Sockel, Katja

Objective Vacuoles E1 enzyme X‐linked autoinflammatory somatic syndrome (VEXAS) is a recently identified rare genetic disorder associated with somatic mutations in the UBA1 gene. VEXAS presents with a combination of inflammatory and hematologic manifestations, leading to increased morbidity and mortality. Methods Given the variability in disease presentation and the limited number of studies to date, no clinical documents currently exist to provide guidance to health care providers about the management of VEXAS. To address this gap, we formed an international multidisciplinary panel of VEXAS experts. Results Through formalized meetings and a voting process, the group developed consensus clinical guidance considerations for the management of VEXAS. These considerations offer practical advice on several key topics: (1) clinical features of VEXAS, (2) UBA1 screening methods, (3) the diagnosis of myelodysplastic syndromes (MDSs) in patients with VEXAS, and (4) prognosis and management. The aim is to provide expert guidance on which patients to test, how to test for VEXAS, how to approach MDS in the context of VEXAS, and considerations for management. Conclusion This work marks the first formal international consensus guidance for VEXAS and is intended to be used as a resource for clinicians seeking to understand the disease and its management.

Abstract “Nonclassical” myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field.

Introduction Patients with lower-risk (LR) myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) experience shortened survival and significant unmet medical need due to limited disease-modifying treatments. The NLRP3 pathway is activated in hematopoietic stem and progenitor cells and in the marrow microenvironment in myeloid neoplasms, contributing to ineffective hematopoiesis and clonal progression. DFV890, a small molecule NLRP3 inhibitor, blocks IL-1β and IL-18 secretion and pyroptotic cell death. Thus, DFV890 may disrupt the smoldering inflammation and provide disease-modifying benefits to patients by restoring normal hematopoiesis and suppressing clonal myeloproliferation. Methods This open-label, phase 1b, multicenter study evaluates DFV890 in patients with very low, low, or intermediate risk MDS per revised International Prognostic Scoring System (IPSS-R) criteria and low or intermediate-1 risk CMML per CMML-specific Prognostic Scoring System (CPSS) criteria (NCT05552469). The study comprises 2 parts: dose optimization and dose expansion. Eligible patients ≥18 years, with ECOG performance status ≤2, carrying a diagnosis of (a) IPSS-R-defined LR-MDS or (b) CPSS-defined LR-CMML, and have failed to respond to or not tolerated established first-line therapies as defined in the protocol. Key exclusion criteria include previous treatment with agents targeting the NLRP3 inflammasome and IL-1 pathway. DFV890 is administered orally twice daily (BID) for a minimum of 24 weeks (6 cycles of treatment) until treatment discontinuation. In the dose-optimization part, patients are randomized to receive either low- or high-dose, stratified by indication. Primary objectives are to assess safety and tolerability and determine the optimal for DFV890. Secondary objectives include assessment of pharmacokinetics, and evaluation of preliminary efficacy of DFV890 based on hematologic improvement (Garcia-Manero, Blood 2023). Exploratory objectives include assessment of peripheral cytokines and genetic alterations in blood and bone marrow, and patient-reported symptoms. Results As of April 15, 2024, 39 patients (median age, 74 years) with a median of 2 prior lines of therapy (range: 1-5) were treated with DFV890 in the dose-optimization part. Based on an 8-week screening period, 8 patients (20.5%) were RBC transfusion independent at baseline. Eighteen patients received low dose (17 with LR-MDS; 1 with LR-CMML), and 21 patients received high dose (18 with LR-MDS; 3 with LR-CMML). At data cutoff, 10 (25.6%) patients had discontinued treatment. Median duration of exposure was 10.7 weeks (range, 0.6-42.0 weeks). Adverse events (AEs) leading to study drug discontinuation were only reported in the high dose arm (2 patients, grade ≥3 neutropenia, n=1 and blood bilirubin increased, n=1). Treatment-related AEs (TRAEs) were reported in 10 patients (25.6%), with 4 (10.3%) experiencing grade ≥3 TRAEs (anemia [n=2], neutropenia, and rash [n=1 each]). No serious AEs related to DFV890 were reported. Peripheral cytokines were assessed as a marker of preliminary activity. Decrease in plasma IL-18 and IL-1RA levels observed in most patients, with a higher frequency in the low dose arm (IL-18 decreased in 8/8 patients in low dose arm vs. 4/7 in high dose arm; IL-1RA in 7/8 vs. 5/7), potentially due to less frequent dose interruptions. Changes in serum IL-6 levels were more heterogeneous; notably, among the patients with complete mutation and biomarker data, both patients with mutations in TET2 showed dramatic decreases in serum IL-6; IL-18 and IL-1RA also decreased in those patients. In addition, out of 8 patients who were transfusion-independent at baseline, 6 reported an increase in hemoglobin with treatment, 4 of whom with an increment >10% from baseline. Updated data including hematologic response assessment according to IWG will be presented at the meeting. Conclusions Preliminary findings from this ongoing study show a favorable safety profile in patients with LR-MDS and LR-CMML, in line with prior human studies with DFV890. Analysis of peripheral cytokines and hematologic parameters showed early indications of activity in a subset of patients, particularly those with mutations in TET2 and those transfusion independent at baseline. These findings will require confirmation with longer follow-up and in the dose expansion phase of the study.

Abstract To determine the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in chronic myelomonocytic leukemias (CMML), we assembled a retrospective cohort of CMML patients 18-70 years old diagnosed between 2000 and 2014 from an international CMML dataset (n = 730) and the EBMT registry (n = 384). The prognostic impact of allo-HCT was analyzed through univariable and multivariable time-dependent models and with a multistate model, accounting for age, sex, CMML prognostic scoring system (low or intermediate-1 grouped as lower-risk, intermediate-2 or high as higher-risk) at diagnosis, and AML transformation. In univariable analysis, lower-risk CMMLs had a 5-year overall survival (OS) of 20% with allo-HCT vs 42% without allo-HCT (P < .001). In higher-risk patients, 5-year OS was 27% with allo-HCT vs 15% without allo-HCT (P = .13). With multistate models, performing allo-HCT before AML transformation reduced OS in patients with lower-risk CMML, and a survival benefit was predicted for men with higher-risk CMML. In a multivariable analysis of lower-risk patients, performing allo-HCT before transformation to AML significantly increased the risk of death within 2 years of transplantation (hazard ratio [HR], 3.19; P < .001), with no significant change in long-term survival beyond this time point (HR, 0.98; P = .92). In higher-risk patients, allo-HCT significantly increased the risk of death in the first 2 years after transplant (HR 1.46; P = .01) but not beyond (HR, 0.60; P = .09). Performing allo-HCT before AML transformation decreases life expectancy in lower-risk patients but may be considered in higher-risk patients.