchie said. The time point of BCR-ABL transcript is debatable, whether three, six, or 12 months is the requirement for predicting outcome of CML patients.
“The earlier the response in CML, the more patients survive. Newer agents definitely have superior cytogenetic and molecular responses when compared with the imatinib 400 mg dose, although the OS is roughly the same.”
Factors predicting for favorable cytogenetic response at three months include older age, low-intermediate Sokal score, imatinib at 800 mg, nilotinib, or dasatinib. “Older patients seem to realize they are more vulnerable and take their medicine every day,” she said. “Sokal score does not tell us when we need more intervention or therapy upfront.”
So how should clinicians choose upfront therapy? “Three-month CCyR and MMR are important in the long-term outlook of CML patients. We need more data to begin to develop prognostic scoring systems to identify patients who are most likely to need second-generation TKIs,” Ritchie said, noting that there are no head-to-head trial data that show that nilotinib, dasatinib, or imatinib 800 mg is superior.
“There is no evidence for monitoring on imatinib and switching therapy if a patient is lagging in response. We need more studies on switching therapies,” she said.
Different side effects profiles may influence a clinician's choice of initial treatment. “We need to find the right fit of TKI for the individual patient,” she said. Imatinib leads to edemas, nausea, GI disturbances, musculoskeletal pain, and cytopenias. Adverse events with nilotinib include rash, alopecia, pruritus, headache, and elevated glucose level. Dasatinib side effects include musculoskeletal pain fatigue, diarrhea, rash, and pleural effusions in 12 to 14 percent of patients.
“The goal is to try to find the right drug for the right patient,” Ritchie said. “There may be a ‘poisoned apple’ we don't know about until all long-term survival data have been obtained. Will there be unknown long-term side effects or will there be increased pressure for transformation? We need CML patients to enroll in clinical trials to truly answer this question so we can learn to risk-stratify CML patients to the appropriate treatment strategy.”
In the question-and-answer session, the moderator, David Steensma, MD, Associate Professor in the Department of Medicine at Harvard Medical School and Attending Physician in Hematologic Oncology at Dana-Farber Cancer Institute, asked when it is appropriate to check for mutational status in a newly diagnosed CML patient.
Ritchie answered: “I don't obtain mutational status unless a patient is not meeting mutational milestones.” Roboz said: “In a young CML patient in his or her early 20s, I might do a mutational analysis upfront. If there is even a small chance of the patient having a T315I mutation, I want to know about it.”