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

PLEASE SEE THE IMPORTANT SAFETY INFORMATION IN THE SECTION BELOW.

COLLAPSE

IMPORTANT SAFETY INFORMATION

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®. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious adverse events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), and increased total bilirubin (TBILI). In some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS) have been reported in the setting of CRS. Interrupt or discontinue BLINCYTO® as outlined in the Prescribing Information (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. 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 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).

Indication

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

Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide, for BLINCYTO®.

BLINCYTO® is a registered trademark of Amgen Inc.

ALCANTARA study design

BLINCYTO® single-agent immunotherapy was evaluated in an open-label, single-arm, multicenter phase 2 study (N=45) in adult patients with relapsed or refractory (R/R) Ph+
B-cell precursor ALL who progressed after or were intolerant to second- or later-generation TKI therapy1,21.BLINCYTO® (blinatumomab) Prescribing Information, Amgen.
2.Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795-1802.

Inclusion criteria

Patients ≥ 18 years of age with Ph+ R/R B-cell precursor ALL:1,21.BLINCYTO® (blinatumomab) Prescribing Information, Amgen.
2.Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795-1802.

Key exclusion criteria22.Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795-1802.

  • Allogeneic HSCT within 12 weeks of starting treatment in this trial
  • Active acute or chronic grade 2 to 4 GVHD
  • Systemic treatment of GVHD within 2 weeks before treatment start
  • History or presence of clinically relevant CNS pathology
  • Active CNS ALL
  • Isolated extramedullary disease

Primary endpoint: CR/CRh* during the first two cycles of treatment22.Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795-1802.

  • Key secondary endpoints: MRD response rate during the first two cycles of treatment, RFS, OS, and allogeneic HSCT after BLINCYTO®-induced remission

Difficult-to-treat patient population

BLINCYTO® was evaluated in difficult-to-treat patients, including those with prior ponatinib exposure, T315I mutation, and prior allogeneic HSCT11.BLINCYTO® (blinatumomab) Prescribing Information, Amgen.

Prior TKI use was not mutually exclusive.22.Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795-1802.

One patient was resistant to imatinib and was never exposed to a second-generation or later TKI (protocol deviation).22.Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795-1802.

§Of 37 patients evaluable for TKI mutational analysis.22.Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795-1802.

ALL, acute lymphoblastic leukemia; CR, complete remission with full hematologic recovery; CRh*, complete remission with partial hematologic recovery; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; GVHD, graft-versus host disease; HSCT, hematopoietic stem cell transplantation; IV, intravenous; MRD, minimal residual disease; OS, overall survival; Ph+, Philadelphia chromosome–positive; RFS, relapse-free survival; TKI, tyrosine kinase inhibitor.

Complete remission/complete remission with partial hematologic recovery (CR/CRh*) was induced in more than one third of patients11.BLINCYTO® (blinatumomab) Prescribing Information, Amgen.

BLINCYTO® induced CR/CRh* within the first 2 treatment cycles in 36% of adult patients with Ph+ B-cell precursor ALL who were R/R to at least 1 second- or later-generation TKI, or intolerant to second-generation TKI and intolerant or refractory to imatinib11.BLINCYTO® (blinatumomab) Prescribing Information, Amgen.

CR was defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/mcL and ANC > 1,000/mcL).11.BLINCYTO® (blinatumomab) Prescribing Information, Amgen.

CRh* was defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/mcL and ANC > 500/mcL).11.BLINCYTO® (blinatumomab) Prescribing Information, Amgen.

ANC, absolute neutrophil count; TKI, tyrosine kinase inhibitor. 

Consistent response across subgroups1,21.BLINCYTO® (blinatumomab) Prescribing Information, Amgen.
2.Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795-1802.

**CR/CRh* in these subgroups was a pre-specified analysis in ALCANTARA; however, the CR/CRh* efficacy in these subgroups was not a study objective and the study was not powered to assess CR/CRh* efficacy in these subgroups33.Data on file, Amgen; October 2014.

††Response in this subgroup is a post-hoc analysis in ALCANTARA, thus the efficacy in this subgroup was not a study objective and the study was not powered to assess efficacy in this subgroup33.Data on file, Amgen; October 2014.

31% of responders (n=5/16) proceeded to allogeneic HSCT11.BLINCYTO® (blinatumomab) Prescribing Information, Amgen.

Complete minimal residual disease (MRD) response

The majority of patients who achieved CR/CRh* with BLINCYTO® had a complete MRD response1,21.BLINCYTO® (blinatumomab) Prescribing Information, Amgen.
2.Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795-1802.

PCR, polymerase chain reaction.

References:

  1. BLINCYTO® (blinatumomab) Prescribing Information, Amgen.
  2. Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795-1802.
  3. Data on file, Amgen; October 2014.
 

IMPORTANT SAFETY INFORMATION

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®. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious adverse events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), and increased total bilirubin (TBILI). In some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS) have been reported in the setting of CRS. Interrupt or discontinue BLINCYTO® as outlined in the Prescribing Information (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. 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 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).

Indication

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

Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide, for BLINCYTO®.

BLINCYTO® is a registered trademark of Amgen Inc.