Blinatumomab

Acute Lymphoblastic Leukemia

Blinatumomab is used in adults and pediatric patients ≥1 month of age for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) ≥0.1%; relapsed or refractory CD19-positive B-cell precursor ALL; and CD19-positive Philadelphia chromosome (Ph)-negative B-cell precursor ALL in the consolidation phase of multiphase chemotherapy.1 The drug has been designated an orphan drug by FDA for these uses.3

Clinical Experience

MRD-positive B-cell Precursor ALL

The indication for blinatumomab in the treatment of MRD-positive B-cell precursor ALL is based primarily on the results of a multicenter, open-label, single-arm, phase 2 study (BLAST).1, 17 The BLAST study enrolled adults ≥18 years of age with B-cell precursor ALL who were in first or subsequent hematologic complete remission (CR) but had persistent or recurrent MRD at a level of ≥0.1% after receiving at least 3 blocks of standard ALL chemotherapy.1, 17 Hematologic CR was defined as <5% blasts in bone marrow, absolute neutrophil count (ANC) >1000/mm³, and platelets >100,000/mm³.1 In this study, 86 patients received IV blinatumomab at a fixed dose of 15 mcg/m² per day (equivalent to the recommended 28 mcg/day) throughout all treatment cycles.1 Patients could receive up to 4 cycles of treatment, with dose adjustments allowed in response to adverse events.1 The primary measure of efficacy was the rate of complete MRD response after cycle 1.1, 17 Complete MRD response was defined as the absence of detectable MRD established in an assay with minimum sensitivity of 0.01%.1 An additional key secondary outcome measure included hematologic relapse-free survival (RFS).1, 17

The median age of patients enrolled in the BLAST study was 43 years (range, 18-76 years).1 Of the 86 patients, 58% were male; 88% were white, 1% were Asian, and 11% were classified as unknown.1 The majority of patients (99%) were Ph-negative.1 In terms of relapse history, 71% were in first hematologic CR (CR1), while 29% were in second CR (CR2).1 Baseline MRD levels varied, with 52% of patients having MRD between 0.1-1%, 40% having MRD between 1-10%, and 8% having MRD ≥10%.1

In the BLAST study, 45 of 61 patients in CR1 (73.8%) and 14 of 25 patients in CR2 (56.0%) proceeded to allogeneic hematopoietic stem cell transplantation (HSCT) while maintaining continuous hematologic remission.1 Overall, 70 patients (81.4%) achieved a complete MRD response within 1 cycle of blinatumomab.1 The median hematologic RFS was 22.3 months.1 Among the 80 patients assessed with an MRD assay sensitivity of at least 0.005%, 65 (81.3%) achieved undetectable MRD.1 The estimated median hematological RFS for these patients was 24.2 months.1

Relapsed or Refractory B-cell Precursor ALL

The indication for blinatumomab as a treatment for relapsed or refractory CD19-positive B-cell precursor ALL is based on 3 studies in adult patients (TOWER, MT103-211, and ALCANTARA) and 1 pediatric study (MT103-205).1, 2, 18, 19, 20

The open-label, phase 3, TOWER study enrolled 405 adults ≥18 years of age with Ph-negative B-cell precursor ALL who were either refractory to primary induction therapy or to salvage with intensive combination chemotherapy; in first relapse with a remission duration <12 months; in second or greater relapse; or relapsed following allogeneic HSCT.1, 18 Patients were randomized (stratified by age, prior salvage therapy, and prior allogeneic HSCT) in a 2:1 ratio to receive either blinatumomab or standard-of-care chemotherapy.1, 18 Blinatumomab was administered at 9 mcg/day on days 1-7 and 28 mcg/day on days 8-28 during cycle 1 (42 days), then 28 mcg/day on days 1-28 during cycles 2-9 (cycles 2-5 were 42-day cycles and cycles 6-9 were 84-day cycles).1, 18 Standard-of-care chemotherapy was given based on the investigator's discretion and consisted of one of the following regimens: a high-dose cytosine arabinoside-based regimen; fludarabine, high-dose cytosine arabinoside, and granulocyte colony-stimulating factor with or without anthracycline; a high-dose methotrexate-based regimen; or a clofarabine-based regimen.1, 18 The primary endpoint was overall survival, with key secondary endpoints including CR and event-free survival.1, 18 Complete remission was defined as having ≤5% blasts in the bone marrow with no signs of disease and was further categorized based on the degree of peripheral blood count recovery.18

The median age of patients in the TOWER study was 37 years, and approximately 60% of patients were male.1 The majority of patients (84% in each group) were white.1 Treatment with blinatumomab resulted in improved overall survival compared to standard chemotherapy.1, 18 The median overall survival was 7.7 months in the blinatumomab group versus 4 months in the standard chemotherapy group.1, 18 Complete remission with full hematologic recovery within 12 weeks was achieved in 34% of patients receiving blinatumomab compared to 16% of patients receiving standard chemotherapy.1, 18 The event-free survival rate at 6 months was 31% with blinatumomab versus 12% with chemotherapy.18

The MT103-211 study was an open-label, phase 2, single-arm study assessing blinatumomab in 185 adults (≥18 years of age) with Ph-negative relapsed or refractory B-cell precursor ALL.1, 2 Patients were enrolled if their disease was primary refractory following induction therapy, had relapsed or was refractory following first salvage therapy, or had relapsed within 12 months of first remission or following allogeneic HSCT.1, 2 Patients enrolled in the study also were required to have ≥10% blast cells in bone marrow.1, 2 In this study, patients received a target blinatumomab dosage of 28 mcg daily by continuous IV infusion for 4 weeks followed by a 2-week rest period; dosage was escalated to the target level during cycle 1 (blinatumomab 9 mcg daily was given by continuous IV infusion for the first week of cycle 1 with a subsequent increase to 28 mcg daily by continuous IV infusion for the remaining 3 weeks of treatment during cycle 1) to reduce the risk of cytokine release syndrome.1, 2 The primary measure of efficacy was CR or complete remission with partial hematologic recovery (CRh) within the first 2 treatment cycles; CR was defined as the presence of 5% or less blasts in bone marrow without evidence of disease and with full recovery of peripheral blood cell counts (platelet count exceeding 100,000/mm³ and ANC exceeding 1000/mm³), and CRh was defined as the presence of 5% or less blasts in bone marrow without evidence of disease and with partial recovery of peripheral blood cell counts (platelet count exceeding 50,000/mm³ and ANC exceeding 500/mm³).1, 2 The median age of patients was 39 years; 34% of the patients had undergone allogeneic HSCT prior to study entry and 17% of patients had received more than 2 prior salvage therapies for their disease.1, 2 Complete remission was achieved in 32.4% of patients, and CRh was achieved in 9.2%; the overall CR or CRh rate was 41.6%.1 Among those who achieved CR or CRh, MRD response (defined as MRD <0.01%) was observed in 80.0% (48/60) of CR patients and 58.8% (10/17) of CRh patients, with an overall MRD response rate of 75.3% (58/77).1 The overall median duration of response/RFS was 5.9 months.1

