Despite their effectiveness, TKIs are associated with certain adverse events. Children treated with imatinib and dasatinib have reported “substantial growth abnormalities,” with prepubertal children evidencing more significant effects.6
TKIs are also associated with vascular toxicity in older patients. Similar adverse effects have not been found with pediatric patients, said Nobuko Hijiya, MD, professor of pediatrics (hematology, oncology, and stem cell transplantation) at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois. It may, however, be too early to tell.
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“It’s rare for kids to have arteriosclerosis or any other vascular issues,” she said. “If a child with CML needs to continue TKI for 30 or 40 years, which is possible, then we don’t know what’s going to happen because TKIs have been here for less than 20 years.”
In November, 2 groups of researchers simultaneously reported that studies using human cell lines and mouse models showed that CML stem cells die when EZH2 is inhibited.7,8 Stuart Orkin, MD, professor of pediatrics at Harvard Medical School in Cambridge, Massachusetts, said the findings offer the promise of completely eradicating CML relatively quickly when used in combination with TKIs.
EZH2 inhibitors could therefore shorten the duration of targeted therapy and achieve a cure. The drugs are already in clinical trials with lymphoma and some genetically defined solid tumors, including rhabdoid tumors in pediatric patients.
Dr Orkin noted, however, that conducting similar trials with CML patients poses a dilemma. “I think because patients do quite well on the TKI inhibitors and have to be maintained on them, the question is an ethical one,” he said. “At what point can you introduce an unknown drug, a drug with the unknown potential for side effects, especially in combination with TKIs, in patients who have a good prognosis?”
But the growing number of patients with TKI-resistant disease, or those who suffer complications from targeted therapy, may encourage investigators to seek other solutions.
RELATED: Chronic Myeloid Leukemia: Persistent Efficacy With Imatinib
“Due to increased patient survival,” the authors of 1 of the 2 studies wrote, “CML will become the most prevalent form of leukemia in the next 20 to 30 years with TKI-persistent LSCs [leukemic stem cells] remaining a significant unmet clinical need for the majority of these patients.”
References
- Shima H, Kiyokawa N, Miharu M, et al. Flow cytometric analysis as an additional predictive tool of treatment response in children with chronic-phase chronic myeloid leukemia treated with imatinib. Pediatr Blood Cancer. 2017 Feb 24. doi: 10.1002/pbc.26478 [Epub ahead of print]
- Hijiya N, Schultz KR, Metzler M, Millot F, Suttorp M. Pediatric chronic myeloid leukemia is a unique disease that requires a different approach. Blood. 2016;127(4):392-9.
- Ries LAG, Smith M, Gurney JG, et al, eds. Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. In: National Cancer Institute, vol. 99. Bethesda, MD: SEER Program; 1999:46-9.
- Gugliotta G, Castagnetti F, Apolinari M, et al. First-line treatment of newly diagnosed elderly patients with chronic myeloid leukemia: current and emerging strategies. Drugs. 2014;74(6):627-43. doi: 10.1007/s40265-014-0207-7
- Henig I, Zuckerman T. Hematopoietic stem cell transplantation-50 years of evolution and future perspectives. Rambam Maimonides Med J. 2014;5(4):e0028. doi: 10.5041/RMMJ.10162
- Hobernicht SL, Schweiger B, Zeitler P, Wang M, Hunger SP. Acquired growth hormone deficiency in a girl with chronic myelogenous leukemia treated with tyrosine kinase inhibitor therapy. Pediatr Blood Cancer. 2011;56(4):671-3.
- Scott M, Korfi K, Saffrey P, et al. Epigenetic reprogramming sensitizes CML stem cells to combined EZH2 and tyrosine kinase inhibition. Cancer Discov. 2016;6(11):1248-57.
- Xie H, Peng C, Huang J, et al. Chronic myelogenous leukemia–initiating cells require polycomb group protein EZH2. Cancer Discov. 2016;6(11):1237-47.
