6519 Background: Acute myeloid leukemia (AML) is characterized by poor survival with Black patients (pts) experiencing worse outcomes compared to White pts. While patient-specific factors such as race have emerged as important predictors for survival in AML, the biologic mechanisms driving these factors are not well characterized. Here, we analyzed the molecular profiles of adults diagnosed with AML to identify potential differences in the frequency of genes commonly mutated in AML and their impact on survival. Methods: This was a retrospective cohort study of adults diagnosed with AML at the Cleveland Clinic between 2008 and 2022. Patients were identified as Black or White based on self-reported race/ethnicity. Molecular data were obtained from next-generation sequencing (NGS) performed at the time of diagnosis. Survival analysis was limited to pts receiving intensive induction chemotherapy and estimated using the Kaplan-Meier method and compared with the log-rank test. Results: 1,144 pts were included in this study: 10% (n = 115) Black and 90% (n = 1029) White. Median age at diagnosis (years) was lower in Black pts compared to White pts (62 vs 66) (p = 0.005). Cytogenetics analysis (MRC 2010) showed a higher proportion of Black pts with favorable-risk disease compared to White pts (15% vs. 8%; p = 0.04) while rates of poor-risk cytogenetics were similar (31% vs. 30%). Mutations in IDH1 , CBL , CEBPA , and NOTCH1 were more common in Black pts than in White pts (p < 0.05). Conversely, mutations in NPM1 were lower in Black pts (16%) vs. White pts (24%) (p = 0.22). We did not observe a difference in the type of induction chemotherapy received (p = 0.23). However, more White pts underwent hematopoietic cell transplant (HCT) compared to Black pts (32% vs. 21%; p = 0.02). The median overall survival (OS) for the whole cohort was 18 months (95% CI: 16-21 months) with a 5-year OS of 31% (95% CI: 27-34%); median follow up time of 63 months. Univariable analysis showed that worse overall survival was associated with older age, poor risk cytogenetics, therapy-related and secondary AML, and not undergoing HCT (p < 0.05), but median OS and 5-year OS rates were similar between Black and White pts (24 months, 28% vs. 17 months, 31%). After adjusting for prognostic variables, age, HCT status and cytogenetic risk remained significant (p < 0.05). Conclusions: Unlike previously reported studies, we did not observe a survival disparity in race in our study cohort. However, we observed lower rates of treatment with HCT in Black pts. We also identified a higher frequency of mutations in genes involved in myeloid transcriptional regulation, epigenetic modification, and cellular signaling. Adequate assessment of the prognostic relevance of these genes is limited by a small sample size and variability in NGS platforms over time. Future studies may explore pooled genetic data across several institutions and genetic ancestry testing over self-reported race/ethnicity.

Donor cell-derived haematological neoplasms (DDHN) are rare disorders and currently do not have standardised diagnostic criteria and therapeutic management. International experts in allogeneic transplantation and haematological malignancies from Europe, the Americas, and Australia worked together on behalf of the EBMT Practice Harmonisation and Guidelines Committee to delineate a pragmatic diagnostic framework and issue guidance for downstream clinical management for DDHN. The team met on Sept 18-19, 2025, in Berlin, Germany, to discuss the definition, molecular insights, treatments, and donor outcomes for DDHN after an intensive review of the literature. In this Review, we present the epidemiology and clinical definitions of DDHN, provide guidance on diagnosis and prevention, address therapeutic considerations, and outline recommendations for donor management.

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.

Large granular lymphocytic leukemia (LGLL) is an uncommon and likely under-diagnosed leukemia that causes severe neutropenia and anemia and can have profound effects on the quality of life for afflicted patients. Frequently associated with various auto-immune phenomena, LGLL is a paradigm for a highly interdisciplinary disease. Recent advances in our pathobiological understanding of LGLL, along with the development of novel agents, have stimulated a growing number of clinical trials and innovative approaches targeting this disease. Currently, the absence of uniform diagnostic and response criteria for LGLL results in significant heterogeneity in diagnosis and response assessment across studies. Furthermore, with the emergence of a variety of novel experimental therapeutics and an increasing number of clinical trials, it becomes critical to better define the key diagnostic, treatment and response parameters for this disease. The International LGLL Consortium was created to develop cross-disciplinary expert consensus on uniform diagnostic, treatment, and response criteria for LGLL suitable for both routine clinical use and interventional trials while facilitating cross-study comparisons. Utilizing an evidence-based framework, along with the international panel that comprises the LGLL Consortium, this report delineates the key criteria that will serve as a foundation for both the clinical management and future investigations in LGLL.

