Background: In vitro studies showed that ofatumumab (O), a type I human antibody that targets a different CD20 epitope compared to rituximab, induces more potent antibody-dependent and complement mediated cell death. We hypothesized that substituting rituximab with ofatumumab, as part of Hyper-CVAD (HCVAD) regimen, may further improve outcomes in pts with Philadelphia chromosome (Ph) negative CD20+ ALL. Methods: Pts received 4 cycles (cy) of HCVAD [cy 1, 3, 5, 7 consisted of cyclophosphamide, doxorubicin, vincristine, and dexamethasone] alternating with 4 cy of methotrexate-cytarabine (MTX-ara-C, even cy 2, 4, 6, 8). Ofatumumab was infused on day 1 and 11 of cy 1 and 3; and day 1 and 8 of cy 2 and 4. For maintenance, pts received POMP, and late intensification with MTX/PEGylated asparaginase and O-HCVAD. Intrathecal MTX-Ara-C was used for CNS prophylaxis. Minimal residual disease (MRD) was assessed using multiparameter flow cytometry. Results: A total of 68 pts were enrolled (Table) and 65 were evaluable for response. Sixty-four pts (98%) achieved CR/CRp, 39/62 (63%) achieved negative MRD at time of CR, and 62/67 pts (93%) achieved negative MRD overall. Time to negative MRD was median 0.7 mo (range, 0.4-7.8). Pts received one to eight (median: 8) cy of intensive phase chemotherapy. The most common non-hematologic grade 3/4 toxicitiy was infection; occurred in 37 (56%) and 55 (81%) pts during induction and consolidation, respectively. At median 27 mo of follow-up (range 4-73), 51 pts (75%) are alive; 17 pts (25%) are receiving maintenance, 15 pts (22%) have relapsed, 14 pts (21%) have completed maintenance, and 12 pts (18%) have received ASCT in CR1. The 2-year CRD and OS were 79% and 81%, respectively. The 2-yr OS was 80% in both pts with <20% and ≥20% CD20 expression. Conclusions: O-HCAVD is highly effective and safe combination regimen in pts with CD20+ Ph-negative ALL. Clinical trial information: NCT01363128