The ALCANTARA study was an open-label, single-arm, phase 2 trial enrolling 45 adults ≥18 years of age with relapsed or refractory Ph-positive B-cell precursor ALL.1, 19 Eligible patients had relapsed or refractory Ph-positive ALL after at least one second-generation tyrosine kinase inhibitor (TKI), including dasatinib, nilotinib, bosutinib, or ponatinib, or were intolerant to second-generation TKIs and failed or were intolerant to imatinib.1, 19 Blinatumomab was administered as a continuous infusion in 4-week cycles, followed by a 2-week treatment-free interval.19 In cycle 1, patients received 9 mcg/day in week 1, then 28 mcg/day during weeks 2-4.1, 19 In subsequent cycles, the dose was 28 mcg/day for 4 weeks.1, 19 The primary efficacy outcome was the proportion of patients attaining CR or CRh within the initial 2 cycles of blinatumomab treatment.19

The median age of patients in the ALCANTARA study was 55 years; 53% of patients were male and the majority were white (87%).1 Most patients received at least 2 prior TKIs, with dasatinib being the most common.19 Additionally, 76% of patients had ≥50% bone marrow blasts at baseline, and 44% had undergone prior allogeneic HSCT.19 The primary outcome was achieved in 35.6% of patients.19 Specifically, 31.1% achieved CR, while 4.4% achieved CRh.19 The median RFS was 6.8 months, while the median overall survival was 9 months.19 Patients who achieved CR or CRh had a significantly longer median overall survival of 23 months, compared to 5.7 months in non-responders.19

Study MT103-205 was a phase 1/2, open-label, single-arm trial conducted in pediatric patients with relapsed or refractory B-cell precursor ALL.1, 20 Patients were eligible if they were <18 years of age, had B-cell precursor ALL with >25% blasts in bone marrow, and had relapsed or refractory disease (i.e., second or later bone marrow relapse, any marrow relapse after allogeneic HSCT, or disease refractory to other treatments).1, 20 Blinatumomab was administered at a dosage of 5 mcg/m² per day on days 1-7 and 15 mcg/m² per day on days 8-28 during the first cycle.1, 20 For subsequent cycles, the dosage was 15 mcg/m² per day on days 1-28.1, 20 The primary efficacy endpoint was the CR rate within the first 2 cycles.20

Among the 70 patients enrolled in MT103-205, the median age was 8 years; 57.1% had previously undergone allogeneic HSCT, and 55.7% had refractory disease.1 A total of 23 patients (32.9%) achieved CR or CRh within the first 2 treatment cycles; of these, 73.9% responded within the first cycle.1 Among those with CR or CRh, 43.5% had an MRD response (defined as MRD <0.01%).1 The overall median RFS was 6 months.1 The HSCT rate among those who achieved CR or CRh was 48%.1

Ph-negative B-cell Precursor ALL in the Consolidation Phase

The indication for blinatumomab as a treatment for CD19-positive Ph-negative B-cell precursor ALL in the consolidation phase of multiphase chemotherapy is based on 2 studies in adult and pediatric patients (Study E1910 and Study 20120215).1, 21, 22

Study E1910 was a phase 3, randomized, multicenter trial evaluating the addition of blinatumomab to consolidation chemotherapy in adults 30-70 years of age with newly diagnosed Ph-negative B-cell precursor ALL.1, 21 Patients were randomized (stratified by age, CD20 status, rituximab use, and intent to undergo allogeneic HSCT) in a 1:1 ratio to receive blinatumomab plus intensive chemotherapy or intensive chemotherapy alone for consolidation.1, 21 Patients in the blinatumomab group received 2 cycles of blinatumomab at a dosage of 28 mcg/day for 4 weeks, with a 2-week break between cycles.1, 21 This was followed by 3 cycles of chemotherapy, then a third cycle of blinatumomab, followed by a fourth cycle of chemotherapy and a fourth cycle of blinatumomab.1, 21 Patients in the chemotherapy-only group underwent the same 4 cycles of consolidation chemotherapy without blinatumomab.1, 21 The primary efficacy endpoint was overall survival in the MRD-negative subgroup; a key secondary endpoint was RFS.21

Among the 224 patients with MRD-negative status in study E1910, the median age was 51 years and 50% of patients were male.21 At a median follow-up of 43 months, blinatumomab plus consolidation chemotherapy improved overall survival compared to consolidation chemotherapy alone, with a 3-year survival rate of 85 versus 68%.21 Similarly, RFS at 3 years was higher in the blinatumomab group compared to the chemotherapy-only group (80 versus 64%).21 In a subsequent analysis with a median follow-up of 4.5 years, 5-year overall survival was 82.4% in the blinatumomab plus chemotherapy group, compared to 62.5% in the chemotherapy-only group.1

Study 20120215 was a phase 3, multicenter, open-label trial that compared blinatumomab to multidrug consolidation chemotherapy as the third cycle of consolidation treatment before allogeneic HSCT in 111 pediatric patients with high-risk first-relapse Ph-negative B-cell ALL.1, 22 Patients were eligible if they were 28 days to 18 years of age and had Ph-negative, high-risk, first-relapsed B-ALL with <25% bone marrow blasts after induction and 2 cycles of consolidation chemotherapy.1, 22 Patients were randomized (stratified by age, MRD status at the end of induction, and bone marrow status at the end of the second block of consolidation chemotherapy) in a 1:1 ratio to receive either 1 cycle of blinatumomab (15 mcg/m² per day for 4 weeks via continuous IV infusion) or standard consolidation chemotherapy according to established protocols.1, 22 The primary measures of efficacy were overall survival and RFS.1

The median age of patients in the blinatumomab and chemotherapy arms was 6 and 5 years, respectively; males accounted for 56 and 40% of each arm, respectively.1 The majority of patients were white.1 The overall population had a median follow-up duration of 55.2 months.1 The overall survival rate at 5 years was 78.4% in the blinatumomab group compared to 41.4% in the chemotherapy group.1 Five-year RFS was 61.1% in the blinatumomab group compared to 27.6% in the chemotherapy group.1

Clinical Perspective

Effective treatment of ALL involves controlling bone marrow and systemic disease while addressing or preventing sanctuary site involvement, particularly in the CNS.23 This approach relies on systemically-administered combination chemotherapy combined with CNS-directed prophylactic therapy.23 The typical duration of treatment for ALL ranges from 1.5-3 years to ensure the elimination of leukemic cells.23 B-cell ALL, a subtype of ALL, is generally not effectively treated with standard ALL therapy.23 Intensive, short-duration, high-intensity regimens similar to treatments for aggressive non-Hodgkin lymphoma have demonstrated high response and cure rates in B-cell ALL.23 Cyclophosphamide-based regimens, resembling those used for aggressive non-Hodgkin lymphoma, have been associated with improved outcomes and prolonged disease-free survival in patients with B-cell ALL.23

