Aggressive systemic mastocytosis (ASM) is a rare hematologic neoplasm characterized by abnormal accumulation of mast cells in the bone marrow and various organs. A D816V mutation in the gene encoding the Kit receptor tyrosine kinase (KIT) is detected in about 90% of patients with this neoplasm. The prognosis is usually poor, with an estimated median survival of 3.5 years.1,2

A 37-year-old man with pancytopenia and splenomegaly was admitted to the hematology department. Complete blood count (CBC) and laboratory workup results were as follows: white blood cells (WBC), 1.71 × 109/l (reference range [RR], 4–10 × 109/l); neutrophils (NEU), 0.74 × 109/l (RR, 2.25–6.8 × 109/l); hemoglobin (Hb), 8.7 g/dl (RR, 13–18 g/dl); platelets (PLT), 58 × 109/l (RR, 130–400 × 109/l); alkaline phosphatase (ALP), 215 IU/l (RR, 10–128 IU/l); albumin, 4.7 g/dl (RR, 3.5–4.2 g/dl). Computed tomography (CT) showed splenomegaly (17 cm × 8.5 cm) and osteosclerotic remodeling of the pelvic bones (Figure 1A–1D). Bone marrow biopsy revealed clusters (>15 cells) of atypical, spindle-shaped mastocytes constituting about 20% of the marrow elements. The tryptase level was above 200 μg/l (RR <⁠10 µg/ml). The KIT D816V mutation was confirmed by Sanger sequencing. Next-generation sequencing was performed and no pathologic variants or mutations were detected. The diagnosis of ASM with bone marrow, spleen, and bone involvement was established.

Figure 1. A, B – low-dose whole-body computed tomography (CT; axial section and multiplanar reconstruction in the frontal plane) showing an enlarged spleen (arrows) measuring 17 cm × 8.5 cm and 23.5 cm vertically (index, 3396; normal, up to 480); C – CT scan showing osteosclerotic remodeling of the pelvic bones: an 8-mm osteolytic area in the right iliac bone (arrow) and osteosclerotic and osteolytic areas of 6 mm each in the head of the femur; D – CT scan showing osteosclerotic bone remodeling (arrows); E, F – bone marrow biopsy before avapritinib treatment G, H – bone marrow biopsy after avapritinib treatment (E, G – hematoxylin and eosin staining; F, H – CD117 immunostaining; magnification × 10); infiltration of the bone marrow by monoclonal mastocytes can be seen in brown in immunohistochemical analysis.

The patient was started on midostaurin at a dose of 200 mg daily. Partial response was observed after 6 months of treatment with stabilization of CBC values and reduction of tryptase levels to 90 µg/l. During the therapy, mild vomiting and abdominal pain were observed.

After 11 months, deterioration was observed, with pancytopenia (WBC, 1.61 × 109/l; NEU, 0.84 × 109/l; PLT, 57 × 109/l), splenomegaly (28 cm × 7.5 cm), and increased levels of tryptase (140.6 ug/l) and ALP (458 IU/l). The patient reported weakness and night sweats. Bone marrow mast cell burden was 40% (Figure 1E and 1F). The disease progression was diagnosed. The patient was referred for avapritinib therapy at a dose of 200 mg daily via the Compassionate Use Program. After the first month, he gained weight, and general symptoms improved. After 3 months, a decrease in the spleen size to 22.3 cm × 6.7 cm, an increase in Hb values to 11 g/dl, and normalization of the tryptase level (4.4 μg/l) were achieved. Bone marrow biopsy revealed single mastocytes, constituting less than 5% of the marrow elements (Figure 1G and 1H). The patient continues the ninth month of the treatment with good tolerance. He is awaiting an allogeneic stem cell transplantation.

So far, the United States Food and Drug Administration (FDA) has registered 3 tyrosine kinase inhibitors (TKIs) for the treatment of ASM: imatinib, whose use is limited to rare cases without the KIT D816V mutation,3 midostaurin, the first multikinase inhibitor,4 and avapritinib, a selective TKI. The efficacy of avapritinib in patients with ASM was evaluated in 2 multicenter, single-arm clinical trials: EXPLORER (NCT02561988) and PATHFINDER (NCT03580655). The objective response rate was 57% (95% CI, 42–70). Importantly, the first complete remission was reported in 28% of cases. On June 16, 2021, the FDA approved avapritinib for adult patients with advanced systemic mastocytosis.5 On March 24, 2022, avapritinib was also approved in the European Union.

Real-world data on avapritinib in ASM are very limited. Initial observations indicate potential efficacy and a favorable safety profile of the drug.