Tyrosine kinase inhibitors lead to ‘dramatic’ improvements in CML

The development of tyrosine kinase inhibitors for chronic myeloid leukemia, including imatinib, was spurred by an increased understanding of the disease’s genetics. Together, these advances have “dramatically” improved outcomes for patients with CML, according to Gabriela S. Hobbs, MD, of Massachusetts General Hospital.

“The approval of imatinib (Gleevec, Novartis) was one of the most important changes in the way we treat cancer,” Hobbs told HemOnc Today. “It really was a watershed moment in oncology. It changed more than the way we think about CML and the way we treat CML – it changed our approach to many other cancers. It demonstrated that, if you understand the genetics of a disease, you can target it with therapies that are specific for those genetic mutations.”

Gabriela S. Hobbs

Determining biology of CML leads to development of TKIs

Clinicians have “a very clear understanding” of the molecular biology of CML, according to Hobbs. This knowledge has made diagnosing the disease easier, facilitated the development of novel therapies and allowed clinicians to monitor the disease very accurately, by monitoring BCR-ABL1 transcript levels. The presence of the BCR-ABL1 protein is the most important marker to consider in regard to the genetics of CML, Hobbs told HemOnc Today.

“Understanding the genetics of CML allowed for the development of therapies,” she said. “TKIs block the activity of BCR-ABL1 and are very powerful and effective.”

A recent study in the Journal of Clinical Oncology demonstrates that the use of TKIs with allogeneic stem cell transplantation has extended the life expectancy of patients with CML to approach that of general population. On average, a man diagnosed with CML at age 55 years would have had 3.5 (95% CI, 2.9-4.1) years of life remaining if he was diagnosed in 1980, compared with 27.3 (95% CI, 25.7-28.8) years if he was diagnosed in 2010. For a man aged 85 years at diagnosis, the life years remaining increased from 0.8 (95% CI, 0.7-1.1) in 1980 to 4.1 (95% CI, 3.4-4.7) in 2010. The life expectancy in 2010 for men and women with CML was within 3 years of the expectancy of the general public in all age categories.

Despite these advantages, TKIs are associated with “a lot of side effects,” Hobbs told HemOnc Today. Some of the most common side effects of dasatinib include headaches, muscle aches, leg swelling, and pleural effusions; gastrointestinal issues, worsening of peripheral vascular disease and rashes are possible with nilotinib, but less likely.

Strategies to lessen these side effects include dose reduction and switching from one TKI to another. Discontinuation of therapy is also being explored and appears promising, according to Hobbs.

“There is a lot of research looking at patients who have been on TKIs for several years and are in a very deep remission,” she said. “Some patients have also been enrolled in discontinuation studies that have demonstrated encouraging results, where 40% to 50% of patients are able to remain off of TKIs for more than 2 years. Some patients have been followed for over 60 months and still haven’t relapsed.”

Recent research demonstrates that discontinuation of therapy – and restarting treatment with the same agent – is feasible with nilotinib (Tasigna, Novartis), dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka) and imatinib. The majority of patients in the single-arm, phase 2 ENESTfreedom study achieved treatment-free remission after relatively short exposure to frontline nilotinib, and almost every patient who required treatment re-initiation again achieved major molecular response. In a separate phase 2 study, patients with CML who achieved a sustained deep molecular response for more than 1 year were able to safely discontinue second-line or maintenance dasatinib treatment, and rapid molecular responses were observed among all patients who re-initiated treatment following relapse.

“There is a group of patients who we are starting to consider for discontinuation of TKIs,” Hobbs said. “It’s not quite standard of care yet, but it will become standard of care in the near future.” – by Julia Ernst, MS

References:

Bower H, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.66.2866.

Breccia M and Alimena G. Lancet Haematol. 2015;doi:10.1016/S2352-3026(15)00130-1.

Hochhaus A, et al. Abstract 7001. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Jain P, et al. Lancet Haematol. 2015;doi:10.1016/S2352-3026(15)00127-1.

Ross DM. Lancet Haematol. 2015;doi:10.1016/S2352-3026(15)00199-4.

Disclosures: Hobbs reports no relevant financial disclosures.