Indication

BLINCYTO® is indicated for the treatment of CD19-positive 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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Intervene in CR1 with BLINCYTO®

The Blast Pivotal Study The Blast Pivotal Study

Study design: N=86, an open-label, single-arm phase 2 study of adult patients with MRD(+) B-cell precursor ALL who had received at least 3 chemotherapy blocks of standard ALL therapy, were in hematologic complete remission (defined as < 5% blasts in bone marrow, absolute neutrophil count > 1 Gi/L, platelets > 100 Gi/L), and had MRD† at a level of ≥ 0.1% using an assay with a minimum sensitivity of 0.01%. Primary endpoint: 81% (n=70/86) of patients had no detectable MRD assessed after 1 treatment cycle with BLINCYTO®.1,† Select secondary endpoints: overall survival, hematologic RFS at 18 months, duration of hematologic remission.2

BLINCYTO® is the only FDA‑approved treatment for MRD(+) B‑cell precursor ALL, with 81% of adult patients in first or second complete remission achieving a complete MRD response after induction treatment1

†Defined as the absence of detectable MRD confirmed in an assay with minimum sensitivity of 0.01% for 6 patients and ≤ 0.005% for 80 patients. Undetectable MRD was achieved by 65 of 80 patients with an assay sensitivity of at least 0.005%.1

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

Primary endpoint: complete MRD response†

81%

(n=70/86)

of patients had no detectable MRD‡

  • Complete measurable residual disease (MRD) response was similar across patient subgroups (age, relapse history, and MRD burden)2
Percentage of patients who proceeded to allogeneic hematopoietic stem cell transplantation (HSCT)1
CR1

74%

(n=45/61)

CR2

56%

(n=14/25)

At 5 years, a median OS had yet to be reached for patients who achieved MRD negativity3,§

Median OS in patients with vs without a complete MRD response**

Median OS in patients

Patient response n Median OS 95% CI
MRD responders at cycle 1 84 NR 29.5–NR
MRD nonresponders at cycle 1 23 14.4 months 3.8–32.3

  • Median follow-up for OS was 59.8 months3
  • An OS benefit has not been demonstrated in a randomized, controlled trial
  • This indication is approved under accelerated approval as a responder analysis based on MRD response rate and hematological relapse-free survival. OS in patients with measurable residual disease (MRD) on BLINCYTO® vs chemotherapy is currently under evaluation as a phase 3 study1
  • Due to the differential effect of HSCT on OS, interpretation of the results of OS cannot exclude potential confounding of HSCT2
  • It is unknown whether achieving MRD negativity alone provides an OS benefit comparable to that of HSCT. Therefore, the survival benefit cannot be isolated to BLINCYTO® treatment alone
  • In the BLAST study, OS was not a primary objective and the study was not powered to assess OS efficacy2
  • Median OS was 36.5 months (95% CI: 22.0–NE) overall§ following treatment with BLINCYTO® and reached a plateau3
  • Median OS was not estimable (ie, not reached) among the subsets of patients who had achieved a complete MRD response with BLINCYTO® in CR1 or who proceeded to HSCT in CCR3
See the safety profile of the BLAST study
Learn more

§OS was evaluated in patients with Ph(–) B-cell precursor ALL with less than 5% blasts at enrollment, and includes 74 patients who received HSCT while in CCR after BLINCYTO®. Analyses of OS by complete MRD response after cycle 1 included 107 patients, of which patients with no central MRD assay (n=1) or inadequate MRD test sensitivity (n=2) were excluded.3

**Patients in this population differ from the USPI population. Analysis includes additional patients: those who achieved CRh* and CRi and/or are in CR3.1,2,4,5

CCR, continuous complete remission; CI, confidence interval; CR3, third complete remission; CRh*, complete remission with partial hematologic recovery; CRi, complete remission with incomplete hematologic recovery; NE, not estimable; NR, not reached; Ph(–), Philadelphia chromosome–negative.

In the BLAST pivotal study, patients††,‡‡ who converted to MRD(–) achieved significantly longer RFS2,6

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

Intervening earlier in CR1 with BLINCYTO® resulted in nearly 3x longer RFS vs CR2

Median RFS‡‡‡ in patients§§§ who were MRD(+) treated in CR1 vs CR2

CR1(n=61)
 
 

35.2 months

(range: 0.4–53.5 months)

CR2(n=25)
 
 

12.3 months

(range: 0.7–42.3 months)

Choose BLINCYTO® after induction in patients with MRD(+) B-cell precursor ALL in first or second complete remission1

†† Patients in this population differ from the USPI population. Analysis includes the following additional patients: those who achieved CRh* and CRi, and/or are in CR3.1,2,4,5

‡‡ Landmark analysis included patients in both the Key Secondary Full Analysis Set and the Primary Endpoint Analysis Set from the BLAST study and excludes patients with an event (death or relapse) or censored before day 45; patients without MRD results (n=1); or insufficient sensitivity of the assay (n=2).2

§§ Kaplan-Meier estimates with 2-sided 95% CIs were used to describe RFS; differences between subgroups were evaluated using log-rank test.2

*** Of the patients in the Key Secondary Full Analysis Set, 67% (74 out of 110) underwent HSCT in continuous remission.2

††† The median RFS was 23.6 months for MRD responders (n=70) vs 10.6 months (n=16) for nonresponders based on an exploratory analysis of the USPI population.5,‡‡

