Molecular Drivers of Myelodysplastic Neoplasms (MDS)—Classification and Prognostic Relevance

Myelodysplastic neoplasms (MDS) form a broad spectrum of clonal myeloid malignancies arising from hematopoietic stem cells that are characterized by progressive and refractory cytopenia and morphological dysplasia. Recent advances in unraveling the underlying pathogenesis of MDS have led to the identification of molecular drivers and secondary genetic events. With the overall goal of classifying patients into relevant disease entities that can aid to predict clinical outcomes and make therapeutic decisions, several MDS classification models (e.g., French–American–British, World Health Organization, and International Consensus Classification) as well as prognostication models (e.g., International Prognostic Scoring system (IPSS), the revised IPSS (IPSS-R), and the molecular IPSS (IPSS-M)), have been developed. The IPSS-M is the first model that incorporates molecular data for individual genes and facilitates better prediction of clinical outcome parameters compared to older versions of this model (i.e., overall survival, disease progression, and leukemia-free survival). Comprehensive classification and accurate risk prediction largely depend on the integration of genetic mutations that drive the disease, which is crucial to improve the diagnostic work-up, guide treatment decision making, and direct novel therapeutic options. In this review, we summarize the most common cytogenetic and genomic drivers of MDS and how they impact MDS prognosis and treatment decisions

Presence but not number of secondary type mutations influences outcome in de novo AML without MDS‐associated or recurring cytogenetic abnormalities

Abstract A group of gene mutations has been identified to be strongly associated with secondary acute myeloid leukemias (AML) arising from prior myeloid neoplasms. The International Consensus Classification (ICC) and proposed 5th edition of the World Health Organization (WHO) classification differ by inclusion of RUNX1. A recent study suggested that having two or more secondary mutations is associated with a particularly poor prognosis. In a study of 294 de novo AML patients, we found that patients with at least one ICC‐defined secondary mutation had shorter survival when compared to those without secondary mutations, and ICC/WHO groups of two or more mutations did not predict for worse outcomes

Distinct SF3B1 Allele HEAT Repeat Location Is Associated with Co-Occurring Mutation Patterns in MDS

