Chronic mast cell leukemia (MCL) with KIT S476I: a rare entity defined by leukemic expansion of mature mast cells and absence of organ damage

Abstract

Mast cell leukemia (MCL) is a rare, life-threatening malignancy defined by a substantial increase in neoplastic mast cells (MCs) in bone marrow (BM) smears, drug-resistance and a poor prognosis. In most patients, the survival-time is less than 1 year. However, exceptional cases may present with a less malignant course. We report on a 49-year-old female patient with MCL Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts diagnosed in 2013. In February 2013, first symptoms, including flushing, headache and diarrhoea, were recorded. In addition, mild anemia was detected. The disease was characterized by a massive increase in well-granulated, mature and often spindle-shaped MCs (80%) in BM smears. The serum tryptase level amounted to 332 ng/mL. Like in most other MCL patients, no skin lesions were detected. However, unlike in other patients, tryptase levels remained stable and no other signs or symptoms of MCL-induced organ damage were found. Sequencing studies revealed an isolated S476I point-mutation in KIT but no mutation in codon 816. The patient received histamine receptor blockers, but refused cytoreductive therapy. After 9 months, still no progression or organ damage was detected. However, progression with transformation to acute MCL occurred after 12 months. We propose that the chronic type of MCL with stable conditions, absence of organ damage and a mature MC morphology, is recognized as a distinct entity that should be distinguished from the acute variant of MCL.

The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm

“…In our series, the proposed subtypes of MCL without C-findings (chronic MCL) and leukemic MCL were only observed in 2 patients each, in line with previously published series, 14 , 15 the latter clearly demonstrating that presence or absence of MCs in PB is only of minor importance for the diagnosis of MCL. We have, however, observed a much higher relative frequency of MCL-AHN than that reported in the literature (71% vs .…”

A scientific treatment approach for acute mast cell leukemia: using a strategy based on next-generation sequencing data

“…Notably, the KIT mutation is the most important and prevalent pro-oncogenic mutation in MCL. In this study, we found the presence of a KIT S476I mutation, which has been discovered previously in chronic MCL [ 15 ]. With our finding, this point mutation becomes the second most common point mutation in MCL, following KIT D816V, which is located in the tyrosine kinase domain.…”

“…Almost 40% of de novo patients with MCL had the KIT D816V mutation [ 1 ]. In addition, S476I, F522C, V654A, V560G, duplication of amino acids 501–502 and 502–503, and deletion of amino acids 501–502 were also reported in a case report [ 10 11 12 13 14 15 ]. Besides the KIT mutation, a TET2 mutation has been investigated in aggressive SM [ 16 ].…”

Systemic Mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology

“…2 Chronic MCL is defined as MCL without C-findings/organ damage and may display a more indolent course over time, but its natural history requires more study. [24][25][26] Immunostaining with Ki-67 has been shown to differentiate between the acute and chronic variants, since most mast cells in chronic MCL stain negative for Ki-67 whereas mast cells in acute MCL frequently display Ki-67. 24 These findings require validation in additional studies.…”

“…In some cases, organdirected biopsy may be useful to determine whether organ damage is related to the SM or AHN or both (eg, liver biopsy in a patient with liver function abnormalities). Although chronic MCL may follow a more indolent disease course compared with acute MCL with organ damage, [24][25][26] cytoreductive therapy should still be considered for such patients given the poor prognosis of both MCL subtypes (see "Treatment for MCL," page 1509, [SM-8]).…”