In the absence of objective disease-modifying markers, improving symptom burden and quality of life for patients with indolent systemic mastocytosis remains paramount in ongoing research, such as the ongoing phase 2/3 HARBOR trial (NCT04910685) evaluating the next-generation , KIT D816V inhibitor elenestinib (BLU-263), according to Deepti Radia, MBBS, BSc, MRCPI, FRCPath, MSc Med Ed.
“Patients with indolent systemic mastocytosis do not have significant end-organ damage. However, they have impaired quality of life quite significantly, despite optimal symptomatic management, because the release of the mast cell mediators, and that can have an impact,” Radia said. “That's been the rationale for all the trials for [patients with] indolent systemic mastocytosis.
HARBOR Trial: Elenestinib in Indolent Systemic Mastocytosis
- Elenestinib is a novel, oral, next-generation TKI featuring high selectivity and potency for KIT D816V mutations.
- Data from part 1 of the HARBOR trial showed that in patients with indolent systemic mastocytosis, elenestinib was well tolerated and improved biomarkers of disease burden across multiple dose levels compared with placebo.
- The ongoing part 2 of HARBOR is randomly assigning patients with indolent mastocytosis to receive elenestinib at 75 mg per day or placebo for up to 48 weeks, with the option to continue treatment during part 3, an open-label extension.
Following a readout of positive data from part 1 of the HARBOR trial, additional parts of the study are ongoing to further explore a potential role for elenestinib in the treatment of patients with indolent systemic mastocytosis.1,2
What is elenestinib’s mechanism of action, and why is it being investigated in indolent systemic mastocytosis management?
Approximately 95% of patients with systemic mastocytosis harbor a KIT D816V mutation, which has been identified as a driver of disease via an increased accumulation of aberrant mast cells in the bone marrow, skin, gastrointestinal tract, and other organs.2 This accumulation may lead to chronic, potentially life-threatening symptoms that affect quality of life.
Although monoclonal mast cell activation syndrome does not cross the threshold for systemic mastocytosis per the World Health Organization diagnostic criteria, KIT D816V mutations are also a hallmark for this condition.
“We are looking at these targeted inhibitors to see if they [can] improve symptoms, but [they] potentially could be disease-modifying at lower doses than we're using for patients with advanced systemic mastocytosis,” Radia explained. “Patients with indolent systemic mastocytosis are anticipated to have a normal life expectancy. However, we know up to 50% to 60% of patients can have a very poor life quality.”
Targeting KIT D816V mutations is not a novel approach in indolent systemic mastocytosis. In May 2023, the FDA approved avapritinib (Ayvakit) for the treatment of adult patients with indolent systemic mastocytosis, marking the first approved therapy for this patient population.3 In 2021, avapritinib received FDA approval for the treatment of adult patients with advanced systemic mastocytosis; however, in both the indolent and advanced indications, this agent is not recommended for patients with a platelet count of less than 50 x 109/L.4
Elenestinib is a novel, oral, next-generation TKI featuring high selectivity and potency for KIT D816V mutations.2
“Avapritinib and elenestinib are both novel, potent, selective inhibitors of the KIT D816V mutation, which drives mast cell proliferation in patients with systemic mastocytosis. If you inhibit that driver, you inhibit the proliferation and expansion of the mast cells, and therefore improve symptom burden in these patients,” Radia said. “The difference between avapritinib and elenestinib, which would be the second-generation [inhibitor], is that elenestinib does not cross the blood-brain barrier, whereas avapritinib does…No intracranial hemorrhages have been seen with avapritinib in [the phase 2] PIONEER trial [NCT03731260] at the doses being used, which are 25 mg and 50 mg. Elenestinib doesn't cross the blood-brain barrier, so hopefully [it has] a safety profile that's comparable [with avapritinib], but we'll have to see what HARBOR proves.”
What data were reported from part 1 of the HARBOR trial?
Part 1 of HARBOR was a double-blinded, placebo-controlled, dose-finding study that enrolled adult patients with centrally confirmed indolent systemic mastocytosis per WHO criteria who had moderate to severe symptoms, defined as an Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) total symptom score (TSS) of at least 28.1
Patients were randomly assigned in a 1:1:1:1 fashion to receive placebo plus best supportive care (BSC; n = 10); elenestinib at 25 mg per day plus BSC (n = 10); elenestinib at 50 mg per day plus BSC (n = 10); or elenestinib at 100 mg per day plus BSC (n = 9). This portion of the study also included additional open-label cohorts to access pharmacokinetics (n = 86).
The primary end points of part 1 were safety and pharmacokinetics/pharmacodynamics. Changes at 12 weeks in regard to serum tryptase levels, bone marrow mast cell levels, KIT D816V variant allele frequency (VAF), and ISM-SAF TSS were secondary end points.
