When it comes to the treatment of chronic myeloid leukemia (CML), one type of therapy has taken center stage: tyrosine kinase inhibitors (TKIs).
CML occurs because of a type of genetic mutation known as a chromosomal translocation, in which parts of two chromosomes switch places; in this case, the translocation takes place in chromosomes 22 and 9, forming what is known as the Philadelphia chromosome. This mutation gives rise to the BCR-ABL “fusion” gene, which produces the BCR-ABL fusion protein. The result is that tyrosine kinase (enzymatic) activity goes into overdrive, causing CML.
TKIs work because they tamp down that overactivity. Once started, these drugs are given indefinitely. Now, experts are exploring whether TKIs can be stopped in CML patients without the risk of cancer returning, since the long-term administration of the drugs can result in a range of adverse events and financial burdens.
Gleevec (imatinib) was the first TKI, and may soon be available in generic form, as its patent expired in July 2015. Meanwhile, there are two other TKIs approved by the U.S. Food and Drug Administration for the first-line treatment of CML (Sprycel [dasatinib] and Tasigna [nilotinib]), and three unique therapies approved for use if resistance to the first-line treatments develops (Synribo [omacetaxine mepesuccinate], Iclusig [ponatinib] and Bosulif [bosutinib]). More such drugs are in the investigational stage.
Experts continue to debate which of the first-line drugs should be favored, as Gleevec tends to be less expensive but the newer agents more effective.
At the same time, they’re considering the larger mystery of whether TKIs, once started in CML patients, can ever be stopped. It’s an important question, since America doesn’t have unlimited resources, says Elias J. Jabbour, associate professor in the Department of Leukemia at MD Anderson Cancer Center, in Houston, Texas.
“For hypertension, we prescribe beta blockers forever and nobody complains of that,” he says. “In CML, we’re pressured by the patient, by the society, by the financial world to stop therapy.”
Experts agree that, in most cases, there isn’t enough evidence yet to support patients and their doctors ever halting TKI treatments for CML. But clinical trials are in progress to test whether CML patients who have gone into remission on TKIs can stop the drugs without their cancer returning.
Some evidence is already in. The STIM1 and STIM2 trials explored the discontinuation of Gleevec in patients with CML who had experienced a sustained molecular response for more than two consecutive years. In a median 12-month follow-up, researchers found that a molecular relapse occurred in 39 percent of patients following the cessation of therapy.
However, at that point, patients were able to achieve a complete molecular remission when put back on a TKI.
More data is in the offing.
The DESTINY trial (NCT01804985), which is enrolling in the U.K., will include patients with CML who have had an excellent response to Gleevec, Tasigna or Sprycel, cutting their standard dose by half for 12 months and then stopping treatment entirely for an additional two years.
The LAST study (NCT02269267), run by the Medical College of Wisconsin at numerous sites around the United States, will assess molecular recurrence and patient-reported health status in CML patients after they stop TKI treatment, with the goal of improving decision-making by patients and their doctors who are weighing a potential halt to such therapy. A similar trial is in progress in Europe, and one is enrolling in Malaysia.
A caveat about the trials is that the number of patients enrolled is still small, meaning that the outcomes of the trial populations are not necessarily widely representative of the responses CML patients will have, said B. Douglas Smith, an oncologist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. On the other hand, there is an as-yet unproven suggestion from previous studies that long-term TKI treatment may contribute to secondary cancers down the line, so avoiding lifelong treatment with TKIs may be a worthwhile idea, especially in younger patients, countered Neil Shah, leader of the Hematopoietic Malignancies Program at the University of California, San Francisco’s Helen Diller Family Comprehensive Cancer Center.
One thing is for sure, experts say: Patients who join these trials must be willing to cooperate with vigilant monitoring to make sure their disease has not returned, since that would necessitate the swift re-initiation of therapy.
Oncologist Stuart L. Goldberg, of John Theurer Cancer Center in New Jersey, would feel comfortable trying treatment cessation with 60 to 70 percent of his CML patients who’ve been in long-term remission due to ongoing treatment with Gleevec. But among his patients on newer TKIs, who have entered remission more recently, he would consider a smaller percentage eligible for such a move.
Whether the patients themselves would be willing to entertain the idea is a different matter. Goldberg estimates that only about half his CML patients would be willing to take that risk.
Furthermore, evidence from the STIM trials shows that only about 20 percent of patients with CML can be cured without the need for ongoing therapy, Jabbour notes. The sticking point is that it’s not yet possible to determine, at the outset of treatment, who those patients are. As a result, the doctor remains skeptical about the idea of stopping TKIs in patients with this disease.
Researchers are looking for biomarkers that may make such distinctions easier.
In the STIM trials, the numbers of natural killer (NK) cells being produced by patients’ immune systems were assessed at the time of treatment discontinuation. In general, patients with sufficient levels of functional NK cells were less likely to relapse when compared with patients who had low levels of NK cells, and dysfunctional cells. These results suggest that NK cell-related immunity may contribute to CML control after TKI cessation.
However, more research is needed to discover whether NK cells can be used as a biomarker to predict relapse.
In select circumstances, patients — typically women wishing to become pregnant — may request that treatment be stopped. If treatment is stopped, these patients should try to conceive as quickly as possible while being monitored closely for relapse, experts say. Additionally, treatment with interferon alfa can be utilized, although it is uncommon. “What I would probably recommend in a person who is determined to stop taking the drug is very close monitoring [and] a recommendation that they see a fertility doctor so that they aren’t spending three, six, nine or 12 months trying to get pregnant,” advises Rafael Bejar, assistant professor of medicine at UC San Diego Health. For male patients, Jabbour adds, there is no need to stop treatment with TKIs while trying to conceive.