Clinical UM Guideline

 

Subject: Bendamustine Hydrochloride
Guideline #: CG-DRUG-98 Publish Date:    06/28/2018
Status: New Last Review Date:    05/03/2018

Description

This document addresses the indications for the use of bendamustine hydrochloride (HCL) (BENDEKA™ and TREANDA®, Teva Pharmaceuticals USA, Inc., North Wales, PA). Bendamustine HCL, a cytotoxic, bifunctional mechlorethamine derivative with alkylator and antimetabolite activities, is administered intravenously and is used to treat several oncologic conditions.

Note: Please see the following related documents for additional information:

Clinical Indications

Medically Necessary:

Bendamustine HCL is considered medically necessary as a treatment for the following indications:

  1. Chronic lymphocytic leukemia (CLL); or
  2. Relapsed or refractory classical Hodgkin lymphoma; or
  3. Non-Hodgkin lymphoma (NHL) (for example, adult T-cell leukemia, AIDS-related B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, gastric MALT lymphoma, mantle cell lymphoma, mycosis fungoides/Sezary syndrome, nodal marginal zone lymphoma, nongastric MALT lymphoma, primary cutaneous B-cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorders, peripheral T-cell lymphoma, small lymphocytic lymphoma, splenic marginal zone lymphoma); or
  4. Multiple myeloma for disease relapse or refractory disease; or
  5. Waldenstrӧm’s macroglobulinemia.

Not Medically Necessary:

Bendamustine HCL is considered not medically necessary when the criteria above are not met and for all other indications, including, but not limited to any of the following:

  1. Metastatic breast cancer;
  2. Small cell lung cancer (SCLC).
Coding

The following codes for treatments and procedures applicable to this guideline 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.

HCPCS

 

 

J9033

Injection, bendamustine HCL (Treanda), 1 mg

 

J9034

Injection, bendamustine HCL (Bendeka), 1 mg

 

 

 

 

ICD-10 Diagnosis

 

C81.10-C81.99

Classical/unspecified Hodgkin lymphoma

C82.00-C86.6

Non-Hodgkin lymphoma

C88.0

Waldenstrӧm’s macroglobulinemia

C88.4

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]

C90.00-C90.32

Multiple myeloma and malignant plasma cell neoplasms

C91.10-C91.12

Chronic lymphocytic leukemia of B-cell type

C91.50-C91.52

Adult T-cell lymphoma/leukemia (HTLV-1 associated)

Discussion/General Information

Bendamustine HCL is an intravenously administered alkylating agent that has low cross-resistance with other alkylating agents due to its unique cytotoxic properties. On March 20, 2008, the U.S. Food and Drug Administration (FDA) approved bendamustine HCL (TREANDA), and in December 2015 approved (BENDEKA). Bendamustine HCL (BENDEKA) is a low-volume preparation with short infusion time. The FDA approved TREANDA and BENDEKA based on the same pivotal trials.

Both products are indicated for chronic lymphocytic leukemia (CLL) and “indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.” (BENDEKA Product label 2017; TREANDA Product Label, 2016).  The product labels note that efficacy for CLL relative to first-line therapies other than chlorambucil is unknown.

The following are proposed indications for bendamustine hydrochloride:

Chronic lymphocytic leukemia (CLL):

Chronic lymphocytic leukemia (CLL) is an indolent form of NHL marked by immunologically less mature lymphocytes and manifested by progressive accumulation of these cells in the blood, bone marrow, and lymphatic tissues. The lymphocytes are characterized by immunophenotype (CD5- and CD23-positive B cells). Additionally, B-cell antigens CD19 and CD20 are also co-expressed on CLL lymphocytes. CLL may progress to a generally enlarged lymphatic system as well as complications resulting from pancytopenia (National Cancer Institute [NCI], 2016). According to the NCI, treatment with "conventional doses of chemotherapy are not curative" for individuals with progressing CLL. Therefore, treatments to prolong disease-free survival for indolent and active disease continue to be studied.

