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The Lancet. Oncology Jan 2017In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving splenomegaly and symptoms in patients with polycythaemia vera with splenomegaly who were inadequately controlled with hydroxyurea. In this study, we assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy.
METHODS
RESPONSE-2 is a randomised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients with polycythaemia vera done in 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and North America. Eligible patients (aged ≥18 years) with polycythaemia vera, no palpable splenomegaly, and hydroxyurea resistance or intolerance were stratified by their hydroxyurea therapy status (resistance vs intolerance) and randomly assigned (1:1) by an interactive response technology provider using a validated system to receive either oral ruxolitinib 10 mg twice daily or investigator-selected best available therapy (hydroxyurea [at the maximum tolerated dose], interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment). Investigators and patients were not masked to treatment assignment; however, the study sponsor was masked to treatment assignment until database lock. The primary endpoint was the proportion of patients achieving haematocrit control at week 28. Analyses were done according to an intention-to-treat principle, including data from all patients randomly assigned to treatment. This study is registered with ClinicalTrials.gov (NCT02038036) and is ongoing but not recruiting patients.
FINDINGS
Between March 25, 2014, and Feb 11, 2015, of 173 patients assessed for eligibility, 74 patients were randomly assigned to receive ruxolitinib and 75 to receive best available therapy. At randomisation, best available therapy included hydroxyurea (37 [49%] of 75 in the best available therapy group), interferon or pegylated interferon (ten [13%] of 75), pipobroman (five [7%] of 75), lenalidomide (one [1%] of 75), no treatment (21 [28%] of 75), and other (one [1%] of 75). Haematocrit control was achieved in 46 (62%) of 74 ruxolitinib-treated patients versus 14 (19%) of 75 patients who received best available therapy (odds ratio 7·28 [95% CI 3·43-15·45]; p<0·0001). The most frequent haematological adverse events of any grade were anaemia (ten [14%] of 74 in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and thrombocytopenia (two [3%] vs six [8%]). No cases of grade 3-4 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3-4 anaemia and three patients (4%) reported grade 3-4 thrombocytopenia in the group receiving best available therapy. Frequent grade 3-4 non-haematological adverse events were hypertension (five [7%] of 74 vs three [4%] of 75) and pruritus (0 of 74 vs two [3%] of 75). Serious adverse events occurring in more than 2% of patients in either group, irrespective of cause, included thrombocytopenia (none in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and angina pectoris (two [3%] of 74 in the ruxolitinib group vs none in the best available therapy group). Two deaths occurred, both in the best available therapy group.
INTERPRETATION
RESPONSE-2 met its primary endpoint. The findings of this study indicate that ruxolitinib could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population.
FUNDING
Novartis.
Topics: Aged; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Nitriles; Polycythemia Vera; Prognosis; Prospective Studies; Pyrazoles; Pyrimidines; Salvage Therapy; Splenomegaly; Survival Rate
PubMed: 27916398
DOI: 10.1016/S1470-2045(16)30558-7 -
The Oncologist Apr 2016The goals of therapy in patients with polycythemia vera (PV) are to improve disease-related symptoms, prevent the incidence or recurrence of thrombosis, and possibly... (Review)
Review
UNLABELLED
The goals of therapy in patients with polycythemia vera (PV) are to improve disease-related symptoms, prevent the incidence or recurrence of thrombosis, and possibly delay or prevent the transformation into myelofibrosis or acute myeloid leukemia (AML). Cytoreductive therapies have been used in older patients and those with a history of thrombosis to achieve these goals. Hydroxyurea (HU) remains the first-line cytoreductive choice; however, up to one in four patients treated with HU over time will develop resistance or intolerance to HU. More importantly, patients who fail HU have a 5.6-fold increase in mortality and a 6.8-fold increase risk of transformation to myelofibrosis or AML; therefore, alternative therapies are needed for these patients. Interferon-α has been used in PV and has shown significant activity in achieving hematologic responses and decreasing JAK2 V617F mutation allele burden. JAK inhibition has also been investigated and recently garnered regulatory approval for this indication. In this review, we will discuss the current treatment options that are available for patients after HU and the novel therapies that are currently under investigation.
