Pending Policies - Prescription Drugs


Blinatumomab (Blincyto)

Number:RX502.039

Effective Date:11-01-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb strength of recommendation or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider to submit documentation from nationally recognized compendia, clinical guidelines, or active Phase III clinical trials supporting the requested regimen.

Blinatumomab (BlincytoTM) may be considered medically necessary as a single agent in the treatment of patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) for:

Philadelphia chromosome-negative disease; OR

Philadelphia chromosome-positive disease refractory to at least two tyrosine kinase inhibitor therapies.

Blinatumomab (BlincytoTM) may be considered medically necessary as a single agent consolidation therapy for B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in:

Adolescent and young adult patients (defined as those diagnosed between 15 and 39 years of age); OR

Adult patients (defined as those between 18 and 64 years of age) without substantial comorbidities.

Blinatumomab (BlincytoTM) is considered experimental, investigational and/or unproven when used in the treatment of any other conditions.

NOTE: Per the prescribing information for Blinatumomab (BlincytoTM) for the 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 the 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.

Description:

Acute lymphoblastic leukemia (ALL) is a cancer of the white blood cells and bone marrow in which there is an overproduction of immature lymphoblasts, B lymphocytes or T lymphocytes. Precursor B-cell ALL is a type of ALL in which an excess of B-cell lymphoblasts are produced.

Some patients with ALL may have a particular genetic abnormality which can be identified as the Philadelphia (Ph) chromosome in their leukemic cells. The estimated number of new cases of ALL in the U.S. in 2018 is 5,960. (1)

Blinatumomab is a bispecific CD19-directed CD3 T-cell engager (BiTE®) immunotherapy indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia. (4) The U. S Food and Drug Administration (FDA) has indicated that BlincytoTM is the first approved drug that engages the body’s T-cells, a type of white blood cell or lymphocyte, to destroy leukemia cells. A treatment cycle with BlincytoTM consists of 4 weeks of continuous intravenous infusion followed by a 2-week treatment free interval. Blincyto’sTM treatment course may consist of up to a total of 5 cycles.

Regulatory Status

The FDA approved BlincytoTM in December 2014 under their accelerated approval program for the treatment of patients with the Philadelphia chromosome-negative relapsed or refractory B-cell B-cell ALL. This indication was approved based on preliminary clinical evidence that the drug may offer a substantial improvement over available therapies. (2)

Blincyto’sTM prescribing information included a warning for Cytokine Release Syndrome and neurological toxicities which may be life-threatening or fatal. Management of these occurrences may require interruption or discontinuation of BlincytoTM.

In July 2017, the FDA issued an updated approval for BlincytoTM which confirmed the clinical benefit required under the initial accelerated approval and also expanded the indication to include Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL. (5) In 2018, the prescribing information was updated to include an additional FDA-approved indication for 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%. (6) Sustained approval of BlincytoTM for this indication is dependent on continued safety and efficacy demonstrated through ongoing confirmatory clinical trials.

Rationale:

This policy was originally developed in 2015 and has been updated with searches of scientific literature through August 20, 2018. Following is a summary of the key literature to date.

Clinical Studies

Philadelphia Chromosome-Negative Disease

The initial U.S. Food and Drug Administration (FDA) approval of Blincyto™ was based on an open-label, multicenter, single-arm study. The treated population consisted of 185 patients who were ≥ 18 years of age with Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). The 185 patients received at least one infusion of Blincyto™; the median number of treatment cycles was 2 (range: 1 to 5). Thirty-two out of 185 patients (17.3%) had received more than 2 prior salvage therapies and 63 out of 185 patients (34.1%) had undergone hematopoietic stem cell transplantation (HSCT) prior to receiving Blincyto™. 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 patients (41.6%) assessed patients reached CR/CRh* within the first 2 treatment cycles. Sixty of 185 patients (32.4%) had no evidence of disease (complete remission) for a median of 6.7 months. (3)

In 2017 Kantarjian et al., studied 405 patients with relapsed or refractory B-cell precursor ALL in a randomized, open label, multicenter clinical trial comparing blinatumomab to standard-of-care chemotherapy. (7) Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. Authors concluded that treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL.

Philadelphia Chromosome-Positive Disease

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) (NCT02000427). (8) 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 Day 1-7 and 28mcg/day on Days 8-28 for Cycle 1, and 28cg/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. The treated population included 45 patients who received at least one infusion of Blincyto™; the median number of treatment cycles was 2 (range: 1 to 5). Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with a minimal residual disease (MRD)-negative CR/CR with CR/CRh* within 2 cycles of treatment with Blincyto™. Efficacy results are shown in Table 1 below.

Table 1. Efficacy Results in Patients ≥ 18 Years of Age With Philadelphia Chromosome-Positive Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia (ALCANTARA Study) (8)

 

N=45

 

CR1

CRh*2

CR/CRh*

n (%)

[95% CI]

14 (31)

[18-47]

2 (4)

[1-15]

16 (36)

[22-51]

MRD response3

n1/n2 (%)4 [95% CI]

12/14 (86)

[57-98]

2/2 (100)

[16, 100]

14/16 (88)

[62-98]

DOR/RFS5

Median (months) (range)

6.7 (3.6-12.0)

NE (3.7-9.0)

6.7 (3.6-12.0)

1 CR (complete remission) was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/microliter and absolute neutrophil counts [ANC] > 1,000/microliter).

2 CRh* (complete remission with partial hematological recovery) was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/microliter and ANC >500/microliter).

3 MRD (minimal residual disease) response was defined as MRD by PCR < 1 x 10-4.

4 n1: number of patients who achieved MRD response and the respective remission status; n2: number of patients who achieved the respective remission status. Six CR/CRh* responders with missing MRD data were considered as MRD-nonresponders.

