Amy E. DeZern

Summary: Calreticulin gene ( CALR ) mutations are seen in 25%–30% of myeloproliferative neoplasms (MPNs). We report outcomes and high‐risk genomic signatures in 149 patients with CALR‐mutated MPN. CALR‐mutated essential thrombocythaemia ( n = 106) progressed to myelofibrosis ( n = 40) at a median of 20.4 years, and 20‐year overall survival (OS) was 81%. In 83 patients with myelofibrosis, the median leukaemia‐free survival (LFS) was 12.9 years, and OS was 13.9 years. Median survival after leukaemia transformation was 6.8 months. High molecular risk (HMR) mutations included ASXL1 , EZH2 , SRSF2 , U2AF1 (Q157), IDH1/2 , TP53 , SETBP1 , KRAS , NRAS and RUNX1 (later five not included in Mutation‐Enhanced International Prognostic Score System [MIPSS70]‐plus v2.0); and were associated with a significantly higher leukaemic transformation, inferior LFS and OS (hazard ratio [HR]: 3.82, 95% confidence interval [CI]: 1.30–11.18); with worst outcomes in patients with ≥2 HMR. Independent of MIPSS70‐plus v2.0, TP53 , KRAS and RUNX1 mutations adversely impacted LFS and OS (HR: 2.87, 95% CI: 1.20–6.88; HR: 3.80, 95% CI: 1.37–10.54; HR: 5.61, 95% CI: 1.53–20.52 respectively). Patients without HMR had a negligible rate of progression. Overall, outcomes are determined not by CALR ‘driver’ mutation, but by the somatic mutations that can emerge during disease evolution. Hence, serial molecular profiling is important for risk stratification. HMR, including TP53 , KRAS and RUNX1 , confer inferior survival and support early transplantation consideration.

Baseline IPSS‐M risk, response to hypomethylating agent (HMA) therapy, and receipt of allogeneic stem cell transplant (allo‐HCT) have all been individually shown to impact overall survival (OS) in patients with myelodysplastic syndromes (MDS). However, the prognostic impact of response when adjusting for IPSS‐M risk and treatment strategy remains unclear. Hence, we used the VALIDATE database of the International Consortium for MDS (icMDS) to evaluate the impact of International Working Group (IWG) 2023 best response on OS in 715 HMA‐treated, higher‐risk MDS patients stratified by baseline IPSS‐M risk and their treatment strategy (subsequent allo‐HCT vs. medical therapy alone) treating both best response and allo‐HCT as time‐dependent variables. Baseline IPSS‐M risk (hazard ratio (HR): 0.5, p < 0.001) and receipt of allo‐HCT (HR: 0.5, p < 0.001) were the strongest independent predictors of OS, whereas achievement of composite complete response (cCR) had a more modest impact on OS (HR: 0.8, p = 0.004). Among patients treated with medical therapy alone, achieving cCR improved OS significantly (HR: 0.7, p = 0.006). In contrast, among transplanted patients, cCR did not retain independent prognostic value for post‐transplant survival after adjusting for baseline IPSS‐M (HR: 0.9, p = 0.634). Achieving cCR did not fully overcome adverse disease biology as OS continued to segregate according to baseline IPSS‐M risk. In summary, achieving cCR improves outcomes in non‐transplanted patients, but it does not significantly impact post‐transplant OS, suggesting that failure to achieve cCR with HMA may not warrant delay or preclude allo‐HCT. Clinical trials should consider response in the context of IPSS‐M risk distribution and treatment strategy (subsequent allo‐HCT vs. medical therapy alone) to avoid overinterpretation of high response rates.

Monotherapy with hypomethylating agents (HMA) remains the standard of care for patients with higher-risk myelodysplastic neoplasms (HR-MDS). Recently, the randomized phase III VERONA study evaluating azacitidine plus venetoclax (VEN) versus azacitidine plus placebo in newly diagnosed HR-MDS showed no difference in overall survival (OS) between the two arms. However, whether the addition of VEN to HMA improves outcomes among subsets of patients with HR-MDS remains debated. We analyzed 1907 patients with HR-MDS from 31 centers in 9 countries who were treated with HMA monotherapy or HMA/VEN in the frontline setting (HMA monotherapy: n = 1773; HMA/VEN: n = 134). Responses were assessed centrally by two investigators using the IWG 2023 response criteria. Addition of VEN improved composite complete remission (cCR) rates (48.8% vs. 27.7%; p < 0.001) but not CR rates (17.1% vs. 11.7%; p = 0.16). In multivariable logistic regression analysis, cCR remained favorable for HMA/VEN vs. HMA monotherapy (Odds Ratio [OR]: 2.49; 95% CI: 1.56-3.96; p < 0.001). However, we did not observe a statistically significant difference in OS for HMA/VEN vs. HMA monotherapy (Hazard Ratio [HR]: 0.83; 95% CI: 0.64-1.07; p = 0.15). In subgroup analyses, patients with TP53 wild-type disease (HR: 0.47; 95% CI: 0.29-0.74; p = 0.002) had a significant improvement in OS and those with ≥10% bone marrow blasts (HR: 0.73; 95% CI: 0.53-1.01; p = 0.06) had a trend towards OS benefit with HMA/VEN.

