Yi, Cecilia Arana

Abstract Background: Systemic mastocytosis (SM) comprises a spectrum of subtypes characterized by neoplastic mast cell (MC) infiltration of tissues and release of MC mediators. Non-advanced SM (NonAdvSM), including indolent SM (ISM), smoldering SM (SSM), and bone marrow mastocytosis (BMM) subtypes, is the most prevalent form of SM. NonAdvSM can be associated with debilitating symptomology which can significantly impair quality of life. The gain-of-function somatic KIT c.2447 C>T (p.D816V) mutation is found in up to 95% of patients with SM. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor with activity against KIT D816V. Results from Summit (NCT05186753) Part 1 informed the recommended phase 2 dose (100 mg QD bezuclastinib) for Part 2. We report topline results from the 24-week assessment of Summit Part 2. Methods: Summit is a multi-center, randomized, double-blind, placebo (PBO)-controlled Phase 2 trial of bezuclastinib in patients with NonAdvSM who had inadequate symptom control despite best supportive care (BSC) medications. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), which is a fit-for-purpose patient-reported outcome measure of NonAdvSM symptom severity. Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase, KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, and MS2D2 TSS, ≥30% TSS reduction. Patients were randomized 2:1 to receive 100mg QD bezuclastinib + BSC or PBO + BSC. Results: As of May 22, 2025, 179 patients were enrolled in Part 2: 119 were randomized to receive bezuclastinib and 60 to placebo. Patients enrolled were representative of the NonAdvSM population with moderate to severe symptoms. Median age (range) was 51 (23-78) years; 65.9% female; mean (SD) baseline MS2D2 TSS 55.6 (19.8); 82% of patients had ISM, 11% had BMM, and 7% had smoldering SSM. At baseline, median (range) KIT p.D816V VAF in whole blood, BM MC burden, and serum tryptase was 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. Bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints. At Week 24, bezuclastinib led to significantly greater symptom improvement vs placebo (LS mean [95% CI] MS2D2 TSS change: –24.3 [–27.6 to –21.1] vs –15.4 [–19.6 to –11.2]; placebo-adjusted difference: –8.9 points; P=0.0002). A ≥50% reduction in serum tryptase was achieved in 87.4% of bezuclastinib-treated patients vs 0% on placebo (P<0.0001). Significantly more patients receiving bezuclastinib achieved ≥50% reductions in KIT D816V VAF, serum tryptase, BM MCs (P<0.0001), MS2D2 TSS (P=0.01), and ≥30% reduction in MS2D2 TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (gr; 70% Gr 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring in greater frequency in the bezuclastinib arm were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased ALT/AST (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased ALP (10.2% vs 3.3%). TEAEs (≥10%) that occurred more often in the placebo group were diarrhea (13% vs 18%), dizziness (10% vs 12%), fatigue (7% vs 12%), and arthralgia (6% vs 15%). ALT/AST elevations ≥Gr 3 were experienced by 5.9% of patients. The only hepatic adverse events (AEs) reported were transient lab abnormalities; none required hospitalization. Treatment-related AEs requiring dose reductions occurred in 11% of patients receiving bezuclastinib. All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved. Conclusions: At 24-weeks, bezuclastinib 100 mg QD demonstrated statistically and clinically significant improvements in symptom burden and biomarkers of disease vs placebo in patients with NonAdvSM. The treatment was generally well-tolerated and effective across a population that is representative of the real-world NonAdvSM population, including SSM. These results support the use of bezuclastinib to reduce SM burden and symptoms in pts with NonAdvSM, and a potentially disease-modifying impact.