Immunotherapies approved for the treatment of ALL include blinatumomab, inotuzumab ozogamicin, and tisagenlecleucel.24 According to some experts, options for patients with relapsed ALL after one prior line of therapy may include enrolling in a clinical trial, receiving blinatumomab or inotuzumab ozogamicin, or undergoing allogeneic HSCT.24 For those with relapsed B-cell ALL and a high disease burden, inotuzumab ozogamicin is recommended as the initial treatment, followed by blinatumomab for persistent disease or MRD positivity.24 Patients with newly diagnosed B-cell ALL who remain MRD-positive after induction chemotherapy should also be considered for treatment with blinatumomab.24

Dosage and Administration ⬆ ⬇

General

Pretreatment Screening

Verify pregnancy status in women of reproductive potential.1
Assess laboratory parameters such as ALT, AST, gamma-glutamyl transferase (GGT), and total bilirubin prior to initiating blinatumomab therapy.1

Patient Monitoring

Monitor laboratory parameters such as white blood cell count (WBC), absolute neutrophil count (ANC), ALT, AST, GGT, and total bilirubin, among others, in patients receiving blinatumomab therapy.1
Monitor for manifestations of neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS).1
Monitor for infection during therapy.1
Monitor for signs or symptoms of cytokine release syndrome (CRS).1
Monitor for signs or symptoms of tumor lysis syndrome (TLS).1
Monitor for signs and symptoms of pancreatitis.1
Monitor pediatric patients at risk for acid-base imbalances (e.g., with immature alcohol metabolism, underlying predisposing conditions, or receiving certain concomitant medications) for new or worsening acidosis when preservative-containing blinatumomab is administered.1 Avoid administration of preservative-containing blinatumomab (72-hour, 96-hour, 7-day infusion) in patients weighing <5.4 kg.1

Premedication and Prophylaxis

Appropriate prophylaxis with pretreatment non-toxic cytoreduction and adequate fluid hydration recommended to prevent TLS.1
Premedication with corticosteroid therapy recommended in all patients prior to the initial cycle of blinatumomab therapy, and may be recommended during subsequent cycles or therapy interruptions (e.g., interruption for ≥4 hours) based on the clinical indication.1
Prophylaxis with intrathecal chemotherapy recommended prior to and during blinatumomab therapy to prevent CNS acute lymphoblastic leukemia (ALL) relapse.1

Dispensing and Administration Precautions

Handling and Disposal

Procedures for proper handling (e.g., use of gloves and protective clothing) and disposal of antineoplastic agents should be followed.1
Medication errors resulting in underdosage or overdosage of blinatumomab have occurred in patients receiving the drug.1 Exercise extra care to ensure proper preparation and administration of blinatumomab.1
Based on the Institute for Safe Medication Practices (ISMP), blinatumomab is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.16

Other General Considerations

Administer in a hospital setting during the first and second treatment cycles; the recommended duration of hospitalization varies depending on the clinical indication for which blinatumomab therapy is being prescribed.1 During initiation of all subsequent cycles and for therapy interruptions (e.g., interruption for ≥4 hours), administration under healthcare provider supervision or in a hospital setting may also be recommended.1

Administration

Blinatumomab is administered by continuous IV infusion over 24 hours or 48 hours (preservative-free), or 72 hours, 96 hours, or 7 days (with preservative).1 The choice of infusion duration should be made by the healthcare provider after considering the frequency of infusion bag changes and the weight of the patient.1 Preservative-containing infusions (72-hour, 96-hour, and 7-day infusions) are not recommended for patients weighing <5.4 kg.1 Prior to administration, blinatumomab lyophilized powder for injection must be reconstituted and diluted; preparation steps differ based on the duration of the blinatumomab infusion.1 Follow the steps specific to the infusion duration during preparation.1 Consult the manufacturer's instructions for use in the blinatumomab prescribing information for more details on the preparation, reconstitution, and administration of blinatumomab.1

Vials of unreconstituted blinatumomab and IV solution stabilizer should be stored in the original package under refrigeration at 2-8°C, and for up to 8 hours at room temperature (23-27°C).1

Parenteral solutions of the drug should be inspected visually for particulate matter and discoloration whenever solution and container permit.1

Reconstituted blinatumomab vials are stable for up to 4 hours when stored at room temperature (23-27°C) or up to 24 hours when stored under refrigeration (2-8°C).1 Final diluted 24-hour and 48-hour (preservative-free) solutions of the drug are stable for up to 8 days after dilution when stored under refrigeration or up to 48 hours (including infusion time) after dilution when stored at room temperature.1 Final diluted 72-hour and 96-hour (preservative-containing) solutions of the drug are stable for up to 14 days after dilution when stored under refrigeration or up to 4 days (including infusion time) after dilution when stored at room temperature.1 The final diluted 7-day infusion solution is stable for up to 14 days after dilution when stored under refrigeration or up to 7 days (including infusion time) after dilution when stored at room temperature.1

Dosage

Adults

MRD-positive B-cell Precursor ALL

For the treatment of CD19-positive B-cell precursor ALL in first or second complete remission in adults with MRD ≥0.1%, the recommended treatment course is 1 cycle of blinatumomab induction, followed by up to 3 additional cycles of consolidation.1 During the induction cycle and consolidation cycles, blinatumomab is administered during each 42-day cycle as a continuous IV infusion on days 1-28, followed by a 2-week rest period.1 The recommended adult dosage of blinatumomab given on days 1-28 of each cycle is based on the patient's weight and schedule as recommended in Table 1.1

Table 1. Recommended Blinatumomab Dosage and Schedule for the Treatment of MRD-positive B-cell Precursor ALL1

Cycle	Patients Weighing ≥45 kg (Fixed-dose)	Patients Weighing <45 kg (BSA-based dose)
Induction Cycle 1
Days 1-28	28 mcg daily	15 mcg/m² daily (maximum 28 mcg daily)
Days 29-42	2-week rest period	2-week rest period
Consolidation Cycles 2-4
Days 1-28	28 mcg daily	15 mcg/m²daily (maximum 28 mcg daily)
Days 29-42	2-week rest period	2-week rest period

Hospitalization is recommended during the first 3 days of the first treatment cycle and for the first 2 days of the second treatment cycle.1 For all subsequent cycle starts and re-initiations (e.g., therapy interruption for ≥4 hours), supervision by a healthcare provider or hospitalization is recommended.1

Premedication with 100 mg of prednisone IV or equivalent (e.g., dexamethasone 16 mg) is recommended 1 hour prior to the first dose of blinatumomab in each cycle.1

Relapsed or Refractory B-cell Precursor ALL

For the treatment of relapsed or refractory CD19-positive B-cell precursor ALL in adults, the recommended treatment course is up to 2 cycles of blinatumomab induction, followed by 3 additional cycles for consolidation, and up to 4 additional cycles of continued therapy.1 A single cycle of blinatumomab induction or consolidation consists of 28 days of continuous IV infusion followed by a 2-week rest period (total of 42 days).1 A single cycle of blinatumomab continued therapy consists of 28 days of continuous IV infusion followed by an 8-week rest period (total of 84 days).1 The recommended adult dosage of blinatumomab given during each cycle is based on the patient's weight and schedule as recommended in Table 2.1

