Photo by D. Meyer
NEW YORK—Evaluating treatment goals is essential when choosing which tyrosine kinase inhibitor (TKI) to prescribe for a patient with newly diagnosed chronic myeloid leukemia (CML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
“Deciding what TKI to start people on really depends on what your goals are for that patient,” said the speaker, Jerald Radich, MD, of the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance in Seattle, Washington.
Because the 3 TKIs approved for frontline treatment of CML—imatinib, dasatinib, and nilotinib—produce “amazingly similar” responses, treatment compliance becomes an important factor in patient outcomes, he noted.
“If you take 90% of your imatinib, your MMR [major molecular response] is 90%,” he said. “Your CMR [complete molecular response] is 40%. So taking drug obviously trumps the decision of what drug to take.”
Dr Radich added that the major goal of treatment is to keep patients out of accelerated-phase blast crisis. Once people progress to blast crisis on a TKI, the median survival is less than 1 year.
“So that’s why you treat people aggressively, that’s why you monitor them molecularly, to prevent that from happening,” he said.
Treatment goals
Aside from preventing patients from progressing to blast crisis, treatment goals vary.
Achieving early molecular response (MR) impacts progression and survival, as does achieving a complete cytogenetic response (CCyR).
A major molecular response (MMR) is considered a “safe haven,” Dr Radich said, because once people achieve it, they almost never progress if they stay on drug.
And with a deep/complete molecular response (CMR), patients may potentially discontinue the drug.
So how your response goals line up determines how you use the agents for your treatment course, Dr Radich said.
In all response categories—patients with CCyR, MMR, MR, CMR—survival is virtually within 95% of survival for the general population.
“This is absolutely astonishing,” Dr Radich said.
He emphasized the importance of molecular testing at 3 months and achieving a BCR-ABL level of less than 10%.
Patients who have more than 10% blasts at 3 months have an 88% chance of achieving MMR at 4 years, while those who still have more than 10% blasts at 6 months have a 3.3% chance of achieving MMR at 4 years.
Toxicity
Side effects common to the 3 frontline TKIs are myelosuppression, transaminase elevation, and change in electrolytes. Dr Radich noted that imatinib doesn’t cause much myelosuppression.
“You can give imatinib on day 28 after allogeneic transplant, and it doesn’t affect the counts, which I think is pretty darn good proof that it doesn’t have any primary hematopoietic toxicity,” he said. “You can’t try that trick with the others.”
Venous and arterial cardiovascular events with TKIs are more recently coming to light.
Cardiovascular events with imatinib are about the same as the general population, Dr Radich said.
“[In] fact, some people think it might be protective,” he noted.
Discontinuation
“When we first started treating people with these drugs, we figured that they would be on them for life . . . ,” Dr Radich said. “[Y]ou’d always have a reservoir of CML cells because you can’t extinguish all the stem cells.”
A mathematical model predicted it would take 30 to 40 years to wipe out all CML cells with a TKI. The cumulative cure rate after 15 years of treatment would be 14%. After 30 years, it would be 31%.
Conducting a discontinuation trial would have been out of the question based on these predictions.
“Fortunately, some of the people who did the next trials hadn’t read that literature,” Dr Radich said.
One discontinuation trial (EURO-SKI) included patients who had been on drug for at least 3 years and had CMR for at least 1 year. About half stayed in PCR negativity, now up to 4 years.
A number of trials are now underway evaluating the possibility of TKI discontinuation, and they are showing that between 40% and 50% of patients can remain off drug for years.
Using generic imatinib
While generic imatinib is good for cost-effective, long-term use, second-generation TKIs are better at preventing accelerated-phase blast crisis, Dr Radich said.
The second generation is also better at producing deep remissions, and discontinuation could bring with it a cost savings.
Dr Radich calculated that it cost about $2.5 million for every patient who achieves treatment-free remission using a TKI, while transplant cost $1.31 million per patient who achieves treatment-free remission.
So generic imatinib is good for low- and intermediate-risk patients, as well as for older, sicker patients.
Second-generation TKIs are appropriate for higher-risk patients until they achieve a CCyR or MMR, then they can switch to generic imatinib.
And second-generation TKIs should be used for younger patients in whom drug discontinuation is important.
Frontline treatment observations
In summary, Dr Radich made the following observations about frontline treatment in CML.
- For overall survival, imatinib is equivalent to second-generation TKIs.
- To achieve a deep MR, a second-generation TKI is better than imatinib.
- Discontinuation is equally successful with all TKIs.
- For lower-risk CML, imatinib is equivalent to second-generation TKIs.
- When it comes to progression and possibly high-risk CML, second-generation TKIs are better than imatinib.
- Second-generation TKIs produce more long-term toxicities than imatinib.
- There is substantial cost savings with generics.