IMPLICATIONS FOR PRACTICE
The outcomes of PV patients who fail or who are intolerant of hydroxyurea are poor. Although pegylated interferon can be considered in younger patients, currently, ruxolitinib is the only U.S. Food and Drug Administration-approved agent in this setting, representing a viable option, leading to hematocrit control and a reduction in spleen size and constitutional symptoms. Although a small number of patients will achieve a molecular response with continuous treatment, the implications of such response on the clinical outcomes are still unknown. Patients whose disease is not adequately controlled with ruxolitinib, or who lose their response, can be treated with low-dose busulfan or pipobroman; however, they should be encouraged to participate in trials with novel therapies.
Topics: Busulfan; Cell Proliferation; Humans; Hydroxyurea; Janus Kinase 2; Leukemia, Myeloid, Acute; Nitriles; Polycythemia Vera; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Thrombosis
PubMed: 26975864
DOI: 10.1634/theoncologist.2015-0380 -
The Journal of Investigative Dermatology Jun 2016
Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Female; Genes, ras; Humans; Indoles; Pipobroman; Protein Multimerization; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib
PubMed: 26854489
DOI: 10.1016/j.jid.2015.12.047 -
Chemistry (Weinheim An Der Bergstrasse,... Feb 2016Resistance towards chemotherapeutics displayed by cancer cells is a significant stumbling block against fruitful cisplatin-based therapy. A unique dual-acting...
Resistance towards chemotherapeutics displayed by cancer cells is a significant stumbling block against fruitful cisplatin-based therapy. A unique dual-acting chemotherapeutic modality, Platin-B, a prodrug of cisplatin and pipobroman-mimicking alkylating agent, was constructed to circumvent tumor resistance. Platin-B exhibited a superior cytotoxicity profile in cisplatin-resistant cancer cells. Enhanced activity and the ability to overcome cancer-induced resistance of Platin-B was related to adduct formation with intracellular glutathione, followed by the activity of Platin-B on the mitochondria of cells, along with its conventional nuclear activity. Alkylating moieties present on Platin-B enhanced its cellular and subcellular concentration and protected it from early drug sequestration by biological thiols.
Topics: Alkylation; Antineoplastic Agents; Cell Line, Tumor; Cisplatin; DNA Repair; Glutathione; Humans; Mitochondria; Organoplatinum Compounds; Oxidation-Reduction; Prodrugs
PubMed: 26807548
DOI: 10.1002/chem.201503866 -
Blood Cancer Journal Nov 2015Polycythemia vera (PV) and essential thrombocythemia (ET) constitute two of the three BCR-ABL1-negative myeloproliferative neoplasms and are characterized by relatively... (Review)
Review
Polycythemia vera (PV) and essential thrombocythemia (ET) constitute two of the three BCR-ABL1-negative myeloproliferative neoplasms and are characterized by relatively long median survivals (approximately 14 and 20 years, respectively). Potentially fatal disease complications in PV and ET include disease transformation into myelofibrosis (MF) or acute myeloid leukemia (AML). The range of reported frequencies for post-PV MF were 4.9-6% at 10 years and 6-14% at 15 years and for post-ET MF were 0.8-4.9% at 10 years and 4-11% at 15 years. The corresponding figures for post-PV AML were 2.3-14.4% at 10 years and 5.5-18.7% at 15 years and for post-ET AML were 0.7-3% at 10 years and 2.1-5.3% at 15 years. Risk factors cited for post-PV MF include advanced age, leukocytosis, reticulin fibrosis, splenomegaly and JAK2V617F allele burden and for post-ET MF include advanced age, leukocytosis, anemia, reticulin fibrosis, absence of JAK2V617F, use of anagrelide and presence of ASXL1 mutation. Risk factors for post-PV AML include advanced age, leukocytosis, reticulin fibrosis, splenomegaly, abnormal karyotype, TP53 or RUNX1 mutations as well as use of pipobroman, radiophosphorus (P(32)) and busulfan and for post-ET AML include advanced age, leukocytosis, anemia, extreme thrombocytosis, thrombosis, reticulin fibrosis, TP53 or RUNX1 mutations. It is important to note that some of the aforementioned incidence figures and risk factor determinations are probably inaccurate and at times conflicting because of the retrospective nature of studies and the inadvertent labeling, in some studies, of patients with prefibrotic primary MF or 'masked' PV, as ET. Ultimately, transformation of MPN leads to poor outcomes and management remains challenging. Further understanding of the molecular events leading to disease transformation is being investigated.