Table 2. Recommended Blinatumomab Dosage and Schedule for the Treatment of Relapsed or Refractory B-cell Precursor ALL1

Cycle	Patients Weighing ≥45 kg (Fixed-dose)	Patients Weighing <45 kg (BSA-based dose)
Induction Cycle 1
Days 1-7	9 mcg daily	5 mcg/m² daily (maximum 9 mcg daily)
Days 8-28	28 mcg daily	15 mcg/m² daily (maximum 28 mcg daily)
Days 29-42	2-week rest period	2-week rest period
Induction Cycle 2
Days 1-28	28 mcg daily	15 mcg/m² daily (maximum 28 mcg daily)
Days 29-42	2-week rest period	2-week rest period
Consolidation Cycles 3-5
Days 1-28	28 mcg daily	15 mcg/m² daily (maximum 28 mcg daily)
Days 29-42	2-week rest period	2-week rest period
Continued Therapy Cycles 6-9
Days 1-28	28 mcg daily	15 mcg/m² daily (maximum 28 mcg daily)
Days 29-84	8-week rest period	8-week rest period

Hospitalization is recommended during the first 9 days of the first treatment cycle and for the first 2 days of the second treatment cycle.1 For all subsequent cycle starts and re-initiations (e.g., therapy interruption for ≥4 hours), supervision by a healthcare provider or hospitalization is recommended.1

Premedicate with 20 mg of dexamethasone IV or oral 1 hour prior to the first dose of blinatumomab in each cycle, prior to a step dose (e.g., cycle 1 day 8), and when therapy is interrupted for ≥4 hours.1

Ph-negative B-cell Precursor ALL in the Consolidation Phase

For the treatment of CD19-positive Ph-negative B-cell precursor ALL in adults in the consolidation phase of multiphase chemotherapy, a single cycle of blinatumomab consolidation consists of 28 days of continuous IV infusion followed by a 2-week rest period (total of 42 days).1 The recommended adult dosage of blinatumomab given during each consolidation cycle is based on the patient's weight and schedule as recommended in Table 3.1

Table 3. Recommended Blinatumomab Dosage and Schedule in the Consolidation Phase of Treatment of B-cell Precursor ALL1

Consolidation Cycle	Patients Weighing ≥45 kg (Fixed-dose)	Patients Weighing <45 kg (BSA-based dose)
Days 1-28	28 mcg daily	15 mcg/m² daily (maximum 28 mcg daily)
Days 29-42	2-week rest period	2-week rest period

Hospitalization is recommended during the first 3 days of the first consolidation cycle and for the first 2 days of the second consolidation cycle.1 During all subsequent cycles and when reinitiating therapy following an interruption lasting ≥4 hours, hospitalization or supervision by a healthcare provider is recommended.1

Premedicate with IV dexamethasone 20 mg administered 1 hour prior to the first infusion of blinatumomab in each cycle.1

Pediatric Patients

MRD-positive B-cell Precursor ALL

For the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) ≥0.1% in pediatric patients ≥1 month of age, the recommended treatment course is 1 cycle of blinatumomab induction, followed by up to 3 additional cycles for consolidation.1 During the induction cycle and consolidation cycles, blinatumomab is administered as a continuous IV infusion on days 1-28, followed by a 2-week rest period (total of 42 days).1 The recommended pediatric dosage of blinatumomab given on days 1-28 of each cycle is based on the patient's weight and schedule as recommended in Table 1.1

Premedication with 5 mg/m²(maximum 20 mg dose) of dexamethasone (IV or oral) is recommended prior to the first dose of blinatumomab in the first cycle and when restarting an infusion after an interruption of ≥4 hours in the first cycle.1

Preservative-containing infusions (72-hour, 96-hour, and 7-day infusions) are not recommended in patients weighing <5.4 kg.1

Relapsed or Refractory B-cell Precursor ALL

For the treatment of relapsed or refractory CD19-positive B-cell precursor ALL in pediatric patients ≥1 month of age, the recommended treatment course is up to 2 cycles of blinatumomab induction, followed by 3 additional cycles for consolidation, and up to 4 additional cycles of continued therapy.1 A single cycle of blinatumomab induction or consolidation consists of 28 days of continuous IV infusion followed by a 2-week rest period (total of 42 days).1 A single cycle of blinatumomab continued therapy consists of 28 days of continuous IV infusion followed by an 8-week rest period (total of 84 days).1 The recommended pediatric dosage of blinatumomab given during each cycle is based on the patient's weight and schedule as recommended in Table 2.1

Premedication with 5 mg/m² (maximum dose of 20 mg) of dexamethasone (IV or oral) is recommended prior to the first dose of blinatumomab in the first cycle, prior to a step dose (e.g., cycle 1 day 8), and when restarting an infusion after an interruption of ≥4 hours during the first cycle.1

Preservative-containing infusions (72-hour, 96-hour, and 7-day infusions) are not recommended in patients weighing <5.4 kg.1

Ph-negative B-cell Precursor ALL in the Consolidation Phase

For the treatment of CD19-positive, Philadelphia chromosome (Ph)-negative B-cell precursor ALL in the consolidation phase of multiphase chemotherapy in pediatric patients ≥1 month of age, a single cycle of blinatumomab consolidation consists of 28 days of continuous IV infusion followed by a 2-week rest period (total of 42 days).1 The recommended pediatric dosage of blinatumomab given during each consolidation cycle is based on the patient's weight and schedule as recommended in Table 3.1

Premedication with IV or oral dexamethasone 5 mg/m² (maximum 20 mg) should be given prior to the first infusion of blinatumomab in the first cycle, and when reinitiating therapy following an interruption lasting ≥4 hours during the first cycle.1

Preservative-containing infusions (72-hour, 96-hour, and 7-day infusions) are not recommended in patients weighing <5.4 kg.1

Dosage Modification for Toxicity

If adverse effects require interruption of blinatumomab therapy for no more than 7 days, the current cycle should be continued for a total of 28 days of blinatumomab treatment (including the days prior to and after the interruption in therapy).1 If blinatumomab therapy is interrupted for more than 7 days, a new cycle should be started.1

Grade 3 or 4 Clinically Relevant Adverse Effects

If grade 3 adverse effects occur in a patient weighing ≥45 kg, blinatumomab therapy should be withheld until the adverse effect has resolved to grade 0 or 1; if the adverse effects resolve within 14 days, therapy may then be resumed at a reduced dosage of 9 mcg daily.1 If the adverse effect does not recur within 7 days, blinatumomab may be re-escalated to a dosage of 28 mcg daily.1 If the adverse effect persists for more than 14 days following interruption of therapy, blinatumomab therapy should be permanently discontinued.1

