Subject:
Blinatumomab (Blincyto)
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Acute lymphoblastic leukemia (ALL) is a malignant disorder that originates in a single B- or T-lymphocyte progenitor. Proliferation and accumulation of blast cells in the marrow result in suppression of hematopoiesis and, thereafter, anemia, thrombocytopenia, and neutropenia. Adult ALL is one of the rarest malignancies, with only approximately 2,000 new cases diagnosed annually in the United States. Of these, approximately 1,400 are Ph- Adult ALL. Based on published treatment response rates and treatment-related mortality rates, each year in the United States approximately 840 patients relapse from a first remission or are refractory to front-line therapy. Fifty-five percent of these will relapse a second time or be refractory to second-line therapy, with worsening prognosis, decreased survival, and a need for a third line of therapy.
BLINCYTO is a bispecific CD19-directed CD3 T-cell engager indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). This indication is approved under a full approval.
The safety and efficacy of BLINCYTO were evaluated in an open-label, multicenter, single-arm study involving 185 patients. Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative relapsed or refractory B-precursor ALL. BLINCYTO was administered as a continuous intravenous infusion. In the first cycle, the initial dose was 9 mcg/day for week 1, then 28 mcg/day for the remaining 3 weeks. The primary endpoint was the complete remission/complete remission with partial hematological recovery (CR/CRh*) rate within 2 cycles of treatment with BLINCYTO. Seventy-seven out of 185 (41.6%) evaluable patients achieved CR/CRh* within the first 2 treatment cycles, with the majority of responses (81%, 62 out of 77) occurring within cycle 1 of treatment. See Table 3 for efficacy results from this study. The HSCT rate among those who achieved CR/CRh* was 39% (30 out of 77).
The second study was an open-label, multicenter, single-arm in pediatric patients with relapsed or refractory B-cell precursor ALL (second or later bone marrow relapse, any marrow relapse after allogenic HSCT, or refractory to other treatments and >25% blasts in bone marrot). BLINCYTO was administered at 5mcg/m2/day on Days 1-7 and 15mcg/m2/day on Days 8-28 for cycle 1 and 15mcg/m2/day on Days 1-28 for subsequent cycles. Dose adjustments were possible in case of adverse events. Patients who responded to BLINCYTO but later relapsed had the option to be retreated with BLINCYTO. Among the 70 treated patients, the median age was 8 years (range: 7 months to 17 years), 40 out of 70 (57.1%) had undergone allogenic HSCT prior to receiving BLINCYTO and 39 out of 70 (55.7%) had refractory disease. Twenty-three out of 70 (32.9%) patients achieved CR/CRh* within the first 2 treatment cycles with 17 out of 23 (73.9%) occurring within cyclye 1 of treatment.
The efficacy of BLINCYTO for treatment of Philadelphia chromosome-positive B-cell precursor ALL was evaluated in an open-label, multicenter, single-arm study (ALCANTARA study). Eligible patients were ≥ 18 years of age with Philadelphia chromosome-positive B-cell precursor ALL, relapsed or refractory to at least 1 second generation or later tyrosine kinase inhibitor (TKI), or intolerant to second generation TKI, and intolerant or refractory to imatinib mesylate. BLINCYTO was administered at 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for subsequent cycles. Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with
an MRD-negative CR/CR with partial hematological recovery (CR/CRh*) within 2 cycles of treatment with BLINCYTO.16 patients achieved complete remission or complete remission with partial hematologic recovery within the first two cycles of treatment, with 14 of the 16 patients achieving complete remission with full hematologic recovery.
In March 2017, Blincyto (blinatumomab) was FDA approved for the treatment of patients with B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. This indication was approved under accelerated approval based on MRD response rate and hematological relapse-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The efficacy of BLINCYTO for this indication was evaluated in an open-label, multicenter, single-arm study (BLAST Study) that included 86 patients who were in hematologic complete remission (defined as < 5% blasts in bone marrow, absolute neutrophil count > 1 Gi/L, platelets > 100 Gi/L) and had MRD at a level of ≥ 0.1%. BLINCYTO was administered at a constant dose of 15 mcg/m2 /day (equivalent to the recommended dosage of 28 mcg/day) intravenously for all treatment cycles. Patients received up to 4 cycles of treatment. Following treatment with BLINCYTO, 45 out of 61 (73.8%) patients in CR1 and 14 out of 25 (56.0%) patients in CR2 underwent allogeneic hematopoietic stem cell transplantation in continuous hematologic complete remission. Efficacy was based on achievement of undetectable MRD within one cycle of BLINCYTO treatment and hematological relapse-free survival (RFS). Overall, undetectable MRD was achieved by 81.4% of patients (95% CI: 71.6%, 89.0%). The median hematological RFS was 22.3 months. Undetectable MRD was achieved by 81.3% of patients (95% CI: 71.0%, 89.1%). The side effects of Blincyto when used to treat MRD-positive B-cell precursor ALL are consistent with those seen in other uses of the drug.