Background: In 2022, the WHO classified a new subtype of myelodysplastic neoplasms (MDS) with low blast count and SF3B1 mutation called MDS- SF3B1. SF3B1 is the major subunit of the SF3B spliceosome complex and is responsible for recognizing 3' splice sites in pre-mRNA for processing into mature mRNA. Mutations in SF3B1 have also been observed in other myeloid neoplasms. While MDS- SF3B1 has been associated with a better survival outcome, allelic variants such as SF3B1 K666N are associated with higher-risk MDS, transformation to AML and decreased OS. Additionally, SF3B1 E592K is more likely to be co-mutated with RUNX1, with a worse prognosis. Thus, not all SF3B1 allelic variants should be treated the same. The IPSS-M model incorporates SF3B1 mutations with different weights depending on co-mutations (i.e. isolated del(5q) or BCOR, BCORL1, RUNX1, NRAS, STAG2, SRSF2 mutations) but did not find a difference based on SF3B1 hotspot mutation. However, these and other studies have focused on specific amino acid substitutions but have not taken into consideration the protein domain structure of SF3B1. Using a large cohort of SF3B1-mutant myeloid malignancies, we determined whether HEAT repeat domain location was associated with differences between SF3B1-mutant myeloid neoplasms when comparing co-mutations and clinical characteristics. Methods: Bone marrow, peripheral blood, or FFPE tissue samples from a cohort of 2,996 unique patients with a suspected myeloid neoplasm from 6/30/2020-5/30/2023 were sequenced using a DNA 297 gene myeloid panel. We also analyzed a separate cohort of 112 patients from Sylvester Comprehensive Cancer Center (SCCC) and the University of Texas Southwestern Medical Center (UTSW) from 06/01/2017-06/30/2023 to validate the findings and assess for associations with clinical parameters such as blast count, time to disease progression, and survival. Statistics were performed using Chi-Square. SF3B1 has 22 HEAT repeats with SF3B1 mutations occurring predominately in HEAT Domains 2-6. For this study, we used UniProt definitions of amino acids 569-603 (HEAT2), 604-641 (HEAT3), 643-677 (HEAT4), 680-718 (HEAT5), and 763-801 (HEAT6) as shown in Figure 1. Results: Out of 2,996 myeloid neoplasm patients with SF3B1 mutations, the SF3B1 allele with the highest prevalence was K700E, which falls into HEAT repeat number 5, followed by K666N/R/T and H662Q in HEAT repeat number 4, and R635C in HEAT repeat number 3. Mutations in HEAT repeat 2 and 6 were less common. Several genes were significantly co-mutated in different SF3B1 heat domains, including ASXL1 (11%, p-value =<0.00001), CUX1 (4.7%, p-value = <0.00001), DNMT3A (22.5%, p-value = <0.00001), EZH2 (4.3%, p-value = 0.07), JAK2 (11.2%, p-value= <0.00001), RUNX1 (7.8%, p-value = <0.00001), STAG2 (3.2%, p-value = <0.00001), and TET2 (28.2%, p-value = 0.003) shown in Table 1. The most common co-mutations within each HEAT domain were: HEAT2- ASXL1 (80.0%), RUNX1 (55%), and STAG2 (25%); HEAT3- TET2 (29.5%), DNMT3A (17.5%), and ASXL1 (12.6%); HEAT4- TET2 (24%), D NMT3A (15.2%), and JAK2 (16.9%); HEAT5- TET2 (31.4%) and DNMT3A (31%);and HEAT6- TET2 (28.9%), ASXL1 (15.8%), DMNT3A (14.5%), and EZH2(10.5%). In a separate cohort of 112 patients with clinical follow-up, 97 were diagnosed with MDS- SF3B1: 53 (55%) were male and the average age at diagnosis of 70 years (range: 27-89 years old). A total of 88 patients had 297 gene myeloid panel information, which revealed a similar HEAT repeat distribution: HEAT3 (19%), HEAT4 (27%), HEAT5 (45%), and HEAT6 (6%). The median OS of the entire cohort was 10.5 years (CI 95% 4.93-NE). With a median follow-up of 2 years; 75, 81, 63 and 80% of patients were alive in HEAT 3, 4, 5 and 6, respectively. Conclusion: Distinct SF3B1 alleles defined by HEAT repeat location reflect distinct co-mutation patterns and may play a role in the biology of myeloid disorders. The relatively most enriched co-mutation patterns included: ASXL1 and RUNX1 in HEAT2, JAK2 in HEAT4, and EZH2 in HEAT6. Despite numerical differences in survival larger multicenter patient cohorts are needed to further define how distinct SF3B1 allelic variants and their HEAT repeat location correlate with prognosis and outcome in MDS and other myeloid neoplasms. In addition, further research is need into whether distinct SF3B1 alleles result in differences in RNA splicing signatures that may influence interactions with co-occurring mutations and disease biology

IMerge: A phase 3 study to evaluate imetelstat in transfusion-dependent subjects with IPSS low or intermediate-1 risk myelodysplastic syndromes that are relapsed/refractory to erythropoiesis-stimulating agent treatment

TPS7056 Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients (pts) with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in MDS pts across all disease stages. IMerge (MDS3001) is a Phase 2/3 global study of imetelstat for TD pts with non-del(5q) LR MDS post ESA therapy. The results from Phase 2 part indicated that imetelstat achieved durable RBC transfusion independence (RBC-TI) and the most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias. Among 38 pts with median follow-up of 24 months, 8-week, 24-week and 1-year TI rates were 42%, 32% and 29%, respectively; these responses were seen across different LR MDS subtypes. Median TI duration was 20 months and the longest TI was 2.7 years. A high and durable hematologic improvement-erythroid (HI-E) rate of 68% for a median duration of 21 months were also achieved. Reduction of variant allele frequency of mutations by imetelstat treatment was observed in some pts and correlated with clinical benefits (Platzbecker et al EHA 2020; Steensma et al JCO 2020). These results support the Phase 3 part of the trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 3 part of the study is open for enrollment to adult pts with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs placebo that will enroll approximately 170 pts and will be conducted at approximately 120 centers in North America, Europe, Asia and Middle East. Imetelstat is administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics, and quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. The study is currently recruiting pts. Clinical trial information: NCT02598661