ALBERT

Description: Abstract 1753 Background: Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life (QoL) in 2 phase 3 studies in patients with myelofibrosis (MF) (the COMFORT studies). These studies compared ruxolitinib with either placebo or best available therapy (BAT). This analysis compares the efficacy outcomes between the placebo arm from COMFORT-I and the BAT arm from COMFORT-II. Methods: COMFORT-I is a randomized (1:1), double-blind, multicenter study comparing ruxolitinib 15 or 20 mg twice daily (bid) with placebo, and COMFORT-II is a randomized (2:1), open-label, multicenter study comparing ruxolitinib 15 or 20 mg bid with BAT (investigator-selected therapy, including no treatment). Both studies met their primary end points with statistical significance (ruxolitinib vs control): the percentage of patients achieving ≥35% reduction in spleen volume at week 24 (COMFORT-I, P

Description: Abstract 1676 Background: Pts treated with nilotinib in the ENESTnd phase 3 trial achieved higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular responses (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), significantly lower rates of progression to accelerated phase/blast crisis (AP/BC), and fewer CML-related deaths compared with imatinib by 1, 2, and 3 y. Here, we report data with a minimum follow-up of 3 y; efficacy and safety data based on longer follow-up of 4 y will be presented to further assess the impact of nilotinib vs imatinib in pts with newly diagnosed Ph+ CML-CP. Methods: Adult pts (N = 846) with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID; n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD; n = 283). MMR, MR4, MR4.5, time to progression to AP/BC, progression-free survival (PFS), and overall survival (OS) were evaluated. Results: Significantly higher rates of MMR, MR4, and MR4.5 by 3 y were achieved in nilotinib- vs imatinib-treated pts (Table). Nilotinib led to the achievement of higher rates of molecular responses regardless of Sokal risk group or age. The difference in the rates of both MR4 and MR4.5 continued to be significantly higher for nilotinib, with the difference in favor of nilotinib increasing from 1 to 3 y (MR4: 9%-14% difference by 1 y, 18%-24% difference by 3 y; MR4.5: 6%-10% difference by 1 y, 13%-17% difference by 3 y). Among patients who achieved MMR, more pts achieved MR4 or MR4.5 on nilotinib 300 mg BID (68%) and nilotinib 400 mg BID (62%) compared with imatinib (49%). No pt in any arm progressed after achieving MR4.5. Significantly fewer pts progressed to AP/BC on nilotinib vs imatinib (Table). No new progressions occurred on core treatment between the 2-y and 3-y analyses. When events occurring after treatment discontinuation were included, the rates of progression to AP/BC were also significantly lower with nilotinib vs imatinib (Table). Nearly twice as many pts had emergent mutations on imatinib (n = 21) vs either nilotinib arm (n = 11 in each arm), with 5 pts overall developing mutations between 2 and 3 y. OS remained similar in all groups at 3 y, but fewer CML-related deaths occurred in both the nilotinib 300 mg BID (n = 5) and 400 mg BID (n = 4) arms vs imatinib (n = 14). Both drugs were well tolerated. Few new adverse events (AEs) and laboratory abnormalities were observed between 2 and 3 y. Rates of discontinuation due to AEs were 10%, 14%, and 11% in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib arms, respectively. Conclusions: Nilotinib continues to demonstrate superiority vs imatinib, yielding faster and deeper molecular responses and a significantly decreased risk of progression. Results of ENESTnd support the use of nilotinib as a standard of care option in newly diagnosed adult pts with Ph+ CML-CP and should be considered to replace imatinib as the standard-of-care frontline therapy for patients with Ph+ CML-CP. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Kim:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding; II-Yang: Research Funding. Clark:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reiffers:BMS: Expense reimbursement for travel expenses Other; Novartis: Expense reimbursement for travel expenses, Expense reimbursement for travel expenses Other. Nicolini:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Hochhaus:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Kemp:Novartis Pharmaceuticals Corp: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Waltzman:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding.