Menin scaffolds the oncogenic histone-lysine-N-methyltransferase (KMT2A)-fusion protein (FP) complex in KMT2A-r and wild-type KMT2A complex in NPM1-m acute myeloid leukemia (AML). Menin inhibitors (MIs) are effective in KMT2A-r AML and NPM1-m AML. However, not all patients respond to MIs as monotherapy. In this preclinical study, we demonstrate that the MI ziftomenib, in combination with the XPO1 inhibitor selinexor, synergistically inhibited the growth of multiple KMT2A-r and NPM1-m AML cell lines (CI<1). The combination suppressed colony formation in primary CD34+ KMT2A-r progenitor cells without affecting normal stem cells. Robust apoptosis and decreased G2/M populations were also evident. The combination downregulated HOXA9 and MEIS1 while upregulating monocytic differentiation marker CD11b in both the AML molecular signatures. RNA sequencing and proteomic analysis in KMT2A-r revealed suppression of multiple bona fide menin-KMT2A target genes. Our mechanistic studies also identified a novel role of XPO1 in stabilizing menin's binding to chromatin and its interactions with KMT2A and KMT2A/MLLT3. XPO1 inhibitor-mediated disruption of these interactions, particularly in combination with ziftomenib, synergistically impairs oncogenic transcriptional programs. In vivo, combination therapy improved survival in both MV4;11 and OCI-AML3 cell line and primary patient-derived KMT2A-r and NPM1-m AML xenograft models in NSG mice, effective even at reduced drug doses. These preclinical findings demonstrate that simultaneous inhibition of the menin-KMT2A interaction and XPO1 can be a more effective translational strategy for treating KMT2A-r and NPM1-m AML than MI monotherapy to deepen responses and delay/prevent relapses.

Chronic myelomonocytic leukemia (CMML) is a heterogeneous myeloid neoplasm with a highly variable prognosis. TET2 is mutated in ∼60% of cases, with several studies linking TET2 mutations and mutation burden to favorable outcomes. However, no prior study has quantitatively characterised TET2 variant allele frequency (VAF) as a continuous, non-linear prognostic variable across large multi-institutional cohorts, nor leveraged it to refine contemporary CMML risk-stratification systems. We examined the prognostic role of TET2 VAF in 1,206 CMML patients across a UK discovery cohort (DC, TET2-mutated: 433/645, 67%), an international validation cohort (VC1, TET2-mutated: 141/291, 48%), and a French CD14+ monocyte-sequenced cohort (VC2, TET2-mutated: 176/270, 65%). Segmented regression of TET2 VAF distributions reproducibly identified two inflection points (DC 32%/55%; VC1 33%/54%; VC2 36%/56%), implying consistent subdivision of TET2 mutation burden across CMML of epidemiological (and potentially biological) relevance. Restricted cubic spline Cox regression revealed a non-linear relationship between TET2 VAF and survival, with risk lowest near VAF 39% (the empirical first quartile), whilst TET2 wild-type patients had hazards comparable to high-VAF cases. Capitalising on this continuous relationship, we constructed TET2-VAF-adjusted CPSS-Mol, GFM, and MMM scores by adding a per-integer-VAF adjustment to each patient's original score. Across cohorts and prognostic tools, the adjusted scores improved discrimination (Harrell's C-index gain in 16/18 comparisons, IDI significant in 18/18, p<0.01), and group-level stratification for overall survival and acute myeloid leukemia-free survival. These findings suggest that TET2 VAF represents a continuous prognostic variable in CMML and provide a robust, reproducible framework for refining standard risk-stratification systems.

