Demographics, Baseline Characteristics, and Disease Symptom Burden in RESPONSE-2: A Randomized, Phase 3 Study of Ruxolitinib in Polycythemia Vera Patients (pts) Who Are Resistant to or Intolerant of Hydroxyurea (HU)
Authors: Passamonti Francesco , Griesshammer Martin , Cavo Michele , Egyed Miklos , Benevolo Giulia , Devos Timothy , Callum Jeannie , Vannucchi Alessandro M. , Sivgin Serdar , Bensasson Caroline , Khan Mahmudul , Mounedji Nadjat , Saydam Guray 
Published: October 2019

Abstract
BACKGROUND: Polycythemia vera (PV) is characterized by increased red cell mass often associated with elevated leukocyte and platelet counts, splenomegaly and significant symptom burden. In the RESPONSE study, which only enrolled PV patients with splenomegaly, ruxolitinib (Rux) demonstrated superior improvements in hematocrit (HCT) control and reductions in spleen volume compared with best available therapy (BAT) in pts who were resistant to or intolerant of HU. Supportive data included clinically meaningful improvements in PV-related symptom burden and quality of life (QOL) measures. Here, we describe the baseline (BL) characteristics and symptom burden of PV pts resistant to or intolerant of HU enrolled in the RESPONSE-2 study, which unlike RESPONSE, enrolled PV patients with a nonpalpable spleen.
METHODS: RESPONSE-2 is an open-label, randomized (1:1), multicenter, phase 3 study evaluating the efficacy and safety of Rux vs BAT in PV pts who are HU-resistant/-intolerant, require phlebotomy (PBT), and have no palpable spleen. Pts' BL symptom burden, BL QOL and BL pt-reported outcomes (PRO) were assessed by using 10-items modified Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), the Pruritus Symptom Impact Scale (PSIS), European QOL Questionnaire (EQ-5D-5L), and Work Productivity and Activity Impairment: Polycythemia Vera V2.0 (WPAI: PV).
RESULTS: A total of 149 pts were enrolled. BL demographic data from both arms combined are summarized in the Table. Forty percent of the patients were resistant whereas 60% were intolerant of HU treatment. Other than HU, prior treatments included interferons (15.4%), alkylating agents (8.1%), alkyl sulfonates (2.7%), pyrimidine analogs (0.7%), and other antineoplastic agents (1.0%). Ninety-seven percent of pts had at least 1 PBT within 16 weeks (wks) prior to screening and 72% had ≥ 2 PBT within 24 wks prior to screening. Past medical histories included hypertension (49%), pruritus (23%) and fatigue (9%). BL demographics of pts in RESPONSE-2 were generally comparable with previous PV studies (Table). Despite using frequent phlebotomy and cytoreductive agents during the screening period prior to randomization, 55% and 52% of pts had WBC counts greater than 10 × 109/L and platelet counts greater than 400 × 109/L, respectively, suggesting inadequately controlled disease even while receiving therapy. Additionally, pts had significant symptom burden at BL as measured by the MPN-SAF with fatigue (3.6) and pruritus (3.4) (Table). As measured by EQ-5D-5L scale, 26% and 19% of pts reported moderate to extreme pain/discomfort and depression, respectively. In WPAI outcomes, 40 of 149 pts reported missing work due to PV accounting for 14.3% of their working time.
SUMMARY/CONCLUSION: Demographic and BL data from the RESPONSE-2 study highlight the significant unmet medical need in this inadequately controlled HU-resistant/-intolerant PV population. As expected, pts in RESPONSE-2 reported lower scores for symptoms associated with splenomegaly (early satiety, 1.8 vs 2.0; abdominal discomfort, 1.7 vs 2.0) as compared with RESPONSE population. In comparison to PV pts with splenomegaly in the RESPONSE trial, pts without splenomegaly in the RESPONSE-2 trial have a distinct but comparable disease burden with marked fatigue and pruritus.
Table 1. Baseline demographics and symptoms (n = 149) Age, median (range), years 66.0 (26.0, 87.0) Time since diagnosis of PV, median, months 80.7 Male, % 57.7 Female, % 42.3 ECOG performance status, % 0 1 72.5 26.8 Hematocrit (%), median,(n=149) 43.0 n (%) < 40 ≥ 40 to ≤ 45 > 45 2 (1.3) 146 (98.0) 1 (0.7) WBC count (x 109/L), median (n=149) 10.6 n (%) ≤ 10 > 10 and ≤ 15 > 15 67 (45.0) 43 (28.9) 39 (26.2) PLT count (x 109/L), median (n=148) 420.0 n (%) < 100 ≥ 100 and < 400 ≥ 400 to < 600 ≥ 600 2 (1.3) 68 (45.6) 38 (25.5) 40 (26.8) JAK2 mutation, n (%) (n=149) Positive Negative Unknown 143 (96.0) 4 (2.7) 2 (1.3) MPN-SAF Symptom (n) Mean (SD) Total score (n=145) 2.0 (1.67) Fatigue (n=146) 3.6 (2.72) Early satiety (n=145) 1.8 (2.47) Abdominal discomfort (n=143) 1.7 (2.44) Inactivity (n=142) 2.1 (2.77) Concentration problem (n=146) 2.3 (2.75) Night sweats (n=145) 2.2 (3.07) Pruritus (n=145) 3.4 (3.37) Bone pain (n=144) 2.1 (2.89) Fever (n=144) 0.2 (0.92) Weight loss (n=142) 0.7 (1.72)

Disclosures
Passamonti: Novartis: Consultancy. Cavo:JANSSEN, CELGENE, AMGEN: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Bensasson:Novartis: Employment. Khan:Novartis: Employment. Mounedji:Novartis: Employment.