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Horizon BCBSNJ
Uniform Medical Policy ManualSection:Drugs
Policy Number:116
Effective Date: 12/06/2019
Original Policy Date:01/28/2014
Last Review Date:11/12/2019
Date Published to Web: 11/28/2018
Subject:
Bendamustine Hydrochloride (Treanda®, Bendeka®, Belrapzo)

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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Bendamustine hydrochloride (Treanda®, Bendeka®) is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional covalent linkage can lead to cell death via several pathways. Bendamustine is active against both quiescent and dividing cells. The exact mechanism of action of bendamustine remains unknown.

Bendamustine hydrochloride (Treanda®), manufactured by Teva Pharmaceuticals USA, Inc., received FDA approval on March 20, 2008 for the treatment of patients with:chronic lymphocytic leukemia (CLL). Subsequently on October 31, 2008 for indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. On December 8, 2015 the FDA approved Bendeka® (bendamustine) for the same indications as Treanda®; safety and efficacy of Bendeka® was confirmed with the same clinical trials used for the approval of Treanda®. Treanda® must be infused over longer times (i.e. 30 minutes vs 10 minutes) and in larger volumes than Bendeka®, however, there are no other differences in regard to dosing.

The safety and efficacy of Treanda® and Bendeka®, for CLL, were evaluated in an open-label, randomized controlled muliticenter trial comparing bendamustine to chlorambucil. The trial was conducted in 301 previously-untreated patients with Binet Stage B or C (Rai Stages I-IV) CLL requiring treatment. Patients were randomly assigned to receiving either Treanda® at 100mg/m2, administered intravenously over a period of 30 minutes on Days 1 and 2 or chlorambucil at 0.8mg/kg administered orally on Days 1 and 15 of each 28-dy cycle. Efficacy endpoints of objective response rate and progression-free survival (PFS) were calculated using pre-specified algorithm based on NCI working group criteria for CLL. The overall response rate (ORR) was 59% vs. 26%, for bendamustine and chlorambucil, respectively (p<0.0001). PFS was a median of 18 months and 6 months, for bendamustine and chlorambucil, respectively (p<0.0001).

The efficacy of bendamustine for NHL was evaluated in a single arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. All patients received bendamustine intravenously at a dose of 120mg/m2 on Days 1 and 2 of a 21-day treatment cycle. Patients were treated for up to 8 cycles. Efficacy was based on the assessments of a blinded independent review committee (IRC) and included overall response rate (complete response + complete response unconfirmed +partial response) and duration of response (DR). 74% of patients had an overall response rate with median 9.3 month duration of response.

In May 2018, the FDA approved BelrapzoTM (bendamustine hydrochloride) for the treatment of patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of rituximab or ritixumab-containing regimen. The approval of BelrapzoTM was based on the clinical studies previously conducted in Bendeka®.


Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)

The requirements of the Horizon BCBSNJ Bendamustine hydrochloride (Treanda®, Bendek, and BelrapzoTM) 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. Bendamustine hydrochloride (Treanda®,Bendeka®, and BelrapzoTM) is medically necessary for the following FDA-approved indications:

      a. Chronic lymphocytic leukemia (CLL)
      i. If the request is for Treanda®, member has had an inadequate response or contraindication to Bendeka® or BelrapzoTM
      b. Indolent B-cell non-Hodgkin lymphoma (NHL)
        i. If there has been progression during or within 6 months of treatment with rituximab or a rituximab-containing regimen.
        ii. If the request is for Treanda®, member has had an inadequate response or contraindication to Bendeka® or BelrapzoTM
    [INFORMATIONAL NOTE: Treanda®, Bendeka®, and BelrapzoTM are contraindicated in patients with a history of hypersensitivity to bendamustine. Bendeka® and BelrapzoTM have additional labeled contraindications for hypersensitivity to polyethylene glycol 400, propylene glycol, or monothioglycerol.]

    II. When medically necessary, bendamustine hydrochloride (Treanda®, Bendeka®, and BelrapzoTM) will be approved for a one time approval of 6 months at the following FDA- recommended doses:
        a. For CLL:
            i. 100mg/m2 infused intravenously on days 1 and 2 of a 28-day cycle, up to 6 cycles

    [INFORMATIONAL NOTE: Treanda®and BelrapzoTM are to be infused intraveneously over 30 minutes while Bendeka is to be infused over 10 minutes.

