Avapritinib Yields Improvements in Bone Density in Advanced Systemic Mastocytosis

Significant and sustained improvements in bone density were observed in patients with systemic mastocytosis treated with avapritinib (Ayvakit), as indicated by improvements in lumbar T-scores over more than 3 years of follow-up, according to data from a subset of patients who underwent serial bone dual-energy X-ray absorptiometry (DXA) scans in the phase 2 PATHFINDER study (NCT03580655).1

Findings presented during the 2024 ASH Annual Meeting showed that among patients in the DXA scan–evaluable population who received avapritinib (n = 56), T-scores in the low bone density cohort (BDlow; n = 12) improved from –2.44 at baseline to –1.63 at the time of their last visit (P = .034). The mean time to best improvement in T-score in this group was 11.5 months at first DXA measurement.

Mean lumbar T-scores were stabilized in the normal (BDnorm; n = 23; P = .82) and high bone density (BDhigh; n = 21; P = .55) cohorts. In the BDlow, BDhigh, and BDnorm cohorts, T-scores from baseline to last visit were improved or stable in 92%, 67%, and 83% of patients, respectively.

Furthermore, avapritinib improved myelofibrosis and osteosclerosis in the evaluable population. Notably, of the 5 patients with osteoporosis in the BDlow population, characterized as a T-score of –2.5 or less, T-scores improved in 4 patients and remained stable in 1 patient.

“[Overall,] we were able to show that…osteopenia, osteoporosis, and osteosclerosis all improved with sequential measurements while on the PATHFINDER study,” study author Daniel DeAngelo, MD, PhD, stated in an exclusive interview with OncLive®. “It’s not normal for a young [patient] to have multiple compression fractures, and many of these patients do have systemic mastocytosis, so that's one of the issues that is nice to finally have some data on.”

DeAngelo is a professor of medicine at Harvard Medical School as well as chief of the Division of Leukemia and an institute physician at Dana-Farber Cancer Institute in Boston, Massachusetts.

Systemic mastocytosis is a rare clonal hematologic neoplasm encompassing a spectrum of disease. Most cases of systemic mastocytosis are driven by the KIT D816V mutation.

“Systemic mastocytosis…comes in basically 2 distinct forms: advanced systemic mastocytosis, which is very life-threatening and difficult to treat, and then indolent systemic mastocytosis,” DeAngelo said. “There are 3 [advanced systemic mastocytosis subtypes]: aggressive systemic mastocytosis, systemic mastocytosis with associated hematologic neoplasm [SN-AHN], and mast cell leukemia.”

Bone disease is a common comorbidity in systemic mastocytosis. Low bone density, classified as either osteopenia or osteoporosis, is primarily associated with indolent systemic mastocytosis. Conversely, high bone density, or osteosclerosis, is more commonly linked with advanced systemic mastocytosis and correlates with poorer prognosis.

Avapritinib, a selective KITD816V inhibitor, is FDA approved for patients with indolent and advanced systemic mastocytosis and has demonstrated durable efficacy across all advanced systemic mastocytosis subtypes and prior treatment statuses.

Updated findings from the PATHFINDER trial presented at the 2024 EHA Congress affirmed the agent’s ability to produce deep, sustained responses.2 The overall response rate with the agent in the overall evaluable population (n = 83) was 73% (95% CI, 63%-83%), including a complete remission/complete remission with partial hematologic recovery rate of 29%. Additionally, the median overall survival (OS) among patients treated with avapritinib (n = 107) was not reached after 3 years of follow-up, and the OS rate at 36 months was 75% (95% CI, 66%-83%).

“PATHFINDER showed that avapritinib is the [current] standard of care for treatment of patients with advanced systemic mastocytosis,” DeAngelo detailed. “Midostaurin [Rydapt] was the first multi-kinase inhibitor [to be FDA] approved in advanced systemic mastocytosis [in 2017]. However, the responses [with this agent] are not as durable, and there's a lot of toxicity, so it's hard to tolerate. [In PATHFINDER,] regardless of the histologic subtype, [there were] very high, durable response rates [with avapritinib], leading to what seemed to be improved survival based on historical controls.”

In the analysis presented at the 2024 ASH Annual Meeting, investigators sought to understand the effect of avapritinib on bone density in patients with advanced systemic mastocytosis who were enrolled in the international, multicenter, open-label, single-arm, PATHFINDER study.1,2 Patients were required to be at least 18 years of age, have a centrally confirmed diagnosis per World Health Organization criteria, and an ECOG performance status of 0 to 3.1 Of the 107 patients originally enrolled onto the study, 2 initiated a 100-mg daily dose of avapritinib; the rest received a 200-mg daily starting dose of avapritinib. The data cutoff date was September 15, 2023.

