Germing, Ulrich

Abstract Background & aim: Myelodysplastic syndromes with isolated deletion of chromosome 5q (MDS-del(5q)) are associated with low-risk features and favorable prognosis. In contrast, TP53 multihit alterations, typically reflecting biallelic inactivation, are associated with high-risk features and adverse outcomes across MDS subtypes. Although current classification systems exclude MDS-del(5q) cases with TP53 multihit from low-risk categories, the prognostic significance of these alterations in this specific context remains unclear. Methods: We conducted an international, multicenter, retrospective study comparing MDS-del(5q) per 2017 WHO criteria with TP53 multihit alterations (MDS-del(5q) TP53 multihit) from 21 international institutions, to MDS with low blast counts with TP53 multihit alterations without isolated del(5q) (MDS-LB TP53 multihit) from the public data from the study of Bernard et al., Nat Med 2020. Clinical and biological data were collected at diagnosis. Genetic profiling included G-banding and NGS of myeloid genes. TP53 multihit was defined as >1 TP53 mutation or a single mutation with 17p deletion, copy-neutral loss of heterozygosity (LOH), or variant allele frequency (VAF) ≥50%. Patients were stratified as lower- or higher-risk based on IPSS-R and IPSS-M scores. Lower-risk included those with IPSS-R ≤3.5 points or very-low, low, or moderate-low IPSS-M, while higher-risk included those with IPSS-R >3.5 points or moderate-high, high, or very-high IPSS-M. Clinical, molecular features, overall survival (OS), and AML progression were compared between MDS-del(5q) TP53 multihit and MDS-LB TP53 multihit groups. Finally, outcomes between patients with likely biallelic TP53 multihit status, defined as harboring a single TP53 mutation accompanied by a co-occurring deletion/LOH of 17p or a TP53 VAF ≥50%, versus those considered less likely to be biallelic, thus still classified as multihit, defined as having >1 TP53 mutation but a combined VAF <50%, were compared in both MDS-del(5q) and MDS-LB groups. Statistical analysis was performed using R (version 4.2.2). Results: We included 113 patients with a median follow-up of 81.1 months (95% CI 74.9–NR). A total of 45 (39.8%) were MDS-del(5q) TP53 multihit, and 68 (60.2%) MDS-LB TP53 multihit. Compared to MDS-LB TP53 multihit, patients with MDS-del(5q) TP53 multihit had significantly higher platelet counts (209 ×10⁹/L vs. 77 ×10⁹/L) and were more frequently classified as lower-risk by both IPSS-R (75.4% vs. 9.8%) and IPSS-M (90.2% vs. 24.6%). The median number of mutations per patient, excluding TP53, was 1 in both groups, and only SF3B1 mutations were significantly more frequent in the MDS-del(5q) TP53 multihit group compared to MDS-LB TP53 multihit (20.5% vs. 2.9%; p<0.01). Regarding survival, MDS-del(5q) TP53 multihit patients showed an improved OS compared to MDS-LB TP53 multihit (median OS of 57.0 months (95%CI, 43.0–112.0) vs 14.0 months (95%CI, 8.6–19.0); p<0.01). Moreover, while the risk of progression to AML at 48 months were comparable between groups (34.9% for MDS-del(5q) TP53 multihit and 33.0% for MDS-LB TP53 multihit; p=0.8), a significant difference was observed in the timing of AML progression: median time to AML evolution of 31.7 months (IQR 23.4–55.3) in the MDS-del(5q) TP53 multihit group and 7.2 months (IQR 4.1–12.9) in the MDS-LB TP53 multihit group (p<0.01). Notably, no significant differences in outcomes were found between TP53 multihit and most likely biallelic cases in both MDS-del(5q) and MDS-LB cohorts. The impact of complex karyotype (CK) in MDS-LB TP53 multihit was also explored. MDS-LB TP53 multihitwith CK showed a significantly worse OS compared to MDS-LB TP53 multihitwithout CK (median OS of 10.0 months (95% CI 7.5–17.0) vs 40.0 months (95% CI 14.0–NA); respectively; p<0.001. However, the incidence of AML and median time to AML evolution were comparable between both groups. Finally, OS between MDS-LB TP53 multihit patients without CK and the MDS-del(5q) TP53 multihit cohort was compared. Median OS was significantly shorter in the former group (median of 40 months) compared to the latter (median of 61 months) (p <0.01) Conclusions: These findings underscore that, in contrast to other TP53-multihit MDS subtypes, MDS-del(5q) with TP53 multihit alterations constitute a clinically distinct entity with better outcomes, thereby warranting reconsideration of its place in current classification systems.

