Bendamustine (Belrapzo, Bendeka, Treanda, Vivimusta) Form

Bendamustine hydrochloride (Belrapzo®, Bendeka®, Treanda®, Vivimusta™) is an alkylating drug. ____ *For Health Insurance Marketplace (HIM), if request is through pharmacy benefit, generic bendamustine is non- formulary and should not be approved using these criteria; refer to the formulary exception policy, HIM.PA.103. FDA Approved Indication(s) Belrapzo, Bendeka, Treanda, and Vivimusta are indicated for the treatment of patients with:
• Chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than • chlorambucil has not been established. Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Policy/Criteria Provider must submit documentation (such as office chart notes and lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Belrapzo, Bendeka, Treanda, and Vivimusta are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (must meet all):

1. Diagnosis of chronic lymphocytic leukemia (CLL) (i.e., small lymphocytic lymphoma [SLL]);

2. Prescribed by or in consultation with an oncologist or hematologist;

   3. Age ≥ 18 years;
   4. Prescribed in combination with rituximab, Arzerra®, or Gazyva®;
   5. Request meets one of the following (a or b): a. Dose does not exceed 100 mg/m2 on Days 1 and 2 of a 28-day cycle, up to 6 cycles; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration:
      Commercial/Medicaid – 6 months HIM – 6 months (refer to HIM.PA.103 for generic bendamustine if pharmacy benefit) Page 1 of 2

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   Bendamustine B. Non-Hodgkin B-Cell Lymphomas (must meet all):

   1. One of the following diagnoses (a through k): a. Indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen; b. Follicular lymphoma; c. Gastric MALT lymphoma; d. Nongastric MALT lymphoma; e. Nodal marginal zone lymphoma; f. Splenic marginal zone lymphoma; g. Mantle cell lymphoma; h. Diffuse large B-cell lymphoma (DLBCL) (as subsequent therapy); i. AIDS-related B-cell lymphoma (as subsequent therapy);
      j. Monomorphic post-transplant lymphoproliferative disorder (PTLD) (B-cell type) (as subsequent therapy); k. High-grade B-cell lymphomas: not otherwise specified or with translocations of MYC and BCL2 and/or BCL6 (double/triple hit lymphoma) (as subsequent therapy);
      *See Appendix B - prior authorization may be required for prior therapies
3. Prescribed by or in consultation with an oncologist or hematologist;
   
   3. Age ≥ 18 years;
   4. For nodal/splenic marginal zone lymphoma or gastric/nongastric MALT lymphoma, prescribed in combination with rituximab or Gazyva*;
4. For mantle cell lymphoma, prescribed in combination with rituximab;
   
   6. Request meets one of the following (a or b): a. Dose does not exceed 120 mg/m2 on Days 1 and 2 of a 21-day cycle, up to 8 cycles; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration:
      Commercial/Medicaid – 6 months HIM – 6 months (refer to HIM.PA.103 for generic bendamustine if pharmacy benefit) C. NCCN Recommended Uses (off-label) (must meet all):

5. Diagnosis of one of the following (a, b, c, d, e, f, or g): a. Classic or nodular lymphocyte-predominant Hodgkin lymphoma (HL) (as subsequent therapy); b. Pediatric HL (as re-induction or subsequent therapy); c. Multiple myeloma (MM); d. T-cell lymphomas (i, ii, iii, or iv): i. Hepatosplenic T-cell lymphoma (HSTCL) (as subsequent therapy); ii. Adult T-cell leukemia/lymphoma (ATLL) (as subsequent therapy); iii. Peripheral T-cell lymphoma (PTCL) (as subsequent therapy)*: relapsed/refractory ALCL, peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, enteropathy-associated T- cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, Page 2 of 3

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   Bendamustine nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype, or follicular T-cell lymphoma; iv. Breast implant-associated ALCL (as subsequent therapy); e. Waldenstrom’s macroglobulinemia (i.e., lymphoplasmacytic lymphoma); f. Systemic light chain amyloidosis (SLCA) in combination with dexamethasone (as subsequent therapy); g. Hematopoietic cell transplantation in combination with etoposide, cytarabine, and melphalan for NHL without central nervous system (CNS) disease or for HL; *See Appendix B - prior authorization may be required for prior therapies

   2. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years, unless diagnosis is pediatric HL;
   4. Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration:
      Commercial/Medicaid – 6 months HIM – 6 months (refer to HIM.PA.103 for generic bendamustine if pharmacy benefit) D. Other diagnoses/indications (must meet 1 or 2):
6. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
7. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. All Indications in Section I (must meet all):
8. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Belrapzo, Bendeka, Treanda, or Vivimusta for a covered indication and has received this medication for at least 30 days;

