Description/Scope

This document addresses uses of blinatumomab (Blincyto, Amgen Inc., Thousand Oaks, CA). Blinatumomab is a bispecific T-cell engager designed to promote the lysis of cancer cells by binding simultaneously with both the CD3 protein on cytotoxic T-cells and the CD19 protein, a B-cell specific lymphocyte antigen expressed in specific types of acute lymphocytic leukemia (ALL).

Position Statement

Medically Necessary:

Blinatumomab is considered medically necessary for the single-agent treatment of individuals with acute lymphocytic leukemia (ALL) when the following criteria are met:

1. CD19+ B-cell precursor ALL; 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.

Investigational and Not Medically Necessary:

Blinatumomab is considered investigational and not medically necessary in individuals when the criteria above are not met and for all other indications, including, but not limited to:

1. Use as first-line of therapy for ALL;
2. Evidence of active ALL central nervous system involvement;
3. Use in combination with other chemotherapy agents;
4. Treatment of diffuse large B-Cell lymphoma (DLBCL).

Rationale

On December 3, 2014, blinatumomab was the first anti-CD19 drug granted approval by United States (U.S.) Food and Drug Administration (FDA). Approval was granted through an accelerated process and only for the single-agent treatment of Philadelphia chromosome-negative (Ph-negative) relapsed or refractory B-cell precursor ALL. Accelerated approval “…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 Product Information [PI] Label, 2018). The FDA label was updated in 2016 to indicate that the safety of blinatumomab in the pediatric population has been established. In 2018 the label was expanded to include the treatment of B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. Sustained approval of blinatumomab for this indication is dependent on continued safety and efficacy demonstrated through ongoing confirmatory clinical trials.

Acute lymphocytic leukemia (ALL)

Initial FDA approval was based on a study by Topp and colleagues (2015) who conducted an open-label, multi-center, single-arm, phase II trial in 189 adults (18 years and older) with primary refractory or recently relapsed (within 12 months) Ph-negative, B-precursor ALL. Participants in this study were required to have at least 10% bone marrow blasts and Eastern Cooperative Oncology Group (ECOG) performance status of 2 or better and be blinatumomab naïve. Notable exclusion criteria included central nervous system (CNS) disease, ALL in the testes, Burkitt’s leukemia, Philadelphia chromosome-positive (Ph-positive) disease, history of a malignancy other than leukemia in the previous 5 years, autoimmune disease or chronic infection, acute or active chronic graft-versus-host disease (GVHD), autologous hematopoietic stem cell transplantation (HSCT) within the past 6 weeks, and allogeneic HSCT within the previous 3 months (Topp, 2015).

Enrolled study participants received at least 2 cycles. A cycle consisted of intravenous blinatumomab administered continuously at a target dose of 28 μg/day for 4 weeks, followed by a 2-week treatment-free period. If participants achieved a complete response (CR) or CR with partial recovery of peripheral blood counts (CRh or partial response [PR]) within the first 2 cycles, they could receive an additional 3 cycles. Disease assessment was performed through bone marrow examination. The primary outcome of interest was CR or CRh within the first 2 treatment cycles. Secondary endpoints included relapse-free survival time, OS, proportion of responders who received allogeneic HSCT after blinatumomab-induced CR or CRh and incidence and severity of adverse events (Topp, 2015).

After 2 treatment cycles with blinatumomab, 81 participants (43%; 95% confidence interval [CI], 36-50%) achieved a CR or CRh (63 [33%] and 18 [10%], respectively), with 79% of the 81 responders achieving a CR or CRh within 1 cycle. A total of 32 (40%) of those who achieved CR or CRh subsequently underwent allogeneic HSCT. After a median follow-up period of 8.9 months, 45% of responders who had achieved a CR or CRh were alive and still in remission. The remaining 45 participants had either relapsed (n=37) or died without documentation of relapse (n=7; 6 of which were following an HSCT, 1 of infection). The median relapse-free survival for the entire cohort was 5.9 months, and 6.9 months for those who had achieved a CR or CRh. The median OS for all 189 participants was 6.1 months, with a median follow-up of 9.8 months. Previous receipt of an HSCT did not appear to affect achievement of CR or CRh in this population. The primary outcomes achieved were especially notable given that the study sample was selected for negative prognostic factors such as 10% or more bone marrow blasts at baseline and 34% had failure of a previous HSCT   The most frequent grade 3 or worse adverse events were febrile neutropenia (n=48; 25%), neutropenia (n=30; 16%), and anemia (n=27; 14%). Grade 3 cytokine release syndrome occurred in 3 (2%) participants. Grade 3 or 4 neurological events occurred in 24 (13%) participants. Sepsis was thought to be the cause of 3 suspected treatment-related deaths. Authors conclude “Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia...Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted” (Topp, 2015). There is evidence, albeit limited, of an adequate safety profile and efficacy in geriatric cases (Schlegel, 2014; Topp, 2015). Further investigation is warranted in this distinct population.

