Brentuximab (Adcetris)

Number: 0823

Policy

Note: Requires PrecertificationFootnotes for Precertification of brentuximab vedotin*

Aetna considers brentuximab vedotin (Adcetris) medically necessary for the following indications:

T-cell Lymphomas

  •  as
     
    • Second-line therapy or subsequent therapy as a single agent for nonresponders to first-line therapy for acute or lymphoma subtypes; or 
    • Combination therapy with CHP (cyclophosphamide, doxorubicin, prednisone) as chemotherapy in nonresponders to first-line therapy for chronic/smoldering subtype, first-line therapy for acute subtype, continued treatment in responders to first-line therapy for acute subtype, first-line therapy for lymphoma subtype, or as continued treatment in responders to first-line therapy for lymphoma subtype.
  • as adjuvant systemic therapy for localized disease to capsule/implant/breast following incomplete excision or partial capsulectomy with residual disease if node positive or radiation therapy is not feasible or for extended disease (stage II - IV) as
     
    • A single agent; or
    • Combination therapy with CHP (cyclophosphamide, doxorubicin, prednisone).

B-cell Lymphomas

  • , primary effusion lymphoma, and HHV8-positive diffuse large B-cell lymphoma, not otherwise specified (NOS) - Second-line or subsequent therapy for relapse in noncandidates for transplant; or
  •   as second-line or subsequent therapy for CD30+ relapsed, progressive,  or refractory disease in noncandidates for transplant,or
  • Marginal zone lymphoma - as treatment of histologic transformation to CD30+ diffuse large B-cell lymphoma in patients who have received multiple lines of chemoimmunotherapy for indolent or transformed disease; or

Hodgkin Lymphoma

  • Classic Hodgkin Lymphoma (> 18 years) as
     
    • Maintenance therapy in adults following high-dose therapy and autologous stem cell rescue for relapsed or refractory disease for patients with high risk of relapse; or
    • Second-line or subsequent systemic therapy (if not previously used) in adults for relapsed or refractory disease as a single agent or as a component of a chemotherapy regimen (i.e, bendamustine or nivolumab); or
    • Primary treatment for adults (> 18 years) in combination with AVD (doxorubicin, vinblastine, dacarbazine) for stage III-IV disease.   
       
  • Classic Hodgkin Lymphoma (> 60 years) as
     
    • Palliative therapy as a single agent for relapsed or refractory disease;or
    • Primary treatment in combination with dacarbazine for stage I-II unfavorable or stage III-IV disease.

Primary Cutaneous Lymphoma

  • Single-agent therapy for symptomatic disease if refractory to all primary treatment options; or
  • with multifocal lesions or cutaneous ALCL with regional nodes (excludes systemic ALCL) - Single-agent therapy as primary treatment or for relapsed or refractory disease; or
  • with regional nodes (excludes systemic ALCL) - as combination therapy with CHP (cyclophosphamide, doxorubicin, prednisone) as primary treatment or for relapsed or refractory disease.

Continued use of brentuximab vedotin is considered not medically necessary for persons whose disease has progressed with brentuximab vedotin or who have developed intolerance to this drug.

Aetna considers brentuximab vedotin contraindicated and experimental and investigational for use in persons diagnosed with progressive multifocal leukoencephalopathy.

Aetna considers use of brentuximab vedotin with bleomycin (Blenoxane) experimental and investigational because the safety and effectiveness of this combination has not been established. Specifically, concomitant use of brentuximab vedotin and bleomycin has been associated with pulmonary toxicity and is contraindicated.

Aetna considers brentuximab vedotin experimental and investigational for all other indications (not an all-inclusive list) because its effectiveness for indications other than the ones listed above has not been established:

  • Mesothelioma
  • Multiple myeloma
  • Renal cell cancer
  • Small cell lung cancer

Note: Footnotes* Precertification of brentuximab vedotin is required of all Aetna participating providers and members in applicable plan designs.  For precertification of bretuximab vedotin, call (866) 752-7021, or fax (866) 267-3277.

Note: A "Boxed Warning" high-lighting the risk of progressive multifocal leukoencephalopathy was added to the drug label of brentuximab vedotin (Adcetris) in January 2012.

Note: Treatment with brentuximab should be continued until disease progression or unacceptable toxicity.