Description: Abstract 795FN2 Background: Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life (QoL) in 2 phase 3 studies in patients with myelofibrosis (MF) (the COMFORT studies). Per-protocol, patient-reported, health-related QoL (HRQoL) and symptoms analyses in the COMFORT-II study are limited. Here we report on additional post hoc analyses of these outcomes. The COMFORT-II study includes 219 patients (ruxolitinib, n=146; best available therapy [BAT], n=73). At entry, all patients were classified into intermediate 2-risk or high-risk prognostic groups (Cervantes F, et al. Blood, 2009;113(13):2895-2901) and had palpable splenomegaly ≥5 cm below the costal margin. Patients could have received prior therapy for MF. On BAT, doses and schedules or no therapy were selected by the investigator; therapy adjustments were permitted during the randomized treatment phase at the investigator's discretion. Patients in both arms continued in the randomized treatment phase as long as there was no protocol-defined disease progression. Methods: The European Organisation for the Research and Treatment of Cancer (EORTC) QoL Questionnaire–Core 30 (QLQ-C30) and Functional Assessment of Cancer Therapy–Lymphoma (FACT-Lym) questionnaires were assessed at baseline and weeks 8, 16, 24, and 48. EORTC QLQ-C30 consists of 30 items combined into 15 subscales (Global Health Status/QoL, 5 functioning subscales, and 9 symptom subscales; scores range from 0 to 100, and higher scores indicate better HRQoL and functioning but a worsening of symptoms). FACT-Lym consists of 42 items combined into 8 subscales (4 well-being subscales; 1 symptom subscale [LymS]; and 3 total scale scores: FACT-General [G], FACT-Lym trial outcome index [TOI], and FACT-Lym total; scores for the different subscales vary from 0–28 to 0–168, and higher scores indicate better outcomes). This analysis includes evaluable patients in the randomized treatment phase and assesses changes from baseline in HRQoL and MF symptom scores, including the EORTC subscales, LymS, and FACT total scores, which incorporate well-being and/or symptom subscales. Mixed-model analyses, adjusted for age, sex, baseline score, and prognostic risk category, are used to evaluate treatment differences at each time point and overall across time. Results: HRQoL and MF symptoms, on average, improved compared with baseline for patients receiving ruxolitinib, but remained the same or worsened for patients receiving BAT. Based on the EORTC QLQ-C30, the treatment differences in physical functioning, role functioning, fatigue, and appetite loss significantly favored ruxolitinib starting at week 8 (P

Description: Epoetin alfa (EPO) 40,000–60,000 U SC once weekly (QW) has been shown to increase hemoglobin (Hb) by ~2 g/dL after 8-12 wks in anemic patients (pts) with cancer receiving chemotherapy (CT). The proportion of pts achieving a hematologic response (HR; Hb ≥12 g/dL and/or Hb increase ≥2 g/dL from baseline [BL]) at this dosage was ~70%. It was hypothesized that higher initiation doses of EPO may result in earlier HR and improved HR rates. This nonrandomized, open-label, pilot study was designed to investigate the safety and efficacy of EPO 80,000 U SC QW for up to 12 wks in anemic (Hb ≤11 g/dL) pts with nonmyeloid malignancies undergoing CT. If Hb increased to 〉13 g/dL, EPO was held until Hb ≤12 g/dL, then dose reduced by 20,000 U. Dose was similarly reduced if Hb increased 〉1.3 g/dL in 2 wks. Primary endpoint was proportion of pts with a major response, defined as HR. Secondary endpoints included proportion of pts with a minor response (Hb increase ≥1 g/dL but