    As per the FDA approved package insert, delay treatment for Grade 4 hematologic toxicity or clinically significant >2 Grade 2 non-hematologic toxicity. Treanda® must be reconstituted and further diluted prior to infusion; Bendeka® and BelrapzoTMcome as a ready to dilute liquid.

    Dose modification for hematologic toxicity: for Grade 3 or greater toxicity, reduce dose to 50mg/m2 on Days 1 and 2; if Grade 3 or greater toxicity recurs, reduce dose to 25mg/m2 on Days 1 and 2. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce dose to 50mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation may be considered.]
        b. For NHL:
            i. 120mg/m2 infused intravenously on days 1 and 2 of a 21-day cycle, up to 8 cycles

    [INFORMATIONAL NOTE: Treanda®and BelrapzoTM are to be infused intraveneously over 60 minutes while Bendeka is to be infused over 10 minutes.

    Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60mg/m2 on Days 1 and 2 of each cycle. Dose modification for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60mg/m2 on Days 1 and 2 of each cycle.]

    III. Bendamustine hydrochloride (Treanda®, Bendeka® and BelrapzoTM) is medically necessary for the following off-label uses below. If the request is for Treanda®, member has had an inadequate response or contraindication to Bendeka® or BelrapzoTM:
            a. Hodgkin Lymphoma - Classical Hodgkin Lymphoma (Treanda® and Bendeka®)
                • Second-line or subsequent systemic therapy (if not previously used) for relapsed or refractory disease in combination with brentuximab vedotin or as a component of gemcitabine/bendamustine/vinorelbine (age ≥18)
                • Third-line or subsequent systemic therapy as a single agent for relapsed or refractory disease (age ≥18)
                • Palliative therapy as a single agent for relapsed or refractory disease in older adults (age >60)
            b. Multiple Myeloma (Treanda® and Bendeka®)
                • Therapy for previously treated myeloma for relapse or for progressive disease
                  • as a single agent (useful under some circumstances)
                  • in combination with lenalidomide and dexamethasone
                  • in combination with bortezomib and dexamethasone
            c. NHL - Adult T-Cell Leukemia/Lymphoma (Treanda® and Bendeka®)
                • Second-line therapy or subsequent therapy as a single agent for nonresponders to first-line therapy for acute or lymphoma subtypes
            d. NHL - AIDS-Related B-Cell Lymphoma (Treanda®, Bendeka® and BelrapzoTM)
                • Second-line or subsequent therapy with or without rituximab for relapse of AIDS-related diffuse large B-cell lymphoma, primary effusion lymphoma, and HHV8-positive diffuse large B-cell lymphoma, not otherwise specified in noncandidates for transplant
            e. NHL - Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (Treanda® and Bendeka®)
                • First-line therapy with rituximab , ofatumumab, or obinutuzumab for CLL/SLL without del(17p)/TP53 mutation in patients age ≥65 years or for younger patients with or without significant comorbidities (creatinine clearance <70 ml/min). Not recommended for frail patients.
                • Therapy for relapsed or refractory disease without del(17p)/TP53 mutation in combination with rituximab without ibrutinib or idelalisib for patients <65 years without significant comorbidities
            f. NHL - Diffuse Large B-Cell Lymphoma (Treanda®, Bendeka® and BelrapzoTM)
                • Subsequent therapy with rituximab in combination with polatuzumab vedotin-piiq after ≥2 prior therapies for relapsed or refractory disease in noncandidates for transplant
            g. NHL - Follicular Lymphoma (Treanda®, Bendeka® and BelrapzoTM)
              • Used as
                • first-line therapy in combination with rituximab or obinutuzumab for stage I (≥7 cm), contiguous stage II (≥7 cm), non-contiguous stage II disease, or for patients with indications for treatment with stage III or IV disease excluding use in combination with involved site radiation therapy for stage I [≥7 cm], contiguous stage II [≥7 cm], non-contiguous stage II disease)
                • second-line or subsequent therapy (if not previously given as first-line) as a single agent or in combination with rituximab or obinutuzumab for refractory or progressive disease in patients with indications for treatment
                • treatment of histologic transformation to diffuse large B-cell lymphoma with or without rituximab in patients who have received multiple lines of chemoimmunotherapy for indolent or transformed disease
            h. NHL - Gastric MALT Lymphoma - (Treanda®, Bendeka® and BelrapzoTM)
              • Used in patients with indications for treatment as
                • first-line therapy in combination with rituximab for stage IIE, or II2, or stage IV disease (distant nodal or advanced stage)
                • additional therapy (if repeat endoscopy shows no response or recurrence after antibiotic therapy and involved site radiation therapy) in combination with rituximab for stage I1, or I2, or stage II1 disease
                • second-line or subsequent therapy for recurrent or progressive disease with rituximab or obinutuzumab
                • additional therapy after ISRT or rituximab alone for stage I1, I2, or stage II1 disease that is lymphoma positive after restaging with endoscopy
            i. NHL - Mantle Cell Lymphoma (Treanda®, Bendeka® and BelrapzoTM)
                • Used for stage I-II disease (localized presentation, extremely rare) as initial therapy, or for partial response, progression, or relapse after initial treatment with involved site radiation therapy alone, or for aggressive stage II bulky, III, or IV disease, or symptomatic indolent stage II bulky, III, or IV TP53 mutation positive disease in patients who are not candidates for high-dose therapy/autologous stem cell rescue as
