Expert Explains State of TKI Treatment in Pediatric CML

Nobuko Hijiya, MD

Discontinuation of tyrosine kinase inhibitor (TKI) treatment may be a possibility for children with chronic myeloid leukemia (CML) and, because they could be on-treatment for decades, treatment-free remission is even more important for pediatric patients than for adults, Nobuko Hijiya, MD, told her audience at the 2018 American Society of Pediatric Hematology/Oncology Conference.

Hijiya, professor of pediatrics at Northwestern University's Feinberg School of Medicine, presented an overview of current questions in pediatric CML. She said the Children’s Oncology Group is planning a study in children, but results from previous studies in adults have shown that discontinuation is feasible. In those trials, which had different criteria to define eligibility for discontinuation and used a variety of TKIs, the treatment-free remission rate ranged from 40% to 60%.

“That means patients in deep sustained molecular remission could stay in molecular remission without TKI treatment,” she said. “The rest of the patients who had molecular relapse were reintroduced to TKIs and most of those patients did go back to molecular remission.”

She noted that children have a much longer life expectancy and may made need multiple decades of treatment, so treatment-free remission could be of vital importance. Physicians already know that TKIs are associated with adverse events, such as diarrhea, nausea, vomiting, and rash. Children being treated for decades could also experience long-term endocrine, hematological, cardiovascular, pulmonary, and/or metabolic toxicities.

“We have had only 15 to 20 years of experience with TKIs—we don’t know much about long-term morbidities,” Hijiya said. “There is still a possibility that those long-term side effects occur after many decades. Children may need 60 or 70 years of treatment if we do not stop TKI [treatment].

“Children are growing. More and more data are coming to show growth disturbance in children. Of course, adults don’t grow anymore, so we didn’t know until now, but in children it’s clear their growth becomes delayed because of TKI treatment.”

The German CML Study IV investigated adverse drug reactions in adults who received imatinib (Gleevec) for more than 10 years. The side effects plateaued after a few years, but Hijiya noted that results may be different for second-generation TKIs.

“Also, there are side effects like endocrine or cardiovascular which may have a cumulative effect, so we need to continue monitoring the patients,” she added.

Hijiya said that the current data only includes adults and does not support discontinuation in children—continuing TKI treatment indefinitely is the current standard of care for children who present with chronic-phase CML and do not progress, and should only be done in the context of a clinical trial.

In the past, hematopoietic stem cell transplant (HSCT) was the only curative option for patients with CML, but with 3 FDA-approved agents in imatinib, dasatinib (Sprycel), and nilotinib (Tasigna), physicians can choose the TKI most likely to induce remission. Hijiya said all 3 are effective and factors such as toxicity or compliance can direct physicians to the ideal treatment.

BCR-ABL kinase domain mutation analysis can drive some of the decision-making. Hijiya said that if, for instance, a patient develops an F359V mutation while on imatinib or nilotinib, results from in vitro studies suggest that the patient should switch to dasatinib. If a patient develops T315I mutation, the physicians can consider switching to ponatinib (Iclusig), which is approved for adults with CML, or a non-TKI like omacetaxine mepesuccinate (Synribo).

“For patients who are resistant or intolerant, in addition to the toxicity profiles, we need to think about compliance,” Hijiya said, adding that patients may find it easier to adhere to regimens that require less-frequent dosing. “Compliance is the biggest issue in terms of patients who are refractory.”

Is There Still a Role for HSCT?

Cost of treatment is also a consideration when choosing a TKI. While some patients may be able to discontinue TKIs, others may be on-treatment for decades and “the cumulative cost could be substantial.” Only imatinib is available as a generic drug and while that might change in the future, Hijiya said cost of care is something physicians should keep in mind when choosing a TKI.The rise of TKIs has led to a reduction in the use of HSCT in this patient population, in part because TKIs are associated with fewer early complications. Furthermore, patients can achieve remission with a second TKI after failing on a first course of treatment and, as stated previously, evidence in adult patients suggests that children may be able to eventually discontinue TKIs.

However, there is a subset of patients who can benefit from HSCT and Hijiya said physicians need more data to identify that population.

Patients with a T315I mutation can achieve molecular response with ponatinib. However, that drug is associated with increased risk for cardiovascular events and requires further study in children.

“I would start looking for a donor if not transplant the patient immediately,” Hijiya said.

If a patient is resistant to 2 or more TKIs or develops unacceptable intolerance or side effects to TKI treatment, then transplant might be appropriate, she said. Transplantation is indicated for patients who present with advanced CML, or who present with chronic phase and progress to accelerated phase or blast crisis. That said, there is a subset of children who stay in molecular remission without transplant, and Hijiya said the question of which patients with pediatric CML should undergo HSCT remains unsettled.

“There is no clear consensus,” she said. “We don’t have enough data to know which patients will benefit from transplant, so we do need more data.”

Hijiya, N. Pediatric CML: a unique disease that requires a different approach. Presented at: the 2018 ASPHO Conference; Man 2-5, 2018; Pittsburgh, PA.

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