SOHO State of the Art Updates and Next Questions: Novel Therapeutic Strategies in Development for Myelofibrosis

Chifotides, Helen T.; Masárová, Lucia; Verstovšek, Srđan

doi:10.1016/j.clml.2022.12.014

Cited by 6 publications

(8 citation statements)

References 110 publications

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“…The dismal median OS noted in patients who discontinued ruxolitinib due to disease progression (e.g., cytopenias) [ 90 , 91 , 92 , 115 ], correlation of ruxolitinib dose with spleen response [ 91 ], and inclusion of ruxolitinib dose <20 mg bid (at baseline, month 3, and month 6) as an adverse prognostic risk factor in the RR6 model [ 116 ] underscore the critical need for non-myelosuppressive JAK inhibitors and other novel treatments in cytopenic patients with MF [ 87 , 91 , 92 , 117 , 118 , 119 , 120 , 121 ]. Pacritinib and momelotinib are non-myelosuppressive JAK inhibitors that have been approved or are in advanced clinical development and have demonstrated significant clinical benefits in MF patients manifesting features of the myelodepletive phenotype (cytopenias).…”

Section: Phenotypes Molecular Profiles and Differentiated Efficacy Of...mentioning

confidence: 99%

“…Combination regimens of novel agents with ruxolitinib have exhibited synergism and are currently being explored in clinical trials [ 117 , 118 ]. In Arm 3 of the MANIFEST trial (NCT02158858), which evaluated pelabresib (inhibitor of bromodomain and extra-terminal proteins) in combination with ruxolitinib in 84 JAK inhibitor-naïve patients, clinical benefits were observed regardless of molecular markers, including HMR mutations [ 147 , 148 ].…”

Section: Phenotypes Molecular Profiles and Differentiated Efficacy Of...mentioning

confidence: 99%

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Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments

Chifotides

Verstovšek

Bose

2023

Cancers

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Myelofibrosis (MF) presents an array of clinical manifestations and molecular profiles. The two distinct phenotypes− myeloproliferative and myelodepletive or cytopenic− are situated at the two poles of the disease spectrum and are largely defined by different degrees of cytopenias, splenomegaly, and distinct molecular profiles. The myeloproliferative phenotype is characterized by normal/higher peripheral blood counts or mildly decreased hemoglobin, progressive splenomegaly, and constitutional symptoms. The myeloproliferative phenotype is typically associated with secondary MF, higher JAK2 V617F burden, fewer mutations, and superior overall survival (OS). The myelodepletive phenotype is usually associated with primary MF, ≥2 cytopenias, modest splenomegaly, lower JAK2 V617F burden, higher fibrosis, greater genomic complexity, and inferior OS. Cytopenias are associated with mutations in epigenetic regulators/splicing factors, clonal evolution, disease progression, and shorter OS. Clinical variables, in conjunction with the molecular profiles, inform integrated prognostication and disease management. Ruxolitinib/fedratinib and pacritinib/momelotinib may be more suitable to treat patients with the myeloproliferative and myelodepletive phenotypes, respectively. Appreciation of MF heterogeneity and two distinct phenotypes, the different clinical manifestations and molecular profiles associated with each phenotype alongside the growing treatment expertise, the development of non-myelosuppressive JAK inhibitors, and integrated prognostication are leading to a new era in patient management. Physicians can increasingly tailor personalized treatments that will address the unique unmet needs of MF patients, including those presenting with the myelodepletive phenotype, to elicit optimal outcomes and extended OS across the disease spectrum.

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Section: Phenotypes Molecular Profiles and Differentiated Efficacy Of...mentioning

confidence: 99%

Section: Phenotypes Molecular Profiles and Differentiated Efficacy Of...mentioning

confidence: 99%

Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments

Chifotides

Verstovšek

Bose

2023

Cancers

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“…Combination with ruxolitinib was more effective than individual therapy 80 . The PRMT5 inhibitor, PRT543, is now being evaluated in MF patients 44 .…”

Section: Molecules In Clinical Developmentmentioning

confidence: 99%

“…In JAK2 V617F cell lines, there was a synergy between JAK2 inhibition and navitoclax, also leading to reversal of the ruxolitinib resistance 104 . Phase 2 clinical trials of this combination were promising with a very significant decrease in the spleen volume, a decrease of fibrosis, including some patients with a resolution of the marrow fibrosis and of the JAK2 V617F /CALR VAF 44 , 105 . Furthermore, the thrombocytopenia was manageable and, surprisingly, the anemia was partially corrected.…”

Section: Molecules In Clinical Developmentmentioning

confidence: 99%

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Recent advances in therapies for primary myelofibrosis

Vainchenker,

Yahmi,

Havelange

et al. 2023

Fac Rev

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Primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET) form the classical BCR-ABL1 -negative myeloproliferative neoplasms (MPNs) that are driven by a constitutive activation of JAK2 signaling. PMF as well as secondary MF (post-ET and post-PV MF) are the most aggressive MPNs. Presently, there is no curative treatment, except allogenic hematopoietic stem cell transplantation. JAK inhibitors, essentially ruxolitinib, are the therapy of reference for intermediate and high-risk MF. However, presently the current JAK inhibitors behave mainly as anti-inflammatory drugs, improving general symptoms and spleen size without major impact on disease progression. A better understanding of the genetics of MF, the biology of its leukemic stem cells (LSCs), the mechanisms of fibrosis and of cytopenia and the role of inflammatory cytokines has led to new approaches with the development of numerous therapeutic agents that target epigenetic regulation, telomerase, apoptosis, cell cycle, cytokines and signaling. Furthermore, the use of a new less toxic form of interferon-α has been revived, as it is presently one of the only molecules that targets the mutated clone. These new approaches have different aims: (a) to provide alternative therapy to JAK inhibition; (b) to correct cytopenia; and (c) to inhibit fibrosis development. However, the main important goal is to find new disease modifier treatments, which will profoundly modify the progression of the disease without major toxicity. Presently the most promising approaches consist of the inhibition of telomerase and the combination of JAK2 inhibitors (ruxolitinib) with either a BCL2/BCL-xL or BET inhibitor. Yet, the most straightforward future approaches can be considered to be the development of and/or selective inhibition of JAK2V617F and the targeting MPL and calreticulin mutants by immunotherapy. It can be expected that the therapy of MF will be significantly improved in the coming years.

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Imetelstat: First Approval

Keam

2024

Drugs

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SOHO State of the Art Updates and Next Questions: Novel Therapeutic Strategies in Development for Myelofibrosis

Cited by 6 publications

References 110 publications

Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments

Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments

Recent advances in therapies for primary myelofibrosis

Imetelstat: First Approval

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