Aetna considers endamustine experimental and investigational for all other indications including the following (not an all-inclusive list):
Acute myeloid leukemia
Breast cancer
Brain metastases from solid tumors
Colorectal cancer
Hairy cell leukemia
Head and neck cancer
Immune thrombocytopenic purpura
Langerhans cell sarcoma
Myelodysplastic syndrome
Non-small cell lung cancer
Small cell lung cancer
Background
Bendamustine (Treanda) is a alkylatic agent used in the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphomas (NHLs). Bendamustine was approved by the U.S. Food and Drug Administration (FDA) in March 2008 for the treatment of CLL, and in October 2008, for treatment of indolent B-cell NHL that have progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.
In a dose-finding study, Koster et al (2004) determine the maximum tolerated dose (MTD) of combined carboplatin/bendamustine in previously untreated patients with extensive-stage small cell lung cancer (SCLC). Carboplatin was administered as a 1-hour infusion on day 1 at increasing dose levels, and bendamustine was administered as a short infusion on days 1 and 2 at increasing dose levels (80 to 120 mg/m(2)). The regimen was administered every 3 weeks. Four dose levels were planned, starting with 80 mg/m(2) bendamustine and carboplatin area under the curve (AUC) 5 (dose level I). The other dose levels were 100 mg/m(2) bendamustine and carboplatin AUC 5 (dose level II), 100 mg/m(2) bendamustine and carboplatin AUC 6 (dose level III), and 120 mg/m(2) bendamustine and carboplatin AUC 6 (dose level IV). A minimum of 3 patients were enrolled at each dose level. Dose-limiting toxicities (DLTs), which included fatigue, infection and tachyarrhythmia, were observed at dose level III. The recommended dose for phase II studies was therefore established at dose level II. The majority of hematological and non-hematological toxicities observed were only mild (grade 1 or 2) in patients at dose levels I and II. None of the patients developed severe alopecia. Objective responses were observed in 8 of the ten patients involved in this trial. The authors concluded that because of its acceptable toxicity and favorable preliminary anti-tumor efficacy, the combination of carboplatin and bendamustine appeared to be a potentially useful chemotherapeutic option in patients with extensive SCLC.
In a phase II study, Lammers et al (2014) determined the time to progression (TTP), response rate (RR), and toxicity for North American patients with relapsed SCLC treated with bendamustine in the 2nd- or 3rd-line setting. Patients with relapsed, histologically confirmed SCLC were eligible for enrollment on study. The study population included patients with both chemotherapy-sensitive and chemotherapy-resistant disease treated with up to 2 prior lines of chemotherapy. Patients were treated with 120 mg/m of bendamustine on days 1 and 2 of a 21-day cycle for up to 6 cycles. Primary end-point was TTP; secondary end-points included toxicity, RR, and overall survival (OS). A total of 59 patients were accrued, 50 patients met eligibility for enrollment. The median age of patients was 62, and 56 % were men; 29 patients (58 %) had chemotherapy-sensitive disease. Median TTP was 4.0 months (95 % confidence interval [CI]: 3.3 to 5.4), median OS was 4.8 months (95 % CI: 3.8 to 6.3), and the RR was 26 % (95 % CI: 13.3 % to 39.5 %). Patients with chemosensitive disease had a median TTP of 4.2 months (95 % CI: 3.3 to 6.0) compared with 3.4 months (95 % CI: 2.7 to ∞) for chemotherapy-resistant disease. The RR was 33 % (95 % CI: 14.2 % to 51.8 %) in patients with chemosensitive disease and 17 % (95 % CI: 0 % to 34.4 %) in those with chemoresistant disease. The most common grade 3/4 adverse events were fatigue (20 %), dyspnea (12 %), and anemia (12 %). The authors concluded that bendamustine has modest activity in relapsed SCLC similar to other agents evaluated in this patient population.