ABSTRACT Background Symptom management in myeloproliferative neoplasms (MPN) remains challenging despite advancements in disease‐directed therapies. This study assessed the impact of demographic, clinical, laboratory and treatment‐related variables on total symptom scores (TSS) and individual symptom scores in patients with polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Methods A cohort of 553 patients (PV: 200; ET: 190; MF: 163) was identified through a retrospective chart review. Symptom scores, demographic information and clinical variables were captured at the time of the first TSS assessment. Laboratory results within 1 month and treatment information within 90 days prior to the symptom assessment were captured. Univariable linear regression, followed by multivariable regression analyses using a robust variance estimator were performed, with a p value < 0.05 indicating a significant association. Results MF patients experienced the highest symptom burden and fatigue was the most reported symptom across all MPN subtypes. In PV, depression ( β : 10.53; p = 0.001) was associated with a higher TSS whereas older age (−0.17; 0.01) and higher hemoglobin (−1.24; 0.003) were associated with a lower TSS. In ET, depression ( β : 14.19; p < 0.001) was associated with a higher TSS, whereas in MF, depression (12.28; < 0.001) and higher WBC count (0.22; 0.02) were associated with a higher TSS. Depression and non‐White race in PV, depression in ET, and depression, low hemoglobin, and higher WBC count in MF were associated with multiple symptoms. Conclusions Integrating depression screening and management and optimizing hematologic parameters alongside disease‐directed therapy is crucial to improving patient outcomes.

Autologous Chimeric antigen receptor (CAR) T-cell therapies have demonstrated substantial efficacy in patients with relapsed or refractory hematologic malignancies; however, their implementation has been constrained by regulatory barriers. Risk Evaluation and Mitigation Strategies (REMS), mandated by the U.S. Food and Drug Administration (FDA), were initially implemented to mitigate risks associated with cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and other treatment-related toxicities. On 27 June 2025, the FDA removed REMS requirements for all approved B-cell maturation antigen (BCMA) and CD19-directed autologous CAR T-cell therapies, citing that current product labeling sufficiently communicates safety information. Key regulatory changes include the elimination of site certification and tocilizumab stocking requirements, a reduction in the recommended post-infusion proximity period from four weeks to two weeks, increased flexibility regarding monitoring locations, and a shortened driving restriction from eight weeks to two weeks. This review examines the rationale for the REMS requirements for CAR T-cell therapies, synthesizes contemporary safety data from clinical trials and real-world practice, and explores the implications of this regulatory shift for access to care, particularly in rural and underserved populations. The removal of REMS requirements may facilitate broader implementation of CAR T-cell therapies and alleviate logistical and institutional barriers, offering the potential to expand access while preserving patient safety.

ABSTRACTCronkhite‐Canada Syndrome (CCS) is a rare non‐hereditary gastroenterological polyposis syndrome without a clear etiology. Myelodysplastic syndromes (MDS) are clonal hematological disorders. Immune dysregulation has been posited as a contributor to the development of both. A 70‐year‐old man developed chronic diarrhea, dysgeusia, and onycholysis. Endoscopic evaluation and testing to exclude hereditary polyposis syndromes resulted in a diagnosis of CCS. Approximately 1 year later, he was noted to have persistent anemia, which was ultimately diagnosed as MDS. He was evaluated with a myeloid disorder next‐generation sequencing panel and found to have mutations in IDH2, SRSF2, and JAK2. This is the second reported case characterizing concomitant MDS and CCS. This is the first case to report the development of MDS after the diagnosis and treatment of CCS. A successful management strategy for both disorders is outlined within this case report.

ABSTRACTThe current study includes 910 patients with systemic mastocytosis (SM) seen at the Mayo Clinic from 1968 to 2024. The primary objective was to examine the prognostic contribution of the International Consensus Classification (ICC), in the context of the Mayo Alliance Prognostic System (MAPS) for SM. World Health Organization classification (WHO‐HAEM5) subcategories included (i) indolent/smoldering SM (ISM/SSM; N = 518), (ii) SM associated with another hematological neoplasm (SM‐AHN; N = 273), with the latter including both myeloid and lymphoid neoplasms, (iii) aggressive SM (ASM; N = 106), and (iv) WHO‐defined mast cell leukemia (MCL; N = 13), which included mast cells with both “mature” and “immature” morphology. The ICC‐defined subcategories were mostly similar with the exception that SM‐AHN was replaced by SM associated with another myeloid neoplasm (SM‐AMN; N = 235) and WHO‐defined MCL was replaced by ICC‐defined MCL (N = 8), which included only those with immature MC morphology. Overall survival (OS) was similar between WHO‐defined MCL (median 1.8 years) vs. SM‐AHN (median 2.3 years; p = 0.3) but significantly different between ICC‐defined MCL (median 0.08 years) vs. SM‐AMN (median 2.0 years; p < 0.01). Significant difference in OS was also apparent between ICC‐defined SM‐AMN and SM associated with lymphoid neoplasm (SM‐ALN; median 8.1 years; HR 3.4; p < 0.01). Multivariable analysis confirmed the inter‐independent prognostic contributions of both ICC‐defined morphologic subcategories and MAPS risk variables, including age > 60 years, anemia, alkaline phosphatase > ULN, and platelet count < 150 × 109/L (p < 0.03 in all instances); the same was not true for WHO‐HAEM5‐defined SM subcategories. The addition of mutational information into the multivariable model resulted in ousting anemia and inclusion of ASXL1 (p < 0.01), SRSF2 (p = 0.01), and NRAS (p = 0.01) mutations as additional risk factors. Classification of SM by ICC is prognostically more accurate, compared to WHO‐HAEM5, and strengthens the prognostic contribution of morphology to current clinical and molecular risk models.

