NEW YORK (Reuters) –, an observational-phase randomized clinical trial showed.
By contrast, the benefits seemed lower for pure venous malformations (VMs).
Asin JAMA Dermatology, Dr. Annabel Maruani of the University of Tours and colleagues studied 59 children (mean age, 11.6 years; 59.3% girls) with a slow-flow vascular malformation. Participants underwent an observational period, then switched to an interventional period during which they received oral sirolimus (target serum levels, 4-12 ng/mL). The switch time was randomized from month 4 to month 8, and the entire study lasted 12 months for each patient.
The primary outcome was change in the volume of vascular malformations per unit of time (that is, between the interventional period and the observational period).
Twenty-two participants (37.3%) had a VM, located mostly on the upper limbs; 18 (30.5%) had an LM, located mostly on the head and neck; and 19 (32.2%) had a combined malformation, with the most frequent location on the lower limbs.
Overall, variations in vascular malformation volumes were not significantly different between the interventional and observational periods.
However, children with pure lymphatic malformations experienced a significant decrease in volume (mean difference, -0.005) after sirolimus treatment. Further, sirolimus had positive effects on secondary outcomes, including pain – especially for combined malformations – and on bleeding, oozing, self-assessed efficacy, and quality of life.
Fifty-six participants experienced 231 adverse events (five serious; none life-threatening). The most frequent adverse event was an oral ulcer (49.2%).
Summing up, the authors state that the study “allows for clarifying the goals of patients and families when starting sirolimus therapy for children older than 6 years. Pure lymphatic malformations seem to be the best indication for sirolimus therapy ... In combined malformations, sirolimus significantly reduced pain, oozing, and bleeding. Benefits seemed lower for pure venous malformations than for the 2 other subgroups, also based on symptoms.”
Dr. Nicole Harter, Division Chief, Pediatric Dermatology at Children’s Hospital and Medical Center in Omaha and Associate Professor at the University of Nebraska Medical Center, commented in an email to Reuters Health, “My clinical experience agrees with the findings.”
“In general, I have not seen rapid reduction in size/volume of slow-flow vascular malformations with use of sirolimus in such a short interval, and I would be most interested to see these patients followed over time,” she said. “I [question] whether the initiation of sirolimus can prevent an exponential increase in volume of vascular malformations, aside from what is expected with normal proportional growth of the child.”
“Further studies will be needed to evaluate if factors aside from clinical symptoms (pain, bleeding, oozing) can guide treatment decisions,” she noted. “Evaluation of the impact of tissue mutational status, clinical exam features, extent/depth of involvement based on imaging studies, and syndromic versus nonsyndromic malformations may be able to provide guidance on optimal timing of sirolimus initiation.”
“Further studies will help elucidate if underlying genetic mutations are tied to greater clinical response or rate of adverse effects,” she added. “This is suggested with the improvement in pain in venous/combined venolymphatic malformations due to sirolimus’ effect on TEK/mTOR signaling and downstream impact on the coagulation cascade.”
Dr. India Hill, Chief of Dermatology at Children’s Hospital New Orleans and Clinical Assistant Professor at Louisiana State University in Baton Rouge also commented by email, noting that the findings “align with our clinical experience ... We have noted improvements in bleeding, oozing, and quality of life in those with both lymphatic malformations and mixed malformations.”
“I was pleased to see the focus on quality-of-life improvements and reduction in oozing and bleeding, aside from purely volumetric improvement,” she said. “Safety of long-term treatment remains a concern.”
“I am interested to see future studies that investigate outcomes for infants and young patients and how early intervention might impact their long-term prognosis,” she added. “I am also eager to see studies correlating genotype with targeted therapies.”
Dr. Maruani did not respond to requests for a comment.
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