Telomerase Activity, Telomere Length and hTERT Expression Correlate with Clinical Outcomes in Higher-Risk Myelofibrosis (MF) Relapsed/Refractory (R/R) to Janus Kinase Inhibitor Treated with Imetelstat

Background: Imetelstat is a first-in-class telomerase inhibitor currently in clinical development for hematologic malignancies. 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 R/R to prior Janus kinase inhibitor treatment. Dose-dependent symptom improvement and favorable overall survival (OS) for 9.4 mg/kg with an acceptable safety profile were reported (Mascarenhas et al ASH 2018 #685). Real-world data confirmed the OS benefit when IMbark data were closely matched against patients (pts) treated with best available therapy (Kuykendall et al EHA 2019 # PS1456).

Aims: To report comprehensive biomarker results and their correlation with clinical benefits of imetelstat.

Methods: Peripheral blood samples pre and post imetelstat administration were collected to analyze 1) telomerase activity (TA) by quantitative telomeric repeat amplification protocol technology; 2) human telomerase reverse transcriptase (hTERT) level by Taqman RT-PCR assay; and 3) driver mutations and variant allele frequency (VAF) by next-generation sequencing. Telomere length (TL) was assessed by high-throughput quantitative fluorescence in situ hybridization technology.

Results: TA and hTERT analyses were done on available, matched, pre- and post-treatment samples. ≥50% TA or hTERT reduction are considered optimal pharmacodynamic (PD) effects for imetelstat per pre-clinical studies. As shown in Fig A, ≥50% TA reduction was achieved in 23/40 pts (57.5%) in 9.4 mg/kg arm vs 10/33 pts (30.3%) in 4.7 mg/kg arm (p=0.033); ≥50% hTERT RNA level reduction was achieved in 35/56 pts (62.5%) in 9.4 mg/kg arm vs 20/48 pts (41.7%) in 4.7 mg/kg arm (p=0.049). In addition, almost all pts who achieved spleen response (≥35% SVR) or symptom response (≥50% TSS reduction) at Week 24 had optimal PD effect; in contrast, in pts who did not achieve spleen or symptom response, less pts had optimal PD effect (Fig B). Furthermore, longer OS was observed in pts who achieved optimal PD vs those who did not (Fig C). These results demonstrated correlation between PD effect (on-target activity) and clinical benefits with imetelstat.

Correlations of baseline TL and hTERT levels to clinical responses were explored for the 9.4 mg/kg arm. Pts with shorter telomeres at baseline had higher response rates vs pts with longer telomeres (spleen response 17.2% vs 4.2%; symptom response 37.9% vs 25%). Furthermore, longer OS was observed in pts with shorter baseline telomeres vs those with longer telomeres: median OS was 30.1 mo (95% CI 23.2, NE) and 27.1 mo (95% CI 16.2, 33.8), respectively. Pts with higher vs lower hTERT levels at baseline also had higher response rates (spleen response 13.8% vs 7.1%; symptom response 37.9% vs 28.6%). All correlative analyses were not statistically significant, possibly due to small sample size.

Dose-dependent reduction in VAF of driver mutations was noted: 42.1% of pts in the 9.4 mg/kg vs 5.6% in the 4.7 mg/kg arm (p=0.02) achieved ≥25% VAF reduction, indicating that imetelstat targets the underlying malignant clone.

Conclusions: Dose-dependent inhibition of telomerase target, evaluated by TA and hTERT reduction, was demonstrated in R/R MF pts treated with imetelstat, and this on-target activity correlated with clinical responses and longer OS. Improved clinical outcomes were noted in pts with shorter telomeres and high hTERT expression. These data are consistent with telomere biology in cancer cells and provide evidence for on-target mechanism of action of imetelstat through telomerase inhibition.