Bendamustine

Number: 0875

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

---

Policy

Note: Requires Precertification:

Precertification of bendamustine (Belrapzo, Bendeka, and Treanda) is required of all Aetna participating providers and members in applicable plan designs. For precertification of bendamustine (Belrapzo, Bendeka, and Treanda), call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (888) 267-3277.

1. Criteria for Initial Approval

   Aetna considers bendamustine (Belrapzo, Bendeka, Treanda) medically necessary for the following indications:

   1. B-cell lymphoma

      For treatment of B-cell lymphomas with any of the following subtypes:

      1. AIDS-related B-cell lymphoma (AIDS-related diffuse large B-cell lymphoma, primary effusion lymphoma, and human herpesvirus-8 (HHV8)-positive diffuse large B-cell lymphoma) when all of the following criteria are met:

         1. The requested drug is used as subsequent therapy; and
         2. The member is not a candidate for transplant or the requested drug will be used as a bridging option until CAR T-cell product is available; or

      2. Diffuse large B-cell lymphoma (DLBCL) when all of the following criteria are met:

         1. The requested drug is used as subsequent therapy; and
         2. The requested drug is used in combination with polatuzumab vedotin-piiq with or without rituximab; and
         3. The member is not a candidate for transplant or the requested drug will be used as a bridging option until CAR T-cell product is available; or
            
      3. Follicular lymphoma; or
      4. High-grade B-cell lymphoma when all of the following criteria are met:
         
         
         1. The requested drug is used as subsequent therapy; and
         2. The requested drug will be used in any of the following regimens:
            
            
            1. As a single agent; or
            2. In combination with rituximab; or
            3. In combination with polatuzumab vedotin-piiq with or without rituximab; and

         3. The member is not a candidate for transplant or the requested drug will be used as a bridging option until CAR T-cell product is available; or

      5. Histologic transformation of indolent lymphomas to diffuse large B-cell lymphoma when all of the following criteria are met:

         1. The requested drug is used in combination with polatuzumab vedotin-piiq with or without rituximab; and
         2. The requested drug is used as subsequent therapy; and
         3. The member is not a candidate for transplant; or

      6. Mantle cell lymphoma (MCL) when either of the following criteria are met:

         1. The requested drug is used in combination with rituximab; or
         2. The requested drug in used as a component of RBAC500 (rituximab, bendamustine, and cytarabine); or

      7. Marginal zone lymphoma:

         1. Nodal marginal zone lymphoma when used in combination with rituximab or obinutuzumab; 
         2. Gastric MALT lymphoma when used in combination with rituximab or obinutuzumab; 
         3. Nongastric MALT lymphoma when used in combination with rituximab or obinutuzumab; 
         4. Splenic marginal zone lymphoma when used in combination with rituximab or obinutuzumab; or

      8. Post-transplant lymphoproliferative disorders when all of the following criteria are met:

         1. The requested drug is used as subsequent therapy; and
         2. The member is not a candidate for transplant or the requested drug will be used as a bridging option until CAR T-cell product is available; and
         3. The requested drug is used in any of the following regimens:
            
            
            1. As a single agent; or
            2. In combination with rituximab; or 
            3. In combination with polatuzimab vedotin-piiq with or without rituximab;

   2. T-cell lymphoma

      For treatment of T-cell lymphomas with any of the following subtypes:

      1. Adult T-cell leukemia/lymphoma (ATLL) when all of the following criteria are met:

         1. The requested drug is used as a single agent; and
         2. The requested drug is used as subsequent therapy; or

      2. Hepatosplenic T-Cell lymphoma when all of the following criteria are met:

         1. The requested drug is used as a single agent; and
         2. The requested drug is used for refractory disease after 2 first-line therapy regimens; or

      3. Peripheral T-cell lymphoma (PTCL) [including the following subtypes: anaplastic large cell lymphoma, peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, enteropathy associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, nodal peripheral T-cell lymphoma with TFH phenotype, or follicular T-cell lymphoma] when all of the following criteria are met:

