Disease-Modifying Effects of Avapritinib in Patients with Advanced Systemic Mastocytosis: Improvements in Bone Density

Background: Systemic mastocytosis (SM) is a rare, clonal hematologic neoplasm driven by the KIT D816V mutation in ~95% of cases. SM is a spectrum of diseases including advanced SM (AdvSM) and its subgroups aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL), as well as indolent SM (ISM). Avapritinib, a highly selective KIT D816V inhibitor, has been approved by the United States Food and Drug Administration and European Medicines Agency for treatment of adult patients (pts) with ISM and AdvSM. Bone disease with measurable changes (e.g. T-score, Z-score) in bone density (BD) at various anatomic sites, assessed by dual-energy X-ray absorptiometry (DXA) scans, is among the most frequent morbidities in SM. Prevalence of low (osteopenia, osteoporosis) and high (osteosclerosis) BD in SM ranges between 30% and 50% and varies among SM subgroups, with ISM at the higher end of this range. Here, we report the effect of avapritinib on BD in AdvSM from a subset of pts enrolled in the PATHFINDER (NCT03580655) study. Methods: DXA scans measuring lumbar spine T-score were the most common bone evaluations, performed at screening and approximately every 12 months during avapritinib treatment, according to local procedures at study centers. Pts were grouped according to baseline T-score into low BD (BDlow, T-score <-1), high BD (BDhigh, T-score >1), or normal BD (BDnorm, T-score ≥-1 and ≤1). Bone marrow mast cell (BMMC) infiltration, basal serum tryptase (BST) levels, and KIT D816V variant allele frequency (VAF) were centrally assessed as objective markers of mast cell (MC) disease burden. Paired t-tests compared measurements obtained at baseline and the last visit available. Results: Serial DXA scans were available in 56/107 (52%) enrolled pts (ASM, n=9, 16%; SM-AHN, n=41, 73%; MCL, n=6, 11%) at baseline and at ≥2 follow-up visits (median 3; range 2-6). Baseline demographic parameters and markers of MC disease burden in pts with serial DXA scans were not significantly different from those without serial DXA scans. The median age was 69 (range 52-88) years; 52% of pts were male. Mean BMMC infiltration was 47.5% (SD±25.8), mean BST level was 286.6 ng/mL (SD±253.5), and mean KIT D816V VAF was 20.8% (SD±16.4). Concomitant anti-bone-resorptive therapy (bisphosphonates and/or denosumab) was administered to 11 (20%) pts. Between baseline and last visit (median 22 months; range 3.7-54.9), the mean lumbar T-score for BDlow pts (n=12, including 1 pt with MCL) improved significantly from -2.44 (SD±0.46) to -1.63 (SD±1.25) (P=0.034). In this group, the lumbar T-score increased by ≥0.5 in 7 (58%) pts (mean increase 1.53; SD±1.01), remained stable (change <0.5) in 4 (33%) pts and decreased by ≥0.5 in 1 (8%) pt. In 5/12 (42%) pts with a T-score ≤-2.5, T-score improved in 4 (80%) pts and remained stable in 1 (20%) pt. Mean lumbar T-scores remained stable in BDhigh (n=21; 2.92 [SD±1.60] at baseline, 2.87 [SD±1.92] at last visit) and BDnorm(n=23; 0.00 [SD±0.49] at baseline, 0.10 [SD±0.80] at last visit) pts. Responses of BMMC infiltration, BST levels, and KIT D816V VAF were not different across the three BD cohorts. In the BDlow cohort, the improvement in BD was accompanied by decreases in BMMC infiltration from 36.4% (SD±25.2) to 7.6% (SD±11.4) (P=0.004), BST levels from 277.7 ng/mL (SD±316.7) to 43.9 ng/mL (SD±64.8) (P=0.025), and KIT D816V VAF from 19.1% (SD±18.8) to 6.6% (SD±11.4) (P=0.011). Conclusions: With >3 years of follow-up, avapritinib elicited improvements in low bone density as reflected by improvements in the lumbar T-score. These results are relevant to all SM subtypes, especially ISM where the high prevalence of osteopenia and osteoporosis remains a challenging, unmet need.