Abstract Introduction: Acute myeloid leukemia (AML) is an aggressive blood cancer driven by genetic changes that disrupt hematopoiesis. It is characterized by poor survival, with two-thirds of patients dying within 5 years. Non-Hispanic Black patients with AML have higher mortality rates compared to White patients despite favorable disease factors like low-risk cytogenetics and younger age. Risk stratification in AML has been greatly improved by the inclusion of tools such as next generation sequencing (NGS) in the prognostication of AML. However, little is known about the molecular landscape and prognostic relevance of mutations in Black patients with AML. This study characterizes the genetic profiles of Black patients with AML at the Cleveland Clinic. Method: This retrospective, single-center, cohort study included patients diagnosed with AML between 2002 and 2022. Clinical data were obtained from electronic medical records and stored securely. Molecular data were obtained from NGS platforms of genes frequently mutated in AML. Overall survival (OS) was limited to patients receiving intensive induction chemotherapy and estimated using Kaplan-Meier method. Results: Overall, there were 118 (9.34%) Black patients among our cohort of 1,264 AML patients. 55% of these patients were male and the median age at diagnosis was 62 years. Karyotype analysis revealed that majority (68%) of Black patients had an abnormal karyotype driven by trisomy 8 (23.0%), -7 or del (7q) (17.6%), or -5 or del (5q) (16.2%) abnormalities, of which the latter two represent adverse risk disease. Most of these patients (65%) were treated with intensive induction chemotherapy and of these 30% (n=23) underwent a bone marrow transplant. NGS was available for 49.1% (n = 58) of Black patients and revealed a predominance of mutations in genes involved in DNA methylation: DNMT3A (24%, n=14) and TET2 (21%, n=12). Median OS was 24 months (95% CI: 14-46months) with a 5-year OS rate of 27% (95% CI:18-40%), lower than the national average of 32.9%. Older age (>60), poor risk cytogenetics, non-intensive chemotherapy, TET2, and ASXL1 were associated with worse survival in univariable analysis (p<0.05). Upon adjusting for prognostic variables, only poor risk cytogenetics remained significant (p=0.02). Conclusion: DNMT3A and TET2 mutations were most observed in Black patients with AML in this cohort at similar frequencies compared to population studies. These genes are observed in clonal hematopoiesis indicating early events in leukemogenesis. Their prognostic significance remains undefined but may inform future studies addressing outcome disparities through better risk stratification and the development of targeted therapies. Study limitations include small sample size, NGS availability and self-reported race/ethnicity. Comparative analysis with White patients and prospective studies with genetic ancestry testing are needed. Citation Format: Eno-obong B. Udoh, Xiaoying (Nicole) Chen, Sarah J. Philip, Yazeed Sawalha, Yazan F. Madanat, Ameera Rose, Teodora Kuzmanovic, John C. Molina, Moaath K. Mustafa Ali, Akriti G. Jain, Abhay Singh, Sophia Balderman, Babal Kant Jha, Ronald Sobecks, Betty K. Hamilton, Sudipto Mukherjee, Aaron Gerds, Hetty Carraway, Jaroslaw P. Maciejewski, Mikkael Sekeres, Anjali Advani. Evaluating the molecular landscape of genetic mutations among Black patients with acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5301.

Clonal expansions in large granular lymphocytic leukemia (LGLL) may arise in response to immune dysregulation in the context of other hematologic malignancies. This study aimed to investigate the co-occurrence of LGLL and plasma cell dyscrasias (PCDs) to assess its prevalence, features, and potential underlying mechanisms. We conducted a cross-sectional study involving 2064 PCD cases and 534 LGLL cases. Of the 534 LGLL cases, 20% co-occurred with PCD, while LGLL was present in 2% of the 2064 PCD cases. Among 117 patients with both conditions, PCDs were predominantly associated with IgM M-protein, while LGLL patients had increased NK-cell proliferation and fewer mutations in STAT3/5B. The co-occurrence was linked to a higher incidence of autoimmune conditions, B-cell neoplasms, and more severe immune-mediated cytopenias. In symptomatic PCD/LGLL patients with low plasma-cell infiltration, B-cell-targeted therapies outperformed immunosuppression, suggesting humoral involvement. Correlation with biological parameters revealed elevated interleukin-6 and inhibitory effects of sera of symptomatic PCD/LGLL patients on hematopoietic cells. Our findings suggest an association between PCD and LGLL, characterized by distinct features that may have significant implications for clinical management. These results highlight the importance of considering hematologic co-occurrences in clinical practice and warrant further investigation into the molecular mechanisms linking these conditions.

