Background: Outcome of pts with R/R ALL is poor. IO, a CD22 monoclonal antibody bound to a toxin, calicheamicin, has single-agent activity in R/R ALL with response rate of 80% and median survival of 7.7 months. Adding IO to low-intensity chemotherapy might further improve clinical outcomes. Methods: Pts ≥18 years with R/R ALL were eligible. Chemotherapy was of lower intensity than standard hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction (DR), no anthracycline, methotrexate at 75% DR, cytarabine at 0.5 g/m² x 4 doses). Rituximab (if CD20+ blasts) and intrathecal chemotherapy were given for first 4 courses. IO was given on day 3 of each of the first 4 courses at a dose of 1.8 mg/m2 for cycle 1 then 1.3 mg/m2 for subsequent cycles. After the occurrence of veno-occlusive disease (VOD), IO was modified to 1.3 mg/m2 for cycle 1 followed by 1.0 mg/m2 for subsequent cycles. Results: Sixty pts with a median age of 35 years (range 18-87) were treated. Overall, 47 pts (80%) responded, 32 of them (54%) achieving complete response. The overall minimal residual disease negativity rate among responders was 82%. Grade 3-4 toxicities included prolonged thrombocytopenia (79%), infections during induction and consolidations (52%, and 73% respectively), and hyperbilirubinemia (13%). VOD of any grade occurred in 9 patients (15%). At a median follow-up of 19 months, the median relapse-free survival (RFS) and overall survival (OS) were 9 and 11 months, respectively. The 2-year RFS and OS rates were 33% and 38%. The 2-year OS rates for patients treated in salvage (S)1, S2, and S3 and beyond were 53%, 0%, and 34%, respectively (p = 0.005). When compared to IO monotherapy in a similar pts population, a significant improvement in OS was observed (11 and 6 months, respectively; p = 0.003). Conclusions: The combination of IO with low-intensity mini-hyper-CVD chemotherapy is effective in pts with R/R ALL. Results are encouraging and appear superior to those obtained with IO alone, particularly in pts treated in S1. The risk of VOD should be considered carefully for transplant candidates and pts with previous liver damage. Lower dose of weekly schedules of IO are being explored Clinical trial information: NCT01371630