TKI Discontinuation Found to Benefit PROs in CML, Study Says

Results from a new clinical trial suggest that discontinuation of tyrosine kinase inhibitors (TKIs) is safe, feasible and is associated with improvements in patient-related outcomes (PROs) in chronic myeloid leukemia (CML).

Discontinuing the use of tyrosine kinase inhibitors (TKIs) is safe and feasible and tends to lead to an improvement in fatigue, diarrhea, and other side effects associated with using them in treatment of chronic myeloid leukemia (CML), according to results of a new clinical trial.

TKIs have improved the survival rates of patients by blocking production of the BCR-ABL protein, which results from a genetic swap known as the Philadelphia chromosome and causes CML cells to grow and divide out of control. TKIs have fewer adverse effects than previous treatments but are associated with fatigue, depression, sleep disturbances, and diarrhea.

The Life After Stopping TKIs (LAST; NCT02269267) study is the first conducted solely in the United States to evaluate patients with CML who achieve treatment-free remission (TFR) and report improvements of outcomes, according to a study published in JAMA Oncology. The study was a nonrandomized trial of 171 patients from 14 US academic medical centers over a 2-year period from 2014-2016, with a minimum follow-up of 3 years.

Study participants were adults with chronic-phase CML treated with 1 of 4 TKIs: imatinib (Gleebvec), dasatinib (Sprycel), nilotinib (Tasigna), or bosutinib (Bosulif).

The results showed that 112 patients remained in major molecular response (MMR), and 104 (60.8%) achieved TFR. Fifty-nine patients (34.5%) had molecular recurrence (MRec), and 67 (39.2%) restarted therapy.

Regarding adverse effects, of the 112 patients in TFR after 12 months, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 90 (80.4%) had improvement in fatigue, 39 (34.8%) showed improvement in diarrhea, and 24 (21.4%) showed improvement in sleep disturbance. There were 5 (4.5%) who reported reduced pain, but the result was not statistically or clinically significant, the study said.

Detectable BRC-ABL1 at the time of discontinuation, however, was associated with a higher risk of MRec. The authors recommended further study on the finding.

Although 60.8% remained in TFR after a 3-year follow-up, a higher percentage (65.5%) maintained MMR, the study said. That result is an indication that some patients restart TKI for other reasons than loss of MMR, including withdrawal syndrome and physician or patient anxiety.

Many patients with detectable BCR-ABL1 transcripts did not see disease progression. The authors said the reasons were unclear but suggested that positivity for BCR-ABL1 arises from memory B lymphocytes.

To the authors’ knowledge, the study was the first to include a comprehensive patient-reported outcome assessment and the first to use the rigorously developed National Institutes of Health PROMIS (Patient-Reported Outcomes Measurement Information System) measures. Previous reports have shown similar patient outcomes.

The authors said they did not conduct a randomized trial primarily because of concerns about patient compliance. Patients who enrolled because they wanted to stop therapy would have little incentive to take their (blinded) pill since their blood was being monitored frequently and they knew they would be restarted on TKI if necessary.

Reference

Atallah E, Schiffer CA, Radich JP, et al. Assessment of outcomes after stopping tyrosine kinase inhibitors among patients with chronic myeloid leukemia: A nonrandomized clinical trial. JAMA Oncol. 2021;7(1):42–50. Published online November 12, 2020. doi:10.1001/jamaoncol.2020.5774