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Although Janus kinase (JAK) inhibition provides symptomatic relief for patients with myelofibrosis (MF), it does not induce long-term remission or alter disease course, and there is currently an unmet need for novel therapies to effectively target the disease at the level of the malignant stem cell. Telomerase is highly upregulated in malignant hematopoietic stem and progenitor cells and causes uncontrolled proliferation. Short telomere length and higher telomerase activity correlate with higher risk and shorter survival in patients with myeloid malignancies. Imetelstat is a first-in-class therapy which competitively inhibits the enzymatic activity of telomerase, thereby impeding the proliferation of malignant cells.
Here we summarize the results of the IMbark phase II trial (MYF2001; NCT02426086) of imetelstat for patients with MF who have relapsed after or are refractory to (R/R) JAK inhibition, including clinical efficacy and pharmacodynamic (PD) data. These were presented by MPN Hub Steering Committee member John Mascarenhas over three sessions during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.1,2,3
Patients with intermediate-2 or high-risk MF, R/R to prior JAK inhibitor treatment, were randomized to receive intravenous imetelstat at a dose of either 9.4 mg/kg (n = 59) or 4.7 mg/kg (n = 48) every 3 weeks.
Primary endpoints:
Secondary endpoints:
Exploratory endpoints:
Key efficacy data is summarised in Table 1.
Table 1. Imetelstat key efficacy data1
BM, bone marrow; CI, confidence interval; OS, overall survival; PFS, progression-free survival. |
||
Clinical benefit |
4.7 mg/kg imetelstat (n = 48) |
9.4 mg/kg imetelstat (n = 59) |
---|---|---|
Reduction in BM fibrosis, % |
20.0 |
43.2 |
Symptom response at Week 24, % |
6.3 |
32.2 |
Spleen response at Week 24, % |
0 |
10.2 |
Median OS, months (95% CI) |
19.9 (17.1–33.9) |
28.1 (22.8–31.6) |
Median PFS, months (95% CI) |
14.8 (8.3–17.1) |
20.7 (12.0–23.2) |
Clinical improvement, % |
16.7 |
25.4 |
Transfusion independence of 12 weeks, % |
14.3 |
25.0 |
Imetelstat treatment at an active dose of 9.4 mg/kg showed clinical benefit across parameters, including BM fibrosis improvement, VAF reduction, and superior OS, when compared with the lower imetelstat dose of 4.7 mg/kg.1
Improved bone marrow fibrosis under imetelstat correlated with reduced risk of death (HR, 0.37; 95% CI, 0.14–0.98; p = 0.04).
Clinical responses were observed regardless of mutational and cytogenetic subtype, including for those with unfavorable profiles.1,2
The anti-tumor activity of imetelstat was observed at both a molecular and cytogenetic level.1,2,3
An optimal PD effect, defined as ≥ 50% reduction in telomerase activity (TA) or human telomerase reverse transcriptase (hTERT) expression, was achieved in a significantly greater proportion of patients receiving the higher dose of imetelstat, compared with the lower dose (Figure 1), and in a significantly greater proportion of patients with higher imetelstat exposure, as determined by Cmax > mean value and AUC0-24h (Figure 2).
Figure 1. Dose-dependent PD effects of imetelstat3
hTERT, human telomerase reverse transcriptase; TA, telomerase activity.
Figure 2. Exposure-dependent PD effects of imetelstat3
AUC0-24h, area under the plasma concentration time curve over a 24h dosing period; Cmax, maximum measured plasma concentration; hTERT, human telomerase reverse transcriptase; PD, pharmacodynamics.
Table 2. Clinical responses according to TL and hTERT expression in patients receiving 9.4 mg/kg imetelstat3
hTERT, human telomerase reverse transcriptase; TL, telomere length. |
||
|
Patients achieving spleen response, % |
Patients achieving symptom response, % |
---|---|---|
TL ≤ median |
17.3 |
37.9 |
TL > median |
4.2 |
25.0 |
hTERT ≤ median |
7.1 |
28.6 |
hTERT > median |
13.8 |
37.9 |
In the phase II IMbark study, patients receiving imetelstat at a triweekly dose of 9.4 mg/kg demonstrated high rates of spleen and symptom responses, and superior OS compared with patients receiving low-dose imetelstat, regardless of cytogenetic and mutational profile. The anti-tumor activity of imetelstat was observed at a cytogenetic and molecular level and disease modifying activity could be observed in patients with isolated deletion of 13q.
Pre-clinical findings suggesting a correlation between PD and anti-tumor activity were validated in this clinical cohort. Dose- and exposure-dependent reductions in TA and hTERT expression, and correlation of clinical response with shorter TL and higher hTERT expression in patients treated with imetelstat, support an on-target mechanism of action through telomerase inhibition.
Overall, the data show promise for imetelstat as a therapy for MF patients with JAK inhibitor failure and will enter phase III clinical testing (IMpactMF, NCT04576156).
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