David P Steensma1, Pierre Fenaux2, Koen Van Eygen3, Azra Raza4, Valeria Santini5, Ulrich Germing6, Patricia Font7, Maria Diez-Campelo8, Sylvain Thepot9, Edo Vellenga10, Mrinal M Patnaik11, Jun Ho Jang12, Helen Varsos13, Jacqueline Bussolari13, Esther Rose13, Laurie Sherman14, Libo Sun14, Ying Wan14, Souria Dougherty14, Fei Huang14, Faye Feller14, Aleksandra Rizo14, Uwe Platzbecker15. 1. Dana-Farber Cancer Institute, Boston, MA. 2. Hôpital Saint-Louis, Université Paris Diderot, Paris, France. 3. Algemeen Ziekenhuis Groeninge, Kortrijk, Belgium. 4. Columbia University Medical Center, New York, NY. 5. MDS Unit, AOU Careggi-University of Florence, Florence, Italy. 6. Klinik für Hämatologie, Onkologie and Klinische lmmunologie, Universitätsklinik Düsseldorf, Heinrich-Heine-Universität, Düsseldorf, Germany. 7. Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain. 8. Hematology Department, The University Hospital of Salamanca, Salamanca, Spain. 9. CHU Angers, Angers, France. 10. Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 11. Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN. 12. Department of Hematology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 13. Janssen Research & Development, Raritan, NJ. 14. Geron Corporation, Menlo Park, CA. 15. Department of Hematology and Cell Therapy, University Clinic Leipzig, Leipzig, Germany.
Abstract
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.
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.
Authors: Johanne Rozema; Eric N van Roon; Robby E Kibbelaar; Nic J G M Veeger; Christiaan L Slim; Harry de Wit; Mels Hoogendoorn Journal: Transfusion Date: 2021-09-03 Impact factor: 3.337