BLINCYTO carries black box warnings for Cytokine Release Syndrome (CRS) and Neurological toxicities, both of which may be life-threatening or fatal and require interruption or discontinuation of BLINCYTO as recommended.
[INFORMATIONAL NOTE: According to the FDA approved package insert, Cytokine Release Syndrome (CRS) and neurologic toxicities, which may be life threatening or fatal, have occurred in patients that received BLINCYTO. Consider disrupting or discontinuing this medication as recommended if this occurs.]
Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance)
The requirements of the Horizon BCBSNJ Blinatumomab (Blincyto) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).
I. Blinatumomab (BLINCYTO) is considered medically necessary based on the following FDA approved indications for adults and pediatric patients at least 1 month old with
- B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% (documentation of medical records required) OR
- relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) (documentation of medical records required) AND
- The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis
II. When Blinatumomab (BLINCYTO) is medically necessary, therapy will be approved at the following FDA-approved doses:
- Treatment of MRD-positive B-cell Precursor ALL for an approval period of 24 weeks:
· A treatment course consists of 1 cycle of BLINCYTO for induction followed by up to 3 additional cycles for consolidation.
o A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).
· For patients greater than or equal to 45 kg in weight:
o In Cycle 1, administer BLINCYTO at 28 mcg/day on Days 1–28.
o For subsequent cycles 2-4, administer BLINCYTO at 28 mcg/day on Days 1–28.
· For patients less than 45 kg in weight:
o In Cycle 1, administer BLINCYTO at 15 mcg/m2/day on Days 1-28. Do not to exceed 28 mcg/day.
o For subsequent cycles 2-4, administer BLINCYTO at 15 mcg/m2/day on Days 1-28. Do not exceed 28 mcg/day.
· Allow for at least 2 weeks treatment-free between cycles of BLINCYTO.
- Treatment of relapsed or refractory B-cell Precursor ALL for an approval period of 30 weeks:
· A treatment course consists of up to 2 cycles of BLINCYTO for induction followed by 3 additional cycles for consolidation treatment and up to 4 additional cycles of continued therapy.
o A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).
o A single cycle of treatment of BLINCYTO continued therapy consists of 28 days of continuous intravenous infusion followed by a 56-day treatment-free interval (total 84 days).
· For patients greater than or equal to 45 kg in weight:
o In Cycle 1, administer BLINCYTO at 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8–28.
o For subsequent cycles 2-5, administer BLINCYTO at 28 mcg/day on Days 1–28.
· For patients less than 45 kg in weight:
o In Cycle 1, administer BLINCYTO at 5 mcg/m2/day on Days 1-7 and at 15 mcg/m2/day on Days 8-28. Do not to exceed 9 mcg/day
o For subsequent cycles 2-5, administer BLINCYTO at 15 mcg/m2/day on Days 1-28. Do not exceed 28 mcg/day.
· Allow for at least 2 weeks treatment-free between cycles of BLINCYTO.
[INFORMATIONAL NOTE:
For treatment of MRD-Positive B-cell Precursor ALL, hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended. As per the FDA approved package insert, patients should be pre-medicated with dexamethasone or equivalent:
o For adult patients, pre-medicate with prednisone 100 mg intravenously or equivalent (e.g., dexamethasone 16 mg) 1 hour prior to the first dose of BLINCYTO in each cycle.
o For pediatric patients, pre-medicate with 5 mg/m2 of dexamethasone, to a maximum dose of 20 mg prior to the first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle.
