Phase 2 Trial of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Background The introduction of inotuzumab ozogamicin (InO) and blinatumomab (blina) has drastically improved the overall survival (OS) of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Older patients with B-ALL have worse outcomes compared with younger patients due to the poor-risk biology of their disease and their inability to tolerate intensive chemotherapy. We aim to study the incorporation of InO and blina with low intensity chemotherapy in older patients with newly diagnosed (ND) B-ALL. Methods Adults ≥60 years with ND Philadelphia chromosome (Ph)-negative B-ALL who were untreated or had received up to two cycles of previous therapy were eligible. Other inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of ≤3 and adequate organ function. Patients with central nervous system (CNS) disease were eligible. Patients received mini-Hyper-CVD (mHCVD, cyclophosphamide 150mg/m 2 q12h D1-3, dexamethasone 20mg daily D1-4, 11-14, and vincristine 2mg D1, 8 alternating with methotrexate (MTX) 250mg/m 2 D1 & cytarabine 500mg/m 2 q12h D2, 3) for up to 8 cycles. Eight doses of intrathecal (IT) MTX /cytarabine were given for CNS prophylaxis; patients with CNS disease had IT hydrocortisone, MTX, and cytarabine twice weekly till CNS clearance, then weekly x4. Eight doses of rituximab 375mg/m 2 were given on D1, 8 of C1-4 if CD20 was ≥20% by flow cytometry. Initially, InO was given at 1.3-1.8mg/m 2 on D3 of C1 and 1.0-1.3mg/m 2 on D3 in C2-4. The protocol was amended from patient 50 such that InO was given in fractionated doses with a maximum cumulative dose of 2.7mg/m 2 (0.6 mg/m 2 on D2 of C1, 0.3 mg/m 2 on D8 of C1, then 0.3 mg/m 2 on D2 and D8 of C2-4). Ursodeoxycholic acid was given to all patients. Four cycles of blina 28µg/day replaced C5-8 of mHCVD + InO. Maintenance was initially with vincristine 2mg D1, prednisolone 50mg daily D1-5, 6-mercaptopurine 50mg BID & MTX 10mg/m 2 weekly (POMP) for three years. After the protocol amendment, this was reduced to 12 cycles of POMP, with one cycle of blina given after every three POMP cycles (total four blina cycles). Results 83 patients with a median age of 68y (range, 60 - 87; ≥70y, 34%) were enrolled (Table 1). Several patients had high-risk features: 25 (39%) harbored TP53 mutations, 9 (18%) had a Ph-like signature, and 19 (23%) had high-risk cytogenetics (12 low hypodiploidy/near triploidy, 3 tetraploidy, 3 complex and 1 t(4;11)). 77 patients were