Dezern, Amy Elizabeth

Introduction: Myelodysplastic syndromes (MDS) occur due to the acquisition of mutational events over time. Tobacco smoking is a risk factor for MDS and has been associated with distinct genetic mutations in solid cancers. We investigated the association between smoking intensity and duration and the number and types of genetic mutations in MDS using a large prospective cohort. Methods: The prospective NHLBI/NCI National MDS Natural History Study includes individuals with suspected or recently diagnosed MDS enrolled between June 2016-August 2023. Patient (Pt) bone marrow samples underwent central pathology review, resulting in diagnoses including MDS, MDS/myeloproliferative neoplasm overlap (MDS/MPN), or precursor conditions, such as clonal cytopenia of undetermined significance (CCUS). Self-reported smoking data were collected at enrollment. Smoking intensity (i.e., light, medium, and heavy) was defined per CDC definitions. Included mutations were those manually annotated to be pathogenic for MDS. Mutation frequency and prevalence, as well as associations with smoking history and other key covariates, were assessed using univariate tests of association and multivariable regression models for counts and proportions. Rates of disease progression were compared between groups using survival analysis methods for cumulative incidence incorporating non-disease death as a competing risk. Results: Of 1898 evaluable pts, 52% (N=979) had a history of cigarette smoking [MDS: 58% (252/436), MDS/MPN: 57% (52/91), CCUS: 57% (230/405)], and 18% still smoked at diagnosis. The mean ± SD cigarettes per day was 15.8 ± 12.5 and the mean ± SD smoking years was 29.8 ± 16.9 years. Compared to non-smokers, smokers were more often males (68% v 54%, p<0.001) in the 70-79 year age group (45% v 34%, p<0.001). Similar proportions of those with and without a smoking history had MDS (41% v 37%, respectively). Within MDS, there was no association between smoking and MDS prognostic risk per revised international prognostic scoring system. Compared to light smokers [1-10 pack-years (PY)], heavy smokers (30+ PY) were more often male (81% v 62%, p<0.001) and had higher rates of cardiovascular disease (38% v 20%, p<0.001). In univariate analyses, smokers and non-smokers had similar numbers of mutations (mean ± SD: 2.0 ± 2.7 in both groups). Pts with CCUS had the least number of mutations (1.5 ± 1.2), followed by MDS (2.3 ± 1.8), and MDS/MPN overlap (3.3 ± 1.8). Within disease groups, smokers and non-smokers had similar numbers of mutations. Mutation prevalence was higher among smokers v non-smokers in gene pathways for chromatin modification (15% v 11%, p<0.01) and RNA splicing (26% v 19%, p<0.001) and for individual genes ASXL1 (12% v 8%, p<0.01), SF3B1 (9% v 6%, p<0.05), U2AF1 (6% v 3%, p<0.05) and ZRSR2 (2% v 1%, p<0.05). In multivariable regression models, after adjustment for sex, age and disease group, smokers had significantly more mutations on average than non-smokers (2.0 v. 1.4, p=0.04). Moreover, the number of mutations increased significantly with PY smoked (p=0.006), and those at the 75th and 90th percentiles of PY had 1.8 and 3.5 times the number of mutations, respectively, compared to non-smokers, indicating a dose-response relationship. After adjustment, mutation prevalence increased with PY smoked in the gene pathways for chromatin modification and RNA splicing (p<0.03 for both) and for the genes ASXL1 and ETNK1 (p<0.05 in both cases). The five-year cumulative incidence of disease progression was significantly higher among long-term smokers compared to non-smokers/those with shorter smoking history (mean [95% CI] proportion progressed, 20+ years vs <20 years smoking: 27% [19%-36%] vs 18% [13%-24%], p < 0.05). Overall survival was significantly lower for smokers compared to non-smokers for CCUS pts [HR 1.91, 95% CI (1.03-3.55), p=0.04] but not for MDS [HR 1.21, 95% CI (0.53-1.30), p=0.41]. Conclusions: In this prospective, national cohort, tobacco smoking was associated with distinct genetic mutations related to MDS, suggesting smoking potentially contributes to its multi-step molecular pathogenesis. A dose-response relationship was also demonstrated, as was an association with progression and survival. Our data suggest that pts with a new MDS diagnosis who are also smokers should be counseled to stop smoking, as it appears to contribute to the acquisition of new genetic mutations that can lead to progression.

