Patnaik, Mrinal M.

ABSTRACT Patients with newly‐diagnosed acute myeloid leukemia (ND‐AML) derive variable survival benefit from venetoclax (Ven) plus hypomethylating agent (HMA) therapy, and the optimal Ven duration across genetic risk groups remains undefined. Among 540 ND‐AML patients receiving Ven‐HMA at Mayo Clinic, outcomes were compared across Ven 7‐ ( n = 33), 14‐ ( n = 117), 21‐ ( n = 96), and 28‐day ( n = 294) schedules during Cycle 1 and stratified by ELN 2024 and Mayo genetic risk groups. At a median follow‐up of 37.7 months, allogeneic stem cell transplant (ASCT) rates were similar across Ven duration groups (15%, 18%, 18%, and 20% for 7‐, 14‐, 21‐, and 28‐day; p = 0.86). Median transplant‐censored survival was comparable across Ven durations (13.3, 11.9, 16.8, and 13.2 months for 7, 14, 21, 28 days, respectively; p = 0.65), with outcomes driven by ELN risk (6.3, 11.5, 18.3 months for high, intermediate, low; p < 0.01) and Mayo genetic risk (6.9, 17.8 months, not reached; p < 0.01). Survival was comparable across Ven durations within ELN intermediate/low‐risk and all Mayo risk groups. Among ELN high‐risk patients, 14‐day Ven was associated with inferior transplant‐censored survival compared to 21‐ and 28‐day schedules ( p < 0.01). Notably, 30‐ and 60‐day mortality were higher with shorter Ven schedules (7‐day: 9%/18%; 14‐day: 7%/15%) versus 28‐day (2%/6%), which likely reflects treatment selection bias. In ND‐AML, no significant difference in transplant‐censored survival was observed across the 7‐, 14‐, 21‐, and 28‐day Ven schedules; prognosis was determined primarily by Mayo and ELN 2024 genetic risk rather than by Ven duration. Prospective trials are needed to establish risk‐adapted Ven dosing strategies.

ABSTRACT Venetoclax (Ven) plus hypomethylating agents (HMA) is standard frontline therapy for newly diagnosed AML (ND‐AML) patients unfit for intensive chemotherapy and is also considered in younger, fit patients. However, consolidation with allogeneic stem cell transplant (ASCT) is often required to secure durable remission. The current study examines posttransplant outcomes in patients with ND‐AML treated with frontline Ven‐HMA who subsequently underwent ASCT. A total of 111 ND‐AML patients (58% male, 60% secondary/therapy‐related, median age 70 years [range, 37–80]) received a median of 3 cycles of Ven‐HMA. Mutations at the time of diagnosis included RUNX1 (18%), SRSF2 (17%), TP53 (16%), ASXL1 , IDH2 , K/NRAS , TET2 (14% each), STAG2 (11%), DNMT3A (8%). All patients were in CR/CRi at the time of transplant including 88% after Ven‐HMA. Measurable residual disease (MRD) by flow cytometry was detectable in 18/76 (24%) patients. Donors were mostly HLA‐matched unrelated (75%); 51% receiving fludarabine/melphalan conditioning and 67% posttransplant cyclophosphamide. At a median follow‐up of 15 months, 42 (38%) of patients have died and 18 (16%) experienced posttransplant relapse. Median posttransplant survival was not reached (NR), with 1‐, 2‐, 3‐year survival rates of 69%/60%/57%, respectively. On multivariate analysis, age ≥ 65 years, STAG2 mutation ( STAG2 MUT ) , and DNMT3A MUT were associated with superior posttransplant survival. Patients were stratified into low‐ (0–1 point), intermediate‐ (2 points), and high‐risk (3 points); age < 65 years, STAG2 wild type, and DNMT3A wild type, with 3‐year survival rates of 89%, 59%, and 19%, respectively ( p < 0.01). Taken together, age, STAG2 MUT and DNMT3A MUT stratified posttransplant survival in Ven‐HMA treated patients with ND‐AML.

Background: Telomeres are repetitive sequences at the end of linear chromosomes that preserve genetic information. Patients with telomere biology disorders (TBDs) are subject to multiorgan manifestations, which include the liver. However, due to the rare nature of the disorder, these manifestations are not fully characterized. Methods: Here, we describe the hepatic manifestations of patients with TBD at a large tertiary center within a specialized TBD clinic; 121 consecutive patients with TBD seen from 2017 to 2024 were included. The median age of the TBD diagnosis was 43 years old, with 60% male. The most common pathogenic/likely pathogenic variant was TERT (25%), followed by RTEL1 (10%) and TERC (7%). Results: Evidence of hepatic involvement in TBD was observed in 60% of patients (73 of 121), as determined by imaging studies or abnormal liver chemistries. Hepatic steatosis was the most prevalent imaging finding (56%), while a cholestatic pattern of liver injury was the predominant laboratory abnormality (73%). Biopsy-proven portosinusoidal vascular disorder was present in 4 patients. Findings of portal hypertension were observed in 25 patients (34%), with decompensation observed in 12 patients (16%). Traditional liver imaging modalities (computer tomography, ultrasound, and MRI) were compared with magnetic resonance elastography in 41 patients. Of these, 7 patients had abnormal magnetic resonance elastography with normal traditional imaging (17%), indicating higher sensitivity of magnetic resonance elastography to detect liver involvement. Conclusions: This study describes the liver manifestations within a cohort of patients with TBD with findings of portosinusoidal vascular disorder and hepatopulmonary syndrome similar to other cohorts and a noted higher prevalence of hepatic steatosis as compared with the general population. Liver stiffness measurements, integrated with imaging and laboratory testing, further improve characterization of hepatic manifestations in TBD.