Optional DXA scans were performed at baseline and approximately every 12 months during treatment with avapritinib, following local procedures at participating study centers. Patients were stratified into groups based on baseline lumbar T-scores, categorized into the BDlow, BDhigh, and BDnorm cohorts according to whether they had T-scores less than –1, greater than 1, or between –1 and 1, respectively. The timing of the last DXA evaluation varied by patient. Additionally, myelofibrosis and osteosclerosis scores were assessed at baseline and at weeks 8, 24, and 40 to monitor changes in these parameters over the course of treatment.

Serial DXA scans were available for 52% of enrolled patients at baseline and at 2 or more follow-up visits, with a median of 3 visits (range, 2-6). The median duration from baseline to the last DXA scan was 22 months (range, 3.7-55). At baseline, 21% of patients had low bone density, and 38% exhibited high bone density.

Baseline demographic and disease characteristics of patients with serial DXA scans were consistent with that of the overall study population, and no significant differences were observed among the 3 bone density cohorts (P > 0.1 for all comparisons). The mean age of patients in the DXA scan–evaluable population was 69 years vs 65 years in the overall study population. A total of 48% and 42% of patients in these respective patient populations were female; of those, 93% and 91%, respectively, were postmenopausal. The majority of patients had the SM-AHN subtype (73%; 66%).

In the DXA scan–evaluable population, the mean bone marrow mast cell (BMMC) burden score was 47.5% (standard deviation [SD], ±25.8%), and the median was 50% (range, 10%-95%); respective scores were 46.8 (± 26.5) and 40% (range, 1%-95%). The mean basal serum tryptase levels were 286.6 (/1 253.5) in the DXA-scan group and 331.5 (± 291.9) in the overall population. The mean KIT D816V variant allele frequencies in peripheral blood were 20.8% (SD, ±16.4%) vs 18.6% (SD, ±16.4%), respectively,

Notably, 4 patients in the BDlow group had a history of bone fractures before study enrollment, with 1 patient experiencing an additional fracture during the study.

There were no substantial differences in the mean dose of avapritinib or the duration of avapritinib treatment across all 3 bone density groups. In the DXA scan–evaluable population, the mean duration of treatment was 27.1 months (SD, ±8.6) and the median was 25.8 months (range, 6-44.1). Notably, 59% of patients were treated with concomitant corticosteroids, followed by calcium or vitamin D (46%) and bisphosphonates (7%).

Additional Data from Histopathology and Bone Marrow Pathology Assessments

Histopathology assessments of myelofibrosis demonstrated improvements in all 3 bone density cohorts, as evidenced by a shift to lower scores. In the BDlow cohort, the percentage of patients with a myelofibrosis score of 0 to 1 at baseline increased from 55% to 90% by their last visit; the proportion of patients with a score of 2 or 3 at baseline (45%) decreased by the last visit (10%). Similar trends were observed in the BDhigh and BDnorm subgroups, with the percentage of patients with a myelofibrosis score of 0 to 1 increasing from 48% to 84%, and 50% to 85%, respectively.

Assessment of osteosclerosis histopathology also showed notable improvements in patients with high baseline scores. In the BDlow cohort, the percentage of patients with an osteosclerosis score of 0 to 1 at baseline (80%) increased to 100% by their last visit. In the BDhigh and BDnorm subgroups, the percentage of patients with a score of 0 to 1 increased from 60% to 73%, and 59% to 93%, respectively.

In the DXA scan–evaluable patient population, bone marrow cellularity and the proportion of patients with BMMC aggregates decreased from first to last pathology assessment. The baseline mean cellularity in the BDlow, BDhigh, and BDnorm groups were 88% (SD, ±13%), 91% (SD, ±13%), and 89% (SD, ±15%), respectively; at their last visit, cellularity in these respective cohorts decreased to 58% (SD, ±23%), 55% (SD, ±24%), and 52% (SD, ±27%). The presence of BMMC aggregates in decreased from 100% at baseline to 42% at the last visit in the BDlowgroup, 95% to 14% in the BDhigh group, and 100% to 26% in the BDnorm group.

“For the first time, we’re seeing some dramatic improvements with one of the major complaints that patients [with systemic mastocytosis] have, which is osteoporosis, osteopenia, and compression fractures,” DeAngelo emphasized. “Whether this [benefit] extends to patients with indolent systemic mastocytosis with lower dosing, or with other agents, is unclear.”

Accordingly, study investigators concluded that future studies are needed to evaluate the potential of avapritinib to improve bone health in systemic mastocytosis, particularly in indolent systemic mastocytosis, where osteopenia and osteoporosis are highly prevalent.

References

1. Luebke J, George T, DeAngelo D, et al. Disease-modifying effects of avapritinib in patients with advanced systemic mastocytosis: improvements in bone density. Blood. 2024;144(suppl 1):4544. doi:10.1182/blood-2024-193774
2. Reiter A, Gotlib J, Radia DH, et al. Avapritinib in patients with advanced systemic mastocytosis (AdvSM): efficacy and safety analysis from the phase 2 PATHFINDER study with 3-year follow-up. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract S224.