Background

Lymphomas are cancers of the lymphatic system.  Hodgkin's lymphoma (HL) and anaplastic large-cell lymphoma (ALCL, a rare type of non-Hodgkin lymphoma) are the two most common tumors expressing CD30.  The National Cancer Institute estimates that about 9,000 new cases of HL will be diagnosed in the United States in 2011 and about 1,300 people will die from the disease.  CD30 is abundantly and selectively expressed on the surface of Hodgkin Reed-Sternberg cells, ALCLs, and other lymphoid malignancies as well as on several non-lymphoid malignancies including selected germ cell tumors.  Expression of CD30 on normal cells is highly restricted, thereby allowing differential targeting of malignant cells.  CD30, a member of the tumor necrosis factor (TNF)-receptor family has pleiotropic biologic functions, and antibodies targeting CD30 and other TNF family receptors can exhibit both agonistic and antagonistic signaling functions (Alley et al, 2010; Deutsch et al, 2011; NCI, 2011).

Patients with relapsed or refractory HL and ALCL usually have a poor prognosis.  Individuals with these histologies who subsequently progress after salvage chemotherapy and autologous stem cell transplantation (ASCT) have very limited treatment options and are in need of novel effective therapies.  Recently, the antibody-drug conjugate (ADC) field has made significant progress as a consequence of careful optimization of several parameters, including mAb specificity, drug potency, linker technology, as well as the stoichiometry and placement of conjugated drugs.  The underlying reason for this has been obtained in pre-clinical biodistribution and pharmacokinetics studies showing that targeted delivery leads to high intra-tumoral free drug concentrations, while non-target tissues are largely spared from chemotherapeutic exposure.  Developments in the field have led to an increase in the number of ADCs being tested clinically.  Recently, ADCs targeting CD30, such as brentuximab vedotin (cAC10-vcMMAE, SGN 35, SGN-35), have shown striking activity in phase I and II clinical studies, with manageable toxicity.  This has defined an important emerging role for targeting of CD30 in the setting of HL, ALCL, and possibly other CD30+ malignancies.  Brentuximab vedotin consists of 3 components:
  1. the chimeric IgG antibody cAC10, specific for human CD30,
  2. the potent microtubule disruptive cytotoxic agent, mono-methyl auristatin E (MMAE), and
  3. a protease-cleavable linker that co-valently attaches MMAE to cAC10 (Ansell, 2011; Deutsch et al, 2011).

Adcetris (brentuximab vedotin) is an antibody‐drug conjugate (ADC), consisting of a monoclonal antibody directed against CD30 which is conjugated to the antitubulin agent monomethyl auristatin E (MMAE) by an enzyme‐cleavable linker. Non‐clinical data suggests that Adcetris (brentuximab vedotin) binds to CD30‐expressing cells, is internalized and releases MMAE via proteolytic cleavage. MMAE causes apoptosis and cell death by binding to tubulin and disrupting the microtubule network within the cell. Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL) are the two most common malignancy types which express CD30.

Adcetris (brentuximab vedotin) is approved by the U.S. Food and Drug Administration (FDA) for:
  • the treatment of patients with classical Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi‐agent chemotherapy regimens in patients who are not ASCT candidates,
  • the treatment of patients with classical HL at high risk of relapse or progression as post‐auto‐HSCT consolidation,
  • the treatment of patients with previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with chemotherapy, and for
  • the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi‐agent chemotherapy regimen. 

On November 16, 2018, Seattle Genetics announced the FDA approval of Adcetris (brentuximab vedotin) in combination with CHP chemotherapy (cyclophosphamide, doxorubicin, and prednisone) for adults with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified. FDA approval is based on the outcome of the phase 3 ECHELON-2 clinical trial that compared Adcetris plus CHP to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Note, the FDA granted Breakthrough Therapy designation and Priority Review to this supplemental Biologics License Application (BLA) and reviewed it under the Real-Time Oncology Review Pilot Program leading to approval less than two weeks after submission of the complete application (Seattle Genetics, 2018).