Topics: Fusion Proteins, bcr-abl; Humans; Leukemia, Myeloid, Acute; Lymphocyte Activation; Polycythemia Vera; Primary Myelofibrosis; Thrombocythemia, Essential
PubMed: 26565403
DOI: 10.1038/bcj.2015.95 -
Annals of Hematology Dec 2014Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by clonal expansion of a hematopoietic progenitor, erythrocytosis, often leukocytosis... (Review)
Review
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by clonal expansion of a hematopoietic progenitor, erythrocytosis, often leukocytosis and/or thrombocytosis, and nearly always an activating mutation in Janus kinase 2 (JAK2). The PV symptom burden can be considerable, in part driven by small or large vessel thrombotic tendency, splenomegaly, fatigue, pruritus, and a chronic risk of disease transformation to myelofibrosis or acute myeloid leukemia. In addition, patients with PV have an increased risk of mortality compared with the general population that often results from cardiovascular complications or disease transformation. Further, healthcare utilization and costs are higher in patients with PV than noncancer controls. First-line therapy options for high-risk patients may effectively manage PV in some instances; however, some patients do not receive adequate benefit from current treatment options and experience a more severe disease burden as a result. This may be especially true for those patients who are resistant to or intolerant of hydroxyurea or interferon-based therapies. New treatments currently being investigated in phase 3 clinical trials may alleviate disease burden in this patient population.
Topics: Clinical Trials, Phase III as Topic; Combined Modality Therapy; Cost of Illness; Disease Progression; Fatigue; Health Care Costs; Hemorrhagic Disorders; Humans; Hydroxyurea; Interferons; Janus Kinase 2; Leukemia, Myeloid, Acute; Mutation, Missense; Neoplasms, Second Primary; Nitriles; Pipobroman; Polycythemia Vera; Primary Myelofibrosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Quality of Life; Therapies, Investigational; Thrombophilia
PubMed: 25270596
DOI: 10.1007/s00277-014-2205-y -
Leukemia & Lymphoma Dec 2014Hydroxyurea (HU) has traditionally been the first-line treatment for patients with polycythemia vera (PV) or essential thrombocythemia (ET) at high risk for vascular... (Review)
Review
Hydroxyurea (HU) has traditionally been the first-line treatment for patients with polycythemia vera (PV) or essential thrombocythemia (ET) at high risk for vascular complications. However, approximately 20-25% of patients develop resistance or intolerance to HU and must be treated with second-line therapies. Resistance is associated with disease transformation and reduced survival. However, given the dearth of large-scale controlled clinical trials in this patient population, there is no clear consensus on how to best treat patients who develop resistance or intolerance to HU. Herein, we review current literature on treatment options for patients with HU-refractory/resistant PV or ET and provide recommendations for treating these patients.
Topics: Antineoplastic Agents; Busulfan; Disease Management; Drug Resistance; Histone Deacetylase Inhibitors; Humans; Hydroxyurea; Interferon-alpha; Janus Kinase 2; Pipobroman; Platelet Aggregation Inhibitors; Polycythemia Vera; Protein Kinase Inhibitors; Quinazolines; Thrombocythemia, Essential; Treatment Outcome
PubMed: 24524340
DOI: 10.3109/10428194.2014.893310