Comprehensive Profiling of Clinical JAK2 Inhibitors in Myeloproliferative Neoplasms

Kong, Tim; Yu, LaYow; Laranjeira, Angelo BA; He, Fan; Allen, Maggie J.; Oh, Stephen T.

doi:10.1182/blood-2022-164925

Cited by 3 publications

(7 citation statements)

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“…61 Whether or not reported differences in transcriptional, proteomic, and phenotypic biomarker profiles, including disparately modulated inflammatory cytokine production and immune function, between momelotinib and other JAKi explain differences in their impact on response patterns and toxicity profile remains to be clarified. 62,63 Momelotinib: published clinical reports…”

Section: Momelotinib: Mechanism(s) Of Actionmentioning

confidence: 99%

Momelotinib (JAK1/JAK2/ACVR1 inhibitor): mechanism of action, clinical trial reports, and therapeutic prospects beyond myelofibrosis

2023

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Janus kinase 2 inhibitors (JAKi) are now part of the therapeutic armamentarium for primary and secondary myelofibrosis (MF). Patients with MF endure shortened survival and poor quality of life (QoL). Allogeneic stem cell transplant is currently the only treatment modality in MF with the potential to cure the disease or prolong survival. By contrast, current drug therapy in MF targets QoL and does not modify the natural history of the disease. The discovery of JAK2 and other JAK-STAT activating mutations (i.e., CALR and MPL) in myeloproliferative neoplasms, including MF, has facilitated the development of several JAKi that are not necessarily specific to the oncogenic mutations themselves but proved effective in countering JAK-STAT signaling, resulting in suppression of inflammatory cytokines and myeloproliferation. This non-specific activity resulted in clinically favorable effects on constitutional symptoms and splenomegaly and, consequently, FDA approval of three small molecule JAKi: ruxolitinib, fedratinib, and pacritinib. A fourth JAKi, momelotinib, is poised for FDA approval soon and has been shown to provide additional benefit in alleviating transfusiondependent anemia in MF. The salutary effect of momelotinib on anemia has been attributed to inhibition of activin A receptor, type 1 (ACVR1) and recent information suggests similar effect from pacritinib. ACRV1 mediates SMAD2/3 signalling that contributes to upregulation of hepcidin production and iron-restricted erythropoiesis. Therapeutic targeting of ACRV1 raises therapeutic prospects in other myeloid neoplasms associated with ineffective erythropoiesis, such as myelodysplastic syndromes with ring sideroblasts or SF3B1 mutation, especially those with co-expression of JAK2 mutation and thrombocytosis.

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Section: Momelotinib: Mechanism(s) Of Actionmentioning

confidence: 99%

Momelotinib (JAK1/JAK2/ACVR1 inhibitor): mechanism of action, clinical trial reports, and therapeutic prospects beyond myelofibrosis

2023

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“…In the current edition of AJH, Kong et al provide comparative information on the in vitro antiproliferative and other biologic profiles for the aforementioned four JAKi, including their effect on hepcidin expression. 28 In a series of relevant experiments, the authors show similar antiproliferative activity, which was attributed to on-target JAK2 inhibition and partially ameliorated by IL3-induced sustained JAK-STAT signaling. However, the four drugs also displayed different off-target profiles, including different potencies of antiproliferative activity in JAK2-unmutated MPN, including dual targeting of JAK2/ FLT3 by pacritinib and fedratinib and, to a lesser extent, by momelotinib.…”

mentioning

confidence: 84%

“…Taken together, the above‐highlighted study by Kong et al 28 suggests shared and unique transcriptional and metabolic profiles, among currently available JAKi, which might underlie their differences in the spectrum of clinical activity and side effects. The mechanisms of anemia and those of treatment action in MF are much more complicated than meets the eye and are often confounded by the biological heterogeneity of the disease, which includes incidental mutations and co‐morbidities.…”

mentioning

confidence: 90%

“…The mechanisms of anemia and those of treatment action in MF are much more complicated than meets the eye and are often confounded by the biological heterogeneity of the disease, which includes incidental mutations and co‐morbidities. As suggested from the study by Kong et al, 28 erythropoietic effect from some but not other JAKi is likely a manifestation of their difference in the scope and degree of their inhibitory activity on several signaling pathways, but might also be affected by drug dose. Going forward, it is important to broaden the research targets outside of ACVR1 and acknowledge the fact that other drugs targeting SMAD signaling (e.g., luspatercept) have so far had limited benefit for the treatment of MF‐associated anemia 30 .…”

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confidence: 97%

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confidence: 99%

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JAK2 inhibitor treatment of anemia in myelofibrosis

Tefferi

Vannucchi

2023

American J Hematol

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The primary objective of treatment in myelofibrosis (MF) is a prolongation of life, a feat currently realized only by allogeneic stem cell transplantation, with 3-year post-transplant survival reports exceeding 50%, despite increased utilization of alternative donors and older age distribution of recipients. 1,2 Non-transplant treatment options in MF are currently palliative in scope and target the triad of quality-of-life (QoL) offenders: anemia, splenomegaly, and constitutional symptoms. 3

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Changes in bone marrow fibrosis during momelotinib or ruxolitinib therapy do not correlate with efficacy outcomes in patients with myelofibrosis

Oh,

Verstovsek,

Gupta

et al. 2024

eJHaem

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Bone marrow fibrosis (BMF) is a pathological feature of myelofibrosis, with higher grades associated with poor prognosis. Limited data exist on the association between outcomes and BMF changes. We present BMF data from Janus kinase (JAK) inhibitor–naive patients from SIMPLIFY‐1 (NCT01969838), a double‐blind, randomized, phase 3 study of momelotinib vs ruxolitinib. Baseline and week 24 bone marrow biopsies were graded from 0 to 3 as per World Health Organization criteria. Other assessments included Total Symptom Score, spleen volume, transfusion independence status, and hemoglobin levels. Paired samples were available from 144 and 160 patients randomized to momelotinib and ruxolitinib. With momelotinib and ruxolitinib, transfusion independence was achieved by 87% and 44% of patients with BMF improvement of ≥1 grade and 76% and 56% of those with stable/worsening BMF; there was no association between BMF changes and transfusion independence for either arm (momelotinib, p = .350; ruxolitinib, p = .096). Regardless of BMF changes, hemoglobin levels also generally increased on momelotinib but decreased on ruxolitinib. In addition, no associations between BMF changes and spleen (momelotinib, p = .126; ruxolitinib, p = .407)/symptom (momelotinib, p = .617; ruxolitinib, p = .833) outcomes were noted, and no improvement in overall survival was observed with ≥1‐grade BMF improvement (momelotinib, p = .395; ruxolitinib, p = .407). These data suggest that the anemia benefit of momelotinib is not linked to BMF changes, and question the use of BMF assessment as a surrogate marker for clinical benefit with JAK inhibitors.

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Comprehensive Profiling of Clinical JAK2 Inhibitors in Myeloproliferative Neoplasms

Cited by 3 publications

References 0 publications

Momelotinib (JAK1/JAK2/ACVR1 inhibitor): mechanism of action, clinical trial reports, and therapeutic prospects beyond myelofibrosis

Momelotinib (JAK1/JAK2/ACVR1 inhibitor): mechanism of action, clinical trial reports, and therapeutic prospects beyond myelofibrosis

JAK2 inhibitor treatment of anemia in myelofibrosis

Changes in bone marrow fibrosis during momelotinib or ruxolitinib therapy do not correlate with efficacy outcomes in patients with myelofibrosis

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