The ECHELON-2 trial was a multi-center, randomized, double-blind, placebo-controlled phase 3 study in which patients were randomized to receive either a combination of Adcetris plus CHP or CHOP for CD30-expressing PTCL. The primary endpoint was progression-free survival (PFS) per BICR facility assessment, with events defined as progression, death due to any cause, or receipt of subsequent anticancer chemotherapy to treat residual or progressive disease. Secondary endpoints included PFS in patients with systemic anaplastic large cell lymphoma (sALCL), complete remission rate, overall survival and objective response rate, in addition to safety. Results from the trial demonstrated that combination treatment with Adcetris plus CHP was superior to CHOP for progression free survival (PFS) (BICR; hazard ratio=0.71; 95% CI, 0.54–0.93; p-value=0.011). This corresponded to a 29 percent reduction in the risk of progression, death, or receipt of subsequent anticancer chemotherapy to treat residual or progressive disease. The Adcetris plus CHP arm also demonstrated superior overall survival (OS) compared to CHOP (hazard ratio=0.66; 95% CI, 0.46-0.95; p-value=0.024). "All other key secondary endpoints, including PFS in patients with sALCL (hazard ratio=0.59; 95% CI, 0.42-0.84; p-value=0.003), complete remission rate (68% vs 56%; p-value=0.007) and objective response rate (83% vs 72%; p-value=0.003) were statistically significant in favor of the Adcetris plus CHP arm" (Seattle Genetics, 2018).

In a phase I, open-label, multi-center dose-escalation study, Younces et al (2010) administered brentuximab vedotin (at a dose of 0.1 to 3.6 mg/kg body weight) every 3 weeks to 45 patients with relapsed or refractory CD30-positive hematologic cancers, primarily HL and ALCL.  Patients had received a median of 3 previous chemotherapy regimens (range of 1 to 7), and 73 % had undergone autologous stem-cell transplantation (ASCT).  The maximum tolerated dose was 1.8 mg/kg, administered every 3 weeks.  Objective responses, including 11 complete remissions, were observed in 17 patients.  Of 12 patients who received the 1.8-mg/kg dose, 6 (50 %) had an objective response.  The median duration of response was at least 9.7 months.  Tumor regression was observed in 36 of 42 patients who could be evaluated (86 %).  The most common adverse events were diarrhea, fatigue, nausea, neutropenia, pyrexia, and peripheral neuropathy.  The authors concluded that brentuximab vedotin induced durable objective responses and resulted in tumor regression for most patients with relapsed or refractory CD30-positive lymphomas in this phase I study.  Treatment was associated primarily with grade 1 or 2 (mild-to-moderate) toxic effects.

Foyil and Bartlett (2011) described the preliminary findings of brentuximab vedotin for the treatment of patients with CD30+ lymphomas in large phase II clinical trials -- response rates of 75 % in relapsed/refractory HL and 87 % in relapsed/refractory systemic ALCL were reported.  Brentuximab vedotin is well-tolerated with manageable side effects including peripheral sensory neuropathy.  This ADC is currently under investigation in numerous clinical trials, including in combination with front-line chemotherapy for high-risk HL and in a placebo-controlled, phase III trial for patients with HL at high risk for residual disease following ASCT.  The impressive response rates and limited toxicity of brentuximab vedotin are very promising for relapsed/refractory patients with few treatment options.  In addition, the possibilities for incorporation into front-line therapies for both HL and systemic ALCL are intriguing.

On August 19, 2011, the Food and Drug Administration (FDA), under its accelerated approval program where surrogate endpoints are acceptable, approved brentuximab vedotin (Adcetris) for the treatment of patients with HL whose disease has progressed after ASCT or after 2 prior chemotherapy treatments for those who are not candidates for ASCT.  The FDA also approved brentuximab vedotin for the treatment of patients with ALCL whose disease has progressed after 1 prior chemotherapy treatment.  Brentuximab vedotin is the first new FDA-approved drug for HL since 1977 and the first drug specifically indicated for the treatment of ALCL.  The effectiveness of brentuximab vedotin in patients with HL was evaluated in a clinical study involving 102 patients.  In the open-lavel, single-arm, multi-center trial, patients were only treated with brentuximab vedotin.  The study’s primary endpoint was objective response rate, the percentage of patients who experienced complete or partial cancer shrinkage or disappearance following treatment.  A total of 73 % of patients achieved either a complete or partial response to the treatment.  On average, these patients responded to the therapy for 6.7 months.  The effectiveness of brentuximab vedotin in patients with systemic ALCL was evaluated in a single clinical study involving 58 patients.  In the phase II, open-label, single-arm, multi-center trial, patients were only treated with brentuximab vedotin.  Similar to the HL trial, the trial’s primary endpoint was objective response rate.  Of the patients receiving brentuximab vedotin for ALCL, 86 % experienced either a complete or partial response and responded on average for 12.6 months.  The most common adverse reactions experienced with brentuximab vedotin were anemia, cough, diarrhea, fatigue, fever, nausea, neutropenia, peripheral sensory neuropathy, thrombocytopenia, upper respiratory infection, and vomiting.

