Tashi, Tsewang

Abstract Introduction: Indolent systemic mastocytosis (ISM) is a clonal mast cell disease driven by the KIT D816V mutation in ~95% of cases and is associated with symptoms of mast cell activation and tissue infiltration. It can cause chronic, debilitating symptoms − including life-threatening anaphylaxis and impaired bone health. While historically most patients have relied on symptom-directed best supportive care (BSC) therapies, avapritinib is used as a new standard of care targeting KIT D816V, the primary driver for SM. 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. Approval was based on results from the phase 2 PIONEER trial. Here, we present the findings from ~3.5-year long-term follow-up. Methods: Adults with centrally confirmed ISM and uncontrolled moderate-to-severe symptoms who completed the randomized dose-finding (Part 1), or randomized, double-blind, placebo-controlled (Part 2) portions of PIONEER (NCT03731260) rolled over to the open-label, long-term extension (Part 3). This cumulative analysis includes patients who initiated avapritinib at the recommended dose of 25 mg once daily (QD) in either Parts 1, 2, or 3. All patients received BSC. Per investigator discretion and based on disease burden, dose titration up to 50 mg QD of avapritinib was permitted in Part 3. Long-term efficacy was assessed by measuring changes in symptoms and QoL, using the ISM-Symptom Assessment Form (ISM-SAF; ©2018 Blueprint Medicines, a Sanofi Company) and the Mastocytosis Quality-of-Life Questionnaire (MC-QoL). Safety was also assessed. Results: Overall, 226 patients initiated avapritinib 25mg QD across Parts 1, 2, and 3. This longer-term analysis is inclusive of 65 patients who dose titrated from 25 mg to 50 mg QD in Part 3. Median (range) treatment duration was 40.0 months (0.7‒67.2) as of February 21, 2025. Longer-term efficacy data with ~3.5 years of follow-up demonstrated sustained disease-related symptom improvements. The mean change (standard deviation [SD]) in total symptom score (TSS, per ISM-SAF), was −19.80 (19.81) at Week 144 (Month 33) and −20.43 (20.57) at Week 168 (Month 39) from a baseline of 48.08 (19.47). Additionally, avapritinib-treated patients demonstrated durable improvement in their most severe symptoms (mean change [SD] from baseline of −3.35 [3.02] at Month 33 and −3.47 [3.19] at Month 39) per ISM-SAF. Sustained responses were observed across all individual symptom domains (0–30) with mean changes (SD) at Month 33 and Month 39 of −3.77 (5.52) and −3.84 (6.05) for the gastrointestinal domain, −8.21 (7.70) and −8.20 (7.85) for the skin domain, and −4.66 (6.24) and −4.87 (6.51) for the neurocognitive domain. The mean percent change (SD) in MC-QoL was −34.67 (40.16) at Month 33 and −40.72 (33.24) at Month 39 from a baseline of 54.24 (18.32). Treatment with avapritinib was well tolerated, and its safety profile was similar to the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were Grades 1–2, and 7% of patients experienced Grade ≥3 TRAEs of which diarrhea, neutrophil count decrease, and weight increase occurred in >1 patient. No Grade ≥3 TRAEs of increase in transaminases were observed. Edema (peripheral and periorbital), the most frequently reported TRAE, was mostly Grade 1 and occurred most frequently during the first 3–4 months of treatment. Three patients (1%) experienced serious adverse events assessed as treatment related. However, none led to treatment discontinuation and no trends were observed. After approximately 3.5 years of follow-up, low rates of treatment discontinuations (n=7, 3%) due to TRAEs were observed. Conclusion: Longer follow-up of patients with ISM treated on the PIONEER trial, including some on avapritinib for up to 5 years, demonstrates that prolonged avapritinib therapy continues to be effective and well tolerated. Additional prospective analyses will be needed to determine effects of selective KIT D816V-inhibition on anaphylaxis. These data support a favorable benefit-risk profile of avapritinib as a chronic treatment for adult patients with ISM.