         1. The requested drug is used as a single agent; and
         2. The requested drug is used as palliative or subsequent therapy; or

      4. Breast implant associated anaplastic large cell lymphoma (ALCL) when all of the following are met:

         1. The requested drug is used as a single agent; and
         2. The requested drug is used as subsequent therapy;

   3. Chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL)

      For treatment of CLL/SLL without chromosome 17p deletion or TP53 mutation;

   4. Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma

      For treatment of Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma when either of the following criteria are met:

      1. The requested drug will be used in combination with rituximab; or
      2. The requested drug will be used as a single agent;

   5. Multiple myeloma (MM)

      For treatment of MM when all of the following criteria are met:

      1. The disease is relapsed or progressive; and 
      2. The requested drug will be used in any of the following regimens:
         1. In combination with lenalidomide and dexamethasone, or
         2. In combination with bortezomib and dexamethasone, or
         3. As a single agent;

   6. Classical Hodgkin lymphoma (cHL)

      For treatment of cHL when all of the following criteria are met:

      1. The requested drug will be used as subsequent therapy or palliative therapy, and
      2. The requested drug will be used in any of the following regimens:
         
         
         1. In combination with brentuximab vedotin, or
         2. In combination with gemcitabine and vinorelbine, or
         3. In combination with carboplatin and etoposide; or
         4. As a single agent;

   7. Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)

      For treatment of nodular lymphocyte predominant Hodgkin lymphoma when all of the following criteria are met:

      1. The requested drug will be used as subsequent therapy; and
      2. The requested drug will be used in combination with rituximab;

   8. Systemic light chain amyloidosis

      For treatment of systemic light chain amyloidosis when both of the following criteria are met:

      1. The requested drug will be used in combination with dexamethasone; and
      2. The requested drug will be used to treat relapsed or refractory disease;

   9. Hematopoietic Cell Transplantation

      For use in hematopoietic cell transplantation when both of the following criteria are met:

      1. The requested drug will be used as conditioning for autologous transplant; and
      2. The requested drug will be used in combination with etoposide, cytarabine and melphalan.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of bendamustine (Belrapzo, Bendeka, Treanda) therapy medically necessary for members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Bendamustine is available as:

• Treanda for injection 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution or 45 mg/0.5 mL  or 180 mg/2 mL (90 mg/mL) in a single-dose vial
• Bendeka for injection 100 mg/4mL (25 mg/mL) in a multiple-dose vial
• Belrapzo for injection 100 mg/4mL (25 mg/mL) as a ready to dilute solution in a multiple-dose vial.

Chronic Lymphocytic Leukemia (CLL)

• 100 mg/m² infused intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles

B-cell Non-Hodgkin Lymphoma (NHL)

• 120 mg/m² infused intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles

Source: Teva Pharmaceuticals, 2021; Eagle, 2021

Experimental and Investigational

Aetna considers bendamustine experimental and investigational for all other indications including the following (not an all-inclusive list):

• Acute myeloid leukemia
• Anaplastic glioma
• Blastic plasmacytoid dendritic cell leukemia
• Breast cancer
• Colorectal cancer
• Hairy cell leukemia
• Head and neck cancer
• Immune thrombocytopenic purpura
• Langerhans cell sarcoma
• Melanoma
• Myelodysplastic syndrome
• Non-small cell lung cancer
• Primary central nervous system (CNS) lymphoma
• Small cell lung cancer
• Systemic light-chain (AL) amyloidosis.

