Genetic tests before treatment and routine blood tests in the first months may help doctors tell which people with advanced systemic mastocytosis (SM) are likely to do well on their current KIT inhibitor and who may need a different approach, a new study found.
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The study, published in journal Leukemia, analyzed data from 255 people with the three forms of 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.: 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 hematological neoplasmSM with an associated hematological neoplasm A form of advanced SM and the second-most common subtype of SM overall. In this subtype, SM occurs alongside another blood disorder. Also called SM with an associated myeloid 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.. Of these, 176 took avapritinib in clinical trials, and 79 took midostaurin in routine clinical care in Germany.
Both drugs are KIT inhibitors, and block a protein that controls 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. growth. In about 95% of advanced SM cases, a mutation called KIT D816V keeps this protein permanently switched on, driving mast cells to multiply uncontrollably. Avapritinib targets the mutated form specifically, while midostaurin also blocks several other proteins.
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Most of the patients also carried mutations in other genes with an impact on SM. The authors noted that while KIT inhibitors have transformed how advanced SM is treated, these additional mutations can affect how a patient responds to treatment.
Doctors already use mutations in SRSF2, ASXL1 and RUNX1 to make predictions about the future health of patients with advanced SM. Building on this, the researchers created a scoring system to predict the outcome each drug would have on patients with extra high-risk mutations.
For both therapies, patients with none of the high-risk mutations did best. Patients with at least one high-risk mutation on avapritinib had a median survival (the point by which half of a group had died) of 49 months, while those on midostaurin had a median survival of 30 months.
The researchers also tracked blood markers during treatment. One was the percentage of KIT gene copies in the blood that carried the D816V mutation, which serves as a marker of how much disease is present. Patients taking avapritinib whose mutation frequency dropped at least 10% from its starting level within 15 days of starting treatment lived longer than those who didn’t have this drop.
Another marker was alkaline phosphatase, an enzyme measured in routine blood tests. In SM, high levels usually signal mast cell damage to the liver. Nearly half of patients on either drug had a temporary “flare,” with levels rising by 25% or more before falling, often below where they started. With avapritinib, this flare was associated with longer survival. A similar trend was noticed with midostaurin, but it wasn’t large enough to prove an association. The researchers hypothesize the flare may reflect mast cells being cleared from the liver.
The researchers noted that these genetic and biomarker findings could help doctors decide on the best treatment for an individual patient. “Our data may therefore help to identify situations where patients on midostaurin should be switched to avapritinib, or where patients on midostaurin or avapritinib might benefit from treatment intensification,” the authors wrote.
The authors noted that their conclusions are limited because the study looked back at existing data; the two groups came from different settings and the gene-based scores have not been confirmed in other patients.