Background and Rationale: Systemic mastocytosis (SM) is a clonal hematologic neoplasm characterized by abnormal accumulation of mast cells which can lead to symptoms related to mast cell degranulation and/or, in the case of advanced systemic mastocytosis (AdvSM), organ dysfunction due to mast cell infiltration. AdvSM is a category of SM comprised of aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). Among these, SM-AHN is the most common subtype, accounting for approximately 70% of AdvSM. A KIT D816V mutation found in up to 95% of SM cases is the primary oncogenic driver, making it a key therapeutic target. Avapritinib, a highly potent and selective inhibitor of D816V mutant KIT, has demonstrated high rates of rapid, deep, and durable responses in all AdvSM subtypes, including SM-AHN (Gotlib et al. Nature Medicine, 2021; DeAngelo et al., Nature Medicine, 2021). However, despite showing prolonged OS and low risk of progression of the SM component, some patients (20%) exhibit progression of the AHN component, including transformation to AML. In some patients, combination therapy with avapritinib and AHN-directed therapy may therefore be necessary for optimal control of SM-AHN. Hypomethylating agents (HMA) form the backbone of therapy for advanced myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN); hematologic neoplasms most likely to co-occur with SM in patients (pts) with SM-AHN. To date, the combination of HMA and KIT inhibitors has not been clinically evaluated. In this study, we aim to assess the safety and tolerability of the combination of avapritinib and decitabine in patients with SM-AHN. Study design and Methods: The primary objective of the study is to establish the recommended dose (RP2D) of avapritinib in combination with decitabine based on dose-limiting toxicity, overall safety, and clinical activity data. A dose evaluation steering committee (DESC) comprised of participating investigators will review the totality of safety and efficacy data to determine RP2D. Secondary endpoints include SM overall response rate by the end of 6 cycles by the m-IWG consensus criteria and proposed ECNM-AIM criteria (Gotlib et al., J Allergy Clin Immunol Pract, 2022) and incidence/frequency of adverse events. Exploratory endpoints include patient reported outcomes, PFS, OS, and correlative biomarkers linked to mast cell disease or AHN. Pts with a diagnosis of SM-AHN by the WHO 2022 criteria will be eligible for inclusion. Pts must have any of the following myeloid AHN per WHO 2022 criteria: MDS, CMML, MDS/MPN with neutrophilia, MDS/MPN with SF3B1 mutation and thrombocytosis, or MDS/MPN-NOS. Patients with MDS must have intermediate, high- or very-high risk by IPSS-R. Patients with very-low or low-risk MDS by IPSS-R must be intolerant/refractory to ESA or have serum EPO > 200 U/L. A baseline platelet count of ≥ 75 x 109/L and ≥ 25 x 109/L will be required for inclusion in the dose-finding and the dose-expansion phases, respectively. Key exclusion criteria include a diagnosis of AML, history of intracranial hemorrhage, prior treatment with avapritinib or decitabine with documented progression in SM or AHN component, respectively, or treatment with alternative KIT inhibitor or azacitidine within 4 weeks of study treatment initiation. In the dose finding part of the study, a Bayesian adaptive design will be employed to assess different doses of avapritinib (50 to 200 mg PO daily) in combination with fixed doses of decitabine (oral decitabine/cedazuridine: 35/100 mg/day or intravenous decitabine: 20 mg/m2/day on days 1-5) in a 28-day treatment cycle. Close attention will be paid to treatment-emergent thrombocytopenia with protocol-driven treatment holds and dose modification strategies employed when platelet count drops below 50 x 109/L. After RP2D is determined, an additional 10 patients will be enrolled in the dose expansion phase. Patients with platelet count ≥ 25 x 109/L and < 75 x 109/L, will receive lead-in dosing with decitabine or decitabine/cedazuridine with the ability to add avapritinib if sufficient platelet thresholds are achieved. Planned correlative studies include serial single-cell multi-omics utilizing scDNA-seq and immunophenotyping to assess impact of combination treatment on a molecularly complex disease state. This study is currently open to accrual (NCT06327685).

