A review of blinatumomab,a novel immunotherapy

Introduction

Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by proliferation of lymphoblasts in the bone marrow and elsewhere. ¹ In 2014, an estimated 6020 new patients were diagnosed and an estimated 1440 deaths were caused by ALL. ² ALL accounts for approximately 80% of pediatric leukemias and 20% of adult leukemias. ¹

Chemotherapy is the main modality of treatment for ALL, and typically consists of multiple courses of an anthracycline, corticosteroids, vincristine, and other agents in combination. A majority of patients treated with chemotherapy will achieve a complete remission (CR); however, long-term disease-free survival occurs in only 30–40% of adults with ALL, including those who undergo hematopoietic stem cell transplantation (HSCT).^3,4

Translocation of chromosomes 9 and 22 (t(9;22), or Philadelphia (Ph) chromosome) leads to expression of the fusion oncogene Bcr-Abl, which produces proteins that act as tyrosine kinases and promote proliferation and survival of tumor cells. Ph-positive ALL is more common in adult ALL (20–30% of cases) compared with pediatric ALL (3–5%). ⁵ While Ph-positivity was historically a poor prognostic factor in adults with ALL, ³ the introduction of tyrosine kinase inhibitors (TKIs) has led to improvements in CR rates and overall survival (OS) when added to chemotherapy,^6–8 and may be useful as maintenance therapy to reduce the risk of relapse after HSCT. ⁹ While TKIs are useful in Ph-positive ALL, there has been a lack of new targeted therapies for Ph-negative disease.

With the exceptions of TKIs and the use of rituximab for CD20-positive B cell ALL, there has been a relative scarcity of targeted therapies for this disease. Blinatumomab is a novel agent recently granted accelerated approval by the US Food and Drug Administration (FDA) for the treatment of relapsed or refractory Ph-negative ALL. The purpose of this review is to summarize important clinical evidence and to inform practitioners of unique administration, safety, and cost concerns.

Pharmacology

Blinatumomab is a bispecific CD19-directed CD3 T cell engager: it binds to surface proteins CD19, expressed by B cells (including B-lineage leukemias and lymphomas), and the CD3 epsilon subunit, part of the T cell receptor complex and found on mature T cells.^10,11 The drug was formerly known as MT-103.

Once blinatumomab binds to a CD3-positive T cell and a CD19-positive B cell, a cytolytic synapse is formed. ¹² Cytotoxicity is then induced by the release of perforin and granzymes from granules in the cytotoxic T cell, the latter inducing apoptosis and lysis of the malignant B cell. Subsequently, the T cell remains activated by blinatumomab and continues to produce perforin and granzymes, which are stored in granules and used to serially attack additional B cells. ¹² This interesting attribute was demonstrated in an in vitro study, where T cells bound to blinatumomab killed 4 to 6 target B cells in a 9-hour period. ¹³ Additionally, inflammatory cytokines are released, and T cell proliferation is promoted.

Pharmacokinetics and pharmacodynamics

Blinatumomab is administered intravenously as a continuous infusion. It exhibits a mean half-life of about 2 hours, with likely linear pharmacokinetics. The steady-state concentration is achieved within 1 day. While the metabolism of blinatumomab is not exactly clear, it likely undergoes enzymatic degradation. There is little renal excretion, and the manufacturer does not recommend adjusting the dose for renal dysfunction. However, the agent was not studied in patients with a creatinine clearance less than 30 mL/min or those on hemodialysis. ¹⁰

The pharmacodynamic response consists of T cell activation and redistribution, a reduction in peripheral B cells, and transient cytokine elevation. ¹⁰ Peripheral B cell counts are depleted within about 2 days, remain depleted during treatment, and do not appear to recover in the 2-week period between cycles. ¹⁴ T cells initially decline and recover to baseline, followed by expansion during weeks 2 and 3 of the first treatment cycle. Of cytokines measured, IL-10, IL-6, and IFN-γ are released in the greatest quantities. Notably, there is high inter-patient variability in cytokine response during the first cycle, and the same response appears to be absent with the second cycle.