Background. Study of myeloid neoplasms (MN) has been rapidly transformed by genome characterization. Gene mutations have been reported to influence disease phenotype and risk of disease progression, and the evaluation of mutational status can provide valuable insights to improve the decision-making process. In this international study, we evaluated the clinical impact of mutational screening in patients with CMML, which is characterized by significant clinical and genomic heterogeneity, including a substantial proportion of patients with poor outcomes and unmet needs. Currently, only limited molecular information has been incorporated into CMML classification and prognostication. Methods. We retrospectively collected 3182 CMML patients. We used MOSAIC, an AI-based framework for multimodal analysis in rare cancers (PMID: 38875514) to develop innovative, molecular-based tools for classification and prognostication. An independent validation of the results on 516 prospectively collected patients was performed. Results. Bayesian Networs and Hierarchical Dirichlet Processes were used to identify genomic associations and define a CMML molecular classification. We identified 11 clusters with distinct clinical and genomic features, including splicing machinery, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures (i.e., AML-like and TP53 mutations). Up to 15% of patients showed clear genomic overlap with other MN. Importantly, extensive multi-color flow cytometry on T lymphocytes, NK and myeloid cells (BD FACSymphony A5 Cell Analyzer) revealed specific immunologic and inflammation signatures associated with molecular subgroups. We then integrated molecular and clinical information to build an international CMML Prognostic Scoring System (iCPSS). We assessed the performance of different statistical and AI-based methods; L1-penalized Cox Model resulted as the best performing method. Selected features included hematological parameters (WBC, Hb, PLT and marrow blasts), cytogenetic abnormalities, and mutations in 10 genes (ASXL1, DNMT3A, EZH2, NRAS, RUNX1, SETBP1, STAG2, TET2, TP53, U2AF1). By Bayesian thresholds optimization, we identified 5 risk classes (i.e., very-low, low, intermediate, high and very-high) with median overall survival (OS) ranging from 99 to 9 months (P<.001), and median leukemia-free survival (LFS) ranging from 210 to 18 months (P<.001). iCPSS provided better patient discrimination across all clinical endpoints compared to currently available prognostic tools, with a Concordance Index (CI) for OS of 0.75 versus 0.62-0.64, respectively. Notably, compared to available scoring systems, up to 40% of patients were reassigned to higher or lower risk classes by the iCPSS. External validation on an independent prospective cohort confirmed that the performance of iCPSS is superior to existing prognostic models (CI for OS 0.71 vs 0.54-0.61, respectively) To demonstrate the clinical utility of iCPSS, we focused on 753 patients who underwent allogeneic stem cell transplantation (HSCT). In multivariable analysis, iCPSS stratified the probability of OS post-HSCT (P<.001) and identified groups of patients with different probabilities of disease relapse, ranging from 9% to 62% (P<.001). We employed a clinical- and genomic-based decision support system (PMID: 38723212) to determine the optimal timing of HSCT. Preliminary analyses indicated that higher-risk patients according to iCPSS (i.e., intermediate, high, and very high) benefit from an immediate HSCT strategy. Lower-risk patients (i.e., very low and low) had life expectancy maximized with delayed HSCT. Modeling decision analysis using iCPSS compared to conventional scores, resulted in a change in transplantation policy for a significant proportion of patients (up to 25%). Conclusion. Molecular information significantly improves the classification of CMML patients, providing a basis for refining diagnostic boundaries with other MN and for a more rational inclusion of patients in clinical trials. The iCPSS demonstrated superior performance over currently available scoring systems and improved HSCT decision making process.