If grade 3 adverse effects occur in a patient weighing <45 kg, blinatumomab therapy should be withheld until the adverse effect has resolved to grade 0 or 1; if the adverse effects resolve within 14 days, therapy may then be resumed at a reduced dosage of 5 mcg/m² daily.1 If the adverse effect does not recur within 7 days, blinatumomab may be re-escalated to a dosage of 15 mcg/m² daily.1 If the adverse effect persists for more than 14 days following interruption of therapy, blinatumomab therapy should be permanently discontinued.1

If grade 4 adverse effects occur in patients of any weight, permanent discontinuance of blinatumomab therapy should be considered.1

Cytokine Release Syndrome

If grade 3 cytokine release syndrome (CRS) occurs in a patient weighing ≥45 kg, blinatumomab therapy should be temporarily withheld until the toxicity has resolved.1 Dexamethasone 8 mg should be administered orally or IV every 8 hours for up to 3 days and tapered thereafter over 4 days.1 Blinatumomab therapy may then be resumed at a reduced dosage of 9 mcg daily.1 If the toxicity does not recur within 7 days, blinatumomab may be re-escalated to a dosage of 28 mcg daily.1

If grade 3 CRS occurs in a patient weighing <45 kg, blinatumomab therapy should be temporarily withheld until the toxicity has resolved.1 Dexamethasone 5 mg/m² (maximum 8 mg) should be administered orally or IV every 8 hours for up to 3 days and tapered thereafter over 4 days.1 Blinatumomab therapy may then be resumed at a dosage of 5 mcg/m² daily.1 If the toxicity does not recur within 7 days, blinatumomab may be re-escalated to a dosage of 15 mcg/m² daily.1

Regardless of patient weight, if grade 4 CRS occurs, blinatumomab therapy should be permanently discontinued.1 Dexamethasone should be administered in accordance with recommendations for grade 3 CRS.1

Neurologic Toxicity

If grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) occurs in a patient weighing ≥45 kg, blinatumomab therapy should be withheld until ICANS has resolved.1 The patient should be managed in accordance with current practice guidance, and systemic corticosteroids should be administered.1 Blinatumomab therapy may then be resumed at a dosage of 9 mcg daily.1 If the toxicity does not recur within 7 days, blinatumomab may be re-escalated to a dosage of 28 mcg daily.1

If grade 2 ICANS occurs in a patient weighing <45 kg, blinatumomab therapy should be withheld until ICANS has resolved.1 The patient should be managed in accordance with current practice guidance, and systemic corticosteroids should be administered.1 Blinatumomab therapy may then be resumed at a dosage of 5 mcg/m² daily.1 If the toxicity does not recur within 7 days, blinatumomab may be re-escalated to a dosage of 15 mcg/m² daily.1

If grade 3 neurologic events, including ICANS, occur in a patient weighing ≥45 kg, blinatumomab therapy should be withheld until the toxicity has resolved to grade 0 or 1 for at least 3 days; therapy may then be resumed at a reduced dosage of 9 mcg daily.1 If the toxicity does not recur within 7 days, blinatumomab may be re-escalated to a dosage of 28 mcg daily.1 If the toxicity occurred at a dosage of 9 mcg daily or persisted for more than 7 days following interruption of therapy, blinatumomab therapy should be permanently discontinued.1 If ICANS occurs, the patient should be managed in accordance with current practice guidance, and systemic corticosteroids should be administered.1

If grade 3 neurologic events, including ICANS, occur in a patient weighing <45 kg, blinatumomab therapy should be withheld until the toxicity has resolved to grade 0 or 1 for at least 3 days; therapy may then be resumed at a reduced dosage of 5 mcg/m² daily.1 If the toxicity does not recur within 7 days, blinatumomab may be re-escalated to a dosage of 15 mcg/m² daily.1 If the toxicity occurred at a dosage of 5 mcg/m² daily or persisted for more than 7 days following interruption of therapy, blinatumomab therapy should be permanently discontinued.1 If ICANS occurs, the patient should be managed in accordance with current practice guidance, and systemic corticosteroids should be administered.1

If more than 1 seizure occurs or if grade 4 neurologic events, including ICANS, occur in any patient, blinatumomab therapy should be permanently discontinued.1 If ICANS occurs, the patient should be managed in accordance with current practice guidance, and systemic corticosteroids should be administered.1

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Cautions ⬆ ⬇

Contraindications

Known hypersensitivity to the drug or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Cytokine Release Syndrome

A boxed warning is included in the blinatumomab prescribing information about the risk of cytokine release syndrome (CRS).1 Cytokine release syndrome, sometimes life-threatening or fatal, has been reported in patients receiving blinatumomab.1 The median onset to cytokine release was 2 days following initiation of blinatumomab infusion, and 5 days among cases that resolved.1 In clinical studies of blinatumomab in patients with relapsed or refractory acute lymphoblastic leukemia (ALL), CRS occurred in 15% of patients receiving blinatumomab.1 Cytokine release syndrome was reported in 7% of patients with minimal residual disease (MRD)-positive ALL receiving blinatumomab and in 16% of patients receiving blinatumomab in the consolidation phase.1 Manifestations of CRS include fever, headache, nausea, asthenia, hypotension, elevated serum aminotransferase (ALT and AST) and bilirubin concentrations, and disseminated intravascular coagulation.1 Infusion-related reactions observed with blinatumomab may be clinically indistinguishable from manifestations of CRS, capillary leak syndrome, and hemophagocytic histiocytosis/macrophage activation syndrome (MAS).1 Patients receiving blinatumomab should be monitored closely for signs and symptoms of these effects.1 Patients receiving blinatumomab on an outpatient basis should be advised to contact their healthcare professional if signs or symptoms of CRS occur.1 If severe CRS occurs, blinatumomab should be temporarily interrupted until symptom resolution.1 If CRS is life-threatening, blinatumomab should be permanently discontinued.1 If severe or life-threatening CRS occurs, administer systemic corticosteroids.1

Neurologic Toxicity, Including Immune Effector Cell-associated Neurotoxicity Syndrome

A boxed warning is included in the blinatumomab prescribing information about the risk of neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS).1 Serious or life-threatening neurologic toxicity, including ICANS, has been reported in patients receiving blinatumomab therapy.1 Neurologic toxicities occurred in approximately 65% of patients receiving blinatumomab in clinical studies.1 The most common neurologic toxicities were headache and tremor, which occurred in ≥10% of patients; the toxicity profile varied by age group.1 Grade 3 or greater neurologic toxicities (e.g., encephalopathy, seizures, speech impairment, disturbances in consciousness, confusion and disorientation, coordination and balance disorders) occurred in approximately 13% of patients following initiation of blinatumomab therapy.1 Cranial nerve disorders were also reported.1 The median time to onset of neurologic toxicity was within 14 days.1 Neurologic toxicity generally resolved following treatment interruption; however, discontinuance of blinatumomab was necessary in some patients.1 Signs and symptoms of ICANS were reported in 7.5% of patients receiving blinatumomab in clinical studies.1 ICANS may occur with or without concurrent CRS or following CRS resolution.1 Blinatumomab has been used in a limited number of patients with active ALL in the CNS or a history of neurologic events.1 Patients with preexisting or current clinically relevant CNS pathologies were excluded from clinical studies of blinatumomab.1 Patients with Down syndrome may have a higher seizure risk when receiving blinatumomab therapy.1 Patients receiving blinatumomab should be monitored for manifestations of neurologic toxicities, including ICANS.1 Patients receiving blinatumomab on an outpatient basis should be advised to contact their healthcare professional if signs or symptoms of neurologic toxicities occur.1 Temporary interruption or discontinuance of blinatumomab and/or treatment with systemic corticosteroids may be necessary if neurologic toxicities occur during therapy with the drug.1

