Reduced-Intensity Chemotherapy with Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: Results from a Phase II Study

Background: Inotuzumab ozogamicin (INO) and blinatumomab both improve overall survival (OS) in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). Use of these effective monoclonal antibodies in the frontline setting may lead to deep and durable remissions in older adults with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL. Methods: Patients (pts) ≥60 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received 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) for up to 8 cycles. INO was initially given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/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. In order to decrease the risk of veno-occlusive disease (VOD), the protocol was amended in 3/2017 (pts 50+) to give INO in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and to administer 4 cycles of blinatumomab following 4 cycles of hyper-CVD plus INO, followed by maintenance with 12 cycles of POMP and 4 cycles of blinatumomab (1 cycle of blinatumomab after every 3 cycles of POMP). The cumulative dose of INO given before and after this most recent amendment was 4.3 mg/m2 and 2.7 mg/m2, respectively. Results: 73 pts have been treated, 70 of whom are evaluable for efficacy (3 pts too early for response assessment). 6 pts were in complete remission (CR) at enrollment and unevaluable for morphological response. Pt characteristics of the 70 evaluable pts are summarized in Table 1. Median age was 68 years (range, 60-81 years); 29 pts (41%) were ≥70 years. 41% were positive for TP53 mutation, 18% were CRLF2 positive by flow cytometry, and 27% had adverse-risk karyotype. 38/64 pts (59%) were CD20+ and received rituximab. Among 64 pts evaluable for morphologic response, 63 (98%) responded (CR, n=56; CRp, n=6; CRi, n=1). MRD negativity by flow cytometry was achieved in 53/66 pts (80%) after 1 cycle and 65/68 pts (96%) overall. There were no early deaths, and the 30-day and 60-day mortality rat