On March 20, 2018, the Food and Drug Administration (FDA), approved Adcetris (brentuximab vedotin) to treat adult patients with previously untreated stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy. The approval for adult patients with previously untreated stage III or IV cHL was based on a clinical trial comparing Adcetris plus AVD chemotherapy (Adriamycin [doxorubicin], vinblastine and dacarbazine) to a AVBD chemotherapy regimen common for cHL treatment (AVD plus bleomycin). The trial measured modified progression-free survival (mPFS), which considers the length of time it took for the disease to progress, death to occur, or new therapy to be initiated in patients who did not achieve a complete response. In the trial of 1,334 patients, after patients received an average of six 28-day cycles of treatment, those treated with Adcetris plus AVD were 23 percent less likely to experience progression, death, or initiation of new therapy compared with those receiving ABVD. There were 117 (18 percent) patients on the Adcetris plus AVD arm who experienced disease progression, death, or began new therapy compared to 146 (22 percent) patients on the ABVD arm.

Black Box Warning and Contraindications

Progressive multifocal leukoencephalopathy (PML)

In addition to Adcetris (brentuximab vedotin) therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new‐onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold Adcetris (brentuximab vedotin) dosing for any suspected case of PML and discontinue Adcetris (brentuximab vedotin) dosing if a diagnosis of PML is confirmed.

In addition, a Contraindication warning against use of Adcetris with bleomycin due to increased risk of pulmonary toxicity was added to the drug label.

Warnings and Precautions

  • Do not use Adcetris (brentuximab vedotin) in patients with hypersensitivity to Adcetris (brentuximab vedotin) or any of its components.
  • Efficacy and Safety has not been established in patients < 18 years of age
  • Peripheral neuropathy (PN): Cases of both peripheral sensory and motor neuropathy have been reported. Of the 54% of patients who experienced PN in clinical trials, 20% had no improvement in symptom. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of Adcetris (brentuximab vedotin).
  • Infusion‐related reactions: If anaphylaxis occurs, immediately and permanently discontinue administration of Adcetris (brentuximab vedotin). Patients who have experienced an infusion-related reaction should be premedicated prior to subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
  • Neutropenia: Prolonged, severe (> 1 week) neutropenia can occur. Nadir is typically expected 8 days after administration.
  • Tumor‐lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.
  • Stevens‐Johnson Syndrome (SJS): If SJS occurs, discontinue Adcetris (brentuximab vedotin) and administer appropriate medical therapy.
  • Advise females of reproductive potential to avoid pregnancy during Adcetris (brentuximab vedotin) treatment and for at least 6 months after the final dose. Advise a pregnant woman of the potential risk to the fetus.
  • Adcetris [A1] (brentuximab vedotin) should not be used in the treatment of lymphocyte predominant Hodgkin lymphoma, unless CD30+ immunophenotype is confirmed.
  • In patients with recurrent Grade 4 despite G-CSF prophylaxis, consider discontinuation or dose reduction.
     

Oki and Younes (2012) noted that brentuximab vedotin has been approved by the FDA for the treatment of relapsed or refractory HL and ALCL.  The effectiveness of brentuximab vedotin in other CD30(+) lymphomas is currently being investigated.  These investigators reviewed the currently available treatment options for systemic peripheral T-cell lymphomas (PTCL) and the role of brentuximab vedotin in relapsed or refractory ALCL.  In addition, ongoing clinical trial of brentuximab vedotin in relapsed PTCL and combination therapy with other chemotherapies for initial treatment of CD30(+) lymphoma were also reviewed.  The authors concluded that brentuximab vedotin has established its role in the treatment of relapsed or refractory HL and ALCL.  In the next few years, the effectiveness of this agent in other CD30(+) lymphomas will be described.  The safety and effectiveness of several brentuximab-based combination regimens, including use as front-line chemotherapy is under investigation.

