Avapritinib for the treatment of KIT mutation–negative systemic mastocytosis

Abstract

Systemic mastocytosis results from the spread of abnormal mast cells in different parts of the body, with variable clinical presentation. It is difficult to diagnose and to determine the appropriate therapy regimen. We present a case of a 53-year-old man diagnosed with KIT-negative advanced systemic mastocytosis based on the 2016 World Health Organization criteria. The patient presented with widespread symptoms that continued to worsen despite supportive therapy and traditional tyrosine kinase inhibitors. He was ultimately started on avapritinib, which reduced his tryptase level and provided symptomatic relief many years after his diagnosis.

Systemic mastocytosis (SM) is an accumulation of clonal mast cells (MC) in different organ systems. The mechanism involves the release of MC-derived mediators such as histamine and tryptase, triggering widespread inflammatory and allergic reactions. Symptoms include but are not limited to neurological, gastrointestinal, and musculoskeletal systems.¹ The World Health Organization indicates that the diagnosis requires meeting at least one major criterion and one minor criterion or meeting three minor criteria. The major criterion is multifocal dense aggregates of ≥15 MC clusters in the bone marrow or extracutaneous tissue. The minor criteria are >25% MC having an abnormal morphology in bone marrow or being spindle-shaped, KIT mutation at codon 816, CD2 and/or CD25 expression, and serum tryptase of >20 ng/mL. The case here fulfilled the major criterion and three minor criteria (spindle-shaped MC, MC in bone marrow exhibiting CD2, and a baseline serum tryptase level of >20 ng/mL).²

CASE DESCRIPTION

A 53-year-old man with a known history of malignant melanoma with excision presented to the leukemia clinic for evaluation of mastocytosis. He had a constellation of symptoms for 2 years including headache, fatigue, weight loss, memory problems, inability to fall asleep, dyspnea on exertion, abdominal pain, diffuse bone and joint pain, diarrhea, intermittent red blood in stool, and pruritic rash in the torso and extremities. He had a macular rash involving the torso and pain on palpation of the left upper quadrant of the abdomen. A complete blood count and comprehensive metabolic panel showed no evidence of anemia, thrombocytopenia, eosinophilia, or abnormal creatinine or liver enzymes; the absolute neutrophil count was low. Ultrasound of the abdomen showed a spleen that was at the upper limit of normal. The initial bone marrow biopsy showed trilineage hematopoiesis with normocellular marrow (50%) and involvement by MC disease of 5% to 10% of the cellular marrow. More than 20 atypical MC aggregates and focal spindle cell proliferation were noted. MCs were positive for tryptase, CD117, and CD2. Molecular studies revealed a normal karyotype, negative PDGFRA mutation, and negative C-kit mutation. Flow cytometry showed no evidence of acute leukemia or a neoplasm. The tryptase level was 36 ng/mL at the time of diagnosis and remained above 30 despite therapy with imatinib, cladribine, nilotinib, hydroxyurea, and midostaurin. Avapritinib 200 mg daily was eventually started with a subsequent decrease in tryptase from 79 to 23 ng/mL. Dose reduction of avapritinib to 100 mg daily stabilized his tryptase level to around 50 ng/mL, and he noted improvement in symptoms 8 years after his diagnosis.

DISCUSSION

Our patient was diagnosed with aggressive SM given the presence of C-findings, representing organ damage produced by MC infiltration, with <20% MC in bone marrow smears. C-findings in our patient included possible splenomegaly, malabsorption, and weight loss.² In >95% of cases, etiology is a gain of function mutation in receptor tyrosine kinase KIT D816V.³ Interestingly, a polymerase chain reaction test for C-kit mutation was negative in our patient, although that does not exclude a diagnosis of SM. D816V mutation screening and serum tryptase measurement, a marker for MC burden, are not required for the diagnosis of SM. The sensitivity of the assay and the MC content of the sample dictate the ability to detect a D816V mutation.⁴

Therapies traditionally used for SM have largely been ineffective. Imatinib and nilotinib are tyrosine kinase inhibitors that have shown limited response against D816V.⁵ D816V mutation shows resistance to imatinib via a change in receptor conformation that blocks the drug from binding.⁶ Similarly, nilotinib has shown only a partial response in MC cytoreduction in patients with a D816V mutation.⁷ Cladribine, a purine analog, has been shown to destroy MC independent of D816V mutation. However, increased susceptibility to infections secondary to immunosuppression has been reported.⁸ Hydroxyurea is a DNA synthesis inhibitor that has been shown to provide symptomatic relief.⁹ Both cladribine and hydroxyurea do not reduce the neoplastic MC burden drastically, and evidence of efficacy is weak since it is from observational studies.¹⁰ The emergence of midostaurin and avapritinib have revolutionized the therapy for SM. Midostaurin, a multikinase inhibitor, has shown a promising response. However, adverse effects including nausea, vomiting, and diarrhea have been reported.¹¹

Avapritinib is a highly selective and potent D816V inhibitor approved by the Food and Drug Administration for SM based on multiple clinical trial data.¹² The PATHFINDER trial showed an overall response rate of 75% in 32 response-evaluable SM patients, with a complete remission rate of 19%. Furthermore, the trial showed reductions of ≥50% from baseline in serum tryptase and bone marrow MC. Responses were seen at all starting doses, with the most rapid response at 200 mg daily or higher. The results corroborated outcomes from the EXPLORER trial,¹³ which showed an overall response rate of 75% in 53 response-evaluable SM patients and a complete remission rate of 36%. Avapritinib was well tolerated with a recommended dose of 200 mg daily. EXPLORER revealed a consistent reduction in total symptom score, with improvements in gastrointestinal symptoms, skin symptoms, and fatigue.¹⁴ Part 1 of the PIONEER trial was set to determine the recommended dose of avapritinib. It showed that 25 to 100 mg daily can rapidly reduce serum tryptase levels in SM.¹⁵ In our patient, the starting dose was 200 mg daily, which led to a rapid decline of tryptase level, with symptomatic improvement within months at a reduced dose of 100 mg. Treatment with avapritinib shows promising results in this difficult-to-treat condition.