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.

ABSTRACT:Myelodysplastic syndromes (MDS) with isolated deletion of chromosome 5q [MDS-del(5q)] constitute a distinct biological entity traditionally associated with favorable outcomes, although up to one-quarter of patients progress to acute myeloid leukemia (AML). Existing prognostic models, developed in heterogeneous MDS populations, may not adequately capture risk within this subgroup. We assembled an international cohort of 682 patients with MDS-del(5q) to evaluate the performance of the Revised International Prognostic Scoring System (IPSS-R) and its molecular version (IPSS-M), identify prognostic variables, and develop a disease-specific prognostic tool, the IPSS-del(5q). Most patients were classified as lower risk by IPSS-R (94.4%) and IPSS-M (85.5%), yet both systems showed limited discriminatory ability (concordance indices [C-indices] ≈0.5). Independent adverse prognostic factors included age of ≥70 years, male sex, anemia (hemoglobin ≤10 g/dL), thrombocytopenia (platelet count ≤100 × 109/L), the presence of 1 additional chromosomal abnormality, ≥2 gene mutations, SF3B1 mutations, and high-risk TP53 status. Six variables were included in the IPSS-del(5q), stratifying patients into standard-risk (74.3%) and high-risk (25.7%) groups with significantly different leukemia-free survival (69.2 months vs 32.0 months, respectively; P< .01). Moreover, this model reclassified 19.1% of patients in lower-risk IPSS-R group and 14.6% of those in lower-risk IPSS-M group into the high-risk IPSS-del(5q) group. However, its discriminative power remained modest, with a C-index of 0.60. Overall, to our knowledge, this study provides the most comprehensive prognostic evaluation of MDS-del(5q) to date, demonstrates the limited discriminatory capacity of existing MDS scores in this entity, and underscores the need to develop refined disease-specific prognostic approaches for this MDS subtype.

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by complement-mediated hemolysis with or without overt hemoglobinuria and is associated with bone marrow failure (BMF). PNH can be classified into 3 subcategories: classical (hemolytic) PNH, PNH with underlying BMF, and subclinical PNH. The optimal approach for patients with underlying BMF or subclinical PNH is not clearly defined. In addition, recommendations for screening and monitoring nonclassical patients are dated. A modified Delphi panel consisting of 10 hematologists and hematologist-oncologists evaluated 414 patient scenarios on 2 separate occasions and participated in a moderated in-person meeting. Consensus statements were developed based on the second round of ratings. After the meeting, the panel agreed on 90% of the ratings and made recommendations on when to screen patients for a PNH clone, when to initiate complement inhibitor treatment, and when to reevaluate patients with a PNH clone who are not yet on treatment. For example, it is appropriate to initiate complement inhibition in patients with a PNH clone size ≥10% who had a recent thrombotic event with laboratory evidence of hemolysis. Further evidence is required to improve recommendations for patients with small (<10%) PNH clone sizes.

Aplastic anemia (AA) results from T-cell-mediated destruction of hematopoietic stem and progenitor cells (HSPCs), driving clonal hematopoiesis via loss of human leukocyte antigen (HLA) risk alleles (HLA loss-of-function mutations or uniparental disomy 6p, UPD6p), paroxysmal nocturnal hemoglobinuria and clonal hematopoiesis of indeterminate potential (CHIP) mutations. Here genomic profiling of 619 patients with AA revealed clonal hematopoiesis in 69% of cases, with ASXL1, BCOR and BCORL1 identified as the most frequent CHIP mutations in pediatric cases. Single-cell multi-omics analysis of 304,902 cells from 48 samples uncovered complex branching clonal architecture, with a median of three HLA loss events per patient, converging to inactivate HLA risk alleles. Single-cell whole-genome sequencing (WGS) resolved up to 15 HLA loss clones per patient and phylogenetic reconstruction indicated that these clones originated years before diagnosis. Long-read WGS precisely mapped UPD6p breakpoints and HLA methylation. HLA loss conferred a protective effect against CHIP, evidenced by their near-absent co-occurrence. Longitudinal single-cell analysis demonstrated that long-lived clones were enriched in the CD34+ HSPC compartment. These findings reveal parallel evolutionary pathways used by hematopoietic cells to evade immune attack.