---

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
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:
0537T	Chimeric antigen receptor T-cell (CAR-T) therapy; harvesting of blood-derived T lymphocytes for development of genetically modified autologous CAR-T cells, per day
0538T	preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage)
0539T	receipt and preparation of CAR-T cells for administration
0540T	CAR-T cell administration, autologous
38204 - 38215	Bone marrow or stem cell services/procedures
38241	Hematopoietic progenitor cell (HPC); autologous transplantation
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 (Treanda), 1 mg
J9034	Injection, bendamustine HCl (Bendeka), 1 mg
J9036	Injection, bendamustine hydrochloride, (Belrapzo/bendamustine), 1 mg
Other HCPCS codes related to the CPB:
J8560	Etoposide; oral, 50 mg
J9042	Injection, brentuximab vedotin, 1 mg
J9045	Injection, carboplatin, 50 mg
J9098	Injection, cytarabine liposome, 10 mg
J9100	Injection, cytarabine, 100 mg
J9181	Injection, etoposide, 10 mg
J9201	Injection, gemcitabine HCl, 200 mg
J9301	Injection, obinutuzumab, 10 mg
J9302	Injection, ofatumumab, 10 mg
J9309	Injection, polatuzumab vedotin-piiq, 1 mg
J9312	Injection, rituximab, 10 mg
J9390	Injection, vinorelbine tartrate, 10 mg
ICD-10 codes covered if selection criteria are met:
C81.00 - C83.59 C83.80 - C83.99	Lymphoma; Hodgkin [Classic Hodgkin’s lymphoma], follicular, non-follicular, mantle, diffuse large B-cell, lymphoblastic (diffuse), splenic marginal zone lymphoma [Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)]
C84.40 - C84.49	Peripheral T-cell lymphoma, not otherwise specified
C84.60 - C84.79	Anaplastic large cell lymphoma
C84.Z0 - C84.99	Other and unspecified mature T/NK-cell lymphoma [Diffuse Large B-Cell Lymphoma]
C85.10 - C85.19	Unspecified B-cell lymphoma [high-grade B-cell lymphoma, AIDS-related B-cell lymphoma]
C85.80 - C85.89	Other specified types of non-Hodgkin lymphoma [Diffuse Large B-Cell Lymphoma]
C86.0 - C86.5	Other specified types of T/NK-cell lymphoma [Diffuse Large B-Cell Lymphoma]
C88.0 - C88.9	Malignant immunoproliferative disease and certain other B-cell lymphomas [gastric/non gastric MALT lymphoma, Waldenstrom’s macroglobulinemia/lymphoplasmacytic lymphoma]
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)]
C91.11	Chronic lymphocytic leukemia of B-cell type in 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)]
C91.50 - C91.52	Adult T-cell lymphoma/leukemia (HTLV-1-associated)
D47.Z1	Post-transplant lymphoproliferative disorder (PTLD)
D47.Z2	Castleman's disease
E85.81	Light chain (AL) amyloidosis
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 [small cell and non-small cell lung cancer]
C50.011 - C50.929	Malignant neoplasm of breast
C72.9	Malignant neoplasm of central nervous system, unspecified [Primary central nervous system (CNS) lymphoma]
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

---

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Chronic lymphocytic leukemia (CLL)
• Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen

Compendial Uses

• Classical Hodgkin lymphoma (cHL)
• Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)
• Multiple myeloma (MM)
• CLL/small lymphocytic lymphoma (SLL)
• B-cell lymphomas:
  
  
  • Acquired immune deficiency syndrome (AIDS)-related B-cell lymphoma
  • Diffuse large B-cell lymphoma (DLBCL)
  • Follicular lymphoma
  • High grade B-cell lymphoma
  • Histologic transformation of indolent lymphomas to diffuse large B-cell lymphoma
  • Marginal zone lymphoma
    
    
    • Nodal marginal zone lymphoma
    • Gastric mucosa associated lymphoid tissue (MALT) lymphoma
    • Nongastric MALT lymphoma
    • Splenic marginal zone lymphoma
      
      
  • Mantle cell lymphoma (MCL)
  • Post-transplant lymphoproliferative disorders
    
    

• T-cell lymphomas:

  • Adult T-cell leukemia/lymphoma (ATLL)
  • Hepatosplenic T-Cell lymphoma
  • Peripheral T-cell lymphoma (PTCL)
  • Breast implant associated anaplastic large cell lymphoma (ALCL)
    
    
• Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma
• Systemic light chain amyloidosis
• Hematopoietic cell transplantation

