Medical Policy



Subject: Bendamustine Hydrochloride
Document #: DRUG.00079 Current Effective Date:    06/28/2017
Status: Revised Last Review Date:    05/04/2017

Description/Scope

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 used for intravenous administration in the treatment of oncologic conditions.

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

Position Statement

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.

Investigational and Not Medically Necessary:

Bendamustine HCL is considered investigational and 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).
Rationale

Chronic lymphocytic leukemia (CLL):

Bendamustine HCL is an intravenously administered alkylating agent with 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), for use as a first-line therapy for individuals with CLL. Bendamustine HCL (BENDEKA) is a low-volume preparation with short infusion time, replacing TREANDA after March 31, 2016, at which time TREANDA will be discontinued from the market. The FDA approved TREANDA and BENDEKA based on the same pivotal trials.

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 FDA evaluated the safety and efficacy of bendamustine HCL in an open-label, randomized, controlled multicenter trial comparing bendamustine HCL to chlorambucil as first-line treatment in individuals with CLL. The study randomly assigned 301 previously untreated participants with Binet Stage B or C (Rai Stages I-IV) CLL to bendamustine HCL (n=153) or chlorambucil (n=148). The populations in both groups were balanced. The reported overall response rate (ORR) was significantly higher in the bendamustine HCL group (59%) compared to those treated with chlorambucil (26%) (p<0.0001) with 8% versus < 1% complete response (CR) rate. The median progression-free survival (PFS) was 18 months for bendamustine HCL compared to 6 months for chlorambucil.

The National Comprehensive Cancer Network® (NCCN) Clinical Practice Guideline (CPG) in Oncology (NCCN Guidelines® , 2017) lists off-label use of bendamustine HCL with or without rituximab in the treatment of CLL without del (11q) or del (17p) as first-line therapy or for treatment of relapsed or refractory disease. The recommendations are based on 2A category of evidence with uniform consensus. The peer reviewed literature consists of case series and randomized controlled trials.

Hodgkin Lymphoma, Classical: 

The National Comprehensive Cancer Network® (NCCN) Drugs and Biologics Compendium ™ and the NCCN CPG for Hodgkin disease (2017) includes a 2A recommendation for off-label use of bendamustine HCL for relapsed or refractory Hodgkin lymphoma (HL). Based on preliminary results from a phase II trial, bendamustine:

Was well tolerated and highly active in heavily pre-treated patients (including those who have failed HDT/ASCR) with relapsed or refractory disease, resulting in an ORR of 56% among evaluable patients (34 out of 36 patients enrolled). The ORR by intent-to-treat analysis was 53% (33% CR and 19% PR). The median response duration was 5 months.

Non-Hodgkin Lymphoma (NHL):

In October 2008 the FDA approved the expanded use of bendamustine HCL (TREANDA), and in December (2015) the FDA approved BENDEKA for the treatment of individuals with indolent B-cell NHL that progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Throughout the years, the methods to classify the various types of lymphomas have been modified as technology and understanding of the role of genetics and immunology have increased. The historical table of classifying NHL by the International Working Formulation (IWF) had been updated by the Revised European American Lymphoma (REAL) classification. Subsequently, the classification has been updated as a result of collaboration between the European and American hematology and pathology societies and the World Health Organization (WHO). For clinical utility, NHL can also be divided into indolent or aggressive lymphomas (NCI, 2017). The use of a particular classification is based on the practitioner's preference. A widely utilized tool as a prognostic indicator for NHL is the International Prognostic Indicator. The index was developed based on clinical characteristics to predict the outcome of aggressive NHL.

Individuals with indolent lymphoma may experience a relapse with a more aggressive histology. Documentation of conversion to a more aggressive histology requires an appropriate change to a therapy applicable to that histologic type. Histologic conversions or transformations are typically treated with the regimens prescribed for aggressive NHL (NCI, 2017).