The National Comprehensive Cancer Network® (NCCN) Clinical Practice Guideline (CPG) on Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (V.5.2018) recommends use of bendamustine HCL with or without a CD20 monoclonal antibody (rituximab, ofatumumab, or obinutuzumab) in the treatment of CLL without del (17p)/TP53 mutation as a first-line therapy in individuals at least 65 years old and in younger individuals with significant comorbidities.  For relapsed/refractory disease, bendamustine HCL is not a preferred treatment but is considered among the “other” recommended options.. The peer reviewed literature evaluating bendamustine HCL consists of randomized controlled trials (Knauf, 2009; Knauf, 2012; Eichhorst 2016) and case series.

Knauf and colleagues (2009) reported on a randomized controlled trial (RCT) comparing bendamustine HCL to chlorambucil as first-line treatment in individuals with CLL. The study randomly assigned 319 previously untreated participants with Binet Stage B or C (Rai Stages I-IV) CLL to bendamustine HCL (n=162) or chlorambucil (n=157). Median follow-up time was 35 months.  The proportion of participants with a complete response (CR) was significantly higher in the bendamustine group than the chlorambucil group (31% versus 2%).  Median progression-free survival (PFS) was also significantly higher with bendamustine (21.6 months) than chlorambucil (8.3 months), p<0.001. Additional data were reported by Knauf and colleagues in 2012. Overall survival did not differ significantly between groups.  However, significantly more participants in the chlorambucil group progressed to receive additional lines of treatment than in the bendamustine group (78% versus 64%, p=0.004).

Hodgkin Lymphoma, Classical:

Hodgkin lymphoma is a type of malignancy which starts in the lymphocytes, a type of white blood cell that fights infection. Hodgkin lymphoma most commonly affects people between the ages of 15 and 40 and people older than age 55. In Hodgkin lymphoma, cells in the lymphatic system grow abnormally and may spread beyond the lymphatic system. As the disease progresses, it compromises the body's ability to fight infection. Many initial signs and symptoms may be similar to those of influenza, such as fever, fatigue and night sweats. Eventually, tumors develop. Hodgkin lymphoma is distinguished by the presence of abnormal Reed-Sternberg cells with majority of cases expressing CD15 and CD30 on immunohistochemistry testing of tissue. In developed countries, classical Hodgkin lymphoma accounts for approximately 95% of all Hodgkin disease (ACS, 2017).

The NCCN CPG for Hodgkin disease (V.1.2018) includes a 2A recommendation for off-label use of bendamustine HCL as a single agent or in combination with gemcitabine and vinorelbine as a second-line or subsequent treatment option for individuals at least 18 years old with relapsed or refractory Hodgkin lymphoma (HL).  The recommendation was based on findings of an open-label phase II trial (Santoro, 2016) which evaluated bendamustine, gemcitabine and vinorelbine (BeGEV) before autologous stem-cell transplantation in individuals with relapsed or refractory HL. After 4 cycles of therapy, 43 of 59 participants (73%) achieved a CR and 6 (10%) achieved a partial response.

Non-Hodgkin Lymphoma (NHL):

There are an estimated 72,240 new cases of NHL and nearly 20,140 deaths from NHL in the United States per year (ASC, 2017). NHL is a collection of more than a dozen different cancers of the lymphatic system, which generates the body's immune defenses. This system includes a network of channels akin to blood vessels through which lymphocytes--important white blood cells of the immune system--patrol the body for invading microbes. Along these lymphatic routes in the neck, armpits, abdomen, and groin are clusters of bean-shaped lymph nodes that house platoons of the infection-fighting lymphocytes. These cells also cluster in areas that serve as gateways to the body, including the mucous membranes lining the respiratory and digestive tracts, and the skin. Lymphocytes travel in the bloodstream, as well. The lymphatic system also includes such organs as the spleen, thymus and tonsils.

According to the NCI (2017), NHL can be divided into two prognostic groups: the indolent lymphomas and the aggressive lymphomas. Indolent NHL types have a relatively good prognosis with a median survival as long as 10 years, but they usually are not curable in advanced clinical stages. Early stage (stage I and stage II) indolent NHL can be effectively treated with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology. The aggressive type of NHL has a shorter natural history, but a significant number of these individuals can be cured with intensive combination chemotherapy regimens. In general, with modern treatment of individuals with NHL, overall survival at 5 years is over 60%, and more than 50% of individuals with aggressive disease can be cured. The vast majority of relapses occur in the first 2 years after therapy. The risk of late relapse is higher in individuals with a divergent histology of both indolent and aggressive disease.

