Hepcidin is elevated in primary and secondary myelofibrosis and remains elevated in patients treated with ruxolitinib

Zhou, Amy; Kong, Tim; Fowles, Jared S.; Jung, Chun‐Ling; Allen, Maggie J.; Fisher, Daniel A.C.; Fulbright, Mary; Nemeth, Elizabeta; Ganz, Tomas; Oh, Stephen T.

doi:10.1111/bjh.18044

Cited by 13 publications

(10 citation statements)

References 17 publications

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“…Across a pro-inflammatory cytokine panel, the addition of pevonedistat to ruxolitinib sustained suppression of interleukin (IL)-6 and interferon-gamma (IFN-γ) in a dose-dependent manner [ Figure 1(d) ]. IL-6, in particular, has been associated with adverse prognosis and remains elevated with ruxolitinib treatment, 15 , 16 which was also observed here in patients who received a low pevonedistat dose. Lastly, iron hemostasis has been found to be dysregulated in MPN, where factors including chronic inflammation upregulate the key iron regulator hepcidin.…”

supporting

confidence: 74%

A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis

Kong,

Gaudin,

Gordon

et al. 2024

Therapeutic Advances in Hematology

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Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable response as single-agent therapy. With the rationale of targeting both pathways, we conducted a phase I dose escalation trial of pevonedistat in combination with ruxolitinib for the treatment of patients with myelofibrosis (NCT03386214). The primary objective was to assess the safety and tolerability of combination therapy with additional objectives of treatment efficacy and alterations of biomarkers. There were no dose-limiting toxicities observed with most adverse events being limited to grades 1/2. In secondary measures, anemia response was observed in two patients. Pro-inflammatory cytokines and iron parameters were longitudinally assessed, which revealed suppression of interleukin-6 and interferon-gamma in a dose-dependent manner across a subset of patients. These results suggest that combination therapy targeting both JAK2 and NFκB may hold clinical merit for MPN patients.

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supporting

confidence: 74%

A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis

Kong,

Gaudin,

Gordon

et al. 2024

Therapeutic Advances in Hematology

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“…Chronic pro‐inflammatory cytokines and bone morphogenetic protein (BMP) molecules in the microenvironment niche induce hepatocytes to upregulate hepcidin production and iron sequestration 27 (Figure 5A). We previously showed that hepcidin levels remain elevated in patients on ruxolitinib treatment 28 which together with clinical evidence of dose‐dependent anemia with ruxolitinib 8 indicate that alternative therapy may be necessary for these patients and that sole JAK1/2 suppression may be insufficient across a subset of patients. As previously discussed, momelotinib in contrast has demonstrated reversal of transfusion dependency and anemia benefit for some MF patients, which has been postulated to be a consequence of hepcidin suppression via inhibition of ACVR1 12 .…”

Section: Resultsmentioning

confidence: 97%

Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms

Kong

Laranjeira

et al. 2023

American J Hematol

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Small molecule inhibitors targeting JAK2 provide symptomatic benefits for myeloproliferative neoplasm (MPN) patients and are among first‐line therapeutic agents. However, despite all having potent capacity to suppress JAK–STAT signaling, they demonstrate distinct clinical profiles suggesting contributory effects in targeting other ancillary pathways. Here, we performed comprehensive profiling on four JAK2 inhibitors either FDA‐approved (ruxolitinib, fedratinib, and pacritinib) or undergoing phase 3 studies (momelotinib) to better outline mechanistic and therapeutic efficacy. Across JAK2‐mutant in vitro models, all four inhibitors demonstrated similar anti‐proliferative phenotypes, whereas pacritinib yielded greatest potency on suppressing colony formation in primary samples, while momelotinib exhibited unique erythroid colony formation sparing. All inhibitors reduced leukemic engraftment, disease burden, and extended survival across patient‐derived xenograft (PDX) models, with strongest effects elicited by pacritinib. Through RNA‐sequencing and gene set enrichment analyses, differential suppressive degrees of JAK–STAT and inflammatory response signatures were revealed, which we validated with signaling and cytokine suspension mass cytometry across primary samples. Lastly, we assessed the capacity of JAK2 inhibitors to modulate iron regulation, uncovering potent suppression of hepcidin and SMAD signaling by pacritinib. These comparative findings provide insight into the differential and beneficial effects of ancillary targeting beyond JAK2 and may help guide the use of specific inhibitors in personalized therapy.

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“…Hepcidin is a peptide hormone that acts as a regulator of iron homeostasis and is elevated in patients with MF. 14 Pacritinib is a potent inhibitor of the key hepcidin regulator, ACVR1. 13 It has been postulated that ACVR1 inhibition reduces hepcidin, increasing iron availability for erythropoiesis.…”

Section: Discussionmentioning

confidence: 99%

“…Pacritinib has been associated with less myelosuppression and hematologic improvement, 1 , 11 , 12 possibly related to its unique kinome profile as an inhibitor of two inflammatory mediators, interleukin-1 receptor–associated kinase 1 (IRAK1), and activin receptor-like kinase 2, also known as activin A receptor type 1 (ACVR1). 13 , 14 …”

Section: Introductionmentioning

confidence: 99%

Long-Term Hematologic Improvement in a Patient With Cytopenic Myelofibrosis Treated With Pacritinib

Yacoub

Mesa

2023

JCO Precision Oncology

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Hepcidin is elevated in primary and secondary myelofibrosis and remains elevated in patients treated with ruxolitinib

Cited by 13 publications

References 17 publications

A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis

A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis

Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms

Long-Term Hematologic Improvement in a Patient With Cytopenic Myelofibrosis Treated With Pacritinib

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