Modified REAL Classification of Lymphoproliferative Diseases (NCI, 2017): 
Non-Hodgkin 
Indolent lymphoma/leukemia 

  1. Follicular lymphoma (follicular small cleaved cell [grade 1], follicular mixed small cleaved and large cell [grade 2], diffuse small cleaved cell)
  2. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
  3. Lymphoplasmacytic lymphoma (Waldenström's macroglobulinemia)
  4. Extranodal marginal zone B-cell lymphoma (MALT lymphoma)
  5. Nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma)
  6. Splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes)
  7. Hairy cell leukemia
  8. Mycosis fungoides/Sézary syndrome
  9. T-cell granular lymphocytic leukemia
  10. Primary cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis (CD30+)
  11. Nodular lymphocyte predominant Hodgkin lymphoma

Aggressive lymphoma/leukemia 

  1. Diffuse large cell lymphoma (includes diffuse mixed cell, diffuse large cell, immunoblastic, T-cell rich large B-cell lymphoma)
    1. Mediastinal large B-cell lymphoma
    2. Follicular large cell lymphoma (grade 3)
    3. Anaplastic large cell lymphoma (CD30+)
    4. Extranodal NK/T-cell lymphoma, nasal type/aggressive NK-cell leukemia/blastic NK-cell lymphoma
    5. Lymphomatoid granulomatosis (angiocentric pulmonary B-cell lymphoma)
    6. Angioimmunoblastic T-cell lymphoma
    7. Peripheral T-cell lymphoma, unspecified
      1. Subcutaneous panniculitis-like T-cell lymphoma
      2. Hepatosplenic T-cell lymphoma
    8. Enteropathy-type T-cell lymphoma
    9. Intravascular large B-cell lymphoma
  2. Burkitt's lymphoma/Burkitt's cell leukemia/Burkitt's-like lymphoma
  3. Precursor B- or T-cell lymphoblastic lymphoma/leukemia
  4. Primary central nervous system (CNS) lymphoma
  5. Adult T-cell leukemia/lymphoma (HTLV 1+)
  6. Mantle cell lymphoma
  7. Posttransplantation lymphoproliferative disorder (PTLD)
  8. AIDS-related lymphoma
  9. True histiocytic lymphoma
  10. Primary effusion lymphoma
  11. B- or T-cell prolymphocytic leukemia
  12. Plasmablastic lymphoma

The FDA expanded approval of bendamustine HCL was based on efficacy evaluated in a multicenter, open-label, single-arm trial of 100 participants with indolent B-cell NHL that had disease progression during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Study findings reported by Kahl and colleagues (2010) found "an ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and 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. According to the FDA news:

The most frequently reported non-hematologic adverse reactions reported were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most frequently reported abnormal hematologic laboratory values were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%).

Grade 3 or 4 adverse reactions were reported in 71% of combined safety populations. The most frequently reported non-hematologic Grade 3 or 4 adverse reactions were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration (each reported in 5% of patients). The most frequently reported grade 3 or 4 hematologic laboratory abnormalities were lymphocytopenia (94%), neutropenia (60%), leukopenia (56%), thrombocytopenia (25%), and anemia (11%).

The NCCN Drugs and Biologics Compendium and the NCCN CPG for non-Hodgkin lymphoma (B-cell lymphoma, 2017; T-cell lymphomas, 2017) 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. The panel reported that bendamustine HCL:

Has shown promising results with acceptable toxicity in patients newly diagnosed as well as heavily pretreated relapsed or refractory indolent or mantle cell histologies or transformed NHL.

Multiple myeloma:

Bendamustine HCL is used in individuals previously treated for myeloma with relapsed disease and in progressive or refractory disease. The NCCN panel, for their practice guideline for multiple myeloma (2016), evaluated use of bendamustine HCL for the treatment option of relapsed/refractory multiple myeloma; the NCCN panel offers a 2A recommendation based on committee consensus, data from two case series and the outcomes of a phase I/II trial. In individuals treated with bendamustine alone:

The ORR was 55%, with a median PFS of 26 weeks for all patients and 36 weeks for patients who received higher doses of bendamustine (90-100mg/m2 ). Toxicity was mild and mainly hematologic. A retrospective analysis of 39 patients reported that bendamustine is effective and tolerable in patients with advanced progressive MM, with an ORR or 36%.

