Aetna considers bendamustine (Bendeka, Treanda) medically necessary for the following indications (see Appendix for selection criteria):
Aetna considers bendamustine experimental and investigational for all other indications including the following (not an all-inclusive list):
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.
National Comprehensive Cancer Network's Drugs & Biologics Compendium (2015) lists adult T-cell leukemia/lymphoma, mycosis fungoides, peripheral T-cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorders, Sezary syndrome, and small cell lung cancer as recommended indications of bendamustine.
Huber et al (2015) stated that bendamustine esters proved to be considerably more potent cytotoxic agents than the parent compound against a broad panel of human cancer cell types, including hematologic and solid malignancies (e.g., malignant melanoma, colorectal carcinoma and lung cancer), which are resistant to bendamustine. Furthermore, NCCN’s clinical practice guideline on “Melanoma” (Version 3.2015) does not mention bendamustine as a therapeutic option.
Non-Follicular Indolent Non-Hodgkin Lymphomas:
In a phase II clinical trial, Luminari and colleagues (2015) determined the activity and safety of 6 cycles of bendamustine and 8 rituximab as first-line treatment of adult patients with advanced stage non-follicular indolent non-Hodgkin lymphomas (INFL). The primary end-point was the complete response rate (CRR) with expected CRR of 75 %. A total of 69 patients were enrolled; median age was 65 years (45 to 75), 65 % were male, 93 % of patients had stage IV disease. Complete and overall response rates were 48 % (95 % CI: 35.6 to 60.2), and 86 % (CI: 75.0 to 92.8). The most common grade 3/4 adverse events were neutropenia (43 %), thrombocytopenia (7 %), anemia (4 %); whereas the rate of febrile neutropenia was very low (3 %). At a median follow-up of 22 months (1 to 43 months), 2-year progression free survival (PFS) was 89 % (CI: 79 to 95), and 2-year OS was 96 % (CI: 87 to 99). The authors concluded that rituximab combination is active and well-tolerated in patients with advanced stage previously untreated INFL. These preliminary findings need to be validated by well-designed studies.
Bendamustine is considered medically necessary for the following indicaitons (based upon current guidelines from the National Comprehensive Cancer Network (NCCN, 2013)):
|CPT Codes / HCPCS Codes / ICD-10 Codes|
|Information in the [brackets] below has been added for clarification purposes.  Codes requiring a 7th character are represented by "+":|
|Other CPT codes related to the CPB:|
|96413||Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug|
|96415||Chemotherapy administration, intravenous infusion technique; each additional hour (list separately in addition to code for primary procedure)|
|HCPCS codes covered if selection criteria are met:|
|J9033||Injection, bendamustine HCL, 1 mg|
|ICD-10 codes covered if selection criteria are met:|
|C81.00 - C83.59
C83.80 - C83.99
|Lymphoma; hodgkin, follicular, non-follicular, mantle, diffuse large B-cell, lymphoblastic (diffuse)
[Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)]
|C84.A0 - C84.A9||Cutaneous T-cell lymphoma, unspecified [Diffuse Large B-Cell Lymphoma, Primary Cutaneous B-Cell Lymphoma]|
|C84.Z0 - C84.99||Other and unspecified mature T/NK-cell lymphoma [Diffuse Large B-Cell Lymphoma, Primary Cutaneous B-Cell Lymphoma]|
|C85.80 - C85.89||Other specified types of non-Hodgkin lymphoma [Diffuse Large B-Cell Lymphoma, Primary Cutaneous B-Cell Lymphoma]|
|C86.0 - C86.6||Other specified types of T/NK-cell lymphoma [Diffuse Large B-Cell Lymphoma, Primary Cutaneous B-Cell Lymphoma]|
|C88.0 - C88.9||Malignant immunoproliferative disease and certain other B-cell lymphomas|
|C90.00||Multiple myeloma not having achieved remission|
|C90.02||Multiple myeloma in relapse|
|C90.10||Plasma cell leukemia not having achieved remission [multiple myeloma]|
|C90.12||Plasma cell leukemia in relapse [multiple myeloma]|
|C90.20||Extramedullary plasmacytoma not having achieved remission|
|C90.22||Extramedullary plasmacytoma in relapse [multiple myeloma]|
|C90.30||Solitary plasmacytoma not having achieved remission|
|C90.32||Solitary plasmacytoma in relapse [multiple myeloma]|
|C91.10||Chronic lymphocytic leukemia of B-cell type not having achieved remission [Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)]|
|C91.12||Chronic lymphocytic leukemia of B-cell type in relapse [Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)]|
|ICD-10 codes not covered for indications listed in the CPB:|
|C19||Malignant neoplasm of rectosigmoid junction|
|C34.00 - C34.92||Malignant neoplasm of bronchus and lung [non-small cell and small cell lung cancer]|
|C50.011 - C50.929||Malignant neoplasm of breast|
|C76.0||Malignant neoplasm of head, face and neck|
|C79.31||Secondary malignant neoplasm of brain [solid tumor brain metastases]|
|C85.10 - C85.29, C85.90 - C85.99||Unspecified B-cell, mediastinal large B-cell, and non-Hodgkin lymphoma, unspecified|
|C91.40 - C91.42||Hairy cell leukemia|
|C92.00 - C92.02
C92.40 - C92.A2
|Acute myeloid leukemia|
|C96.4||Sarcoma of dendritic cells (accessory cells) [Langerhan's cell sarcoma]|
|D46.0 - D46.9||Myelodysplastic syndromes|
|D69.3||Immune thrombocytopenic purpura|