A more sensitive test for the KIT p.D816V mutation — the cause behind most cases of systemic mastocytosis (SM) — may help doctors better understand disease burden in SM, according to a study published recently in the Journal of Allergy and Clinical Immunology: Global.
The study found that KIT p.D816V mutation levels were higher in bone marrow than blood and were associated with measures of how much SM was present. Among patients with 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., higher mutation levels in blood were also associated with skin involvement.
Researchers analyzed 107 blood and bone marrow samples from 91 patients with SM using an ultrasensitive test called superRCA, which can detect very small amounts of the KIT p.D816V mutation by repeatedly copying the genetic material containing the mutation. The test successfully measured the mutation in 99 of 107 samples (93%).
Sign up here to get the latest news, perspectives, and information about SM sent directly to your inbox. Registration is free and only takes a minute.
Six patients (6.6%) had no detectable KIT p.D816V mutation, consistent with previous research on how often the mutation occurs in patients with SM.
The test was able to find the mutation even when it was only present in very small amounts: When 660 ng of DNA was available, superRCA could detect the mutation when it was present in as little as 0.0016% of the tested genetic material. This percentage, called the variant allele fraction (VAF), indicates how much of the genetic material carries the mutation.
Among 17 patients who had both blood and bone marrow samples, KIT p.D816V VAF was significantly higher in bone marrow, often by as much as 10-fold. One patient had a mutation detected in bone marrow but not blood, while another had the opposite pattern. Mutation levels were also higher in patients with 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. than those with indolent SM and in patients meeting the major diagnostic criterion for SM.
Higher mutation levels generally reflected greater disease burden. 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., a blood marker associated with mast cellMast cell A type of white blood cell produced in the bone marrow. They help defend against infections and play a key role in allergic reactions. In SM, mast cells become overactive and build up throughout the body. activity and burden, correlated with KIT p.D816V VAF in both bone marrow and blood. In indolent SM, bone marrow VAF also correlated with the percentage of bone marrow occupied by mast cells.
The relationship was less clear for individual symptoms.
“Blood KIT p.D816V VAF was higher in [indolent] SM cases with mastocytosisMastocytosis Rare disease caused by the buildup of mast cells. Cutaneous mastocytosis primarily affects the skin and is more common in children, while systemic mastocytosis affects internal organs and is more common in adults. in the skin compared to cases without skin involvement, and we hypothesize that KIT p.D816V mutated progenitors in blood may home to skin and cause the cutaneous phenotype,” explained the study’s investigators.
No significant differences in VAF were found according to osteoporosis or gastrointestinal symptoms. There was a tendency toward lower VAF among patients with anaphylaxisAnaphylaxis A severe allergic reaction that can turn fatal without treatment. Patients with SM are at a higher risk of developing anaphylaxis..
For patients, the findings could eventually help clinicians assess SM more precisely, although the superRCA test is not yet a replacement for standard testing. Among 33 bone marrow samples tested by both super RDC and standard methods, 32 had matching positive or negative results; superRCA detected one mutation that routine testing classified as inconclusive.
The researchers noted that bone marrow testing may be appropriate in select patients whose blood test is negative because the mutation can occasionally be detected in bone marrow alone. Larger studies are needed to determine how ultrasensitive testing should be incorporated into routine SM care.
Read more about SM testing: “Solving the puzzle: How genetic testing helps diagnose systemic mastocytosis“
