Saha, Chandan

Abstract MAJIC is a phase II trial of Ruxolitinib (RUX) vs Best Available Therapy (BAT) in polycythemia vera (PV) patients with resistance/intolerance to Hydroxycarbamide (HC). This analysis involved a primary comparison between the RUX and BAT arms for quality of life (QOL) durability over 60 months, with secondary comparisons of best QOL response within first year in complete hematologic responders (CR) vs a group of partial or no response (NR/PR). This is a unique analysis due to cross-over nature of prior studies. Patients were stratified by treatment arm with either RUX or BAT. QOL was assessed over 0-60 months using the Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF). MPN-SAF Total Symptom Score (TSS) was computed as the average of all completed items multiplied by 10 (scale 0-100, higher score represents higher symptom burden). Estimates of change from baseline and between arm differences in change by timepoint were made using a linear mixed model with compound symmetry covariance structure, which included covariates for categorical time point, treatment arm, and the interaction between time point and treatment arm. The difference between arms in proportion of patients with best post-baseline TSS response of 50% or greater was testing using a Chi-square test. In this study, 147 of the 190 trial patients had started treatment and completed at least their baseline assessment and were included in the analysis with 39 patients completing through 60 months. Groups were comprised of 76 patients in the RUX group (31 females, 45 males, mean age 64.2 [SD 11.4]) and 71 patients in the BAT group (29 females, 42 males, mean age 64.6 [SD 11.5]). Symptom scores at baseline were similar between arms, with MPN-SAF weight loss the only statistically significant difference (BAT 0.7 [SD 1.71] vs RUX 1.7 [SD 2.83], p=0.02). Significant, durable improvements in TSS were noted in RUX patients with symptom improvements lasting a mean of 52 months. BAT patients experienced a worsening of their symptom burden with improvements back to baseline notable at 56 months (Figure 1). MPN-SAF TSS there were significant differences between treatment arms in change from baseline to months 2-32, 44, and 48 (all p<0.05). In all months the trend was in the direction of larger improvement in the RUX arm, with the point estimate for difference ranging from 2.1 (at month 56) to 11.3 (at month 4) with most prominent changes occurring between months 2 and 32. Of the 80 patients with MPN-SAF TSS scores at baseline and at least one post-baseline timepoint, 13/41 (31.7%) BAT and 24/39 (61.5%) RUX patients had TSS reduction of 50% or greater in at least one time point, which was statistically significant (p=0.008). In regard to specific symptoms, there was a statistically significant between arm difference seen in over 5 timepoints for fatigue, early satiety, night-sweats, itching, bone pain, and weight loss. Comparing MPN-SAF TSS in Complete Response (CR n=51) vs Non-Responder/Partial Responders (NR/PR) (n=96) there was no difference at baseline in any of the measures at any time point. A possible limitation of this study is the potential for bias in which the patients who were lost to follow up could be different then the patients who remained in the study through all 60 months which would affect generalization, particularly at time points at the later years. The novel findings of this investigation demonstrate that Ruxolitinib ameliorates the PV symptom burden in patients resistant or intolerant to HC in a robust durable manner over at least four years, while patients receiving BAT have worsening of their symptom burden over this same time period. Figure 1 Figure 1. Disclosures Mead: Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Yap: Celgene: Honoraria; Faron Pharmaceuticals: Honoraria. Scherber: Incyte Corporation: Current Employment, Current holder of stock options in a privately-held company. Knapper: Novartis: Consultancy, Research Funding, Speakers Bureau; Astellas: Ended employment in the past 24 months, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Drummond: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI: Membership on an entity's Board of Directors or advisory committees. McMullin: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Research Funding, Speakers Bureau. Mesa: CTI: Research Funding; AOP: Consultancy; Celgene: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Pharma: Consultancy; Promedior: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; CTI: Research Funding; Samus: Research Funding; Sierra Oncology: Consultancy, Research Funding; Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; Abbvie: Research Funding; La Jolla Pharma: Consultancy. Harrison: CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Sierra Oncology: Honoraria; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract The myeloproliferative neoplasms (MPN) polycythaemia vera (PV) and essential thrombocythaemia (ET) are associated with significant symptom burden with