Burotto et al (2013) determined tolerability and for the first time explored efficacy of bendamustine-rituximab (BR) in multiply relapsed/refractory hairy cell leukemia (HCL), using 2 different dose levels of bendamustine. Patients with HCL with greater than or equal to 2 prior therapies requiring treatment received rituximab 375 mg/m(2) days 1 and 15 plus bendamustine 70 (n = 6) or 90 (n = 6) mg/m(2), days 1 and 2, for 6 cycles at 4-week intervals. At 70 and 90 mg/m(2)/dose of bendamustine, overall response rate was 100 %, with 3 (50 %) and 4 (67 %) complete remissions (CR) in each respective group. Minimal residual disease (MRD) was absent in 67 % and 100 % of CRs, respectively. All 6 without MRD remain in CR at 30 to 35 (median of 31) months of follow-up. Soluble CD22 and CD25 levels decreased with all responses, with median values decreasing from 17.7 and 42 ng/ml at baseline to undetectable and 2 ng/ml after CR, respectively (p < 0.001). Of 12 patients receiving 72 cycles of BR, the most common toxicities were hematologic, including thrombocytopenia (83 %), lymphopenia (75 %), leukopenia (58 %), and neutropenia (42 %). Grade III and IV hematologic toxicity included lymphopenia and thrombocytopenia (each 75 %), leukopenia (58 %), and neutropenia (25 %). No significant dose-related differences were detected in response or toxicity. The authors concluded that BR has significant activity in HCL. Bendamustine at either 70 or 90 mg/m(2)/dose was highly effective in multiply relapsed/refractory HCL and could be considered for achieving durable CRs without MRD in patients after failure of standard therapies. As it was not dose-limiting, 90 mg/m(2)/dose was chosen for future testing.
Pan et al (2014) performed a phase I study to evaluate the DLTs and to determine the MTD/recommended phase II dose of bendamustine with concurrent whole brain radiation (WBR) in patients with brain metastases (BM) from solid tumors. Four doses of intravenous weekly bendamustine were administered with 3 weeks of WBR at 3 dose levels (60, 80, and 100 mg/m(2)) according to a standard 3 + 3 phase I design. A total of 12 patients with solid tumor BM were enrolled in the study (6 with non-small cell lung cancer, 4 with melanoma, 1 with breast cancer, and 1 with neuroendocrine carcinoma). The first 2 dose levels had 3 patients each, and the 3rd dose level had 6 total patients. Plasma pharmacokinetic studies of bendamustine demonstrated no significant differences from pharmacokinetic characteristics of bendamustine in other studies. No DLTs were noted at any dose levels, and no grade 4 toxicities occurred. The MTD of weekly bendamustine with concurrent WBR was 100 mg/m(2). The majority of trial patients died from progressive systemic disease rather than their brain disease. The combination of weekly bendamustine with concurrent WBR was acceptably tolerated. They stated that the efficacy of this combination may be evaluated in a phase II trial with stratification by histologies.
Miyazawa et al (2014) reported the case of a 40-year old man who was diagnosed with Langerhans cell histiocytosis (LCH) in October 2010. His LCH was refractory to conventional chemotherapy, and thus worsened to Langerhans cell sarcoma (LCS) in May 2011. Although these investigators repeated combinational chemotherapies, new infiltration of the liver and bone marrow, as well as primary lesions of the bone, lymph nodes, and skin, appeared. These intensive chemotherapies caused candida liver abscesses, invasive aspergillosis, disseminated varicella zoster virus infection and bacterial sepsis. These researchers administered bendamustine for chemotherapy, which resulted in a partial response (PR) with no severe adverse events. Because of pancytopenia caused by secondary myelodysplastic syndrome, these researchers stopped the bendamustine chemotherapy after 2 courses. Partial response was maintained for 4 months. These investigators planned to perform allogeneic hematopoietic stem cell transplantation from a sibling donor after a conditioning regimen. The authors concluded that optimal therapy for adult LCH, which is a rare and treatment-resistant disease, has yet to be established; and bendamustine is a potential chemotherapeutic agent for standard treatment of LCS.