Indolent NHL is usually responsive to radiation therapy and chemotherapy. However, a continuous rate of relapse is usually seen in advanced stages. Individuals can be re-treated with considerable success as long as the disease histology remains low grade. Individuals who present with or convert to aggressive forms of NHL may have sustained complete remissions with combination chemotherapy regimens or aggressive consolidation with marrow or stem cell support (NCI, 2017).

The FDA approval of bendamustine HCL for indolent B-cell NHL was based on efficacy evaluated in a multicenter, open-label, single-arm trial of 100 participants with indolent B-cell NHL who had disease progression during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Study findings were reported by Kahl and colleagues (2010) who found an overall response rate (ORR) of 75%, of which 14% of individuals had a CR. The median duration of response was 9.2 months and the median PFS was 9.3 months. Safety was evaluated in 176 participants, the above 100 participants with an additional 76 participants with B-cell NHL who received prior rituximab.

The NCCN CPG for non-Hodgkin lymphoma (B-cell lymphoma, V.2.2018; T-cell lymphomas, V.3.2018) lists off-label use of bendamustine HCL (with or without rituximab or obinutuzumab) for individuals with both indolent and aggressive forms of NHL. The recommendations were based on both level 1 and 2A category of evidence and uniform consensus.

Multiple Myeloma:

Multiple myeloma is a systemic malignancy of plasma cells that accumulate in the bone marrow, leading to destruction of bone and failure of the bone marrow. The American Cancer Society (ACS, 2017) has estimated 30,280 new cases of multiple myeloma in the United States per year, with an estimated 12,590 deaths. The disease is staged by estimating the myeloma tumor cell mass on the basis of the amount of monoclonal (or myeloma) protein (M-protein) in the serum and/or urine along with various clinical parameters, such as the hemoglobin and serum calcium concentrations, the number of lytic bone lesions, and the presence or absence of renal failure. The stage of the disease at presentation is a strong predictor of survival, but has little influence on the choice of therapy since almost all individuals (except for those with solitary bone tumors or extramedullary plasmacytomas) have generalized disease. The age and general health of the individual, prior therapy and the presence of complications of the disease influence treatment selection. Clinical response is transitory in all cases despite achievement of complete remission and apparent eradication of disease, and multiple myeloma is considered incurable with current approaches.

Bendamustine HCL is used in individuals previously treated for myeloma with relapsed disease and in progressive or refractory disease. The NCCN CPG on multiple melanoma (V.4.2018) lists bendamustine, in combination with bortezomib and dexamethasone or with lenalidomide and dexamethasone among “other recommended regimens” for previously treated multiple myeloma. Bendamustine monotherapy is considered by NCCN to be “useful in certain circumstances.” The recommendations are based on phase I/II and phase II trials.

Waldenström's Macroglobulinemia:

Waldenström's macroglobulinemia is an indolent lymphoproliferative disease also known as Lymphoplasmacytic lymphoma. Waldenström's macroglobulinemia usually includes involvement of the bone marrow, lymph nodes, spleen, and may develop into hyperviscosity syndrome. The monoclonal serum paraprotein immunoglobulin M (IgM) gammopathy is typically associated with Waldenström's (NCI, 2017). Treatment of acute symptoms usually includes plasmapheresis; long-term management of individuals with serum viscosity of four centipoise or less is typically managed with chemotherapeutic agents.

The NCCN CPG for Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma (V.1. 2018) lists the use of bendamustine plus rituximab as a preferred regimen as primary therapy, or for previously treated disease.  Bendamustine monotherapy is among other recommended regimens for both indications.  All recommendations are category 2A. The peer-reviewed literature consists of case series and randomized, multicenter phase III trials.

Other indications:

The published peer reviewed literature regarding the off-label use of bendamustine HCL in treatment of metastatic breast cancer and SCLC is not sufficient to draw reasonable conclusions regarding the long-term clinical effectiveness and improvement on net health outcomes and safety.