Description: Abstract 3166 Background: In ENESTnd, nilotinib (NI) significantly reduced progression and demonstrated superior molecular response rates vs. imatinib (IM) in patients newly diagnosed with Philadelphia chromosome positive chronic phase chronic myelogenous leukemia (CML-CP). Additionally, fewer NI patients discontinued therapy vs. IM (Table 1). Previously reported 24-month analyses of PROs indicated similar health-related quality of life (HRQoL) and functioning mean scores between the treatment arms, and scores similar to general population norms. Aim: To evaluate the PROs for patients in ENESTnd with minimum follow-up of 36 cycles and to understand cohort-level (per treatment arm) HRQoL outcomes Methods: In ENESTnd, nNewly diagnosed CML-CP patients were randomized to NI 300 mg twice daily (BID), NI 400 mg BID, or IM 400 mg once daily (QD). HRQoL was assessed using the Functional Assessment of Cancer Therapy – Leukemia (FACT-Leu) and the Short Form 36 Health Survey (SF-36). The FACT-Leu has two components: a) the FACT-General (FACT-G) which measures physical, social/family, emotional, and functional well-being and b) a 17-item leukemia specific subscale. The SF-36 assesses eight domains (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health) that enable a mental component score (MCS) and physical component score (PCS). Questionnaires were administered at enrollment and end of cycles 3, 12, 24, and 36. Mixed effects models for longitudinal data were used to compare trends over time between treatment arms. Study discontinuation prevented collection of PROs from patients with inadequate response or intolerance to treatment. Pattern-mixture models were fit to attempt to control for missing PRO data resulting from discontinuation or other reasons. Separately, missing data were imputed consistently across arms for cohort-level analysis of the FACT-Leu subscale so mean cohort scores could be reported (Table 1). Results: In both mixed effects and pattern-mixture models, FACT-Leu subscale, FACT-G, and SF-36 scores (PCS and MCS) were similar across treatment arms over time. Of the patients remaining on study and completing PRO questionnaires, SF-36 PCS and MCS scores at cycle 36 in all arms were comparable to the general US population; FACT-G scores were slightly better (Table 2). In the cohort-level analysis with imputation according to reason, IM FACT-Leu subscale scores began to trend increasingly lower vs. NI arms beginning at day 168 (Figure 1). By day 1008, the IM arm mean score is 10% and 13% lower than the NI 300 mg and NI 400 mg arms, respectively (Figure 1). Higher rates of discontinuation in the IM arm are the main factors that lead to the HRQoL deficit. Conclusions: In ENESTnd, patients who respond to and tolerate treatment have consistent HRQoL that is comparable to the general population. Cohort-level analysis indicates that discontinuation rates due to inadequate response and intolerance must be considered when determining the HRQoL across the entire cohort. These results suggest that in a population of newly diagnosed patients with CML-CP, NI results in higher HRQoL than IM. These findings may have particularly important implications for payers and policy makers when evaluating treatment options. Disclosures: Beaumont: Novartis: Research Funding. Magestro:Novartis: Employment. Coombs:Novartis: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Kemp:Novartis Pharmaceuticals Corp: Employment. Waltzman:Novartis: Employment.

