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1753 Long-Term Efficacy and Safety (5 Years) in RESPONSE, a Phase 3 Study Comparing Ruxolitinib (rux) with Best Available Therapy (BAT) in Hydroxyurea (HU)-Resistant/Intolerant Patients (pts) with Polycythemia Vera (PV)

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Poster I
Hematology Disease Topics & Pathways:
Diseases, Non-Biological, MPN, Polycythemia vera, Clinically relevant, Myeloid Malignancies, pharmacology
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Jean-Jacques Kiladjian, MD, PhD1, Pierre Zachée2*, Masayuki Hino, MD, PhD3, Fabrizio Pane4, Tamas Masszi, MD, Prof.5, Claire N. Harrison, MD, DM, FRCP, PRCPath6, Ruben A. Mesa, MD7, Carole B. Miller, MD8*, Francesco Passamonti, MD9*, Simon Durrant, FRCP, FRCPath, MBBS10, Martin Griesshammer, MD, PhD11*, Keita Kirito, MD12, Carles Besses, MD. PhD13*, Beatriz Moiraghi14*, Elisa Rumi, MD15*, Vittorio Rosti, MD16, Igor W. Blau17*, Nathalie Francillard18*, Tuochuan Dong19*, Monika Wroclawska, M.D.20*, Alessandro M. Vannucchi, MD21 and Srdan Verstovsek, MD, PhD22

1Centre d’Investigations Cliniques, Hôpital Saint-Louis, Université Paris Diderot, Paris, France
2Ziekenhuis Netwerk Antwerpen Stuivenberg, Antwerpen, Belgium
3Department of Hematology, Osaka City University Graduate School of Medicine, Osaka, Japan
4Hematology - Departments of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
53rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
6Department of Haematology, Guy's and St Thomas NHS Foundation Trust, London, United Kingdom
7UT Health San Antonio Cancer Center, San Antonio, TX
8St. Agnes Healthcare Cancer Institute, Baltimore, MD
9University Hospital Ospedale Di Circolo E Fondazione Macchi, Varese, Italy
10Royal Brisbane & Women's Hospital, Brisbane, Australia
11Department of Hematology, Oncology, Hemostaseology and Palliative Care, Johannes Wesling Clinic, Minden, Germany
12Department of Hematology and Oncology, University of Yamanashi, Chuo, Japan
13Hematology Department, Hospital del Mar-IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Universidad Autónoma de Barcelona., Barcelona, Spain
14Hospital Jose Maria Ramos Mejía, Buenos Aires, Argentina
15Department of Hematology Oncology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
16Center for the Study of Myelofibrosis, Laboratory of Biochemistry Biotecnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
17Department of Hematology, Charité University School of Medicine, Berlin, Germany
18Novartis Pharma S.A.S, Rueil Malmaison, France
19Novartis Pharmaceuticals Corporation, East Hanover
20Novartis Pharma AG, Basel, Switzerland
21CRIMM; Center Research and Innovation of Myeloproliferative Neoplasms, AOUC, University of Florence, Firenze, Italy
22Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX


RESPONSE is a randomized (1:1), open-label, phase 3 study of rux vs BAT in pts with PV who are resistant/intolerant of HU. In RESPONSE, significantly more pts achieved the primary composite end point (hematocrit control [Hct] and a ≥ 35% reduction in spleen volume [SVR]) with rux compared to BAT (23% vs 1%; P ˂ .0001). The 4-year (y) follow-up confirmed that primary and clinicohematologic (CLHM) responses were sustained with the rux treatment, and the safety profile was consistent with previous reports. Here, we report the long-term efficacy and safety after 5 ys (256 weeks [wks]) of treatment (after last pt first treatment visit) in RESPONSE.


PV pts resistant/intolerant of HU (per modified ELN criteria) with splenomegaly requiring phlebotomy (PBT) for Hct control were randomized to rux 10 mg BID or BAT (selected based on investigator’s choice). The primary response was a composite end point of achieving both Hct control without PBT (defined as no PBT eligibility between wks 8 to 32 with no more than 1 PBT eligibility from randomization to wk 8) through wk 32 and a ≥ 35% SVR by imaging at wk 32. Key secondary endpoints were durability of the primary response, overall CLHM (Hct control without PBT, platelet count ≤ 400 × 109/L, WBC count ≤ 10 × 109/L, SVR ≥35% by imaging), and long-term safety. Overall survival (OS) was an exploratory end point. Pts randomized to BAT could cross over (CO) to rux after wk 32.