The NCCN CPG on small cell lung cancer (SCLC) (V.2.2018) includes a list of medications, in order of preference, for individuals with SCLC who have relapsed within 6 months of initial treatment.  The list contains a total of 11 medications.  Bendamustine is last on the list, and is the only medication with a 2B recommendation (the others have 2A recommendations).  The NCCN guideline cites Lammers 2014, a phase II study that included 50 individuals with relapsed SCLC who were treated with bendamustine. The median time to progression (TTP) was 4.0 months and the median overall survival (OS) was 4.8 months. This study did not have a comparison or control group.

The NCCN CPG on breast cancer (V1. 2018) does not address use of bendamustine HCL.

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.

Disease-free survival (DFS): In cancer, the length of time after primary treatment for a cancer ends that the individual survives without any signs or symptoms of that cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works.

Line of therapy:

Partial response (PR): A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment; also called partial remission.

Progression-free survival (PFS): The time from random assignment in a clinical trial to disease progression.

Progressive disease (PD): Cancer that is growing, spreading, or getting worse; also called disease progression.

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

Relapsed disease: The worsening of an oncologic disease after a period of improvement or remission.

References

Peer Reviewed Publications:

  1. Eichhorst B, Fink AM, Bahlo J et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): An international, open-label, randomized, phase 3, non-inferiority trial. Lancet Oncol 2016; 17:928: 942.
  2. Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer. 2010; 116(1):106-114.
  3. Knauf WU, Lissitchkov T, Aldaoud A, et al: Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia: updated results of a randomized phase III trial. Br J Haematol. 2012; 159(1):67-77.
  4. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009; 27:4378-4384.
  5. Lammers PE, Shyr Y, Li C-I et al. Phase II study of bendamustine in relapsed chemotherapy sensitive or resistant small cell lung cancer. J Thorac Oncol 2014; 9: 559-562.
  6. Santoro A, Mazza R, Pulsoni A et al. Bendamustine in Combination With Gemcitabine and Vinorelbine Is an Effective Regimen As Induction Chemotherapy Before Autologous Stem-Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma: Final Results of a Multicenter Phase II Study. J Clin Oncol 2016; 20(34):3293-3299.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Bauer K, Rancea M, Roloff V, et al. Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2012;(11):CD008079.
  2. BENDEKA [Product information]. North Wales, PA. Teva Pharmaceuticals USA, Inc.; Revised February 2017. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208194s005lbl.pdf . Accessed on April 2, 2018.
  3. 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 3, 2018.  
    • B-Cell Lymphoma (V.2.2018). Revised February 26, 2018.
    • Breast Cancer (V.1.2018). Revised March 20, 2018.
    • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (V.5.2018). Revised March 26, 2018.  
    • Hodgkin Lymphoma (V.1.2018). Revised December 20, 2017.
    • Multiple Myeloma (V.4.2018). Revised February 12, 2018.
    • Small Cell Lung Cancer (V.2.2018). Revised January 17, 2018.
    • T-Cell Lymphomas (V.3.2018). Revised February 22, 2018.
    • Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma (V.1 2018). Revised March 7, 2018.
  4. Siegel R, Ma J, Zou A, Jemal A. Cancer Statistics 2015. CA Cancer J Clin. 2015; 65:5-29.
  5. TREANDA [Product information]. North Wales, PA. Teva Pharmaceuticals USA, Inc; Revised October 18 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022249s022lbl.pdf. Accessed on April 2, 2018.
Websites for Additional Information
  1. American Cancer Society (ACS). Leukemia: Chronic Lymphocytic. Available at: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Accessed on April 2, 2018.
  2. American Cancer Society. Types of non-Hodgkin lymphoma. Revised February 29, 2016. Available at: http://www.cancer.org/cancer/non-hodgkinlymphoma/detailedguide/non-hodgkin-lymphoma-types-of-non-hodgkin-lymphoma. Accessed on April 2, 2018.
  3. National Cancer Institute (NCI). Available at: http://www.cancer.gov/publications/pdq. Accessed on April 2, 2018.
Index

Bendamustine hydrochloride (HCL)
BENDEKA
TREANDA

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.

History

Status

Date

Action

New

05/03/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

New

05/02/2018

Hematology/Oncology Subcommittee review. Initial document development. Moved content of DRUG.00079 Bendamustine Hydrochloride to new clinical utilization management guideline document with the same title. Updated Discussion/General Information and References sections.