A multicenter phase I/II trial investigated the combination of bendamustine, lenalidomide, and dexamethasone as treatment for patients (n=29) with relapsed MM. PR rate was seen in 52% (n=13) of patients, with VGPR in 24% (n=6) of patients. The median PFS in the trial was 6.1 months (95% CI, 3.7-9.4 months), and the one-year PFS rate was 20% (95% CI, 6%-41%).

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.

In an interim update, the  NCCN CPG for Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma (2017) lists the off-label use of bendamustine HCL with or without rituximab as primary therapy, or for use in disease unresponsive to primary therapy or progressive or relapsed disease. These recommendations were based on a 2A category of evidence and uniform consensus. The peer-reviewed literature consists of case series and randomized, multicenter phase III trials.

Other indications:

The updated NCCN CPG in oncology (2017) on small cell lung cancer (SCLC) provides a Category 2B recommendation for bendamustine HCL as subsequent therapy for relapsed SCLC.

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. Currently there are ongoing clinical trials investigating the use of bendamustine HCL as a treatment option for these conditions.

Background/Overview

Chronic lymphocytic leukemia (CLL):

According to the NCI (2017), an estimated 20,110 individuals will be diagnosed with CLL in the U.S., and nearly 4660 deaths will occur in 2017. The American Cancer Society (ACS, 2017) indicates more than one-third of all new cases of leukemia are CLL, mainly affecting older adults.

CLL is a related type of indolent NHL characterized by a clonal proliferation of mature B lymphocytes and blood and bone marrow involvement.CLL is often characterized by infectious or autoimmune complications, enlarged lymph nodes, liver, and spleen, increased lymphocyte count, and impaired hematopoiesis (Bauer, 2012). The clinical course and prognosis of CLL is highly variable, with some individuals experiencing no to minimal symptoms for many years with normal life expectancy, while others are immediately symptomatic at diagnosis or soon thereafter (Wierda, 2010).

Hodgkin Lymphoma:

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).

Non-Hodgkin Lymphoma (NHL):

In 2017 an estimated 72,240 new cases of NHL will be diagnosed and nearly 20,140 deaths estimated in the United States (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).

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 in 2017, 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 (BENDEKA) 2017 FDA product Information label includes the following warnings and precautions:

Myelosuppression: Delay or reduce dose. Restart treatment based on ANC and platelet count recovery. Complications of myelosuppression may lead to death.

Infections: Monitor for fever another signs of infection and treat promptly.

Anaphylaxis and Infusion Reactions: Severe anaphylactic reactions have occurred. Monitor clinically and discontinue drug for severe reactions. Premedicate in subsequent cycles for milder reactions.

Tumor Lysis Syndrome: May lead to acute renal failure and death; anticipate and use supportive measures in patients at high risk.

Skin reactions: Discontinue for severe skin reactions. Cases of SJS and TEN, some fatal have been reported when bendamustine hydrochloride was administered concomitantly with allopurinol and other medications known to cause these syndromes.

Hepatotoxicity: Monitor liver chemistry tests prior to and during treatment.

Other malignancies: Pre-malignant and malignant diseases have been reported.

Extravasation: Take precautions to avoid extravasation, including monitoring intravenous infusion site during and after administration.

Embryo-fetal toxicity: Fetal harm can occur when administered to a pregnant woman. Women should be advised to avoid becoming pregnant when receiving bendamustine hydrochloride.

Information for use in specific populations includes:

Renal impairment: Do not use if CrCL is <40 mL/min. Use with caution in lesser degrees of renal impairment.

Hepatic impairment: Do not use in moderate or severe hepatic impairment. Use with caution in mild hepatic impairment.

Bendamustine HCL (TREANDA) 2016 FDA product Information label includes the following warnings and precautions:

Myelosuppression: Delay or reduce dose. Restart treatment based on ANC and platelet count recovery. Complications of myelosuppression may lead to death.

Infections: monitor for fever and other signs of infection and treat properly.

Anaphylaxis and Infusion Reactions: Severe and anaphylactic reactions have occurred; monitor clinically and discontinue TREANDA. Pre-medicate in subsequent cycles for milder reactions.

Tumor Lysis Syndrome: Acute renal failure and death: anticipate and use supportive measures.

