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Myeloploriferative Disorders
Dynamics of mutations in patients with essential thrombocythemia treated with imetelstat
Elisabeth Oppliger Leibundgut,1,2 Monika Haubitz,2 Bart Burington,3
Oliver G. Ottmann,4 Gary Spitzer,5 Olatoyosi Odenike,6 Michael A. McDevitt,7 Alexander Röth,8 David S. Snyder9 and Gabriela M. Baerlocher1,2
1Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Bern, Switzerland; 2Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland; 3Geron Corporation, Menlo Park, CA, USA (at time of study); 4Department of Haematology, Cardiff University, Cardiff, UK; 5Cadex Genomics, Redwood City, CA, USA; 6University of Chicago Medical Center, Chicago, IL, USA; 7Johns Hopkins University School of Medicine, Divisions of Hematology, and Hematological Malignancy, Baltimore, MD, USA (at time of study); 8Department of Hematology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany and 9Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, CA, USA
ABSTRACT
In a phase II study, the telomerase inhibitor imetelstat induced rapid hematologic responses in all patients with essential thrombocythemia who were refractory to or intolerant of prior therapies. Significant molecular responses were achieved within 3-6 months in 81% of patients with phenotypic driver mutations in JAK2, CALR and MPL. Here, we investigated the dynamics of additional somatic mutations in response to imetelstat. At study entry, 50% of patients carried one to five additional mutations in the genes ASXL1, CBL, DNMT3A, EZH2, IDH1, SF3B1, TET2, TP53 and U2AF1. Three patients with baseline mutations also had late-emerging mutations in TP53, IDH1 and TET2. Most clones with addi- tional mutations were responsive to imetelstat and decreased with the driver mutation, including the poor prognostic ASXL1, EZH2 and U2AF1 mutations, while SF3B1 and TP53 mutations were associated with poorer molecular response. Overall, phenotypic driver mutation response was significantly deeper in patients without additional mutations (P=0.04) and correlated with longer duration of response. In conclusion, this detailed molecular analysis of heavily pretreated and partly resistant patients with essential thrombocythemia reveals a high individual patient complexity. Moreover, imetelstat demonstrates potential to inhibit efficiently co-inci- dent mutations occurring in neoplastic clones in patients with essential thrombocythemia. (ClinicalTrials.gov number, NCT01243073).
Introduction
Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA tem- plate of hTERC and can, therefore, inhibit activity of telomerase and cell prolifera- tion in cancer cells.1 hTERT, the catalytic subunit of telomerase that is generally not found in somatic cells, is expressed in megakaryocytes of patients with essential thrombocythemia (ET), a myeloproliferative neoplasm (MPN).2 Previously, we demonstrated a dose-dependent inhibition of megakaryocytic colony-forming units from patients with ET but not from healthy individuals in vitro.3 In a phase II study of ET patients who were refractory to or intolerant of prior treatment, ime- telstat induced rapid and durable hematologic responses in all patients, and molec- ular responses were achieved in the majority of patients within 3-6 months.4
In ET, JAK2 V617F, CALR and MPL mutations are phenotypic driver mutations present in around 90% of patients; the remaining cases are termed “triple negative”. Non-canonical gain-of-function mutations have been identified in the JAK2 and MPL genes in a minority of triple-negative patients.5,6
Ferrata Storti Foundation
Haematologica 2021 Volume 106(9):2397-2404
Additional recurrent somatic mutations occur at lower frequencies in a number
Correspondence:
ELISABETH OPPLIGER LEIBUNDGUT
elisabeth.oppliger@insel.ch
GABRIELA M. BAERLOCHER
gabriela.baerlocher@hematology.ch
Received: March 23, 2020. Accepted: July 21, 2020. Pre-published: July 30, 2020.
https://doi.org/10.3324/haematol.2020.252817 ©2021 Ferrata Storti Foundation
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