Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy

Abstract

Purpose: Targeting the BCL-XL pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models. This phase II trial investigated the efficacy and safety of adding BCL-XL/BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response to ruxolitinib monotherapy (ClinicalTrials.gov identifier: NCT03222609).

Methods: Thirty-four adult patients with intermediate-/high-risk myelofibrosis who had progression or suboptimal response on stable ruxolitinib dose (≥ 10 mg twice daily) were administered navitoclax at 50 mg once daily starting dose, followed by escalation to a maximum of 300 mg once daily in once in weekly increments (if platelets were ≥ 75 × 109/L). The primary end point was ≥ 35% spleen volume reduction (SVR35) from baseline at week 24. Secondary end points included ≥ 50% reduction in total symptom score (TSS50) from baseline at week 24, hemoglobin improvement, change in bone marrow fibrosis (BMF) grade, and safety.

Results: High molecular risk mutations were identified in 58% of patients, and 52% harbored ≥ 3 mutations. SVR35 was achieved by 26.5% of patients at week 24, and by 41%, at any time on study, with an estimated median duration of SVR35 of 13.8 months. TSS50 was achieved by 30% (6 of 20) of patients at week 24, and BMF improved by 1-2 grades in 33% (11 of 33) of evaluable patients. Anemia response was achieved by 64% (7 of 11), including one patient with baseline transfusion dependence. Median overall survival was not reached with a median follow-up of 21.6 months. The most common adverse event was reversible thrombocytopenia without clinically significant bleeding (88%).

Conclusion: The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR35, improved TSS, hemoglobin response, and BMF. Further investigation is underway to qualify the potential for disease modification.

