A four-year follow-up of the PATHFINDER clinical trial demonstrated that avapritinib treatment leads to deep, sustained responses in patients with advanced systemic mastocytosis (SM), according to findings recently published in Blood Advances.
“As the largest and longest prospective interventional study of any KIT inhibitor in
[advanced SMAdvanced SM In these subtypes of SM, mast cells begin to damage organs. Advanced SM includes the subtypes aggressive SM, mast cell leukemia and SM with an associated hematological neoplasm.], results of the PATHFINDER study provide important guidance and support for the use of avapritinib in clinical practice,” the authors wrote.
What is the difference between advanced and nonadvanced SMNonadvanced SM In these subtypes of SM, mast cells accumulate in the body but do not usually cause severe organ damage. Nonadvanced SM includes the subtypes indolent SM and smoldering SM.?
Nonadvanced SM comprises the indolent SMIndolent SM A subtype of nonadvanced SM caused by the abnormal accumulation of mast cells in the bone marrow and other organs. Indolent SM accounts for around 90% of SM cases. and smoldering SMSmoldering SM A subtype of nonadvanced SM, with a higher mast cell burden than the indolent subtype. Smoldering SM has a higher likelihood of progressing to an advanced form. subtypes. Advanced SM includes aggressive SMAggressive SM A subtype of advanced SM marked by a high mast cell burden that leads to organ damage. Aggressive SM accounts for less than 10% of SM cases., SM with an associated hematologic neoplasm and mast cell leukemiaMast cell leukemia The most severe subtype of SM, caused by the rapid buildup of immature mast cells in the bone marrow and blood. Mast cell leukemia accounts for less than 5% of SM cases and has a poor prognosis..
The trial included 107 patients who were followed for a median of 49.1 months. Participants had a median age of 68 years, and 42% of the sample were women. In addition, 96% tested positive for the KIT D816V mutation at baseline.
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The authors evaluated 83 patients for treatment response. These individuals experienced an overall response rate of 73%. Furthermore, 30% demonstrated complete remission or complete remission with partial hematologic recovery. Participants also displayed notable reductions in bone marrow mast cells, serum tryptaseTryptase A protein enzyme that is primarily produced by mast cells and stored in small pockets within the cells, known as granules. High levels of tryptase are a key indicator of SM. levels and spleen volume.
The median duration of treatment response was 58 months. The median overall and progression-free survival, respectively, were 51 and 62 months.
Over the study period, 21 of the 107 participants experienced disease progression, with six participants developing acute myeloid leukemia. 19 of the patients experiencing progression had SM with an associated hematologic neoplasm or mast cell leukemia at baseline.
The most commonly reported adverse events included thrombocytopenia, swelling around the eyes, anemia, swelling of the lower limbs or hands and diarrhea. While 11 patients died due to adverse events during the follow-up period, the clinical trial’s lead researcher attributed only one of these cases to avapritinib—an 80-year-old man “with a medical history of reduced kidney function and increased blood creatinine who died due to acute kidney injury in the context of treatment with antibiotics for bilateral pneumonia complicated by diarrhea and vomiting.”
Approximately one-third of patients developed cognitive changes, most of which were Grade 1 or Grade 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events grading system, meaning the changes were mild or moderate in severity. These included cognitive disorder, memory alterations and confusion. Most of these changes were alleviated with adjustments in dose.
The researchers reported that 20 individuals stopped treatment following adverse events that the study investigator assessed as likely or possibly related to the drug.
“With prolonged follow-up, the well-characterized safety profile of avapritinib remained consistent with prior reports, supporting that administration of avapritinib over an extended period maintains a favorable benefit-risk profile in patients with [advanced SM],” the researchers concluded.
Avapritinib is an oral medication that blocks the D816V mutation in the KIT gene. It is currently approved in the United States for individuals with advanced SM.
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