Prithviraj Bose, MD


Associate Professor
Department of Leukemia
Division of Cancer Medicine
MD Anderson

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.

KOL Insight and Perspective

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.

  • Patients with Intermediate-2 or High-risk MF (Int-2/High-risk) patients who have relapsed after or are refractory to prior treatment with a janus kinase (JAK) inhibitor
  • Relapsed or refractory to JAKi defined as documented progressive disease during or after JAKi:
    • Patients must have worsening of splenomegaly-related abdominal pain at any time after the start of JAKi therapy and EITHER:
      • No reduction in spleen volume or size after 12 weeks of JAKi therapy, OR
      • Worsening splenomegaly at any time after the start of JAKi therapy documented by:
        • Increase in spleen volume from nadir by 25% measured by MRI or CT, or
        • Increase in spleen size by palpation

References

  1. Newberry KJ, Patel K, Masarova L, Luthra R, Manshouri T, Jabbour E, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. 2017 Aug 31;130(9):1125-31.
  2. Palandri F, Breccia M, Bonifacio M, Polverelli N, Elli EM, Benevolo G, et al. Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer. 2019 Dec 20.
  3. Kuykendall AT, Shah S, Talati C, Al Ali N, Sweet K, Padron E, et al. Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation. Ann Hematol. 2018 Mar;97(3):435-41.
  4. Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Jourdan E, Silver RT, et al. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. Am J Hematol. 2020 Mar 4.
  5. Harrison CN, Vannucchi AM, Platzbecker U, Cervantes F, Gupta V, Lavie D, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017 Dec 20.
  6. Gerds AT, Savona MR, Scott BL, Talpaz M, Egyed M, Harrison CN, et al. Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis. Blood Adv. 2020 Nov 24;4(22):5825-35.
  7. Talpaz M, Rampal RK, Verstovsek S, Harrison CN, Drummond MW, Kiladjian J, et al. CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, As Monotherapy in Advanced Myelofibrosis Patients Refractory/Intolerant to JAK Inhibitor: Update from Phase 2 MANIFEST Study. Blood. 2020;136:2163-.
  8. Al-Ali H, Delgado RG, Lange A, Pluta A, McLornan DP, Vachhani P, et al. KRT-232, A First-in-Class, Murine Double Minute 2 Inhibitor, For Myelofibrosis Relapsed or Refractory to Janus-Associated Kinase Inhibitor Treatment. Hemasphere. 2020;4(S1):S215-.
  9. Yacoub A, Pettit K, Bradley TJ, Gerds AT, Tartaczuch M, Shortt J, et al. A Phase 2 Study of the LSD1 Inhibitor IMG7289 (bomedemstat) for the Treatment of Advanced Myelofibrosis. Blood. 2020;136:51-.
  10. Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, et al. A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. N Engl J Med. 2015 Sep 3;373(10):908-19.
  11. Mascarenhas JO, Komrokji RS, Cavo M, Martino B, Niederwieser D, Reiter A, et al. Favorable Overall Survival with Imetelstat Treatment Correlates with Other Clinical Benefits in Intermediate 2 or High Risk Myelofibrosis Relapsed/Refractory to Janus Kinase Inhibitor. Blood. 2020;136:53-.
  12. Mascarenhas JO, Komrokji RS, Cavo M, Martino B, Niederwieser D, Reiter A, et al. 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. Blood. 2020;136:346-.
  13. Kiladjian J, Mascarenhas JO, Komrokji RS, Cavo M, Martino B, Niederwieser D, et al. Imetelstat Treatment Results in Clinical Benefits, Including Improved Overall Survival, in Patients with Higher-Risk Triple-Negative Myelofibrosis Relapsed/Refractory to Janus Kinase Inhibitors (JAKi). Blood. 2020;136:3084-.
  14. Mascarenhas JO, Komrokji RS, Cavo M, Martino B, Niederwieser D, Reiter A, et al. 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. Blood. 2020;136:347-.