Patients at risk for progression from myeloid precursor states (idiopathic cytopenia of undetermined significance [ICUS] and clonal cytopenia of undetermined significance [CCUS]) to myelodysplastic syndrome (MDS) are not well defined. Epidemiologic risk factors, clonal changes for MDS development, and evolution from one MDS state to another were available in the MDS Natural History Study (NHS), a prospective cohort enrolled at diverse US sites. Extensive clinical data and biospecimens were collected at baseline and follow-up. A total of 1177 (56%) individuals with MDS or MDS-related precursor conditions (ICUS/idiopathic dysplasia of undetermined significance [IDUS], CCUS, and MDS/myeloproliferative neoplasm overlap) were enrolled and diagnosed in the MDS NHS. The median age was 74 years, with 89% aged ≥60 years, and most were male patients. Median follow-up time was 1.6 years and was similar among ICUS/IDUS, CCUS, and MDS. During follow-up period, 68% of participants terminated the study, 35% died, and 38% had disease progression. Using a refined clinical definition of progression, the greatest proportion of progression was observed among higher-risk-MDS (116 [73%]), followed by lower-risk-MDS (170 [52%]); fewer progression events were observed among participants with CCUS (65 [22%]) and ICUS/IDUS (46 [17%]). Predictors of progression are delineated, including female sex, higher quantity of mutations, the presence of TP53 mutation, and poor/very poor cytogenetic score. Based on these prospective data, guidelines for clinical management including monitoring and surveillance are outlined. The MDS NHS provides real-world data to illustrate how clinical and genotypic differences inform the classification, disease course, and approach to therapy, with informed monitoring guidelines for patients. This trial was registered at www.ClinicalTrials.gov as NCT02775383.

Background: Large language models (LLMs) perform well on standardized medical exam questions, but their reliability for complex hematology decision making is uncertain. We compared four general-purpose LLMs (GPT-4o, GPT-o3, Claude Sonnet 4, and DeepSeek-V3) with a Virtual MDS Panel (VMP), a coordinated multi-agent AI system in which domain-specialized, rule-bound software agents (WHO/ICC guidelines; IPSS-R/IPSS-M; NCCN) collaborate to generate tumor-board-level recommendations. Methods: Each model generated diagnostic, prognostic, and treatment recommendations for 30 myelodysplastic syndrome cases. Nine international MDS experts from five institutions, blinded to model identity, completed 3,000 structured ratings using 5-point Likert scales for diagnosis, prognosis, and therapy and classified errors by severity. Results: General-purpose LLMs achieved modest expert ratings (overall mean scores: 3.7 for GPT-o3, 3.2 for GPT-4o, 3.1 for DeepSeek, and 3.0 for Claude) and contained major factual errors in at least 24% of responses. The VMP increased the proportion of outputs rated 4 or higher to 87% (vs. 34-66% for general-purpose models), improved mean scores to 4.3 overall (4.3 for diagnosis, 4.4 for prognosis, and 4.1 for therapy), and reduced major errors to 8%. Conclusions: In this blinded evaluation of 30 complex MDS cases, general-purpose LLMs produced clinically important errors at rates that raise safety concerns for autonomous hematology decision making. The VMP, a rule-bound, multi-agent architecture, approached expert-level accuracy supporting its potential role as an effective decision-support tool for MDS in the future.

Clonal hematopoiesis (CH) results from the acquisition and expansion of somatic mutations in hematopoietic stem and progenitor cells and is associated with age-related clinical sequelae, including an increased risk for cardiovascular disease, myeloid neoplasms and complications related to cancer therapy. Chemotherapy and radiation can accelerate CH expansion and further elevate the risk of adverse events, including cardiotoxicity and therapy-related myeloid neoplasms. Although CH is increasingly recognized as a clinically relevant precursor state and predictive biomarker, the long-term dynamics of CH expansion in humans remain poorly understood. Longitudinal data are often collected but not integrated with mathematical prediction. Mathematical modeling is essential for characterizing CH evolution, estimating clone fitness, inferring stem cell pool dynamics and enabling patient-level predictions. This study summarizes the current evidence on CH dynamics in humans, compares mathematical models used to predict CH progression, assesses the validity of model assumptions and discusses the implications for clinical management of individuals with these precursor conditions.