Blincyto Adverse Reactions

The following clinically significant adverse reactions are described elsewhere in the monograph: Cytokine Release Syndrome [see Cytokine Release Syndrome under Precautions]; Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome [see Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome under Precautions]; Infections [see Infections under Precautions]; Tumor Lysis Syndrome [see Tumor Lysis Syndrome under Precautions]; Neutropenia and Febrile Neutropenia [see Neutropenia and Febrile Neutropenia under Precautions]; Effects on Ability to Drive and Use Machines [see Effects on Ability to Drive and Use Machines under Precautions]; Elevated Liver Enzymes [see Elevated Liver Enzymes under Precautions]; Pancreatitis [see Pancreatitis under Precautions]; Leukoencephalopathy [see Leukoencephalopathy under Precautions].
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of BLINCYTO in adult and pediatric patients one month and older with MRD-positive B-cell precursor ALL (n = 137), relapsed or refractory B-cell precursor ALL (n = 267), and Philadelphia chromosome-negative B-cell precursor ALL in consolidation (n = 165) was evaluated in clinical studies. The most common adverse reactions (≥20%) to BLINCYTO in this pooled population were pyrexia, infusion-related reactions, headache, infection, musculoskeletal pain, neutropenia, nausea, anemia, thrombocytopenia, and diarrhea.
MRD-positive B-cell Precursor ALL: The safety of BLINCYTO in patients with MRD-positive B-cell precursor ALL was evaluated in two single-arm clinical studies in which 137 adult patients were treated with BLINCYTO. The median age of the study population was 45 years (range: 18 to 77 years).
The most common adverse reactions (≥20%) were pyrexia, infusion-related reactions, headache, infections (pathogen unspecified), tremor, and chills. Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection. Adverse reactions of Grade 3 or higher were reported in 64% of patients. Discontinuation of therapy due to adverse reactions occurred in 17% of patients; neurologic events were the most frequently reported reasons for discontinuation. There were 2 fatal adverse reactions that occurred within 30 days of the end of BLINCYTO treatment (atypical pneumonia and subdural hemorrhage).
Table 20 summarizes the adverse reactions occurring at a ≥10% incidence for any grade or ≥5% incidence for Grade 3 or higher. (See Table 20.)

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Additional adverse reactions in adult patients with MRD-positive ALL that did not meet the threshold criteria for inclusion in Table 20 were: Blood and lymphatic system disorders: anemia.
General disorders and administration site conditions: edema peripheral, pain, and chest pain (includes chest pain and musculoskeletal chest pain).
Hepatobiliary disorders: blood bilirubin increased.
Immune system disorders: hypersensitivity and cytokine release syndrome.
Infections and infestations: viral infectious disorders, bacterial infectious disorders, and fungal infectious disorders.
Injury, poisoning and procedural complications: medication error and overdose (includes overdose and accidental overdose).
Investigations: blood alkaline phosphatase increased.
Musculoskeletal and connective tissue disorders: pain in extremity and bone pain.
Nervous system disorders: seizure (includes seizure and generalized tonic-clonic seizure), speech disorder, and hypoesthesia.
Psychiatric disorders: confusional state, disorientation, and depression.
Respiratory, thoracic and mediastinal disorders: dyspnea and productive cough.
Vascular disorders: hypertension (includes blood pressure increased and hypertension), flushing (includes flushing and hot flush), and capillary leak syndrome.
Relapsed or Refractory B-cell Precursor ALL: The safety of BLINCYTO was evaluated in a randomized, open-label, active-controlled clinical study (TOWER Study) in which 376 adult patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL were treated with BLINCYTO (n = 267) or standard of care (SOC) chemotherapy (n = 109). The median age of BLINCYTO-treated patients was 37 years (range: 18 to 80 years), 60% were male, 84% were White, 7% Asian, 2% were Black or African American, 2% were American Indian or Alaska Native, and 5% were Multiple/Other.
The most common adverse reactions (≥20%) in the BLINCYTO arm were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia. Adverse reactions of Grade 3 or higher were reported in 87% of patients. Discontinuation of therapy due to adverse reactions occurred in 12% of patients treated with BLINCYTO; neurologic events and infections were the most frequently reported reasons for discontinuation of treatment due to an adverse reaction. Fatal adverse events occurred in 16% of patients. The majority of the fatal events were infections.
The adverse reactions occurring at a ≥10% incidence for any grade or ≥5% incidence for Grade 3 or higher in the BLINCYTO-treated patients in first cycle of therapy are summarized in Table 21. (See Table 21.)

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Selected laboratory abnormalities worsening from baseline Grade 0-2 to treatment-related maximal Grade 3-4 in first cycle of therapy are shown in Table 22. (See Table 22.)

