Chronic mast cell leukaemia with exon 9 KIT mutation A502_Y503dup: a rare imatinib responsive variant

Description

Mast cell leukaemia (MCL) is a very rare aggressive form of systemic mastocytosis (SM), representing <1% of cases of adult SM in the USA. The diagnosis of MCL requires the presence of SM criteria accompanied by mast cells accounting for at least 20% of nucleated cells in bone marrow (BM) aspirate or 10% of peripheral blood white cells; cutaneous lesions are often absent.¹ In patients with MCL, the absence of organ damage, the so-called ‘C findings’, serves as a diagnostic criterion of the chronic subvariant of MCL.² Herein, we present a case of an aleukaemic chronic MCL with a rare KIT exon 9 mutation A502_Y503dup. A 60-year-old man developed recurrent episodes of flushing, headaches, dizziness and fluctuating blood pressure. Complete blood count showed a white blood cell count 13×10⁹/L, haemoglobin 123 g/L, haematocrit 35.7%, mean corpuscular volume 98 fL and platelets 213×10⁹/L. A tryptase level was 71.9 μg/L. Initial BM evaluation was consistent with SM with aberrant expression of CD2 and CD25. Allele-specific PCR for the KIT D816V mutation was negative. Repeat BM biopsy was obtained for KIT gene sequencing and showed an extensive mast cell infiltrate that was positive for CD2 (moderate, 27%) and CD25 (weak, 29%) and represented 60%–70% of marrow cellularity (figures 1–4). Next-generation sequencing revealed a KIT exon 9 mutation A502_Y503dup with an allele frequency of 3.4%, as well was an ASXL1 variant (p.R402Q). Systemic imaging did not show any evidence of hepatosplenomegaly or lymphadenopathy. The absence of C findings, relatively low tryptase, low Ki-67 (<5%) and the preponderance of immature mast cells without blastic morphology were compatible with the non-WHO described chronic MCL variant of MCL. Cladribine or interferon-alpha are no longer considered first-line treatments for cytoreduction due to modest overall response rates. Midostaurin is a multikinase/KIT inhibitor that is FDA-approved for the treatment of advanced SM, including MCL.³ Imatinib is effective in a minority of SM patients only, as the most common KIT mutation (D816V) is resistant to imatinib.⁴ In this case, given the presence of the rare variant exon 9 KIT mutation, imatinib was recommended as initial therapy. The patient had persistent anaphylaxis that was refractory to standard supportive care, and omalizumab was recommended. The patient was recently started on imatinib 800 mg daily. The anaphylactic episodes have resolved. MCL is a rare form of advanced SM, and in the absence of the typical KIT D816V mutation, a search for other mutations by sequencing the entire KIT gene should be considered, as this can influence the choice of treatment. The KIT exon 9 mutation A502_Y503dup was previously reported in patients with gastrointestinal stromal tumours. There has been no case of chronic MCL with this variant KIT mutation reported in the literature. Only one case of acute MCL with this variant KIT mutation has been reported previously in the literature, with a favourable response to imatinib.⁵

Figure 1.

Wright-Giemsa stained bone marrow aspirate showing mast cells on 100× view.

Figure 2.

H&E stained bone marrow trephine biopsy showing large mononuclear or spindle mast cells on 20× view.

Figure 3.

Immunohistochemistry of bone marrow core biopsy showing positive staining of tryptase containing mast cells on 40× view.

Figure 4.

Immunohistochemistry of bone marrow core biopsy showing the CD117 positivity of mast cells on 20× view.

Learning points.

• Mast cell leukaemia (MCL) is a rare and aggressive form of systemic mastocytosis (SM) characterised by leukaemic expansion of mostly immature mast cells, organ damage, drug-resistance and confers a poor prognosis.

• The diagnosis of MCL requires the presence of SM criteria accompanied by mast cells accounting for at least 20% of nucleated cells in bone marrow aspirate or 10% of peripheral blood white cells. The absence of organ damage, the so-called ‘C findings’, serves as a diagnostic criterion of the chronic subvariant of MCL.

• Neoplastic mast cells display KIT D816V in only 50%–70% of the cases. In the remaining MCL cases, other KIT mutations or no KIT mutations are found. A search for other mutations by sequencing the entire KIT gene should be considered, as this can influence the choice of treatment.

• Chronic MCL is an extremely rare but morphologically recognisable pathological variant of MCL.