Background/Objectives: DDX41, DEAD-box RNA helicase 41 gene located on chromosome 5q25.3, is one of the most mutated genes in patients with germline predisposition to myeloid neoplasms. Germline and somatic mutations often have different locations and patterns of mutation, with some hotspots displaying diversity based on ethnicity. We aimed to explore clinical outcomes in patients with various DDX41 hot-spot mutations. Methods: This was a retrospective study of patients at Mayo Clinic with DDX41 mutation identified through Next Generation Sequencing (NGS) between 2018 and 2024. We completed unadjusted comparisons using continuous or categorical variables, and survival rates were assessed using the Kaplan–Meier method and cox regression analysis. Results: Overall survival appears to be higher in those with p.M1| when compared to p.Asp140GlyFs*2 and p.Arg525His, with comparable survival between p.Arg525His and p.Asp140GlyFs*2. Among males with p.M1| who underwent bone marrow transplant, those who underwent bone marrow transplant appeared to have lower survival rates, although not statistically significant. Our study was limited by a small sample size, therefore limiting our ability to reach significance. Conclusions: Our findings suggest potential implications for clinical outcomes based on DDX41 mutation hot-spots.

Abstract This retrospective analysis aimed to provide evidence-based risk stratification of TP53-mutated (TP53mut) myeloid neoplasms (MNs). Of 580 MNs harboring TP53mut with variant allele frequency (VAF) ≥2%, 219 (37.8%), 194 (33.4%), 92 (15.9%), and 75 (12.9%) were classified as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) with low blasts (MDS-LB), MDS with excess blasts (MDS-EB)-2, and -EB1 according to the revised fourth edition of the World Health Organization (WHO) classification, respectively. Hierarchical analysis identified the following 4 risk groups with distinct survival: (1) MDS-LB, (2) MDS-EB1/EB2/AML VAF &lt;10%, (3) MDS-EB1/EB2 VAF ≥10%, and (4) AML VAF ≥10%. We next evaluated the impact of allelic status, VAF, and complex karyotype (CK). In our cohort, the significance of biallelic status was limited to MDS with &lt;5% blasts and not for blasts 5% to 9%, as proposed by the International Consensus Classification (ICC), or 5% to 19%, as proposed by the fifth edition of the WHO (WHO-5). MDS-EB1 and -EB2 with VAF ≥10% had comparable survival (9.6 vs 7.2 months; P = .12), regardless of allelic status. Contrary to the ICC proposal, MDS-EB1/EB2 with VAF &lt;10% and CK had poor survival compared with those without CK, comparable to MDS-EB1/EB2 with VAF ≥10% (5.6 vs 26.2 vs 6.3 months; P = .003). Survival of TP53mut AML was poor (median 3.9 months) regardless of allelic/CK status. Thus, using ICC or WHO-5 may underestimate prognosis of MDS with blasts 5% to 19% and 5% to 9%, respectively. Collectively, the hierarchical model acknowledges poor survival of 91.9% TP53mut MDS and AML compared with 36.5% and 80.7% by WHO-5 and ICC, respectively.