The second part of the study sought to find a biological mechanism for these differences in fatigue. Muscle biopsies were performed on all participants and were subject to tests for mitochondrial density and function. Investigators found no difference between patients with CML and controls, nor differences between patients with CML with muscle complaints compared with those without.

“It is important that people are paying attention to patient-reported side effects now. Since we know how well these drugs work, it’s increasingly important to make [the drugs] more tolerable for people who have to take them [on a] lifelong [basis],” said Professor Richard Larson, MD, director of the Hematologic Malignancies Clinical Research Program at The University of Chicago, Illinois.

However, one caveat of the work was that patients who could not complete the exercise tasks were excluded from the study.

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“Patients with extreme muscle complaints were not included, and therefore, the differences in muscle function found in this study might be underestimated,” said Dr Janssen, noting that the study was representative of the majority of CML patients with muscle complaints and that extreme cases are rare.

“The study is interesting, but not definitive — certainly myalgias and fatigue have been noted in all of the clinical trials for CML. They tend to be low grade, but they may persist for a long time and may lead to discontinuation of the initial TKI and [a] switch to another drug to try and combat this,” said Dr Larson.

So, if the findings of this study are indeed representative of CML patients on TKIs and disruptions in mitochondrial function are not responsible for muscle complaints and fatigue, what would the next step of investigation be?

“The differences in muscle contraction and muscle relaxation in fatigued muscles between patients with and without muscle complaints might point into the direction of a disturbance in calcium homeostasis,” speculated Dr Janssen.

Giving patients calcium supplements to treat muscle symptoms has been discussed in the scientific literature,5 but this theory has paltry scientific evidence to back it up.

“Calcium supplementation may relieve symptoms in some patients. However, randomized controlled trials on the effects of calcium supplementation on muscle complaints are completely lacking,” said Dr Janssen.

References

  1. American Cancer Society. Survival rates for chronic myeloid leukemia. Updated June 19, 2018. Accessed April 18, 2019.
  2. Caldemeyer L, Dugan M, Edwards J, Akard L. Long-term side effects of tyrosine kinase inhibitors in chronic myeloid leukemiaCurr Hematol Malig Rep. 2016;11(2):71-79.
  3. Kekäle M, Peltoniemi M, Airaksinen M. Patient-reported adverse drug reactions and their influence on adherence and quality of life of chronic myeloid leukemia patients on per oral tyrosine kinase inhibitor treatmentPatient Prefer and Adherence. 2015;9:1733-1740.
  4. Janssen L, Frambach SJCM, Allard NAE, et al. Skeletal muscle toxicity associated with tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia [published online March 14, 2019]. Leukemia. doi: 10.1038/s41375-019-0443-7
  5. DeAngelo DJ. Managing chronic myeloid leukemia patients intolerant to tyrosine kinase inhibitor therapyBlood Cancer J. 2012;2(10):e95.