‡‡‡ Relapse was defined as either hematological or extramedullary relapse, secondary leukemia, or death due to any cause; includes time after transplantation; Kaplan-Meier estimate.1

§§§ 74% (45/61) of patients in CR1 and 56% (14/25) of patients in CR2 underwent HSCT.1

BLAST study design and baseline characteristics of patients

BLAST study design: a single-arm, phase 2 study of BLINCYTO® treatment for adult patients with MRD(+) B-cell precursor ALL1,2,4

N=86

Adults ≥ 18 years of age with B-cell precursor ALL in hematologic CR1 or CR2 with MRD ≥ 0.1%****

BLINCYTO® single-agent immunotherapy

  • 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
5-year survival follow-up

Primary endpoint:2

  • Complete MRD response†††† after 1 treatment cycle

Select secondary endpoints:2

  • Overall survival
  • Hematologic RFS at 18 months
  • Duration of hematologic remission
Key inclusion criteria1
Adults ≥ 18 years of age with B-cell precursor ALL in hematologic CR
Measurable residual disease (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 criteria3
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 (%)
Positive 1 (1)
Negative 85 (99)
Relapse history, n (%)
In first complete remission (CR1) 61 (71)
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)
71% were in CR1
Choose BLINCYTO®, a BiTE® immunotherapy, for a different approach to treating MRD(+) B-cell precursor ALL as early as CR11

****As determined by an assay with a minimum sensitivity of 0.01%.1

††††Defined as the absence of detectable MRD confirmed in an assay with minimum sensitivity of 0.01% for 6 patients and ≤ 0.005% for 80 patients. Undetectable MRD was achieved by 65 of 80 patients with an assay sensitivity of at least 0.005%.1

‡‡‡‡Also referred to as minimal residual disease.

§§§§In an assay with a minimum sensitivity of 0.01%, MRD level of ≥ 0.1% after ≥ 3 intensive chemotherapy treatments.1

ANC, absolute neutrophil count; BiTE, Bispecific T-cell Engager; CNS, central nervous system; IV, intravenous.



The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include blinatumomab (BLINCYTO®) as the only recommended treatment option for adult patients with Ph(–) B-cell precursor ALL who have persistent or rising MRD after induction therapy and when possible, recommend “therapy aimed at eliminating MRD prior to allogeneic HCT”7

Retrospective study

In a retrospective study (Keating, et al), BLINCYTO® converted nearly all pediatric patients to MRD(–), who then proceeded to HSCT8


A multi-institutional, retrospective study to report outcomes using BLINCYTO® as therapy prior to allogeneic hematopoietic stem cell transplantation (HSCT)8
  • Pediatric patients (N=15) aged 0–21 years with MRD(+) B-cell precursor ALL8,*****
  • All patients were in CR††††† at enrollment8
    • One-third of patients (5/15) were in CR2
  • More than half of patients (9/15) had unfavorable risk cytogenetic abnormalities8
  • 93% (n=14/15) of patients had no detectable MRD following BLINCYTO® therapy8
  • Median time from end of BLINCYTO® treatment to preparative regimen for HSCT was 14 days (range: 1–35 days)8
    • All patients had successful neutrophil engraftment with a median time of 19 days (range: 11–35 days)
  • There are ongoing trials investigating BLINCYTO® in MRD(+) patients1
The NCCN Guidelines® for Pediatric ALL recommend blinatumomab (BLINCYTO®) as a treatment option for pediatric patients with B-cell precursor ALL who test MRD(+)‡‡‡‡‡ in CR1 or CR2, including those in early first relapse, and prior to HSCT9

*****Most patients (n=12) received a single 4-week course of BLINCYTO® at 15 mcg/m2/day; 2 patients had their initial cycle of BLINCYTO® shortened to start HSCT preparative therapy (at days 18 and 20), and 1 patient received 2 courses for a total of 66 days.8

†††††Defined as < 5% blasts in the bone marrow.8

‡‡‡‡‡The threshold for MRD positivity may vary based on the protocol being followed and/or the assay being used.9

HCT, hematopoietic cell transplantation.

See more

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® and treat with corticosteroids 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 and the median time to resolution of CRS was 5 days among cases that resolved. 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. Administer corticosteroids for severe or life-threatening CRS.
  • 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 CD19-positive 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.

See more

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® and treat with corticosteroids as recommended.
  • Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO®. Interrupt or discontinue BLINCYTO® as recommended.

References: 1. BLINCYTO® (blinatumomab) prescribing information, Amgen. 2. 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. 3. Gökbuget N, Zugmaier G, Dombret H, et al. Curative outcomes following blinatumomab in adults with minimal residual disease B-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma. 2020;61:2665-2673. 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(suppl):1522-1531. 5. Data on file, Amgen; 2018. 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 June 30, 2021. 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia v.1.2022. National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed May 20, 2022. 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. 8. Keating AK, Gossai N, Phillips CL, et al. Reducing minimal residual disease with blinatumomab prior to HCT for pediatric patients with acute lymphoblastic leukemia. Blood Adv. 2019;3:1926-1929. 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pediatric Acute Lymphoblastic Leukemia v.1.2022. National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed May 20, 2022. 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.

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