5 DOR (duration of response)/RFS (relapse-free survival) was defined as time since first response of CR or CRh* to relapse or death, whichever is earlier. Relapse was defined as hematological relapse (blasts in bone marrow greater than 5% following CR) or an extramedullary relapse.

NE: Not evaluable.

Minimal Residual Disease-Positive B-cell precursor ALL

The efficacy and safety of blinatumomab in MRD-positive ALL patients was evaluated in an open-label, multicenter, single arm study (BLAST Study) (NCT01207388) published by Gokbuget et al. in 2018. (9) This confirmatory, phase 2 study included 116 patients. The patients with B-cell precursor ALL in hematologic complete remission with MRD (≥10-3) received blinatumomab 15 µg/m2 per day by continuous IV infusion for up to 4 cycles. Patients could undergo allogeneic hematopoietic stem-cell transplantation any time after cycle 1. The primary end point was complete MRD response status after 1 cycle of blinatumomab. Eighty-eight (78%) of 113 evaluable patients achieved a complete MRD response. In the subgroup of 110 patients with Ph-negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In landmark analyses, complete MRD responders had longer RFS (23.6 vs 5.7 months; P = .002) and OS (38.9 vs 12.5 months; P = .002) compared with MRD nonresponders. Adverse events were consistent with previous studies of blinatumomab. Twelve (10%) and 3 patients (3%) had grade 3 or 4 neurologic events, respectively. Four patients (3%) had cytokine release syndrome grade 1, n = 2; grade 3, n = 2), all during cycle 1. After treatment with blinatumomab in a population of patients with MRD-positive B-cell precursor ALL, a majority achieved a complete MRD response, which was associated with significantly longer RFS and OS compared with MRD nonresponders.

Professional Guidelines and Position Statements

The National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium® (10) recommends use of single-agent blinatumomab therapy for:

Consolidation therapy for Philadelphia chromosome-negative B-ALL in adolescent and young adult (AYA) patients with minimal residual disease positive (MRD+) following a complete response to induction therapy;

Consolidation therapy for Philadelphia chromosome-negative B-ALL in adult patients <65 years of age without substantial comorbidities with MRD+ following a complete response to induction therapy;

Relapsed/refractory Philadelphia chromosome-positive tyrosine kinase inhibitors intolerant/refractory B-ALL;

Relapsed/refractory Philadelphia chromosome-negative B-ALL.

The NCCN guidelines Version 2.2018 Adolescent and Young Adult Oncology define an adolescent and young adult patient as an individual who is 15 to 39 years of age at the time of initial diagnosis. (11)

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

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.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

J9039

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. American Cancer Society: Leukemia—Acute Lymphocytic. Key Statistics for Acute Lymphocytic Leukemia. Available at <http://www.cancer.org> (accessed - 2018 August 20).

2. FDA approves Blincyto to treat a rare form of acute lymphoblastic leukemia. Available at <http://www.fda.gov> (accessed - 2015 April 7).

3. FDA – Drugs @FDA: Highlights of Prescribing Information, BLINCYTOTM (blinatumomab) reference ID: 3667235. Available at <http://www.fda.gov> (accessed - 2015 April 7).

4. News Releases FDA Approves BLINCYTO TM (Blinatumomab) Immunotherapy for the Treatment of Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia. Available at <http://www.amgen. com> (accessed - 2015 April 7).

5. FDA grants regular approval to blinatumomab and expands indication to include Philadelphia chromosome-positive B cell. Available at <http://www.fda.gov> (accessed - 2017 December 4).

6. FDA – Drugs @FDA: Highlights of Prescribing Information, BLINCYTOTM (blinatumomab) reference ID: 3667235. Available at <http://www.fda.gov> (accessed - 2018 August 7).

7. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017 Mar 2; 376(9):836-847. PMID 28249141

8. FDA – Drugs @FDA: Highlights of Prescribing Information, BLINCYTOTM (blinatumomab) reference ID: 4123274. Available at <http://www.fda.gov> (accessed - 2017 December 4).

9. Gokbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018 Apr 5; 131(14):1522-1531. PMID 29358182

10. Blinatumomab. NCCN Drugs and Biologics Compendium. National Comprehensive Cancer Network 2018. Available at <https://www.nccn.org> (accessed – 2018 August 13).

11. NCCN – Adolescent and Young Adult Oncology –NCCN Clinical Practice Guidelines in Oncology, Version 2 (2018). National Comprehensive Cancer Network (2017 October 11). Available at <http://www.nccn.org> (accessed – 2018 August 20).

Policy History:

Date Reason
11/1/2018 Document updated with literature review. The following changes were made to Coverage: 1) Added medically necessary coverage for Blinatumomab (Blincyto TM ) as a single agent in 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%. 2) To the note added “for the treatment of relapsed or refractory B-cell precursor ALL” and “For the 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.” References 6, 9, and 11 added.
5/1/2018 Document updated with literature review. The following changes were made to Coverage: 1) Added “as a single agent”; and 2) Added “at least two” to the refractory tyrosine kinase inhibitor therapies criterion.
7/15/2016 Reviewed. No changes.
11/1/2015 New medical document. Blinatumomab (BLINCYTO TM ) may be considered medically necessary in the treatment of patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) for: Philadelphia chromosome-negative disease; OR Philadelphia chromosome-positive disease refractory to tyrosine kinase inhibitor therapy. Blinatumomab (BLINCYTO TM ) is considered experimental, investigational and/or unproven when used in the treatment of any other conditions.

Archived Document(s):

Title:Effective Date:End Date:
Blinatumomab (Blincyto)05-01-201810-31-2018
Blinatumomab (BLINCYTO)07-15-201604-30-2018
Blinatumomab (BLINCYTOâ„¢)11-01-201507-14-2016
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