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685 Imetelstat Is Effective Treatment for Patients with Intermediate-2 or High-Risk Myelofibrosis Who Have Relapsed on or Are Refractory to Janus Kinase Inhibitor Therapy: Results of a Phase 2 Randomized Study of Two Dose Levels

Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical: Emerging Therapies and Prognostic Scoring in Myelofibrosis and Other MPNs
Hematology Disease Topics & Pathways:
Diseases, Adult, Therapies, Non-Biological, MPN, Polycythemia vera, Study Population, Clinically relevant, Myeloid Malignancies, hematopoiesis
Monday, December 3, 2018: 10:30 AM
Grand Hall A (Manchester Grand Hyatt San Diego)

John Mascarenhas, MD1, Rami S. Komrokji, MD2, Michele Cavo, MD3*, Bruno Martino, MD4*, Dietger Niederwieser, MD5, Andreas Reiter, MD6*, Bart L Scott, MD7, Maria R. Baer, MD8, Ronald Hoffman, MD9, Olatoyosi Odenike, MD10, Jacqueline Bussolari, PhD11, Eugene Zhu, PhD11*, Fei Huang, PhD12, Esther Rose, MD11*, Laurie Sherman, BSN12, Souria Dougherty, BS, MBA12*, Faye M. Feller, MD11 and Jean-Jacques Kiladjian, MD, PhD13

1Icahn School of Medicine at Mount Sinai, New York, NY
2Department of Malignant Hematology, H Lee Moffitt Cancer Center, Tampa, FL
3”Seràgnoli” Institute of Hematology Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
4Hematology Department, Grande Ospedale Metropolitano-G.O.M. Bianchi-Melacrino-Morelli, Reggio Calabria, Italy
5Department of Hematology and Oncology, University Hospital Leipzig, Leipzig, Germany
6Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany
7Fred Hutchinson Cancer Research Center, Seattle, WA
8University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
9Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY
10Section of Hematology/Oncology, University of Chicago, Chicago, IL
11Janssen Research & Development, LLC, Raritan, NJ
12Janssen Research & Development, LLC, Spring House, PA
13Centre d’Investigations Cliniques, Hôpital Saint-Louis, Université Paris Diderot, Paris, France

Background: Imetelstat, a 13-mer oligonucleotide that specifically targets the RNA template of human telomerase, is a potent competitive inhibitor of telomerase enzymatic activity (Asai Cancer Res 2003; Herbert Oncogene 2005). Clinical activity and an acceptable safety profile were reported in a 33-patient pilot study in intermediate-2 (int-2) or high-risk myelofibrosis (MF), where 48% of patients had been previously treated with a Janus Kinase inhibitor (JAKi) (Tefferi N Engl J Med 2015). Here, we report the results of a phase 2 clinical study of imetelstat at two dose levels in patients with MF (MYF2001, NCT02426086).

Methods: A randomized, multicenter, phase 2 study of two doses of imetelstat (9.4 mg/kg or 4.7 mg/kg IV, every 3 weeks) was performed in adults with DIPSS int-2 or high-risk MF that was relapsed/refractory to prior JAKi therapy (ie, either no reduction in splenomegaly after 12 weeks or worsening splenomegaly at any time after the start of JAKi therapy). Diagnosis of primary, post-essential thrombocythemia, or post-polycythemia vera MF was required; other eligibility criteria included measurable splenomegaly (by magnetic resonance imaging [MRI]), active MF-related systemic symptoms and platelet count ≥75 x 109/L. Primary endpoints were spleen response rate (% achieving ≥ 35% spleen volume reduction [SVR] by MRI) and symptom response rate (% achieving ≥ 50% reduction in total symptom score [TSS] per Myelofibrosis Symptom Assessment Form (MFSAF) v2 at week 24. Key secondary endpoints included safety, overall survival (OS), treatment response, molecular response, and pharmacokinetic and pharmacodynamic relationships.

Results: 107 patients were enrolled at 55 institutions (48 on 4.7 mg/kg; 59 on 9.4 mg/kg). Baseline characteristics are shown in the Table. Additionally, median time on JAKi was 23 (0.9-89.7) mo, and median platelet count was 147 x 109/L. Triple-negative (TN; ie, no mutations of JAK2, MPL, or CALR) comprised 24.8% of patients and 67.6% were considered high molecular risk (HMR; ie, ≥ 1 mutation of ASXL1, EZH2, SRSF2, or IDH1/2).