The National Comprehensive Cancer Network (NCCN)’s Drugs & Biologics Compendium (2019) lists the following indications for brentuximab vedotin (Adcetris):

  • B-Cell Lymphomas -
     
    • Follicular Lymphoma (grade 1-2) - Treatment of histologic transformation to CD30+ diffuse large B-cell lymphoma in patients who have received multiple lines of chemoimmunotherapy for indolent or transformed disease
    • Histologic Transformation of Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma - Treatment of patients who have received multiple lines of chemoimmunotherapy for indolent or transformed disease
    • Diffuse Large B-Cell Lymphoma - Second-line or subsequent therapy for partial response, no response, relapsed, progressive, or refractory CD30+ disease in noncandidates for transplant
    • Diffuse Large B-Cell Lymphoma - Second-line or subsequent therapy for partial response, no response, relapsed, progressive, or refractory CD30+ primary cutaneous diffuse large B-cell lymphoma, leg type in noncandidates for transplant
    • High-Grade B-Cell Lymphomas - Second-line or subsequent therapy for partial response, no response, relapsed, progressive, or refractory CD30+ disease in noncandidates for transplant
    • AIDS-Related B-Cell Lymphomas - Second-line or subsequent therapy for relapse of CD30+ AIDS-related diffuse large B-cell lymphoma, primary effusion lymphoma, and HHV8-positive diffuse large B-cell lymphoma, not otherwise specified (NOS) in noncandidates for transplant
    • Post-Transplant Lymphoproliferative Disorders - Second-line and subsequent therapy for patients with partial response, persistent or progressive disease after receiving chemoimmunotherapy as first-line treatment for CD30+ monomorphic PTLD (B-cell type)
       
  • Hodgkin Lymphoma -
     
    • Classic Hodgkin Lymphoma (Age ≥18 years) - Primary treatment in combination with AVD (doxorubicin, vinblastine, dacarbazine) for stage III-IV disease (useful in certain circumstances)
    • Classic Hodgkin Lymphoma (Age ≥18 years) - Second-line or subsequent systemic therapy (if not previously used) for relapsed or refractory disease as a single agent, in combination with bendamustine, or in combination with nivolumab
    • Classic Hodgkin Lymphoma (Age ≥18 years) - Maintenance therapy following high-dose therapy and autologous stem cell rescue (HDT/ASCR) for relapsed or refractory disease for patients with high risk of relapse
       
      • if Deauville 1-3 prior to transplant
      • if Deauville 4 prior to transplant
         

      Note: Patients with 2 or more of the following risk factors are considered high risk: remission duration less than 1 year, extranodal involvement, PET+ response at time of transplant, B symptoms, and/or >1 salvage/subsequent therapy regimen

    • Classic Hodgkin Lymphoma in Older Adults (Age >60 years) - Primary treatment in combination with dacarbazine for stage I-II unfavorable or stage III-IV disease
    • Classic Hodgkin Lymphoma in Older Adults (Age >60 years) - Palliative therapy as a single agent for relapsed or refractory disease
       
  • Primary Cutaneous Lymphomas -
     
    • Mycosis Fungoides/Sezary Syndrome - Preferred systemic therapy as primary treatment for
       
      • stage IA mycosis fungoides (MF) with B1 blood involvement, with or without skin-directed therapy
      • stage IB-IIA MF with a higher disease burden (eg, predominantly plaque disease), with or without skin-directed therapy
      • stage IIB MF with limited tumor lesions, with or without local radiation therapy
      • stage IIB MF with generalized tumor lesions, with or without skin-directed therapy
      • stage III MF, with or without skin-directed therapy
      • stage IV Sezary syndrome
         
    • Mycosis Fungoides/Sezary Syndrome - Systemic therapy as primary treatment for
       
      • stage IA mycosis fungoides (MF) with B1 blood involvement, with or without skin-directed therapy
      • stage IB-IIA MF with a higher disease burden (eg, predominantly plaque disease) and B1 blood involvement, with or without skin-directed therapy
      • stage IIB MF with generalized tumor lesions, with or without skin-directed therapy (preferred)]
      • stage III MF, with or without skin-directed therapy
      • stage IV Sezary syndrome, with or without skin-directed therapy
      • stage IV non-Sezary or visceral disease (solid organ), with or without radiation therapy for local control (preferred)
      • large cell transformation (LCT) with generalized cutaneous or extracutaneous lesions, with or without skin-directed therapy (preferred)
         
