Monitoring of Calr Allele burden in patients with Essential Thrombocythemia treated with Imetelstat, a telomerase inhibitor, reveals rapid and substantial molecular responses

Background: In essential thrombocythemia(ET), mutations in the calreticulingene (CALR) are found in the majority of patients that are negative for mutations in the JAK2 and MPL genes. Patients with mutated CALR have a better prognosis and lower thrombosis risk than those with mutated JAK2. Recently, decreases in the CALR mutant allele burden have been observed with interferon alpha after long-term treatment of two- and four-years, respectively (NEJM 2014, 371;2:188-9, Cassinat B. et al.). From the clinical phase II ET study with imetelstat(IT), a first in class, potent, specific inhibitor of telomerase, we reported a substantial and rapid decrease in the JAK2V617F allele burden. 7/8 patients (88%) reached a partial molecular response (MR: >50% reduction from baseline), 6 within the first 3 months and 1 after 12 months. Aims: We aimed to monitor molecular response to imetelstattherapy in ET patients with CALR mutations by serial measurements of CALR mutant allele burden. Methods: The study enrolled patients with ET who had failed or were intolerant to ≥1 prior therapy, or refused standard therapy. During the induction phase, patients were treated with IT 7.5 mg/kg or 9.4 mg/kg IV weekly until attainment of platelet (plt) count ~250-300x10 9 /L. Maintenance phase was then commenced with dosing titrated to platelet count. CALR mutations were detected by Sanger sequencingand quantification of the allele burden was performed by fragment analysis. Results: 18 patients with ET (10 patients with JAK2V617F, 5 patients with CALR and 2 patients with MPL mutations) were enrolled and were treated in the study. 4 of the 5 CALR positive patients achieved complete hematologic responses (CR: Plts 9 /L for 4 weeks) after a median of 6 weeks (range 5 to 14 weeks) and the 5th patient achieved a partial response after 19 weeks, with weekly imetelstatdoses starting at 7.5 mg/kg in 2 patients and 9.4 mg/kg in 3 patients. CALR mutations consisted of three cases with type 1 (52-bp deletion; c.1092_1143del), one with type 2 (5-bp insertion; c.1154_1155insTTGTC) and one unknown mutation type (32-bp deletion; c.1092_1124del). Molecular monitoring of CALR allele burden at cycles 3, 6 and 9 demonstrated a rapid decrease in the CALR-mutated patients. 3 pts had a 35-50% reduction from baseline within 4 months and 1 pt had an 11% decrease within 8 months. One of these patients had a 48% reduction in 2 months and a second one had a deepening of response after 10 months to a 55% reduction. All 3 patients with CALR allele burden reductions of 35% or more also achieved hematologic CR. Conclusions: In 4 of 5 patients with CALR-mutated ET, IT induced a rapid CR and in 3 patients hematologic CR was associated with a substantial decrease in the allele burden of 35-50% after 4 months which is more rapid than what has so far been seen with other treatments for ET. Overall 9/13 patients with JAK2 or CALR mutations reached a >35-50% decrease of the mutant clone within 4 months of treatment with IT, providing clinical confirmation of imetelstat’s inhibition of neoplastic clonogenic cell growth in vivo . This additional evidence of reduction in the clonal burden supports IT’s potential to modify the biology of MPNs long-term. Disclosures Baerlocher: Geron Corporation: Research Funding. Odenike: Incyte Pharmaceuticals, Sanofi Aventis, Suneisis, Algeta, Spectrum Pharaceuticals: Honoraria. Roeth: Geron Corporation: Research Funding. Shih: Geron: Employment, Equity Ownership. Burington: Geron Corporation: Employment, Equity Ownership. Leibundgut: Geron Corporation: Research Funding.