Lionberger et al (2014) performed a phase I/II clinical trial for newly-diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) patients aged greater than or equal to 50 years using a Bayesian approach to determine whether 1 of 3 doses of bendamustine (45, 60, 75 mg/m(2) days 1 to 3), together with idarubicin (12 mg/m(2) days 1 to 2), might provide a complete response (CR) rate greater than or equal to 40 % with less than 30% grade 3 to 4 non-hematological toxicity. These researchers treated 39 patients (34 AML; 5 MDS with greater than 10 % marrow blasts; median age of 73 years). None of the 3 bendamustine doses in combination with idarubicin met the required CR and toxicity rates; the 75 mg/m(2) dose because of excess toxicity (2 of 3 patients) and the 60 mg/m(2) dose because of low efficacy (CR rate 10/33), although no grade 3 to 4 non-hematological toxicity was seen at this dose. Median survival was 7.2 months. All patients began treatment as out-patients but hospitalization was required in 90 % (35/39). Although these investigators did not find a dose of bendamustine combined with idarubicin that would provide a CR rate of greater than 40 % with acceptable toxicity, bendamustine may have activity in AML/MDS patients, suggesting its addition to other regimens may be warranted.
Tsimberidou et al (2014) stated that bendamustine has shown promising results in solid tumors. An investigator-initiated phase I clinical trial of the anti-vascular endothelial growth factor (VEGF) agent bevacizumab and bendamustine was conducted in patients with advanced cancer, because the 2 drugs have different mechanisms of anti-tumor activity and non-overlapping toxicity. Patients were treated with escalating doses of intravenous bendamustine (70, 80, 90, and 100 mg/m(2); days 1 and 2) and intravenous bevacizumab (10 mg/kg; days 1 and 15). A conventional "3 + 3" study design was used. A total of 42 patients were treated: 23 women and 19 men. The median age was 60 years. Patients had received a median of 4 prior therapies (range of 1 to 10). The most common cancer types were colorectal (n = 9), head and neck (n = 8), non-small cell lung (n = 6), and breast (n = 5). Overall, 117 cycles were administered (median per patient of 2; range of 1 to 8). No dose-limiting toxicities were noted during the escalation phase. Therefore, the highest dose (level 4) of bendamustine (100 mg/m(2)) was used in the expansion phase. The most common toxicities were fatigue (n = 22), nausea (n = 14), anorexia (n = 9), and thrombocytopenia (n = 7). Of 38 patients who were evaluable for response, 23 (61 %) had stable disease, including 2 (5.2 %) who had stable disease for 6 months or more (1 with adenoid cystic carcinoma and 1 with non-small cell lung cancer [NSCLC]). This regimen of bendamustine (100 mg/m(2)) and bevacizumab (10 mg/kg) was well-tolerated and yielded disease stabilization in selected heavily pre-treated patients with advanced cancer.
Appendix
Bendamustine is considered medically necessary for the following indicaitons (based upon current guidelines from the National Comprehensive Cancer Network (NCCN, 2013)):
Classical Hodgkin Lymphoma - Second-line or salvage therapy as a single agent with or without radiation therapy prior to autologous stem cell rescue for progressive disease or for relapsed disease
Lymphocyte-predominant Hodgkin Lymphoma (LPHL) - Second-line therapy as a single agent or in combination with rituximab for symptomatic progressive or relapsed disease
Multiple myeloma - Salvage therapy on or off clinical trials for disease relapse or for progressive or refractory disease
as a single agent
in combination with lenalidomide and dexamethasone
AIDS-Related B-Cell Lymphoma - Second-line therapy with or without rituximab for relapsed disease in noncandidates for high-dose therapy
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) - Treatment for CLL without del(17p) or with or without del(11q)
as first-line therapy with or without rituximab for stage II-IV disease
with or without rituximab for relapsed or refractory disease
Diffuse Large B-Cell Lymphoma - Second-line therapy with or without rituximab for relapsed or refractory disease in noncandidates for high-dose therapy
Follicular Lymphoma - Used in patients with the indications for treatment as
first-line therapy in combination with rituximab
second-line or subsequent therapy as a single agent or in combination with rituximab
