Efficacy and safety of ruxolitinib in the treatment of patients with myelofibrosis

Yi, Cecilia Arana; Tam, Constantine S.; Verstovšek, Srđan

doi:10.2217/fon.14.272

Cited by 60 publications

(29 citation statements)

References 89 publications

(143 reference statements)

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“…Our study is comparable to other studies where the initial support of ruxolitinib was based on the consequences of two essential phase III clinical trials, restricted MF study with oral JAK inhibitor management (COMFORT)-I and -II [17,18]. Ruxolitinib reduced inflammatory cytokines circulating levels, eliminated neoplastic cells and prolonged myeloproliferative neoplasm survival [19,20]. The inflammatory cytokines gene might be probable to be up regulated in PMF as well.…”

Section: Discussionsupporting

confidence: 82%

INTERLEUKIN 1β LEVEL AND C- REACTIVE PROTEIN ROLES IN PRIMARY MYELOFIBROSIS PATIENTS TREATED WITH HYDROXYUREA AND RUXOLITINIB

Matti¹,

Sabir²,

Khaleq³

et al. 2017

Int. Res. J. Pharm.

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Primary Myelofibrosis (PMF) is one of development of the myeloproliferative neoplasms that occurs during change in the DNA of a single hematopoietic stem cell. About 50 % of people with MF have an alteration called V617F JAK2 that initiate in the Janus kinases (JAK2) gene. The gene alteration causes unusual signaling in the JAK pathway, which regulates the production of blood cell. There is many theories suggesting the deregulated irritation and immune genes have a role in patients with myeloproliferative neoplasm (MPN). Aim of this study is to characterize the serum levels of IL-1β and C-reactive protein in PMF patients, also to assess their relationship to the treatments and to the spleen size between different patients of PMF received hydroxyurea and ruxolitinib. The study was conducted between November 2014 up to September 2015, during this period 60 Iraqi patients of primary myelofibrosis receiving hydroxyurea for at least 6 months are taken and 30 samples were also taken from healthy persons as control group. Ultarsongraphy of abdomen to assess the spleen size and peripheral blood indices were taken from patient's records at time of sampling. Screening for interleukin 1β level and C-reactive protein were performed to all patients. Out of these 60 patients, 10 patients with high interleukin 1β level and high C-reactive protein switched to received ruxolitinib therapy to determine its effect in correlation with hydroxurea treated patients and control patients. There was significantly lower IL-1β and CRP in control normal group compared to both patients groups. Patients received ruxolitinib treatment had lower IL-1β and CRP compare to hydroxyurea group but it was not statistically significant. The relationship between CRP and IL 1β in all studied group was significant with non-linear relationship between CRP and IL-1β and only patients on hydroxyurea had significant relationship between CRP and IL-1β. In patients with PMF there ishigh level of IL 1βlevel and C reactive protein which may have a role in the pathogenesis of the disease and new treatment of PMF like ruxolotinib may have ability to reduce their levels through controlling the disease pathogensis, further follow-up and larger sample is needed to assess the cytokine levels on long term follow up.

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Section: Discussionsupporting

confidence: 82%

INTERLEUKIN 1β LEVEL AND C- REACTIVE PROTEIN ROLES IN PRIMARY MYELOFIBROSIS PATIENTS TREATED WITH HYDROXYUREA AND RUXOLITINIB

Matti¹,

Sabir²,

Khaleq³

et al. 2017

Int. Res. J. Pharm.

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“…While ruxolitinb has been known to correlate with decreased spleen size, improved quality of life and overall survival benefit,17 18 the imaging features of EMH on ruxolitinib has also not been reported previously in any of these case reports. On 2 years follow-up, there was no significant decrease in the size of spleen.…”

Section: Discussionmentioning

confidence: 71%

Idiopathic myelofibrosis with disseminated hepatosplenic, mesenteric, renal and pulmonary extramedullary haematopoeisis, portal hypertension and tuberculosis: initial presentation and 2 years follow-up

