Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial

Harrison, Claire; Nangalia, Jyoti; Boucher, Rebecca H.; Jackson, Aimee L.; Yap, Christina; O’Sullivan, Jennifer; Fox, Sonia; Ailts, Isaak; Dueck, Amylou C.; Geyer, Holly; Mesa, Ruben A.; Dunn, William G.; Nadezhdin, Eugene; Curto-García, Natalia; Gréen, Anna; Wilkins, Bridget S.; Coppell, Jason; Laurie, John; Garg, Mamta; Ewing, Joanne; Knapper, Steven; Crowe, Josephine; Chen, Frederick; Koutsavlis, Ioannis; Godfrey, Anna L.; Arami, Siamak; Drummond, Mark; Byrne, J L; Clark, Fiona; Mead-Harvey, Carolyn; Baxter, E. Joanna; McMullin, Mary Frances; Mead, Adam J.

doi:10.1200/jco.22.01935

Cited by 43 publications

(30 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our take on the RESPONSE and MAJIC-PV clinical trials is that they clearly show salvage value for ruxolitinib, in the presence of symptoms reminiscent of post-PV myelofibrosis and, in patients suffering from drug-refractory pruritus or symptomatically enlarged spleen. 141 As was reported in the MAJIC-PV trial, 145 we and others have also shown an association between JAK2 inhibitor-induced response and longer survival, in the context of myelofibrosis. [152][153][154][155][156] However, such observations might represent response-enabled identification of long-lived patients, rather than a reflection of diseasemodifying activity for a specific drug.…”

Section: Recommendationssupporting

confidence: 71%

“…141,143 The benefit of ruxolitinib as salvage therapy for HU-resistant/intolerant PV was again demonstrated in another randomized phase-2 study (MAJIC-PV; N = 180) 145 ; CR was reported in 43% of patients on ruxolitinib versus 26% on BAT; in addition, ruxolitinib-treated patients displayed longer duration of response and better control of symptoms; event-free survival at 1 year was reported to be superior in patients with CR; ruxolitinib therapy was also associated with a decline in JAK2V617F allele burden and was associated with superior event-free and overall survival. 145 The efficacy of oral busulfan (dosed at 2-4 mg/day) in patients with advanced PV or ET refractory or intolerant to hydroxyurea was assessed in two recent studies 146,147 ; in one study of 36 patients with a treatment duration of 256 days, which included 15 patients with PV, 146 complete hematological response was reported in 83% of the patients, which was sustained in the majority of the patients at 2 years. Busulfan was discontinued in 18 (67%) patients because of unmaintained remission, which is a unique feature of busulfan treatment response in patients with MPN; and 33% of informative cases demonstrated partial molecular response.…”

Section: Treatment Choices Beyond Hydroxyurea or Pegylated Interferonmentioning

confidence: 93%

See 1 more Smart Citation

Polycythemia vera: 2024 update on diagnosis, risk‐stratification, and management

Tefferi

Barbui

2023

American J Hematol

View full text Add to dashboard Cite

Disease Overview Polycythemia vera (PV) is a JAK2‐mutated myeloproliferative neoplasm characterized by clonal erythrocytosis; other features include leukocytosis, thrombocytosis, splenomegaly, pruritus, constitutional symptoms, microcirculatory disturbances, and increased risk of thrombosis and progression into myelofibrosis (post‐PV MF) or acute myeloid leukemia (AML). Diagnosis A working diagnosis is considered in the presence of a JAK2 mutation associated with hemoglobin/hematocrit levels of >16.5 g/dL/49% in men or 16 g/dL/48% in women; morphologic confirmation by bone marrow examination is advised but not mandated. Cytogenetics Abnormal karyotype is seen in 15%–20% of patients with the most frequent sole abnormalities being +9 (5%), loss of chromosome Y (4%), +8 (3%), and 20q− (3%). Mutations Over 50% of patients harbor DNA sequence variants/mutations other than JAK2, with the most frequent being TET2 (18%) and ASXL1 (15%). Prognostically adverse mutations include SRSF2, IDH2, RUNX1, and U2AF1, with a combined incidence of 5%–10%. Survival and Prognosis Median survival is ⁓15 years but exceeds 35 years for patients aged ≤40 years. Risk factors for survival include older age, leukocytosis, abnormal karyotype, and the presence of adverse mutations. Twenty‐year risk for thrombosis, post‐PV MF, or AML are ⁓26%, 16% and 4%, respectively. Risk Factors for Thrombosis Two risk categories are considered: high (age >60 years or thrombosis history) and low (absence of both risk factors). Additional predictors for arterial thrombosis include cardiovascular risk factors and for venous thrombosis higher absolute neutrophil count and JAK2V617F allele burden. Treatment Current goal of therapy is to prevent thrombosis. Periodic phlebotomy, with a hematocrit target of <45%, combined with once‐ or twice‐daily aspirin (81 mg) therapy, absent contraindications, is the backbone of treatment in all patients, regardless of risk category. Cytoreductive therapy is reserved for high‐risk disease with first‐line drugs of choice being hydroxyurea and pegylated interferon‐α and second‐line busulfan and ruxolitinib. In addition, systemic anticoagulation is advised in patients with venous thrombosis history. Additional Treatment Considerations At the present time, we do not consider a drug‐induced reduction in JAK2V617F allele burden, which is often incomplete and seen not only with peg‐IFN but also with ruxolitinib and busulfan, as an indicator of disease‐modifying activity, unless accompanied by cytogenetic and independently‐verified morphologic remission. Accordingly, we do not use the specific parameter to influence treatment choices. The current review also includes specific treatment strategies in the context of pregnancy, splanchnic vein thrombosis, pruritus, perioperative care, and post‐PV MF.

