Efficacy and safety of ruxolitinib in intermediate‐1 IPSS risk myelofibrosis patients: Results from an independent study

Palandri, Francesca; Tiribelli, Mario; Benevolo, Giulia; Tieghi, Alessia; Cavazzini, Francesco; Breccia, Massimo; Bergamaschi, Micaela; Sgherza, Nicola; Polverelli, Nicola; Crugnola, Monica; Isidori, Alessandro; Binotto, Gianni; Heidel, Florian H.; Buccisano, Francesco; Martino, Bruno; Latagliata, Roberto; Spinsanti, Marco; Kallenberg, Lydia; Palumbo, Giuseppe A.; Abruzzese, Elisabetta; Scaffidi, Luigi; Cuneo, Antonio; Cavo, Michèle; Vianelli, Nicola; Bonifacio, Massimiliano

doi:10.1002/hon.2429

Cited by 35 publications

(42 citation statements)

References 23 publications

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“…There is also considerable evidence that ruxolitinib is more efficacious when initiated earlier in the disease process. 27 37 38 51 As such, continued efforts to develop JAK inhibitors with improved characteristics over the two currently registered makes sense, as does the development of novel, ruxolitinib- and fedratinib-based combinations. Although many agents with distinct mechanisms of action are being explored as monotherapy after “failure” of ruxolitinib (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

“… 35 36 Finally, although only intermediate-2 and high risk patients were included in the COMFORT trials, a large body of data supports the use of ruxolitinib in patients with intermediate-1 risk disease, in whom it may be more effective and less toxic. 37 38 39 40 While technically not approved in the US for use in low risk patients, consensus guidelines from the National Comprehensive Cancer Network support the use of ruxolitinib under certain circumstances, such as in symptomatic, low risk patients. 41 However, guidelines from the European LeukemiaNet and the Italian Society of Hematology do not recommend the use of ruxolitinib with a goal of improving survival in the absence of significant splenomegaly or symptoms.…”

Section: Ruxolitinibmentioning

confidence: 99%

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JAK Inhibition for the Treatment of Myelofibrosis: Limitations and Future Perspectives

Bose

Verstovšek

2020

HemaSphere

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The 2011 approval of ruxolitinib ushered in the Janus kinase (JAK) inhibitor era in the treatment of myelofibrosis (MF), and 2019 saw the US approval of fedratinib. The first therapeutic agents approved by regulatory authorities for MF, these drugs attenuate the overactive JAK-signal transducer and activator of transcription (STAT) signaling universally present in these patients, translating into major clinical benefits in terms of spleen shrinkage and symptom improvement. These, in turn, confer a survival advantage on patients with advanced disease, demonstrated in the case of ruxolitinib, for which long-term follow-up data are available. However, JAK inhibitors do not improve cytopenias in most patients, have relatively modest effects on bone marrow fibrosis and driver mutation allele burden, and clinical resistance eventually develops. Furthermore, they do not modify the risk of transformation to blast phase; indeed, their mechanism of action may be more anti-inflammatory than truly disease-modifying. This has spurred interest in rational combinations of JAK inhibitors with other agents that may improve cytopenias and drugs that could potentially modify the natural history of MF. Newer JAK inhibitors that are distinguished from ruxolitinib and fedratinib by their ability to improve anemia (eg, momelotinib) or safety and efficacy in severely thrombocytopenic patients (eg, pacritinib) are in phase 3 clinical trials. There is also interest in developing inhibitors that are highly selective for mutant JAK2, as well as “type II” JAK2 inhibitors. Overall, although current JAK inhibitors have limitations, they will likely continue to form the backbone of MF therapy for the foreseeable future.

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Section: Discussionmentioning

confidence: 99%

Section: Ruxolitinibmentioning

confidence: 99%

JAK Inhibition for the Treatment of Myelofibrosis: Limitations and Future Perspectives

Bose

Verstovšek

2020

HemaSphere

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“…Two cases of tuberculosis were reported in the extended‐phase publication of COMFORT II (Colomba et al , ; Harrison et al , ) and five cases occurred in the primary analysis of the phase IIIb JUMP trial (Al‐Ali et al , ). Furthermore, 11 case reports (Lee et al , ; Hopman et al , ; Chen et al , ; Keizer et al , ; Palandri et al , ; Shamil et al , ; Abidi et al , ; Branco et al , ; Malkan & Haznedaroglu, ; Tsukamoto et al , ; Lescuyer et al , ) described 14 patients experiencing mycobacterial infections in patients treated with ruxolitinib outside of a clinical trial, including a case of Mycobacterium avium complex (MAC) disease; another case was reported in a retrospective study (Palandri et al , ). The vast majority of these mycobacterial infections developed in the absence of specific prophylaxis.…”

