FDA Approval of Bosulif Adds to Toolkit of Treatment Options for Children With CML

The Food and Drug Administration (FDA) has approved Bosulif (bosutinib) for the treatment of children as young as 1 year old with newly diagnosed or resistant/intolerant to prior therapy chronic phase Philadelphia (Ph)-positive chronic myelogenous leukemia (CML).

This approval marks a significant addition to the toolkit of treatment options for patients with pediatric CML, as Dr. Mallorie B. Heneghan told CURE.

“There are lots of tyrosine kinase inhibitors (TKIs) that are approved in adults that aren't approved in pediatrics, and while pediatric CML is rare, it certainly affects pediatric patients with CML,” said Heneghan, an assistant professor of pediatrics at the University of Utah and in the division of pediatric hematology/oncology at Primary Children´s Medical Center. “And (pediatric patients) develop CML, obviously, at a younger age, and so they have a long life ahead of them with good treatment.

“And so, what I've seen in my patients is that not every patient responds to frontline therapy, and so it's really important that we have options for patients because we expect they're going to be on tyrosine kinase inhibitors for a long time. And so, having Bosulif in our toolkit — either for patients (where) we can use that up front, and it has a different toxicity side effect profile, or for patients that aren't responding to other frontline TKIs — to get them into those deep molecular remissions and get them really good disease control, I think, is really important.”

The FDA’s approval of Bosulif, announced in late September, was based on findings from the BCHILD trial, a phase 1/2 study indented to identify a recommended once-daily oral dosage of Bosulif, as well as its safety, tolerability and efficacy, for patients with newly diagnosed chronic phase Ph+ CML (ND CML) and pediatric patients with Ph+ CML who have received at least one prior TKI (R/I CML).

Bosulif was initially approved by the FDA for the treatment of adult patients with Ph+ CML who have resistance or intolerance to prior therapy in September 2012, and as a first-line treatment for patients with Ph+ CML in December 2017.

Heneghan explained why it then took more than a decade after its first approval for Bosluif to be subsequently approved by the FDA for the treatment of children.

“The reason that that takes so long is we're fortunate that CML is not that common in pediatrics. I don't want more children getting CML. But what that does mean is that that process is really slow to gather enough data, and it really takes, like (in) this (trial), international consortiums and working together internationally to get that data to garner enough support for FDA approval. And so that's hard. And so that's another reason this this is exciting; we need options for rare diseases in pediatric cancer in general, and so it's nice to see more attention paid to that and the FDA thinking about that.”

According to its listing on clinicaltrials.gov, the BCHILD trial began in April 2020 and is expected to be completed in December 2023.

Findings from the study, published in the Journal of Clinical Oncology, stated that Bosulif “was well-tolerated, despite common grade 1 to 2 gastrointestinal (side effects). The preliminary efficacy seems comparable to published data from other second generation TKIs in children and to (newly diagnosed) adult patients treated with bosutinib.”

According to the FDA, the recommended dose of Bosulif for pediatric patients with newly diagnosed, chronic phase Ph+ CML is 300 mg/m2 orally once daily with food. The agency stated that the recommended dosage for pediatric patients with resistant/intolerant, chronic phase, Ph+ CML is 400 mg/m2 orally once daily with food. When treating patients who are unable to swallow capsules, the capsules can be mixed with applesauce or yogurt, the FDA noted.

The FDA has also approved a new capsule dosage of Bosulif, available in 50-milligram and 100-milligram strengths.

The major cytogenic response (where 35% of fewer of the cells in the bone marrow have the Philadelphia chromosome) was 76.2% and complete cytogenic response (less than 1% of the cells in the bone marrow have the Philadelphia chromosome) was 71.4% among newly diagnosed participants in the trial. At a median duration of follow-up of 14.2 months, the major molecular response was 28.6%.

Major and complete cytogenic responses were 82.1% and 78.6%, respectively, with a major molecular response of 50%, among patients with resistant or intolerant disease, with the FDA noting that two of the 14 patients who had a major molecular response lost their responses at 13.6 and 24.7 months.

Explaining the science behind TKIs such as Bosulif, Heneghan said “I always kind of think of it as, in CML, it's like a light switch, and the light switch got mismatched in that instead of your light switch being programmed to turn on your light, your light switch turns on your blender and so now your blender is on all the time. And that's CML cell growth, and so that growth is just out of control growing in cells that normally you want them to grow sometimes and stop, but now they're growing out of control.

“And so, when I think of a tyrosine kinase inhibitor, … is that it turned that light switch back off for you, it stopped the blender from always being on and kind of cut that switch for you. That's now telling the CML cells that they shouldn't just keep growing out of control.”

The most common side effects of Bosulif, observed in at least 20% of patients, included diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic (liver) dysfunction, headache, pyrexia (fever), decreased appetite and constipation.

“There are a couple of tyrosine kinase inhibitors that are approved in this space already,” Heneghan said. “There's imatinib (Gleevec), which is the kind of first-generation tyrosine kinase inhibitor, there's dasatinib (Sprycel) and then there's nilotinib (Tasigna), which are all approved in pediatrics. (Sprycel and Tasigna), as second-generation tyrosine kinase inhibitors, do seem to have a little bit of a quicker mechanism action, similar to Bosulif, and so those drugs are available. But again, the side effect profile and who will respond to each of those medications is patient-to-patient specific.

“And so, specifically with Bosulif, they're seeing less of some of the other side effects, including malaise and fatigue that can be really troublesome to patients' lives, and myalgias — so muscle soreness, joint pain, rashes, you're seeing less of that. And so, I think it certainly depends on the patient and what potential side effects they're most concerned about, (that) is how I kind of choose my therapy choice.”

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