Bendamustine is available as Belrapzo (Eagle Pharmaceuticals, Inc.), Bendeka (Teva Pharmaceuticals USA, Inc.), and Treanda (Teva Pharmaceuticals USA, Inc.) and is a bifunctional mechlorethamine derivative. Mechlorethamine and its derivatives dissociate into electrophilic alkyl groups. These groups form covalent bonds with electron‐rich nucleophilic moieties. The bifunctional covalent linkage can lead to cell death via several pathways. Bendamustine is active against both quiescent and dividing cells. The nitrogen mustard alkylating activity of bendamustine may be related to crosslinking of DNA single and double strands. The benzimidazole ring may also have purine and amino acid antagonist activity, although the contribution of this effect to antitumor effects has not been clearly demonstrated. The exact mechanism of action of bendamustine, however, remains unknown.

Bendamustine is a alkylating agent used in the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphomas (NHLs).  Bendamustine (Treanda, Teva Pharmaceuticals USA, Inc.) 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. Efficacy relative to first line CLL therapies (other than chlorambucil) has not been established.

Per the prescribing information, bendamustine (Belrapzo, Bendeka, and Treanda) carries the following warnings and precautions:

• Myelosuppression
• Infections
• Anaphylaxis and infusion reactions
• Tumor lysis syndrome
• Skin reactions
• Hepatotoxicity
• Other malignancies
• Extravasation injury
• Embryo-fetal toxicity.

The most common non-hematologic adverse reactions for CLL (frequency ≥ 15%) are pyrexia, nausea, and vomiting; for NHL (frequency ≥ 15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia (Teva Pharmaceuticals, 2019; 2020; Eagle 2020).

Per the prescribing information, bendamustine (Belrapzo, Bendeka, and Treanda) are contraindicated in patients with a history of a hypersensitivity reaction to bendamustine. Additionally, bendamustine (Belrapzo and Bendeka) are contraindicated in patients with a history of a hypersensitivity reaction to polyethylene glycol 400, propylene glycol, or monothioglycerol. 

On May 15, 2018, the FDA approved Belrapzo (Eagle Pharmaceuticals, Inc.) ready-to-dilute (RTD) bendamustine hydrochloride (HCl) solution in a 500 mL admixture for the treatment of patients with chronic lymphocytic leukemia (CLL) and patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Eagle’s bendamustine HCl injection does not require reconstitution and is administered as a 500 mL admixture over 30 or 60 minutes. The approval of Belrapzo was based on the clinical studies previously conducted in Bendeka (Teva Pharmaceuticals USA, Inc.). 

Anaplastic Gliomas

Chamberlain and colleagues (2017) stated that there is no standard therapy for recurrent anaplastic glioma (AG).  Salvage therapies include alkylator-based chemotherapy, re-resection with or without carmustine implants, re-irradiation and bevacizumab.  Bendamustine is a novel bi-functional alkylator with central nervous system (CNS) penetration never previously evaluated in AG.  In a phase II clinical  trial, these researchers evaluated response and toxicity of bendamustine in patients with recurrent AG.  Adults with radiation and temozolomide refractory recurrent AG were treated with bendamustine.  A cycle of bendamustine was defined as 2 consecutive days of treatment (100 mg/m2/day) administered once every 4 weeks. Success of treatment was defined as PFS at 6 months of 40 % or better; 26 adults [16 men; 10 women: median age of 40 years (range of 30 to 65)] were treated, 12 at 1st recurrence and 17 at 2nd recurrence.  Prior salvage therapy included re-resection (n = 14), chemotherapy (n = 11) and re-radiation (n = 2).  Grade 3 treatment-related toxicities included lymphopenia (11 patients; grade-IV in 3), myalgia, pneumonia, diarrhea, leukopenia, allergic reaction and thrombocytopenia in 1 patient each; 1 patient discontinued therapy due to toxicity.  There were 5 instances of bendamustine dose delays all due to lymphopenia.  There were no dose reductions due to toxicity.  The median number of cycles of therapy was 3 (range of 1 to 8).  Best radiographic response was progressive disease in 12 (46 %), stable disease (SD) in 13 (50 %) and PR in 1 (4 %).  Median, 6- and 12-month PFS was 2.7 months (range of 1 to 52), 27 and 8 % respectively.  In patients with recurrent AG refractory to temozolomide, bendamustine has manageable toxicity and modest single agent activity though not meeting pre-specified study criteria.  The clinical value of bendamustine in the treatment of temozolomide refractory recurrent anaplastic glioma needs to be further investigated.

