On September 24, 2018 Amgen (NASDAQ:AMGN) reported that the Japanese Ministry of Health, Labour and Welfare has granted marketing approval for BLINCYTO (blinatumomab) for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) (Press release, Amgen, SEP 25, 2018, View Source;p=RssLanding&cat=news&id=2368696 [SID1234530180]). BLINCYTO was developed in Japan by Amgen Astellas BioPharma K.K. (AABP), a joint venture between Amgen and Astellas Pharma Inc., a pharmaceutical company headquartered in Tokyo.

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"As proof-of-concept for our bispecific T cell engager technology, BLINCYTO has laid the groundwork for Amgen to deliver on our passion of addressing cancer by exploring numerous biologic pathways and therapeutic modalities," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "This innovation is a good example of how we provide new options to patients with serious illnesses like cancer. In bringing BLINCYTO to Japanese patients, we reinforce our commitment to deliver novel cancer therapies on behalf of patients worldwide."

BLINCYTO is the first-and-only bispecific T cell engager (BiTE) immunotherapy construct approved globally. It is also the first approved immunotherapy from Amgen’s BiTE platform, an innovative approach that helps the body’s immune system target cancer cells.

"Today’s approval of BLINCYTO marks a significant milestone that reinforces our commitment to addressing unmet medical needs of patients in Japan," said Steve Sugino, president and representative director, AABP. "As our first oncology treatment approved in the region, we are proud to provide a much-needed innovative treatment option for adults and children with relapsed or refractory B-cell ALL, one of the most aggressive B-cell malignancies."

Hitoshi Kiyoi, M.D., Ph.D., professor of internal medicine, Hematology and Oncology, Nagoya University Graduate School of Medicine said, "The standard therapy for relapsed or refractory B-cell ALL has not been established in Japan and therefore different chemotherapy regimens have been selected, depending on the condition and background of each patient. BLINCYTO is a much-needed and important new treatment option for patients with relapsed or refractory B-cell ALL, as demonstrated by the efficacy and survival benefit seen in the TOWER study."

The approval is based on data from multiple global studies, including the Phase 3 TOWER study and Japan Phase 1b/2 Horai study. In the TOWER study, BLINCYTO demonstrated a superior improvement in median overall survival (OS) versus standard of care (SOC) chemotherapy. Median OS was 7.7 months (95 percent CI: 5.6, 9.6) for BLINCYTO versus 4.0 months (95 percent CI: 2.9, 5.3) for SOC (HR for death=0.71; p=0.012). Safety results among subjects who received BLINCYTO were comparable to those seen in the previous Phase 2 studies of BLINCYTO in adult patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor ALL. In the TOWER study, major adverse reactions were pyrexia (39.0 percent), decrease in white blood cell count (14.6 percent), cytokine release syndrome (13.5 percent), febrile neutropenia (10.9 percent), headache (10.1 percent), elevated liver enzyme (10.1 percent) and decrease in platelet count (10.1 percent). In the Phase 1b/2 Horai study, BLINCYTO was administered to 35 Japanese adult and pediatric patients with relapsed or refractory B-cell precursor ALL. The safety results from the Horai study were comparable to those seen in the global studies, including TOWER. In the Horai study, major adverse reactions in adult patients were cytokine release syndrome (46.2 percent), pyrexia (46.2 percent), decrease in white blood cell count (38.5 percent) and decrease in platelet count (34.6 percent), and major adverse reactions in pediatric patients were elevated liver enzyme (66.7 percent), pyrexia (66.7 percent), cytokine release syndrome (55.6 percent) and abdominal pain (44.4 percent).

BLINCYTO is now approved in 57 countries, including the United States (U.S.), all member countries in the European Union (EU) and the European Economic Area, Canada and Australia.

About the TOWER Study
The TOWER study was a Phase 3, randomized, active-controlled, open-label study investigating the efficacy of BLINCYTO versus SOC chemotherapy in 405 adult patients with Ph- relapsed or refractory B-cell precursor ALL. The study enrolled a difficult-to-treat patient population which included patients with one or more relapses or refractory disease. In the BLINCYTO arm, this included 35 percent of patients that had relapsed post-allogenic hematopoietic stem cell transplant (alloHSCT) and excluded those with late first relapse (≥12 months after initial remission). Patients were randomized in a 2:1 ratio to receive BLINCYTO (n=271) or treatment with investigator choice of SOC chemotherapy (n=134). The determination of efficacy was based on OS. These results were published in The New England Journal of Medicine.1

About the Horai Study
The Horai study is a Phase 1b/2, single-arm, open-label study evaluating the safety and efficacy of BLINCYTO in Japanese adult and pediatric patients with relapsed or refractory B-cell precursor ALL. The primary endpoint for the Phase 1b portion was incidence of dose-limiting toxicities; the primary endpoint for the Phase 2 portion was complete remission or complete remission with partial hematologic recovery within 12 weeks of treatment with BLINCYTO. Secondary endpoints include duration of response, OS and relapse-free survival. An extension of the study is ongoing. For more information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT02412306.

