Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia.

In adults with acute lymphoblastic leukemia (ALL), advances in chemotherapy have improved hematologic response rates to greater than 80% and relapses rates to below 50%. Leukemic cells not detected by conventional morphological methods may persist or reappear after chemotherapy as minimal residual disease (MRD), defined as at least 10 (0.01%) leukemic cells detected by quantitative polymerase chain reaction. Patients aged 15 to 55 years with MRD after consolidation have a 5-year relapse-free survival (RFS) rate of 25%, compared with a rate of 67% among those without MRD. Allogeneic hematopoietic stem cell transplantation (HSCT) in patients with MRD improves the 5-year RFS to 44% (versus 11% without allogeneic HSCT), but fewer than 50% of patients with MRD undergo allogeneic HSCT, often because of rapidly occurring relapse. Blinatumomab, a bispecific T-cell engager (BiTE) antibody construct with dual specificity for CD19 and CD3, demonstrated efficacy in the treatment of relapsed or refractory B-lineage ALL in two phase 2 studies, with response rates of 43% to 69% and median RFS of 5.9 to 7.6 months. A randomized phase 3 study showed significantly improved overall survival with blinatumomab compared to standard-of-care chemotherapy in adults with relapsed or refractory ALL. The data summarized here represent the final analysis of 5-year RFS in a single-arm phase 2 study in adult patients with B-lineage ALL who had persistent MRD or MRD relapse after intensive chemotherapy. The full study methods were described previously. Patients aged ≥18 years with B-lineage ALL in hematologic complete remission (CR) with quantifiable MRD of ≥10 after consolidation I of first-line therapy using GMALL protocols were enrolled between January 2008, and August 2009. Each patient received up to four cycles of initial treatment with blinatumomab and up to three additional cycles if hematologic relapse had not occurred. Each cycle included open-label blinatumomab 15 mg/m/day by continuous intravenous infusion over 4 weeks, followed by a 2week treatment-free interval. The primary endpoint was MRD response within the first four cycles, defined as BCR-ABL or MLL-AF4 below the detection limit or individual rearrangements of immunoglobulin or T-cell receptor genes <10. An institutional review board or independent ethics committee approved the protocol for each study center. In the primary analysis, after all patients had completed blinatumomab treatment, the rate of MRD response was 80% (16 of 20 evaluable patients) and all MRD responses had occurred in the first cycle. Patients completed follow-up visits for RFS assessment for up to 5 years. In the first follow-up analysis after a median follow-up of 33 months, 12 of 20 evaluable patients (60%) were still in remission. The final analysis reported here was conducted after the last patient completed the last study visit, with a median follow-up of 50.8 months. Ten patients (50%) were still in remission 5 years after the start of blinatumomab treatment. Per study protocol, patients could receive allogeneic HSCT any time after the first cycle of blinatumomab treatment. Nine patients proceeded to transplantation: