The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis

Deininger, Michael W.; Radich, Jerald P.; Burn, Timothy C.; Huber, Reid; Paranagama, Dilan; Verstovšek, Srđan

doi:10.1182/blood-2015-03-635235

Cited by 156 publications

(132 citation statements)

References 18 publications

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“…45,46 Long-term therapy may halt bone marrow fibrosis, and gradual decreases in mutant allele burden are seen. 47,48 Complete histopathological and/or molecular remission has rarely been observed. 48,49 Finally, recent data suggest that the likelihood of treatment success and durability, that is, the likelihood of achieving spleen response and time to treatment failure, diminishes incrementally with the presence of multiple adverse prognostic mutations.…”

Section: Jak Inhibition Targeted Therapy For Mpnmentioning

confidence: 99%

Emerging treatments for classical myeloproliferative neoplasms

Vannucchi

Harrison

2017

Blood

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There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients’ major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibrosis. Raised awareness of the molecular abnormalities and cellular pathways involved in the pathogenesis of MPN is facilitating the development of clinical trials with novel target drugs, either alone or in combination with ruxolitinib. Although for most of these molecules a convincing preclinical rationale was provided, the results of early phase 1 and 2 clinical trials have been quite disappointing to date, and toxicities sometimes have been limiting. In this review, we critically illustrate the current landscape of novel therapies that are under evaluation for patients with MPN on the basis of current guidelines, patient risk stratification criteria, and previous experience, looking ahead to the chance of a cure for these disorders.

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Section: Jak Inhibition Targeted Therapy For Mpnmentioning

confidence: 99%

Emerging treatments for classical myeloproliferative neoplasms

Vannucchi

Harrison

2017

Blood

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“…However, in the large majority of patients, ruxolitinib does not markedly reduce the JAK2 V617F allele burden (%V617F) 5, 6, 7…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of combination therapy of interferon‐α2 and ruxolitinib in polycythemia vera and myelofibrosis

et al. 2018

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Interferon‐α2 reduces elevated blood cell counts and splenomegaly in patients with myeloproliferative neoplasms (MPN) and may restore polyclonal hematopoiesis. Its use is limited by inflammation‐mediated toxicity, leading to treatment discontinuation in 10‐30% of patients. Ruxolitinib, a potent anti‐inflammatory agent, has demonstrated benefit in myelofibrosis (MF) and polycythemia vera (PV) patients. Combination therapy (CT) with these two agents may be more efficacious than monotherapy with either, potentially improving tolerability of interferon‐α2 as well. We report the preliminary results from a phase II study of CT with pegylated interferon‐α2 and ruxolitinib in 50 MPN patients (PV, n = 32; low‐/intermediate‐1‐risk MF, n = 18), the majority (n = 47) being resistant and/or intolerant to interferon‐α2 monotherapy. Objectives included remission (2013 revised criteria encompassing histologic, hematologic, and clinical responses), complete hematologic response (CHR), molecular response, and toxicity. Follow‐up was 12 months. Partial remission (PR) and sustained CHR were achieved in 9% and 44% of PV patients, respectively. In MF patients, complete or partial remission was achieved in 39%, and sustained CHR in 58%. The median JAK2V617F allele burden declined significantly in both groups. Hematologic toxicity was the most common adverse event and was managed by dose reduction. Thirty‐seven serious adverse events were recorded in 23 patients; the discontinuation rate was 20%. We conclude that CT with interferon‐α2 and ruxolitinib is efficacious in patients with low‐/intermediate‐1‐risk MF and, to a lesser extent, in patients with PV. These preliminary results encourage phase III studies as well as a study with CT in newly diagnosed MPN patients.

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“…Ruxolitinib is a Janus kinase inhibitor which inhibits the dysregulated JAK signaling. [2][3][4] Ruxolitinib as a JAK1 and JAK2 inhibitor drug has recently been approved for the treatment of patients with high-or intermediate-risk myelofibrosis (MF) with symptomatic splenomegaly. 5 This approval in MF depends upon two different phase 3 randomized clinical trials (RCT) namely COMFORT-I and COMFORT-II.…”

Section: Introductionmentioning

confidence: 99%

The Impact of Jak1/Jak2 Inhibitor Ruxolitinib on the Spleen Size and Symptom Burden in Myeloproliferative Diseases.

Aktimur¹

2016

UHOD

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Ruxolitinib as a JAK1 and JAK2 inhibitor drug has recently been approved for the treatment of patients with high-or intermediate-risk myelofibrosis with symptomatic splenomegaly. Clinical development of ruxolitinib has currently focused on the Ph* negative myeloproliferative neoplastic disorders (MPN). The aim of this study is to assess the impact of ruxolitinib treatment on the clinical course of Ph* negative myeloproliferative disorders. Forty-three patients who were under ruxolitinib treatment and followed-up between years 1987-2015 in Hacettepe University Medical School Hematology Clinic and Ondokuz Mayis University Hematology Clinic with myeloproliferative disease without Philadephia chromosome translocation were retrospectively analyzed. The constitutional symptoms were decreased in 97% of patients after ruxolitinib treatment. The mean spleen sizes before and after ruxolitinib treatment were 229±35 versus 202±31 mm, respectively (p< 0.001). In this study, we observed a reduction in spleen size after ruxolitinib treatment in Turkish patients with MPN and this reduction was statistically significant. Moreover, nearly all of the MPN patients' constitutional symptoms were improved. Those observations are concordant with other geographical MPN data obtained from different countries. Further experimental and clinical studies into the efficacy and safety of ruxolitinib in patients with MPN are necessary to elucidate its role in special subgroups of MPN patients, such as patients undergoing hematopoietic stem cell transplantation and the patients with vascular disorders such as hepatoportal thrombosis.

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The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis

Abstract: Key Points The JAK2p.V617F mutation leads to constitutive activation of JAK2 and contributes to dysregulated JAK signaling in myelofibrosis. Long-term ruxolitinib treatment decreased JAK2p.V617F allele burden, with some patients achieving complete or partial molecular remissions.

Cited by 156 publications

References 18 publications

Emerging treatments for classical myeloproliferative neoplasms

Emerging treatments for classical myeloproliferative neoplasms

Safety and efficacy of combination therapy of interferon‐α2 and ruxolitinib in polycythemia vera and myelofibrosis

The Impact of Jak1/Jak2 Inhibitor Ruxolitinib on the Spleen Size and Symptom Burden in Myeloproliferative Diseases.

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