Conflict of interest statement

Claire N. HarrisonHonoraria: Celgene, Novartis, CTI BioPharma Corp, Roche/Genentech, Geron, AOP Orphan Pharmaceuticals, BMSi, Constellation PharmaceuticalsConsulting or Advisory Role: Promedior, Celgene, AOP Orphan Pharmaceuticals, Galectin Therapeutics, Sierra OncologySpeakers' Bureau: Novartis, CTI BioPharma Corp, Gilead Sciences, Incyte, Celgene, Janssen OncologyResearch Funding: Novartis (Inst), Celgene (Inst), Constellation Pharmaceuticals (Inst) Jacqueline S. GarciaConsulting or Advisory Role: AbbVie, Takeda, Astellas PharmaResearch Funding: AbbVie (Inst), Pfizer (Inst), Genentech/Roche (Inst), Lilly (Inst), AstraZeneca (Inst), Prelude Therapeutics (Inst) Tim C.P. SomervailleHonoraria: Novartis, Celgene/Bristol Myers SquibbConsulting or Advisory Role: NovartisResearch Funding: Imago Biosciences, Cellcentric James M. ForanConsulting or Advisory Role: SERVIER, Bristol Myers Squibb/Celgene, Stemline Therapeutics, Taiho Pharmaceutical, Syros Pharmaceuticals, Sanofi, Certara Inc, Novartis, Pfizer, Revolution Medicines, Revolution MedicinesResearch Funding: AbbVie (Inst), Actinium Pharmaceuticals (Inst), Aprea Therapeutics (Inst), Aptose Biosciences (Inst), Boehringer Ingelheim (Inst), H3 Biomedicine (Inst), Kura Oncology (Inst), Sellas Life Sciences (Inst), Takeda (Inst), Trillium Therapeutics (Inst), Xencor (Inst) Srdan VerstovsekConsulting or Advisory Role: Constellation Pharmaceuticals, Sierra Oncology, Incyte, Novartis, CelgeneResearch Funding: Incyte (Inst), Celgene (Inst), Protagonist Therapeutics (Inst), Sierra Oncology (Inst), PharmaEssentia (Inst), Telios (Inst), Constellation Pharmaceuticals (Inst), AbbVie (Inst), Geron (Inst), Galecto Biotech (Inst), Kartos Therapeutics (Inst) Catriona JamiesonStock and Other Ownership Interests: Aspera Biomedicines, IncPatents, Royalties, Other Intellectual Property: Patent Royalties—Methods for Manipulating Phagocytosis Mediated by CD47, Patent #US20090191202A1 Ruben MesaHonoraria: Novartis, shire, AOP Orphan Pharmaceuticals, Sierra Oncology, AbbVie, Geron, BMSConsulting or Advisory Role: Baxalta, Galena Biopharma, Incyte, NovartisResearch Funding: Incyte (Inst), Genentech (Inst), CTI (Inst), Promedior (Inst), NS Pharma (Inst), Gilead Sciences (Inst), Pfizer (Inst), PharmaEssentia (Inst), Celgene (Inst), AbbVie (Inst), Imago Pharma (Inst)Travel, Accommodations, Expenses: Novartis, Incyte, AOP Orphan Pharmaceuticals, PharmaEssentia Ellen K. RitchieConsulting or Advisory Role: Incyte, Celgene, Pfizer, Novartis, Bristol Myers SquibbSpeakers' Bureau: Celgene, IncyteResearch Funding: Astellas Pharma (Inst), Novartis (Inst), Pfizer (Inst), Jazz Pharmaceuticals (Inst)Travel, Accommodations, Expenses: Pfizer Srinivas K. TantravahiHonoraria: Novartis, Karyopharm TherapeuticsConsulting or Advisory Role: Karyopharm Therapeutics, NovartisResearch Funding: Karyopharm Therapeutics Pankit VachhaniConsulting or Advisory Role: Blueprint Medicines, Incyte, AbbVie, Jazz Pharmaceuticals, CTI BioPharma Corp, Novartis, Amgen, PfizerSpeakers' Bureau: IncyteResearch Funding: Seattle Genetics (Inst), Amgen (Inst), Astex Pharmaceuticals (Inst), Incyte (Inst), Blueprint Medicines (Inst), Kartos Therapeutics (Inst), Gilead/Forty Seven (Inst), Constellation Pharmaceuticals (Inst), AbbVie (Inst), CTI BioPharma Corp (Inst), Takeda (Inst) Casey L. O'ConnellResearch Funding: Astex Pharmaceuticals (Inst), Genentech (Inst) Rami S. KomrokjiStock and Other Ownership Interests: AbbVieConsulting or Advisory Role: Novartis, Bristol Myers Squibb, Jazz Pharmaceuticals, AbbVie, Geron, Acceleron PharmaSpeakers' Bureau: Jazz Pharmaceuticals, Bristol Myers Squibb, AgiosTravel, Accommodations, Expenses: Jazz Pharmaceuticals, Bristol Myers Squibb, Agios Jason HarbEmployment: AbbVieStock and Other Ownership Interests: AbbVie Jessica E. HuttiEmployment: AbbVieStock and Other Ownership Interests: AbbVie Leanne HolesEmployment: AbbVie, Bristol Myers Squibb/Celgene/JunoStock and Other Ownership Interests: AbbVie Abdullah A. MasudEmployment: AbbVieStock and Other Ownership Interests: AbbVie Silpa NuthalapatiEmployment: AbbVieStock and Other Ownership Interests: AbbVie Jalaja PotluriEmployment: AbbVieStock and Other Ownership Interests: AbbVie Naveen PemmarajuEmployment: MD Anderson Cancer CenterLeadership: ASH, ASCO.Honoraria: Incyte, Novartis, LFB Biotechnologies, Stemline Therapeutics, Celgene, AbbVie, MustangBio, Roche Molecular Diagnostics, Blueprint Medicines, DAVA Pharmaceuticals, Springer, Aptitude Health, Neopharm, CareDXConsulting or Advisory Role: Blueprint Medicines, Pacylex, Immunogen, Bristol Myers Squibb, Clearview Healthcare Partners, Astellas Pharma US Inc, Protagonist Therapeutics, Inc, Triptych Health Partners, CTI BioPharma CorpResearch Funding: Novartis, Stemline Therapeutics, Samus Therapeutics, AbbVie, Cellectis, Affymetrix/Thermo Fisher Scientific, Daiichi Sankyo, Plexxikon, MustangBioTravel, Accommodations, Expenses: Stemline Therapeutics, Celgene, AbbVie, DAVA Oncology, MustangBio(OPTIONAL) Uncompensated Relationships: Dan's House of Hope(OPTIONAL) Uncompensated Relationships: Oncology TimesNo other potential conflicts of interest were reported.

Figures

FIG 1.

Percentage change from baseline in (A) spleen volume and (B) TSS at week 24 and (C) BMF improvement from baseline at any time on study. aPatients with nonmissing percent change from baseline at week 24. BMF, bone marrow fibrosis; SV, spleen volume; SVR35, spleen volume reduction of ≥ 35%; TSS, total symptom score; TSS50, ≥ 50% reduction in total symptom score.

FIG 2.

Kaplan-Meier curve of OS in all patients (N = 34). NE, not estimable; NR, not reached; OS, overall survival.

FIG 3.

Mean platelet count over time. Platelet nadir was defined as 9 cells/L as indicated by the dashed line. SD, standard deviation; Wk, week.