A multicentre UK snapshot audit of symptom burden in patients with indolent systemic mastocytosis utilising the ISM-SAF ©

Abstract

Abstract Background: Indolent systemic mastocytosis (ISM) is a rare clonal haematological neoplasm driven by KIT D816V mutation in 95% of cases leading to uncontrolled proliferation and accumulation of mast cells. It can be associated with debilitating mast cell mediator symptoms affecting skin, gastrointestinal (GI) tract, neurocognitive function, bone turnover and anaphylaxis which significantly impact quality of life. Treatment is limited to symptom management and there are no approved targeted therapies available in the UK. The ISM symptom assessment form (ISM-SAF ©; Taylor et al.[2021]) is a validated and effective symptom assessment tool developed specifically for ISM patients focusing on 11 symptoms over a 24-hour recall period: bone pain, abdominal pain, nausea, skin spots, itch, flushing, fatigue, dizziness, brain fog, headache and diarrhoea. Each symptom is scored on a scale from 0 (no symptom) to 10 (worst imaginable symptom). We present UK-wide data of 101 patients from four centres as a re-audit of a previous single-centre cohort of 76 patients by Veitch et al.[2023]. Methods: Adults with ISM diagnosed on a bone marrow biopsy and/or extracutaneous tissue as per World Health Organization classification were identified between June 2023 to July 2025 retrospectively. 101 patients participated across four centres in the UK [Guy′s and St Thomas' Hospital (68), University College London Hospital (14), St James University Hospital (10) and Nottingham University Hospital (9)]. Over a four-week period, patients were invited to complete the ISM SAF © by telephone or in person. Demographic, clinical data, anti-mediator therapy and anaphylaxis history were also collected. This study also focused on the impact of ISM on bone health, quality of life and working hours. All consultations were conducted by a haematology clinician in each institute. Results: Of the 101 patients, median age at diagnosis was 46 years (range 11-76) with female predominance (62.4%). Median time to ISM diagnosis was 4.1 years (range 0.1-55.6). Median latest serum tryptase was 37.5 mcg/L (range 7.9-196; n=99) and 2 patients had levels >200 mcg/L. 88 patients (87.1%) were noted to have the KIT D816V mutation (6.9% KIT D816V-negative, 4.9% not available and 0.99% equivocal). Bone marrow trephine mast cell infiltrate ranged between 2-70%. 30 patients (29.7%) had a history of anaphylaxis at least once in their lifetime and 6.6 % (n=2) reported using an adrenaline autoinjector within the last 12 months. The median total symptom score (TSS) was 31 (range 0-90). The highest scoring symptom was fatigue (mean score 5.1) followed by skin spots (mean score 4), flushing (mean score 3.7), brain fog (mean score 3.5) and itch (mean score 3.4). 55 patients (54.5%) had a TSS ≥28 and 35 patients (34.7%) had TSS of ≥42 indicating moderate and severe disease, respectively. 89 patients had a DEXA scan of which 16 patients (17.9%) had osteoporosis, 32 (35.9%) had osteopenia. 10 of 16 patients (62.5%) with osteoporosis were on bisphosphonate therapy. ISM is a recognised contributor to bone density loss and bone pain. Among patients with moderate disease (TSS ≥28), 41 patients (74.5%) were on ≥2 medications (needing combinations of up to 5 different classes of anti-mast cell mediator therapies). Medications included H1 antihistamines (n=89), H2 antihistamines (n=49), proton pump inhibitors (n=22), sodium cromoglicate (n=23), montelukast (n=12), oral corticosteroid (n=1) and omalizumab (n=3). 18 patients (17.8%) had to take time off their work in the last year due ISM related symptoms (range 1-90 days) and 11 patients (10.8%) reported reducing their working hours or retiring early because of ISM. Conclusion: Our re-audit highlights an additional 101 ISM patients across 4 centres in the UK with significant real-world symptom burden. This aligns with findings from the previous single-centre audit and the PRISM study (M. Triggiani et al. [2025]). This is the first UK audit to verify the impact of symptom burden on quality of life, 28.6% of patients having to adjust their working practice due to their ISM. A significant proportion of patients, 40.5% had TSS ≥28 and required two or more anti-mediator therapies. This compares to the original audit (36%), indicating a substantial unmet need in many patients receiving currently available standard therapies. These patients may benefit from treatment with tyrosine kinase inhibitors, presently accessible onlythrough clinical trials in the UK.