Moving beyond ruxolitinib failure in myelofibrosis: evolving strategies for second line therapy

ABSTRACT

Introduction

Ruxolitinib has been the cornerstone of pharmacologic therapy for myelofibrosis for over a decade. However, the last several years have witnessed the regulatory approval of other Janus kinase (JAK) inhibitors for myelofibrosis, i.e. fedratinib, pacritinib, and US approval of momelotinib is widely anticipated in 2023.

Areas covered

Due to the multifaceted clinical presentation of myelofibrosis, a watertight definition of ruxolitinib failure has remained elusive, as “progression” on ruxolitinib can take many forms and management is highly nuanced. Yet, the availability of other JAK inhibitors and potential future availability of non-JAK inhibitor agents for myelofibrosis make a consensus on management of ruxolitinib failure critically important. This consensus paper summarizes a discussion between multiple academic and community physician experts, a pharmacist and an advanced practice provider around the issues to be considered for the optimal care of patients with myelofibrosis whose disease is refractory to or does not respond adequately to ruxolitinib, or who exhibit intolerance to ruxolitinib.

Expert opinion

The panel identified several areas of consensus, as well as some areas where more data to inform evidence-based practice are needed. In some situations, maintaining ruxolitinib while adding another agent, e.g. to address anemia, is appropriate, whereas in others, switching to a different drug has merit.

KEYWORDS:

• myelofibrosis
• JAK inhibitor failure
• ruxolitinib failure
• fedratinib
• pacritnib
• momelotinib
• consensus
• treatment selection
• treatment failure definitions
• emerging agents
• clinical trials
• therapeutic options

Abbreviations

ACVR1 activin receptor type 1

AML acute myeloid leukemia

BAT best available therapy

Bcl-2 B-cell leukemia/lymphoma 2 protein

BET bromodomain and extraterminal domain

BMF bone marrow fibrosis

CT computed tomography

FDA Food and Drug Administration

HCT hematopoietic cell transplant

HMR high molecular risk

IPSS International Prognostic Scoring System

IWG-MRT International Working Group for MPN Research and Treatment

JAK Janus kinase

JAK2i Janus kinase-2 inhibitor

LCM left costal margin

LSD1 lysine-specific demethylase 1

MDM2 murine double minute 2

MF myelofibrosis

MF-SAF myelofibrosis symptom assessment form

MPN myeloproliferative neoplasm

MPN-SAF myeloproliferative neoplasms symptom assessment form

MRI magnetic resonance imaging

NR not reported

PIM1 proviral integration site for Moloney murine leukemia virus-1

PI3Kδ delta isoform of phosphatidylinositol-3 kinase

PTX-2 pentraxin-2

QOL quality of life

RBC red blood cell

RDS ruxolitinib discontinuation syndrome

RR6 ruxolitinib after 6 months

SINE selective inhibitor of nuclear export

SVR spleen volume reduction

SVR35 % of patients achieving 35% spleen volume reduction

SAF symptom assessment form

STAT signal transducer and activator of transcription

TD → TI conversion from transfusion-dependent to transfusion-independent

TIMP tissue inhibitor of metalloproteinase

TNF tumor necrosis factor

TSS total symptom score

TSS50 % of patients achieving ≥50% decrease in total symptom score

VAF variant allele frequency.

Declaration of interest

P Bose has declared receiving research support from Blueprint Medicines, Bristol Myers Squibb, Cogent BioSciences, CTI BioPharma Corp, Disc Medicine, Geron Corporation, Incyte Corporation, Ionis Pharmaceuticals, Janssen Pharmaceuticals, Kartos Therapeutics, Morphosys, Sumitomo Oncology Pharma, Telios Pharma. As well as honoraria/consulting fees from AbbVie, Blueprint Medicines, Bristol Myers Squibb, Cogent BioSciences, CTI BioPharma Corp, GSK, Incyte Corporation, Karyopharm Therapeutics, Morphosys, Novartis, PharmaEssentia.

D M Harting has declared stock ownership at Bio-Rad Laboratories, (relationship has ended), Danaher Corporation (relationship has ended), Halozyme Therapeutics, Laboratory Corp of America (relationship has ended), Merck & Co., (relationship has ended), Moderna, (relationship has ended), Northwest Biotherapeutics, PerkinElmer, (relationship has ended), Thermo Fisher Scientific, (relationship has ended).

K A Farina has declared being a Consultant/Speaker at Bristol Myers Squibb.

S E Kurtin has declared being a Consultant at AbbVie/Pharmacyclics, Amgen, AstraZeneca, Bristol Myers Squibb, Epizyme/Ipsen (relationship has ended), GSK (relationship has ended), Incyte Corporation, Takeda Pharmaceutical Company.

A Kuykendall has declared being an Advisor at AbbVie, Blueprint Medicines (relationship has ended), Celgene/Bristol Myers Squibb, CTI BioPharma (relationship has ended), Imago Biosciences (relationship has ended), Incyte Corporation (relationship has ended), Novartis (relationship has ended). As well as a Speaker for Blueprint Medicines (relationship has ended), Celgene/Bristol Myers Squibb, Incyte Corporation (relationship has ended). A Researcher at Blueprint Medicines (relationship has ended), Celgene/Bristol Myers Squibb, Sierra Oncology. And has received honoraria from Sierra Oncology.

J O Mascarenhas has declared being a Consultant at Galecto, Sierra Oncology, GSK, Imago BioSciences, Constellation Pharmaceuticals/MorphoSys. Consultant/Researcher (paid to institution) at AbbVie, CTI BioPharma Corp, Celgene/Bristol Myers Squibb, Geron Corporation, Incyte Corporation, Kartos Therapeutics, Novartis, PharmaEssentia, Roche. A Researcher (paid to the institution) at Merck (relationship has ended). And on the Data and Safety Monitoring Board at Karyopharm Therapeutics.

R Mesa has declared being a Consultant at Constellation Pharmaceuticals/MorphoSys, La Jolla Pharmaceutical Company, Novartis, Sierra Oncology. Received grants from AbbVie, Celgene/Bristol Myers Squibb, Constellation Pharmaceuticals/MorphoSys, CTI BioPharma Corp, Genotech Pharma, Incyte Corporation, Promedior/Roche, Samus Therapeutics, P30 Support Grant from National Cancer Institute (CA054174).

C B Miller has declared receiving research support (paid to institution) from Sierra Oncology, Celgene/Bristol Myers Squibb, CTI BioPharma Corp and Incyte Corporation. And has been a Consultant/Speaker at Celgene/Bristol Myers Squibb, Incyte Corporation, and CTI BioPharma.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The multidisciplinary panel exercise and the production of this manuscript were made possible by educational grants from Bristol-Myers Squibb Company, CTI Biopharma Corp., and Sierra Oncology, Inc. to the University of Texas MD Anderson Cancer Center and MediCom Worldwide, Inc. The grantors had no input into the selection of panelists, nor the planning, conduct, analysis, or reporting of the panel proceedings. Panelists received compensation from MediCom in the form of honoraria for their participation and work on the panel.