Other Warnings and Precautions

Infections

Serious infections, such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, have been reported in approximately 25% of patients with ALL receiving blinatumomab in clinical studies and may be life-threatening or fatal.1

Prophylactic anti-infective therapy should be initiated as appropriate and surveillance testing should be employed during blinatumomab therapy.1 Patients should be monitored for signs and symptoms of infection and should receive appropriate anti-infective treatment as clinically indicated.1

Tumor Lysis Syndrome

Tumor lysis syndrome, sometimes life-threatening or fatal, has been reported in patients receiving blinatumomab.1 In clinical studies of blinatumomab in patients with relapsed or refractory ALL, tumor lysis syndrome occurred in 4% of patients receiving the drug.1

The manufacturer states that patients should be monitored for signs and symptoms of tumor lysis syndrome during blinatumomab therapy and, if present, interruption or discontinuance of blinatumomab therapy may be necessary.1 Appropriate prophylactic measures (e.g., pretreatment nontoxic cytoreduction, adequate hydration during therapy) should be used.1

Neutropenia and Febrile Neutropenia

Neutropenia and febrile neutropenia, sometimes life-threatening, have been reported in patients receiving blinatumomab.1 In clinical studies in patients with relapsed or refractory ALL, neutropenia occurred in 16% of patients receiving blinatumomab and Grade 3 or greater neutropenia was reported in 15% of patients receiving the drug.1

Complete blood cell (CBC) counts, including differential, should be monitored during blinatumomab therapy.1 Therapy should be interrupted if prolonged neutropenia occurs.1

Effects on Ability to Drive and Use Machines

Because neurologic toxicities resulting in loss of consciousness, ICANS, or seizures may occur, patients receiving blinatumomab should be advised to avoid driving a motor vehicle or engaging in hazardous occupations or activities (e.g., operating hazardous machinery) while receiving the drug.1

Elevated Liver Enzymes

Transient increases in hepatic enzyme concentrations have occurred in patients receiving blinatumomab.1 In patients receiving blinatumomab for ALL in clinical trials, the median time to onset of elevated hepatic enzyme concentrations was 3 days.1 Elevations in hepatic enzyme concentrations mostly occur in association with CRS; however, grade ≥3 elevations in liver enzymes were reported in approximately 7% of patients without CRS and resulted in discontinuance of blinatumomab in <1% of patients.1 The median time to onset of elevated hepatic enzyme concentrations without concurrent CRS was 19 days.1

Serum aminotransferase (ALT and AST), γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP), and total bilirubin concentrations should be evaluated prior to and during blinatumomab therapy.1 If ALT and/or AST concentrations exceed 5 times the upper limit of normal (ULN) or total bilirubin concentrations exceed 3 times the ULN, treatment should be interrupted.1

Pancreatitis

Cases of pancreatitis, some fatal, have been reported in patients receiving blinatumomab in combination with dexamethasone.1

Patients who develop signs and symptoms of pancreatitis should be evaluated.1 Management of pancreatitis may involve temporary interruption or discontinuation of blinatumomab and dexamethasone.1

Leukoencephalopathy

Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving blinatumomab, particularly in those who previously received cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine).1 The clinical importance of these changes is not known.1

Preparation and Administration Errors

Medication errors resulting in underdosage or overdosage of blinatumomab have occurred in patients receiving the drug.1 The proper procedure for preparing a final blinatumomab infusion solution from the reconstituted solution varies according to the dosage, infusion time of the IV bag, and rate of infusion.1 Extra care should be exercised to ensure proper preparation and administration of blinatumomab.1

Immunization

The safety of immunization with live virus vaccines during or following blinatumomab therapy has not been studied.1 It is recommended to avoid vaccination with live virus vaccines for at least 2 weeks prior to initiating blinatumomab, during treatment, and until immune system recovery after the last blinatumomab cycle.1

Benzyl Alcohol Toxicity in Neonates

Serious, sometimes fatal adverse effects, including neonatal “gasping syndrome,” have been reported in very-low-birth weight (VLBW) neonates weighing <1500 grams at birth, and in early preterm neonates (born earlier than 34 weeks' gestation) who received IV medications containing benzyl alcohol as a preservative.1 Early preterm VLBW neonates may have a higher likelihood of developing these adverse effects due to a lessened ability to metabolize benzyl alcohol.1

Neonatal patients receiving blinatumomab with preservatives should be monitored for new or worsening acidosis.1 The minimum threshold of benzyl alcohol at which serious adverse effects can occur is not known.1 The blinatumomab 72-hour infusion with preservatives and 96-hour infusion with preservatives contain 2.5 mg of benzyl alcohol per mL; the blinatumomab 7-day infusion with preservatives contains 7.4 mg of benzyl alcohol per mL.1 These preparations of blinatumomab (72-hour, 96-hour, and 7-day infusion) are not recommended for use in patients weighing <5.4 kg.1

Fetal/Neonatal Morbidity and Mortality

Due to its mechanism of action, blinatumomab may cause fetal harm when administered during pregnancy.1 Blinatumomab activates T-cells and causes cytokine release.1 Because of immune activation, pregnancy maintenance may be compromised.1 Blinatumomab can also cause B-cell lymphocytopenia in infants exposed to blinatumomab in utero.1 Women should be informed of the potential fetal risk with blinatumomab.1

Verify pregnancy status in females of reproductive potential prior to initiation of blinatumomab.1 Advise females of reproductive potential to use effective contraception during treatment and for 48 hours following the last dose of blinatumomab.1

Immunogenicity

In clinical studies, anti-blinatumomab antibody formation occurred in <2% of patients receiving blinatumomab; neutralizing antibodies were detected in 78% of these patients.1 Pharmacokinetics of blinatumomab may be affected by anti-blinatumomab antibody formation.1 Overall, clinical evidence suggests that anti-blinatumomab antibodies do not affect clinical efficacy or safety of blinatumomab.1

Specific Populations

Pregnancy

Based on its mechanism of action, blinatumomab may cause fetal harm if administered to pregnant women.1 No data are available on blinatumomab use in pregnant women to evaluate for a drug-associated risk.1 Animal reproductive studies have shown that a murine surrogate molecule administered to pregnant mice crosses the placenta.1

Blinatumomab activates T-cells and causes cytokine release.1 Because of immune activation, pregnancy maintenance may be compromised.1 Blinatumomab can also cause B-cell lymphocytopenia in infants exposed to blinatumomab in utero.1 Inform women of the potential fetal risk.1