                    • less aggressive induction therapy with rituximab
                • Second-line therapy for stage I-II disease aggressive stage II bulky, III, or IV disease, or symptomatic indolent stage II bulky, III, or IV disease to achieve a complete response after partial response to induction therapy, or for relapsed or progressive disease following an extended response duration to prior chemoimmunotherapy (> expected median progression free survival)
                    • as a single agent or in combination with rituximab (if not previously given)
            j. NHL - Mycosis Fungoides (MF)/Sezary Syndrome (SS) (Treanda® and Bendeka®)
                • Systemic therapy as primary treatment for
                    • stage IV non Sezary or visceral disease (solid organ), with or without radiation therapy for local control
                    • large cell transformation with generalized cutaneous or extracutaneous lesions, with or without skin-directed therapy
                • Systemic therapy as treatment for
                    • stage IIB MF with limited tumor lesions refractory to multiple previous therapies or progression, with or without skin-directed therapies
                    • relapsed or refractory stage IIB MF with generalized tumor lesions, with or without skin-directed therapies
                    • stage IIB MF with generalized tumor lesions that is refractory to multiple previous therapies or progression
                    • stage IV non Sezary or visceral disease (solid organ) that is relapsed or persistent, with or without radiation therapy for local control
                    • relapsed or persistent stage IA mycosis fungoides with B1 blood involvement, with or without skin directed therapy
                    • relapsed or persistent stage IB IIA MF with B1 blood involvement, with or without skin directed therapy
                    • relapsed or persistent stage III MF, with or without skin directed therapy
                    • stage III MF that is refractory to multiple previous therapies
                    • LCT with limited cutaneous lesions that is refractory to multiple previous therapies
                    • relapsed or persistent LCT with generalized cutaneous or extracutaneous lesions, with or without skin directed therapy
                    • relapsed or persistent stage IV Sezary syndrome
            k. NHL – Nodal Marginal Zone Lymphoma (Treanda®, Bendeka® and BelrapzoTM)
              • Used in patients with indications for treatment as
                • first-line therapy in combination with rituximab for stage I (≥7 cm), contiguous stage II (≥7 cm), non-contiguous stage II, or stage III or IV disease (excluding use in combination with involved site radiation therapy for stage I [≥7 cm], contiguous stage II [≥7 cm], non-contiguous stage II disease)
                • second-line or subsequent therapy for refractory or progressive disease in combination with rituximab or obinutuzumab
            l. NHL - Nongastric MALT Lymphoma (Treanda®, Bendeka® and BelrapzoTM)
              • Used in patients with indications for treatment as
                • first-line therapy for stage IV disease or recurrent stage I-II disease in combination with rituximab
                • second-line or subsequent therapy for refractory or progressive disease in combination with rituximab or obinutuzumab
            m. NHL - Peripheral T-Cell Lymphoma (Treanda® and Bendeka®)
                • Second-line or subsequent therapy for relapsed or refractory angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, nodal peripheral T-cell lymphoma with TFH phenotype, or follicular T-cell lymphoma, as a single agent
            n. NHL - Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders (Treanda® and Bendeka®)
              • Single-agent therapy for relapsed or refractory
                • primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions
                • cutaneous ALCL with regional nodes (excludes systemic ALCL)
            o. NHL - Splenic Marginal Zone Lymphoma (Treanda®, Bendeka® and BelrapzoTM)
              • Used in patients with indications for treatment as
                • first-line therapy in combination with rituximab for recurrent disease following initial treatment for splenomegaly
                • second-line (if prior treatment with rituximab) or subsequent therapy for disease recurrence following initial treatment for splenomegaly in combination with rituximab or obinutuzumab
            p. Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma (Treanda® and Bendeka®)
                • Used as a single agent or in combination with rituximab as
                  • primary therapy
                  • therapy for previously treated disease that does not respond to primary therapy or for progressive or relapsed disease
            q. Histologic Transformation of Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma (Treanda®, Bendeka® and BelrapzoTM)
                  · Treatment of histologic transformation to diffuse large B-cell lymphoma with or without rituximab after multiple lines of chemoimmunotherapy for indolent or transformed disease
            r. Post-Transplant Lymphoproliferative Disorders (Treanda®, Bendeka® and BelrapzoTM)
                  · Second-line and subsequent therapy with or without rituximab for patients with partial response, persistent or progressive disease after receiving chemoimmunotherapy as first-line treatment for monomorphic PTLD (B-cell type)
            s. High-grade B cell lymphoma (Treanda®, Bendeka® and BelrapzoTM)
                · Subsequent therapy with rituximab in combination with polatuzumab vedotin-piiq after ≥2 prior therapies for partial response, no response, relapsed, progressive, or refractory disease in noncandidates for transplant
            t. NHL – Hepatosplenic Gamma-Delta T-Cell Lymphoma (Treanda® and Bendeka®)
              · Second-line and subsequent therapy as a single agent for refractory disease after 2 primary treatment regimens