show abstract

Section: Recommendationssupporting

confidence: 71%

Section: Treatment Choices Beyond Hydroxyurea or Pegylated Interferonmentioning

confidence: 93%

Polycythemia vera: 2024 update on diagnosis, risk‐stratification, and management

Tefferi

Barbui

2023

American J Hematol

View full text Add to dashboard Cite

show abstract

“…Thromboembolic event-free survival was significantly improved with ruxolitinib (hazard ratio [HR], 0.56; 95% CI, 0.32 to 1.00; p = .05). 27 The overall safety profile observed in the study was consistent with that observed in prior studies of ruxolitinib, with no new safety signals identified. 21,22,25,28 Overall, the results from this observational study build on the data and evidence from the earlier pivotal studies RESPONSE and RESPONSE-2 and provide real-world evidence of the efficacy and safety of ruxolitinib in clinical practice.…”

Section: Discussionsupporting

confidence: 83%

Ruxolitinib in patients with polycythemia vera resistant and/or intolerant to hydroxyurea: European observational study

Theocharides,

Gisslinger,

De Stefano

et al. 2023

European J of Haematology

View full text Add to dashboard Cite

BackgroundHydroxyurea (HU) is a commonly used first‐line treatment in patients with polycythemia vera (PV). However, approximately 15%–24% of PV patients report intolerance and resistance to HU.MethodsThis phase IV, European, real‐world, observational study assessed the efficacy and safety of ruxolitinib in PV patients who were resistant and/or intolerant to HU, with a 24‐month follow‐up. The primary objective was to describe the profile and disease burden of PV patients.ResultsIn the 350 enrolled patients, 70% were >60 years old. Most patients (59.4%) had received ≥1 phlebotomy in the 12 months prior to the first dose of ruxolitinib. Overall, 68.2% of patients achieved hematocrit control with 92.3% patients having hematocrit <45% and 35.4% achieved hematologic remission at month 24. 85.1% of patients had no phlebotomies during the study. Treatment‐related adverse events were reported in 54.3% of patients and the most common event was anemia (22.6%). Of the 10 reported deaths, two were suspected to be study drug‐related.ConclusionThis study demonstrates that ruxolitinib treatment in PV maintains durable hematocrit control with a decrease in the number of phlebotomies in the majority of patients and was generally well tolerated.

show abstract

“…Moreover, conventional anti-platelet therapy does not fully mitigate thrombotic risk and cytoreductive therapy has shown limited potential to alter natural history of the disease to date 45 . Recent data suggest 46 that disease course may be modified with targeted treatments, however options remain limited, with incomplete understanding of why patients fail first line therapy with few available alternatives. One approach that is increasingly recognized as highly valuable in identifying novel therapeutic targets as well as molecular markers of disease (especially at a systems level) is to leverage pertinent multi-omic [47][48][49] datasets.…”

Section: Discussionmentioning

confidence: 99%

Platelet proteo-transcriptomic profiling validates mediators of thrombosis and proteostasis in patients with myeloproliferative neoplasms

Kelliher,

Gamba,

Weiss

et al. 2023

Preprint

View full text Add to dashboard Cite

Patients with chronic Myeloproliferative Neoplasms (MPN) including polycythemia vera (PV) and essential thrombocythemia (ET) exhibit unique clinical features, such as a tendency toward thrombosis and hemorrhage, and risk of disease progression to secondary bone marrow fibrosis and/or acute leukemia. Although an increase in blood cell lineage counts (quantitative features) contribute to these morbid sequelae, the significant qualitative abnormalities of myeloid cells that contribute to vascular risk are not well understood. Here, we address this critical knowledge gap via a comprehensive and untargeted profiling of the platelet proteome in a large (n= 140) cohort of patients (from two independent sites) with an established diagnosis of PV and ET (and complement prior work on the MPN platelet transcriptome from a third site). We discover distinct MPN platelet protein expression and confirm key molecular impairments associated with proteostasis and thrombosis mechanisms of potential relevance to MPN pathology. Specifically, we validate expression of high-priority candidate markers from the platelet transcriptome at the platelet proteome (e.g., calreticulin (CALR), Fc gamma receptor (FcγRIIA) and galectin-1 (LGALS1) pointing to their likely significance in the proinflammatory, prothrombotic and profibrotic phenotypes in patients with MPN. Together, our proteo-transcriptomic study identifies the peripherally-derived platelet molecular profile as a potential window into MPN pathophysiology and demonstrates the value of integrative multi-omic approaches in gaining a better understanding of the complex molecular dynamics of disease.

show abstract

Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial

Cited by 43 publications

References 19 publications

Polycythemia vera: 2024 update on diagnosis, risk‐stratification, and management

Polycythemia vera: 2024 update on diagnosis, risk‐stratification, and management

Ruxolitinib in patients with polycythemia vera resistant and/or intolerant to hydroxyurea: European observational study

Platelet proteo-transcriptomic profiling validates mediators of thrombosis and proteostasis in patients with myeloproliferative neoplasms

Contact Info

Product

Resources

About