Bendamustine and Rituximab in Elderly Patients with Low-Tumor Burden Follicular Lymphoma

Gyan and colleagues (2018) stated that the treatment of low-tumor burden follicular lymphoma (LTBFL) remains a challenge.  Rituximab-based strategies may be improved by adding chemotherapy.  This Lymphoma Study Association multi-center phase-II clinical trial evaluated rituximab and bendamustine in 63 patients with untreated LTBFL who were aged over 60 years old and had a follicular lymphoma International Prognostic Index (FLIPI) score of greater than or equal to 2.  Induction comprised 4 weekly cycles of rituximab 375 mg/m2 intravenously combined with 2 cycles of bendamustine 90 mg/m2 days 1 to 2 with a 28-day interval, followed by 12 cycles of 375 mg/m2 rituximab maintenance therapy every 8 weeks.  The primary end-point was CR/unconfirmed CR (CRu), at 12 weeks.  Median age was 67·4 years and median FLIPI was 3.  Ultimately, 18 patients (29 %) had high tumor burden according to Groupe d'Etude des Lymphomes Folliculaires criteria.  The 12-week CR/CRu rate was 54.0 % and the ORR was 93.7 %.  Surprisingly, 3 patients died during maintenance (2 sepsis, 1 neoplasm); PFS was 85.4 % at 24 months.  In LTBFL patients with FLIPI greater than or equal to 2, 2 cycles of rituximab and bendamustine resulted in a CR rate of 54.0 %.  However, the treatment-related deaths observed did not allow this regimen to be recommended for LTBFL patients aged over 60 years.

Bendamustine for Systemic Light-Chain (AL) Amyloidosis

Zumbo and associates (2017) noted that systemic light-chain (AL) amyloidosis is an infiltrative disorder associated with an underlying plasma cells dyscrasia, in which monoclonal immunoglobulin light chains accumulate in an abnormal misfolded form as amyloid fibrils in the extra-cellular space.  Symptoms and prognosis are governed by which organs are affected, and cardiac involvement is the major determinant of survival.  Diagnosis requires demonstration of amyloid deposition and confirmation of the fibril protein type.  These investigators focused on the available treatments for systemic AL amyloidosis and on new drug targets and therapeutic approaches.  At present, the choice of up-front treatment lies between autologous stem cell transplantation (ASCT) and combination chemotherapy.  Chemotherapy agents include dexamethasone, melphalan, cyclophosphamide, thalidomide, bortezomib, lenalidomide, bendamustine in various combinations.  Few randomized controlled trials (RCTs) have been performed in AL amyloidosis and treatment has been substantially influenced by clinical practice in myeloma.  It has become clear that the best prospects of survival and preservation or improvement in amyloid related organ function require as near complete suppression as possible of the underlying hematological disorder.  The authors concluded that future directions include therapies designed to target amyloid deposits directly, in particular anti-amyloid antibodies which are now well advanced in development and are showing great potential.

Furthermore, an UpToDate review on “Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis and light and heavy chain deposition diseases” (Dispenzieri, 2022) states that “For patients who relapse after or are refractory to initial therapy (bortezomib-based regimen, melphalan plus dexamethasone, or hematopoietic cell transplantation [HCT]), treatment options include proteasome-inhibitor-based regimens and immunomodulatory-based regimens.  There are no good data to determine which of these regimens will be of most benefit; the choice will be dictated by prior therapy, patient and physician preferences, expected toxicity, drug availability, and insurance coverage.  As an example, a bortezomib-based regimen may be preferred for patients with severe cardiac involvement, while a lenalidomide-based regimen may be preferred for patients with peripheral neuropathy.  Lenalidomide-based regimens are also preferred for patients who received bortezomib as part of their original therapy. 

