Changes in long-term bone health in patients receiving avapritinib for the treatment of indolent systemic mastocytosis in the pioneer study

Abstract

Abstract Introduction: Indolent systemic mastocytosis (ISM) is a clonal mast cell disease driven by the KIT D816V mutation in ~95% of patients and is associated with symptoms of mast cell activation and tissue infiltration. ISM is associated with increased risk for osteoporosis (~25%), osteopenia (~30%), and fragility fractures (~30% lifetime risk). Impaired bone health may reflect increased mast cell–derived cytokines that promote bone resorption and decreased bone formation. An increase in bone mineral density (BMD) of 1.4–3.2% may reduce the fracture risk in primary osteoporosis. 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. In a previous subset analysis of data from a single site (n=15) from the phase 2, randomized, PIONEER study (NCT03731260), patients with ISM treated with avapritinib had improvements in BMD. We expanded that analysis of BMD across PIONEER and examined changes in the bone turnover marker, tartrate-resistant acid phosphatase 5b (TRAcP-5b; associated with osteoclast activity; typically elevated in primary osteoporosis), to comprehensively assess bone health in patients with ISM receiving avapritinib. Methods: Adults with centrally confirmed ISM and uncontrolled moderate-to-severe symptoms, despite treatment with ≥2 best supportive care (BSC) medications, were eligible for enrollment in PIONEER. Physician-reported medication use supporting BMD was collected at enrollment and throughout the study. Optional dual-energy X-ray absorptiometry (DXA) scans assessed BMD at screening, at 6 months in Part 2, and at 12 months and annually thereafter in Part 3. TRAcP-5b was retrospectively measured in healthy donors and in the subgroup of patients with plasma samples at baseline and while on therapy. Paired t-test was used for comparing TRAcP-5b at baseline and 48 weeks of avapritinib, and Welch's t-test for comparing baseline TRAcP-5b in patients versus healthy donors. Results: In total, 79 patients (median [range] age 51.0 [22–73] years; 75% female) receiving avapritinib had baseline and ≥1 post-baseline DXA scans. Of these, 13 patients (16%) used anti-osteoporosis therapy while receiving avapritinib. Mean (standard deviation [SD]) BMD at baseline for the lumbar spine, left hip, and left femoral neck was 1.02 (0.18) g/cm2, 0.93 (0.14) g/cm2, and 0.84 (0.16) g/cm2, respectively. Mean (SD) percent change in lumbar spine BMD was 1.66% (5.57%) at Year 1 (n=59) and 4.05% (5.78%) at Year 3 (n=26). Mean (SD) percent change in left hip BMD at Year 1 (n=37) and Year 3 (n=24) was 2.19% (4.25%) and 3.31% (5.75%), respectively. Corresponding value for the left femoral neck at Year 1 (n=43) was 1.62% (5.89%) and Year 3 (n=24) was 2.08% (6.10%). Increases in BMD were seen regardless of concomitant anti-osteoporosis therapy with avapritinib: mean lumbar BMD at Year 3 was 3.0% in 6 patients taking anti-osteoporosis medications and 4.4% in 20 patients not receiving such therapy. TRAcP-5b was measured in 20 age- and sex-matched healthy donors and 131 patients with ISM (median [range] age: 52 [22–79] years; 75% female). Of these, 90 patients had paired baseline and treatment samples tested. Baseline TRAcP-5b concentration was significantly lower in patients receiving avapritinib (mean [SD], 1.66 [0.91] U/L; n=90; P<0.05), compared to healthy donors (mean [SD], 2.72 [1.82] U/L; n=20). This was observed with and without concomitant anti-osteoporosis therapy: 1.55 (0.94) U/L (n=14; P<0.05) and 1.68 (0.90) U/L (n=76; P<0.05), respectively. By Week 48, TRAcP-5b concentration significantly increased above baseline toward the normal range in patients receiving avapritinib (mean [SD], 2.08 U/L [1.05]; n=90); P<0.05), including those not receiving concomitant anti-osteoporosis therapy (mean [SD], 2.09 U/L [1.09]; n=76; P<0.05). Conclusion: Long-term avapritinib therapy (~3 years) led to improvements in BMD. These favorable changes were observed regardless of concomitant use of other medications known to increase bone density. Unexpectedly, TRAcP-5b was lower at baseline in patients with ISM from PIONEER compared to healthy donors and an increase in TRAcP-5b was observed while on avapritinib. These results provide an impetus for pursuing longitudinal follow-up studies assessing changes in BMD and bone dysregulation with KIT D816V-targeted therapy in larger cohorts of patients with ISM.