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 AdvSM, 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 antihistamines for flushing and skin manifestations and allogeneic stem cell transplantation — current advanced SM 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 cell 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 SM?
Nonadvanced SM comprises the indolent SM and smoldering SM subtypes. Advanced SM includes aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia.
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.
