Treatment with Anti-CD19 BiTE Antibody Blinatumomab (MT103 / MEDI-538) Is Able to Eliminate Minimal Residual Disease (MRD) in Patients with B-Precursor Acute Lymphoblastic Leukemia (ALL): First Results of An Ongoing Phase II Study.

Blinatumomab is designed to link T cells with CD19-expressing target cells resulting in a non-restricted cytotoxic T-cell response and T-cell activation. Several preclinical studies showed that very low concentrations of blinatumomab mediate redirected lysis of human B lymphoma and leukemia cells. A phase I study has demonstrated significant clinical activity of the BiTE antibody in relapsed B-cell non-Hodgkin’s lymphoma (NHL). Based on these results, a phase II dose-escalating study was designed in collaboration with the German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia to investigate efficacy, safety, and tolerability of blinatumomab in ALL patients who achieved a complete hematological remission, but remained MRD-positive. MRD is an independent prognostic factor that reflects primary drug resistance and is associated with a high relapse risk after start of consolidation. MRD was measured with standardized methods either by quantitative detection of individual rearrangements of immunoglobulin or T-cell receptor (TCR) rearrangements, or by bcr-abl fusion transcripts. The study population includes patients with acute B-precursor ALL at a minimum age of 18 years who show a bcr/abl signal above detection limit and/or at least one marker by rearrangement with a sensitivity of ≥10⁻⁴. Primary endpoint is the conversion rate to MRD negative status as defined by a bcr/abl signal below detection limit and/or by individual rearrangements of immunoglobulin or T-cell receptor (TCR) genes below 10⁻⁴. Secondary endpoints are time to hematological relapse, time to MRD progression, and time to molecular relapse. One treatment cycle of blinatumomab is a 4-week continuous intravenous infusion, which can be followed by allogeneic stem cell transplantation after the first cycle, or by repeated cycles after a 2-week treatment-free interval. MRD status is controlled after each treatment cycle. The starting dose level is 15 microgram/m²/24 hr, which may be escalated to 30 microgram/m²/24 hr and higher dose levels based on clinical activity and safety data. Four patients aged 31, 57, 62, and 65 years have so far been enrolled at the initial dose level of 15 microgram/m²/24 hr. Three out of the 4 patients had MRD by rearrangements at levels of 10⁻⁴, 10⁻³ and 10⁻¹, and one patient had bcr/abl fusion transcripts at a level of 10⁻⁴. Three out of the 3 patients with rearrangements turned MRD negative after the first treatment cycle, independently from the level of MRD positivity at baseline. The other patient had stable bcr/abl level without signs of hematological relapse after the initial treatment cycle. Except for fever on the first 3 days of treatment, no clinically significant toxicities were recorded.

Conclusion: These preliminary results indicate that treatment with blinatumomab is able to convert MRD positive ALL into an MRD negative status, and that this is well tolerated. Further exploration is warranted, as this may be a promising alternative treatment option especially for ALL refractory to chemotherapy.