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.

Background. The inclusion of gene mutations and chromosomal abnormalities in the 2022 WHO and ICC Classifications of MDS has enhanced diagnostic precision and is expected to improve clinical decision-making process. Although these two systems share similarities, clinically relevant discrepancies still exist and potentially cause inconsistency in their adoption in a clinical setting. In this study on behalf of the International Consortium for MDS (icMDS), we adopted a data-driven approach to provide a harmonization roadmap between the 2022 WHO and ICC classification for MDS. A modified Delphi Process consensus approach is currently ongoing among icMDS experts to finalize a harmonized MDS classification scheme. Methods. We analyzed retrospective international cohorts of patients with a diagnosis of MDS (n=7017) and AML (n=1002) according to WHO 2016 criteria. Hierarchical Dirichlet Processes were applied to define clusters capturing broad dependencies among all gene mutations and cytogenetic abnormalities. To investigate the features of importance and their impact on the clustering process, we employed the SHapley Additive exPlanations approach (SHAP). This allowed to define harmonized labels for each clinical entity. The clinical relevance of the unsupervised clustering was assessed through the analysis of phenotypic features and outcomes among each group. ( Blood 2022;140: 9828-9830) Results. Patients' characteristics are summarized in Table 1. We identified 9 clusters, defined by specific genomic features. The cluster of highest hierarchical importance was characterized by biallelic inactivation of TP53 (biTP53). According to SHAP analysis, bi TP53 was defined as 2 or more TP53 mutations, or 1 mutation with copy number loss or cnLOH. Most patients assigned to bi TP53 cluster had TP53 VAF>10% (77.9%) and complex karyotype (70.1%). Assignment to bi TP53 cluster was irrespective of blast count. Patients with monoallelic TP53 mutation segregated into other clusters. Hierarchically, the second cluster included patients with del(5q). SHAP analysis highlighted 5q deletion alone, or with one other chromosomal abnormality other than -7, and absence of bi TP53, as the most relevant features. Most of these patients had blast counts <5% (88.1%). The third distinct cluster included patients with SF3B1 mutations (in the absence of concurrent del(7q), abn3q26.2, complex karyotype or RUNX1 mutation). Most patients with MDS and SF3B1 mutation had <5% blasts (94.2%). Common co-mutated variants in the SF3B1 cluster included mutant DNMT3A (25.2%) and TET2 (38.3%). Morphologically defined MDS cases (i.e., not meeting criteria for bi TP53, del(5q) or SF3B1) were preferentially assigned to the following additional clusters: SF3B1 and concurrent higher-risk mutations (e.g., RUNX1 and ASXL1); SRSF2 and concomitant TET2 mutations; U2AF1 mutations with del(20q), del(7q) or -7; SRSF2 with TET2 mutations and co-mutational patterns including RUNX1 and ASXL1; and AML-like genomic signatures. Our analyses suggest that morphologically defined MDS is characterized by a large heterogeneity in terms of mutation profiles, not entirely captured by the presence of unilineage versus multilineage dysplasia, percentage of bone marrow blasts, and presence of hypocellularity and fibrosis. To better investigate the continuum between high risk MDS (i.e., patients with ≥10% blasts) and AML, an exploratory comparison was made using a cohort of AML (defined according to WHO 2016) patients analyzed using the same statistical methods. Only a partial overlap in genetic signatures was observed between MDS with ≥10% blasts and AML. However, similarities were observed between the AML-like MDS clusters (characterized by mutant NPM1, bZIP CEBPA, and Core Binding Factor abnormalities) and AML clusters defined by the same genetic signature, thus supporting the classification of these entities as AML, irrespective of blast count. Conclusion. Our study demonstrated the utility of a data-driven approach based on advanced statistical methods to generate a harmonized classification for MDS. Table 2 shows a provisional, hierarchical classification algorithm. Further refinement of entity labels and classification criteria is the subject of the ongoing modified Delphi Process consensus approach among icMDS experts.

