Prithviraj Bose, MD
Department of Leukemia
Division of Cancer Medicine
A Randomized Open-Label, Phase 3 Study to Evaluate Imetelstat Versus Best Available Therapy (BAT) in Patients with Intermediate-2 or High-Risk Myelofibrosis (MF) Refractory to Janus Kinase (JAK) Inhibitor
Blood (2020) 136 (Supplement 1). 43–44.
Imetelstat for patients with myelofibrosis failing ruxolitinib: update from ASH 2020
Current treatment options for patients with myelofibrosis (MF) who fail ruxolitinib remain unsatisfactory, and this continues to represent an area of major unmet medical need. Multiple groups have reported the median overall survival of MF patients after ruxolitinib discontinuation to be 13-14 months.(1-3) Using a stringent definition of ruxolitinib failure (Table 1), a re-analysis of the JAKARTA-2 trial of fedratinib after ruxolitinib showed an SVR35 (≥35% spleen volume reduction) rate of 30% and a TSS50 (≥50% reduction in total symptom score) rate of 27% at 24 weeks.(4) Clinical activity in the post-ruxolitinib setting has been demonstrated for several investigational compounds, e.g., the JAK inhibitors momelotinib(5) and pacritinib,(6) the bromodomain and extraterminal (BET) inhibitor CPI-0610 (pelabresib),(7) the murine double minute 2 (MDM2) inhibitor KRT-232(8) and the lysine-specific demethylase 1 (LSD1) inhibitor, bomedemstat.(9) However, the suggestion of a robust survival benefit in the post-ruxolitinib setting for the telomerase inhibitor imetelstat in the IMBARK™ trial has generated substantial enthusiasm, and a pivotal phase 3 trial (IMpactMF, NCT04576156) of this agent compared to best available therapy (excluding Janus kinase (JAK) inhibitors) with OS as the primary endpoint is now underway.
Imetelstat was first studied in a small, pilot study at the Mayo Clinic, and led to complete and partial remissions in 7 of 33 patients (21%), unusual in MF clinical studies.(10) The multi-center IMBARK™ trial then evaluated both 4.7 mg/kg (n=48) and 9.4 mg/kg (n=59) of imetelstat, administered intravenously every 3 weeks, in 107 patients with MF who had failed JAK inhibitor therapy (Table 2). The lower dose arm was subsequently closed due to insufficient activity, and the patients on active treatment allowed to cross over to the higher dose arm. While the rate of SVR35 at 24 weeks in the 9.4 mg/kg arm was a modest 10.2% and the rate of TSS50 was a reasonable 32.2%, median OS was a striking 28.1 months.(11) Furthermore, greater than 40% of patients experienced ≥1 grade improvements in bone marrow fibrosis and ≥25% decreases in driver mutation variant allele frequency (VAF). Reduction in bone marrow fibrosis significantly correlated with OS improvement, while spleen and symptom responders showed trends towards survival benefit compared with non-responders. Additionally, ≥20% VAF reduction correlated with improved clinical benefits, including higher rates of spleen and symptom responses, bone marrow fibrosis improvement and longer OS.(12) Intriguingly, imetelstat appeared to particularly benefit patients with “triple negative” disease, a known poor-prognosis subgroup. In these patients at the 9.4 mg/kg dose, median OS was 35.9 months, the 24-week rate of SVR35 was 18.8% and that of TSS50 was 50%.(13) Shorter telomere length at baseline and higher baseline expression levels of human telomerase reverse transcriptase (hTERT) predicted for improved clinical outcomes with imetelstat at the 9.4 mg/kg dose, and these characteristics were enriched for among the patients with triple negative disease. Finally, the pharmacodynamic effects of imetelstat (decrease in telomerase activity and/or hTERT expression level) were dose- and exposure-dependent, and ≥50% decreases in one or both of these parameters correlated with better clinical response rates and longer OS.(14)
Table 1. Stringent criteria for ruxolitinib (RUX) failure used in the reanalysis of JAKARTA-2
|Relapsed||RUX ≥ 3 mos with regrowth (defined as < 10% SVR or < 30% decrease in spleen size from baseline following an initial response)|
|Refractory||RUX ≥ 3 mos with < 10% SVR or < 30% decrease in spleen size from baseline|
|Intolerant||RUX ≥ 28 days complicated by development of RBC transfusion requirement (≥ 2 units/mos for 2 mos); or grade ≥ 3 thrombocytopenia, anemia, hematoma/hemorrhage while on RUX|
Table 2. Major inclusion criteria for the IMBARK™ trial of imetelstat in MF.