Imetelstat Is Effective Treatment for Patients with Intermediate-2 or High-Risk Myelofibrosis Who Have Relapsed on or Are Refractory to Janus Kinase Inhibitor Therapy: Results of a Phase 2 Randomized Study of Two Dose Levels

Background: Imetelstat, a 13-mer oligonucleotide that specifically targets the RNA template of human telomerase, is a potent competitive inhibitor of telomerase enzymatic activity (Asai Cancer Res 2003; Herbert Oncogene 2005). Clinical activity and an acceptable safety profile were reported in a 33-patient pilot study in intermediate-2 (int-2) or high-risk myelofibrosis (MF), where 48% of patients had been previously treated with a Janus Kinase inhibitor (JAKi) (Tefferi N Engl J Med 2015). Here, we report the results of a phase 2 clinical study of imetelstat at two dose levels in patients with MF (MYF2001, NCT02426086).

Methods: A randomized, multicenter, phase 2 study of two doses of imetelstat (9.4 mg/kg or 4.7 mg/kg IV, every 3 weeks) was performed in adults with DIPSS int-2 or high-risk MF that was relapsed/refractory to prior JAKi therapy (ie, either no reduction in splenomegaly after 12 weeks or worsening splenomegaly at any time after the start of JAKi therapy). Diagnosis of primary, post-essential thrombocythemia, or post-polycythemia vera MF was required; other eligibility criteria included measurable splenomegaly (by magnetic resonance imaging [MRI]), active MF-related systemic symptoms and platelet count ≥75 x 10⁹/L. Primary endpoints were spleen response rate (% achieving ≥ 35% spleen volume reduction [SVR] by MRI) and symptom response rate (% achieving ≥ 50% reduction in total symptom score [TSS] per Myelofibrosis Symptom Assessment Form (MFSAF) v2 at week 24. Key secondary endpoints included safety, overall survival (OS), treatment response, molecular response, and pharmacokinetic and pharmacodynamic relationships.

Results: 107 patients were enrolled at 55 institutions (48 on 4.7 mg/kg; 59 on 9.4 mg/kg). Baseline characteristics are shown in the Table. Additionally, median time on JAKi was 23 (0.9-89.7) mo, and median platelet count was 147 x 10⁹/L. Triple-negative (TN; ie, no mutations of JAK2, MPL, or CALR) comprised 24.8% of patients and 67.6% were considered high molecular risk (HMR; ie, ≥ 1 mutation of ASXL1, EZH2, SRSF2, or IDH1/2).

At the time of clinical cutoff, patients were followed for a median 22.6 (0.2-27.4) mo, including a median treatment duration of 6.2 (0.0-27.2) mo. Median duration on treatment was longer on the 9.4 mg/kg arm (7.7 mo) than on the 4.7 mg/kg arm. Six (10.2%) patients in the 9.4 mg/kg arm had a spleen response per MRI, with no responses on the 4.7 mg/kg arm (Figure 1). Nineteen (32%) patients in the 9.4 mg/kg arm and 3 (6%) patients in the 4.7 mg/kg arm had a symptom response (TSS reduction ≥ 50%) (Figure 2).

Median OS in the 9.4 mg/kg arm has not been reached, while median OS was 19.9 mo in the 4.7 mg/kg arm. The 18-mo survival rates were 76.7% and 62.9% for the 9.4 mg/kg and 4.7 mg/kg arms, respectively. Sensitivity analyses censoring patients at time of dose escalation for subsequent JAKi therapy or allogeneic stem cell transplant generated similar results. In the 9.4 mg/kg arm, an association was observed between patients who were TN and OS (median OS has not been reached for TN patients and was 23.6 mo for non-TN patients). Spleen response rate was higher in patients with 1 HMR mutation (ASXL1, EZH2, SRSF2, or IDH1/2.

The most common adverse events on treatment (all grades) at 9.4 mg/kg were thrombocytopenia (49%), anemia (44%), neutropenia (36%), and nausea (34%) and at 4.7 mg/kg were diarrhea (38%), nausea (31%), anemia (31%), and thrombocytopenia (23%). Grade 3/4 neutropenia and thrombocytopenia were more frequent with 9.4 mg/kg (34% and 42%, respectively) than 4.7 mg/kg (13% and 29%, respectively); most cytopenias resolved within 4 weeks. Grade 3/4 LFT elevations were observed in 7 patients on study. Imetelstat-related hepatic toxicities, confirmed by an independent Hepatic Review Committee, were not observed.

Conclusions: Imetelstat at 9.4 mg/kg IV every 3 weeks has demonstrated clinical activity in int-2 or high-risk MF patients who are relapsed/refractory to JAKi, notably in observed OS. Though no formal study has reported survival for patients who are truly relapsed/refractory to JAKi, median OS of patients who were previously treated with JAKi has been reported to be 12-14 mo (Kuykendall Ann Hematol 2018; Newberry Blood 2017). The safety profile for imetelstat was considered acceptable for this poor-prognosis population. Imetelstat at 9.4 mg/kg IV every 3 weeks is a promising agent for JAKi-pretreated MF patients and warrants further testing in clinical trials.

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