Background: Chemoimmunotherapy is an effective frontline therapy for acute lymphoblastic leukemia (ALL). Ofatumumab (O) binds to a proximal small-loop epitope on CD20 and is more potent in vitro than rituximab. Here we report interim results of its combination with hyper-CVAD (HCVAD) in adult patients (pts) with CD20+ ALL. Methods: Since 7/2011, we have enrolled 63 pts with Ph-negative CD20+ ALL (59 newly diagnosed, 4 previously treated). For the intensive phase, pts received 4 cycles (cy) of HCVAD (odd cy 1, 3, 5, 7) alternating with 4 cy of methotrexate-cytarabine (MTX-Ara-C, even cy 2, 4, 6, 8), and ofatumumab during cy 1-4. For maintenance, pts received POMP for ~30 months (mos), and intensification with MTX/PEGylated asparaginase on mos 6 and 18, and O-HCVAD on mos 7 and 19. Intrathecal MTX-Ara-C was used for CNS prophylaxis. Bulky mediastinal disease was irradiated when indicated. Results: Median age was 41 years (range: 18-71) and median WBC count was 4.6 x10⁹/L (range: 0.6-201 x10⁹/L). 22 pts (35%) had diploid cytogenetics and 8/35 pts (23%) had TP53 mutation. CD20 expression was > 20% in 38 pts (60%), 10-20% in 6 pts (10%) and 1-10% in 16 pts (25%). Median follow-up was 20 mos (range: 1-58) and median number of cy was 8 (range: 1-8). 3 pts (5%) were in CR at the time of enrollment. Of 60 pts evaluable for response, 58 pts (97%) achieved CR; 1 pt achieved CRp and 1 pt died during cy 1 from sepsis. Flow cytometric minimal residual disease (MRD) was negative in 57/62 pts (92%) overall, and in 36/57 pts (57%) at CR. Median time to negative MRD was 0.7 mos. Median time to platelet and neutrophil recovery in cy 1 was 21 and 18 days, respectively. The most common grade 3/4 non-hematological toxicities were infections during induction (49%) and consolidation (72%), elevated transaminases (35%), and hyperbilirubinemia (21%). 5 pts (7%) experienced a grade 3/4 transfusion reaction. 8 pts (13%) received stem cell transplantation in CR1. 10 pts (16%) have relapsed (8 morphological, 2 MRD only). Overall survival and 2-year CR duration rates were 80% and 81%, respectively. Survival outcomes were independent of percentage of CD20 expression. Conclusions: O-HCVAD is safe, effective and results in durable responses in pts with CD20+ ALL. Clinical trial information: NCT01363128