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Addressing Off-Target Effects of TKIs in Pediatric CML

Angelica Welch
Published: Monday, Dec 10, 2018

blood cellsIn early 2018, the tyrosine kinase inhibitor (TKI) nilotinib (Tasigna) joined imatinib (Gleevec) and dasatinib (Sprycel) as a treatment for pediatric patients with chronic myeloid leukemia (CML).

TKIs are currently the go-to treatment for these patients, as they are known to have a survival benefit, explained Briana Patterson, MD. However, there have been some concerns on the impact of TKI therapy on the endocrine systems of growing children. These off-target effects can stunt growth and may impact the reproductive system, she explained.

In an interview with OncLive, Patterson, an assistant professor in the Division of Endocrinology, Aflac Cancer Center, Department of Pediatrics, Emory University School of Medicine, discussed the off-target effects of TKIs in pediatric patients with CML.

OncLive: What is the prevalence of TKI use in children? 

Patterson: Since the early 2000s when TKIs were first approved for pediatrics, imatinib has been used extensively in pediatric CML. Within the last year, dasatinib and nilotinib have been approved for pediatric use in CML. Those are considered first-line agents for chronic-phase CML in children now. For children who have more acute presentations, or other treatment considerations, whether they should receive a TKI or undergo transplant is a question for the oncologist. For children who present with chronic-phase CML, a first- or second-generation TKI will be the drug of choice.

What is the concern with endocrine effects of TKIs in children?

Everyone became interested in this quite a few years ago. Imatinib was initially released to treat adults with CML, and was later approved to treat pediatric patients with CML. That drastically changed the way that we approach children with CML, and it greatly improved survival. However, as a class, TKIs have a lot of off-target effects.

Therefore, the goal of the drug is to interact with this particular receptor target to address the CML, but there are many other TKI-associated receptor systems within the body—particularly the endocrine system. These types of drugs can interact with them. All of the TKI drugs interact with those receptors to some extent; however, each specific agent has a somewhat unique profile and different [mechanism of] action.

How can TKIs affect pediatric patients in the long-term?

Pediatric patients with CML are very different than adult patients with CML, predominantly because they are still growing. More or less, across the board with TKIs in children, we do see decreased linear growth velocity; therefore, children become shorter than their peers, which is a concern. Likewise, it can impact things like thyroid function, which is also important in children for growth, metabolism, and cognition. It can also affect things such as glucose metabolism. 

A unique concern in pediatrics is that there is very little known about the impact of TKIs on reproductive health. That is less of an issue if you are talking about the typical geriatric-aged CML population. However, if you are talking about young children, their future reproductive potential needs to be understood; this will be a source of concern for the parents, and ultimately, the patients.

What is important for oncologists to understand when treating pediatric patients with TKIs?

The main message would be to monitor their growth, consider referral to an endocrinologist if they see problems, and keep an eye on things that are modifiable. We know that TKIs affect a variety of aspects of bone health and bone metabolism, and it can cause phosphatemia. Keep an eye on calcium levels, phosphate levels, and vitamin D levels, since you can modify those and keep them normal when the patient is on the therapy. Also, just monitor for any other subtle endocrine changes in respect to thyroid or glucose metabolism. 

Moving forward, what other challenges would you like to see addressed?

Certainly, one of the things that needs to be addressed going forward is the impact on reproductive health, and trying to understand what the agent-specific effects of each TKI are in terms of endocrine toxicities. We know that not all these drugs are exactly the same; they interact with different TKI receptors in different ways, so we would like to know exactly what drugs do what. 



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