In infants exposed to blinatumomab in utero, due to the risk of B-cell lymphocytopenia, monitoring of the infant's B lymphocytes before the initiation of live virus vaccines is recommended.1

Lactation

There are no data on whether blinatumomab is distributed into human milk.1 The effects on the breast-fed child from exposure to blinatumomab through the breast milk and the effects on milk production are not known.1 Because many drugs are distributed into human milk and because of the potential for serious adverse reactions to blinatumomab in nursing infants, including B-cell lymphocytopenia, advise patients to avoid breastfeeding during blinatumomab therapy and for 48 hours following the last dose.1

Females and Males of Reproductive Potential

Blinatumomab may cause fetal harm when administered during pregnancy.1

Pediatric Use

The safety and effectiveness of blinatumomab in pediatric patients <1 month of age have not been established for any indication.1

Safety and effectiveness of blinatumomab for the treatment of CD19-positive B-cell precursor ALL in first or second complete remission with MRD ≥0.1% have been established in pediatric patients ≥1 month of age.1 This indication is supported by evidence from 2 randomized controlled trials in pediatric patients with first-relapsed, MRD-positive, B-cell precursor ALL that included 6 infants (1 month to <2 years of age), 165 children (≥2 years to <12 years of age), and 70 adolescents (12 years to <17 years of age).1 Adverse effects experienced in pediatric patients in these students were generally similar to those in adult patients with MRD-positive ALL.1 No differences in safety were detected between the different pediatric age groups.1

Safety and effectiveness of blinatumomab for the treatment of relapsed or refractory B-cell precursor ALL have been established in pediatric patients ≥1 month of age.1 This indication is supported by evidence from 1 single-arm study of pediatric patients with relapsed or refractory B-cell precursor ALL enrolling 10 infants (≥1 month to <2 years of age), 40 children (≥2 years to <12 years of age), and 20 adolescents (≥12 years to <18 years of age).1 No differences in efficacy of blinatumomab were noted between age groups.1 Adverse effects experienced in pediatric patients with relapsed or refractory B-cell precursor ALL in the single-arm study were similar to those observed in adults with relapsed or refractory B-cell precursor ALL; however, some adverse effects occurred ≥10% more frequently in the pediatric population, including pyrexia (80% versus 61%), hypertension (26% versus 8%), anemia (41% versus 24%), infusion-related reactions (49% versus 34%), thrombocytopenia (34% versus 21%), leukopenia (24% versus 11%), and weight increases (17% versus 6%).1 The incidence of neurologic toxicities was not different in pediatric patients <2 years of age compared to other age groups; however, the presentation differed.1 Agitation, headache, insomnia, somnolence, and irritability were reported.1 There was an increased incidence of hypokalemia (50%) in infants compared to other pediatric age groups (15-20%) and adults (17%).1

Safety and effectiveness of blinatumomab for the treatment of Philadelphia-chromosome (Ph)-negative B-cell precursor ALL in the consolidation phase have been established in pediatric patients ≥1 month of age.1 This indication is supported by data extrapolated from 1 randomized controlled trial in adults and data from 2 randomized controlled trials in pediatric patients.1

Serious, sometimes fatal adverse effects, including neonatal “gasping syndrome” (characterized by CNS depression, metabolic acidosis, and gasping respirations), have been reported in VLBW neonates weighing <1500 grams at birth, and in early preterm neonates (born earlier than 34 weeks' gestation) who received IV medications containing benzyl alcohol as a preservative.1 Adverse effects can also include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.1 Cases of neonatal “gasping syndrome” have occurred at benzyl alcohol dosages of 99-234 mg/kg daily that resulted in high concentrations of benzyl alcohol and its metabolite in the blood and urine.1 The minimum amount of benzyl alcohol in neonates that may lead to these serious adverse effects is not known.1

When possible, preservative-free preparations of blinatumomab should be used in neonatal patients.1 If blinatumomab with preservatives is used in a neonatal patient, the combined daily metabolic load of benzyl alcohol from blinatumomab and other products containing benzyl alcohol or excipients such as ethanol or propylene glycol should be considered, as these agents compete with benzyl alcohol for the same metabolic pathway.1 The blinatumomab 72-hour infusion with preservatives and 96-hour infusion with preservatives contain 2.5 mg of benzyl alcohol per mL; the blinatumomab 7-day infusion with preservatives contains 7.4 mg of benzyl alcohol per mL.1 These preparations of blinatumomab (72-hour, 96-hour, and 7-day infusion) are not recommended for use in patients weighing <5.4 kg.1

Administration of benzyl alcohol-containing products may contribute to metabolic acidosis in pediatric patients, particularly in those with immature alcohol metabolism, or in those with underlying conditions or in those receiving concomitant mediations that predispose patients to acid-base imbalance.1 Monitor pediatric patients receiving blinatumomab with preservatives for new or worsening metabolic acidosis.1

Geriatric Use

In clinical studies evaluating blinatumomab for MRD-positive, CD19-positive B-cell precursor ALL in first or second complete remission, relapsed or refractory CD19-positive B-cell precursor ALL, and CD19-positive, Ph-negative B-cell precursor ALL in the consolidation phase, approximately 7% of patients were ≥65 years of age.1 Of the total number of patients receiving blinatumomab in these studies, 8% were ≥65 years of age and 1% were ≥75 years of age.1 Although efficacy and safety of blinatumomab generally were similar regardless of patient age in these studies, neurologic toxicities (e.g., cognitive disorder, encephalopathy, confusion) and serious infections occurred more frequently in geriatric patients compared with younger patients.1

Hepatic Impairment

No clinically significant differences in blinatumomab pharmacokinetics have been observed in patients with mild hepatic impairment (total bilirubin ≤ULN and AST>ULN or total bilirubin >1-1.5 times ULN with any AST) or moderate hepatic impairment (total bilirubin >1.5-3 times ULN with any AST).1 The effect of severe hepatic impairment (total bilirubin >3 times ULN with any AST) on blinatumomab pharmacokinetics is not known.1

Renal Impairment

Analysis of available pharmacokinetic data indicates an approximately 2-fold difference in mean blinatumomab clearance between patients with moderate renal impairment (creatinine clearance of 30-59 mL/minute) and those with normal renal function.1 However, high interpatient variability was apparent and clearance values for patients with renal impairment were within the range observed in patients with normal renal function.1 The effects of severe renal impairment (creatinine clearance 15-29 mL/minute) or hemodialysis on the pharmacokinetics of blinatumomab have not been established.1

Common Adverse Effects

Adverse effects reported in ≥20% of patients receiving blinatumomab in clinical studies include pyrexia, infusion-related reactions, infection, headache, musculoskeletal pain, neutropenia, nausea, anemia, thrombocytopenia, and diarrhea.1