impaired quality of life (QoL). In the MAJIC study patients refractory/intolerant to hydroxycarbamide (HC), were randomised to treatment with ruxolitinib (Rux) or best available therapy (BAT). In this unique and comprehensive analysis we explore quality of life (QoL) outcomes in the MAJIC study using the MPN10 Self-Assessment Form (SAF) in particular using this unique dataset to explore for the first time differences between JAK2 ET vs PV, and JAK2 ET vs CALR ET at baseline and 12 months of therapy with Rux or BAT. Methods 306 patients were randomised, (190, PV and 116 ET arm) and followed for 5 years, no cross over was permitted. MPN10 SAF was assessed at baseline, 2, 4, 8 and 12 months in both arms. Equal variance two sample t-tests were used to test differences between diagnosis groups (JAK2 ET vs PV & JAK2 ET vs CALR ET) in baseline scores and 12-month change from baseline scores, here negative change from baseline indicates improvement. QoL data was also collected using MD Anderson Symptoms Inventory (MDASI) and 5 level EQ5D at the same time points as the MPN10 SAF. Results JAK2 ET vs PV 110 participants with JAK2 mutation were included in the analysis for JAK2 ET vs PV. 81 (74%) had PV and 29 (26%) had JAK2 ET; 44 patients (54.3%) with PV and 18 (62.1%) patients with ET were randomised to Rux, and 37 (45.6%) patients with PV and 11 (37.9%) with ET to BAT. Baseline mean total symptom score (TSS) was similar (JAK2 ET: 18.9. SD 18.4 and PV: 23.7, SD 17.81 (p=0.27). Mean for pruritus was 1.9 (SD 2.47) in JAK2 ET and 3.5 (SD 2.99) in PV (p=0.03). Other baseline scores were comparable: mean scores for fatigue was 3.3 (SD 3.07) for JAK2 ET vs 4.7 (SD 2.68) for PV, for early satiety was 2.6 (SD 2.78) for JAK2 ET vs 2.1 (SD 2.40) for PV, for abdominal discomfort 3.0 (SD 3.34) for JAK2 ET vs 2.0 (SD 2.78) for PV, for inactivity was 2.4 (SD 2.86) for JAK2 ET vs 3.2 (SD 2.72) for PV; for concentration problems was 2.2 (SD 2.51) for JAK2 ET vs 2.9 (SD 3.11) for PV, for night sweats was 1.6 (SD 2.20) for JAK2 ET vs 2.1 (SD 2.66) for PV, for bone pain was 1.8 (SD 2.97) for JAK2 ET vs 2.0 (SD 2.86) for PV, for fever was 0.5 (SD 1.46) for JAK2 ET vs 0.5 (SD 1.70) for PV and for weight loss was 0.3 (SD 0.73) for JAK2 ET vs 1.0 (SD 2.15) for PV (p>0.05 for all). Concerning change at 12 months, mean (SD) change in TSS was -0.5 (SD 10.86) for JAK2 ET (n=21) vs -0.8 (SD 13.32) for PV (n=66) (P=0.93). Mean for individual symptom scores at 12 months were also not significantly different between the two phenotypic disease group (P>0.05 for all parameters). (Fig 1, top panels). CALR vs JAK2 ET Exploring symptoms for CALR vs JAK2 ET: 45 patients were included; 9/16 (56.3%) CALR and 18/29 (62.1%) JAK2 patients were assigned to Rux (p=0.70). 10/16 (62.5%) CALR ET and 19/29 (65.5%) JAK2 ET. Baseline mean total symptom score (TSS) was similar (JAK2 ET: 18.9, SD 18.4 and CALR ET: 18.8, SD 16.99 (p=0. 0.98). All other baseline scores were comparable in this intolerant/ refractory population (p>0.05 for all. Concerning change at 12 months, mean (SD) change in TSS was -0.5 (SD 10.86) for JAK2 ET vs -2.8 (SD 9.96) for CALR ET (P=0.56). Mean for individual symptom scores at 12 months were also not significantly different between the two phenotypic disease group (P>0.05 for all parameters); the mean change in night sweats approached but did not reach significance similar (JAK2 ET: 0.2 (SD 1.89) and CALR ET: 1.8 (SD 3.07) (p=0. 0.06). (Fig 1, lower panels). Preliminary analysis of the MDASI and EQ5D-5L data at baseline and at 12 months shows similar results and will be presented. Conclusion This first analysis of its kind compared the symptom burden and other parameters of QoL of patients with PV and ET, resistant/intolerant to HC shows that with the exception of pruritus at baseline there were no substantial differences between JAK2 ET or PV. Equally changes in symptom burden across 12 months did not substantially differ between JAK2 ET or PV. A second analysis of JAK2 vs CALR ET also failed to show substantial differences. This data should be expanded in a larger cohort but supports a symptom continuum of JAK2 ET and PV and also JAK2 vs CALR ET. Figure 1 Figure 1. Disclosures Mead: Abbvie: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau. Yap: Faron Pharmaceuticals: Honoraria; Celgene: Honoraria. Knapper: Novartis: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Drummond: CTI: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mesa: Pharma: Consultancy; CTI: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Gilead: Research Funding; AOP: Consultancy; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy; La Jolla Pharma: Consultancy; Samus: Research Funding; Promedior: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding; CTI: Research Funding. Scherber: Incyte Corporation: Current Employment, Current holder of stock options in a privately-held company. McMullin: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding. Harrison: CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.