ABSTRACT:Telomere length shortening has been associated with genomic instability and acquisition of molecular lesions, but these processes have not been systematically studied across large cohorts of myeloid neoplasia (MN). As proof of concept for a novel, cross-validated whole-genome sequencing-based method of telomere content (TC) determination combined with mutations, transcriptomics, and functional assays, we studied TC in correlation with specific molecular features of a large cohort (N = 1804) of patients with MN, including acute myeloid leukemia (AML) and myelodysplastic syndrome. When compared with healthy participants and patients with nonclonal diseases such as persistent polyclonal B-cell lymphocytosis, both MN and nonmalignant controls with clonal disease, such as paroxysmal nocturnal hemoglobinuria and aplastic anemia, exhibited decreased TC. Furthermore, we show that TC is lowered in adult MN abrogating correlation with age with considerable TC diversification among certain morphologic and molecular subtypes. For instance, AML harbored the lowest TC. Furthermore, MN originating from a more mature cell of origin (eg, acute promyelocytic leukemia) or characterized by hyperproliferative driver mutations (eg, RAS pathway genes) had lower TC, possibly indicating a loss of telomere maintenance capacity. In contrast, compared with other mutations, MN subtypes arising in a context of profound genetic alterations, such as TP53 mutations and complex karyotype, exhibited a relatively higher/preserved TC. This phenomenon did not involve alternative lengthening processes but was rather consistent with an increased TC due to preserved activity of the telomerase complex. Our results describe a common and genotype-specific telomeric makeup of a large cohort of patients with MN providing a molecular benchmark for future therapeutic targeting of the telomere machinery.

Abstract STAG2 is the most frequently mutated cohesin gene in myeloid neoplasms, yet the significance of multiple mutations within this X-linked tumor suppressor remains unknown. We analyzed a cohort of 1,967 adult patients with myeloid neoplasms and identified 233 cases (12%) harboring STAG2 mutations, including 38 cases (16%) with multiple STAG2 hits. Patients with multi-hit STAG2 mutations exhibited increased multilineage dysplasia compared with single-hit cases and experienced inferior overall survival, an effect driven primarily by patients with myelodysplastic syndromes (MDS). To investigate the molecular basis of recurrent STAG2 acquisition, we performed long-read sequencing in representative cases with phaseable STAG2 mutations. In the informative case examined, distinct truncating STAG2 mutations did not co-occur on the same DNA molecule, supporting independent acquisition rather than stepwise allelic inactivation. Cohort-level variant allele frequency patterns were consistent with recurrent evolutionary targeting of STAG2 across related clonal populations. Together, these findings support a model in which multi-hit STAG2 mutations arise through convergent evolution and define a biologically distinct, adverse-risk subset of MDS. Key points Multi-hit STAG2 mutations identify a high-risk subset of MDS characterized by increased multilineage dysplasia and inferior survival. Long-read sequencing supports convergent evolutionary acquisition of STAG2 mutations rather than stepwise allelic inactivation.