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Other important adverse reactions from pooled relapsed or refractory B-cell precursor ALL studies were: Blood and lymphatic system disorders: lymphadenopathy, hematophagic histiocytosis, and leukocytosis (includes leukocytosis and white blood cell count increased).
General disorders and administration site conditions: chills, chest pain (includes chest discomfort, chest pain, musculoskeletal chest pain, and non-cardiac chest pain), pain, body temperature increased, hyperthermia, and systemic inflammatory response syndrome.
Hepatobiliary disorders: hyperbilirubinemia (includes blood bilirubin increased and hyperbilirubinemia).
Immune system disorders: hypersensitivity (includes hypersensitivity, anaphylactic reaction, angioedema, dermatitis allergic, drug eruption, drug hypersensitivity, erythema multiforme, and urticaria).
Injury, poisoning and procedural complications: medication error and overdose (includes overdose, medication error, and accidental overdose)
Investigations: weight increased, decreased immunoglobulins (includes immunoglobulins decreased, blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, and hypogammaglobulinemia), blood alkaline phosphatase increased, and hypertransaminasemia.
Metabolism and nutrition disorders: tumor lysis syndrome.
Musculoskeletal and connective tissue disorders: back pain, bone pain, and pain in extremity.
Nervous system disorders: tremor (resting tremor, intention tremor, essential tremor, and tremor), altered state of consciousness (includes altered state of consciousness, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, stupor, and somnolence), dizziness, memory impairment, seizure (includes seizure, and atonic seizure), aphasia, cognitive disorder, speech disorder, hypoesthesia, encephalopathy, paresthesia, and cranial nerve disorders (trigeminal neuralgia, trigeminal nerve disorder, sixth nerve paralysis, cranial nerve disorder, facial nerve disorder, and facial paresis).
Psychiatric disorders: insomnia, disorientation, confusional state, and depression (includes depressed mood, depression, suicidal ideation, and completed suicide).
Respiratory, thoracic and mediastinal disorders: dyspnea (includes acute respiratory failure, dyspnea, dyspnea exertional, respiratory failure, respiratory distress, bronchospasm, bronchial hyperreactivity, tachypnea, and wheezing), cough, and productive cough.
Vascular disorders: hypotension (includes blood pressure decreased, hypotension, hypovolemic shock, and circulatory collapse), hypertension (includes blood pressure increased, hypertension, and hypertensive crisis), flushing (includes flushing and hot flush), and capillary leak syndrome.
B-cell Precursor ALL in the Consolidation Phase: Study E1910: The safety of a consolidation regimen comprised of multiple cycles of BLINCYTO monotherapy in addition to multiple cycles of chemotherapy (BLINCYTO arm) was evaluated in a randomized trial in adult patients with newly diagnosed Philadelphia chromosome-negative B-cell precursor ALL (Study E1910) [NCT02003222] [see Pharmacology: Pharmacodynamics: Clinical Studies: Philadelphia Chromosome-Negative B-cell Precursor ALL in the Consolidation Phase under Actions] which included 111 patients treated in the BLINCYTO arm and 112 patients treated in the chemotherapy alone arm. In the BLINCYTO arm, the median (range) of cycles was 8 (1-8) (4 cycles of BLINCYTO and 4 cycles of chemotherapy). In the chemotherapy alone arm, the median (range) of cycles was 4 (1-4).
Fatal adverse reactions occurred in 2 patients (2%) during BLINCYTO cycles and were due to infection (n = 1) and coagulopathy (n = 1). Permanent discontinuation of BLINCYTO due to an adverse reaction occurred in 2% of patients. Dosage interruptions of BLINCYTO due to an adverse reaction occurred in 5% of patients. Dose reductions of BLINCYTO due to an adverse reaction occurred in 28% of patients.
The most common (≥20%) adverse reactions during consolidation cycles in the BLINCYTO arm were neutropenia, thrombocytopenia, anemia, leukopenia, headache, infection, nausea, lymphopenia, diarrhea, musculoskeletal pain, and tremor. The adverse reactions occurring at a difference between arms in incidence of ≥10% for All Grades or ≥5% for Grade 3 or higher are summarized in Table 23. (See Table 23.)

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Study 20120215: The safety of BLINCYTO as the 3^rd cycle of the consolidation phase was evaluated in a randomized, open-label study (Study 20120215) following induction and two cycles of consolidation chemotherapy in pediatric and young adult patients with high-risk first-relapsed B-cell precursor ALL [see Pharmacology: Pharmacodynamics: Clinical Studies: Philadelphia Chromosome-Negative B-cell Precursor ALL in the Consolidation Phase under Actions]. The study included 54 patients treated with one cycle of BLINCYTO and 52 patients treated with one cycle of chemotherapy.
Serious adverse reactions occurred in 28% of patients who received BLINCYTO. Permanent discontinuation of BLINCYTO due to an adverse reaction occurred in 4% of patients. Adverse reactions that led to discontinuation included nervous system disorder and seizure. Dosage interruptions of BLINCYTO due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dosage interruption in >2% of patients included nervous system disorder.
The most common (≥20%) adverse reactions in the BLINCYTO arm were pyrexia, nausea, headache, rash, hypogammaglobulinemia, and anemia. The adverse reactions occurring at a difference of ≥10% incidence for any grade or at a difference of ≥5% incidence for Grade 3 or 4 between the BLINCYTO arm and chemotherapy arm are summarized in Table 24. (See Table 24.)

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Postmarketing Experience: The following adverse reactions have been identified during post approval use of BLINCYTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Fatal pancreatitis in patients receiving BLINCYTO in combination with dexamethasone.