Bonadonna, Patrizia

Abstract Introduction: Indolent systemic mastocytosis (ISM) is a clonal mast cell disease driven by the KIT D816V mutation in ~95% of cases and is associated with symptoms of mast cell activation and tissue infiltration. It can cause chronic, debilitating symptoms − including life-threatening anaphylaxis and impaired bone health. While historically most patients have relied on symptom-directed best supportive care (BSC) therapies, avapritinib is used as a new standard of care targeting KIT D816V, the primary driver for SM. Avapritinib is an oral, potent, selective KIT D816V inhibitor, and the first and only approved targeted therapy for adult patients with ISM in the USA and the EU. Approval was based on results from the phase 2 PIONEER trial. Here, we present the findings from ~3.5-year long-term follow-up. Methods: Adults with centrally confirmed ISM and uncontrolled moderate-to-severe symptoms who completed the randomized dose-finding (Part 1), or randomized, double-blind, placebo-controlled (Part 2) portions of PIONEER (NCT03731260) rolled over to the open-label, long-term extension (Part 3). This cumulative analysis includes patients who initiated avapritinib at the recommended dose of 25 mg once daily (QD) in either Parts 1, 2, or 3. All patients received BSC. Per investigator discretion and based on disease burden, dose titration up to 50 mg QD of avapritinib was permitted in Part 3. Long-term efficacy was assessed by measuring changes in symptoms and QoL, using the ISM-Symptom Assessment Form (ISM-SAF; ©2018 Blueprint Medicines, a Sanofi Company) and the Mastocytosis Quality-of-Life Questionnaire (MC-QoL). Safety was also assessed. Results: Overall, 226 patients initiated avapritinib 25mg QD across Parts 1, 2, and 3. This longer-term analysis is inclusive of 65 patients who dose titrated from 25 mg to 50 mg QD in Part 3. Median (range) treatment duration was 40.0 months (0.7‒67.2) as of February 21, 2025. Longer-term efficacy data with ~3.5 years of follow-up demonstrated sustained disease-related symptom improvements. The mean change (standard deviation [SD]) in total symptom score (TSS, per ISM-SAF), was −19.80 (19.81) at Week 144 (Month 33) and −20.43 (20.57) at Week 168 (Month 39) from a baseline of 48.08 (19.47). Additionally, avapritinib-treated patients demonstrated durable improvement in their most severe symptoms (mean change [SD] from baseline of −3.35 [3.02] at Month 33 and −3.47 [3.19] at Month 39) per ISM-SAF. Sustained responses were observed across all individual symptom domains (0–30) with mean changes (SD) at Month 33 and Month 39 of −3.77 (5.52) and −3.84 (6.05) for the gastrointestinal domain, −8.21 (7.70) and −8.20 (7.85) for the skin domain, and −4.66 (6.24) and −4.87 (6.51) for the neurocognitive domain. The mean percent change (SD) in MC-QoL was −34.67 (40.16) at Month 33 and −40.72 (33.24) at Month 39 from a baseline of 54.24 (18.32). Treatment with avapritinib was well tolerated, and its safety profile was similar to the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were Grades 1–2, and 7% of patients experienced Grade ≥3 TRAEs of which diarrhea, neutrophil count decrease, and weight increase occurred in >1 patient. No Grade ≥3 TRAEs of increase in transaminases were observed. Edema (peripheral and periorbital), the most frequently reported TRAE, was mostly Grade 1 and occurred most frequently during the first 3–4 months of treatment. Three patients (1%) experienced serious adverse events assessed as treatment related. However, none led to treatment discontinuation and no trends were observed. After approximately 3.5 years of follow-up, low rates of treatment discontinuations (n=7, 3%) due to TRAEs were observed. Conclusion: Longer follow-up of patients with ISM treated on the PIONEER trial, including some on avapritinib for up to 5 years, demonstrates that prolonged avapritinib therapy continues to be effective and well tolerated. Additional prospective analyses will be needed to determine effects of selective KIT D816V-inhibition on anaphylaxis. These data support a favorable benefit-risk profile of avapritinib as a chronic treatment for adult patients with ISM.

Mastocytosis is a hematologic neoplasm characterized by expansion and focal accumulation of neoplastic mast cells (MC) in diverse organs, including the skin, bone marrow (BM), spleen, liver, and gastrointestinal tract. The World Health Organization classification divides the disease into prognostically distinct variants of cutaneous mastocytosis (CM) and systemic mastocytosis (SM). Although this classification remains valid, recent developments in the field and the advent of new diagnostic and prognostic parameters created a need to update and refine definitions and diagnostic criteria in MC neoplasms. In addition, MC activation syndromes (MCAS) and genetic features predisposing to SM and MCAS have been identified. To discuss these developments and refinements in the classification, we organized a Working Conference comprised of experts from Europe and the United States in August 2020. This article reports on outcomes from this conference. Of particular note, we propose adjustments in the classification of CM and SM, refinements in diagnostic criteria of SM variants, including smoldering SM and BM mastocytosis (BMM), and updated criteria for MCAS and other conditions involving MC. CD30 expression in MC now qualifies as a minor SM criterion, and BMM is now defined by SM criteria, absence of skin lesions and absence of B- and C-findings. A basal serum tryptase level exceeding 20 ng/mL remains a minor SM criterion, with recognition that hereditary alpha-tryptasemia and various myeloid neoplasms may also cause elevations in tryptase. Our updated proposal will support diagnostic evaluations and prognostication in daily practice and the conduct of clinical trials in MC disorders.