At the time of clinical cutoff, patients were followed for a median 22.6 (0.2-27.4) mo, including a median treatment duration of 6.2 (0.0-27.2) mo. Median duration on treatment was longer on the 9.4 mg/kg arm (7.7 mo) than on the 4.7 mg/kg arm. Six (10.2%) patients in the 9.4 mg/kg arm had a spleen response per MRI, with no responses on the 4.7 mg/kg arm (Figure 1). Nineteen (32%) patients in the 9.4 mg/kg arm and 3 (6%) patients in the 4.7 mg/kg arm had a symptom response (TSS reduction ≥ 50%) (Figure 2).

Median OS in the 9.4 mg/kg arm has not been reached, while median OS was 19.9 mo in the 4.7 mg/kg arm. The 18-mo survival rates were 76.7% and 62.9% for the 9.4 mg/kg and 4.7 mg/kg arms, respectively. Sensitivity analyses censoring patients at time of dose escalation for subsequent JAKi therapy or allogeneic stem cell transplant generated similar results. In the 9.4 mg/kg arm, an association was observed between patients who were TN and OS (median OS has not been reached for TN patients and was 23.6 mo for non-TN patients). Spleen response rate was higher in patients with 1 HMR mutation (ASXL1, EZH2, SRSF2, or IDH1/2.

The most common adverse events on treatment (all grades) at 9.4 mg/kg were thrombocytopenia (49%), anemia (44%), neutropenia (36%), and nausea (34%) and at 4.7 mg/kg were diarrhea (38%), nausea (31%), anemia (31%), and thrombocytopenia (23%). Grade 3/4 neutropenia and thrombocytopenia were more frequent with 9.4 mg/kg (34% and 42%, respectively) than 4.7 mg/kg (13% and 29%, respectively); most cytopenias resolved within 4 weeks. Grade 3/4 LFT elevations were observed in 7 patients on study. Imetelstat-related hepatic toxicities, confirmed by an independent Hepatic Review Committee, were not observed.

Conclusions: Imetelstat at 9.4 mg/kg IV every 3 weeks has demonstrated clinical activity in int-2 or high-risk MF patients who are relapsed/refractory to JAKi, notably in observed OS. Though no formal study has reported survival for patients who are truly relapsed/refractory to JAKi, median OS of patients who were previously treated with JAKi has been reported to be 12-14 mo (Kuykendall Ann Hematol 2018; Newberry Blood 2017). The safety profile for imetelstat was considered acceptable for this poor-prognosis population. Imetelstat at 9.4 mg/kg IV every 3 weeks is a promising agent for JAKi-pretreated MF patients and warrants further testing in clinical trials.

Disclosures: Mascarenhas: Roche: Research Funding; Merck: Research Funding; Novartis: Research Funding; Promedior: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Komrokji: Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Cavo: Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Niederwieser: Novartis: Research Funding; Miltenyi: Speakers Bureau. Reiter: Incyte: Consultancy, Honoraria. Scott: Celgene: Consultancy, Research Funding; Agios: Consultancy; Alexion: Consultancy; Novartis: Research Funding. Hoffman: Janssen: Research Funding; Merus: Research Funding; Incyte: Research Funding; Summer Road: Research Funding; Formation Biologics: Research Funding. Odenike: ABBVIE: Honoraria, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Agios: Research Funding; Celgene: Research Funding; NS Pharma: Research Funding; Janssen: Research Funding; Astex: Research Funding; Gilead Sciences: Research Funding. Bussolari: Janssen: Employment, Equity Ownership. Zhu: Janssen: Employment, Equity Ownership. Huang: Janssen: Employment, Equity Ownership. Rose: Janssen: Employment, Equity Ownership. Sherman: Janssen: Employment, Equity Ownership. Dougherty: Janssen: Employment, Equity Ownership. Feller: Janssen: Employment, Equity Ownership. Kiladjian: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Provided Ruxolitinib ; Hoffmann-La Roche AG: Other: Provided Pegylated Interferon Alpha 2a.

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