    • Mycosis Fungoides/Sezary Syndrome - Preferred systemic therapy as treatment for
       
      • stage IA mycosis fungoides (MF) with B1 blood involvement that is relapsed, persistent, or refractory to multiple previous therapies, with or without skin-directed therapy
      • relapsed or persistent stage IB-IIA MF with a higher disease burden (eg, predominantly plaque disease), with or without skin-directed therapy
      • relapsed or persistent stage IIB MF with limited tumor lesions, with or without local radiation therapy
      • stage IIB MF with limited tumor lesions refractory to multiple previous therapies, with or without skin-directed therapy
      • relapsed or persistent stage IIB MF with generalized tumor lesions, with or without skin-directed therapy
      • stage IIB MF with generalized tumor lesions refractory to multiple previous therapies
      • relapsed or persistent stage III MF, with or without skin-directed therapy
      • stage III MF that is refractory to multiple previous therapies
      • relapsed or persistent stage IV Sezary syndrome
      • relapsed or persistent stage IV non Sezary or visceral disease (solid organ), with or without radiation therapy for local control
      • large cell transformation (LCT) with limited cutaneous lesions that is refractory to multiple previous therapies
      • relapsed or persistent LCT with generalized cutaneous or extracutaneous lesions, with or without skin-directed therapy
         
    • Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorder - Therapy for primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions, or cutaneous ALCL with regional nodes (excludes systemic ALCL), as a single agent for
       
      • primary treatment (preferred)
      • relapsed/refractory disease
         
    • Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders - Therapy for cutaneous anaplastic large cell lymphoma (ALCL) with regional nodes (excludes systemic ALCL) as a component of brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, prednisone) for
       
      • primary treatment
      • relapsed/refractory disease
         
    • Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders - Therapy for lymphomatoid papulosis (LyP) with extensive lesions as a single agent for relapsed/refractory disease following clinical trial, observation, retreatment with primary treatment, or treatment with alternative regimen not used for primary treatment
       
  • T-Cell Lymphomas
     
    • Peripheral T-Cell Lymphomas - Preferred first-line therapy for stage I, II ALK-positive anaplastic large cell lymphoma as a component of brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, prednisone)
    • Peripheral T-Cell Lymphomas - Preferred first-line therapy for stage III, IV ALK-positive anaplastic large cell lymphoma as a component of brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, prednisone)
    • Peripheral T-Cell Lymphomas - Preferred first-line therapy for CD30+ stage I-IV peripheral T-cell lymphoma not otherwise specified, ALK-negative anaplastic large cell lymphoma, 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, as a component of brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, prednisone)
    • Peripheral T-Cell Lymphomas - Preferred second-line and subsequent therapy for relapsed/refractory anaplastic large cell lymphoma, CD30+ peripheral T-cell lymphoma, or CD30+ angioimmunoblastic T-cell lymphoma, as a single agent
    • Breast Implant-Associated ALCL - Adjuvant systemic therapy for localized disease to capsule/implant/breast following incomplete excision or partial capsulectomy with residual disease if node positive or radiation therapy is not feasible, or consider for extended disease (stage II - IV)
       
      • as a single agent
      • as a component of brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, prednisone)
         
    • Adult T-Cell Leukemia/Lymphoma - Used as a component of brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, prednisone) for CD30+ cases as chemotherapy in nonresponders to first-line therapy for chronic/smoldering subtype
       
      • first-line therapy for acute subtype
      • continued treatment in responders to first-line therapy for acute subtype
      • first-line therapy for lymphoma subtype
      • continued treatment in responders to first-line therapy for lymphoma subtype
         
    • Adult T-Cell Leukemia/Lymphoma - Preferred second-line or subsequent therapy as a single agent for nonresponders to first-line therapy for acute or lymphoma subtypes (for CD30 expressing cases)
    • Extranodal NK/T-Cell Lymphoma, nasal type - Preferred therapy as a single agent for CD30+ relapsed/refractory disease following additional therapy with an alternate combination chemotherapy regimen (asparaginase-based) not previously used
    • Hepatosplenic Gamma-Delta T-Cell Lymphoma - Used a component of brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, prednisone) for CD30+ cases
       
      • as preferred primary treatment
      • consider as an alternate induction regimen if not used in primary treatment
         
    • Hepatosplenic Gamma-Delta T-Cell Lymphoma - Preferred second-line and subsequent therapy as a single agent for CD30+ refractory disease after 2 primary treatment regimens