Internal-tandem-duplication of the receptor tyrosine kinase FLT3 (FLT3-ITD) generates ligand-independent signaling and is highly recurrent in acute myeloid leukemias (AMLs). One way signaling pathways can quickly influence cell fates is by phosphorylating key fate-determining proteins to trigger their proteolysis. We investigated the master transcription factor (MTF) driver of granulo-monocytic lineage-fates, CEBPA, for regulation by this mechanism because we found high CEBPA mRNA but little CEBPA protein in FLT3-ITD versus FLT3-wildtype AML cells, and inhibiting FLT3-ITD signaling with tyrosine kinase inhibitors (TKI) rapidly rescued CEBPA protein. Mass spectrometry analyses of CEBPA and its interactome demonstrated prominent interactions with major ubiquitin-proteosome pathway (UPP) components UHRF1 and USP7. TKI treatments decreased CEBPA and USP7 phosphorylations at serine 21 and serine 18 respectively alongside shifts in CEBPA interactions from degradative ubiquitin-ligase UHRF1 toward protective deubiquitinase USP7. The rescued CEBPA activated granulocytic-differentiation. Supporting that the serine-phosphorylations were 'phospho-degrons', UPP-inhibitors (bortezomib, MG132) increased phosphorylated and total CEBPA and USP7. The MTF regulator of apoptosis p53 is a known USP7 client, therefore, we also evaluated p53 status: TKIs and UPP-inhibitors stabilized USP7 and p53, triggering apoptosis in addition to granulocytic-differentiation specifically in FLT3-ITD but not FLT3-wildtype AML cells. UPP-inhibitors produced these consequences in TKI-resistant FLT3-ITD AML cells also. These data predicted genetic loss-of-function to CEBPA or TP53 is redundant in the FLT3-ITD context, borne out by mutual exclusivity of the mutations in clinical series. In summary, FLT3-ITD signals for CEBPA and p53 proteolysis to block lineage-maturation and apoptosis, positioning UPP-inhibitors as therapeutic candidates acting downstream of TKIs.

Abstract Secondary acute myeloid leukemia (AML) comprises heterogeneous entities, unified by poor prognosis. We evaluated the associations of genetic profiles with blast counts and patients’ history in a cohort of 924 patients with myelodysplastic syndrome (MDS)/AML or AML, classified according to the International Consensus Classification (ICC). The cohort included 109 patients with “mutated TP53,” 497 with “myelodysplasia-related (MDR) gene mutation,” 93 with “MDR-cytogenetic abnormality,” 77 were therapy-related, and 136 controls, categorized as “not otherwise specified” (NOS) AML. Exploring the ICC hierarchy, AML and MDS/AML categories with “mutated TP53” and “MDR-cytogenetic abnormality” presented similar biology and prognosis, irrespective of blast counts. Conversely, in MDS/AML with “MDR gene mutation” and NOS, profiles significantly differed from AML and were characterized by a higher number of mutations in STAG2, SRSF2, ASXL1 and TET2. This corresponded to improved survival in MDS/AML vs AML (MDR-gene mutation: median overall survival 24.8 vs 13.6 months, P< .0001; and NOS: 49.9 vs 19.2 months, P = .028). Within each ICC-defined AML category, a prior MDS history vs de novo onset did not impact on patients’ prognosis. We then analyzed secondary AML, defined by “prior MDS or MDS/MPN” or “therapy-related” (t-AML), as diagnostic qualifiers. According to European LeukemiaNet (ELN) 2022, AML progressing from MDS or MDS/myeloproliferative neoplasm (MPN) (AML post-MDS) mostly clustered in the adverse-risk group (84.1%), whereas t-AML showed more heterogeneous ELN profiles (12.9% favorable, 33.8% intermediate, and 53.3% adverse risk) reflecting diverse overall survival. Our findings underscore that genetic features and the ICC classification reliably capture disease biology, refine risk stratification, and ultimately guide treatment decisions in most secondary AML and MDS/AML.

