Likely Determinants of Successful TKI Treatment Stoppage Identified in CML

Tyrosine kinase inhibitor (TKI) therapy enables patients with chronic myeloid leukemia (CML) to reach life expectancies equivalent to the general population and treatment-free remission (TFR), but QOL can deteriorate with treatment. A recent review set out to uncover factors likely to keep patients in TFR following TKI discontinuation, and the results appeared in World Journal of Clinical Oncology.

With long-term TKI treatment having such serious adverse effects (AEs) as neutropenia, thrombocytopenia, anemia, hepatic toxicity, cerebrovascular arterial events, and pleural effusion, the investigators also wanted to be able to better predict which patients could safely discontinue treatment after achieving TFR.

According to the authors, having a low Sokal score, long-term (4-plus years) treatment with TKIs, and duration and depth of molecular response (MR) influence the likelihood of ongoing TFR, according to data from the TWISTER, STIM1, and EURO-SKI studies.

For example, in TWISTER, 51% of patients with a low SOKAL score achieved TFR. And in STIM1 and EURO-SKI, a higher likelihood of TFR was seen in patients on TKI therapy for more than 4.5 years and those who reached MR in at least 1 year and were on TKIs for longer than 5.8 years, respectively. In addition, results from the STAT2 trial out of Japan show a significantly higher rate of TFR with 3-year TKI use among patients with undetectable molecular residual disease compared with those without: 76.6% vs 48.6%.

To be able to safely discontinue treatment, better selection of patients likely to have ongoing survival is vital. For that, consensus on the clinical criteria patients should meet is necessary, the authors stated. However, at present, “there is still no European or international consensus regarding what criteria are important for selecting patients for a discontinuation attempt,” they noted.

They believe biomarkers for patients who achieve TFR vs those with disease relapse could better predict successful discontinuation of TKI treatment and ongoing remission, in addition to defining safer discontinuation attempts. Potential biomarkers include levels of natural killer cells and CD3+, CD8+, and CD62L+ T cells, based on study results showing TFR was more likely to continue the higher these cell levels.

“The identification of predictive factors for TFR in CML will inform the clinic on the best candidates to include in future discontinuation attempts and will help define criteria for safer discontinuation attempts with a greater probability of success,” the authors concluded. “Moreover, it would potentially give more patients a chance at stopping TKI treatment.”

They also highlight prospective cost savings from not having to treat ongoing AEs from TKI treatment, such as hepatic toxicity or cardiovascular comorbidities. At present, TKI treatment can reach well into 5 figures.

Areas to concentrate on going forward include determining the molecular factors associated with TFR, investigating the safety of a second discontinuation attempt if there is disease progression after a first attempt, and the patient perspective on QOL. This last factor is especially important, the authors note, because of the increased need for testing and molecular monitoring in the initial years of treatment stoppage.

Reference

Stuckey R, López-Ródriguez JF, Sánchez-Sosa S, et al. Predictive indicators of successful tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia. World J Clin Oncol. 2020;11(12):996-1007. doi:10.5306/wjco.v11.i12.996