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.

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For patients with MRD+ B‑cell precursor acute lymphoblastic leukemia (ALL)

Intervene in CR1 with BLINCYTO®

BLINCYTO® is the first and only FDA‑approved therapy for MRD+ B‑cell precursor ALL1,2

BLAST study design: A single-arm phase 2 study of BLINCYTO® treatment for adult patients with MRD+ B-cell precursor ALL1,3

N=86

Adults ≥ 18 years of age with B‑cell precursor ALL in hematologic CR1 or CR2 with MRD1 ≥ 0.1%

BLINCYTO® single-agent
immunotherapy1,3

  • Continuous IV infusion for up to 4 cycles
  • Treatment cycle: 4 weeks on therapy, 2 weeks off
  • Dosing: 15 mcg/m2/day (equivalent to 28 mcg/day)
  • Eligible patients could undergo HSCT after 1 cycle

Follow-up: 30 days (safety);
24 months plus survival follow-up4

Primary endpoint3

  • Complete MRD response after 1 treatment cycle

Secondary endpoints3

  • Overall survival
  • Hematologic RFS at 18 months
  • Duration of hematologic remission
Blinatumomab (BLINCYTO®) is the only therapeutic agent recommended by the 2018 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for patients with Ph– B-cell precursor ALL who are MRD+ after induction treatment.5
Key inclusion criteria1
  • Adults ≥ 18 years of age with B-cell precursor ALL in hematologic CR
  • MRD level of ≥ 0.1% (molecular relapse or molecular failure)**
  • < 5% blasts in bone marrow
  • ANC > 1 Gi/L
  • Platelets > 100 Gi/L
Key exclusion criteria4
  • Prior HSCT
  • Presence of circulating blasts or current extramedullary disease
  • History of relevant CNS pathology or current relevant CNS pathology
  • Prior systemic cancer chemotherapy within 2 weeks or radiotherapy within 4 weeks

Most patients were in CR1 at baseline1

Baseline characteristics of patients (N=86)
Age
Median, years (min, max)43 (18, 76)
≥ 65 years, n (%)10 (12)
Males, n (%)50 (58)
Philadelphia chromosome disease status, n (%)
Positive1 (1)
Negative85 (99)
Relapse history, n (%)
In first complete remission (CR1)61 (71) 71% were in CR1
In second complete remission (CR2)25 (29)
Baseline MRD levels, n (%)
≥ 10%7 (8)
≥ 1% and < 10%34 (40)
≥ 0.1% and < 1%45 (52)

In the BLAST study, BLINCYTO® converted most patients to MRD–1,3

Primary endpoint: complete MRD response††

81% (n=70/86)

of patients had no detectable MRD‡‡

  • Complete MRD response was similar across patient subgroups (age, relapse history, and MRD burden)1,3
Percentage of patients who proceeded to HSCT1
CR1

74%

(n=45/61)

CR2

56%

(n=14/25)

Zero in on MRD and intervene1 as early as CR1

Patients§§,*** who converted to MRD– achieved significantly longer RFS3,6

RFS††† in patients with vs without complete MRD response‡‡‡,§§§

Patients treated with BLINCYTO® achieved nearly 3x longer RFS1 when treated in CR1 vs CR2

Median RFS**** in patients†††† who were MRD+ treated in CR1 vs CR2

12.3 months
(range: 0.7–42.3 months)
CR2 (n=25)
35.2 months
(range: 0.4–53.5 months)
CR1 (n=61)
Intervening earlier with BLINCYTO® gave patients
a better chance to live relapse-free longer1

References: 1. BLINCYTO® (blinatumomab) prescribing information, Amgen. 2. Food and Drug Administration. FDA expands approval of Blincyto for treatment of a type of leukemia in patients who have a certain risk factor for relapse. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm603151.htm. Accessed September 27, 2018. 3. Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131:1522-1531. 4. Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-precursor acute lymphoblastic leukemia. Blood. 2018;131:1522-1531. Appendix, Supplementary Appendix; http://www.bloodjournal.org/content/bloodjournal/suppl/2018/122/blood-2017-08-798322.DC1/blood-2017-08-798322-1.pdf. Accessed September 27, 2018. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia V.1.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed September 27, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 6. Food and Drug Administration. BLINCYTO® (blinatumomab) for minimal residual disease positive (MRD+) B-cell precursor acute lymphoblastic leukemia (ALL). https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM603411.pdf. Accessed September 27, 2018. 7. Data on file, Amgen; 2018.

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 15% of patients with R/R ALL and in 7% of patients with MRD-positive ALL. The median time to onset of CRS is 2 days after the start of infusion. Closely monitor and advise patients to contact their healthcare professional 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, and hemophagocytic histiocytosis/macrophage activation syndrome. If severe CRS occurs, interrupt BLINCYTO® until CRS resolves. Discontinue BLINCYTO® permanently if life-threatening CRS occurs.
  • 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, 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 (91%), infusion-related reactions (77%), headache (39%), infections (pathogen unspecified [39%]), tremor (31%), and chills (28%). 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.
  • Adverse reactions that were observed more frequently (≥ 10%) in the pediatric population compared to the adults with relapsed or refractory B-cell precursor ALL 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 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.

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

BLINCYTO® is a registered trademark of Amgen Inc.