Skin Reactions: Discontinue for severe skin reactions. Cases of SJS and TEN, some fatal, have been reported when TREANDA and administered concomitantly with allopurinol and other medications known to cause these syndromes.

Other Malignancies: Pre-malignant and malignant diseases have been reported.

Extravasation: Assure good venous access and monitor infusion site during and after administration.

Embryo-fetal toxicity: Fetal harm can occur when administered to a pregnant woman. Women should be advised to avoid becoming pregnant when receiving TREANDA.

Information for use in specific populations includes:

Renal impairment: No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild or moderate renal impairment. TREANDA should not be used in patients with CrCL < 40mL/min.

Hepatic impairment: No formal studies assessing the impact of hepatic impairment on the pharmacokinetics and bendamustine have been conducted. TREANDA should be used with caution in patients with mild hepatic impairment. TREANDA should not be used in patients with moderate (AST or ALT 2.5-10 X ULN and total bilirubin 1.5-3 X ULN) or severe (total bilirubin > 3 X ULN) hepatic impairment.

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.

Coding

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

When services are Medically Necessary:

HCPCS    
J9033 Injection, bendamustine HCL (Treanda), 1 mg  
J9034 Injection, bendamustine HCL (Bendeka), 1 mg  
     
ICD-10 Diagnosis  
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]
C91.10-C91.12 Chronic lymphocytic leukemia of B-cell type
C91.50-C91.52 Adult T-cell lymphoma/leukemia (HTLV-1 associated)

When services may be Medically Necessary when criteria are met:
For the procedure codes listed above for the following diagnoses:

ICD-10 Diagnosis  
C81.10-C81.99 Classical/unspecified Hodgkin lymphoma
C90.00-C90.32 Multiple myeloma and malignant plasma cell neoplasms