Gastric MALT Lymphoma - Used in patients with the indications for treatment as
first-line therapy in combination with rituximab
second-line therapy for recurrent or progressive disease as a single agent or in combination with rituximab
Mantle Cell Lymphoma -- Used as
less aggressive induction therapy with rituximab
second-line therapy with or without rituximab for relapsed, refractory, or progressive disease
Nongastric MALT Lymphoma - Used in patients with the indications for treatment as
first-line therapy for stage III-IV disease in combination with rituximab
second-line therapy for recurrent stage I-II disease or for progressive disease as a single agent or in combination with rituximab
Primary Cutaneous B-Cell Lymphoma
Therapy for primary cutaneous marginal zone or follicle center lymphoma as
first-line therapy for newly diagnosed generalized extracutaneous disease in combination with rituximab
second-line therapy for refractory generalized cutaneous disease or relapsed generalized extracutaneous disease as a single agent, in combination with rituximab, or as a component of BVR (bendamustine, bortezomib, and rituximab) regimen
Second-line therapy with or without rituximab for relapsed or refractory primary cutaneous diffuse large B-cell lymphoma, leg type in noncandidates for high-dose therapy
Splenic Marginal Zone Lymphoma - Used in patients with the indications for treatment as
first-line therapy in combination with rituximab for disease progression following initial treatment for splenomegaly
second-line therapy for progressive disease as a single agent or in combination with rituximab
Other lymphatic and hematopoietic neoplasms [Multiple Myeloma, Diffuse Large B-Cell Lymphoma, Gastric MALT Lymphoma, Mantle Cell Lymphoma, Nongastric MALT Lymphoma, Primary Cutaneous B-Cell Lymphoma, Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma]
The above policy is based on the following references:
Cephalon, Inc. Treanda (bendamustine hydrocyloride) for injection, for intravenous infusion. Prescribing Information. TRE-40238. North Wales, PA: Teva Pharmaceuticals, Inc.; revised August 2013.
[No authors listed]. Bendamustine (Treanda) for CLL and NHL. Med Lett Drugs Ther. 2008;50(1299):91-92.
National Comprehensive Cancer Network (NCCN). Bendamustine. NCCN Drugs and Biologics Compendium. Fort Washington, PA: NCCN; 2013.
Bendamustine. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2012.
National Cancer Institute (NCI). Chronic lymphocytic leukemia (PDQ). Health Professional Information. Bethesda, MD: NCI; 2012.
National Comprehensive Cancer Network (NCCN). Non-Hodgkins lymphomas. NCCN Clinical Practice Gudielines in Oncology, v.2.2012. Fort Washington, PA: NCCN; 2012.
Treanda. DRUGDEX System [Internet database]. Greenwood Village, CO: Thomson Micromedex; 2012.
Koster W, Stamatis G, Heider A, et al. Carboplatin in combination with bendamustine in previously untreated patients with extensive-stage small cell lung cancer (SCLC). Clin Drug Investig. 2004;24(10):611-618.
Burotto M, Stetler-Stevenson M, Arons E, et al. Bendamustine and rituximab in relapsed and refractory hairy cell leukemia. Clin Cancer Res. 2013;19(22):6313-6321.
Lammers PE, Shyr Y, Li CI, et al. Phase II study of bendamustine in relapsed chemotherapy sensitive or resistant small-cell lung cancer. J Thorac Oncol. 2014;9(4):559-562.
Pan E, Yu D, Zhao X, et al. Phase I study of bendamustine with concurrent whole brain radiation therapy in patients with brain metastases from solid tumors. J Neurooncol. 2014;119(2):413-420.
Miyazawa Y, Tahara K, Yuzuriha A, et al. Clinical experience of bendamustine for adult Langerhans cell sarcoma. Rinsho Ketsueki. 2014;55(5):563-569.
Lionberger JM, Pagel JM, Sandhu VK, et al. Outpatient bendamustine and idarubicin for upfront therapy of elderly acute myeloid leukaemia/myelodysplastic syndrome: A phase I/II study using an innovative statistical design. Br J Haematol. 2014;166(3):375-381.
Tsimberidou AM, Adamopoulos AM, Ye Y, et al. Phase I clinical trial of bendamustine and bevacizumab for patients with advanced cancer. J Natl Compr Canc Netw. 2014;12(2):194-203.
George JN, Arnold DM. Immune thrombocytopenia (ITP) in adults: Second- and third-line therapies. UpToDate Inc., Waltham, MA. Last reviewed August 2014.
Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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