A study led by NewYork-Presbyterian and Columbia oncologist shows that nilotinib, a second-generation tyrosine kinase inhibitor (TKI), is safe and effective for long-term use in children with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP). Although growth delays, a common TKI side effect, were apparent in the longer-term analysis, children on nilotinib did not experience the serious cardiovascular and blood glucose events that affect some adults on these agents. This five-year phase 2 DIALOG study is the longest follow-up study of pediatric patients with CML receiving treatment with a TKI.
“As we expected, patients on the drug in the longer follow-up continue to do well in terms of disease control,” says lead study author Nobuko Hijiya, MD, a pediatric oncologist at NewYork-Presbyterian and Columbia and section head of Pediatric Oncology at Columbia. “By taking nilotinib or other TKIs that have been approved, these children can have a pretty normal quality of life, which is wonderful.”
As we expected, patients on the drug in the longer follow-up continue to do well in terms of disease control. By taking nilotinib or other TKIs that have been approved, these children can have a pretty normal quality of life, which is wonderful.
— Dr. Nobuko Hijiya
More TKIs for pediatric patients
The introduction of TKIs revolutionized the treatment of CML in children. But not every patient can benefit from previously approved therapies, including imatinib and dasatinib, and some children become resistant to them. Imatinib, a first-generation therapy, failed more than a quarter of pediatric patients in one phase 3 trial.
Nilotinib represents a new weapon in the armamentarium. Bosutinib, another potent second-generation TKI, was approved in late 2023. “Before nilotinib, two TKIs were approved in children—imatinib, a first generation TKI approved 20 years ago, and dasatinib, the first second generation TKI,” says Dr. Hijiya. “If someone did not respond to imatinib, there was only dasatinib, which was not yet approved. Now there are four drugs that are approved by FDA for children with CML. So, there are multiple options not only for response to treatment, but if someone cannot tolerate one drug, there is a possibility that we can switch it to another.”
Tailoring treatment to patients
Because pediatric patients need the treatment for CML potentially for decades, side effects are a major concern. “Patients with CML need to take medicine for a long time in general,” says Dr. Hijiya. “All the conventional treatments for CML so far have been shown to cause a growth delay in children, which means they become shorter than they are supposed to be. Unfortunately, this study confirmed that this long-term side effect does occur with nilotinib.”
But nilotinib may have some advantages over other TKIs. “The drugs all have different toxicity profiles,” says Dr. Hijiya. “Nilotinib has less musculoskeletal side effects such as bone and muscle pain compared to imatinib, and also less gastrointestinal toxicities compared to bosutinib.”
However, there are some practical concerns. “Nilotinib needs to be taken twice daily, which is different from the other TKIs that are all once daily,” says Dr. Hijiya. “Also, nilotinib needs to be taken on an empty stomach, which is not easy, especially for young children.”
Picking a treatment for newly diagnosed patients requires consideration of side effects and quality of life. “Some doctors say starting with imatinib is fine, but others think second-generation TKIs are more potent and that may result in a deep molecular remission more quickly,” says Dr. Hijiya.
Now there are four drugs that are approved by FDA for children. So, there are multiple options not only for response to treatment, but if someone cannot tolerate one drug, there is a possibility that we can switch it to another.
— Dr. Nobuko Hijiya
In adults, Dr. Hijiya says, oncologists prefer to start with imatinib, especially for older patients with comorbidities like cardiovascular issues, because subsequent generations of TKIs may cause more issues. However, children on nilotinib avoided that cardiovascular toxicity observed in adult patients.
Study specifics
In the study, 58 patients were treated—33 were resistant to or unable to tolerate prior TKIs; 25 were newly diagnosed. Most of the patients were male and the median age was 13. At the end of the study, the cumulative major molecular response (MMR) rate in patients who were resistant or intolerant to older TKIs was 60%. Among newly diagnosed patients, the best overall MMR rate was 76%. Three of these patients had a loss of MMR.
The overall safety profile of the drug was consistent with earlier research. And as with earlier research, patients in both cohorts experienced growth deceleration over time.
No significant mutations emerged among the patients. “The incidence of mutation was not very high,” says Dr. Hijiya. “And if it occurs, we can use a different TKI for some patients and overcome the mutation.”
Dr. Hijiya credits NewYork-Presbyterian and Columbia for the ability to conduct such groundbreaking research. “There’s a great structure and support for research here, not just clinical research but also basic research,” she says.
Dr. Hijiya has led several other key trials in children with CML. In addition to research underpinning the recent approval of bosutinib by FDA, she has an active study of treatment-free remission in the Children’s Oncology Group.
The approach to treatment-free remission is standard of care in adults taking TKIs. “After a certain period of time they remain in deep molecular remission, and then they stop the TKI,” Dr. Hijiya says. “In half of the patients, the disease comes back, but the other half stays in deep molecular remission without treatment, which is pretty amazing. The pediatric trial is still on-going, and we don’t have the results yet, but that’s what we’re aiming for.”