Bendamustine in the Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Relapsed / Refractory Lymphoma

Shabbir-Moosajee and colleagues (2019) noted that bendamustine is an attractive option for the management of both de-novo and relapsed lymphomas.  It is being increasingly used in the conditioning regimen for autologous stem cell transplantation (SCT) and can be an alternative to the traditionally-used carmustine.  These researchers determined the safety and efficacy of bendamustine in the conditioning regimen for autologous SCT in refractory / relapsed (R/R) lymphomas.  They designed a descriptive study to evaluate bendamustine in combination with etoposide, cytarabine, and melphalan (BeEAM) in the conditioning regimen for autologous SCT.  A total of 14 patients (median age of 28 years) with Hodgkin's lymphoma (HL) (n = 8), non-Hodgkin's lymphomas (NHL) (n = 5), or peripheral T-cell lymphoma, not otherwise specified (PTCL NOS) (n = 1) were included in the study.  A median number of 5.95 × 106 CD34+ cells/kg were transfused.  Median times to absolute neutrophil count and platelet engraftment were 17 days and 24 days, respectively.  The 100-day transplantation mortality rate was 28 % (4 patients); 8 patients (57.14 %) had GII-III acute kidney injury, 4 patients (28.5 %) had GIII-IV hyperbilirubinemia, and 12 patients (85 %) had GII-III diarrhea.  After 3 months, 37 % (5 patients) and 21.4 % (3 patients) demonstrated CR and PR, respectively.  The median follow-up was 5.5 months (15 days to 19 months).  At the final follow-up, 7 patients (50 %) were alive and in CR.  The authors concluded that the findings of this study showed that bendamustine is a potentially toxic agent in the conditioning regimen for autologous SCT, resulting in significant liver, kidney, and gastro-intestinal (GI) toxicity.  These researchers stated that bendamustine should be used with caution; and prospective comparative studies are needed to confirm the appropriate dose and schedule of bendamustine, and to further evaluate the toxicities noted in retrospective studies before it is routinely adopted in clinical practice.

Blastic Plasmacytoid Dendritic Cell Leukemia

Betrian and colleagues (2017) stated that optimal treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare entity of dismal prognosis previously described as CD4+/CD56+ hematodermic malignancies, is not defined.  These investigators reported 5 cases of relapsed BPDCN treated with bendamustine.  All patients were above the age of 50 years and in advanced disease (early 1st relapse in 2, subsequent relapse in 3; multi-organ involvement in 4; previous intensive chemotherapy in 5; and stem cell transplantation [SCT] in 4); 4 patients were evaluable for response -- 2 failed therapy, 1 died from tumor lysis syndrome after rapid blast clearance from blood, and 1 reached and maintained CR for 7 months.  The authors concluded that bendamustine should be further evaluated in BPDCN.

Combined Bendamustine and Brentuximab for Relapsed or Refractory Hodgkin Lymphoma

