Background: Outcome of older pts with ALL and those with R/R disease is poor. Addition of IO to effective low-intensity chemotherapy might improve outcome. IO is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in R/R ALL. Methods: Pts ≥60 years (yrs) with newly-diagnosed ALL and pts ≥18 yrs with R/R disease were eligible. Chemotherapy was low intensity and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m² x 4 doses). Rituximab and IT chemotherapy were given for first 4 courses. IO was given on Day 3 of each of the first 4 courses. The first 6 pts received 1.3 mg/m² for course 1 and 0.8 mg/m² for subsequent cycles; pt 7 onwards received 1.8 mg/m² for course 1 and 1.3 mg/m² for subsequent cycles. Results: 44 pts were treated so far (Table). Grade 3-4 non-hematological toxicity included increased LFTs in 5 (11%): VOD in 1 (2%). 10 pts (23%) were switched early to maintenance due to thrombocytopenia and infectious complications. Of the 20 pts with de novo ALL, 16 (80%) are alive:14 (70%) in CR from 1 to 25 mos, 2 relapsed after 12 and 3 mos; and 4 died, 3 in CR (sepsis in 2, gun shot in 1) and 1 did not achieve CR and died 2 mos later after receiving a salvage regimen. At the last follow-up, 17 of the 24 pts (71%) with R/R ALL are alive:15 (63%) in response from 1 to 10 mos, 2 relapsed after 1 and 2 mos; and 7 died: 4 early death within 3 weeks, and 3 from resistant disease. Conclusions: IO + low-intensity mini-hyper-CVD is safe and shows very encouraging results (95% ORR) in the frontline setting in older pts with ALL and as a salvage approach (75% ORR). These results appear to be better than those achieved with a chemotherapy only approach and may become the new standard of care. Clinical trial information: NCT01371630.