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 VEXAS (vacuoles, E1-ubiquitin-like modifier activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described autoinflammatory disorder caused by acquired UBA1 mutations in hematopoietic precursor cells. The prevalence, clinical significance, and genomic landscape of UBA1variants in patients with hematologic malignancies (HM) remains unexplored. We analyzed the genomic profiles of 86 patients carrying 17 different UBA1variants amongst an unbiased cohort of 8,976 HM patients. Specific genetic and clinical features seen more frequently in patients with UBA1 pathogenic variants (PV) versus those with variants of uncertain significance (VUS) included: marked male predominance (98% versus 80%, P=0.002), macrocytic anemia (MCV 105 ± 1.4 fl versus 96 ± 1.4 fl, p=0.01), frequent dominant clones without concurrent somatic variants (53% versus 15%, p=0.004), and association with molecularly distinct low-risk myelodysplastic syndrome (MDS; 13%) with superior overall survival (OS). Interestingly, while the genetic profiles of UBA1 PV patients resemble patients with clonal cytopenia of unknown significance (CCUS), rapid UBA1 clonal expansion predispose patients to convert to low-grade MDS with a notably hastened progression compared to UBA1 wild-type CCUS. This “clone surge to clinical stability” (CS) is a mechanism that emphasizes the unique pathobiology of UBA1mutations in VEXAS and supports it as a distinct entity.

Introduction Indolent systemic mastocytosis (ISM) is a rare clonal mast cell disease driven by the KIT D816V mutation in nearly all patients. Patients with ISM can present with debilitating acute and chronic cutaneous, gastrointestinal, neurocognitive, and systemic symptoms caused by the release of inflammatory mediators from abnormal mast cells. In some patients, symptoms are not adequately controlled with best supportive care (BSC) medications. Elenestinib (BLU-263) is a novel, investigational, oral, next-generation tyrosine kinase inhibitor that potently and selectively inhibits KIT D816V with limited central nervous system penetration and pharmacokinetics (PK) that support once daily dosing. HARBOR (NCT04910685) is a randomized, double-blind, placebo-controlled, phase 2/3 study assessing efficacy and safety of elenestinib in patients with ISM. Methods Eligible adult patients with ISM, confirmed following central review of bone marrow (BM) pathology, clinical, and laboratory findings per World Health Organization criteria and a moderate-to-severe symptom score based on minimum mean total symptom score (TSS) of the ISM-Symptom Assessment Form (ISM-SAF©2018), were stratified by baseline serum tryptase (<20 ng/mL vs ≥20 ng/mL) and randomly assigned 3:1 to elenestinib 25 mg, 50 mg, or 100 mg once daily + BSC (“elenestinib”) or placebo + BSC (“placebo”). The primary objective of Part 1 was to determine the recommended dose based on safety, PK, and pharmacodynamics. Secondary endpoints included changes in biomarkers of disease burden (serum tryptase, KIT D816V variant allele fraction [VAF], and BM mast cells) and ISM-SAF TSS. Three additional open-label PK groups enrolled patients at 50 mg, 75 mg, and 100 mg to further characterize PK and safety. Results As of data cutoff on July 3, 2023, a total of 122 patients with ISM have received their assigned treatment in Part 1 of the study; 39 were blinded and randomized to elenestinib or placebo, and 83 were treated with open-label elenestinib in the PK groups (21 patients at 50 mg, 34 patients at 75 mg, and 28 patients at 100 mg). Baseline demographics were similar to those reported for the general ISM population. After 12 weeks of therapy, symptom improvement was observed for all dose cohorts, and symptom reduction by TSS was greater for patients on elenestinib versus placebo in the blinded portion of Part 1. Patients receiving elenestinib at 25 mg, 50 mg, and 100 mg doses showed reduction (mean percent) from baseline for tryptase (-15.4%, -50.9%, and -68.4% vs 3.3%, respectively) and KIT D816VVAF (-37.5%, -70.3%, and -77.0% vs -2.5%, respectively) as compared to placebo. Similar reductions in TSS and disease-related biomarkers were observed in the open-label PK cohorts. After a median treatment duration of 35.3 weeks, elenestinib was well-tolerated at all dose levels. There were no treatment-related serious adverse events and no treatment-related adverse events that led to drug discontinuation. Conclusion Elenestinib at all tested doses demonstrated beneficial effects on disease-related symptoms and biomarkers of mast cell burden in this large and maturing cohort of patients with ISM with a moderate-to-severe symptom burden. Elenestinib was well tolerated across all dose levels with a promising early benefit-risk profile in ISM. These preliminary findings will inform dosing for the planned Part 2 of HARBOR, which will examine elenestinib versus placebo in a randomized, blinded, placebo-controlled setting.

