Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study

doi:10.1016/S2352-3026(19)30207-8

The Lancet Haematology

Volume 7, Issue 3, March 2020, Pages e226-e237

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https://doi.org/10.1016/S2352-3026(19)30207-8 Get rights and content

Summary

Background

Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea.

Methods

We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov, NCT01243944.

Findings

We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9–12·3) in the ruxolitinib group and 9·3 years (4·9–13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51–88). The probability of maintaining complete haematological remission was 55% (95% CI 32–73) and the probability of maintaining overall clinicohaematological responses was 67% (54–77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4–95·9) with ruxolitinib therapy and 91·0% (82·8–95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment.

Interpretation

We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population.

Funding

Novartis Pharmaceuticals Corporation.

Introduction

Polycythaemia vera is a clonal myeloproliferative neoplasm that arises because of mutations in the Janus kinase 2 (JAK2) gene, and is primarily characterised by an elevation in the red blood cell mass.¹ A rise in white blood cell and platelet counts is seen in approximately 40% of patients with polycythaemia vera.² Splenomegaly is a common feature of advanced disease.³ Patients with polycythaemia vera have a substantial symptom burden,³ increased risk of thromboembolic events,⁴ and shortened survival.⁵ Hence, the main goals of therapy are to ease the symptom burden, reduce the risk of thromboembolic events, and minimise the transformation to myelofibrosis or acute myeloid leukaemia.¹ In patients at high risk, either hydroxyurea or interferon alfa is the recommended therapy.6, 7 Approximately 25% of patients at high risk given the first-line therapy (hydroxyurea or interferon) become resistant to or intolerant of treatment.8, 9, 10 In addition, many patients have persisting polycythaemia vera associated symptoms despite being given standard therapies.¹¹

Ruxolitinib, a JAK1 and JAK2 inhibitor, has shown efficacy in treating patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea in the large, randomised, phase 3 RESPONSE study (Randomised Study of Efficacy and Safety in Polycythemia Vera with JAK Inhibitor INCB018424 versus Best Supportive Care).¹² In the primary analysis of RESPONSE, ruxolitinib was superior to best available therapy in providing haematocrit control along with a 35% or more reduction in spleen volume from baseline at week 32 (primary endpoint 22·7% vs 0·9% of patients in the ruxolitinib vs best available therapy group; p<0·001) in patients with polycythaemia vera who were inadequately controlled with hydroxyurea.¹² These results supported the United States Food and Drug Administration and the European Medicines Agency approvals of ruxolitinib for the treatment of polycythaemia vera in patients who are resistant to or intolerant of hydroxyurea.12, 13, 14

The long-term follow-up in RESPONSE showed that ruxolitinib provided durable haematocrit control, spleen volume reduction, complete haematological remission, and clinicohaematological response in these patients with an acceptable safety profile.15, 16 The analyses from RESPONSE-2 (a phase 3 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea and had a non-palpable spleen) further confirmed the benefits of ruxolitinib in patients with polycythaemia vera who were inadequately controlled with hydroxyurea.17, 18 The European LeukemiaNet and National Comprehensive Cancer Network guidelines now include ruxolitinib as the recommended treatment for patients who are resistant to or intolerant of hydroxyurea.7, 19

Here, we present the long-term efficacy and safety results from a planned analysis after all patients completed 256 weeks (approximately 5 years) of treatment or had discontinued from the RESPONSE study.

Section snippets

Study design and participants

We did an international, multicentre, randomised, open-label, phase 3 study (RESPONSE) comparing the safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera (appendix p 7). Patients were enrolled at 109 sites across North America, South America, Europe, and the Asia-Pacific region (appendix p 15–18). The methods of this study have been published previously.¹² The study population comprised patients (18 years and older) with polycythaemia vera who were

Results

We enrolled patients between Oct 27, 2010 (first patient first visit), and Feb 13, 2013, and the study concluded on Feb 9, 2018 (last patient last visit). Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive either ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The baseline characteristics of patients and the primary results of the study have been reported previously¹² and were mostly balanced between the treatment groups (appendix p 2).

Discussion

The results from this final analysis of the RESPONSE study add to the evidence for the efficacy and safety of ruxolitinib in patients with polycythaemia vera who are inadequately controlled with hydroxyurea either because of resistance or intolerance. The primary analysis of this study showed the superiority of ruxolitinib compared with best available therapy¹² (including interferon)²⁰ in terms of achieving haematocrit control, spleen response, complete haematological remission, and overall

Data sharing

This trial data availability is according to the criteria and process described on the ClinicalStudyDataRequest website. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymised to respect the privacy of patients who have participated in the trial in line with