Section: Clinical Scenario 3 Tuberculosis Reactivation Riskmentioning

confidence: 99%

A journey through infectious risk associated with ruxolitinib

Sant’Antonio

Bonifacio

Breccia³

et al. 2019

Br J Haematol

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Summary Ruxolitinib has proved to be effective for the treatment of patients with myelofibrosis (either primary or secondary) and polycythaemia vera, and its approval led to a significant change in the current treatment algorithm. Despite its efficacy and beyond its well described haematological toxicity, a peculiar immunosuppressive effect emerged as our clinical experience grew, both within and outside of a clinical trial setting. Definite and negative interactions with multiple pathways of the immune system of patients have been reported so far, involving both adaptive and innate immune responses. These pathophysiological mechanisms may contribute to the increased risk of reactivation of silent infections (e.g., tuberculosis, hepatitis B virus and varicella zoster virus) that have been associated with the drug. Even though such infectious events may be fatal or may lead to significant impairment of organ function, compromising the eligibility of patients for an allotransplant procedure, there are no dedicated guidelines that may help us in assessing and managing the risk of developing serious infections. On this basis, our aim for the present work was to review the current knowledge on the pathophysiological mechanisms through which ruxolitinib may exert its immunosuppressive effect, and to illustrate our personal approach to the management of three peculiar clinical scenarios, for which a risk‐based algorithm is suggested.

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“…JAK1-2 inhibitor treatment with ruxolitinib reduces disease- related symptoms and splenomegaly, and it may prolong survival in patients with MF. 13 , 14 , 16 , 18 , 19 Furthermore, ruxolitinib reduces elevated blood cell counts and symptom burden in patients with PV. 15 , 17 Inflammation is a critical element of myeloproliferative neoplasms, and the effect of ruxolitinib seems to be mediated mainly by antiinflammatory mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Ruxolitinib and interferon-α2 combination therapy for patients with polycythemia vera or myelofibrosis: a phase II study

et al. 2020

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We report the final 2-year end-of-study results from the first clinical trial investigating combination treatment with ruxolitinib and low-dose pegylated interferon-α2 (PEG-IFNα2). The study included 32 patients with polycythemia vera and 18 with primary or secondary myelofibrosis; 46 patients were previously intolerant of or refractory to PEGIFNα2. The primary outcome was efficacy, based on hematologic parameters, quality of life measurements, and JAK2 V617F allele burden. We used the 2013 European LeukemiaNet and International Working Group- Myeloproliferative Neoplasms Research and Treatment response criteria, including response in symptoms, splenomegaly, peripheral blood counts, and bone marrow. Of 32 patients with polycythemia vera, ten (31%) achieved a remission which was a complete remission in three (9%) cases. Of 18 patients with myelofibrosis, eight (44%) achieved a remission; five (28%) were complete remissions. The cumulative incidence of peripheral blood count remission was 0.85 and 0.75 for patients with polycythemia vera and myelofibrosis, respectively. The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score decreased from 22 [95% confidence interval (95% CI):, 16-29] at baseline to 15 (95% CI: 10-22) after 2 years. The median JAK2 V617F allele burden decreased from 47% (95% CI: 33-61%) to 12% (95% CI: 6-22%), and 41% of patients achieved a molecular response. The drop-out rate was 6% among patients with polycythemia vera and 32% among those with myelofibrosis. Of 36 patients previously intolerant of PEG-IFNα2, 31 (86%) completed the study, and 24 (67%) of these received PEG-IFNα2 throughout the study. In conclusion, combination treatment improved cell counts, reduced bone marrow cellularity and fibrosis, decreased JAK2 V617F burden, and reduced symptom burden with acceptable toxicity in several patients with polycythemia vera or myelofibrosis. #EudraCT2013-003295-12.

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Efficacy and safety of ruxolitinib in intermediate‐1 IPSS risk myelofibrosis patients: Results from an independent study

Cited by 35 publications

References 23 publications

JAK Inhibition for the Treatment of Myelofibrosis: Limitations and Future Perspectives

JAK Inhibition for the Treatment of Myelofibrosis: Limitations and Future Perspectives

A journey through infectious risk associated with ruxolitinib

Ruxolitinib and interferon-α2 combination therapy for patients with polycythemia vera or myelofibrosis: a phase II study

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