Background: Chemoimmunotherapy is standard of care for patients (pts) with CD20+ ALL. Ofatumumab targets a unique small-loop epitope on CD20 and is more potent in vitro than rituximab. The combination of ofatumumab with hyper-CVAD may improve outcomes in ALL. Methods: 53 pts with Ph- CD20+ ALL, newly diagnosed (n = 49) or previously treated with 1 course of therapy (n = 4, 3 of whom were in CR at enrollment), received 8 cycles (cy) of hyper-CVAD (cy 1, 3, 5, 7) alternating with methotrexate (MTX) and cytarabine (cy 2, 4, 6, 8); ofatumumab was given during cy 1-4. Pts then received POMP maintenance for approximately 30 months (mos), interrupted by intensification with MTX/pegylated asparaginase in mos 6 and 18 and hyper-CVAD plus ofatumumab in mos 7 and 19. Results: Median age was 41 years (range: 18–71); median WBC was 4.6 x 10⁹/L (range: 1-201 x 10⁹/L). 19 pts (36%) had diploid karyotype. 32 pts (60%) had CD20 expression > 20%, 5 (9%) 10-20 % and 13 (25%) 1-10%. Of 50 pts evaluable for response, 49 (98%) achieved complete remission (CR) after 1 cycle; 1 pt died of sepsis during cycle 1. 48/52 pts (92%) became negative for minimal residual disease (MRD) as assessed by multicolor flow cytometry; of them 34 (67%) at CR. Median time to MRD negativity was 0.7 mos (range: 0.4-7.8). Median number of cy given was 7 (range: 1-8). Median times to neutrophil and platelet recovery after cycle 1 were 18 and 21 days, respectively. 67% of pts had febrile neutropenia during induction and 89% during consolidation. Grade ≥ 3 toxicity included high AST/ALT in 13 pts (32%), hyperbilirubinemia in 7 (17%), neuropathy in 3 (7%) and infusion reaction in 3 (7%). With a median follow-up of 16 mos (range: 1-53), 44 pts (83%) are alive: 41 in CR, 16 of whom are receiving POMP maintenance and 5 have completed all treatment. 6 pts received an allogeneic stem cell transplant after a median of 5 mos from treatment start (range: 4-8). 9 pts have died: 6 of relapse, 2 of sepsis and 1 of intracranial hemorrhage. The 2-year CR duration and overall survival rates were 74% and 83%, respectively. Conclusions: The combination of ofatumumab with hyper-CVAD is safe and highly effective in pts with CD20+ Ph- ALL. Clinical trial information: NCT01363128