Anecdotal evidence supports further study of imatinib in children with FOP

[Author: Laura Cowen]

Children treated for fibrodysplasia ossificans progressiva (FOP) with imatinib in an off-on-off-on (O4) regimen have fewer flare-ups, decreased swelling, and improved function when on versus off treatment, US researchers report.

Frederik Kaplan (The University of Pennsylvania, Philadelphia) and colleagues explain that imatinib – a tyrosine kinase inhibitor – was originally developed for use in patients with chronic myeloid leukemia but also attacks multiple targets (eg, c-Kit, HIF1-α, Smad1, and PDGFR) involved in the early hypoxic and inflammatory stages of FOP flare-ups.

They also note that the drug was recently reported to decrease flare-ups in seven isolated cases among young children with FOP.

In the current analysis, the authors retrospectively reviewed data for three children (one girl and two boys, aged 2, 6, and 7 years, respectively) with classic FOP and the ACVR1 R206H mutation who experienced severe back flare ups that did not respond to standard FOP treatments.

The children received imatinib 340 mg/m2 per day in an O4 regimen. During the first ‘on’ phase, imatinib was given for 44, 15, and 7 months to child 1, 2, and 3, respectively, and resulted in decreased intensity and frequency of flare-ups according to their parents.

The children discontinued imatinib after each of these periods in order to join a phase 3 clinical trial of palovarotene but they all experienced a recurrence of flare-ups and subsequently exited the trial and restarted imatinib after a wash-out period.

At the time of the current report, child 1 had been back on imatinib for 10 months, child 2 for 21 months, and child 3 for 23 months.

“All three children again experienced fewer flare-ups, less swelling and improved function with activities of daily living when they were “on” imatinib than when they were “off” imatinib according to the parents and the treating physician,” write Kaplan and co-authors in Bone.

The parent of child 2 told the researchers: “Our son will still flare [on imatinib], but NOTHING like what was happening. The pain is 90% less, and he is able to be a kid.”

The investigators note that the median time to symptomatic improvement was 2–3 weeks on imatinib and the drug was well-tolerated without any need for dose de-escalation. Two of the three children experienced mild gastrointestinal irritation that was improved by taking the medication with food.

Kaplan et al conclude that O4 regimens “offer an opportunity to rapidly assess the potential symptomatic efficacy and tolerability of a medication with a limited number of patients and may aid in the design of more focused clinical trials that are amenable to enrollment.”

Indeed, they believe that their “anecdotal O4 experience with imatinib […] supports the design of a brief placebo controlled trial to assess the potential efficacy of imatinib in reducing the symptoms in children with refractory flare-ups of FOP.”

The researchers say that they are now developing “[a] tool to prospectively measure and quantitate flare-up symptoms” that will be validated and used in future trials.

FOP clinical diagnosis quiz image references

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