A case of aleukemic mast cell leukemia with an underlying myeloproliferative neoplasm: Morphological and molecular characteristics of a highly aggressive disease
Authors: Giuseppe G. Loscocco, Francesco Mannelli, Lara Mannelli, Federica Vergoni, Francesca Gesullo, Giada Rotunno, Paola Guglielmelli, Alessandro M. Vannucchi
Journal: American Journal of Hematology (2020)

A 70-year-old man was admitted to our institution with a 3-months history of severe fatigue and unintentional weight loss of 15 kg. In the patient's medical history, there was a sustained asymptomatic, not further investigated thrombocytosis (around 900 × 109/L) since 2015. Physical examination revealed hepatosplenomegaly; hemoglobin was 6.7 g/dL, platelets 89 × 109/L, leukocytes 1.6 × 109/L and serum lactate dehydrogenase was mild increased (298 U/L). Peripheral blood (PB) smear showed a normal differential count without abnormal cells. Conversely, bone marrow (BM) aspirate documented a massive infiltration (>90% of all nucleated cells) of atypical, partly degranulated, mast cells (MC, Figure 1A). Flow cytometry confirmed the presence of an aberrant MC population, representing 50% of total BM cellularity, positive for CD117, CD33, CD25, CD22, CD2 and negative for HLA-DR, CD34, CD11b, CD15, CD36, CD14, CD5, CD7, CD19 and CD10 (Figure 2A-C). Histopathology documented a diffuse proliferation, with cohesive growth, of atypical MC with large cytoplasm, most with fusiform morphology, and bilobed or convoluted nuclei (Figure 1B). Immunohistochemical staining confirmed positivity for CD117, CD30 (not shown), CD25, tryptase; Gomori stain revealed a grade 3 reticulin fibrosis (Figure 1C-F). All these findings were consistent with a diagnosis of aleukemic mast cell leukemia (aMCL). Serum tryptase was markedly elevated at 890 μg/L, but mediator symptoms were absent. The KIT-D816V mutation was detected in BM aspirate by droplet digital polymerase chain reaction (dd-PCR) with variant allele frequency (VAF) of 25%; targeted next generation sequencing (NGS) on PB cells identified the following additional mutations: JAK2V617F, MPLW515R and DNMT3AF755S, with respective VAF of 6%, 7% and 58%. There was a complex karyotype involving chromosomes 2, 12, 14 and 19. Due to the presence of canonical KIT mutation, patient started therapy with midostaurin at the dose of 100 mg twice daily, and rapidly experienced considerable improvement of his severe asthenia. The treatment was well tolerated, except for mild gastrointestinal toxicity and asymptomatic neutropenia, and no treatment interruption was necessary. After 3 months on midostaurin, BM evaluation showed a significant reduction of MC infiltration (10% of total BM cells) and KIT-D816V mutation burden, tested by dd-PCR (0.11%). Furthermore, the serum tryptase level decreased to 72 μg/L. Note, aMCL is a rare and aggressive form of systemic mastocytosis (SM) that can be rarely associated with a hematologic neoplasm (AHN). In this case, considering the previous thrombocytosis and the presence of JAK2 and MPL mutations, we hypothesize that the aggressive onset of aMCL masked an underlying, pre-existing, myeloproliferative neoplasm (MPN). However, precise classification of the latter according to World Health Organization (WHO) is not available, since thrombocytosis had not been investigated. Due to age, the patient was not eligible for allogenic stem cell transplantation, to date the most effective treatment option, and started immediately midostaurin that is successfully continuing after 8 months from diagnosis. At last BM evaluation, 8 months after starting midostaurin, the patient was in complete remission without pathological mast cells by flow-cytometry, and with KITD816V mutation showing negative by dd-PCR. All these findings, along with normalization of serum tryptase level (18 μg/L), PB count and hepatosplenomegaly were consistent with a complete response (CR) according to IWG-MRT criteria.1 Next generation sequencing on PB confirmed the presence of JAK2V617F, MPLW515R and DNMT3AF755S with a VAF similar to diagnosis, while KITD816V was confirmed absent. These molecular findings suggested the persistence of a pre-existing MPN clone, while the mast cell clone (either an independent one or as a subclone from the previous MPN clone) were no longer detectable under midostaurin. The case reiterates that full morphologic, cytofluorimetric and molecular characterization of abnormal mast cells, particularly for advanced variants such as aMCL and SM-AHN, is crucial to address a suspicion of SM and eventually start promptly adequate treatment.2 The study was supported by AIRC 5 × 1000 caLL “Metastatic disease: the key unmet need in oncology” to MYNERVA project, #21267 (MYeloid NEoplasms Research Venture AIRC). A detailed description of the MYNERVA project is available at http://www.progettoagimm.it The authors declare no competing financial interests.