Long-Term Avapritinib Use Improves Bone Health Regardless of Concomitant Anti-Osteoporosis Therapy in Indolent SM

Long-term use of avapritinib (Ayvakit) improved bone mineral density (BMD) in patients with indolent systemic mastocytosis (SM) and uncontrolled moderate-to-severe symptoms, regardless of whether anti-osteoporosis therapies were also administered, according to long-term data on changes in bone health from the phase 2 PIONEER trial (NCT03731260) shared at the 2025 ASH Annual Meeting.¹

Among patients with both baseline and 1 or more post-baseline DXA scans (n = 79), increases in mean BMD from baseline at 1 year and 3 years of treatment with avapritinib were observed in the lumbar spine (1 year, 1.66%, standard deviation [SD], 5.57%; 3 years, 4.05%, SD, 5.78%), left total hip (2.19%, SD, 4.25%; 3.31%, SD, 5.75%), and left femoral neck (1.62%, SD, 5.90%; 2.08%, SD, 6.10%).

In an interview with OncLive®, Tsewang Tashi, MD, discussed these bone health findings, noting how they reinforce the importance of baseline and follow-up DXA scans for patients with indolent SM, and support the enactment of longitudinal follow-up studies assessing changes in BMD and bone dysregulation with KIT-targeted therapies in larger patient cohorts.

“It is important to remember that osteoporosis is one of the major morbidities in indolent mastocytosis patients,” Tashi, a hematologist/oncologist at the University of Utah Huntsman Cancer Institute in Salt Lake City, asserted. “We still need to gather better data regarding the precise [effect] on bone health when mastocytosis is managed with KIT inhibitors.”

In another portion of the interview, Tashi expanded on the long-term efficacy and safety data from part 3 of the PIONEER trial, which were concurrently presented during ASH 2025. These results showed deep and durable symptom control and tolerability with avapritinib at a median follow-up of 3 years and were comparable with the 24-week follow up data shown in part 2 of the trial.²

OncLive: What are some common bone health concerns associated with indolent SM?

Tashi: Indolent SM is associated with premature bone loss, such as osteopenia and osteoporosis. It is seen in [approximately] one-third to half of patients and can lead to an increased risk for fractures. [Although] we still do not know the exact mechanism, we believe it is strongly associated with the underlying disease: mastocytosis. Managing the disease may have a positive effect on bone health, and we are currently trying to examine that.

What methods were used in the bone health analysis of the PIONEER study?

The PIONEER study was the first study conducted in indolent SM. As the protocol was initially written, bone health was not part of the primary or secondary analyses. [Consequently], the bone health data were mainly [collected] retrospectively. It is important to keep in mind when interpreting the data that assessing bone density using DXA scans was optional per the protocol. There were [246] total patients [enrolled onto] the PIONEER study.¹ [However], bone density assessments were only available for [79] of those patients.

What results from the bone health analysis of avapritinib use in indolent SM were reported at ASH 2025?

We retrospectively analyzed those patients who had DXA scans. Many of those who had osteoporosis or osteopenia were also receiving anti-osteoporosis therapy, which is one of the confounding factors to consider when interpreting these data. Overall, however, the bone density data showed that treatment with avapritinib in these patients demonstrated a trend toward increased BMD. [This indicates] a positive [effect of avapritinib] on bone health, regardless of whether patients were receiving concurrent osteoporosis therapy.

How might these data, in addition to other ongoing analyses of bone health in indolent SM, inform clinical practice going forward?

The [phase 2/3] HARBOR trial [NCT04910685] is currently ongoing, evaluating the newer KIT inhibitor elenestinib [(BLU-263) in patients with indolent SM].³ Effects on bone health are some of the major secondary end points being examined in that trial. We expect to get much cleaner and better data once that trial is conducted and the results are available.

Overall, the overarching message is that indolent SM—and SM in general—is associated with premature osteoporosis and osteopenia. It is vital to follow these patients and treat them appropriately; we will have clearer data on the effect of treating the underlying mastocytosis on bone health after the HARBOR trial data are released in the future.

References

1. Castells M, Sundaresh V, Gotlib J, et al. Changes in long-term bone health in patients receiving avapritinib for the treatment of indolent systemic mastocytosis in the PIONEER Study. Blood. 2025;146(suppl 1):5582. doi:10.1182/blood-2025-5582
2. Tashi T, Elberink HO, Akin C, et al. Avapritinib achieves deep and durable symptom control with a well-tolerated safety profile in ism: long-term outcomes from pioneer. Blood. 2025;146(suppl 1):2024. doi:10.1182/blood-2025-2024
3. (HARBOR) study to evaluate efficacy and safety of BLU-263 versus placebo in patients with indolent systemic mastocytosis. ClinicalTrials.gov. Updated November 3, 2025. Accessed January 6, 2026. https://clinicaltrials.gov/study/NCT04910685