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.
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.