Background and Rationale: Systemic mastocytosis (SM) is a clonal hematologic neoplasm characterized by abnormal accumulation of mast cells which can lead to symptoms related to mast cell degranulation and/or, in the case of advanced systemic mastocytosis (AdvSM), organ dysfunction due to mast cell infiltration. AdvSM is a category of SM comprised of aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). Among these, SM-AHN is the most common subtype, accounting for approximately 70% of AdvSM. A KIT D816V mutation found in up to 95% of SM cases is the primary oncogenic driver, making it a key therapeutic target. Avapritinib, a highly potent and selective inhibitor of D816V mutant KIT, has demonstrated high rates of rapid, deep, and durable responses in all AdvSM subtypes, including SM-AHN. However, a recent analysis of the EXPLORER study showed that avapritinib-treated patients were still at risk for progression of the AHN component, despite continued control of mast cell disease burden, indicating that combination therapy is likely to be required for optimal control of SM-AHN due to its inherent molecular complexity. Hypomethylating agents (HMA) form the backbone of therapy for advanced myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN), hematologic neoplasms most likely to co-occur with SM in patients (pts) with SM-AHN. To date, the combination of HMA and KIT inhibitors has not been clinically evaluated. In this study, we aim to assess the safety and tolerability of the combination of avapritinib and decitabine in patients with SM-AHN. Study design: The primary objective of the study is to establish the recommended dose (RP2D) of avapritinib in combination with decitabine based on dose-limiting toxicity, overall safety, and clinical activity data. A dose evaluation steering committee (DESC) comprised of participating investigators will review the totality of safety and efficacy data to determine RP2D. Secondary endpoints include SM overall response rate by the end of 6 cycles by the m-IWG consensus criteria and proposed ECNM-AIM criteria ( Gotlib et al., J Allergy Clin Immunol Pract, 2022), as well as incidence and frequency of adverse events. Exploratory endpoints will consist of patient reported outcomes, progression free survival, overall survival, and correlative biomarkers linked to mast cell disease or AHN. Adult pts with a diagnosis of SM-AHN by the WHO 2022 classification criteria will be eligible for inclusion. Eligible pts must have any of the following myeloid AHN per WHO 2022 criteria: MDS, chronic myelomonocytic leukemia, MDS/MPN with neutrophilia, MDS/MPN with SF3B1 mutation and thrombocytosis, or MDS/MPN- not otherwise specified. Patients with MDS must have intermediate, high- or very-high risk by IPSS-R. Patients with very-low or low-risk MDS by IPSS-R must be intolerant/refractory to ESA or have serum EPO > 200 U/L. A baseline platelet count of ≥ 75 x 10 9/L and ≥ 25 x 10 9/L will be required for inclusion in the dose-finding and the dose-expansion phases, respectively (Figure). Key exclusion criteria include a diagnosis of acute myeloid leukemia, history of intracranial hemorrhage or risk of major hemorrhage, prior treatment with avapritinib or decitabine with documented progression in SM or AHN component, respectively, or history of treatment with alternative KIT inhibitor or azacitidine within 4 weeks of study treatment initiation. In the dose finding part of the study, a Bayesian adaptive design will be employed to assess different doses of avapritinib (50 to 200 mg PO daily) in combination with fixed doses of decitabine (oral decitabine/cedazuridine: 35/100 mg/day or intravenous decitabine: 20 mg/m 2/day on days 1-5) in a 28-day treatment cycle. Close attention will be paid to treatment-emergent thrombocytopenia with protocol-driven treatment holds and dose modification strategies employed when platelet count drops below 50 x 10 9/L. After RP2D is determined, an additional 10 patients will be enrolled in the dose expansion phase. Patients with platelet count ≥ 25 x 10 9/L and < 75 x 10 9/L, will receive lead-in dosing with decitabine or decitabine/cedazuridine with the ability to add avapritinib if sufficient platelet thresholds are achieved. This study will open at 7 sites in the United States and is anticipated to open in January 2024.