3143 Background: GLP-1 receptor agonists (GLP-1RAs) are pleiotropic medications, initially developed for diabetes, yet with beneficial effects on obesity and cardiovascular disease. Given the rapidly expanding therapeutic use of these agents and emerging preclinical data suggesting immunomodulatory effects, we examined whether GLP-1RA exposure following cancer diagnosis was associated with altered risk of progression to metastatic disease. Methods: Utilizing the TriNetX Global Health Research Network, we identified 10,225 patients with stage I-III cancer who initiated GLP-1RA therapy after diagnosis. GLP-1RA-exposed patients were propensity-matched 1:1 to DPP-4 inhibitor controls across seven cancers: breast adenocarcinoma, prostate adenocarcinoma, NSCLC, colorectal adenocarcinoma (CRC), hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and pancreatic adenocarcinoma. Matching included demographics, BMI, glycemic factors, smoking, comorbidities, screening frequency, oncologic treatments, and concurrent medications. Primary outcome was progression to stage IV disease. Additionally, we used The Cancer Genome Atlas (TCGA) data to assess whether GLP-1R expression correlated with overall survival. Results: GLP-1RA exposure demonstrated reduced metastatic progression across 6/7 malignancies, with statistically significant reductions in four cancer types: NSCLC, breast, CRC, and HCC (Table 1). No significant safety signals or increased adverse events were observed in GLP-1RA-exposed patients compared to controls. Additionally, high tumor GLP-1R expression correlated with improved survival across the seven tumors (HR=0.67, 95% CI 0.54-0.83, p<0.001), most notably in breast cancer (HR=0.55, 95% CI 0.35-0.87, p=0.011). Conclusions: In this large propensity-matched cohort, GLP-1RA initiation after cancer diagnosis was associated with dramatically reduced metastatic progression across multiple solid tumors. Corroborating these clinical findings, elevated GLP-1R expression independently predicted improved overall survival. These findings warrant validation in prospective randomized controlled trials and mechanistic investigation of potential antineoplastic pathways driven by GLP-1RAs. Effect of GLP1-1RA exposure compared to DPP-4i exposure on progression of stage I-III cancer to stage IV cancer. Cancer Type Matched Pairs (n) Events GLP-1RA/DPP-4i Cumulative Incidence (%) Hazard Ratio (95% CI) P-value NSCLC 2,157 215/482 10.0 vs 22.3 0.50 (0.43-0.59) <0.001 Breast 1,187 121/239 10.2 vs 20.1 0.57 (0.46-0.71) <0.001 Colorectal 784 105/174 13.4 vs 22.2 0.69 (0.54-0.88) 0.003 HCC 275 52/78 18.9 vs 28.4 0.62 (0.44-0.89) 0.009 Prostate 1,010 83/137 8.2 vs 13.6 0.79 (0.60-1.04) 0.09 RCC 523 75/99 14.3 vs 18.9 0.95 (0.71-1.29) 0.76 Pancreatic 120 28/37 23.3 vs 30.8 0.69 (0.42-1.13) 0.14

Iptacopan, a first-in-class, oral, selective complement factor B inhibitor, demonstrated efficacy and safety as monotherapy in C5 inhibitor (C5i)-experienced (APPLY-PNH [NCT04558918]) and C5i-naive (APPOINT-PNH [NCT04820530]) patients with paroxysmal nocturnal hemoglobinuria (PNH). In APPLY-PNH and APPOINT-PNH, changes in fatigue (FACIT-Fatigue) and health-related quality of life (HRQOL; EORTC QLQ-C30) from baseline to Day 168 were evaluated. The proportion of patients achieving meaningful within-patient change (MWPC) on the FACIT-Fatigue and 4 EORTC QLQ-C30 subscales (physical functioning, role functioning, fatigue, dyspnea) was evaluated using anchor-based thresholds. Correlations between FACIT-Fatigue scores, lactate dehydrogenase (LDH), and hemoglobin (Hb) levels were also assessed. In APPLY-PNH (iptacopan, n=62; C5i, n=33), more patients in the iptacopan group reached the MWPC threshold for FACIT-Fatigue than in the C5i group (51% vs 11%). More patients achieved MWPC on domains of the EORTC QLQ-C30 in the iptacopan group (39%-49%) than the C5i group (9%-20%). In APPOINT-PNH (N=40), 56% achieved MWPC on the FACIT-Fatigue, and the proportion of patients who achieved MWPC on the EORTC QLQ-C30 ranged from 41% to 55%. In C5i-experienced patients, increased Hb levels correlated with improvement in FACIT-Fatigue scores (R=0.48, P<0.001). In C5i-naive patients treated with iptacopan, increased Hb (R=0.42, P<0.001) and decreased LDH (R=−0.53, P<0.001) correlated with improved FACIT-Fatigue scores. C5i-experienced and -naive patients receiving iptacopan exhibited meaningful improvement in fatigue, HRQOL, and disease-related symptoms, which correlated with clinical improvement in hematologic markers of disease control. These trials are registered at www.ClinicalTrials.gov as NCT04558918 (APPLY-PNH) and NCT04820530 (APPOINT-PNH).