Abstract Introduction: Imetelstat is a first-in-class telomerase inhibitor that targets cells with high telomerase activity and human telomerase reverse transcriptase (hTERT) expression, characteristics observed in MDS patients (pts) across all disease stages. IMerge (MDS3001, NCT02598661) is a Phase 2/3 global study of imetelstat for red blood cell (RBC) transfusion dependent (TD) pts with non-del 5q LR-MDS ESA-R/R, who have limited treatment options. The results from the Phase 2 part indicated that imetelstat achieved durable transfusion independence (TI) with a manageable safety profile. Among 38 pts with median follow-up of 24 months, ≥8-week (w), ≥24-w, ≥1-year (y) TI rates were 42%, 32% and 29%, respectively (Steensma JCO 2020, Platzbecker ASH 2020). Aims: To assess the correlation between imetelstat's on-target activity with clinical benefits and safety data as of 10-May 2021 in the Phase 2 part of IMerge. Methods: Peripheral blood samples pre and after 1 and 2 cycles of imetelstat administration were collected to analyze hTERT level by Taqman RT-PCR assay. ≥50% hTERT reduction by imetelstat was considered optimal pharmacodynamic (PD) effect. Correlation analyses between the optimal PD and efficacy, including TI rates ≥8-w, ≥24-w, and ≥1-y, duration of the longest TI, and OS, as well as hematological and liver function lab parameters were performed. Results: hTERT analyses on 35/38 pts with matched pre- and post-1 to 2 cycles of treatment samples available demonstrated on-target activity/optimal PD effect of imetelstat in 54.3% (19/35) of pts. Pts who achieved optimal PD had significantly higher rates of TI compared to pts who did not achieve optimal PD: 63.2% (12/19) vs 25% (4/16) had ≥8-w TI (p=0.0411); 57.9% (11/19) vs 12.5% (2/16) had ≥24-w TI (p=0.0125); and 52.6% (10/19) vs 6.3% (1/16) had ≥1-y TI (p=0.0125) (Fig A). Pts who achieved optimal PD effect had a greater reduction in transfusions (both absolute change in transfusion units and % of change in transfusion burden) in the best 8-week interval compared to pts who did not. In addition, pts who achieved optimal PD had a significantly longer median TI duration (68.4 w, 95% CI 4.9, 92.4) compared to those who did not (5.5 w, 95% CI 2.3, 6.6) with a hazard ratio of 0.364 (95% CI 0.167, 0.794, log-rank p value=0.0087, Fig B). Furthermore, median OS was 57.0 months (95% CI 34.6, -) in pts who achieved optimal PD vs 40.7 months (95% CI 26.9, -) in pts who did not, and the 4-year OS rate was 58.4% vs 31.0%, respectively, although not statistically significant. Pts who achieved optimal PD also had lower rates of Grade 3+neutropenia (52.6%), thrombocytopenia (57.9%), or liver function elevations (5.3%) compared to pts who did not achieve optimal PD (68.8%, 68.8% and 18.8%, respectively), although the differences were not statistically significant. Conclusion: Optimal PD effect of imetelstat treatment was demonstrated by ≥50% hTERT reduction. A significant correlation was observed between optimal PD effect of imetelstat and durable TI and improved 4-year OS rate, effectively linking imetelstat activity to clinical efficacy. Additionally, pts who achieved an optimal PD effect by imetelstat treatment did not have higher rates of cytopenias or liver enzyme elevations compared to pts without optimal PD effect. Enrollment is ongoing for the Phase 3 part of IMerge, a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo. Figure 1 Figure 1. Disclosures Santini: Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux: JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Raza: Celgene Inc: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Genoptix: Speakers Bureau; Kura Oncology: Research Funding; Janssen R&D: Research Funding; Syros Pharmaceuticals: Research Funding; Onconova Therapeutics: Research Funding, Speakers Bureau. Germing: Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria. Font: CELGENE-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses; GILEAD: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Abbvie: Other: Travel, accomodations, expenses. Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Sherman: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Platzbecker: Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Celgene/BMS: Honoraria. OffLabel Disclosure: Imetelstat, a first-in-class telomerase inhibitor, is under clinical development but not approved for treatment of MDS

PURPOSE Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. We report efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs. PATIENTS AND METHODS In this two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid. RESULTS Data from the phase II part of the study are reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks. CONCLUSION Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.

Key Points In the largest study of HMAs in RR-AML to date, 16% of patients achieved CR/CRi and experienced a median OS of 21 months. Low proliferative disease (peripheral blood blasts <5%) was associated with improved response and OS.

Abstract Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation.