8058 Background: R-CHOP14 delivery in pts with poor IPI score and/or EBV+ and cardiac morbidity, may be hampered by acute, early and late cardiac toxicity from dose-dense doxorubicin. Non-pegylated liposome-encapsulated doxorubicin (NPLD) is accounted as equivalent to free doxorubicin with less cardiac adverse events (CAE). Methods: Untreated pts (median age 73 y, r 62-82) with IPI 3-5 DLBCL and moderate-high ‘life threat’ impact cardiac comorbidity [lymphoma-validated NIA/NCI index (Janssen-Heijnen 2005)], entered a phase II study of 6 biweekly courses of R-COMP14 (R-CHOP with doxo replaced by 50 mg/m2 of NPLD; Myocet). Therapy was given as inpatients with close cardiac monitoring. A CrCl >30 ml/min and left ventricular ejection fraction (LVEF) ≥0.45 were required. Age-adjusted Charlson Comorbidity Index (aaCCI) was used to weight comorbidity. Results: 41 pts were enrolled and 208 courses delivered at a median interval of 15.6 days (r 13-29); 67% of pts received all 6 courses. ORR was 73 %, with 68% CRs and 72% of 4y-DFS. Time to treatment failure (TTF) was 49% at 4 y (95% CI, 33-65%, median 19.2 mo.s). At a median of 27 mo.s, 20 failures occurred: 3 early deaths [day +12 (undefined) and +13 (sepsis), 1st cycle; day +18 (sepsis), 2nd cycle]; 8 therapy discontinuations due to no-response (n=2) and toxicity (n=6) [widespread zooster (n=1), CTCAE v3.0 G3 decrease in LFEV (n=3) and G3 arrhythmia (n=2)]; 6 relapses; 3 deaths in cCR due to cyrrhosis (n=1) and late CAE (n=2). Cumulative incidence of CAE-related failures was 7/41 (17%, 95% CI: 8-31%). AaCCI correlated with failures (P= 0.007) and pts with score ≤ 7 had a longer survival (66% vs 29%; P = 0.009). Time to progression (TTP) at 4 y was 77%; 4 CRs (TTP: 12, 16, 20+, 29+ mo.s) and 2 PRs (TTP: 8 and 14 mo.s) were registered among pts discontinuing treatment for toxicity. The estimated 4-y OS was 67%. Conclusions: R-COMP14 ensures a 'curative' strategy with high DFS to high risk elderly pts who would have been denied active treatment due to cardiac morbidity. Early occurrence of CAE, irrespective of total NPLD dose, dictates a close cardiac monitoring and/or shorter therapy. The aaCCI score predicts treatment failure due to CAE and early death.