About ALL in Japan
ALL is a rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children.2,3 Japan is reported to have approximately 5,000 ALL patients, and it is estimated that of these, there are around 520 patients with relapsed or refractory ALL annually.4-7 Adults with relapsed or refractory ALL typically have a very poor prognosis, with a median OS of three to five months.8 Prognosis for children with ALL who are refractory or experience a relapse is extremely poor, and post-relapse survival is only achieved in 40-50 percent of patients.9-11

About BiTE Technology
Bispecific T cell engager (BiTE) antibody constructs are a novel immune-oncology technology that can be engineered to target any tumor antigen expressed by any type of cancer. The modified antibodies are designed to kill malignant cells using the patient’s own immune system by bridging T cells to tumor cells. BiTE antibody constructs help connect the T cells to the targeted cell, with the intent of causing T cells to inject toxins which trigger cancer cell death (apoptosis). Amgen is developing BiTE antibody constructs to uniquely (or specifically) target numerous hematologic malignancies and solid tumors.

About BLINCYTO (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) immunotherapy that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of effector T cells. BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration (FDA) in 2014, and now carries full approval in the U.S. for the treatment of relapsed or refractory B-cell precursor ALL in adults and children. In the U.S., BLINCYTO is also approved under accelerated approval for the treatment of adults and children with B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1 percent.

BLINCYTO is approved in the EU for the treatment of Ph- relapsed or refractory B-cell precursor ALL in adults and children.

Important Japan Product Information

Indication:
Relapsed or refractory B-cell acute lymphoblastic leukemia

Dosage and Administration:
In general, blinatumomab (Genetical Recombination) is administered as continuous intravenous infusion with the following dosing regimen for 28 days followed by a 14-day treatment-free interval. This constitutes one cycle and is repeated up to 5 cycles. After that, blinatumomab (Genetical Recombination) is administered with the following dosing regimen for 28 days followed by a 56-day treatment-free interval. This constitutes one cycle and is repeated up to 4 cycles. Of note, dose of BLINCYTO can be reduced as appropriate depending on patient’s condition.

Patients with a body weight of ≥45 kg: 9 μg/day on Days 1 to 7 of Cycle 1, then 28 μg/day.
Patients with a body weight of <45 kg: 5 μg/m2 (body surface area [BSA])/day on Days 1 to 7 of Cycle 1, then 15 μg/m2 (BSA)/day. The dose should not exceed the dose for patients with a body weight of ≥45 kg.
For more information, see the latest Japan Package Inserts.

Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication
BLINCYTO is indicated for the treatment of B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and children. This indication is approved under accelerated approval based on MRD response rate and hematological relapse-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

BLINCYTO is indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children.

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications

BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. The median time to onset of CRS is 2 days after the start of infusion. Closely monitor patients for signs and symptoms of serious adverse events such as fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS). In clinical trials of BLINCYTO, CRS was reported in 15% of patients with relapsed or refractory ALL and in 7% of patients with MRD-positive ALL. Interrupt or discontinue BLINCYTO as outlined in the PI.
Neurological Toxicities: Approximately 65% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to the first event was within the first 2 weeks of BLINCYTO treatment and the majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity were headache and tremor. Severe, life‐threatening, or fatal neurological toxicities occurred in approximately 13% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO in clinical trials experienced serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.
Tumor Lysis Syndrome (TLS), which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.
Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.
Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment with a median time to onset of 3 days. In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.
Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.
Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative: Serious and fatal adverse reactions including "gasping syndrome," which is characterized by central nervous system depression, metabolic acidosis, and gasping respirations, can occur in neonates and infants treated with benzyl alcohol-preserved drugs including BLINCYTO (with preservative). When prescribing BLINCYTO (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion with preservative contain benzyl alcohol and are not recommended for use in any patients weighing < 22 kg.
Adverse Reactions

The most common adverse reactions (≥ 20%) in clinical trial experience of patients with MRD-positive B-cell precursor ALL (BLAST Study) treated with BLINCYTO were pyrexia, infusion related reactions, headache, infections (pathogen unspecified), tremor, and chills. Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection.
The most common adverse reactions (≥ 20%) in clinical trial experience of patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (TOWER Study) treated with BLINCYTO were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia.
Adverse reactions that were observed more frequently (≥ 10%) in the pediatric population compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increased (17% vs. 6%).
In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).
Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).