Treatment with Imetelstat Improves Myelofibrosis-Related Symptoms and Other Patient-Reported Outcomes in Patients with Relapsed or Refractory Higher-Risk Myelofibrosis

Background: Myelofibrosis (MF) is a life-threatening myeloproliferative neoplasm characterized by splenomegaly and debilitating symptoms, such as fatigue, pruritus, night sweats, fever, bone pain, and weight loss that impact quality of life (QoL). Imetelstat, a first-in-class telomerase inhibitor, demonstrated clinical benefits in terms of symptom response and potential improvement in overall survival in a pilot study in MF patients (pts) (Tefferi et al, NEJM 2015) and in IMbark, a Phase 2 study in MF pts relapsed or refractory (R/R) to a Janus associated kinase (JAK) inhibitor (Mascarenhas et al, ASH 2018 #685).

Aims: We assessed the effects of imetelstat on MF symptom burden and QoL in IMbark, and the correlations of MF-related symptoms measured by modified Myelofibrosis Symptom Assessment Form (MFSAF) 2.0 and other patient-reported outcome (PRO) endpoints.

Methods: IMbark (MYF2001; NCT02426086) is a two-dose, randomized, single-blinded, Phase 2 study of imetelstat in R/R intermediate-2/high-risk MF pts, who received imetelstat 9.4 mg/kg or 4.7 mg/kg IV every 3 weeks. Symptom response, one of the co-primary endpoints, was defined as ≥50% reduction in total symptom score (TSS) from baseline to Week 24 as measured by the modified MFSAF 2.0 e-diary. The TSS was calculated as the 7-day average of daily TSS, which is the summation of 6 individual symptom scores (night sweats, itchiness, abdominal discomfort, pain under ribs on left side, early satiety, bone or muscle pain). Correlation of TSS with other PROs was explored: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Brief Pain Inventory (BP-I), and Patient Global Impression of Change (PGIC).

Results: All 107 pts enrolled in IMbark were symptomatic, with baseline mean TSS scores of 25.7 in the 9.4 mg/kg arm (N=59) and 24.6 in the 4.7 mg/kg arm (N=48), indicating a high symptom burden. Pts in both arms had ≥96.5% mean compliance rates with completion of the e-diary.

Treatment with imetelstat demonstrated a statistically significant dose-related improvement in TSS symptom response rate at Week 24 for 9.4 mg/kg vs 4.7 mg/kg (32.1% vs 6.3%, p=0.001) and at any time (52.5% vs 27.1%, p=0.010). A higher proportion of pts in the 9.4 mg/kg arm than in the 4.7 mg/kg arm achieved ≥50% reduction in 5 individual symptoms, including night sweats, itchiness, abdominal pressure, pain under left ribs, and early satiety.

Based on EORTC QLQ-C30, improvements at Week 24 relative to baseline were seen in the imetelstat 9.4 mg/kg arm for global health status, all 5 function subscales, and all 3 symptoms. Notably for fatigue (a common MF symptom which was not measured in MFSAF v2.0), pts in the 9.4 mg/kg arm had improvement at Week 24 relative to baseline, compared to the pts in the 4.7 mg/kg arm (LS means -13.3 vs -3.1, p=0.042).

The TSS symptom responses were shown to correlate with other PROs. Compared to pts in the 4.7 mg/kg arm, TSS symptom responders in the 9.4 mg/kg arm achieved significantly greater improvements in the global health status (p=0.004), fatigue (p=0.009), pain (p=0.033), and most of the functional scales in EORTC QLQ-C30. Pain scores per the modified MFSAF v2.0 correlated with the pain scores in EORTC QLQ-C30 and BP-I (correlation coefficients 0.5-0.6). More than 90% of TSS symptom responders in the 9.4 mg/kg arm also characterized their condition as having had either "very much improvement" (36.4%) or "somewhat improvement" (54.6%) in PGIC.

Conclusion: These data show a dose-related, clinically meaningful improvement in overall and individual MF symptoms as measured by MFSAF 2.0 with imetelstat treatment in pts who are JAK inhibitor R/R. TSS symptom responders treated with imetelstat 9.4 mg/kg also had improvement in QoL as measured by EORTC QLQ-C30. The data further support the robustness of overall and individual symptom improvement in pts with MF as evidenced by the correlation of modified MFSAF v2.0 with other PROs such as EORTC QLQ-C30, PGIC, and BP-I.