ABSTRACT The recently published BLAST clinical risk model for chronic myelomonocytic leukemia (CMML) and its molecular version (BLAST‐Mol) differentiate low, intermediate, and high‐risk groups. The objective of the current retrospective study was to examine the survival impact of allogeneic stem cell transplant (ASCT) in a consecutive series of Mayo Clinic patients ( n = 775; 68% males, median age 71 years) with CMML, overall and adjusted for baseline BLAST/BLAST‐Mol risk categories. At a median follow‐up of 77 months, 151 (20%) patients underwent ASCT. Overall survival (OS) was longer in the ASCT compared to the non‐ASCT cohorts (median 77 vs. 28 months; p < 0.01). The significant difference in OS between the ASCT and non‐ASCT cohorts was retained after adjusting for BLAST clinical risk groups: high‐risk (median 50 vs. 14 months; p < 0.01), intermediate‐risk (81 vs. 28 months; p < 0.01), and low‐risk (111 vs. 65 months; p = 0.04), respectively. The same was mostly the case when OS comparison was adjusted for BLAST‐Mol with respective p values of < 0.01, < 0.01, and 0.08, respectively. Time‐dependent cox models confirmed the favorable survival impact of ASCT in the BLAST/BLAST‐Mol high‐ and intermediate‐risk groups. The current study highlights the benefit of ASCT for BLAST/BLAST‐Mol high‐ and intermediate‐risk groups in CMML and its potential to overcome the adverse impact of some high risk cytogenetic or molecular abnormalities. These observations support the early use of ASCT in CMML, ideally before BT and regardless of genetic characteristics.

ABSTRACT We examined the prognostic value of routine NGS data in newly diagnosed acute myeloid leukemia (AML) treated with intensive (7 + 3 backbone) induction, specified by AML subtype. A contemporary (2015–2025) series of 545 Mayo Clinic patients (median age 56 years, females 44%) was considered. Median follow‐up was 49 months with 341 (63%) allogeneic hematopoietic stem cell transplantations (AHSCT) recorded. AML subtypes included core‐binding factor (CBF; N = 72; 13%), primary non‐CBF ( N = 403; 74%), post‐myelodysplastic syndromes (MDS) or post‐myelodysplastic/myeloproliferative neoplasms (post‐MDS‐MDS/MPN; N = 28; 5%), post‐MPN ( N = 15; 3%), and therapy‐related (t‐AML; N = 27; 5%). Corresponding complete remission rates, with/without count recovery (CR/CRi), were 89%, 76%, 64%, 27%, and 78% ( p < 0.01) and 5‐year transplant‐censored survival rates 68%, 57%, 21%, 0%, and 55% ( p < 0.01). In multivariable analyses, the prognostic value of specific mutations was mostly limited to primary non‐CBF AML where adverse karyotype (OR 1.9; p = 0.04) predicted inferior and FLT3 ‐ITD (OR 0.4; p < 0.01) or NPM1 MUT / FLT3 WT (OR 0.1; p < 0.01) superior CR/CRi while KRAS MUT (HR 8.8; p < 0.01), TP53 MUT (HR 5.4; p < 0.01), and TET2 MUT (HR 2.3; p = 0.01) predicted inferior and NPM1 MUT / FLT3 WT (HR 0.3; p = 0.01) superior survival. Prognostication in intensively‐treated AML should start with subtype specification and recognition of the limited value of NGS in non‐primary AML. Post‐MPN AML is particularly associated with dismal outcomes and should be prognostically distinguished from post‐MDS‐MDS/MPN AML. In primary non‐CBF AML, in addition to previously established risk factors, the favorable impact of FLT3 ‐ITD on achieving CR/CRi and the unfavorable impact of KRAS MUT and TET2 MUT on transplant‐censored survival were noted and require confirmation from additional studies.

Objective Vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome (VEXAS) syndrome is characterized by a complex spectrum of inflammatory and hematologic manifestations. Clinical research to identify effective therapies is urgently needed but is hindered by the lack of validated outcome measures. A VEXAS‐specific disease activity index (DAI) is an essential tool for reliably capturing changes in disease activity over time, thereby supporting clinical research and informing patient care in this emerging disease. This study aimed to develop a comprehensive DAI to assess disease‐related inflammation across affected organ systems in patients with VEXAS syndrome. Methods Inflammatory manifestations of VEXAS were previously identified through a systematic literature review and expert input. A multinational expert advisory committee developed the VEXAS‐DAI using modified Delphi methodology until consensus (defined as ≥75% concurrence) was reached. Item grading was adapted from the Common Terminology Criteria for Adverse Events. Scoring criteria were developed based on 158 test cases using the Physician Global Assessment of Inflammation. Results Consensus on the VEXAS‐DAI was achieved after four Delphi rounds. The index assesses inflammatory activity at the time of evaluation across 12 domains: inflammatory rash, chondritis, periorbital, ophthalmologic, joint, pulmonary, cardiovascular, genitourinary, neurologic, oral and gastrointestinal, renal, and constitutional symptoms. The total score ranges from 0 to 40. Conclusion The VEXAS‐DAI is a novel instrument designed to quantify active inflammation over time in patients with VEXAS. Prospective validation within a clinical trial setting is ongoing. image

Abstract Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_PM) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort ( n = 5136) and transcriptomic data from a prospective cohort ( n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “ TP53 ‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, bi TET2 , SF3B1 , and TP53 ‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.