Slide 1: Potential Disease-Modifying Activity of Imetelstat in Relapsed/Refractory Myelofibrosis
Abstract #346 Potential Disease-Modifying Activity of Imetelstat Demonstrated By Reduction in Cytogenetically Abnormal Clones and Mutation Burden Leads to Clinical Benefits in Relapsed/Refractory Myelofibrosis Patients John Mascarenhas, MD1, Rami S. Komrokji MD2, Michele Cavo, MD3, Bruno Martino, MD
Slide 2: Disclosure
Disclosure ❑ Presenter: John Mascarenhas, MD ❑ Affiliations: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY, USA ❑ Disclosure: – Consultancy: Celgene/BMS, Incyte, Roche, PharmaEssentia, Constellation, Kartos, Prelude, Geron, Abbvie – Research funding: CTI Biopharma, Incyte, Jans
Slide 3: Background
Background ❑ Myelofibrosis (MF) is a clonal stem cell disease characterized by bone marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. ❑ Both cytogenetic abnorma
Slide 4: Imetelstat: First-in-Class Telomerase Inhibitor with Disease-Modifying Potential
Imetelstat: First-in-Class Telomerase Inhibitor with Disease-Modifying Potential Apoptosis of Imetelstat binds to RNA template, malignant cells preventing maintenance of telomeres Malignant Malignant (hTERT) hematopoietic progenitor stem cells cell (hTR ) X Telomerase Upregulation Mechanism of Actio
Slide 5: IMbark Phase 2 Trial: Study Design
IMbark Phase 2 Trial: Study Design Imetelstat Co-primary endpoints: Spleen response rate and symptom response rate Randomize (1:1) 9.4 mg/kg every 3 weeks Secondary endpoints: Int-2 or High- Risk MF n=59 CR, PR and CI, anemia response per 2013 IWG-MRT R/R to JAKi treatment criteria, duration of resp
Slide 6: IMbark Phase 2 Trial Results: Dose-dependent Clinical Benefits from Imetelstat treatment
IMbark Phase 2 Trial Results: Dose-dependent Clinical Benefits from Imetelstat treatment Key efficacy findings suggest potential disease modifying activity of imetelstat 4.7 mg/kg 9.4 mg/kg Clinical Benefits (N = 48) (N = 59) Median OS, months (95% CI) 19.9 (17.1, 33.9) 28.1 (22.8, 31.6) Reduction i
Slide 7: Potential Improvement in OS with Imetelstat Treatment
Potential Improvement in OS with Imetelstat Treatment OS improvement with 9.4 mg/kg imetelstat treatment in MF R/R to JAK inhibitor Similar results were observed when sensitivity analyses accounted for confounding factors of subsequent therapies, including hematopoietic stem cell transplantation and
Slide 8: Lower Risk of Death Correlates with Improved Bone Marrow Fibrosis
Lower Risk of Death Significantly Correlates with Improved Bone Marrow Fibrosis in Patients Treated with Imetelstat ❑ Dose related improvement in bone marrow fibrosis ❑ Patients with bone marrow fibrosis stable or improvement had lower risk of death than those who had worsening bone marrow fibrosis
Slide 9: Enrichment for Triple Negative and High Molecular Risk Patients on the study
Enrichment for Triple Negative and High Molecular Risk Patients on the study n (%) 4.7 mg/kg 9.4 mg/kg Total Biomarker population, n 48 57 105 With ≥ 1 mutation 48 (100) 55 (96.5) 103 (98) ≥ 3 mutations 40 (83) 38 (67) 78 (74) Triple Negative (TN)a 10 (21) 16 (28) 26 (25) JAK2 V617F 32 (67) 32 (56)
Slide 10: Encouraging Clinical Benefits in TN MF Patients Treated with Imetelstat 9.4 mg/kg
Encouraging Clinical Benefits in TN MF Patients Treated with Imetelstat 9.4 mg/kg Higher spleen and symptom response rates Prolonged OS in TN MF patients in TN MF patients than non-TN MF patients treated by 9.4 mg/kg imetelstat Higher rates of clinical response in 60% TN vs. Non-TN in 9.4mg/kg % of
Slide 11: Encouraging Clinical Benefits in HMR Patients Treated with 9.4 mg/kg of Imetelstat
Encouraging Clinical Benefits in HMR Patients Treated with 9.4 mg/kg of Imetelstat Treatment with 9.4 mg/kg imetelstat achieved higher rates Improved survival by 9.4 mg/kg of spleen and symptom responses observed in both LMR and imetelstat treatment in HMR subgroup HMR groups compared to 4.7 mg/kg 4
Slide 12: Dose-dependent Complete Elimination of Mutation Burden with Imetelstat Treatment
Dose-dependent Complete Elimination of Mutation Burden with Imetelstat Treatment Significant dose-dependent ≥20% VAF Imetelstat treatment had dose-dependent complete reduction by imetelstat treatment elimination of mutation burden in multiple genes, including driver- and non-driver genes 60% 9.4 mg/
Slide 13: ≥20% VAF Reduction Leads to Improved Clinical Benefits
≥20% VAF Reduction Leads to Improved Clinical Benefits Higher rates of spleen response, symptom response Longer median OS and higher survival rate in and bone marrow fibrosis improvement in patients patients who achieved ≥ 20% VAF reduction who achieved greater mutation VAF reduction 60% 54.4% 50% 4
Slide 14: Symptom Response Across Different Cytogenetic Subsets
Symptom Response Across Different Cytogenetic Subsets ❑ 83 (77.6%) patients had baseline cytogenetic results available – 38 (45.8%) with normal karyotype – 45 (54.2%) had an abnormal karyotype: 32 (71.1%) with sole abnormality and 13 (28.8%) >=2 abnormalities ❑ Symptom response (≥ 50% total symptom
Slide 15: Reduction of Cytogenetically Abnormal Clones with Imetelstat Treatment
Reduction of Cytogenetically Abnormal Clones with Imetelstat Treatment Among 24 patients who had cytogenetic abnormalities at baseline and matched post-treatment cytogenetic results available, 5 (20.8%) achieved ≥50% reduction in their cytogenetically abnormal clones, all had isolated deletion of 13
Slide 16: Conclusions
Conclusions ❑ Spleen and symptom responses were observed across different molecularly defined subtypes regardless of the baseline mutational or cytogenetic profile, including those with poor prognostic subtypes such as TN, HMR or unfavorable cytogenetics. ❑ Significant dose-dependent reduction of mu
Slide 17: Acknowledgements
Acknowledgements The authors thank all the patients for their participation in this study and acknowledge the collaboration and commitment of all investigators and their staff