Long‐term follow‐up of salvage therapy using a combination of inotuzumab ozogamicin and mini–hyper‐CVD with or without blinatumomab in relapsed/refractory Philadelphia chromosome–negative acute lymphoblastic leukemia

BACKGROUND The outcome of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. The combination of inotuzumab with low‐intensity mini–hyper‐CVD (mini‐hyper‐CVD; cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 × 4 doses) chemotherapy has shown encouraging results. The sequential addition of blinatumomab might improve outcome in patients with R/R ALL. METHODS We used lower intensity chemotherapy, 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) compared to conventional hyper‐CVAD. RESULTS Ninety‐six patients with a median age of 37 years (range, 18‐87 years) were treated. Overall, 77 patients (80%) responded, 55 (57%) of whom achieved complete response. The overall measurable residual disease negativity rate among responders was 83%. Forty‐four (46%) patients underwent later allogeneic stem cell transplantation. Veno‐occlusive disease of any grade occurred in 10 (10%) patients. The rates were 13% with the original schedule and 3% with the use of lower‐dose inotuzumab and sequential blinatumomab. With a median follow‐up of 36 months, the median overall survival (OS) was 13.4 months, with 3‐year OS rates of 33%. The 3‐year OS rate for patients with CD22 expression ≥70% and without adverse cytogenetics (KMT2A rearrangements, low hypodiploidy/near triploidy) was 55%. CONCLUSION The combination of inotuzumab and low‐intensity mini‐hyper‐CVD chemotherapy with or without blinatumomab shows sustained efficacy in patients with R/R ALL. Low‐intensity chemo‐immunotherapy is safe and highly effective in patients with relapsed/refractory acute lymphoblastic leukemia. Reduced and weekly fractionated inotuzumab with sequential blinatumomab and selection of the least hepatotoxic preparative regimens can reduce toxicities and veno‐occlusive disease rates and may further improve outcomes.