Therapeutic use

An early phase 2 study of blinatumomab was conducted in 21 adult patients (age 20 to 77 years) with minimal residual disease (MRD) after induction and consolidation chemotherapy. ¹⁵ The goal of the study was to determine the efficacy of single-agent blinatumomab in inducing MRD-negativity. The drug was dosed at 15 mcg/m²/24 hours over 4 weeks followed by a 2-week treatment-free period, and patients received up to three cycles as consolidation after induction, as an alternative to allogeneic HSCT. The MRD response rate was 80% (16/20 patients) after one cycle. This includes 12 patients with molecularly refractory disease, and four with molecular relapse. Response occurred even with high levels of MRD. All 16 patients were in hematologic remission at median 405 days follow up, translating to 78% relapse-free survival (RFS). Of note, this study included five patients with Ph-positive disease refractory to TKIs, three of which responded.

A follow-up analysis reported long-term survival for the aforementioned phase 2 trial. ¹⁵ In the 20 evaluable patients, hematologic RFS was estimated at 61% at a median of 33 months observation. ¹⁶ With one death in CR, nine of the 20 patients had a suitable donor and underwent allogeneic HSCT after at least the first cycle of blinatumomab. At the time of follow-up, six of the nine patients were in hematologic CR (65% RFS). Of these, two patients had CD19-positive relapse at month 19 and month 31, and one patient died of GVHD at 1 year.

Eleven patients did not receive HSCT, six of whom were in ongoing hematologic CR (60% RFS estimated at median follow-up of 31 months) without receiving further treatment after blinatumomab. Of the eleven patients who did not undergo HSCT, four had relapsed after 3.2 to 6.5 months. Two were CD19-negative hematologic relapses, and one each relapsed in the cerebrospinal fluid and testis.

Blinatumomab was evaluated in a separate phase 2 study performed in 36 patients (age 18 to 77 years) with relapsed or refractory Ph-negative B-precursor ALL. ¹⁷ All patients had undergone at least induction and consolidation chemotherapy, and 42% had relapsed after HSCT. The primary endpoint was CR or CR with partial hematologic recovery (CRh). Secondary endpoints included MRD response, rate of HSCT realization, RFS, OS, and adverse events (AEs).

The study included a dose-finding stage with three cohorts, followed by an extension stage. Based on the rate of AEs among the cohorts, the dosing chosen for the extension stage was 5 mcg/m²/24 hours for 1 week followed by 15 mcg/m²/24 hours for 3 weeks, with subsequent cycles dosed at 15 mcg/m²/24 hours for 4 weeks.

CR or CRh was achieved in 69% (25 patients) within the first two treatment cycles, and among the responders, 88% achieved MRD response. Notably, patients who relapsed post-HSCT had a lower proportion of CR or CRh (8/15) compared with patients in first salvage (11/11) or second salvage (6/10). The median OS was 9.8 months (95% CI, 8.5 to 14.9), with median RFS of 7.6 months (95% CI, 4.5 to 9.5). Of those achieving CR or CRh, 52% underwent HSCT. The most common AE was fever, which occurred in 81% of patients, and was grade 3 in severity in 6%. Blinatumomab infusion was interrupted in two patients due to cytokine release syndrome (CRS): one permanently discontinued treatment and one was successfully re-challenged. Nervous system disorders requiring interruption occurred in three patients with encephalopathy, tremor, aphasia, and confusion, while another three patients experienced epilepsy and convulsions. The patients with epilepsy or convulsions were successfully re-challenged with blinatumomab, after the addition of anti-seizure prophylaxis.

A larger, multi-center phase 2 study was conducted in 189 patients (age 18 years or older) with relapsed or refractory Ph-negative ALL determined to be at high risk of poor outcome after relapse. ¹⁸ For inclusion, patients had either early relapse (within 12 months of first remission), or were receiving therapy for second or subsequent salvage, including relapse within 12 months after HSCT. Notable exclusion criteria were Ph-positive ALL and active disease in the CNS or testes.

Blinatumomab was administered during cycle 1 at a dose of 9 mcg/24 hours for 1 week followed by 28 mcg/24 hours for 3 weeks followed by 2 weeks rest. As premedication, dexamethasone 20 mg was administered on day 1, 1 hour prior to starting the infusion, and 1 hour prior to the “dose step” on day 8. The primary endpoint was CR or CRh within the first 2 treatment cycles. Secondary endpoints were RFS, OS, proportion of responders undergoing allogeneic HSCT after CR or CRh, 100-day mortality post-HSCT, and adverse events.

CR or CRh was achieved in 43% of patients (95% CI, 36 to 50). Of those achieving CR or CRh, 40% went on to allogeneic HSCT. Hundred-day mortality post-HSCT was 11% (95% CI, 0 to 23). While the length of follow-up was limited and patients could proceed to HSCT at the investigator’s discretion, the authors note an absence of increased morbidity or mortality related to HSCT after receiving blinatumomab. Adverse events were consistent with previous trials, and included pyrexia, headache, neutropenia with and without fever, anemia, edema, nausea, hypokalemia, CRS, and a spectrum of neurologic toxicities. Three deaths were thought to be treatment-related, and were due to sepsis (unspecified organism), E. coli sepsis, and Candida.

A phase 3 randomized trial in adult patients with newly diagnosed Ph-negative ALL (E1910) is currently in progress. ¹⁹

In pediatric ALL, where OS is now about 90%, an estimated 10–20% of patients will relapse. ²⁰ Blinatumomab does not have FDA approval for pediatric patients; however, several clinical trials have been performed to date. In a small study of three patients with pre-B ALL relapsed after HSCT, blinatumomab was administered at 15 mcg/m²/day for 4 to 6 weeks. All patients, aged 7, 12, and 15 years, achieved MRD-negative CR after blinatumomab: one went on to receive a second HSCT. The second remained in CR at day 42, but subsequently relapsed, and the third had a central nervous system relapse 4 weeks after the fourth course blinatumomab was completed. ²¹ In a later case series of nine pediatric patients (age 4 to 18 years) who had also relapsed after HSCT, blinatumomab was administered at 5 or 15 mcg/m²/day for 4 weeks. ²² This analysis included two patients from the previously described case series. ²² After one cycle of blinatumomab, four patients had achieved CR. Two patients did not respond to the 5 mcg/m²/day dosing, and went on to receive chemotherapy, followed by blinatumomab at 15 mcg/m²/day for 1 cycle: at this point, both achieved CR. However, three patients did not respond and died from leukemia progression. While data are limited, blinatumomab has demonstrated activity in relapsed pediatric ALL. A phase 3 trial in this population is planned. ²³

Safety

Blinatumomab carries two boxed warnings for serious adverse events: neurotoxicity and CRS. Neurotoxicity may present in a variety of signs and symptoms, ranging from somnolence, confusion, and dizziness, to tremor, seizure, encephalopathy, speech disorders, and loss of consciousness. While grade 3 and higher events are less common, some type of neurologic adverse effect occurred in about half of patients in clinical trials. These effects are also more common in adults over 65 years of age. Importantly, routine seizure prophylaxis is not recommended. In a clinical trial previously mentioned, three patients who experienced a seizure were allowed to receive additional blinatumomab after starting antiepileptic medications. Accordingly, the package labeling recommends discontinuation of blinatumomab with the occurrence of more than one seizure. ¹⁰

CRS occurs as a result of the immune stimulation induced by blinatumomab. While important for the pharmacodynamic response, CRS is responsible for many adverse effects, including pyrexia, hepatotoxicity, disseminated intravascular coagulation, hypotension, and capillary leak syndrome. Headache, nausea, and weakness are possible. Specific guidance is included in the package labeling for dose interruptions and permanent discontinuation of therapy in the case of serious adverse effects (Tables 1 and 2).

OPEN IN VIEWER

Table 1.

Cytokine release syndrome (CRS) presentation and dose adjustments for toxicity. ¹⁰

Signs and symptoms	Prophylaxis	Dose adjustments
Pyrexia Headache Nausea Weakness Hypotension Increased transaminases Increased bilirubin Disseminated intravascular coagulation Capillary leak syndrome Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS)	Cycle 1: Dexamethasone 20 mg IV prior to starting infusion on day 1 and prior to starting infusion on day 8. Cycle 2 and beyond: Dexamethasone 20 mg IV prior to starting infusion on day 1. All cycles: Dexamethasone 20 mg IV prior to re-starting infusion if held for 4 hours or longer.	Grade 3: Interrupt therapy until resolved, then resume at 9 mcg/day. Increase to 28 mcg/day after 7 days if toxicity does not recur. Grade 4: Discontinue permanently

OPEN IN VIEWER

Table 2.

Neurotoxicity presentation and dose adjustments for toxicity. ¹⁰

Signs and symptoms	Prophylaxis	Dose adjustments
Encephalopathy Convulsions Speech disorders Disturbances in consciousness Confusion Disorientation Coordination and balance disorders	No prophylaxis specific to neurologic adverse effects (e.g. anticonvulsants) is recommended.	Grade 3: Interrupt therapy until toxicity is Grade 1 or less (mild), then resume at 9 mcg/day. Increase to 28 mcg/day after 7 days if toxicity does not recur. Permanently discontinue if toxicity takes \gt14 days to resolve. Grade 4: Discontinue permanently. Seizure: Discontinue permanently if more than once occurrence.

Note: If treatment is interrupted for ≤7 days, continue cycle to total 28 days inclusive of days before and after treatment interruption. If treatment is interrupted for \gt7 days, start a new cycle.

The most common adverse effects are pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), constipation (20%). ¹⁰ Serious adverse reactions occurred in 65% of patients in clinical studies and include pneumonia, sepsis, device-related infection, tremor, encephalopathy, confusion, and Staphylococcal bacteremia. Tumor lysis syndrome is also possible, and care should be taken to monitor for, prevent, and treat this potentially serious condition on a patient-specific basis. ¹⁰

Clinical controversies and off-label uses

Blinatumomab lacks FDA approval for patients with Ph-positive ALL despite the inclusion of a small number of these patients in a phase 2 trial. ¹⁵ The mechanism of action provides rationale for use in Ph-positive ALL; however, the studies leading to FDA approval did not focus on this population. The manufacturer is currently sponsoring a phase 2 single-arm multicenter clinical trial in patients with Ph-positive B-precursor ALL, relapsed or refractory to at least one second-generation TKI (dasatinib, nilotinib, bosutinib, ponatinib) or intolerant to second-generation TKIs and intolerant or refractory to imatinib. ²⁴ Blinatumomab may fulfill a currently unmet need in this population.

There are some concerns regarding dosing in underweight adult patients, as the package labeling states that only patients who are at least 45 kg should receive standard dosing. However, this leaves the concern of how to appropriately dose patients who are less than 45 kg but of adult age. Though the manufacturer has not published any recommendations, prescribers may consider two options: to use standard adult dosing and potentially observe increased adverse effects, or to use pediatric dosing, which while studied, is not FDA-approved. ²² Currently there is a lack of guidance for underweight adult patients.

One of the most significant adverse reactions experienced by patients receiving blinatumomab is CRS, for which an optimal approach to management is not well defined. Due to the mechanism of CRS, the clearest clinical choice in pharmacological management is the use of corticosteroids to reduce cytokine levels. While corticosteroids are cytotoxic to lymphocytes and play a major role in the treatment of ALL, it is theoretically possible that the addition of steroids may affect the T cell activation produced by blinatumomab, in effect blunting the desired immune response. A specific dose threshold above which the efficacy of blinatumomab may be sacrificed is unknown. There is not an agent of choice or specific dosing strategy for corticosteroids that have been established in the management of CRS. Another strategy reported in the treatment of CRS is to use an agent to directly target a cytokine, such as the IL-6 receptor antagonist, tocilizumab. This agent has been used with success in a patient with severe CRS caused by blinatumomab. ²⁵ This use of tocilizumab is off-label, and may be limited by its cost. For example, an 8 mg/kg dose as used in the case report would cost approximately $2823 for a 75-kg patient. ²⁶ Additionally, one should consider the severity of CRS in the case report. After 36 hours of blinatumomab infusion, the patient experienced multi-system organ failure and hemophagocytic lymphohistiocytosis (HLH), which improved after tocilizumab. While serious, the degree of reaction to blinatumomab in this case appears to be rare. Therefore, clinicians may consider tocilizumab for the management of severe, life-threatening CRS without adequate response to corticosteroids.

Blinatumomab has been shown to have activity in a variety of B cell malignancies outside of Ph-negative ALL due to the target antigen CD19, which is ubiquitous in cells of B cell lineage. The antibody has been studied in non-Hodgkin lymphoma (NHL) subtypes such as diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia (CLL) with high response rates.^24,27–29 Blinatumomab is not currently FDA approved for these indications. ²⁷

Product description

Blinatumomab is available in a kit which includes one 35-mcg drug vial (upon reconstitution) and a 10-mL vial of solution stabilizer, utilized to prevent adhesion of blinatumomab to the infusion bag and tubing. ¹⁰ All doses of blinatumomab are prepared with a pre-filled 250 mL 0.9% sodium chloride infusion bag, which must be made of polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl acetate (EVA). The manufacturer notes that these bags typically contain overfill with a total volume ranging from 265 to 275 mL and suggests that if necessary, the bag should be manipulated to achieve a starting volume in this range. Preparation of each dose of blinatumomab is unique to the dose as well as the infusion rate (Table 3). The general procedure for all doses is to transfer the appropriate amount of solution stabilizer to the pre-filled 250 mL 0.9% sodium chloride infusion bag, after which the bag is gently mixed, not shaken, to avoid foaming. Depending on the dose, one or two vials of blinatumomab are then reconstituted with 3 mL each of preservative-free sterile water for injection. The reconstituted blinatumomab vial is then gently swirled, and the volume required for the dose is removed and transferred to the pre-filled 250 mL 0.9% sodium chloride infusion bag containing the solution stabilizer. The appropriate tubing is then attached and primed with a 0.2-micron in-line filter.

OPEN IN VIEWER

Table 3.

Drug preparation and administration. ¹⁰

	Daily dose	Infusion duration and rate	IV solution stabilizer	Reconstituted drug volume added to bag
Cycle 1, days 1–7	9 mcg	24 hours at 10 mL/hour	5.5 mL	0.83 mL (from 1 vial)
		48 hours at 5 mL/hour	5.5 mL	1.7 mL (from 1 vial)
Cycle 1, days 8–28 Cycle 2 and beyond, days 1–28	28 mcg	24 hours at 10 mL/hour	5.6 mL	2.6 mL (from 2 vials)
		48 hours at 5 mL/hour	5.6 mL	5.2 mL (from 2 vials)

Premedication with dexamethasone 20 mg IV must be administered 1 hour prior to the first dose of each cycle, prior to a dose step (e.g. dose increase on day 8 of cycle 1) or when restarting the infusion after a drug interruption of 4 hours or greater. Blinatumomab must be infused at a constant rate using an infusion pump that is programmable, lockable, non-elastomeric, and has an alarm. ¹⁰

The dose of blinatumomab that is prepared according to the instructions above contains overfill; however, the pharmacy label for the drug should indicate that a total of 240 mL of blinatumomab solution is to be infused at a rate of 10 mL/hour for a duration of 24 hours or a rate of 5 mL/hour for a duration of 48 hours. It is essential that the IV tubing containing blinatumomab is never flushed, as this can result in excess dosage and potential toxicity. Hospitalization is recommended by the manufacturer for the first 9 days of blinatumomab in the first cycle and the first 2 days of the second cycle. After this point, patients are typically discharged with an ambulatory infusion pump to complete the cycle in the outpatient setting with close follow up. If there are dose interruptions of four or more hours in the outpatient setting, the manufacturer recommends hospitalization or supervision by a healthcare professional with re-initiation of blinatumomab. ¹⁰

The cost of blinatumomab kit (35 mcg) is approximately $3815. ²⁶ This translates to a cost of about $89,000 per cycle, and treatment may consist of up to five consecutive 28-day cycles with a 14-day rest period following each cycle. Due to the substantial acquisition cost, clinics, hospitals and health systems may consider seeking insurance pre-approval on a patient-specific basis prior to initiating therapy to avoid the risk of absorbing the high cost of non-reimbursement. On a larger scale, cost-effectiveness analyses should be pursued.

Perspectives on use

Blinatumomab is a novel agent recently granted accelerated approval for the treatment of relapsed or refractory Ph-negative ALL . An ongoing clinical trial aims to assess the utility of blinatumomab in the first-line setting for patients with Ph-negative ALL when added to chemotherapy. Clinical trials continue in Ph-positive ALL and other B cell malignancies, and additional FDA-approved indications are possible.

Oncology pharmacists must recognize the unique preparation and administration requirements with blinatumomab. Safe administration necessitates collaboration between pharmacists, the prescribing physician, and nursing colleagues. In addition, providers must be aware of the adverse effects related to blinatumomab which may be life-threatening and require diligent monitoring. Going forward, optimal strategies for managing CRS are needed, and must be an area of research as the use of this agent becomes more widespread.