Background: Inotuzumab ozogamicin (InO) is an anti-CD22 antibody-toxin conjugate that is effective in patients (pts) with relapsed/refractory ALL. Given the poor tolerance of elderly pts to intensive chemotherapy, we evaluated the safety and efficacy of low-intensity chemotherapy (mini-hyper-CVD) plus InO as frontline treatment for older pts with newly diagnosed ALL. Methods: Pts ≥60 years of age with newly diagnosed Ph-negative pre-B ALL received mini-hyper-CVD (no anthracycline, dose reductions of cyclophosphamide, dexamethasone, MTX and Ara-C). Pts received InO 1.3-1.8 mg/m2 on day 3 of cycle 1 and 0.8-1.3 mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. Results: 47 pts have been treated, 4 of whom were in CR at enrollment. Median age was 68 years (range, 60-81) and median CD22 expression was 97% (range, 72-100%). Among 43 pts evaluable for response, 41 (95%) achieved CR or CRp (CR, n = 36, CRp, n = 5). 1 pt achieved CRi and 1 did not respond. MRD negativity by 6-color flow cytometry was achieved in 31/41 pts (76%) after 1 cycle and in 44/46 pts (96%) overall. Median times to platelet and ANC recovery in cycle 1 were 23 and 16 days, respectively, and for subsequent cycles were 22 and 17 days, respectively. Prolonged thrombocytopenia ( > 6 weeks) occurred in 37 pts (79%). 4 pts (9%) developed VOD, 1 after allogeneic stem cell transplant (ASCT) and 3 unrelated to ASCT. Only 1 pt developed severe VOD. Among 46 responders, 6 (13%) relapsed, 3 (7%) underwent ASCT in CR1, 27 (59%) remain on treatment or have completed maintenance, and 10 (22%) died in CR/CRp. With a median follow-up of 24 months, the 3-year continued remission and OS rates were 72% and 54%, respectively. Compared to a historical cohort of older pts treated with hyper-CVAD ± rituximab (n = 79), mini-hyper-CVD + InO resulted in significantly higher 3-year OS (54% vs 31%; P = 0.007). Conclusions: Mini-hyper-CVD plus InO is safe and effective in elderly pts with newly diagnosed ALL and appears to improve outcomes compared to hyper-CVAD in this population. Clinical trial information: NCT01371630