Drug Active in Myeloproliferative Disorders
Essential thrombocythemia, myelofibrosis respond to telomere targeting
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by Charles Bankhead
Staff Writer, MedPage Today
Treatment with a drug that targets the chromosome-lengthening enzyme telomerase led to hematologic responses in all treated patients with essential thrombocythemia, a preliminary clinical trial showed.
In 16 of 18 cases, patients achieved complete hematologic responses with imetelstat. Additionally, seven of eight patients with Janus kinase 2 (JAK2) V617F mutations had molecular responses, and mutant allele burdens were reduced by as much as 66%.
Most adverse events were mild or moderate, and grade ≥3 neutropenia occurred in four of the 18 patients. All 18 patients had at least one abnormal liver-function test, as reported online in the New England Journal of Medicine.
"Imetelstat ... had a clinically significant effect on disease burden in patients with essential thrombocythemia who had not had a response to previous treatment or who had had unacceptable side effects from conventional therapies," Gabriela M. Baerlocher, MD, of University Hospital of Bern in Switzerland, and co-authors wrote in conclusion.
"Furthermore, molecular responses were observed in patients with mutated JAK2 and CALR molecular signatures," they added. "This finding suggests therapeutic activity in the malignant clones that are the underlying source of essential thrombocythemia."
Another report in the same issue of the journal showed imetelstat activity in about a fifth of patients with high- and intermediate-risk myelofibrosis.
But both studies failed to show an association between clinical activity and telomere shortening, the drug's presumed mechanism of action, the authors of an accompanying editorial noted. Pinning down the drug's target will be essential to future clinical evaluation of the drug.
"Myelosuppression, especially thrombocytopenia, is a common side effect of phosphorothioate antisense oligonucleotides [such as imetelstat]," said Mary Armanios, MD, and Carol W. Greider, PhD, of Johns Hopkins' Sidney Kimmel Comprehensive Cancer Center. "These side effects are independent of the antisense sequence and are thought to be mediated through mechanisms that include binding to cell-surface receptors such as toll-like receptor 9."
"If such an off-target effect is the primary mechanism of imetelstat action in myeloproliferative neoplasms, this knowledge will be critical for patient selection, for understanding mechanisms of resistance, and for future drug development in myeloproliferative neoplasms."
Greider shared the 2009 Nobel Prize in Physiology or Medicine for her research in telomeres.
Unresolved mechanistic issues notwithstanding, the results of the two trials "spark new possibilities for the treatment of myeloproliferative neoplasms," Armanios and Greider added. "Further analysis of both the mechanisms and, more importantly, the long-term side effect profile of imetelstat may provide a new approach to treat these debilitating disorders."
Essential thrombocythemia is a clonal disorder of multipotent hematopoietic progenitor cells, Baerlocher and colleagues noted in their background information. The disease often arises in association with mutations in JAK2 and in genes encoding the thrombopoietin receptor (MPL) and calreticulin (CALR).
Previous studies of imetelstat demonstrated inhibition of spontaneous proliferation in megakaryocytic colonies from patients with essential thrombocythemia but not cytokine-induced megakaryocytic colonies from healthy donors. Taken together, the data suggest "an intrinsic sensitivity of essential thrombocythemia megakaryocytes to telomerase inhibition," the authors noted.
Baerlocher and colleagues investigated the clinical activity of imetelstat in a phase II trial involving 18 adults with World Health Organization-defined essential thrombocythemia. All patients had received at least one prior therapy, which had proven ineffective or unacceptably toxic. The patients had a baseline median platelet count of 788,000, and 15 patients had mutant allele burdens (eight with JAK2 V617F, five with CALR, and two with MPL W515L or W515K).
The patients received 7.5 or 9.4 mg/kg weekly until platelet count declined to 250,000 to 300,000/mm3 or development of unacceptable toxicity. Patients who achieved hematologic response, as defined by platelet recovery, continued weekly maintenance therapy at doses of 7.5 to 11.7 mg/kg.
The primary endpoint was best hematologic response, as defined by 2009 European LeukemiaNet criteria. The results showed that all 18 patients enrolled in the study met response criteria, including 16 who had complete responses. The two patients with partial responses initially met criteria for complete response but did not maintain the response. The higher initial dose was associated with a trend toward more rapid response. Otherwise, the response outcomes were similar.
Telomerase has been shown to be active in most cancer cells but not normal cells, Ayalew Tafferi, MD, of the Mayo Clinic in Rochester, Minn., and co-authors noted in their introduction. Previous studies had provided evidence of telomere shortening and upregulation of telomerase activity in myeloproliferative disorders, providing a rationale to evaluate imetelstat in myelofibrosis.
Investigators enrolled 18 patients with primary myelofibrosis, 10 with post-polycythemia vera myelofibrosis, and five with post-essential thrombocythemia myelofibrosis. The patients received 9.4 mg of imetelstat every 3 weeks or weekly for 4 weeks followed by administration every 3 weeks. Genomic analysis showed that 26 of the 33 patients had the JAK2 V617F mutation, six had CALR mutation, and one had an MPL mutation.
The primary endpoint was conventionally determined overall response rate after nine cycles of therapy. The results showed that seven (21%) patients achieved objective responses. Patients with JAK2-mutant disease had a response rate of 27% as compared with 0% for patients with JAK2 mutations. Analysis of specific mutation subtypes showed response rates of 32% for ASXL1 and 38% for SF3B1 or U2AF1.
Notable adverse effects included grade 4 thrombocytopenia in 18% of patients, grade 4 neutropenia in 12%, and grade 3 anemia in 30%. Grade 1/2 laboratory abnormalities included total bilirubin in 12%, alkaline phosphatase in 21%, and aspartate aminotransferase in 27%.
Despite not finding specific clues to imetelstat's mechanism of action, the authors said "it is reasonable to hypothesize that certain spliceosome mutations contribute to suboptimal telomerase upregulation through altered splicing, which in turn might have affected patients vulnerable to further telomerase deprivation by imetelstat."
Both studies were supported by Geron.
Baerlocher disclosed relationships with Geron, Janssen, Novartis, Bristol-Myers Squibb, Pfizer, and Ariad. One or more co-authors disclosed relationships with Geron, Alexion, Astex, Celgene, Eisai, Eli Lilly, Novartis, NS-Pharma, S*Bio, Gilead, MEI-Pharma, Topotarget, Sunesis, Incyte, Spectrum, Sanofi, Algeta, CTI Bio Pharma, Pfizer, KaloBios, and ProNAi Therapeutics.
Tefferi disclosed relationships with Geron and a pending patent interest related to treatment of hematologic malignancies. One or more co-authors disclosed relationships with Geron.
Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
LAST UPDATED 09.02.2015
New England Journal of Medicine