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SOHO State of the Art Update and Next Questions: Novel Therapies for Polycythemia Vera
2024, Clinical Lymphoma, Myeloma and Leukemia
In the recent years, landmark advancements in the treatment of polycythemia vera (PV) have been achieved. We witnessed the regulatory approval of ropeginterferon and the advanced clinical development of other novel agents that may affect the underlying pathophysiological mechanisms of the disease. Agents with the potential of disease modification may soon overtake preceding treatment options that were based on the patient's age and history of thrombosis. Recent studies using ropeginterferon in low-risk PV patients earlier in the disease course challenge the current treatment paradigm and shift the focus on modifying the course of the disease. Hepcidin mimetics offer an excellent alternative to phlebotomy, providing better quality of life, and may lead to improved outcomes in PV by tight hematocrit control. Novel agents, such as histone deacetylase inhibitors, hold promise to complement the therapeutic landscape of PV and might be particularly promising in rationale combinations. Ruxolitinib is well established as an approved second-line treatment for PV. In the frontline setting, the precise role of ruxolitinib, which also represents an appealing agent in combination regimens, will be determined in ongoing research studies. Longer follow-up is necessary to assess whether novel agents/regimens elicit fewer thromboembolic/ hemorrhagic events and halt disease progression to myelofibrosis and acute myeloid leukemia. We aspire that disease-modifying approaches in PV are on the horizon, and that we will be empowered to ultimately change the natural course of the disease and profoundly impact the lives of PV patients in the near future.
Moving toward disease modification in polycythemia vera
2023, Blood
Polycythemia vera (PV) belongs to the BCR-ABL1–negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient’s age and a history of thrombosis in patients with low-risk PV treated with therapeutic phlebotomy and aspirin alone, whereas cytoreductive therapy with either hydroxyurea or interferon alfa (IFN-α) is added for high-risk disease. However, other disease features such as significant disease-related symptoms and splenomegaly, concurrent thrombocytosis and leukocytosis, or intolerance of phlebotomy can constitute an indication for cytoreductive therapy in patients with otherwise low-risk disease. Additionally, recent studies demonstrating the safety and efficacy (ie, reduction in phlebotomy requirements and molecular responses) of ropegylated IFN-α2b support its use for patients with low-risk PV. Additionally, emerging data suggest that early treatment is associated with higher rates of molecular responses, which might eventually enable time-limited therapy. Nonetheless, longer follow-up is needed to assess whether molecular responses associate with clinically meaningful outcome measures such as thrombosis and progression to myelofibrosis or AML. In this article, we provide an overview of the current and evolving treatment landscape of PV and outline our vision for a patient-centered, phlebotomy-free, treatment approach using time-limited, disease-modifying treatment modalities early in the disease course, which could ultimately affect the natural history of the disease.
The gut microbiota in patients with polycythemia vera is distinct from that of healthy controls and varies by treatment
2023, Blood Advances
Chronic inflammation is believed to play an important role in the development and disease progression of polycythemia vera (PV). Because an association between gut microbiota, hematopoiesis, and inflammation is well established, we hypothesized that patients with PV have a gut microbiota distinct from healthy control participants (HCs). Recombinant interferon alfa 2 (IFN-α2)-treatment of patients with PV is reportedly disease modifying in terms of normalization of elevated blood cell counts in concert with a reduction in the JAK2V617F allelic burden. Therefore, we hypothesized that patients treated with IFN-α2 might have a composition of the gut microbiota toward normalization. Herein, via amplicon-based next-generation sequencing of the V3 to V4 regions of the 16S ribosomal RNA gene, we report on an abnormal gut microbiota in 102 patients with PV compared with 42 HCs. Patients with PV had a lower alpha diversity and a lower relative abundance of several taxa belonging to Firmicutes (45%) compared with HCs (59%, P <.001). Furthermore, we report the composition of the gut microbiota to differ between the treatment groups (IFN-α2, hydroxyurea, no treatment, and combination therapy with IFN-α2 and ruxolitinib) and the HCs. These observations are highly interesting considering the potential pathogenetic importance of an altered gut microbiota for development of other diseases, including chronic inflammatory diseases. Our observations call for further gut microbiota studies to decipher potential causal associations between treatment and the gut microbiota in PV and related neoplasms.
JAK2<sup>V617F</sup> allele burden in polycythemia vera: burden of proof
2023, Blood
Polycythemia vera (PV) is a hematopoietic stem cell neoplasm defined by activating somatic mutations in the JAK2 gene and characterized clinically by overproduction of red blood cells, platelets, and neutrophils; a significant burden of disease-specific symptoms; high rates of vascular events; and evolution to a myelofibrosis phase or acute leukemia. The JAK2^V617F variant allele frequency (VAF) is a key determinant of outcomes in PV, including thrombosis and myelofibrotic progression. Here, we critically review the dynamic role of JAK2^V617F mutation burden in the pathogenesis and natural history of PV, the suitability of JAK2^V617F VAF as a diagnostic and prognostic biomarker, and the utility of JAK2^V617F VAF reduction in PV treatment.