Findings from part 1 presented at the 2023 ASH Annual Meeting and Exposition showed that at a median treatment duration of 22 weeks, elenestinib was well-tolerated across all dose levels, with the majority of adverse effects (AEs) reported at grade 1 or 2. No grade 4/5 AEs, serious treatment-related AEs, or AEs leading to treatment discontinuation occurred. All patients remained on treatment at the time of data cutoff.
Furthermore, all 3 dose levels of elenestinib were associated with improvements in biomarkers of disease burden compared with placebo. The mean change in serum tryptase levels was –15.4% for elenestinib at 25 mg, –50.9% for elenestinib at 50 mg, –68.4% for elenestinib at 100 mg, and 3.3% for placebo. Regarding mean reductions in KIT D816V VAF, these respective rates were –37.5%, –70.4%, –77.0%, and –2.5%. The mean reductions in bone marrow mast cell levels were –22.6%, –28.1%, –57.9%, and –20.0%, respectively.
Clinically meaningful improvements in ISM-SAF TSS were also reported without clear dose dependence vs placebo. The mean reductions were –28.5% for elenestinib at 25 mg, –31.8% for elenestinib at 50 mg, –33.6% for elenestinib at 100 mg, and –22.2% for placebo.
How are subsequent parts of the HARBOR trial designed?
In the ongoing part 2 of HARBOR, investigators are enrolling patients at least 18 years of age with centrally confirmed indolent systemic mastocytosis per WHO diagnostic criteria who have not achieved adequate symptom control for at least 1 baseline symptom.2 Patients are also required to have an ECOG performance status of 0 to 2, and they must be receiving stable symptom-directed therapy for symptoms of indolent systemic mastocytosis for at least 14 days prior to screening.
Investigators are excluding patients who have been diagnosed with another systemic mastocytosis subclassification, such as associated hematologic neoplasm or C-findings attributable to systemic mastocytosis. Other key exclusion include treatment with radiotherapy or psoralen and ultraviolet A therapy less than 14 days prior to screening; receipt of any hematologic growth factor within 14 days of screening; or current treatment with an investigational agent in another interventional study.
In part 2, approximately 350 patients are being randomly assigned 2:1 to receive elenestinib at 75 mg per day or placebo for up to 48 weeks in a double-blinded fashion. The study also includes a cohort for patients who have received prior treatment with a KIT D816V inhibitor, and these patients are receiving elenestinib at 75 mg per day with the option to escalation to 100 mg. There is also a smoldering systemic mastocytosis cohort, where patients are receiving elenestinib at 100 mg per day.
Part 3 of the study is serving as an open-label extension, where all patients from the randomized portion of the study can receive elenestinib at 75 mg per day (with optional escalation to 100 mg) for up to 4 years.
Mean change in baseline ISM-SAF TSS is serving as the primary end point in the randomized, part 2 portion of the study. Key secondary end points in part 2 include the proportion of patients experiencing normalization of serum tryptase levels; those achieving undetectable KIT D816V VAF or at least a 50% reduction in this VAF; and patients experiencing symptom control per TSS. Other secondary end points comprise changes in bone marrow mineral density, annualized rate of anaphylaxis, and quality of life.
In the part 3, open-label extension, long-term safety and changes in ISM-SAF TSS are the primary end points. Within the post–KIT D816V inhibitor and smoldering mastocytosis cohorts, the main objectives are mean change in ISM-SAF TSS, safety and tolerability, and changes in measures of disease burden.
“It's an exciting era for patients with systemic mastocytosis. We've had good data for those with advanced disease, and the field is opening up [by] making [lives better] for patients with indolent systemic mastocytosis in terms of their quality of life,” Radia said. “We're also now finding other benefits, which hopefully will bear out in the longitudinal follow-up of these trials to make an even better difference for these patients who need it.”
References
- Tashi T, Hermine O, Castells M, et al. Elenestinib, an investigational, next generation KIT D816V inhibitor, reduces mast cell burden, improves symptoms, and has a favorable safety profile in patients with indolent systemic mastocytosis: analysis of the HARBOR trial. Blood. 2023;142(suppl 1):76. doi:10.1182/blood-2023-188904
- Castells M, Livideanu CB, Hermine O, et al. HARBOR: an ongoing phase 2/3 study of elenestinib in patients with indolent systemic mastocytosis. Presented at: 2025 AAAI/WAO Joint Congress; February 28, 2025 to March 3, 2025; San Diego, CA. Abstract 170.
- FDA approves Ayvakit (avapritinib) as the first and only treatment for indolent systemic mastocytosis. News release. Blueprint Medicines Corporation. May 22, 2023. Accessed February 5, 2026. https://ir.blueprintmedicines.com/news-releases/news-release-details/fda-approves-ayvakitr-avapritinib-first-and-only-treatment
- Ayvakit. Prescribing information. Blueprint Medicines. Updated November 2024. Accessed February 5, 2026. https://www.blueprintmedicines.com/wp-content/uploads/uspi/AYVAKIT.pdf