O'Connor and colleagues (2018) noted that brentuximab vedotin (BV) is currently approved for patients with relapsed or refractory Hodgkin's lymphoma (HL) who previously received an autologous stem cell transplant (ASCT) or 2 previous multi-agent chemotherapy regimens, and for patients with relapsed or refractory systemic anaplastic large-T-cell lymphoma who previously received at least 1 chemotherapy regimen.  A high proportion of patients with CD30-expressing relapsed or refractory lymphomas have durable responses to single-agent BV and showed longer PFS than do patients treated with chemotherapy.  In patients with HL and peripheral T-cell lymphoma, treatment with bendamustine alone only achieved modest improvements in PFS compared with that for chemotherapy.  In an international, multi-center, single-arm, phase 1/2 clinical trial, these researchers examined the safety and clinical activity of the combination of BV plus bendamustine in heavily pre-treated patients with relapsed or refractory HL and anaplastic large-T-cell lymphoma.  Eligible patients were aged 18 years or older, had histologically confirmed relapsed or refractory HL or anaplastic large-T-cell lymphoma, had biopsy-proven CD30-positive tumors, had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and received at least 1 previous multi-agent chemotherapy regimen.  In phase-1, patients were assigned following a 3+3 dose-escalation design to 1 of 4 cohorts to receive 1 dose of either 1.2 mg/kg or 1.8 mg/kg of BV intravenously on day 1 of a 21-day cycle, plus 1 dose of bendamustine (70 mg/m2, 80 mg/m2, or 90 mg/m2) on days 1 and 2 of the treatment cycle.  In phase-2, all patients were assigned to receive BV plus bendamustine at the recommended phase-2 dose from phase-1.  The primary end-points were MTD and DLT for phase-1, and the proportion of patients achieving an overall response in phase-2.  For both phases 1 and 2, all patients receiving at least 1 dose of study drug were evaluable for toxicity and all patients completing at least 1 cycle of therapy were evaluable for response.  The study is ongoing but no longer recruiting patients.  Between July 26, 2012, and May 31, 2017, these investigators enrolled and assigned 65 patients to treatment (64 [98 %] with HL and 1 [2 %] with anaplastic large-T-cell lymphoma; 28 [43 %] during phase-1 and 37 [57 %] during phase-2).  In the phase-1 part, the MTD of the combination was not reached; DLTs were observed in 3 (11 %) of 28 patients, including grade 4 neutropenia at 1.8 mg/kg BV plus 80 mg/m2 of bendamustine in 2 (7 %) patients and diffuse rash at 1.2 mg/kg BV plus 70 mg/m2 of bendamustine in 1 (4 %) patient.  The recommended phase-2 dose was deemed to be 1.8 mg/kg of BV and 90 mg/m2 of bendamustine, which were the standard doses of the drugs when given as single agents.  In the phase-2 part, an overall response was achieved in 29 (78 % [95 % CI: 62 to 91]) of 37 patients.  Serious adverse events (AEs) included grade 3 lung infection in 5 (14 %) of 37 patients in the phase-2, and grade 3 to 4 neutropenia in 16 (25 %) of 65 patients across phases 1 and 2.  There were no treatment-related deaths.  The authors concluded that the findings of this study showed that BV plus bendamustine, with a favorable safety profile, was an active salvage regimen for heavily pre-treated patients with relapsed or refractory HL.  They stated that this salvage regimen could potentially serve as a safe and efficacious alternative to platinum-based chemotherapy before ASCT.

LaCasce and co-workers (2018) stated that ASCT is standard of care for patients with HL who have relapsed/refractory disease after frontline chemotherapy.   Achievement of CR with pre-ASCT salvage chemotherapy predicts favorable outcomes post-ASCT.  In a phase 1/2 clinical trial, these researchers evaluated the combination of BV plus bendamustine as a 1st salvage regimen in relapsed/refractory HL.  A total of 55 patients (28 primary refractory and 27 relapsed) were enrolled.  Patients received BV (1.8 mg/kg) on day 1 and bendamustine (90 mg/m2) on days 1 and 2 of a 21-day cycle for up to 6 cycles.  Patients could undergo ASCT any time after cycle 2.  Following ASCT or completion of combination therapy if not proceeding to ASCT, patients could receive BV monotherapy for up to 16 cycles of total therapy.  After a median of 2 cycles of combination therapy (range of 1 to 6), the objective response rate (ORR) among 53 efficacy-evaluable patients was 92.5 %, with 39 patients (73.6 %) achieving CR; 40 patients underwent ASCT; 31 patients (25 of whom underwent ASCT) received BV monotherapy (median of 10 cycles; range of 1 to 14).  After a median of 20.9 months of follow-up, the estimated 2-year PFS was 69.8 % and 62.6 % for patients who received ASCT and all patients, respectively; 31 patients (56.4 %) experienced infusion-related reactions (IRRs), with a majority occurring during cycle 2 of combination therapy.  The authors concluded that the combination of brentuximab vedotin and bendamustine as 1st-line salvage therapy in relapsed/refractory HL was highly active and had a manageable toxicity profile, with the vast majority of patients proceeding to ASCT after just 2 cycles of therapy.  They stated that future studies could build on this trial by adding other active agents to the regimen to further enhance activity and by evaluating whether subsets of patients might achieve long-term disease control without the need for high-dose chemotherapy and ASCT.

