Distinct Diagnostic and Clinical Features of Bone Marrow Mastocytosis: A Study of the Registry of the European Competence Network on Mastocytosis (ECNM)

Background. Bone marrow mastocytosis (BMM) is characterized by accumulation of neoplastic mast cells (MC) in the bone marrow (BM), absence of skin lesions and lack of overt infiltration of other extra-cutaneous organs by neoplastic MC. Although clinically relevant due to its association with life-threatening anaphylaxis, BMM is considered a provisional sub-entity of indolent systemic mastocytosis (ISM) in the 2016 WHO classification.

Aims and methods. To define clinical and biological features of BMM we evaluated 1,343 adult patients (pts) with non-advanced systemic mastocytosis (SM) enrolled in the European Competence Network on Mastocytosis (ECNM) registry. The following characteristics were compared between pts with BMM (n=260), ISM (n=1,027) and smouldering SM (SSM, n=56): age, gender, diagnostic criteria, biochemical parameters at diagnosis [blood counts, albumin, alkaline phosphatase (AP), lactate dehydrogenase, tryptase], presence of mediator-related symptoms (diarrhea, flushing, headache, pruritus, hypotension, blistering, cramping, bone pain) and their severity (classified according to Valent P. et al. Eur J Clin Invest. 2007;37:435-53), constitutional symptoms, osteoporosis/osteopenia and allergy. The Student- t and the χ² tests were used to assess the statistical significance of differences for continuous and categorical variables, respectively. Event-free survival (EFS) was calculated from diagnosis to progression into more severe SM (i.e. SSM, aggressive SM, SM associated with another hematological neoplasm or mast cell leukemia) or death.

Results. Median age at diagnosis was 53 years (yrs) (range 19-83) for BMM vs 46 yrs (range 19-82) for ISM vs 52 yrs (range 25-79) for SSM (p<0.001). Male/female ratio was significantly higher in BMM (1.54:1) than in ISM (0.64:1) or SSM (0.75:1) (p<.001). Compact MC aggregates in BM biopsies (major diagnostic criterion) were demonstrable in 69%, 89% and 100% of BMM, ISM and SSM respectively (p<.001). Median percentage of MC infiltrates in BM was significantly lower in BMM than in the other groups (5% vs 10% vs 35%, respectively; p<.001). Only 56% of BMM pts had a tryptase value >20 ng/mL at diagnosis, while 77% of ISM and 100% of SSM pts fulfilled this criterion. If performed, atypical MC morphology in BM smears, aberrant MC immunophenotype (i.e. CD25 and/or CD2 expression) and KIT D816V mutation were demonstrable in the majority of pts (CD25 and/or CD2-positive BM MC: n=918, 95%; KIT D816V positive: n=910, 86%), without differences between the three groups. As a consequence, in 31% of BMM and 11% of ISM cases the diagnosis was made on the basis of minor criteria only.

BMM pts had significantly higher hemoglobin levels compared to pts with ISM/SSM (median 14.5 vs 13.9 g/dL, respectively, p<.001) while platelet and leukocyte counts were comparable in the three groups. AP was significantly different between BMM (median 67 U/L, range 19-142), ISM (median 75 U/L, range 30-317) or SSM pts (median 116 U/L, range 38-345) (p<<.001). Median basal tryptase level was 22.4, 34.3 and 200 ng/mL for BMM, ISM and SSM respectively (p<.001).

BMM pts had less frequent and less severe (grade 0-2) mediator-related symptoms as compared to ISM/SSM, except for hypotension, mainly due to the association of BMM with severe allergic reactions. Indeed, 76% of the BMM pts had a history of anaphylaxis, a significant difference compared to ISM or SSM pts (34% and 31%, respectively; p<.001). Of note, hymenoptera venom was the single trigger of anaphylaxis in 61.5% of BMM pts, while allergy/hypersensitivity to drugs or food was mainly reported in ISM (13%) and SSM pts (17.8%) but less frequently in BMM (7%). Osteoporosis/osteopenia were documented in 51% and 43% of BMM and ISM/SSM pts, respectively (p=0.026).

Long-term prognosis was similar for all groups, even though SSM tended to a less favourable course: EFS at 10 years was 88.9% (95%CI: 73.6-95.6) for BMM, 88.1% (95%CI: 83.4-91.6) for ISM and 78.8% (95%CI:55.7-90.8) for SSM (p=0.2).

Conclusions. BMM is a distinct subgroup of non-advanced SM characterized by male predominance, low burden of neoplastic MC, low level of serum tryptase and AP, limited frequency and severity of mediator-related symptoms, except hypotension, and a striking association with anaphylaxis, mainly triggered by hymenoptera. These data support the proposal of considering BMM as a distinct variant of mastocytosis.