A literature review focusing on the current challenges and future perspectives in managing advanced systemic mastocytosis (SM) was recently published in the Journal of Blood Medicine.
“In this review, we summarize the present and future therapeutics landscape of AdvSMAdvanced 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., highlighting the development of novel KIT inhibitors including elenestinib and bezuclastinib,” the authors stated.
Old and new treatments
Apart from support treatment aimed at specific symptoms — such as antihistaminesAntihistamines Medications that block the effects of histamine, the chemical found in mast cells that is responsible for many of the symptoms of SM, as well as many allergic reactions. for flushing and skin manifestations and allogeneic stem cell transplantation — current 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. treatment is based around KIT inhibitors. These drugs target the KIT receptor, which in most patients with SM carries the D816V mutation. KIT activation is a critical step in 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. multiplication and extended survival.
Read more about SM treatment and care
The two main KIT inhibitors used for advanced SM management are midostaurin and avapritinib.
Midostaurin received U.S. Food and Drug Administration approval for treating advanced SM in 2017; approval came after clinical trials demonstrated it reversed organ damage and improved overall survival. But some studies suggested that an important percentage of patients do not respond to it, and its associated adverse effects led to treatment discontinuation in up to 22% of patients.
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..
Avapritinib appears to have a higher response rate than midostaurin and leads to complete remission in up to 33% of patients; however, it is associated with severe hematological and cognitive adverse effects that can limit its use.
Elenestinib and bezuclastinib are novel KIT inhibitors currently being assessed in clinical trials, with promising preliminary reports. Both drugs appear to have similarly positive effects on SM without producing as many adverse effects as previously available options.
Unresolved clinical challenges
The current standard of care is centered around KIT inhibition. But a significant percentage of patients are refractory to KIT inhibition or relapse after initial improvement. There is a need for research focusing on alternative pathways that can be targeted alone or in combination with KIT inhibitors.
“Thanks largely to collaborations between academia and the pharmaceutical industry as well as patient advocacy groups, the increased attention directed towards this rare disease will continue to propel therapeutic advances that can improve the quantity and quality of life for patients with AdvSM,” the authors said in the study.
