Long-Term Use of TKIs in Pediatric CML

An important difference between pediatric and adult CML is the potential duration of TKI therapy. The TKI era has resulted in substantial improvements in survival among all patients with CML.8  As a result, pediatric patients are likely to remain on life-long TKI therapy for decades, which raises additional considerations.

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Few studies of long-term TKI use have been published in the pediatric population. “Imatinib for pediatrics was approved in 2003 and although there were children who received imatinib for CML and Ph+ ALL before that, the experience we have is from no more than the last 20 years. We therefore have very limited data for long-term morbidity,” Dr Hijiya said.

Long-Term Adverse Effects

A known long-term effect of imatinib, and likely dasatinib, in children is growth abnormalities.1 Dr Hijiya said that “in the last 10 years we have started seeing children whose growth has slowed because of TKIs — that is pretty clear — but we do not know the exact mechanisms.” She noted that TKIs are known to have some off-target effects, which likely play a role in growth abnormalities.

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Children, especially those who start treatment during the prepubertal phase, demonstrate a lower expected final height as predicted by midparental height. Though there are some reports of using growth hormone or IGF-1 to help mitigate this issue, there are no large studies that have demonstrated the efficacy or safety of this approach. Dr Hijiya commented that these are “based on very few cases. I cannot say that we should apply that to all children who have growth retardation.”

TKIs are associated with cardiovascular toxicity and thyroid dysfunction among adults, but these have not been reported in children. “We have not seen any serious side effects with cardiovascular issues; however, our experience is limited to only the last 10 to 15 years, especially for the second generation TKIs. So, we need to continue monitoring those children,” Dr Hijiya said.

Once pediatric patients with CML reach adulthood, the issue of fertility becomes important as well. the effects of long-term TKI use on fertility remain largely unknown, highlighting the need for follow-up and more research on this issue.

Long-Term Quality of Life

“Usually patients with CML on TKIs have a pretty good quality of life, based on our observations. However, we are doing some studies to better evaluate quality of life,” Dr Hijiya said. She noted that patients who are intolerant with symptoms such as nausea and vomiting, now have the option to switch to another TKI.

Another potential issue with long-term TKI use is financial burden. Dr Hijiya noted that TKIs are expensive, though a generic form of imatinib is now available and may slightly reduce costs. “that is a substantial amount that you need to pay, especially if the child needs the TKI for 6 or 7 decades,” she said.