Olivier Lortholary

Mastocytosis can lead to organ failure as well as systemic symptoms that can be disabling, with considerable deterioration in quality of life. Beside symptomatic treatments, interferon-α and purine analogues have been shown to be effective but complete or long-term remission is rarely obtained with these drugs. We conducted a phase II, multicentre, study to investigate thalidomide in severely symptomatic indolent and aggressive systemic mastocytosis. Twenty patients were enrolled of whom 16 were analysed for response. The overall response rate was 56%. Responses were observed in the skin in 61% of patients with a significant decrease in the pruritus score. Mast cell mediator-related symptoms responded in 71% of cases and 25% of aggressive systemic mastocytosis patients had a response in terms of B/C findings (borderline/cytoreduction needed). Bone marrow mast cell infiltration decreased in five of the eight evaluable patients. There was no significant improvement in the AFIRMM (Association Française pour les Initiatives de Recherche sur le Mastocyte et Les Mastocytoses), Quality of Life or Hamilton scores. Grade 3-4 toxicities consisted of peripheral neuropathy (11%) and myelosuppression (neutropenia: 5%; thrombocytopenia: 11%). In conclusion, thalidomide might be useful in mastocytosis and in the treatment of mast cell-related symptoms. It might be considered in selected patients, taking into account the benefit/risk balance and the individual patient evaluation.

Background: mutation and/or aberrant expression of CD2 and/or CD25 on bone marrow (BM) mast cells (MCs), but without MC activation syndrome (MCAS) criteria. Methods: We included eligible patients from two countries diagnosed between 2011 and 2021. These patients are reported herein as monoclonal MC with clinical significance (MMCS). MMCS patients were compared with 432 patients with indolent SM (ISM) and 51 with BM mastocytosis (BMM) from the CEREMAST database. Findings: 816 mutation did not differ significantly with regard to the prevalence of anaphylaxis and basal tryptase level. Anaphylaxis, often in the context of hymenoptera venom allergy, was more frequent in MMCS than in ISM (78% vs 35%, respectively; p < 0.001). Osteoporosis was similarly prevalent in MMCS and BMM (45% vs 32%, p = ns). The median baseline serum tryptase level was lower in MMCS compared with ISM or BMM (13 vs 26 vs 23 ng/mL, respectively; p < 0.001). Hereditary alpha-tryptasemia was similarly represented in MMCS and BMM (14.3% vs 19.7% respectively, p = ns). Interpretation: Clonal BMMCs may be associated with clinically relevant symptoms even if criteria for SM or MCAS are not fulfilled. These MMCS patients may require specific management and follow-up to capture potential transition to SM and/or MCAS. Funding: None.

Mastocytosis, a clonal disorder characterized by the accumulation of mast cells in various tissues, affects both adults and children. Adults frequently exhibit KIT activating mutations, usually in the phospho-transferase domain (PTD KIT mutations). Our previous findings revealed that children also harbor oncogenic KIT activating mutations, but more commonly within the extra-cellular domain (non-PTD KIT mutations). While the disease persists chronically in adults, it often regresses spontaneously in children through an unknown mechanism. Here, we report that tumor senescence in childhood mastocytosis may be triggered by significantly shortened telomeres in mast cells harboring non-PTD KIT mutations compared to those with PTD KIT mutations. In vitro models further demonstrated a senescent phenotype associated with shorter telomeres for the non-PTD KIT mutant compared to the PTD KIT mutant. Mechanistically, we found that telomere shortening in mast cells from children with non-PTD KIT mutations is linked with increased p38 MAP-kinase activation, resulting in lower TRF2 occupancy on telomeres. Thus, non-PTD KIT mutations trigger distinct signaling pathways leading to telomere shortening and cellular senescence, providing mechanistic insights into the differing outcomes between childhood- and adult-onset mastocytosis.