Imetelstat Rapidly Induces and Maintains Substantial Hematologic and Molecular Responses in Patients with Essential Thrombocythemia (ET) Who Are Refractory or Intolerant to Prior Therapy: Preliminary Phase II Results
Authors: Baerlocher Gabriela M. , Leibundgut Elisabeth Oppliger , Ayran Christina , Blaney Martha , Burington Bart , Morfeld Dianne , Odenike Olatoyosi , Ottman Oliver , Reddy Anita , Roeth Alexander , Spitzer Gary , Stuart Monic J. , Verstovsek Srdan , Snyder David S. 
Published: October 2019

Abstract
Abstract 179

Background:
Myeloproliferative neoplasms (MPNs), such as essential thrombocythemia (ET), are driven by neoplastic progenitor cells. The JAK2 V617F mutation can be detected in approximately 50% of patients (pts) with ET, and the JAK2 V617F allele burden can be used to measure the treatment-induced molecular response (MR) over time. Telomerase is upregulated in neoplastic progenitor cells and sustains indefinite replication. Imetelstat is a first in class, potent, specific inhibitor of telomerase which selectively distributes to bone marrow and inhibits thrombopoiesis. In vitro studies demonstrate that imetelstat selectively inhibits spontaneous megakaryocytic colony-forming unit (CFU-Meg) growth from the blood of pts with ET but not from healthy individuals. Phase I studies have demonstrated that imetelstat inhibits telomerase activity in pts at doses of 7.5 mg/kg and above.
Therefore, unlike conventional cytoreductive therapy and JAK2 kinase inhibitors, imetelstat may be uniquely able to selectively inhibit proliferation of neoplastic clonogenic cells in pts with ET and modify the biology and progression of the disease.

Methods:
A phase II study enrolled pts with ET who had failed or were intolerant to at least one prior therapy, or who refused standard therapy. Pts were treated with imetelstat 7.5 mg/kg or 9.4 mg/kg IV weekly. After attainment of best platelet response in the induction phase, maintenance dosing with imetelstat was commenced with dosing based upon platelet count. Primary endpoint was best overall hematologic response (HR) with complete response (CR) defined as platelet count <400 × 103/μl maintained for at least 4 consecutive weeks in the absence of new thromboembolic events. A key secondary endpoint was rate of MR in patients with JAK2 V617F molecular mutations. JAK2 V617F allele burden was measured by allele-specific quantitative real-time PCR with a limit of detection of 0.1%. CFU-Meg growth pre- and post-treatment and tolerability were also assessed.

Results:
As of July 9, 2012, 13 pts were treated. Median age was 60 yrs (range 21–83) with a median of 2 prior treatments (range 1–3). Median years since initial diagnosis were 5.8 (range 0.3 to 24.9) and initial platelet count was 809 × 103/μl (range 601 to 1359 × 103/μl).
Best overall HR was 100%, with 11 of 13 pts achieving a confirmed CR after a median of 6.1 weeks (range 5.1 to 14.1 wks). Twelve of 13 pts remain on maintenance therapy (median time on study 26.1 weeks) and despite transient elevations of platelets above best response, pts continue to be responsive to imetelstat. Four pts have reached 1 year of therapy and continue to be treated with ongoing HR. Dosing frequency on maintenance therapy was generally reduced with time.
A substantial decrease in JAK2 V617F allele burden was demonstrated in all 5 JAK2 V617F-positive pts (mean allele burden reduction of 82%; range of 59–94%, see table below). Four pts who were eligible for MR assessment by LeukemiaNetcriteria (initial JAKV617F allele burden >10%) reached molecular partial responses (PR): one pt after 12 weeks, which has been maintained through 1 year, and 3 other pts at 24, 36 and 48 weeks of therapy. One additional pt with JAK2 V617F levels of 4.8% prior to therapy has also had a 75% reduction after 12 weeks of treatment.
A reduction in the spontaneous growth of CFU-Meg was also observed in the 2 pts tested, with 93% and 96% reduction from baseline, respectively.
Long-term administration of imetelstat was generally well tolerated. Common adverse events reported on therapy were mild to moderate gastrointestinal toxicities, reductions in neutrophil counts, and fatigue.

Conclusions:
Imetelstat rapidly induces and maintains hematologic responses in pts with ET who have failed or are intolerant to conventional therapies. Importantly, substantial MR is observed in all JAK2 V617F-positive pts and inhibition of the neoplastic clonogenic growth ex-vivo is demonstrated. The reduction in JAK2 V617F allele burden and cytokine-independent growth of CFU-Meg suggests that imetelstat has a relatively selective inhibitory effect on the growth of the neoplastic clone(s) which drive ET and has the potential to modify the underlying biology of MPNs. Additional data will be presented from this ongoing study.

Disclosures:
Baerlocher: Geron Corporation: Research Funding. Oppliger Leibundgut:Geron Corporation: Research Funding. Ayran:Geron Corporation: Employment. Blaney:Geron Corporation: Employment. Burington:Geron Corporation: Employment. Morfeld:Geron Corporation: Employment. Odenike:Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reddy:Geron Corporation: Employment. Roeth:Geron Corporation: Research Funding. Stuart:OncoMed Pharmaceuticals: Consultancy; Geron Corporation: Consultancy, Employment.