Abstract 1126 Poster Board I-148 Background The IRIS study demonstrated superior safety and efficacy of imatinib (IM) relative to interferon-αa + cytarabine. Based on results from this trial, IM is currently recommended as front-line therapy for CML-CP patients (pts). We report 8-yr follow-up of IRIS, evaluating long-term efficacy and safety of IM.Methods The 553 pts randomized to first-line IM were evaluated for cytogenetic and molecular responses, event-free survival (EFS), progression to accelerated-phase (AP) or blast crisis (BC), overall survival (OS), discontinuations, and frequency of serious adverse events (SAEs). EFS was defined as time until the first occurrence of any of the following: death from any cause, progression to AP/BC, loss of a complete hematologic response or major cytogenetic response, or an increasing white cell count to > 20 × 109/L. Yearly progression rates were calculated using the life-table method considering available follow-up. Following study drug discontinuation, pts were followed for OS and stem cell transplant (SCT) information.Results At the 8-yr data cut-off, 304 (55%) pts remained on IM study treatment, and 45% had discontinued treatment due to adverse events (AEs)/safety (6%), unsatisfactory therapeutic outcome (16%), SCT (3%), death (3%) or other reasons (17% for withdrawal or lack of renewal of consent and miscellaneous). No new safety issues were identified in a long-term analysis of serious adverse events.Estimated EFS at 8 yr was 81% and freedom from progression to AP/BC was 92%. Estimated OS was 85% at 8 yr, and 93% when only CML-related deaths and those prior to SCT were considered. Three events occurred in yr 8: 1 progression to AP/BC and 2 deaths unrelated to CML (chronic obstructive pulmonary disease ; pneumonia aspiration ). The annual rates of progression to AP/BC in yr 4 to 8 after initiation of therapy were 0.9%, 0.5%, 0%, 0%, & 0.4%, respectively. Only 15 (3%) pts who achieved complete cytogenetic response (CCyR) progressed to AP/BC, all but 1 within 2 yr of achieving CCyR.BCR-ABL transcript numbers were monitored sequentially in 98 pts. Among these, the rate of major molecular response (MMR, < 0.1% BCR-ABL/control gene ratio on international scale) increased from 24% at 6 months (mo) and 39% at 12 mo to a best observed MMR rate of 86% with current follow-up. None of the pts with documented MMR at 12 mo progressed to AP/BC.To establish the relationship between early cytogenetic response (CyR) status and subsequent outcomes during 8 yr of IM treatment, we compared the cumulative incidence of achieving stable CCyR (defined as CCyR without subsequent event) vs the probability of an event (as described above but excluding CML-unrelated deaths) according to levels of CyR at 3, 6, 12, & 18 mo (Table 1). Pts with minor to partial CyR (> 0–65% Ph+ metaphases) at 3 mo and those with partial CyR (PCyR; > 0–35% Ph+ metaphases) at 6 & 12 mo were more likely to achieve a stable CCyR than have an event. Among pts with less than CCyR at 18 mo, the probability of an event was comparable to the probability of achieving stable CCyR. Time on therapy at karyotypingCytogenetic Response (% Ph+)3 mo6 mo12 mo18 moStable CCyR %Est. event rate %Stable CCyR %Est. event rate %Stable CCyR %Est. event rate %Stable CCyR %Est. event rate % 0 (CCyR) −6 [1,11]−7 [3,11]−6 [2,9]−3 [1, 6] >0–35 (PCyR) 72 [65,80]10 [5,15]63 [53,73]17 [8,26]57 [42,72]20 [7,33]29* [16,42]31* [15,46] >35–65 (minor) 55 [39,71]30 [15,45]35 [15,55]38 [16,60]14* [2,25]62* [42,81] >65–95 (minimal) 37 [19,54]32 [13,51]25 [3,47]45 [20,71] >95 (None) 32 [16,47]40 [22,58]32* [10,53]36* [12,60]↵* Cytogenetic response is considered “failure” according to European LeukemiaNet (ELN) guidelines.Table 1. Cumulative incidence of CCyR vs estimated event rate 8 yr after starting IM [with 95% confidence interval]Conclusions CML-CP pts responding to IM had a low overall risk of progression to AP/BC. Most AP/BC events occurred early, with minimal risk after yr 3 and no evidence for an increase over time. Minor CyR at 3, PCyR at 6 and 12, and CCyR at 18 mo were associated with stable CCyR over the observation period. The safety profile of IM remains unchanged after 8 yr, with no previously unreported AEs identified over the past 36 mo. These data suggest that pts responding to IM are likely to maintain their responses on long-term therapy and confirm a favorable risk-benefit ratio in CML-CP pts.Disclosures Deininger: Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding. O'Brien: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Wyeth: Research Funding. Guilhot: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Goldman: Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau. Hochhaus: Novartis: Research Funding. Hughes: Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Radich: Novartis: Consultancy, Honoraria, Research Funding. Hatfield: Novartis: Employment, Equity Ownership, Patents & Royalties. Mone: Novartis: Employment. Filian: Novartis: Employment. Reynolds: Novartis: Employment. Gathmann: Novartis: Employment. Larson: Novartis: Consultancy, Honoraria, Research Funding. Druker: OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding.