Avapritinib (Ayvakit, Blueprint Medicines), a novel agent that targets a specific mutation found in 90% of patients with systemic mastocytosis, reduces skin lesions and mast cell burden, according to safety results from the phase 2 PIONEER study.
"We're very excited. For the first time we have a treatment modality that goes to the root causes," said lead investigator Cem Akin, MD, from Michigan Medicine in Ann Arbor.
"Until now, we've only had blocking agents, such as antihistamines, for symptoms, which don't do anything for underlying disease," he told Medscape Medical News.
There are three forms of mastocytosis: cutaneous, systemic, and idiopathic.
With the idiopathic form, mast cell activation can cause anaphylaxis, which is unpredictable. "These patients tend to have regular allergies, but the anaphylactic episodes are not caused by their allergy," he explained. And patients don't always know they have the condition.
Systemic mastocytosis is a clonal mast cell neoplasm driven by the KIT D816V mutation, which hyperactivates mast cells in various organs. The disease leads to debilitating skin, gastrointestinal, neurocognitive, and systemic symptoms, including pigmented skin legions, itching, hives, extreme fatigue, flushing, nausea, abdominal pain, gastroesophageal reflux, hypotension, bloating, and diarrhea.
These symptoms are "highly disturbing to our patients' quality of life," said investigator Karin Hartmann, MD, from the University of Basel in Switzerland, who presented the study results at the European Academy of Allergy and Clinical Immunology (EAACI) 2020 Digital Congress.
There are currently no therapies available for this rare blood disorder. "We are encouraged that this will help our patients who desperately want something to get rid of skin lesions," she said.
A diagnosis is made when dense infiltrates of mast cells can be seen in bone marrow and other tissue, aggregates consist of at least 15 mast cells, and a blood test shows mast cell proliferation and accumulation in various organs, most commonly the skin.
For their study, Akin, Hartmann, and their colleagues evaluated avapritinib — the oral precision therapy that selectively inhibits KIT- and PDGFRA-mutant kinases — in 39 patients 18 years and older.
All participants had an ECOG performance status of 0 to 2, a confirmed diagnosis of systemic mastocytosis that met WHO criteria, and moderate to severe symptoms during the 14-day eligibility screening period despite receiving standard-of-care treatment.
In the safety part of the study, 30 participants received once-daily avapritinib for 24 weeks — 10 at 25 mg, 10 at 50 mg, and 10 at 100 mg — and nine participants received placebo.
At 24 weeks, six of the 10 patients in the 25 mg group experienced a reduction in the Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) total symptom score of at least 30%, the primary end point. And seven of the 10 experienced a reduction in serum tryptase of at least 50%, a secondary end point.
There were no grade 4 or 5 adverse events in the study cohort, and there were no grade 3 events in the 25 mg group. The one grade 3 cognitive disorder reported in the 100 mg group resolved after the patient's dose was changed to 25 mg.
Adverse events were more common with avapritinib than with placebo, such as nausea (37% vs 22%), dizziness (33% vs 22%), headache (30% vs 11%), diarrhea (23% vs 11%), and fatigue (20% vs 11%). None of the study participants experienced neutropenia, anemia, thrombocytopenia, or intracranial bleeding.
"Regulators are afraid of intracranial bleeding with tryptase inhibitors," Hartmann told Medscape Medical News. Nobody in our study developed any bleeding, "but we need to study this drug further. It's still early to talk in detail about adverse events."
With the safety of avapritinib confirmed, it is expected that the efficacy part of this trial, using the 25 mg dose, will commence imminently, Hartmann reported.
Quality of Life
A new tool for assessing quality of life in patients with mastocytosis was also presented at the EAACI Congress.
These patients "have very specific quality-of-life issues and symptoms, which are not typical of general population quality-of-life surveys," said Natalia Spolak-Bobryk, MD, from the Medical University of Gdansk in Poland.
To help assess the burden of disease, Spolak-Bobryk and her colleagues developed the Quality of Life in Mastocytosis Scale (QLMS) and validated the questionnaire in 85 patients with mastocytosis. The researchers hope the tool will be used in other clinics.
"Recognizing high-burden areas of disease can help treat these patients," Spolak-Bobryk said.
Hartmann is a consultant for Blueprint and has received honoraria from Allegro. Akin is a consultant for Blueprint. Spolak-Bobryk has disclosed no relevant financial relationships.
European Academy of Allergy and Clinical Immunology (EAACI) 2020 Digital Congress.
Medscape Medical News © 2020
Cite this: Avapritinib Promising for Systemic Mastocytosis Treatment - Medscape - Jun 16, 2020.