Data presented during the 57th Annual Meeting and Exposition of the American Society of Hematology (ASH) in Orlando, Florida shows that Amgen’s blinatumomab (Blincyto®) shows positive results in the treatment of patients with acute lymphoblastic leukemia or ALL.
Blinatumomab is part of Amgen’s Bispecific T Cell Engager (BiTE®) Immunotherapy platform, and is the first BiTE® to be approved in the US and Europe. The data demonstrates positive outcomes in patients with B-cell precursor ALL with minimal residual disease (MRD), as well as encouraging results for other high-risk ALL patient subpopulations. The results of the blinatumomab phase II BLAST trial were included in the “Best of ASH” seminar on December 8, 2015.
Hard to treat disease
Acute lymphoblastic leukemia or ALL is a rare cancer of the blood and bone marrow, and it is characterized by a median overall survival of just three to five months in adult patients. For certain high-risk subpopulations, a very low survival rate is typical. In adult patients with ALL, relapse is the most common cause of treatment failure, even after achieving complete remission. Currently, there is no broadly accepted standard treatment regimen for adult patients with refractory of relapsed ALL after chemotherapy. 
Scientists believe that the data from blinatumomab shows great potential for difficult to treat ALL patient sub-populations, and is especially encouraging when it comes to the status of MRD. Additionally, they believe the data is supportive of the potential for BiTE® Immunotherapy to be applied in a broader spectrum of ALL, as well as use in earlier stages of treatment.
BiTE® antibodies are dual-binding constructs that are designed to enhance the effects of the immune system by bridging T-cells (a type of white blood cell that targets and kills cells perceived to be threats) to
These investigational antibodies use the variable domains of two monoclonal antibodies, one aimed at targeting a cancer cell antigen, and the other to engage CD3 on the surface of a T-cell. As a result, a cancer cell and T-cell are forced within close proximity, creating a synapse between the two. The activated T-cells are then able to destroy a cancer cell by cytolytic mechanisms. These T-cells are not consumed during tumor cell lysis, so an activated T-cell can continue to initiate cell lysis on other local cancer cells. Likewise, the BiTE® antibody is designed to move through the local environment and continue to target additional cells. Since these mechanisms continue to occur, a higher degree of complete cancer cell elimination is possible. 
Blinatumomab is an antibody construct that has a binding region specific to CD19 expressed on the surface of B-lineage origin. Monotherapy with blinatumomab has shown positive outcomes in the phase II confirmatory multicenter single arm trial (BLAST) in adult patients with B-cell precursor ALL with
Minimal Residual Disease or MRD refers to the presence of a small number of leukemic cells that remain in a patient after treatment or when a patient is in remission. For patients with ALL, MRD is a powerful predictor of outcome and signifies a higher risk of relapse. 
The 116 patient trial, the largest in patients with ALL with MRD, 78% of patients were rendered MRD negative in one cycle. The MRD negative patients showed positive outcomes with regards to overall survival (OS), relapse free survival (RFS), and duration of remission (DOR) when compared to those who did not show a complete MRD response. 
“MRD status is a very powerful prognostic factor and predictor of outcome for patients with ALL,” explained David Reese, MD, senior vice president of translational Sciences at Amgen, “If you can detect residual leukemia on a molecular level, it is no surprise that is associated with a higher risk of relapse.” After being declared MRD negative, a number of patients in the trial were able to receive an allogenic hemopoietic stem cell transplantation (alloHSCT), and those that were not eligible could undergo additional blinatumomab treatment cycles.
High-Risk Ph+/ Ph- ALL Patients
Other presentations at ASH demonstrated blinatumomab’s potential in a high risk population of patients with relapsed or refractory Philadelphia chromosome-positive (Ph+) B-precursor ALL, as well as confirmed efficacy in patients with relapsed or refractory Philadelphia chromosome-negative (Ph-) ALL after an alloHSCT.  
In the phase II, multicenter ALCANTARA study, patients with Ph+ B-precursor ALL- a population which is typically characterized by very low prognosis, showed a complete molecular and hematologic response after blinatumomab treatment. Patients in this study had previously failed at least one second generation tyrosine kinase inhibitor therapy. Of this group, 36% of patients showed a complete remission (CR) or complete remission with partial hematological recovery (CRh) during the first two treatment cycles. A complete MRD response was shown in 88% of the patients who achieved CR/CRh. Patient incidence of grade 3 or higher adverse events (AEs) was 82%, with the most common including febrile neuropenia (27%), thrombocytopenia (22%), and anemia (18%). 
Furthermore, in a subset of 64 heavily treated patients with Ph- ALL who had relapsed or were refractory after an alloHSCT, treatment with blinatomumab induced a CR/CRh rate of 45%. Adverse events of grade 3 or higher were seen in 88% of these patients, the most common being neutropenia (22%), febrile nuetropenia (20%), anemia (17%), and thrombocytopenia (14%). Graft vs. host disease was present in six patients, with two being of grade 3 or higher. 
Researchers at Amgen believe BiTE® will serve as a broad based technology, and are invested in developing the platform for both hematological malignancies and solid tumors. Additionally, they are confident it will be another step in companion diagnostics and the development of more customized and personalized therapeutics.
For researchers at Amgen, positive outcomes with blinatumomab for high-risk, poor prognosis patients are steps needed to further the advancement of personalizing therapies, especially when it comes to better understanding factors such as MRD, which can help with the molecular characterization of tumors. “One of our core principles is something we call modality independence,” noted Reese, “Our goal is to understand the disease and target, and then decide what kind of modality is best… I think MRD status is going to be one of those things that helps customize therapy for patients moving forward.”
Reese further noted that with technologies like BiTE®, knowledge of both tumor and the patient immune system will need to be investigated in order to allow for customized therapies. And while this adds a layer of complexity, many in the field see customized therapies as the promising future for cancer treatment. “We are not interested in sort minor or incremental advances,” stated Reese, “our mission is drugs for serious diseases….and our goal is have a significant impact and to change the practice of medicine.”
Note: This article written by Sonia Portillo, is, in part, based on an conversational interview between David Reese, MD, senior vice president of translational Sciences at Amgen and Peter Hofland, PhD, Executive Editor or ADC Review / Journal of Antibody-drug Conjugates during the 57th Annual Meeting and Exposition of the American Society of Hematology (ASH) in Orlando, Florida.