The safety and efficacy of blinatumomab in the pediatric population was established in a phase I/II clinical trial which enrolled 70 children with relapsed or refractory ALL, ages 1 month thorough 18 years. Safety and efficacy in this population was not found to be substantially different than previously reported results in adults. Among those treated, 39% (n=27) achieved a CR within the first two cycles (primary endpoint) (von Stackelberg, 2016).

The National Comprehensive Cancer Network^® (NCCN^®) Clinical Practice Guidelines (CPG) for ALL (2018) includes a 2A recommendation for the use of blinatumomab to treat Ph-positive disease that is refractory to tyrosine kinase inhibitor (TKI) therapy. This recommendation is based on data from the Alcantara clinical trial. A Phase II study of 45 individuals with relapsed/refractory Ph-positive ALL intolerant to at least one TKI. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Of 45 participants, 16 (36%; 95% CI, 22-51%) achieved CR/CRh; 88% of CR/CRh responders achieved a complete MRD response, a key secondary endpoint. A total of 7 responders (44%) proceeded to allogeneic hematopoietic stem-cell transplantation, including 55% (6 of 11) of transplant-naıve responders. Median relapse-free survival and overall survival were 6.7 and 7.1 months, respectively. The most frequent adverse events were pyrexia, febrile neutropenia, and headache. A grade 1 or 2 cytokine release syndrome occurred in 3 study participants, and 3 had grade 3 neurologic events, one of which (aphasia) required temporary treatment interruption.

The efficacy and safety of blinatumomab in MRD-positive ALL was evaluated in a single-arm, unpublished clinical trial, known as the BLAST study, which included 86 individuals in first or second complete remission who had detectable MRD in at least 0.1% of cells in their bone marrow. Efficacy was based on achievement of undetectable MRD in an assay that could detect at least one cancer cell in 10,000 cells after one cycle of blinatumomab treatment, in addition to the length of time that the study participants remained alive and in remission (hematological relapse-free survival). Undetectable MRD, the primary outcome, was achieved by 70 study participants (81.4%; 95% CI, 71.6-89.0%). The median relapse-free survival was 22.3 months. The most common adverse reactions were pyrexia, infusion related reactions, headache, infections, tremor, and chills. Serious adverse reactions occurred in 61% of study participants, the most common included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection (FDA PI Label).

Lymphoma

The safety and efficacy of blinatumomab as a single-agent treatment for lymphoma has been investigated in the setting of a Phase II dose-finding clinical trial of 21 participants with relapsed/refractory diffused large B-cell lymphoma (DLBCL) (Viardot, 2016). Following a single cycle, the overall response rate was 43% including 4 who achieved a CR (19%). A total of 5 participants (22%) discontinued treatment due to adverse events (mostly grade 3 neurologic events). There is currently no NCCN recommendation for the use of blinatumomab as a treatment option for DLBCL. Further research is warranted into the safety and efficacy of blinatumomab as a treatment for relapsed/refractory DLBCL.

Background/Overview

ALL is an aggressive type of leukemia that involves an overabundance of lymphoblasts or lymphocytes in the bone marrow and peripheral blood. In 2018, there will be an estimated 5960 new cases of ALL and 1470 deaths (American Cancer Society, 2018). Although more than 80% of individuals treated for ALL achieve a CR, nearly half will relapse. A safe, consistently effective treatment for refractory and relapsed ALL continues to present a challenge to the oncologic community (Topp, 2011). At this time, HSCT is the most effective treatment option for relapsed/refractory ALL; however, achievement of CR is a vital step in the transplantation process (Topp, 2015).

Blinatumomab, received U.S. FDA breakthrough therapy designation and accelerated approval for the treatment of Ph-negative precursor B-cell ALL. This monoclonal antibody is a bispecific T-cell engager designed to promote the lysis of cancer cells by binding simultaneously with both the CD3 protein on cytotoxic T-cells and the CD19 protein expressed in specific types of ALL (FDA PI Label, 2018).

