Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study

Harrison, Claire; Schaap, Nicolaas; Vannucchi, Alessandro M.; Kiladjian, Jean‐Jacques; Tiu, Ramon V.; Zachée, Pierre; Jourdan, Éric; Winton, Elliott F.; Silver, Richard T.; Schouten, Harry C.; Passamonti, Francesco; Zweegman, Sonja; Talpaz, Moshe; Lager, Joanne; Shun, Zhenming; Mesa, Ruben A.

doi:10.1016/s2352-3026(17)30088-1

Cited by 261 publications

(203 citation statements)

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“…13 A second study of 64 patients treated in a real-life comparison confirmed that responses to salvage treatments are rare. 14 Understanding that the outcome after ruxolitinib is important for identifying patients who may benefit from specific interventions, such as allogeneic stem cell transplantation, 15 second-generation JAK inhibitors, [16][17][18] drugs with alternative mechanisms of action, 19,20 or investigational agents in combination with ruxolitinib. 21 Here, we report the outcome of 218 patients after ruxolitinib.…”

Section: Introductionmentioning

confidence: 99%

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis

Palandri

Breccia

Bonifacio

et al. 2019

Cancer

113

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Background After discontinuing ruxolitinib, the outcome of patients with myelofibrosis reportedly has been poor. The authors investigated whether disease characteristics before the receipt of ruxolitinib may predict drug discontinuation in patients with myelofibrosis and whether reasons for drug discontinuation, disease phase at discontinuation, and salvage therapies may influence the outcome. Methods A centralized electronic clinical database was created in 20 European hematology centers, including clinical and laboratory data for 524 patients who received ruxolitinib for myelofibrosis. Results At 3 years, 40.8% of patients had stopped ruxolitinib. Baseline predictors of drug discontinuation were: intermediate‐2–risk/high‐risk category (Dynamic International Prognostic Score System), a platelet count <100 ×109 per liter, transfusion dependency, and unfavorable karyotype. At last contact, 268 patients (51.1%) had discontinued therapy, and the median drug exposure was 17.5 months. Fifty patients (18.7%) died while taking ruxolitinib. The reasons for discontinuation in the remaining 218 patients were the lack (22.9%) or loss (11.9%) of a spleen response, ruxolitinib‐related adverse events (27.5%), progression to blast phase (23.4%), ruxolitinib‐unrelated adverse events (9.2%), and allogeneic transplantation during response (5.1%). The median survival after ruxolitinib was 13.2 months and was significantly better in the 167 patients who discontinued ruxolitinib in chronic phase (27.5 vs 3.9 months for those who discontinued in blast phase; P < .001). No survival differences were observed among patients who discontinued ruxolitinib in chronic phase because of lack of response, loss of response, or ruxolitinib‐related adverse events. The use of investigational agents and/or ruxolitinib rechallenge were associated with improved outcome. Conclusions The survival of patients with myelofibrosis after discontinuation of ruxolitinib is poor, particularly for those who discontinue in blast phase. Salvage therapies can improve outcome, emphasizing the need for novel therapies.

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Section: Introductionmentioning

confidence: 99%

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis

Palandri

Breccia

Bonifacio

et al. 2019

Cancer

113

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“…Very recently, Fedratinib has been FDA approved for intermediate‐2 and high‐risk myelofibrosis, but its clinical development had been prematurely discontinued due to a full clinical hold, placed in 2013, and lifted in 2017. FDA hold was placed when accrual of JAKARTA‐2 had just been completed, so that patients received a median of six cycles of treatment while on trial, while the median duration of fedratinib exposures in JAKARTA were 28 to 30 weeks …”

Section: Resultsmentioning

confidence: 99%

“…FDA hold was placed when accrual of JAKARTA-2 had just been completed, so that patients received a median of six cycles of treatment while on trial, while the median duration of fedratinib exposures in JAKARTA were 28 to 30 weeks. 82,83 Moreover, many patients treated with JAK inhibitors were pretreated with hydroxyurea or with alkylating agents; thus, the risk of LPN could be the result of a cumulative phenomenon of immunosuppression and dysregulated immunological surveillance.…”

Section: Resultsmentioning

confidence: 99%

Myeloproliferative and lymphoproliferative disorders: State of the art

Rumi

Baratè

Benevolo

et al. 2019

Hematological Oncology

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Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal disorders complicated mainly by vascular events and transformation to myelofibrosis (for PV and ET) or leukemia. Although secondary malignancies, in particular, lymphoproliferative disorders (LPNs), are rare, they occur at a higher frequency than found in the general population, and there has been recent scientific discussion regarding a hypothetical relationship between treatment with JAK inhibitors in MPN and the risk of development of LPN. This has prompted increased interest regarding the coexistence of MPN and LPN. This review focuses on the role of JAK2 and the JAK/STAT pathway in MPN and LPN, whether there is a role for the genetic background in the occurrence of both MPN and LPN and whether there is a role for cytoreductive drugs in the occurrence of both MPN and LPN. Furthermore, whether an increased risk of lymphoma development is limited to patients who receive the JAK inhibitor ruxolitinib, is a more general phenomenon that occurs following JAK1/2 inhibition or is associated with preferential JAK1 or JAK2 targeting is discussed.

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“…As illustration, fedratinib, a JAK2 inhibitor, was previously shown to be superior to placebo for control of splenomegaly and symptoms in patients with MF in the Jakarta 1 and 2 studies. 70 Further development of fedratinib was discontinued in November 2013 due to concerns of Wernicke's encephalopathy (WE) observed in 8 of the 877 total patients treated with fedratinib. However, a reanalysis in late 2017 suggested that only one of these eight patients met the diagnostic criteria for WE, and the drug is now being redeveloped.…”

Section: Sm In the Midostaurin Eramentioning

confidence: 99%

“…The majority of other Type 1 JAK2 inhibitors have had their clinical development discontinued largely due to the emergence of serious neurotoxicity. As illustration, fedratinib, a JAK2 inhibitor, was previously shown to be superior to placebo for control of splenomegaly and symptoms in patients with MF in the Jakarta 1 and 2 studies . Further development of fedratinib was discontinued in November 2013 due to concerns of Wernicke's encephalopathy (WE) observed in 8 of the 877 total patients treated with fedratinib.…”

Section: Introductionmentioning

confidence: 99%

Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms

Mughal

Pemmaraju

Radich

et al. 2019

Hematological Oncology

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The 60th American Society of Hematology (ASH) held in San Diego in December 2018 was followed by the 13th Post‐ASH chronic myeloproliferative neoplasms (MPNs) workshop on December 4 and 5, 2018. This closed annual workshop, first introduced in 2006 by Goldman and Mughal, was organized in collaboration with Alpine Oncology Foundation and allowed experts in preclinical and clinical research in the chronic MPNs to discuss the current scenario, including relevant presentations at ASH, and address pivotal open questions that impact translational research and clinical management. This review is based on the presentations and deliberations at this workshop, and rather than provide a resume of the proceedings, we have selected some of the important translational science and treatment issues that require clarity. We discuss the experimental and observational evidence to support the intimate interaction between aging, inflammation, and clonal evolution of MPNs, the clinical impact of the unfolding mutational landscape on the emerging targets and treatment of MPNs, new methods to detect clonal heterogeneity, the challenges in managing childhood and adolescent MPN, and reflect on the treatment of systemic mastocytosis (SM) following the licensing of midostaurin.

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Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study

Abstract: Sanofi.

Cited by 261 publications

References 20 publications

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis

Myeloproliferative and lymphoproliferative disorders: State of the art

Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms

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