Potential Disease-Modifying Activity of Imetelstat Demonstrated By Reduction in Cytogenetically Abnormal Clones and Mutation Burden Leads to Clinical Benefits in Relapsed/Refractory Myelofibrosis Patients

Background: Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Both cytogenetic abnormalities and gene mutations in MF carry prognostic significance. Development of novel agents for treatment of MF to target the underlying malignant clones remains a significant area of unmet need. IMbark (MYF2001; NCT02426086) is a randomized Phase 2 study of imetelstat (9.4 mg/kg or 4.7 mg/kg) in intermediate-2/high-risk MF relapsed/refractory to prior Janus kinase inhibitor treatment. Comparing the 9.4 mg/kg arm to the 4.7 mg/kg arm, the rate of symptom response (total symptom score [TSS] reduction ≥50%) was 32.2% and 6.3%, respectively (Mascarenhas et al ASH 2018 #685), and median overall survival (OS) was 28.1 months (mos) (95% confidence interval [CI]: 22.8, 31.6) and 19.9 mos (95% CI: 17.1, 33.9) with an overall study follow up of 42 mos (Mascarenhas et al, EHA 2020, EP1107). Dose-dependent target inhibition as evaluated by reduction of telomerase activity and human telomerase reverse transcriptase level correlated with clinical responses and longer OS; also, reduction in variant allele frequency (VAF) of driver mutations by imetelstat was reported (Mascarenhas et al EHA 2020 #EP1098).

Aims: To evaluate imetelstat activity on depletion of malignant cells (cytogenetically abnormal clones and mutation burden); to assess the relationships between baseline cytogenetic status and change in mutation VAF with clinical benefits such as spleen volume reduction, symptom response, bone marrow fibrosis improvement, and OS.

Methods: Cytogenetic analyses were performed on bone marrow aspirates. Peripheral blood samples pre and post imetelstat administration were collected and granulocytes were isolated to analyze mutations and VAF by next-generation sequencing (NGS) using the Illumina TruSight Myeloid Sequencing Panel. Bone marrow fibrosis was assessed by a central pathologist.

Results: 83 patients (pts) had baseline cytogenetic results available; 45 (54.2%) had an abnormal karyotype, including 32 (71.1%) with a sole abnormality, the most prevalent being deletions 13q- (24.4%) and 20q- (8.8%), and 5 (11.1%) with a complex karyotype. Spleen and symptom responses were observed in pts with or without abnormal karyotype. Of the 24 pts that had identified cytogenetic abnormalities at baseline and with matched post-treatment cytogenetic results available, 5 (20.8%) achieved ≥50% reduction in their cytogenetically abnormal clones, and interestingly they all had sole deletion 13q-.

49 pts had matched pre- and post-imetelstat treatment (3-14 mos) NGS data and had at least one mutation at baseline. 46.2% of pts (12/26) in the 9.4 mg/kg vs 17.4% (4/23) in the 4.7 mg/kg arm (p=0.0321) achieved ≥20% VAF reduction in any of the mutated genes present at baseline. In addition, pts who achieved ≥20% VAF reduction had higher rates of spleen response (12.5% vs 3%), symptom response (31.3% vs 24.2%) or bone marrow fibrosis improvement (54.4% vs 25%) compared to pts who did not have VAF reduction regardless of dose level (Fig. 1A). Furthermore, a prolonged median OS was seen (Fig. 1B) in pts who achieved ≥20% VAF reduction (31.6 mos, 95% CI: 21.5, NE) vs those with no VAF reduction (22.8 mos, 95% CI: 17.1, 31.6). The 3-year survival rate was 45.5% for pts who achieved ≥20% VAF reduction vs 14.9% for pts with no VAF reduction.

Conclusions: Clinical responses to imetelstat treatment were observed regardless of baseline cytogenetic status, and a subset of pts achieved ≥50% reduction in cytogenetically abnormal clones. Significant dose-dependent reductions of mutation burden by imetelstat were noted and correlated with improved overall clinical benefits including higher rates of spleen and symptom responses, bone marrow fibrosis improvement, and prolonged OS. Together with the clinical data that suggest improvement in median OS in these pts, the data presented here further demonstrate that imetelstat has disease-modifying activity by targeting malignant cells, as evidenced by depletion of cytogenetically abnormal clones and reduction in mutation burden. These results will be confirmed in the planned Phase 3 study in refractory MF.