Adverse Events and Warnings

Black box warnings from the FDA PI Label (2018) include the following information and recommendations:

• Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in individuals receiving blinatumomab. Interrupt or discontinue blinatumomab as recommended.
• Neurological toxicities, which may be severe, life-threatening, or fatal, occurred in individuals receiving blinatumomab. Interrupt or discontinue blinatumomab as recommended.

Additional Warnings from the FDA PI Label (2018) include:

• Cytokine Release Syndrome: Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in individuals receiving blinatumomab. Infusion reactions have occurred with the blinatumomab infusion and may be clinically indistinguishable from manifestations of CRS. Serious adverse events that may be associated with CRS included pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these events infrequently led to blinatumomab discontinuation. Life-threatening or fatal CRS was infrequently reported in individuals receiving blinatumomab. In some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) have been reported in the setting of CRS. Individuals should be closely monitored for signs or symptoms of these events. Management of these events may require either temporary interruption or discontinuation of blinatumomab.
• Neurological Toxicities: In individuals receiving blinatumomab in clinical trials, neurological toxicities have occurred in approximately 65% of individuals. The median time to onset of any neurological toxicity was 7 days. Grade 3 or higher (severe, life-threatening, or fatal) neurological toxicities following initiation of blinatumomab administration occurred in approximately 13% of individuals and included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The majority of events resolved following interruption of blinatumomab, but some resulted in treatment discontinuation. Monitor individuals receiving blinatumomab for signs and symptoms of neurological toxicities, and interrupt or discontinue blinatumomab as recommended.
• Infections: In individuals receiving blinatumomab in clinical trials, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of individuals, some of which were life-threatening or fatal. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with blinatumomab. Monitor individuals for signs and symptoms of infection and treat appropriately.
• Tumor Lysis Syndrome: Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in individuals receiving blinatumomab. Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used for the prevention of TLS during blinatumomab treatment. Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of blinatumomab.
• Neutropenia and Febrile Neutropenia: Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in individuals receiving blinatumomab. Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during blinatumomab infusion. Interrupt blinatumomab if prolonged neutropenia occurs.
• Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including seizures, individuals receiving blinatumomab are at risk for loss of consciousness. Advise individuals to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while blinatumomab is being administered.
• Elevated Liver Enzymes: Treatment with blinatumomab was associated with transient elevations in liver enzymes. Although the majority of these events were observed in the setting of CRS, some were observed outside of this setting. For these events, the median time to onset was 15 days. Interrupt blinatumomab if the transaminases rise to greater than 5 times the upper limit of normal or if bilirubin rises to more than 3 times the upper limit of normal.
• Leukoencephalopathy: Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in individuals receiving blinatumomab, especially in those with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown.
• Pancreatitis: Fatal pancreatitis has been reported in individuals receiving blinatumomab in combination with dexamethasone in clinical studies and the post-marketing setting.

Blinatumomab is currently being investigated as a treatment for newly diagnosed ALL and in combination with other chemotherapy drugs.

Definitions

Complete response (CR): The disappearance of all signs of cancer as a result of treatment; also called complete remission; does not indicate the cancer has been cured.

Graft versus host disease (GVHD): A life-threatening complication of bone marrow transplants in which the donated marrow causes an immune reaction against the recipient's body.

Hematopoietic stem cells: Cells that give rise to distinct daughter cells, one cell that replicates the stem cell and one cell that will further proliferate and differentiate into a mature blood cell.

Line of therapy:

• First-line therapy: The first or primary treatment for the diagnosis, which may include surgery, chemotherapy, radiation therapy or a combination of these therapies.
• Second-line therapy: Treatment given when initial treatment (first-line therapy) is not effective or there is disease progression.
• Third-line therapy: Treatment given when both initial (first-line therapy) and subsequent treatment (second-line therapy) are not effective or there is disease progression.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Partial response: A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment. Also called partial remission.

Refractory disease: Illness or disease that does not respond to treatment.