SOHO State of the Art Updates and Next Questions | Polycythemia Vera: Is It Time to Rethink Treatment? Treatment Updates in Polycythemia Vera
2023, Clinical Lymphoma, Myeloma and Leukemia
Citation Excerpt :
Patients were randomized to receive RUX or BAT (more than half of cases represented by HU), and crossover from the latter was allowed. Primary composite endpoints were Hct control in the absence of PHLs (both studies) and 35% reduction in spleen volume (SVR35) at week 32.56-60 In the RESPONSE trial, the primary composite endpoint was achieved in 21% of patients in the RUX cohort vs 1% on BAT.56
Polycythemia vera (PV) is a Philadelphia-negative myeloproliferative neoplasm characterized by excessive myeloid cells production, mostly secondary to mutations in the Janus kinase 2 (JAK2) gene. PV natural history might be burdened by thrombotic events (TEs) and evolution into post-PV myelofibrosis (PPV-MF) or blast phase (BP). To date, no treatment strategies have been shown to have disease modifying effects, so therapy is directed at preventing TEs. All patients require phlebotomies (PHLs) to keep hematocrit below 45% and once-daily low dose aspirin (if not contraindicated). Apart from patients at “high risk” because of age over 60 years or a thrombosis history, cytoreductive therapies (CT) should be given to patients with relevant signs of myeloproliferation or intolerance to PHLs. Approved choices both for first and second line CT are hydroxyurea (HU) and pegylated forms of interferon (peg-IFN), the latter probably being better for young patients, and subjects without critical and recent vascular events or massive splenomegaly. The JAK1/2 inhibitor ruxolitinib is the treatment of choice in case of resistance/intolerance to HU, with proved efficacy in terms of thrombotic prevention. Data are too preliminary to consider CT for “low risk” PV cases, but ropeg-IFN is being studied in this setting with a short follow-up. A careful monitoring for signs of evolution into PPV-MF is fundamental for optimizing patient management.
Skin cancers under Janus kinase inhibitors: A World Health Organization drug safety database analysis
2022, Therapies
Citation Excerpt :
In response trial, a randomised, open-label phase 3 study with 222 patients randomly assigned to receive either ruxolitinib (n = 110) or best available therapy (n = 112), the rates of non-melanoma skin cancer were 5.1 in those originally randomly assigned to ruxolitinib, 2.7 with best available therapy, and 2.7 in the crossover population [7]. However, due to prior exposure of a majority of patients in these studies to hydroxyurea (a drug responsible for skin cancers), these skin cancers could never be directly attributed to ruxolitinib [6–9]. For tofacitinib and baricitinib, recent meta-analyses do not appear to show any specific over-risk of skin cancers [10–12].
Janus kinase (JAK) inhibitors are targeted therapies with a potential imunomodulatory and anti-inflammatory effect, indicated in various dysimmune pathologies. Skin cancers have been reported to occur in patients treated with JAK inhibitors. However, drug safety in clinical trials did not confirm that risk, but these studies are performed on controlled population and in a limited time of follow up.
The aim of this study is to evaluate in real life condition if a disproportionality signal exists between JAK inhibitors treatment and skin cancers.
We performed cases/non cases analysis in VigiBase® (the World Health Organization international database of suspected adverse drug reaction) using information component to search for a disproportionality signal of skin cancers from JAK inhibitor. We extracted all reports of skin cancers from the French Pharmacovigilance database occurring since 1978 up to 31^st December 2019 for the three existing JAK inhibitors on market: ruxolitinib, tofacitinib and baricitinib. Only melanoma, squamous cell carcinoma and Merkel cell carcinoma were analyzed, according to the pathophysiology of these cancers and their link with immunosuppression.
A disproportionality signal was found positive for squamous cell carcinoma with ruxolitinib (IC025 = 3.92) and tofacitinib (IC025 = 0.82), for melanoma with ruxolitinib (IC025 = 0.81) and tofacitinib (IC025 = 0.74), and Merkel cell carcinoma with ruxolitinib (IC025 = 4) and tofactinib (IC025 = 1.01) and only for Merkel cell carcinoma with baricitinib (IC025 = 0.53). Moreover, Merkel cell carcinoma, a very rare skin cancer more prevalent in immunodepressed patients was particularly represented in our sample and was associated with a significant disproportionality signal with all the studied JAK inhibitors.
Our study shows that JAK inhibitors could be associated with an extra risk to develop skin cancers. Could an anti-viral or immunovigilance disruption mechanism brought by JAK inhibitors explain an over-risk with Merkel cell carcinoma, which were notably represented in our sample? Considering pharmacovigilance method limitations, further pharmacoepidemiological studies are required to assess a causal link between JAK inhibitors treatment and skin cancers development.

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ArticlesLong-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Data sharing

Am J Med

Blood

Blood

Lancet Oncol

Blood

Myeloproliferative neoplasms

N Engl J Med

Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study

Leukemia

Symptomatic profiles of patients with polycythemia vera: implications of inadequately controlled disease

J Clin Oncol

Vascular and neoplastic risk in a large cohort of patients with polycythemia vera

J Clin Oncol

Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet

J Clin Oncol

Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet

Leukemia

Articles
Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study