Bhatt and colleagues (2013) stated that primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma characterized by short survival with current therapies, emphasizing the urgent need to develop new therapeutic approaches.  Brentuximab vedotin is an effective treatment of relapsed CD30-expressing HL and systemic ALCL.  These researchers demonstrated that PEL cell lines and primary tumors express CD30 and thus may serve as potential targets for brentuximab vedotin therapy.  In-vitro treatment with brentuximab vedotin decreased cell proliferation, induced cell cycle arrest, and triggered apoptosis of PEL cell lines.  Furthermore, in-vivo brentuximab vedotin promoted tumor regression and prolonged survival of mice bearing previously reported UM-PEL-1 tumors as well as UM-PEL-3 tumors derived from a newly established and characterized Kaposi's sarcoma-associated herpesvirus- and Epstein-Barr virus-positive PEL cell line.  The authors concluded that these findings demonstrated for the first time that brentuximab vedotin may serve as an effective therapy for PEL and provide strong pre-clinical indications for evaluation of brentuximab vedotin in clinical studies of PEL patients.

The American College of Radiology’s “Appropriateness Criteria® pediatric Hodgkin lymphoma” (Terezakis et al, 2012) stated that “Newer drugs promise great efficacy with less toxicity.  Targeted therapy with brentuximab vedotin, an antibody-drug conjugate that targets CD30, has shown excellent results in early clinical trials.  Pediatric trials are underway to assess its efficacy and toxicity, and discussions about incorporating it into large clinical trials are under way”.

Newland et al (2013) noted that HL and systemic ALCL (sALCL), which is a subtype of non-Hodgkin lymphoma (NHL), are relatively uncommon lympho-proliferative types of cancer.  These malignancies are highly curable with initial treatment.  Nonetheless, some patients are refractory to or relapse after first- and second-line therapies, and outcomes for these patients are less promising.  Brentuximab vedotin is a CD30-directed antibody-cytotoxic drug conjugate that has demonstrated efficacy in response rates (objective response rates and complete response) when given to patients with refractory or relapsed HL and sALCL.  Although not compared directly in clinical trials, the response rates with brentuximab vedotin are higher than those of several current treatments for refractory or relapsed HL and sALCL.  Adverse effects associated with brentuximab vedotin are considered manageable.  Nonetheless, several serious adverse effects (e.g., neutropenia, peripheral sensory neuropathy, tumor lysis syndrome, Stevens-Johnson syndrome, and progressive multifocal leukoencephalopathy, resulting in death) have been reported with its use.  Despite a lack of survival and patient reported outcome data, the FDA granted accelerated approval to brentuximab vedotin for the treatment of HL after failure of ASCT or at least 2 combination chemotherapy regimens, and for sALCL after failure of at least 1 combination chemotherapy regimen.  With this approval, brentuximab vedotin is the first FDA-approved agent for the treatment of HL in over 3 decades and the first agent specifically indicated to treat sALCL.  Results of ongoing prospective trials should determine if brentuximab vedotin has a survival benefit when compared directly with standard treatment and if brentuximab vedotin is safe and effective when given earlier in the disease process, or when used with other chemotherapy for the treatment of HL and sALCL or other CD30-positive malignancies.

Forero-Torres et al (2012) stated that brentuximab vedotin induces durable objective responses in patients with relapsed or refractory HL after ASCT.  The objective of this post-hoc analysis was to characterize the safety and effectiveness of brentuximab vedotin for patients with relapsed or refractory HL who refused or were ineligible for ASCT.  This case series included 20 transplant-naive patients who were enrolled in 2 phase I multi-center studies.  Patients received brentuximab vedotin intravenously every 3 weeks or every week for 3 out of 4 weeks.  The majority of patients were transplant-naïve because of chemo-refractory disease.  Median age was 31.5 years (range of 12 to 87 years).  Treatment-emergent adverse events in greater than 20 % of patients were peripheral neuropathy, fatigue, nausea, pyrexia, diarrhea, weight decreased, anemia, back pain, decreased appetite, night sweats, and vomiting; most events were grade 1 or 2.  Six patients obtained objective responses: 2 complete remissions and 4 partial remissions.  Median duration of response was not met; censored durations ranged from greater than 6.8 to greater than 13.8 months; 3 of 6 responders subsequently received ASCT.  The authors concluded that brentuximab vedotin was associated with manageable adverse events in transplant-naïve patients with relapsed or refractory HL.  The objective responses observed demonstrated that anti-tumor activity is not limited to patients who received brentuximab vedotin after ASCT.  They stated that the promising activity observed in this population warrants further study.