Pts were randomized to rux (n = 110) and BAT (n = 112). Baseline characteristics were mostly balanced between arms. At baseline, pts randomized to rux were reported to have longer prior exposure to HU compared to BAT (162.9 vs 145.6 wks) and higher frequency of prior nonmelanoma skin cancer (NMSC) or pre-cancerous skin conditions (10.9 vs 6.3%). No pt remained on randomized BAT treatment after wk 80 and median CO time was 34.7 wks. At study completion, 72 pts (66%) in the rux arm and 64 of the 98 pts (65%) who crossed over from BAT completed 5 ys of on-study treatment. Main reason for discontinuation in the BAT arm was lack of efficacy (89%). Adverse events (AEs; 15% and 16%), disease progression (11% and 9% ) and pt decision (6% and 6%) primarily led to treatment discontinuations in the rux arm and CO population, respectively.

At final analysis, the KM estimated probability of maintaining primary response for 224 wks (starting from wk 32) in the rux arm was 0.74 (95% CI: 0.51, 0.88) (Figure 1); 6/25 primary responders had progressed by the time of study completion. The probability of maintaining CLHM response for 224 wks (starting from wk 32) was 0.67 (95% CI: 0.54, 0.77) with 21/70 pts who achieved CLHM at wk 32 had progressed. Median duration of primary and CLHM responses had not been reached. In the intent-to-treat analysis not accounting for CO, KM estimates for OS at 5 ys in the rux and BAT arms were 91.9% (95% CI: 84.4, 95.9) and 91.0% (95% CI: 82.8, 95.4), respectively (HR = 0.95 [95% CI: 0.38, 2.41]). There were 2 on-treatment deaths in the rux arm (adenocarcinoma gastric [n = 1, investigator suspected event to be related to study drug] and neoplasm malignant [n = 1, not related to study drug]). In the CO population, 4 pts had fatal AEs leading to 4 on-treatment deaths (not related to rux). No pt died while on BAT.

With longer exposure of rux, there was no notable increase in rate of AEs. The most common AEs (exposure-adjusted rate ≥ 5) in the rux arm and CO population were anemia (8.9 and 8.8), pruritus (7.0 and 6.1), diarrhea (7.0 and 3.6), weight increased (6.1 and 4.2), headache (5.8 and 5.2), arthralgia (5.6 and 3.3), fatigue (5.1 and 3.9) and muscle spasms (5.1 and 3.3). Rates (per 100 pt-y) of thromboembolic events were lower in rux-treated pts (1.2) and the CO population (2.7) compared to BAT pts (8.2). The exposure adjusted rates of second malignancies were 7.0 (rux) vs 4.5 (CO) vs 4.1 (BAT). The exposure-adjusted rate of NMSC was 5.1 (rux) vs 2.7 (CO) vs 2.7 (BAT). Rates of transformation to myelofibrosis and acute myeloid leukeimia in the rux arm were 2.1 and 0.2 per 100 pt-y, 1.8 and 0.6 per 100 pt-y in CO population, and 1.4 and 0.0 per 100 pt-y in BAT arm, respectively.


In HU resistant/intolerant PV pts, clinical benefits of rux treatment (Hct control and CLHM) were durable with long-term therapy. Considering that the OS findings from this analysis are confounded by extensive CO, the observed HR from this analysis represents a conservative estimate of rux benefit. The long-term safety was consistent with previous findings.

Disclosures: Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Other: Provided Ruxolitinib ; Celgene: Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche AG: Other: Provided Pegylated Interferon Alpha 2a; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hino: Otsuka Pharmaceutical Co., Ltd.: Research Funding; Novartis: Research Funding. Pane: Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau. Masszi: Pfizer: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Harrison: Celgene: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; CTI BioPharma: Consultancy, Honoraria; Gilead: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Mesa: CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Miller: Gilead: Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; CTI: Research Funding; Novartis: Honoraria, Speakers Bureau. Passamonti: Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy. Durrant: Novartis: Honoraria, Speakers Bureau. Griesshammer: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kirito: Novartis Pharma KK: Honoraria. Besses: Novartis: Honoraria, Research Funding; Shire: Honoraria. Francillard: Novartis: Employment. Dong: Novartis: Employment, Equity Ownership. Wroclawska: Novartis: Employment, Equity Ownership. Verstovsek: Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH