Description
Blinatumomab is a bispecific CD19-directed CD3 T-cell engager (BiTE) antibody construct product. Blinatumomab engages the T lymphcytes to destroy leukemia cells (FDA, 2014). The drug acts as a connector between CD19 protein, which is found on the surface of most B-cell lymphoblasts, and CD3 protein, which is found on T-cell lymphocytes. BiTE antibody constructs are modified antibodies that are designed to engage two different targets simultaneously, thereby juxtaposing T cells to cancer cells. BiTE^® antibody constructs help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger apoptosis.

The FDA granted Blincyto breakthrough therapy designation, priority review and orphan product designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies; the drug had the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition; and the drug is intended to treat a rare disease, respectively (FDA, 2014).  

The FDA approval of Blincyto was based on results of Amgen's '211 trial, a phase 2, multicenter, single-arm open-label study involving 185 adults with Philadelphia chromosome-negative relapsed or refractory precursor B-cell ALL (Amgen, 2014). Eligible patients were greater than 18 years of age with Ph- relapsed or refractory B-cell precursor ALL. Relapsed or refractory was defined as relapsed with first remission duration of less than 12 months in the first salvage, or relapsed or refractory after first salvage therapy, or relapsed within 12 months of allogeneic hematopoietic stem cell transplantation (HSCT), and had greater than 10 percent blasts in bone marrow. All participants were treated with blinatumomab for at least four weeks via infusion. Of the 185 patients evaluated in the trial, 41.6 percent (77/185; 95 percent CI: 34.4 – 49.1) achieved complete remission or complete remission with partial hematologic recovery (CR/CRh*) within two cycles of treatment with blinatumomab, which was the primary endpoint of the study. The majority of responses (81 percent [62/77]) occurred within the first cycle of treatment. Among patients who achieved CR/CRh*, 39 percent (30/77) went on to HSCT, and 75.3 percent (58/77 95 percent CI: 64.2 – 84.4) achieved minimal residual disease (MRD) response. 

Blincyto was approved under the FDA’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients (FDA, 2014). The FDA is requiring the manufacturer to conduct a study to verify that the drug improves survival in participants with relapsed or refractory Philadelphia-negative precursor B-cell ALL. 

Blincyto carries a boxed warning that some clinical trial participants had problems with cytokine release syndrome (CRS), or neurological toxicities which may be life threatening or fatal (FDA, 2014). The labeling recommends that blinatumomab be interrupted or discontinued in patients experiencing these side effects.

The most common adverse reactions (≥ 20 percent) were pyrexia (62 percent), headache (36 percent), peripheral edema (25 percent), febrile neutropenia (25 percent), nausea (25 percent), hypokalaemia (23 percent), rash (21 percent), tremor (20 percent) and constipation (20 percent) (Amgen, 2014). Serious adverse reactions were reported in 65 percent of patients. The most common serious adverse reactions (≥ 2 percent) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia and headache.

Life-threatening or fatal cytokine release syndrome (CRS) occurred in patients receiving blinatumomab (Amgen, 2014). The labeling states that manifestations of CRS may be indistinguishable from Infusion reactions. The labeling states that patients should be closely monitored for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). The labeling recommends that blinatumomab be interrupted or discontinued if CRS occurs. 

Approximately 50% of patients receiving blinatumomab in clinical trials experienced neurological toxicities (Amgen, 2014). Severe, life-threatening, or fatal neurological toxicities occurred in approximately 15% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The median time to onset of any neurological toxicity was 7 days. The labeling recommends monitoring patients for signs or symptoms and recommends interrupting or discontinuing blinatumomab if these occur. 

Approximately 25% of patients receiving blinatumomab experienced serious infections, some of which were life-threatening or fatal (Amgen, 2014). The labeling recommends administration of prophylactic antibiotics surveillance testing as appropriate during treatment. The labeling states that patients should be monitored for signs or symptoms of infection and treated appropriately, including interruption or discontinuation of blinatumomab as needed.

Life-threatening or fatal tumor lysis syndrome (TLS) has been observed with blinatumomab (Amgen, 2014). The labeling recommends use of preventive measures, including pretreatment nontoxic cytoreduction and on treatment hydration, during blinatumomab treatment. Patients should be monitored for signs and symptoms of TLS and blinatumomab interrupted or discontinued as needed to manage these events.

Neutropenia and febrile neutropenia, including life-threatening cases, have been observed with blinatumomab (Amgen, 2014). Appropriate laboratory parameters should be monitored during blinatumomab infusion and blinatumomab should be interrupted if prolonged neutropenia occurs.

Due to the possibility of neurological events, including seizures, patients receiving blinatumomab are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while blinatumomab is being administered (Amgen, 2014).

Transient elevations in liver enzymes have been associated with blinatumomab treatment (Amgen, 2014). The majority of these events were observed in the setting of CRS. The median time to onset was 15 days. Grade 3 or greater elevations in liver enzymes occurred in 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. ALT, AST, gamma-glutamyl transferase (GGT), and TBILI should be monitored prior to the start of and during blinatumomab treatment. The labeling states that blinatumomab treatment should be interrupted if transaminases rise to greater than 5 times the upper limit of normal (ULN) or if TBILI rises to greater than 3 times ULN.

Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving blinatumomab, especially in patients previously treated with cranial irradiation and anti-leukemic chemotherapy (Amgen, 2014).

Blinatumomab is contraindicated to patients with known hypersensitivity to blinatumomab or to any component of the product formulation (Amgen, 2014). The labeling of Blincyto recommends that patients be monitored for signs and symptoms of infection and treated appropriately. The labeling states that patients should be advised to refrain from driving and engaging in hazardous occupations or activities such as driving, operating heavy or potentially dangerous machinery while blinatumomab is being administered.

Blinatumomab is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm. The labeling for Blincyto recommends hospitalization for the first 9 days of the first cycle and the first 2 days of the second cycle (Amgen, 2014). A single cycle of treatment consists of 4 weeks of continuous intravenous infusion followed by a 2-week treatment-free interval. For patients at least 45 kg in weight, in Cycle 1, blinatumomab is administered at 9 mcg/day on Days 1 – 7 and at 28 mcg/day on Days 8 – 28. For subsequent cycles, blinatumomab is administered at 28 mcg/day on Days 1 – 28. The labeling states that it is important to strictly follow instructions for preparation (including admixing) and administration to prevent overdose and underdose.

The FDA approved Blincyto with a Risk Evaluation and Mitigation Strategy (REMS), which consists of a communication plan to inform health care providers about the serious risks and the potential for preparation and administration errors (FDA, 2014).

Policy
Blincyto is MEDICALLY NECESSARY for the treatment of CD19+ B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children when the following criteria is met:

1. Blinatumomab is used as a single agent AND
2. Relapsed or refractory disease OR
3. Minimal residual disease greater than or equal to 0.1%, following a first or second complete response to induction therapy

Blincyto is considered INVESTIGATIONAL for all other indications. 

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be MEDICALLY NECESSARY if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and NOT MEDICALLY NECESSARY.

Dosing

• Dosage
  • Hospitalization is recommended for the first 9 days of the the first cycle and the first 2 days of the second cycle.
  • A single cycle of treatment consists of 4 weeks of continuous intravenous infusion followed by a 2-week treatment-free interval.
  • For patients at least 45 kg in weight, in Cycle 1, administer BLINCYTO at 9 mcg/day on Days 8 – 28. For subsequent cycles, administer BLINCYTO at 28 mcg/day on Days 1 – 28.
• Administration
  • Premedicate with dexamethasone 20 mg intravenously 1 hour prior to the first does of BLINCYTO of each cycle, prior to a step dose (such as Cycle 1 Day 8), or when restarting an infusion after an interruption of 4 or more hours.
  • Administer as a continuous intravenous infusion at a constant flow rate using an infusion pump.
  • The IV bag should be infused over 24 hours or 48 hours.
  • BLINCYTO should be infused through a dedicated lumen.
• Preparation
  • IV Solution Stabilizer is provided and is used to coat the prefilled IV bag prior to addition of reconstituted BLINCYTO.
  • Reconstitute BLINCYTO with Sterile Water for Injection, USP, only.
  • Aseptic technique must be strictly observed when preparing the solution for infusion since BLINCYTO does not contain antimicrobial preservatives.
  • Use the specific volumes described in the admixing instruction.  

References

1. U.S. Food and Drug Administration (FDA). FDA approves Blincyto to treat a rare form of acute lymphoblastic leukemia. FDA News Release. Silver Spring, MD: FDA; December 3, 2014.
2. Amgen Inc. Blincyto (blinatumomab) for injection, for intravenous use. Prescribing Information. Thousand Oaks, CA: Amgen; revised December 2014.
3. Amgen Inc. FDA approves Blincyto (blinatumomab) immunotherapy for the treatment of telapsed or refractory B-cell precursor acute lymphoblastic leukemia. News Release. Thousand Oaks, CA: Amgen; December 3, 2014.
4. Topp MS, Gökbuget N, Zugmaier G, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014 Nov 10. [Epub ahead of print]
5. Topp MS, Gökbuget N, Zugmaier G, et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012;120(26):5185-5187.
6. Topp MS, Kufer P, Gökbuget N, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29(18):2493-2498.
7. National Comprehensive Cancer Network (NCCN). Blinatumomab. NCCN Drug & Biologics Compendium. Fort Washington, PA: NCCN; 2014.

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

Appendix

Examples of tyrosine kinase inhibitors: 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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