Ruxolitinib for Myelofibrosis

doi:10.1056/nejmc1203704

Cited by 15 publications

(7 citation statements)

References 28 publications

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“…The mainstay of treatment for the MPNa included hydroxyurea, as well as JAK inhibitors in MF patients. Reduction in grade-2 varices to grade-1 was noted in a case report on a patient treated in COMFORT-II trial 17 . Our patients did not have any meaningful change in grade of varices after treatment with JAK1/2 inhibitor.…”

Section: Discussionmentioning

confidence: 83%

Clinical Features of Patients With Philadelphia-Negative Myeloproliferative Neoplasms Complicated by Portal Hypertension

Yan

Geyer

Mesa

et al. 2015

Clinical Lymphoma Myeloma and Leukemia

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Backgroud Portal hypertension (PHTN) has been reported to afflict 7-18% of patients with Philadelphia-negative myeloproliferative neoplasms (MPNs), with complications of variceal bleeding and ascites. The clinical features and outcomes of these patients are unclear. Patients and Methods In this multi-centre retrospective study, we evaluated the clinical features of 51 patients with MPNs complicated by PHTN. Results The diagnosis of underlying MPN was most frequently polycythemia vera (PV) (39%) and primary myelofibrosis (MF) (35%), followed by post-PV myelofibrosis (18%), essential thrombocythemia (ET) (4%) and post-ET myelofibrosis (4%). Frequency of JAK2 V617F mutation appears as expected in the underlying MPN. Thrombosis within the splanchnic circulation was prevalent in patients with polycythemia compared to other MPNs (76% vs. 26%, p=0.0007). Conclusions PV and MF patients have a higher incidence of PHTN in our population, with thrombosis contributing to PHTN development in PV patients. Patients with splanchnic circulation thrombosis are potential candidates for screening for portal hypertension. These data may be useful for developing screening strategies for early detection of PHTN in patients with MPN.

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Section: Discussionmentioning

confidence: 83%

Clinical Features of Patients With Philadelphia-Negative Myeloproliferative Neoplasms Complicated by Portal Hypertension

Yan

Geyer

Mesa

et al. 2015

Clinical Lymphoma Myeloma and Leukemia

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“…In view of these findings, we tested the effects of ruxolitinib (INCB01842), one of the first oral JAK1 and JAK2 inhibitors with clinical activity, 27 , 28 on the ability of IHCA-associated gp130 mutants to activate STAT3. The treatment of Hep3B cells with ruxolitinib impaired the capacity of all nine IHCA-associated gp130 mutants to signal to STAT3 in a dose-dependent fashion, with an IC 50 of ~50 nM (Fig.…”

Section: Resultsmentioning

confidence: 99%

Biochemical and functional analyses of gp130 mutants unveil JAK1 as a novel therapeutic target in human inflammatory hepatocellular adenoma

et al. 2013

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Inflammatory hepatocellular adenomas (IHCAs) are benign liver lesions that can be characterized histologically by the presence of an inflammatory infiltrate and at the molecular level by the overexpression of acute phase inflammatory response genes. Recurrent somatic mutations of the interleukin-6 (IL-6) signal transducer (IL6ST) locus, encoding the critical component of the IL-6 signal transduction machinery gp130, are present in 60% of IHCAs and in a subset (2%) of hepatocellular carcinoma (HCCs). By screening of 256 human hepatic adenoma specimens (the largest genetic analysis of IL6ST performed to date in this setting), we identified 24 distinct somatic IL6ST mutations among 66 mutant adenomas. The functional analysis of nine different gp130 mutants expressed in hepatic cancer cell lines consistently revealed the constitutive and IL-6-independent activation of the JAK/STAT signaling pathway. We further demonstrated that the signaling activity of mutant gp130 in IHCA remains responsive to suppressor of cytokine signaling 3 (SOCS3), a physiological gp130 inhibitor. Specifically, cells expressing a double mutant variant of gp130 with a disrupted SOCS3-binding site at residue 759 (Y186/Y759F) displayed a hyperactivation of signal transducer and activator of transcription 3 (STAT3) as compared with cells expressing the endogenous IHCA-associated Y186 gp130 mutant. Notably, we identified that constitutive signaling via gp130 in IHCA requires the Janus kinase family member JAK1, but not JAK2 or tyrosine kinase 2. In support of this notion, AG490, a tyrosine kinase inhibitor that selectively blocks JAK2, had no effect on gp130 activity. In stark contrast, we showed that ruxolitinib, a JAK1/JAK2-selective tyrosine kinase inhibitor used to treat patients with myelofibrosis, dramatically impaired JAK1-STAT signaling downstream of all IHCA-associated gp130 mutants. In conclusion, our findings provide a rationale for the use of JAK1 inhibitors for the treatment of HCAs expressing mutant gp130 as well as a subset of HCCs that bear similar mutations.

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“…29 Ruxolitinib binds in the adenosine triphosphate–binding pocket of JAK2, which is distinct from the region of JAK2 that contains the V617F mutation; therefore, it inhibits both mutant and wild-type JAK2. Ruxolitinib also inhibits JAK1.…”

Section: Ruxolitinibmentioning

confidence: 99%

“…In addition, any clinical benefit of ruxolitinib on JAK2V617F allele burden should be interpreted with caution, although this question is being investigated in an ongoing study. 31 …”

Section: Ruxolitinibmentioning

confidence: 99%

Ruxolitinib: An Oral Janus Kinase 1 and Janus Kinase 2 Inhibitor in the Management of Myelofibrosis

Verstovšek

2013

Postgraduate Medicine

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Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are referred to as the classic Philadelphia chromosome (BCR-ABL1)-negative myeloproliferative neoplasms. Although each has distinct pathologic features, all 3 display alterations in Janus kinase (JAK) signal transduction activator of transcription signaling. Myelofibrosis is the most serious of the 3, associated with shortened survival (median survival, 5–7 years); bone marrow failure with anemia; progressive splenomegaly; and chronic, burdensome symptoms, including fatigue, night sweats, itching, abdominal discomfort, loss of appetite/early satiety, unintentional weight loss, and bone, chest, and abdominal pain. Treatments for MF have been mainly palliative, with the exception of allogeneic stem cell transplantation, which, although potentially curative, is feasible only in a small subpopulation of patients. In November 2011, ruxolitinib, an inhibitor of JAK1 and JAK2, was approved by the US Food and Drug Administration for the treatment of intermediate- or high-risk MF, including primary MF, post-PV MF, and post-ET MF. In clinical trials, ruxolitinib was shown to reduce spleen volume and improve MF-related symptoms and quality-of-life measures. Evidence also suggests that ruxolitinib therapy has a survival advantage over placebo and best available therapy. Thrombocytopenia and anemia were the most common adverse events with treatment. Ongoing trials are assessing the efficacy and safety of ruxolitinib therapy in patients with PV and ET.

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Ruxolitinib for Myelofibrosis

Cited by 15 publications

References 28 publications

Clinical Features of Patients With Philadelphia-Negative Myeloproliferative Neoplasms Complicated by Portal Hypertension

Clinical Features of Patients With Philadelphia-Negative Myeloproliferative Neoplasms Complicated by Portal Hypertension

Biochemical and functional analyses of gp130 mutants unveil JAK1 as a novel therapeutic target in human inflammatory hepatocellular adenoma

Ruxolitinib: An Oral Janus Kinase 1 and Janus Kinase 2 Inhibitor in the Management of Myelofibrosis

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