Background: Oral decitabine/cedazuridine (ASTX727) is a fixed dose combination of decitabine (35 mg) and the cytidine deaminase inhibitor cedazuridine (100 mg) given once daily X 5 days on a 28-day cycle producing pharmacokinetic (PK) exposure equivalent to the standard intravenous (IV) decitabine regimen of 20 mg/m 2 daily X 5 days on a 28-day cycle. This was demonstrated in the pivotal ASCERTAIN study (Garcia-Manero, et al, ASH 2019) as it provided a PK bridge to existing decitabine data and demonstrated median OS was 31.7 mo. (Savona,et al. Intl. MDSF International Congress on MDS, 2021). Subjects were initially classified by the International Prognosis Scoring System (IPSS) for historical reasons, however IPSS-R and IPSS-M are enhancements to IPSS that provide dynamic risk assessment for predicting clinical outcomes in MDS. Here, the objective was to re-classify the MDS subjects enrolled on the ASCERTAIN study by IPSS-R and IPSS-M and measure the impact of informing patient outcomes based on re-calculated risk assessment. Methods: One hundred thirty-three subjects with MDS/CMML (chronic myelomonocytic leukemia) were enrolled in ASCERTAIN and were randomly assigned either IV decitabine for cycle 1 and oral decitabine/cedazuridine for cycle 2 or the opposite treatment sequence. All subjects continuing beyond cycle 2 received oral decitabine/cedazuridine for all subsequent cycles until treatment discontinuation for disease progression, toxicity, patient's decision, or HSCT. Whole blood collected prior to treatment was used for DNA isolation and molecular abnormalities identified using next-generation sequencing (NGS) hematologic malignancy panel of 179 genes including all genes commonly mutated in MDS. In the initial analysis of clinical outcomes, subjects were classified by IPSS with response assessment by IWG 2006 IPSS low and Int-1 risk levels were categorized as lower-risk MDS (LR-MDS), whereas IPSS Int-2 and high-risk categories were categorized as higher-risk MDS (HR-MDS). Subjects with sufficient data based on (e.g., available heme parameters, cytogenetics, NGS etc.) were reclassified by IPSS-R and IPSS-M. Subjects with IPSS-R score of ≤3.5 or IPSS-M of either very low, low, or moderate low were categorized as LR-MDS. Similarly subjects with IPSS-R score of >3.5 or an IPSS-M categorization of either moderate high, high, or very high were categorized as HR-MDS. Reclassified subjects were reassessed for CR (Complete Response), OS, and LFS and Harrell's concordance index (c-index) was used to describe the level of agreement between each scale and outcomes. Results: Based on the available data, the number of MDS subjects in the different risk classifications were the following: IPSS: 117, IPSS-R: 104, and IPSS-M: 105. Thirteen and 12 subjects on the IPSS could not be reclassified in the IPSS-R and IPSS-M, respectively, including 5 Int-1 and 2 low-risk MDS cases. CMML subjects were excluded from these analyses. Re-classification generally resulted in the upgrade of the subjects from LR-MDS to HR-MDS (Fig. 1). Thirty-one (26.5%) subjects from IPSS were reallocated in the IPSS-R to different risk categories; 3 (9.7%) were downgraded and 28 (90.3%) were upgraded. Similarly on reclassification with IPSS-M 34 (32.4%) of the patients reclassified; 5 (14.8%) were downgraded and 29 (85.3%) were upgraded. For IPSS LR-MDS, 23.2% of patients achieved CR, and 22.9% in the IPSS HR-MDS. Similarly, 21.6% patients achieved CR in the IPSS-R LR-MDS, and 23.9% in the IPSS-R HR-MDS; 26.3% patients achieved CR in the IPSS-M LR-MDS, and 20.9% in the IPSS-M HR-MDS. The c-index for the IPSS was .64 (OS) and .67 (LFS), IPSS-R was .70 (OS) and .71 (LFS), and .75 (OS) and .78 (LFS) for the IPSS-M (Table1). Conclusion: Reclassification from IPSS to IPSS-R or IPSS-M upgraded multiple subjects from a LR to a HR category, describing the ASCERTAIN patient population as a majority higher risk population with worse prognosis than previously assumed based on the IPSS. The efficacy as measured by the CR rates did not change when the LR and HR categories were defined by the different risk stratification systems. In contrast, the c-index improves with migration from IPSS to IPSS-R to IPSS-M, indicating an increased discriminatory ability of IPSS-M score in comparison to IPSS and IPSS-R, to predict patient outcomes.