9. Member is responding positively to therapy;

   3. If request is for a dose increase, request meets (a or b):* a. New dose does not exceed (i or ii): i. CLL/SLL: 100 mg/m2 on Days 1 and 2 of a 28-day cycle, up to 6 cycles; Page 3 of 4

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   Bendamustine ii. Non-Hodgkin indolent B-cell lymphoma: 120 mg/m2 on Days 1 and 2 of a 21- day cycle, up to 8 cycles; b. New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). *Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration:
   Commercial/Medicaid – 12 months HIM – 12 months (refer to HIM.PA.103 for generic bendamustine if pharmacy benefit) B. Other diagnoses/indications (must meet 1 or 2):

10. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

11. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ALCL: anaplastic large cell lymphoma ATLL: adult T-cell leukemia/lymphoma CLL: chronic lymphocytic leukemia CNS: central nervous system DLBCL: diffuse large B-cell lymphoma
    FDA: Food and Drug Administration HL: Hodgkin lymphoma HSTCL: hepatosplenic gamma-delta T- cell lymphoma
    MF: mycosis fungoides MM: multiple myeloma NCCN: National Comprehensive Cancer Network NHL: non-Hodgkin lymphoma PTCL: peripheral T-cell lymphoma PTLD: post-transplant lymphoproliferative disorder SLCA: systemic light chain amyloidosis
    SLL: small lymphocytic lymphoma SS: Sezary syndrome Page 4 of 5

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    Bendamustine Appendix B: Therapeutic Alternatives
    This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
    Drug Name Dosing Regimen Dose Limit/ Maximum Dose Examples of primary therapies (NCCN) DLBCL RCHOP (Rituxan® [rituximab], cyclophosphamide, doxorubicin, vincristine, prednisone) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + Rituxan® (rituximab) AIDS-related B-cell lymphoma EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + Rituxan® (rituximab) CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + Rituxan® (rituximab) PTCL CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) ATLL CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with high-dose methotrexate and cytarabine HSTCL DHAP (dexamethasone, cisplatin, cytarabine) ICE (ifosfamide, carboplatin, etoposide) MM Bortezomib/liposomal doxorubicin/dexamethasone Carfilzomib/lenalidomide/dexamethasone Daratumumab/bortezomib /dexamethasone Monomorphic PTLD (B-cell type) RCHOP (Rituxan® [rituximab], cyclophosphamide, doxorubicin, vincristine, prednisone) RCEPP (Rituxan® [rituximab], cyclophosphamide, etoposide, prednisone, procarbazine) Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Page 5 of 6

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    Bendamustine Drug Name Dosing Regimen Dose Limit/ Maximum Dose SLCA Daratumumab and hyaluronidase- fihj/bortezomib/cyclophosphamide/dexamethasone Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Varies Varies Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Belrapzo, Bendeka: patients with a history of a hypersensitivity reaction to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol o Treanda: patients with a history of a hypersensitivity reaction to bendamustine o Vivimusta: patients with a history of a hypersensitivity reaction to bendamustine, polyethylene glycol 400, dehydrated alcohol, or monothioglycerol • Boxed warning(s): none reported V. Dosage and Administration
    Indication CLL/SLL Dosing Regimen Bendeka: 100 mg/m2 IV over 10 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles Maximum Dose See regimen Belrapzo, Treanda: 100 mg/m2 IV over 30 minutes on days 1 and 2 of a 28-day cycle, up to 6 cycles Indolent B-cell lymphoma Vivimusta: 100 mg/m2 IV over 20 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles Bendeka: 120 mg/m2 IV over 10 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles See regimen Belrapzo, Treanda: 120 mg/m2 IV over 60 minutes on days 1 and 2 of a 21-day cycle, up to 8 cycles Vivimusta: 120 mg/m2 IV over 20 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles *Non-Hodgkin lymphomas VI. Product Availability
    Drug Name Bendamustine (Belrapzo, Bendeka, Vivimusta) Bendamustine (Treanda) Availability Solution (multiple-dose vial): 100 mg/4 mL Solution (single-dose vial): 45 mg/0.5 mL; 180 mg/2 mL Lyophilized powder (single-dose vial): 25 mg in a 20 mL vial; 100 mg in a 20 mL vial Page 6 of 7

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    Bendamustine VII.