ABSTRACT
Introduction
Cytopenic myelofibrosis is increasingly recognized as a phenotype of myelofibrosis presenting with low blood counts, lower driver mutation allele burden, increased likelihood of arising de novo, i.e. primary myelofibrosis, greater genomic complexity, worse survival, and higher rates of leukemic transformation compared to the more traditional ‘myeloproliferative’ phenotype. Both anemia and thrombocytopenia are very common, often coexist, and can be worsened by treatment. Several JAK inhibitors with different kinome profiles are now available for routine clinical use. Additionally, ancillary therapies can also provide some, albeit non-durable, benefit.
Areas covered
In this review, we discuss the prevalence and clinical significance of cytopenias in myelofibrosis. We then discuss the various Janus kinase (JAK) inhibitors and ancillary therapies available with a special focus on their use in cytopenic populations, ability to improve cytopenias, and notable adverse events. Articles included were selected through literature searches using the PubMed database.
Expert Opinion
Pacritinib and momelotinib are new treatment options for patients with cytopenic myelofibrosis. These JAK inhibitors are less myelosuppressive and allow for cytopenia stabilization or improvement while providing additional benefits. It is likely that their use will expand and these newer JAK inhibitors will become backbones for future combinations with novel, ‘disease modifying’ agents.
Article highlights
Myelofibrosis (MF) presents with “”myeloproliferative“ or ”cytopenic” phenotypes. These are not mutually exclusive, and patients may evolve over time from the former to the latter.
If not already at presentation, virtually all patients with MF will develop anemia, and the majority will become thrombocytopenic over time.
Cytopenic myelofibrosis behaves like a bone marrow failure state enriched for primary rather than post-PV/ET myelofibrosis, lower JAK2 V617F allele burden, frequent cytopenias, less prominent splenomegaly, greater genomic complexity, increased risk for infections and bleeding, higher rates of leukemic transformation and worse survival.
Ruxolitinib has good efficacy in myelofibrosis patients with higher JAK2 VA617F allele burden and less genomic complexity, i.e. the myeloproliferative phenotype of MF. However, both ruxolitinib and fedratinib worsen cytopenias and therefore, may not be ideal for cytopenic MF.
Ancillary therapies like danazol or erythroid stimulating agents (ESAs) provide some cytopenia stabilization, but responses are not durable and limited to cytopenia improvements alone, with little benefit in terms of splenomegaly and symptoms.
New JAK inhibitors, e.g. pacritinib (JAK2, IRAK1, FLT3, and ACVR1 inhibitor) and momelotinib (JAK1/2 and ACVR1 inhibitor) provide new treatment options for thrombocytopenic and anemic myelofibrosis patients.
Emerging data and experience will help clarify the roles of pacritinib and momelotinib in patients with both anemia and thrombocytopenia. They are likely to increasingly serve as the backbone of JAK inhibitor therapies in future combination approaches with novel, ‘disease modifying’ therapies.
Declaration of interest
P Vachhani has disclosed research support from Seattle Genetics, Amgen, Astex Pharmaceuticals, Incyte, Blueprint Medicines, Kartos Therapeutics, Gilead/Forty Seven, Constellation Pharmaceuticals, AbbVie, CTI BioPharma Corp, Takeda, and honoraria/consulting fees from AbbVie, Amgen, Blueprint Medicines, Cogent Biosciences, Incyte, CTI BioPharma Corp, Daiichi Sankyo, GlaxoSmith Kline, Novartis, Pfizer, Genentech, Servier, Stemline, and MorphoSys.
S Verstovsek has disclosed research support from Incyte, Roche, NS Pharma, Celgene, Gilead, Promedior, CTI BioPharma Corp., BMS, Novartis, Sierra Oncology, Pharma Essentia, Italfarmaco, Protagonist Therapeutics, Galecto, and honoraria/consulting fees from
Constellation, Sierra, Incyte, Novartis, Celgene, BMS.
P Bose has disclosed research support from Incyte, BMS, CTI BioPharma, Kartos, Telios, Morphosys, Blueprint Medicines, Cogent BioSciences, Disc Medicine, Ionis, NS Pharma, Promedior, Pfizer, and Astellas, and honoraria/consulting fees from Incyte, BMS, CTI BioPharma, GSK, Morphosys, AbbVie, Karyopharm, Kartos, Pharma Essentia, Blueprint Medicines, Cogent BioSciences, and Novartis.
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.
Author contributions
All authors have contributed to the manuscript writing and final approval of the manuscript.