Drug Interactions ⬆ ⬇

No formal drug interaction studies have been performed to date.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Following initiation of blinatumomab therapy, a transient release of cytokines may result in suppression of cytochrome P-450 (CYP) isoenzymes and potentially increase serum concentrations of other drugs metabolized by CYP isoenzymes.1, 8

Risk of drug interactions is highest during days 1-9 of cycle 1 and days 1-2 of cycle 2 in patients receiving drugs metabolized by CYP isoenzymes, particularly those with a low therapeutic index that require individualized dosing (e.g., warfarin, cyclosporine).1 Patients receiving certain drugs metabolized by CYP isoenzymes should be monitored for toxicity and/or changes in serum concentrations, and dosages of these drugs should be adjusted as needed.1

Other Information ⬆ ⬇

Description

Blinatumomab, a CD3 T-cell-engaging anti-CD19 monoclonal antibody, is an antineoplastic agent; the drug also is referred to as a bispecific T-cell-engager (BiTE) monoclonal antibody.1, 11, 12, 13, 15 The drug is a single-chain antibody composed of the variable fragments of antibodies to CD3 and CD19.11, 12, 14 The 2 antibodies are connected by a nonglycosylated, nonimmunogenic linker protein, which allows for rotational flexibility and close proximity of malignant CD19⁺ B cells to CD3⁺ T cells.11, 12, 14, 15 Blinatumomab binds specifically to the CD3 signaling chain of the T-cell receptor (TCR) complex and to antigen CD19, a transmembrane glycoprotein expressed on the surface of normal and malignant B lymphocytes, including precursor B-cell acute lymphoblastic leukemia cells.1, 2, 11, 12, 13 Following activation of endogenous T cells, proinflammatory cytokines (interleukin-2 [IL-2], interleukin-4 [IL-4], interleukin-6 [IL-6], interleukin-10 [IL-10], tumor necrosis factor [TNF; TNF-α], interferon gamma)11, 15 are released and upregulation of cell adhesion molecules induces the release of cytotoxic granules containing perforins and granzymes, which results in activation of caspases and apoptosis (programmed cell death) of CD19⁺ B cells.1, 11, 13, 14

Initial redistribution of peripheral T cells, a decrease in peripheral B-cell counts, and transient release of proinflammatory cytokines are observed in patients receiving blinatumomab therapy.1 Redistribution of peripheral T cells occurred following initiation of blinatumomab infusion or dosage escalation.1 In most patients, T-cell counts decreased during the initial 1-2 days of therapy and returned to baseline levels within 7-14 days; however, elevation of T-cell counts above baseline was observed in some patients.1 Blinatumomab decreased peripheral B-cell counts to 10 cells/mm³ or less during the first treatment cycle in most patients receiving blinatumomab 5 mcg/m² or more daily or 9 mcg or more daily.1 Peripheral B-cell recovery was not observed during the 2-week rest period between treatment cycles.1 Following administration of blinatumomab, the proinflammatory cytokines IL-2, IL-4, IL-6, IL-10, TNF-α, and interferon gamma are released;11, 15 levels of IL-6, IL-10, and interferon gamma increase immediately following initiation of an infusion in most patients.1, 5 Cytokine levels are highest 1-2 days following initiation of the blinatumomab infusion and return to baseline within 24-48 hours during the infusion.1 The incidence and intensity of elevated cytokine levels are decreased in subsequent treatment cycles compared with elevations observed during the initial 48 hours of the first treatment cycle.1

In patients receiving blinatumomab by continuous IV infusion, steady-state concentrations are reached within 1 day and remain stable over time.1, 5 Steady-state concentrations of blinatumomab are proportional to dose over the dosage range of 5-90 mcg/m² daily.1 The metabolic pathway of blinatumomab has not been characterized.1 As with other therapeutic proteins, the drug is expected to be degraded into small peptides and amino acids via catabolic pathways.1 Following administration of blinatumomab 60 mcg/m² daily, negligible amounts of the drug were detectable in urine at steady state.1, 5 The mean elimination half-life of blinatumomab in adult patients is 2.2 hours.1

In pediatric patients, the pharmacokinetics of blinatumomab are linear over the IV dosage range of 5-30 mcg/m² daily.1 The pharmacokinetics of blinatumomab continuous IV infusion in pediatric patients with MRD-positive, B-cell precursor ALL and in pediatric patients with B-cell precursor ALL in the consolidation phase are similar to those observed in pediatric patients with relapsed or refractory ALL.1 Steady-state concentrations of blinatumomab are similar in adult and pediatric patients at equivalent dosages based on body surface area (BSA).1 In pediatric patients with ALL, the elimination half-life of blinatumomab in cycle 1 was approximately 2.14 hours.1

Pharmacokinetic parameters of blinatumomab do not appear to be affected by age (range of 0.6-80 years), sex, race (72% white, 17% Asian, 3% Black), ethnicity, or Ph status.1 The effect of other races on the pharmacokinetic parameters of blinatumomab are not known.1 The pharmacokinetics of blinatumomab are influenced by BSA (0.4-2.9 m²), which supports BSA-based dosing in patients weighing <45 kg.1

Advice to Patients

Advise patients to read the manufacturer's medication guide before beginning treatment and each time blinatumomab is administered.1
Inform patients of the risk of cytokine release syndrome and infusion-related reactions.1 Advise patients to immediately report signs and symptoms of such reactions (e.g., pyrexia, fatigue, nausea, vomiting, chills, hypotension, rash, wheezing).1
Inform patients of the risk of neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS).1 Advise patients to inform their clinician immediately if signs and symptoms of neurologic toxicity (e.g., seizures, speech impairment, loss of consciousness, confusion, loss of balance) occur.1 Advise patients to avoid driving or engaging in hazardous occupations or activities (e.g., operating hazardous machinery) while receiving the drug.1
Inform patients of the risk of infections.1 Instruct patients to immediately contact their clinician if symptoms suggestive of an infection develop.1 Advise patients to keep the IV injection site clean in order to reduce the risk of catheter-related infection.1
Inform patients of the risk of pancreatitis and advise them to contact their healthcare provider immediately for signs and symptoms of pancreatitis, including severe and persistent stomach pain (with or without nausea and vomiting).1
Advise patients to avoid adjusting settings on the infusion pump.1 Advise patients to inform their clinician immediately if a problem with the infusion pump occurs or if the pump alarm sounds.1
Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1 Inform patients of the potential fetal risk.1 Advise women of reproductive potential to use effective contraception during blinatumomab therapy, and for 48 hours following the final dose.1 Advise patients not to breast-feed during therapy and for 48 hours following the final dose.1
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1
Advise patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Handling and Disposal

Table 1. Recommended Blinatumomab Dosage and Schedule for the Treatment of MRD-positive B-cell Precursor ALL1

Table 2. Recommended Blinatumomab Dosage and Schedule for the Treatment of Relapsed or Refractory B-cell Precursor ALL1

Table 3. Recommended Blinatumomab Dosage and Schedule in the Consolidation Phase of Treatment of B-cell Precursor ALL1

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

Blinatumomab

Copyright ⬆ ⬇

References ⬆