Sandow L, et al. Leukemia Research Reports, 2024, 21, 100409.
Avapritinib is a highly selective KIT D816V inhibitor approved for the treatment of advanced systemic mastocytosis (ASM). Recent studies have shown that Avapritinib is also effective against other KIT mutations located in exon 11 and exon 17.
Systemic mastocytosis is a rare haematological malignancy that results in the accumulation of tumorous mast cells in the bone marrow, visceral organs and skin. Most patients have mutations in the receptor tyrosine kinase KIT, most commonly a gain-of-function mutation in KIT D816V.
In this case, we report a case of ASM without a KIT D816V mutation but with a novel mutation (KITp.D816_N822delinsMIDSI) in the same region, which was treated with Avapritinib and achieved a sustained clinical response.
The patient's initial trypsin-like enzyme level was 60.1 ng/mL. at diagnosis, the patient had normal liver enzymes, a white blood cell count of 18.7 × 10³ /uL, and a platelet count of 740 × 10³ /uL. the patient was initially treated with midostaurin, but developed grade 4 pneumonitis after approximately three months, which led to discontinuation of the drug. Prior to this, the patient had continued to experience diarrhoea and fatigue with persistently elevated tryptase-like levels. Given the activated nature of the patient's mutation, the decision was made to initiate treatment with Avapritinib 200 mg daily.
At the two-week follow-up, the patient reported a significant reduction in the frequency of diarrhoea and a 50% decrease in trypsin-like enzyme levels. Over the next two weeks, the patient developed grade 2 arthralgia and joint swelling, which resolved with steroid therapy. Laboratory tests showed a continued decrease in tryptase-like levels with no other adverse drug reactions. Follow-up CT imaging showed a decrease in lymph node enlargement, indicating an imaging response to Avapritinib.
During the first four months of treatment, the patient's trypsin-like enzyme levels continued to decrease and symptoms improved, particularly diarrhoea. Other adverse drug reactions were minor and included grade 1 and 2 periorbital oedema, alopecia, lack of concentration and depression, which improved with the use of steroids. Given the favourable response in the first six months, the patient's Avapritinib dose was reduced to 100 mg daily, but the trypsin-like levels rose again and he was hospitalised with hypotension due to an episode of depigmentation, so the dose of 200 mg daily was resumed and the trypsin-like levels fell.
Despite subsequent hospitalisation for urinary sepsis and anaemia, the patient's clinical condition stabilised after re-increasing the Avapritinib dose, with a decrease in trypsin-like enzyme levels, cessation of degranulation episodes, and almost complete resolution of diarrhoea and gastrointestinal symptoms. As of the last follow-up visit, the patient continued to take 200 mg Avapritinib, tolerated the treatment well, and had improved symptoms.
Although Avapritinib is known to potently inhibit the D816V mutation, this case suggests that the drug may also be effective against other rare KIT mutations in ASM and could be a potential therapeutic option for cases with de novo KIT mutations (involving KIT exon 17).
Sandow L, et al. Leukemia Research Reports, 2023, 19, 100371.