For treatment of Relapsed or Refractory B-cell Precursor ALL, hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiating (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended. As per the FDA approved package insert, patients should be pre-medicated with dexamethasone
o For adult patients, pre-medicate with 20 mg dexamethasone 1 hour prior to the first dose of BLINCYTO of each cycle, prior to a step dose (such as cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours
o For pediatric patients, pre-medicate with 5 mg/m2 of dexamethasone, to a maximum dose of 20 mg prior to the first dose of BLINCYTO in the first cycle, prior to a step dose, and when restarting an infusion after an interruption of 4 or more hours in the first cycle ]
III. BLINCYTO is considered medically necessary for continued use for the treatment of :
· A. Relapsed or refractory B-cell precursor ALL
1. If the following criteria are met:
- Absence of unacceptable toxicity from the drug, including Cytokine Release Syndrome, neurological toxicities, serious infections, pancreatitis, tumor lysis syndrome, neutropenia/febrile neutropenia, elevation of LFTs, leukoencephalopathy, etc.; AND
- Treatment response or stabilization of disease as indicated by CBC, bone marrow cytogenic analysis, QPCR, or FISH; AND
- Member has not exceeded a total of 4 cycles of continued therapy or 9 total cycles of Blincyto for the treatment of relapsed or refractory disease
2. When BLINCYTO is medically necessary for continued use for the treatment of relapsed or refractory B-cell precursor ALL at the following FDA approved recommended doses of:
- For subsequent cycles 6-9
- For patients greater than or equal to 45 kg: Administer BLINCYTO at 28 mcg/day on days 1-28 followed by a 56 day treatment free interval
- For patients less than 45 kg: Administer BLINCYTO at 15 mcg/m2/day on Days 1-28 followed by a 56 day treatment free interval. Do NOT exceed 28mcg/day
· B. For the treatment of MRD+ ALL continued use is NOT considered medically necessary.
IV. Blinatumomab (BLINCYTO) is considered medically necessary for off-label indications that have in effect a rating of 'Category 1' or 'Category 2A' in the current recommendations in the National Comprehensive Cancer Network (NCCN) compendium. Refer to National Comprehensive Cancer Network: Drugs and Biologics Compendium - blinatumomab. Available at: [https://www.nccn.org/professionals/drug_compendium/content/].
V. Blinatumomab (BLINCYTO) is considered investigational for all other indications.
Medicare Coverage
There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Noridian Healthcare Services, LLC, the Local DME Medicare Carrier for jurisdiction JA, has determined that this service is covered when LCD L33794 and Policy Article A52507 criteria are met. For eligibility and coverage, refer to LCD L33794 External Infusion Pumps. Available at: https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=33794&ContrId=389&ver=50&ContrVer=1&CntrctrSelected=389*1&Cntrctr=389&s=38&DocType=All&bc=AggAAAQAAAAAAA%3d%3d&.
Please refer to Local Coverage Article: External Infusion Pumps - Policy Article (A52507). Available at: https://www.cms.gov/medicare-coverage-database/details/article-details.aspx?articleId=52507&ver=29&LCDId=33794&ContrId=389&ContrVer=1&CntrctrSelected=389*1&Cntrctr=389&s=38&DocType=All&bc=AggAAAQAIAAAAA%3d%3d&.
Medicaid Coverage
For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Blinatumomab
Blincyto
Acute lymphoblastic leukemia
References:
1. BlincytoTM Prescribing Information. Amgen. Thousand Oaks, CA. April 2019.
2. 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.
3. Klinger M, Brandl C, Zugmaier G, et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood. 2012 Jun 28;119(26):6226-33.
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. pii: JCO.2014.56.3247.
5. Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia. J Clin Oncol. 2014 Nov 10. pii: JCO.2014.56.3247.
6. National Comprehensive Cancer Network: Blinatumomab. [Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=414 (accessed 12/17/2019)
7. Kantarjian, Hagop, et al. “Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia.” New England Journal of Medicine, vol. 376, no. 9, Feb. 2017, pp. 836–847., doi:10.1056/nejmoa1609783
8. FDA News Release. FDA expands approval of Blincyto for treatment of a type of leukemia in patients who have a certain risk factor for relapse. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm603151.htm. Accessed April 2018.
9. ClinicalTrials.gov. Confirmatory Phase II Study of Blinatumomab (MT103) in Patients With Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia (ALL) (BLAST). Available at: https://clinicaltrials.gov/ct2/show/NCT01207388. Accessed April 2018.
Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
HCPCS
J9039
* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.
The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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