Relapse: After a period of improvement, the return of signs and symptoms of illness or disease.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS
J9039	Injection, blinatumomab, 1  microgram [Blincyto]
ICD-10 Procedure
XW03351	Introduction of blinatumomab antineoplastic immunotherapy into peripheral vein, percutaneous approach, new technology group 1
XW04351	Introduction of blinatumomab antineoplastic immunotherapy into central vein, percutaneous approach, new technology group 1
ICD-10 Diagnosis
C91.00-C91.02	Acute lymphoblastic leukemia [ALL]

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

1. Franca R, Favretto D, Granzotto M, et al. Epratuzumab and blinatumomab as therapeutic antibodies for treatment of pediatric acute lymphoblastic leukemia: Current status and future perspectives. Curr Med Chem. 2017; 24(11):1050-1065.
2. Goekbuget N, Dombret H, Bonifacio M, et al. BLAST: A confirmatory, single-arm, phase 2 study of blinatumomab, a bispecific T-Cell engager (BiTE®) antibody construct, in patients with minimal residual disease B-precursor acute lymphoblastic leukemia (ALL). Blood 2014. 124:379. Available at: http://www.bloodjournal.org/content/124/21/379. Accessed on April 09, 2018.
3. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017; 376(9):836-847.
4. Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor ccute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-Arm, multicenter study. J Clin Oncol. 2017; 35(16):1795-1802.
5. Schlegel P, Lang P, Zugmaier G, et al. Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab. Haematologica. 2014; 99(7):1212-1219.
6. Topp MS, Gökbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015; 16(1):57-66.
7. 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.
8. 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; 32(36):4134-4140.
9. 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.
10. Viardot A, Goebeler ME, Hess G, et al. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016; 127(11):1410-1746.
11. von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/Phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol. 2016; 34(36):4381-4389.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Amgen, Inc. Thousand Oaks, CA. Phase 2 Trial of Blinatumomab in Philadelphia Positive/BCR-ABL Positive Acute Lymphoblastic Leukemia. NLM Identifier: NCT02000427. Last updated January 02, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT02000427. Accessed on April 09, 2018.
2. Blinatumomab. In: DrugPoints^® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated April 04, 2018. Available at: http://www.micromedexsolutions.com. Accessed on April 02, 2018.
3. Blinatumomab Monograph. Lexicomp^® Online, American Hospital Formulary Service^® (AHFS^®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 22, 2016. Accessed on April 09, 2018.
4. Blincyto^® [Product Information]. Thousand Oaks, CA. Amgen, Inc; Updated March 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125557s013lbl.pdf.  Accessed on April 09, 2018.
5. National Comprehensive Cancer Network (NCCN)^®. NCCN Drugs & Biologic Compendium^® (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on April 09, 2018.
6. NCCN Clinical Practice Guidelines in Oncology^®. © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on April 9, 2018.
   • Acute Lymphocytic Leukemia (V.1.2018). March 12, 2018.

Websites for Additional Information

1. American Cancer Society (ACS). What are the key statistics about acute lymphocytic leukemia? Available at: http://www.cancer.org/cancer/leukemia-acutelymphocyticallinadults/detailedguide/leukemia-acute-lymphocytic-key-statistics. Updated on January 05, 2017. Accessed on March 24, 2017.
2. National Cancer Institute (NCI). Adult acute lymphoblastic leukemia treatment (PDQ^®). Updated March 22, 2018. Available at: https://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq. Accessed on April 09, 2018.
3. National Cancer Institute (NCI).  Blinatumomab. Updated April 05, 2018. Available at: https://www.cancer.gov/about-cancer/treatment/drugs/blinatumomab.  Accessed on April 09, 2018.

Index

Acute Lymphocytic Leukemia
Blinatumomab (Blincyto)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status	Date	Action
Revised	05/03/2018	Medical Policy & Technology Assessment Committee (MPTAC) review.
Revised	05/02/2018	Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Added MRD to the MN criteria. Updated Rationale, Background/Overview and References sections. Updated Coding section, added ICD-10 PCS codes XW03351, XW04351.
Revised	05/04/2017	MPTAC review.
Revised	05/03/2017	Hematology/Oncology Subcommittee review. Added DLBCL to the INV/NMN criteria. Updated Rationale, Background/Overview and References sections.
Revised	05/05/2016	MPTAC review.
Revised	05/04/2016	Hematology/Oncology Subcommittee review. Added CD19+ to the MN criteria. Updated Reference section.
	01/01/2016	Updated Coding section with 01/01/2016 HCPCS changes, removed C9449 deleted 12/31/2015; also removed ICD-9 codes.
New	05/07/2015	MPTAC review.
New	05/06/2015	Hematology/Oncology Subcommittee review. Initial document development.