Tapan Maniar

Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study

BACKGROUND Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia. METHODS In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 μg/day for the first 7 days and 28 μg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179. FINDINGS Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36-50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment-related by the investigators. INTERPRETATION Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted. FUNDING Amgen.

Unleashing the clinical power of T cells: CD19/CD3 bi-specific T cell engager (BiTE®) antibody construct blinatumomab as a potential therapy

Multi-agent chemotherapy is the standard treatment for most B cell malignancies. Since chemotherapy can be associated with significant toxicity and since relapses resistant to chemotherapy often develop, new therapies are needed. Blinatumomab (AMG 103 or MT103) is a late-stage candidate in clinical development, which belongs to a novel class of antibody constructs termed bi-specific T cell engager antibodies. This antibody construct has dual specificity for CD19 and CD3 and can re-direct polyclonal cytotoxic T lymphocytes toward the tumor. This review focuses on the pre-clinical and clinical development of blinatumomab as a powerful new tool in the treatment of B cell malignancies.

Erratum to: Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer [Supportive Care in Cancer, (2015), DOI:10.1007/s00520-015-2904-5]

1 University of Arizona Cancer Center, Tucson, AZ, USA 2 Institut Gustave Roussy, University of Paris Sud, Villejuif, France 3 Centre Hospitalier Universitaire Brugmann, Université Libre de Bruxelles, Brussels, Belgium 4 Cancer Research UK Experimental Cancer Medicine Centres, St James’s University Hospital, Leeds, UK 5 Weston Park Hospital, University of Sheffield, Sheffield, UK 6 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA 7 Center for Comprehensive Gynecology Clinic, Mannheim, Germany Support Care Cancer (2016) 24:457–458 DOI 10.1007/s00520-015-2985-1

Immunotherapy using bispecific T cell engager (BiTE®) antibodies: preclinical and clinical experience in acute leukemia

BiTE® antibodies are novel recombinant single chain Ig domain constructs that leverage the endogenous cytotoxic potential of polyclonal T cells to target malignant cells by utilizing the specific binding properties of variable domains from two different antibodies. Antibody-based immunotherapy represents a promising strategy in cancer. BiTE® antibodies have demonstrated efficacy in hematologic malignancies, both preclinically and clinically. Two investigational BiTE antibodies are under development targeting leukemia. The most advanced BiTE® antibody, Blinatumomab, directs cytotoxic T cells to CD19-expressing target cells. Blinatumomab has shown anti-leukemia activity in adult relapsed/refractory (r/r) B-precursor ALL. Its efficacy and toxicity was evaluated in a large confirmatory Phase II study. Patients with Ph-negative r/r ALL (N = 189; refractory; 1st relapse Given the anti-leukemia activity of single-agent Blinatumomab in a difficult-to-treat population with r/r ALL, another BiTE® antibody targeting CD33, AMG 330, was developed for its suitability as immunotherapy in AML. To simulate the natural setting of target and T cells in AML patients, a long-term culture system was developed that supports the growth of primary AML cells ex-vivo for up to 5 weeks. AMG 330 activated and expanded residual autologous T cells within primary AML patient samples and eliminated CD33+ blasts even at very low effector to target ratios. The functional relevance of CD33 expression levels was shown by faster lysis kinetics of CD33BRIGHT versus CD33DIM AML cell lines and primary AML cells in ex-vivo cytotoxicity assays. However, by extending the exposure time to AMG 330, potent anti-leukemic activity was observed in both CD33BRIGHT and CD33DIM cells. AMG 330 treated T cells were shown to up-regulate the activation markers CD25, PD-1, TIM3 and LAG3, which was partially reversible after complete target cell elimination Clinical experience with Blinatumomab in ALL and ex-vivo activity of AMG 330 in primary AML samples supports further development of BiTE® antibodies for targeted T cell-mediated immunotherapy of patients with malignancies.