The drawbacks of this study included the single-arm study design, which made efficacy comparison with other salvage regimens difficult.  Furthermore, follow-up was currently relatively brief, so additional time would be needed to fully assess long-term PFS.  In addition, this study was not designed to assess the impact of BV monotherapy post-ASCT in patients treated with BV and bendamustine prior to ASCT.

Hepatic Lymphoma

Liao and colleagues (2017) noted that primary hepatic lymphoma (PHL) is an uncommon cause of hepatic space-occupying lesions.  These researchers described the case of a 73-year old man with PHL, who presented with a low-grade fever and lower limb weakness that had progressed in the past 2 months.  Abdominal ultrasound (US) and computed tomography (CT) showed multiple small hepatic tumors.  Echo-guided biopsy of the hepatic tumor demonstrated primary hepatic diffuse large B-cell lymphoma (DLBCL).  Moreover, bone marrow was uninvolved, but the bone marrow smear disclosed hemophagocytosis, which was uncommon in DLBCL.  Chemotherapy with bendamustine and rituximab treatment was initiated with a dramatic response: hepatic tumors markedly shrank in size shown by follow-up CT and the patient returned to his normal life.  Nevertheless, the response was sustained for only 8 months.  Finally, the disease resisted further chemotherapy and the patient died of a severe Klebsiella pneumoniae infection.  The authors concluded that chemotherapy with bendamustine and rituximab showed a dramatic, but not durable, response in the present case with old age and multiple co-morbidities.  They stated that further studies to determine appropriate chemotherapy treatment for PHL are needed.

Hepatosplenic Gamma-Delta T-Cell Lymphoma

National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2019) lists hepatosplenic gamma-delta T-cell lymphoma as a recommended indication of bendamustine -- 2nd-line and subsequent therapy as a single-agent for refractory disease after 2 primary treatment regimens.

Melanoma

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. 

Non-Follicular Indolent Non-Hodgkin Lymphomas

In a phase II clinical trial, Luminari and colleagues (2016) 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.

Primary Central Nervous System (CNS) Lymphoma

Cho and colleagues (2016) stated that primary central nervous system lymphoma (PCNSL) involves extra-nodal lymphomas arising exclusively in the CNS.  It accounts for 2 % to 3 % of newly diagnosed primary CNS tumors and systemic NHLs.  Although survival outcomes have improved with the introduction of high-dose methotrexate (MTX)-based regimens, with or without cranial irradiation, relapse is still common.  Approximately 35 % to 60 % of patients show relapse and most relapses occur within the 1st 2 years following diagnosis.  The prognosis of relapsed PCNSL remains poor, with limited therapeutic options.  Furthermore, the aggressive course of relapsing PCNSL dramatically decreases performance status, particularly in elderly patients.  These investigators described an elderly patient with recurrent/relapsed PCNSL who was successfully treated with 4 cycles of R-BAD (rituximab, bendamustine, cytarabine, and dexamethasone) as a salvage treatment.  These researchers stated that given the data from a number of trials and clinical series that have documented rituximab and bendamustine activity in patients with CNS lymphomas as monotherapy or a combined regimen, they hypothesized that the incorporation of rituximab and bendamustine into the cytarabine regimen for recurrent PCNSL may benefit patients with recurrent/relapsed primary CNS lymphoma.  In this case, these investigators showed that the R-BAD regimen was effective as a salvage therapy in an elderly patient with recurrent/relapsed PCNSL.  The authors concluded that although this was a single-case report, they proposed that R-BAD chemotherapy is an effective and well-tolerated salvage treatment regimen for patients with relapsed/refractory primary CNS lymphoma.  Moreover, they stated that larger, prospective trials are needed to yield higher-grade evidence and enable stronger recommendations for PCNSL salvage treatments.

Small Cell Lung Cancer

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.

---

References