Abstract Myelodysplastic neoplasms (MDS) are a collection of hematopoietic disorders with widely variable prognoses and treatment options. Accurate pathologic diagnoses present challenges because of interobserver variability in interpreting morphology and quantifying dysplasia. We compared local clinical site diagnoses with central, adjudicated review from 918 participants enrolled in the ongoing National Heart, Lung, and Blood Institute National MDS Natural History Study, a prospective observational cohort study of participants with suspected MDS or MDS/myeloproliferative neoplasms (MPNs). Locally, 264 (29%) were diagnosed as having MDS, 15 (2%) MDS/MPN overlap, 62 (7%) idiopathic cytopenia of undetermined significance (ICUS), 0 (0%) acute myeloid leukemia (AML) with <30% blasts, and 577 (63%) as other. Approximately one-third of cases were reclassified after central review, with 266 (29%) diagnosed as MDS, 45 (5%) MDS/MPN overlap, 49 (5%) ICUS, 15 (2%) AML with <30%, and 543 (59%) as other. Site miscoding errors accounted for more than half (53%) of the local misdiagnoses, leaving a true misdiagnosis rate of 15% overall, 21% for MDS. Therapies were reported in 37% of patients, including 43% of patients with MDS, 49% of patients with MDS/MPN, and 86% of patients with AML with <30% blasts. Treatment rates were lower (25%) in cases with true discordance in diagnosis compared with those for whom local and central diagnoses agreed (40%), and receipt of inappropriate therapy occurred in 7% of misdiagnosed cases. Discordant diagnoses were frequent, which has implications for the accuracy of study-related and national registries and can lead to inappropriate therapy. This trial was registered at www.clinicaltrials.gov as #NCT05074550.

Abstract Health-related quality of life (HRQoL) and vulnerability are variably affected in patients with myelodysplastic syndromes (MDS) and other cytopenic states; however, the heterogeneity of these diseases has limited our understanding of these domains. The National Heart, Lung, and Blood Institute-sponsored MDS Natural History Study is a prospective cohort enrolling patients undergoing workup for suspected MDS in the setting of cytopenias. Untreated patients undergo bone marrow assessment with central histopathology review for assignment as MDS, MDS/myeloproliferative neoplasm (MPN), idiopathic cytopenia of undetermined significance (ICUS), acute myeloid leukemia (AML) with <30% blasts, or “At-Risk.” HRQoL data are collected at enrollment, including the MDS-specific Quality of Life in Myelodysplasia Scale (QUALMS). Vulnerability is assessed with the Vulnerable Elders Survey. Baseline HRQoL scores from 449 patients with MDS, MDS/MPN, AML <30%, ICUS or At-Risk were similar among diagnoses. In MDS, HRQoL was worse for vulnerable participants (eg, mean Patent-Reported Outcomes Management Information Systems [PROMIS] Fatigue of 56.0 vs 49.5; P < .001) and those with worse prognosis (eg, mean Euroqol-5 Dimension-5 Level [EQ-5D-5L] of 73.4, 72.7, and 64.1 for low, intermediate, and high-risk disease; P = .005). Among vulnerable MDS participants, most had difficulty with prolonged physical activity (88%), such as walking a quarter mile (74%). These data suggest that cytopenias leading to MDS evaluation are associated with similar HRQoL, regardless of eventual diagnosis, but with worse HRQoL among the vulnerable. Among those with MDS, lower-risk disease was associated with better HRQoL, but the relationship was lost among the vulnerable, showing for the first time that vulnerability trumps disease risk in affecting HRQoL. This study is registered at www.clinicaltrials.gov as NCT02775383.