2016

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A 35-year-old man with a 12-year history of idiopathic myelofibrosis (IMF) presented in 2014 with fatigue and abdominal distension. CT scan revealed massive hepatosplenomegaly with focal splenic lesions, soft tissue around renal pelvis, mesenteric masses compressing bowel loops and perilymphatic nodules in lungs. There was portal hypertension, ascites, pleural effusion, bilateral psoas abscesses and necrotic retroperitoneal lymphadenopathy. MRI additionally revealed hypointense periportal infiltrative lesions in liver, not seen on CT scan. None of these lesions showed diffusion restriction. Biopsy from mesenteric masses revealed extramedullary haematopoeisis. Aspiration from psoas abscess confirmed tuberculosis. Follow-up after 6 weeks of ruxolitinib (JAK2 tyrosine kinase inhibitor) and 9 months of antitubercular therapy revealed resolution of psoas abscesses and lymph nodes. Mild reduction was noted in mesenteric masses and ascites while perirenal soft tissue had increased. Follow-up imaging after another 1 year of ruloxitinib showed new-onset bilateral paravertebral and presacral foci of extramedullary haematopoeisis.

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“…Ruxolitinib is a JAK inhibitor currently approved for the treatment of JAK-STAT dependent myeloproliferative syndromes (MFI, in both USA and Europe) and graft-versus-host disease (USA). As previously explained, due to its mechanism of action, the drug presents potent immunosuppressive and anti-inflammatory properties on both innate (dendritic cells, macrophages, and neutrophils) and adaptive (T cells) immune effectors ( 71 – 74 ) and reduces the secretion of several pro-inflammatory mediators including IL-6 and TNF-alpha ( 75 ). Additionally, thanks to it safety profile, ruxolitinib has been shown to be suitable even for elderly population with myelofibrosis ( 76 ).…”

Section: Targeting the Jak Signaling: The Promise Of Ruxolitinibmentioning

confidence: 99%

COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm

et al. 2021

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Since SARS-CoV-2 outbreak in December 2019, world health-system has been severely impacted with increased hospitalization, Intensive-Care-Unit (ICU) access and high mortality rates, mostly due to severe acute respiratory failure and multi-organ failure. Excessive and uncontrolled release of proinflammatory cytokines (cytokine release/storm syndrome, CRS) have been linked to the development of these events. The recent advancements of immunotherapy for the treatment of hematologic and solid tumors shed light on many of the molecular mechanisms underlying this phenomenon, thus rendering desirable a multidisciplinary approach to improve COVID-19 patients’ outcome. Indeed, currently available therapeutic-strategies to overcome CRS, should be urgently evaluated for their capability of reducing COVID-19 mortality. Notably, COVID-19 shares different pathogenic aspects with acute graft-versus-host-disease (aGVHD), hemophagocytic-lymphohistiocytosis (HLH), myelofibrosis, and CAR-T-associated CRS. Specifically, similarly to aGVHD, an induced tissue damage (caused by the virus) leads to increased cytokine release (TNFα and IL-6) which in turn leads to exaggerated dendritic cells, macrophages (like in HLH) and lymphocytes (as in CAR-T) activation, immune-cells migration, and tissue-damage (including late-stage fibrosis, similar to myelofibrosis). Janus Kinase (JAK) signaling represents a molecular hub linking all these events, rendering JAK-inhibitors suitable to limit deleterious effects of an overwhelming inflammatory-response. Accordingly, ruxolitinib is the only selective JAK1 and JAK2-inhibitor approved for the treatment of myelofibrosis and aGVHD. Here, we discuss, from a molecular and hematological point of view, the rationale for targeting JAK signaling in the management of COVID-19 patients and report the clinical results of a patient admitted to ICU among the firsts to be treated with ruxolitinib in Italy.

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Efficacy and safety of ruxolitinib in the treatment of patients with myelofibrosis

Cited by 60 publications

References 89 publications

INTERLEUKIN 1β LEVEL AND C- REACTIVE PROTEIN ROLES IN PRIMARY MYELOFIBROSIS PATIENTS TREATED WITH HYDROXYUREA AND RUXOLITINIB

INTERLEUKIN 1β LEVEL AND C- REACTIVE PROTEIN ROLES IN PRIMARY MYELOFIBROSIS PATIENTS TREATED WITH HYDROXYUREA AND RUXOLITINIB

Idiopathic myelofibrosis with disseminated hepatosplenic, mesenteric, renal and pulmonary extramedullary haematopoeisis, portal hypertension and tuberculosis: initial presentation and 2 years follow-up

COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm

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