NEW YORK—With second-generation tyrosine kinase inhibitors available, should imatinib still be first-line treatment for patients with chronic myelogenous leukemia (CML)? Two experts debated the question here at the International Congress on Hematological Malignancies.
Harry Erba, MD, PhD, Professor of Internal Medicine and Director of the Hematologic Malignancy Program at the University of Alabama at Birmingham, argued for continued reliance on imatinib—but he did so under protest. As often happens at such debates, speakers can be “voluntelled” to one side or the other, though Erba did his best to score some points for imatinib.
On the other side, Michael Mauro, MD, Associate Professor at the Knight Cancer Institute's Center for Hematologic Malignancies at Oregon Health & Science University, had more conviction in his presentation, arguing that nilotinib or dasatinib could now replace imatinib.
Longer History, Similar Survival
“I think imatinib could remain the standard of care for initial therapy of adults with CML in chronic phase,” Erba said. He supported that statement, saying that long-term follow-up data are available for imatinib but not for the second-generation TKIs, but that overall survival and progression-free survival are not different among the three TKIs.
“Cytogenetic and molecular response rates are higher with second-generation ABL TKIs compared with imatinib for the initial therapy of adults with CML in chronic phase, but these are at early time points, and the most important—complete cytogenetic remission—appears to not be as significantly different with more time,” he said. Long-term toxicities have not been reported with imatinib as they have been with nilotinib or dasatinib, particularly vascular problems seen with both of the newer drugs.
Late pleural effusions and pulmonary hypertension are concerns with dasatinib, he continued. For nilotinib, the side effects to be concerned about are peripheral arterial occlusive disease, and control of hyperglycemia in patients with diabetes that could lead to long-term complications.
But the elephant in the room, Erba said, is cost of therapy: “Everyone knows that in 2015, imatinib will be generic, and it will almost certainly cost less than today's $8,000 per month.”
Nilotinib and dasatinib currently cost about the same as imatinib. “We have to ask, is the data so compelling for the second-generation drugs that it is worth that investment of money? Someone is going to have to do that cost analysis to convince Medicare and third-party payers.”
He concluded: “From the patients' perspective, it's wonderful that there are multiple options, but I don't see a reason to switch from imatinib.”
As Erba left the stage he breathed a heavy sigh and said sotto voce, “You don't know how hard that was for me to say.”
At the break, Erba shared his true feelings: “There are a number of reasons I personally favor the second-generation TKIs, and the most important issue to me is prevention of progression to advanced phases of the disease. Patients who progress have worse survival, you need to consider chemotherapy and transplants, and they don't do very well.”
He said this is a rare event, and that in the IRIS, DASISION, and ENESTnd trials the risk of progression for imatinib in the control arm in the first two to three years was a consistent five to six percent. But, he added, there were fewer progressions with nilotinib and with dasatinib in the ENESTnd and DASISION trials, respectively.
“The numbers are very small but we cannot predict who will progress, and those lower numbers of progression are the most compelling reasons to use nilotinib or dasatinib as first-line therapy.”
In his presentation, Mauro said the real questions are about early, meaningful response and overcoming resistance.
He offered three axioms for CML:
- “This is not like treating an infection with antibiotics, where you ‘save the big guns’ for resistance if you need them.”
- “You have one chance to do it right for chronic-phase CML.”
- “Treating resistant CML is like a chess match, with sequential and now compound mutations coming like a sequence of moves—blast crisis is the check mate.”
Early response makes a difference, he said, as rapid disease volume reduction probably stops instability and allows patients to continue going into a deeper molecular remission.
Mauro cited data for nilotinib from the ENESTnd trial and dasatinib data from DASISION showing that each drug very statistically significantly superior to imatinib in almost all major molecular response and complete molecular response landmarks at 12 and 24 months.
He admitted that emerging and late side effects of the newer TKIs is a question still under investigation and needs to be followed, but said he didn't think there is enough of a concern at this time to not use them.
Mauro finished with a look at the big picture: The field is moving toward a cure for CML, and it may be possible to have patients exposed to a TKI for only a number of years and then discontinue TKI therapy, achieving a CML that is non-proliferative, stable, and in remission off-therapy.
“In that situation, it makes even more sense to use the newer drugs first because you might stop the patients from having resistance, and produce a stable remission that is a functional cure.”