Momelotinib expands the therapeutic armamentarium for myelofibrosis: Impact on hierarchy of treatment choices

Tefferi, Ayalew; Pardanani, Animesh; Gangat, Naseema

doi:10.1002/ajh.27163

Cited by 6 publications

(1 citation statement)

References 80 publications

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“…Moreover, MF CD34+ cells harboring calreticulin (CALR) mutation exhibit higher levels of ROS and apoptosis than those with the Janus kinase (JAK) 2617F mutation [17]. JAK inhibitors act by reducing the activity of the JAK-STAT pathway, and the newly approved molecules also evidenced a reduction in the grade of BM fibrosis [18,19].…”

Section: Introductionmentioning

confidence: 99%

Targeted Metabolomics Highlights Dramatic Antioxidant Depletion, Increased Oxidative/Nitrosative Stress and Altered Purine and Pyrimidine Concentrations in Serum of Primary Myelofibrosis Patients

Mangione,

Giallongo,

Duminuco

et al. 2024

Antioxidants

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To date, little is known concerning the circulating levels of biochemically relevant metabolites (antioxidants, oxidative/nitrosative stress biomarkers, purines, and pyrimidines) in patients with primary myelofibrosis (PMF), a rare form of myeloproliferative tumor causing a dramatic decrease in erythropoiesis and angiogenesis. In this study, using a targeted metabolomic approach, serum samples of 22 PMF patients and of 22 control healthy donors were analyzed to quantify the circulating concentrations of hypoxanthine, xanthine, uric acid (as representative purines), uracil, β-pseudouridine, uridine (as representative pyrimidines), reduced glutathione (GSH), ascorbic acid (as two of the main water-soluble antioxidants), malondialdehyde, nitrite, nitrate (as oxidative/nitrosative stress biomarkers) and creatinine, using well-established HPLC method for their determination. Results showed that PMF patients have dramatic depletions of both ascorbic acid and GSH (37.3- and 3.81-times lower circulating concentrations, respectively, than those recorded in healthy controls, p < 0.0001), accompanied by significant increases in malondialdehyde (MDA) and nitrite + nitrate (4.73- and 1.66-times higher circulating concentrations, respectively, than those recorded in healthy controls, p < 0.0001). Additionally, PMF patients have remarkable alterations of circulating purines, pyrimidines, and creatinine, suggesting potential mitochondrial dysfunctions causing energy metabolism imbalance and consequent increases in these cell energy-related compounds. Overall, these results, besides evidencing previously unknown serum metabolic alterations in PMF patients, suggest that the determination of serum levels of the aforementioned compounds may be useful to evaluate PMF patients on hospital admission for adjunctive therapies aimed at recovering their correct antioxidant status, as well as to monitor patients’ status and potential pharmacological treatments.

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Section: Introductionmentioning

confidence: 99%

Targeted Metabolomics Highlights Dramatic Antioxidant Depletion, Increased Oxidative/Nitrosative Stress and Altered Purine and Pyrimidine Concentrations in Serum of Primary Myelofibrosis Patients

Mangione,

Giallongo,

Duminuco

et al. 2024

Antioxidants

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Efficacy, safety, and survival findings after long‐term follow‐up of ZGJAK002: A phase 2 study comparing jaktinib at 100 mg twice daily (BID) and 200 mg once daily (QD) in patients with myelofibrosis

Zhang,

Zhou,

Jiang

et al. 2024

American J Hematol

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Myelofibrosis (MF) is a Philadelphia-negative myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, anemia, splenomegaly, constitutional symptoms, leukemia transformation, and reduced survival. Currently, Janus kinase inhibitors (JAKi) still the recommended first-line treatment for intermediate-and high-risk myelofibrosis. Jaktinib, a deuterated form of momelotinib, 1,2 is a JAK (JAK1, JAK2, JAK3, and TYK2) and ACVR1 inhibitor. It has exhibited promising results in treating patients with MF. Patients treated with jaktinib have shown spleen reduction, symptom relief, and improvement in anemia in both JAKi-naïve (ZGJAK002, 3 ZGJAK016 4 ) and ruxolitinib-intolerant (ZGJAK006 5 ) or -resistant (ZGJAK017 6 ) clinical trials. The ZGJAK002 study is a phase 2 trial aimed at assessing the efficacy and safety of jaktinib at doses of 100 mg BID and 200 mg QD in JAKi-naïve patients with intermediate-or high-risk MF per DIPSS-plus criteria. The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR35) at week 24. The secondary endpoints included symptom response (TSS50, MPN-SAF TSS decreased by ≥50%), improvement of anemia, and safety profile. The initial findings from this study indicate that jaktinib promptly reduces spleen size, enhances symptoms, and alleviates anemia in patients.

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New drugs in myelofibrosis: Critical assessment of additional value to monotherapy with JAK inhibitors

Gangat,

Tefferi

2024

American J Hematol

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Among the JAK2 mutation-prevalent myeloproliferative neoplasms, myelofibrosis (MF) is prognostically the worst with median survival estimates ranging from less than 2 years to over 10 years, depending on the presence or absence of specific genetic and clinical risk factors. 1 Moreover, quality of life (QoL) in MF is severely compromised by progressive anemia, splenomegaly, and constitutional symptoms. At present, the only treatment modality in MF with the potential to cure the disease or prolong survival is allogeneic hematopoietic stem cell transplant. 2 On the other hand, current drug therapy, including that with JAK inhibitors (JAKi), has been shown to be effective in improving QoL by way of alleviating constitutional symptoms, reducing spleen size, reversing cachexia, and, in some instances, resulting in resolution of red cell transfusion need. 3 Ruxolitinib was the first JAKi to receive the United States Food and Drug Administration (FDA) approval in 2011, followed by approval of three additional JAKi, namely, fedratinib (2019), pacritinib (2022), and momelotinib (2023), the latter two in the context of thrombocytopenia (platelet count <50 Â 10 9 /L), and anemia, respectively. 4 All four FDA-approved JAKi alleviate

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Momelotinib expands the therapeutic armamentarium for myelofibrosis: Impact on hierarchy of treatment choices

Cited by 6 publications

References 80 publications

Targeted Metabolomics Highlights Dramatic Antioxidant Depletion, Increased Oxidative/Nitrosative Stress and Altered Purine and Pyrimidine Concentrations in Serum of Primary Myelofibrosis Patients

Targeted Metabolomics Highlights Dramatic Antioxidant Depletion, Increased Oxidative/Nitrosative Stress and Altered Purine and Pyrimidine Concentrations in Serum of Primary Myelofibrosis Patients

Efficacy, safety, and survival findings after long‐term follow‐up of ZGJAK002: A phase 2 study comparing jaktinib at 100 mg twice daily (BID) and 200 mg once daily (QD) in patients with myelofibrosis

New drugs in myelofibrosis: Critical assessment of additional value to monotherapy with JAK inhibitors

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