Schwaab, Juliana

Background and Significance: Systemic mastocytosis (SM) is a rare heterogeneous disease characterized by the aberrant accumulation of neoplastic mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of KIT. Advanced SM (AdvSM) is a life-threatening form of SM and includes three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Despite improvement in disease control with approval of tyrosine kinase inhibitors (TKIs), there is still unmet need for improved tolerability and efficacy in AdvSM treatments. Bezuclastinib, an oral and selective type 1 TKI that potently inhibits KIT D816V, is being studied in patients diagnosed with AdvSM in the Apex study (NCT04996875). Results from the Part 1 dose optimization portion of Apex were presented previously. Part 1 randomized 32 patients 1:1:1:1 to receive bezuclastinib at 50, 100, or 200 mg BID or 400 mg QD. Initial results from the Part 1 dose optimization portion of the Apex trial in patients with AdvSM demonstrated encouraging safety profile and signs of clinical activity, as well as deep reductions across biomarkers of MC burden including bone marrow MC burden, serum tryptase levels, and KIT D816V variant allele fraction (VAF). In addition, 94%, 93%, and 100% of patients demonstrated ≥50% reduction in serum tryptase, KIT D816V VAF, and bone marrow MC burden, respectively. Exposure achieved with 100 mg BID of bezuclastinib original formulation resulted in optimal efficacy and safety outcomes. 150 mg QD of an optimized formulation is expected to deliver bezuclastinib exposures consistent with the 100 mg BID of the original formulation. Part 2 is further evaluating the efficacy and safety of bezuclastinib in patients with AdvSM at the selected Part 2 dose of 150mg QD of the optimized formulation. Study Design and Methods: Apex is a multicenter, Phase 2 open-label study of bezuclastinib in patients with AdvSM as defined per the WHO criteria. Enrollment includes previously treated and treatment-naïve patients. Part 2 is enrolling approximately 65 patients including up to 15 patients without measurable mIWG C-findings. The Part 2 expansion portion of the Apex study is designed to evaluate the efficacy and safety of bezuclastinib in patients with AdvSM, including ASM, SM-AHN, or MCL. Key eligibility criteria include measurable disease (centrally adjudicated) according to modified IWG-MRT-ECNM criteria and clinically acceptable laboratory values including platelet count ≥50,000/µL. The primary efficacy endpoint of Part 2 is overall response rate (ORR = complete response [CR] + complete remission with partial hematologic recovery [CRh] + partial response [PR] + clinical improvement [CI]) per mIWG-MRT-ECNM criteria according to mIWG-MRT-ECNM response criteria and will be confirmed by a Central Response Review Committee. Secondary endpoints include further characterization of safety and tolerability, pure pathologic response, biomarker response (including changes in bone marrow MC burden, serum tryptase level, and KIT D816V mutational burden), duration of response, time to response, progression-free survival, and overall survival (OS). Apex Part 2 is actively enrolling. Study sites are enrolling in North America, Asia-Pacific, and Europe. In addition, a high-risk SM-AHN sub-study assessing the safety and feasibility of the combination of bezuclastinib 150 mg QD and azacitidine may enroll up to 20 patients who are currently receiving or indicated for azacitidine and have biopsy-proven SM with an associated high- or very high-risk myeloid neoplasm. Patients with SM-AHN from Part 1 or Part 2 who have demonstrated AHN progression may enroll in an additional rollover cohort to receive bezuclastinib with concomitant azacitidine or hydroxyurea.

Abstract Eosinophilia and eosinophil activation are recurrent features in various reactive states and certain hematologic malignancies. In patients with hypereosinophilia (HE), HE‐induced organ damage is often encountered and may lead to the diagnosis of a hypereosinophilic syndrome (HES). A number of known mechanisms and etiologies contribute to the development of HE and HES. Based on these etiologies and the origin of eosinophils, HE and HES are divided into primary forms where eosinophils are clonal cells, reactive forms where an underlying reactive or neoplastic condition is detected and eosinophils are considered to be “non‐clonal” cells, and idiopathic HE and HES in which neither a clonal nor a reactive underlying pathology is detected. Since 2012, this classification and the related criteria have been widely accepted and regarded as standard. However, during the past few years, new developments in the field and an increasing number of markers and targets have created a need to update these criteria and the classification of HE and HES. To address this challenge, a Working Conference on eosinophil disorders was organized in 2021. In this conference, a panel of experts representing the relevant fields, including allergy, dermatology, hematology, immunology, laboratory medicine, and pathology, met and discussed new markers and concepts as well as refinements in definitions, criteria and classifications of HE and HES. The outcomes of this conference are presented in this article and should assist in the diagnosis and management of patients with HE and HES in daily practice and in the preparation and conduct of clinical trials.

Mastocytosis is a hematologic neoplasm characterized by expansion and focal accumulation of neoplastic mast cells (MC) in diverse organs, including the skin, bone marrow (BM), spleen, liver, and gastrointestinal tract. The World Health Organization classification divides the disease into prognostically distinct variants of cutaneous mastocytosis (CM) and systemic mastocytosis (SM). Although this classification remains valid, recent developments in the field and the advent of new diagnostic and prognostic parameters created a need to update and refine definitions and diagnostic criteria in MC neoplasms. In addition, MC activation syndromes (MCAS) and genetic features predisposing to SM and MCAS have been identified. To discuss these developments and refinements in the classification, we organized a Working Conference comprised of experts from Europe and the United States in August 2020. This article reports on outcomes from this conference. Of particular note, we propose adjustments in the classification of CM and SM, refinements in diagnostic criteria of SM variants, including smoldering SM and BM mastocytosis (BMM), and updated criteria for MCAS and other conditions involving MC. CD30 expression in MC now qualifies as a minor SM criterion, and BMM is now defined by SM criteria, absence of skin lesions and absence of B- and C-findings. A basal serum tryptase level exceeding 20 ng/mL remains a minor SM criterion, with recognition that hereditary alpha-tryptasemia and various myeloid neoplasms may also cause elevations in tryptase. Our updated proposal will support diagnostic evaluations and prognostication in daily practice and the conduct of clinical trials in MC disorders.