Description: Background: An exploratory endpoint of the IRIS trial was measurement of BCR-ABL transcripts over time and its correlation with long-term outcomes. BCR-ABL measured by polymerase chain reaction (PCR) was required per protocol only after achievement of a complete cytogenetic response (CCyR). However, preplanned substudies occurred at sites in Germany and Australia who conducted PCR measurements on pts at intervals from the start of treatment independent of cytogenetic response (CyR). Additionally, other IRIS investigators contributed non-protocol specified molecular assessments. This first entire PCR dataset from IRIS assesses the prognostic value of molecular response (MR) at specific time points. Methods: 553 pts were enrolled onto the IM arm of IRIS; of these, 476 pts with at least one PCR measurement form the basis for this analysis. A major molecular response (MMR) is defined as the ratio of BCR-ABL/control gene (BAC) of ≤0.1%. Analyses were conducted at 6, 12 and 18 mo relating BAC percent reduction to event free survival (EFS), where events were defined as death during study treatment, loss of complete hematologic response, loss of Major CyR (MCyR), progression to accelerated phase (AP) or blast crisis (BC), or an increasing white blood cell count to 〉 20 × 109/L. Results: Among pts receiving first line IM for CML-CP, MMR was observed in 13% of samples available for study at 3 mo, 33% at 6 mo, 50% at 12 mo, 65% at 18 mo, 75% at 48 mo, 85% at 60 mo, and 86% at 72 mo. The degree of molecular response in pts who achieved CCyR is described in Table 1. This exploratory analysis demonstrates close correlation between CCyR and BAC ≤1% at 6 months and beyond. Table 1. Correlation of CCyR with molecular response at 3, 6, 12 and 18 mo. Time point Pts with CCyR and PCR samples available (n) CCyR and ≤0.1% BAC [MMR], n (%) CCyR and ≤1% BAC, n (%) 3 mo 51 17 (33%) 38 (75%) 6 mo 127 61 (48%) 114 (90%) 12 mo 177 110 (62%) 168 (95%) 18 mo 163 127 (78%) 154 (94%) At 6 mo, half of the pts with BAC 〉10% who also had a cytogenetic assessment at the same time had at least a partial cytogenetic response (PCyR) with an EFS of 91% at 72 mo, and 64% of these pts achieved MMR later. The other half of the pts with 〉10% BAC who did not have a PCyR at 6 mo had an EFS of 43%, and 31% later achieved MMR. A separate landmark analysis by CyR status alone showed EFS rates at 72 mo of 92% for pts in CCyR, 86% for pts in PCyR, 60% for Minor/Minimal CyR and 49% for No CyR. At 12 mo, pts with BAC ≤ 1% had excellent long term outcomes (72 month EFS of 〉90%, 〉95% without progression to AP/BC). Those pts with BAC 〉 1–≤ 10% (n = 36) had a 67% EFS, and 44% later achieved an MMR. These molecular analyses compare similarly to cytogenetic analyses alone (Baccarani et al; ASH 2006), with 60 mo EFS of 93% for pts in CCyR, 78% for pts in PCyR and 61% for pts without PCyR At 18 mo, pts with MMR could be statistically distinguished from pts with BAC 〉0.1–≤ 1%; EFS was 98% versus 89%, p=0.0137 (with 6 events in each group). The rate without AP/BC at 72 mo was not significantly different (with only 2 events in the 〉0.1 – ≤ 1% group). Baccarani et al (ASH 2006) reported an EFS at 60 mo of 96% for pts in CCyR, 80% for pts in PcyR and 69% for pts without PCyR. Table 2: Long-term outcomes (estimated rates at 72 mo) by MR levels at 6, 12 and 18 mo. BCR-ABL categories ≤0.1% (MMR) 〉0.1 −≤1% 〉1 −≤10% 〉10% *P=.0137. None of the other comparisons between MMR and 〉 0.1–≤1% BAC were statistically significant. 6 mo landmark N=86 N=89 N=44 N=39 EFS rate at 72 mo 90% 94% 88% 55% Without AP/BC at 72 mo 96% 100% 95% 74% 12 mo landmark N=153 N=90 N=36 N=26 EFS rate at 72 mo 94% 93% 67% 46% Without AP/BC at 72 mo 100% 96% 83% 76% 18 mo landmark N=164 N=48 N=25 N=16 EFS rate at 72 mo 98%* 89%* 67% 47% Without AP/BC at 72 mo 100% 96% 83% 82% Conclusion: In pts on first-line IM, MMR rates increase over time, and in pts who achieved an MMR at any time point progression is rare. Achievement of a CCyR correlated well with BAC of ≤1% from 6 mo onwards. Exploratory molecular analyses show pts with BAC 〉10% at 6 mo have EFS rates distinguishable by their cytogenetic status. At 12 mo, pts with a BAC 〉 1% or without CCyR, fare more poorly than those with BAC ≤ 1% or those in CCyR. At 18 mo pts with BAC ≤ 1% have excellent long term outcomes, with the best outcomes seen in those with BAC ≤ 0.1%. Molecular and cytogenetic evaluations are recommended until at least CCyR is achieved, with molecular assessments measured indefinitely thereafter.

Description: Abstract 279 Background: COMFORT-II is a randomized, open-label, phase 3 study evaluating the safety and efficacy of ruxolitinib, a potent and selective oral inhibitor of JAK1 and JAK2, in patients with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). Patients who received ruxolitinib had significantly greater reductions in spleen volume compared with those who received best available therapy (BAT). The primary and key secondary endpoints of the study were both met: the proportion of patients achieving ≥35% reduction in spleen volume at week 48 (28.5%, ruxolitinib; 0%, BAT; P