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Cortelezzi A, Sciumè M, Liberati AM, et al. Bendamustine in combination with ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA Multicenter Phase II Trial. Leukemia. 2014; 28(3):642-648.
  2. Damaj G, Gressin R, Bouabdallah K, et al. Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphoma: the BENTLY trial. J Clin Oncol. 2013; 31:104-110.
  3. Dennie TW, Kolesar JM. Bendamustine for treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B-cell non-Hodgkin lymphoma. Clin Ther. 2009; 31(2):2290-2311.
  4. Flinn IW, van der Jaqt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014; 123(19):2944-2952.
  5. Friedberg JW, Cohen P, Chen L, et al. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results form a phase II multicenter, single-agent study. J Clin Oncol. 2008; 26(2):204-210.
  6. Friedberg JW, Neuberg D, Gribben JG, et al. Autologous bone marrow transplantation after histologic transformation of indolent B cell malignancies. Biol Blood Marrow Transplant. 1999; 5:262-268.
  7. 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.
  8. 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.
  9. 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.
  10. Knop S, Straka C, Haen M, et al. The efficacy and toxicity of bendamustine in recurrent multiple myeloma after high-dose chemotherapy. Haematologica. 2005; 90:1287-1288.
  11. Lammers PE, Shyr Y, Li CL, et al. Phase II study of bendamustine in relapsed chemotherapy sensitive or resistant small-cell lung cancer. J Thorac Oncol. 2014; 9:559-562.
  12. Moskowitz AJ, Hamlin PA, Perales MA, et al. Phase II study of bendamustine in relapsed or refractory Hodgkin lymphoma. J Clin Oncol. 2013; 31:456-460.
  13. Ohmachi K, Niitsu N, Uchida T, et al. Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2013; 31:2103-2109.
  14. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment in patients with indolent and mantle-cell lymphomas: an open-label, multicenter, randomized, phase 3 non-inferiority trial. Lancet. 2013; 381:1203-1210.
  15. Treon SP, Hanzis C, Tripsas C, et al. Bendamustine therapy in patients with relapsed or refractory Waldenström's macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2011; 11(1):133-135.
  16. Ujjani C, Ramzi P, Gehan E, et al. Ofatumumab and bendamustine in previously treated chronic lymphocytic leukemia and small lymphocytic lymphoma. Leuk Lymphoma. 2015; 56(4):915-920.
  17. Vacirca JL, Acs Pl, Tabbara IA, et al. Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Ann Hematol. 2014; 93:403-409.
  18. Wierda WG, Kipps TJ, Durig J, et al. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood. 2011; 117(24):6450-6458.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Arbeitsgemeinschaft medikamentoese Tumortherapie. Capecitabine + bendamustine in women with pretreated locally advanced or metastatic Her2-negative breast cancer (MBC-6). NLM Identifier: NCT01891227. Reviewed December 22, 2016. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01891227?term=bendamustine+AND+breast+cancer&rank=2 . Accessed on March 14, 2017.
  2. 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.
  3. Bendamustine Hydrochloride. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated November 29, 2016. Available at: http://www.micromedexsolutions.com. Accessed on March 14, 2017.
  4. Bendamustine Hydrochloride. Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ). Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised June 29, 2016. Accessed on March 14, 2017.
  5. 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 March 14, 2017.
  6. National Cancer Institute. Randomized phase II trial of rituximab with either pentostatin or bendamustine for multiply relapsed or refractory hairy cell leukemia. NLM Identifier: NCT01059786. Updated January 24, 2017. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01059786?term=bendamustine+and+hairy+cell+leukemia&rank=1 . Accessed on March 14, 2017.
  7. National Comprehensive Cancer Network® . NCCN® Drugs & Biologic Compendium™ (electronic version). For additional information visit the NCCN website: http://www.nccn.org/index/asp. Accessed on March 27, 2017.
  8. NCCN Clinical Practice Guidelines in Oncology® . © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on March 14, 2017.
    • B-Cell Lymphoma (V.3.2017). March 27, 2017.
    • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (V.2.2017). February 21, 2017.
    • Hodgkin Lymphoma (V.1.2017). March 1, 2017.
    • Multiple Myeloma (V.3.2017). November 28, 2016.
    • Small Cell Lung Cancer (V.3.2017). February 23, 2017.
    • T-Cell Lymphomas (V.2.2017). February 21, 2017.
    • Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma (V.1 2017). January 31, 2017.
  9. Siegel R, Ma J, Zou A, Jemal A. Cancer Statistics 2015. CA Cancer J Clin. 2015; 65:5-29.
  10. TREANDA [Product information]. North Whales, PA. Teva Pharmaceuticals USA, Inc; Revised October 18 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022249s022lbl.pdf. Accessed on March 14, 2017.
  11. Vidal L, Garter-Gvili A, Gurion R, et al. Bendamustine for patients with indolent B cell lymphoid malignancies including chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2012;(9):CD009045.
Websites for Additional Information
  1. American Cancer Society. Cancer facts and figures 2017. Available at: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html . Accessed on March 14, 2017.
  2. American Cancer Society (ACS). Leukemia: Chronic Lymphocytic. Available at: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Accessed on March 14, 2017.
  3. 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 March 14, 2017.
  4. National Cancer Institute (NCI). Available at: http://www.cancer.gov/publications/pdq. Accessed on March 14, 2017.
    • Adult Hodgkin Lymphoma Treatment (PDQ® ). Last modified January 27, 2017.
    • Adult Non-Hodgkin's Lymphoma Treatment (PDQ). Last modified January 26, 2017.
    • Chronic Lymphocytic Leukemia Treatment (PDQ). Last modified January 20, 2017.
    • Plasma Cell Neoplasms (including Multiple Myeloma) (PDQ) Treatment. Last modified February 3, 2017.
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.

Document History
Status Date Action
Revised 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Revised 05/03/2017 Hematology/Oncology Subcommittee review. Added nodal marginal zone lymphoma and peripheral T-cell lymphoma to the list of examples of NHL considered Medically Necessary. Updated formatting in Position Statement section. Updated Description, Rationale, Background, References, and Websites sections.
  01/01/2017 Updated Coding section with 01/01/2017 HCPCS changes.
Reviewed 05/05/2016 MPTAC review.
Reviewed 05/04/2016 Hematology/Oncology Subcommittee review. Title revised to Bendamustine Hydrochloride. Updated Description, Rationale, Background, References, Websites and Index sections.
New 11/05/2015 MPTAC review.
New 11/04/2015 Hematology/Oncology Subcommittee review. Initial document development.