Salvage Chemotherapy with Inotuzumab Ozogamicin (INO) Combined with Mini-Hyper-CVD for Adult Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Background: Outcome of patients with R/R ALL is very poor. INO is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in R/R ALL with a response rate of 58% and median survival of 6.3 months. The addition of non-myelosuppressive therapy to effective low-intensity chemotherapy might further improve clinical outcome. Methods: Patients ≥18 years with R/R ALL were eligible. The chemotherapy was lower intensity than conventional hyper-CVAD 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 intrathecal chemotherapy were given for first 4 courses. IO was given on Day 3 of each of the first 4 courses. Patients received INO at 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. Results: Forty-eight patients (23 men, 25 women) have been enrolled so far. Patient characteristics and outcome are summarized in Table 1. Median age is 35 years (range 9-87). Median follow-up is 9.4 months (range, 1-27), and patients received a median of 2 cycles (1-8). Of 46 evaluable patients (2 patients, too early to assess response), 5 patients (11%) were refractory to mini-hyper-CVD + INO and died of progressive disease. Early death was encountered in 7 (15%) patients. The overall response rate was 74%: 24 (52%) CR, 8 (17%) CRp, and 2 (4%) marrow CR. Grade 3-4 non-hematological toxicities included infections, mucositis, increased LFTs, and VOD (n=6; 1 in a patient who had prior allo-SCT; 1 at D35 of CAR T-cell; and 3 post allo-SCT following INO therapy). Four (9%) patients were switched early to maintenance therapy due to poor performance status (n=1), infectious complications (n=2), and prolonged myelosuppression (n=1). Nineteen (41%) patients proceeded to receive allo-SCT. At the last follow-up, 20 (43%) patients are alive in response; 2 (4%) too early to assess response; 4 (8%) relapsed post transplantation. 22 (43%) patients died: 7 early death; 5 refractory disease; 5 post relapse after subsequent salvage, 1 post-transplantation VOD, 3 due to post-transplant complications, and 1 in response to IO due to sepsis and multiple organ failure. The 1-year PFS and OS rates were 60% and 46%, respectively. Median survival for patients with CR/CRp/marrow CR was 18 months versus 1 month in patients with refractory disease (p Conclusions: The combination of INO with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with R/R ALL. The risk of VOD should be considered carefully for patients with previous liver damage and transplant candidate. Lower dose schedule of INO are being explored. Disclosures O9Brien:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Cortes:ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.