    V. Other uses of bendamustine hydrochloride (Treanda®,Bendeka®, and BerapzoTM) are considered investigational including, but not limited to:
        a. Advanced ovarian cancer
        b. Low grade lymphoma
        c. Other Hematologic malignancies
        d. Anaplastic Large Cell lymphoma (ALCL)
        e. Other Lymphoid malignancies
        g. Acute Lymphoblastic leukemia/lymphoma (ALL)
        h. Advanced or Metastatic Her2-negative breast cancer
        i. Soft tissue sarcoma (STS)
        j. Small Cell Lung Cancer


    Medicare Coverage:
    There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.

    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:
    Bendamustine Hydrochloride (Treanda®, Bendeka®, Belrapzo)
    Treanda® (Bendamustine Hydrochloride)
    Bendeka® (Bendamustine Hydrochloride)
    Belrapzo (Bendamustine Hydrochloride)

    References:
    1. Treanda® (bendamustine hydrochloride) [Prescribing Information]. Teva Pharmaceuticals USA, Inc. North Wales, PA. December 2017.

    2. Knauf WU, Lissitchkov T, Aldaoud A, et al. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol. 2012 Oct;159(1):67-77.

    3. NCCN Drugs and Biologics Compendium. Treanda®. [Available at: http://www.nccn.org/professionals/drug_compendium/mainpage.aspx] (accessed on October 24, 2019).

    4. Gressin R, Damaj GL, Bouabdallah K, et al. Multicenter, phase II study of bendamustine in refractory or relapsed T-cell lymphoma: The BENTLY trial. J Clin Oncol 30, 2012 (suppl; abstr 8026)

    5. Bendeka® (bendamustine hydrochloride) [Prescribing Information]. Teva Pharmaceuticals USA, Inc. North Wales, PA. October 2019.

    6. NCCN Drugs and Biologics Compendium. Bendeka®. [Available at: http://www.nccn.org/professionals/drug_compendium/mainpage.aspx (accessed on October 24, 2019).

    7. Belrapzo (bendamustine hydrochloride) [Prescribing information]. Eagles Pharmaceuticals. Woodcliff Lake, NJ. December 2018

    8. NCCN Drugs and Biologics Compendium. BelrapzoTM. [Available at: http://www.nccn.org/professionals/drug_compendium/mainpage.aspx (accessed on October 24, 2019).

    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

      J9033
      J9034
      J9036
    * CPT only copyright 2019 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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