Hadley (2012) stated that “Brentuximab vedotin is being developed in a joint collaboration between Seattle Genetics and Millennium: The Takeda Oncology Company.  In August 2011, it was approved by the FDA for the treatment of patients with HL and anaplastic large cell lymphoma (ALCL).  Brentuximab vedotin is an antibody-drug conjugate that specifically targets the TNF receptor superfamily member 8 (CD30) antigen on the surface of cancer cells to induce cell death.  Brentuximab vedotin has shown efficacy in inducing apoptosis in HL and ALCL cell lines that express CD30 and reducing tumor size in preclinical models.  Brentuximab vedotin is under clinical evaluation for the treatment of relapsed or refractory HL and ALCL in both adults and children.  It is being investigated for use as a combination agent with pre-existing frontline chemotherapies and as a stand-alone salvage therapy for use prior to autologous stem cell transplant.  Treatment with brentuximab vedotin is generally well-tolerated although it is associated with grade 1-2 adverse reactions such as neutropenia and there have been reports of grade 3-4 serious adverse events.  In particular its use with chemotherapy regimens that include bleomycin is contraindicated because of adverse pulmonary effects”.

Isidori and colleagues (2013) noted that HL has been a fascinating challenge for physicians and investigators since its recognition during the 19th century.  However, many questions still remain unanswered.  One issue regards high-dose therapy followed by ASCT, which has yet to find its place among several guidelines.  Other topics are still controversial with respect to transplantation for HL, including its role for newly diagnosed patients with advanced stage disease, the optimal timing of transplantation, the best conditioning regimen and the role of allogeneic/haplo-identical SCT.  Moreover, the potential use of localized radiotherapy or immunologic methods to decrease post-transplant recurrence, the role of novel agents such as brentuximab vedotin and their positioning in the treatment algorithm of resistant/relapsed HL patients, either before transplant to boost salvage therapy or after transplant as consolidation/maintenance, are burning questions without an answer”.

Burris (2013) noted that with the recent approvals of brentuximab for the treatment of refractory HL and ado-trastuzumab emtansine for relapsed metastatic HER2+ breast cancer, the hope for delivering targeted chemotherapy in the form of an ADC against many cancers is rapidly growing.  The strategy of delivering a potent cytotoxic via a monoclonal antibody to a tumor has been made feasible by marked advances in the technology of formulating and manufacturing these ADCs.  The development of stable linkers together with the identification of relevant biomarkers has been a key to the success of this class of agent.  The possibilities for deploying this technology in the treatment of a wide range of solid cancers are limited only by the discovery of suitable targets, those which are highly expressed on cancer cells and not, or minimally, on normal tissues.  That said, with the improved linker engineering, the ADC affords the best opportunity at shrinking tumors while minimizing side effects.  The authors stated that a variety of ADCs are in clinical trials studying a number of different tumor types as diverse as small cell lung and renal cell cancer.

Also, per NCCN’s Drugs & Biologics Compendium (2018) does not list use prior to autologous stem cell transplantation as recommended indications of brentuximab (Adcetris).

Brentuximab as First-Line Therapy for Relapsed/Refractory CD30-Positive Malignancies

Fanale et al (2014) stated that front-line treatment of PTCL involves regimens such as cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and results in a 5-year overall survival (OS) rate of less than 50 %. In a phase I, open-label study, these researchers evaluated the safety and activity of brentuximab vedotin administered sequentially with CHOP or in combination with CHP (CHOP without vincristine) as front-line treatment in patients with CD30(+) PTCL. Patients received sequential treatment (once every 3 weeks) with brentuximab vedotin 1.8 mg/kg (2 cycles) followed by CHOP (6 cycles) or brentuximab vedotin 1.8 mg/kg plus CHP (BV+CHP) for 6 cycles (once every 3 weeks). Responders received single-agent brentuximab vedotin for 8 to 10 additional cycles (for a total of 16 cycles). The primary objective was assessment of safety; secondary end-points included objective response rate (ORR), complete remission (CR) rate, progression-free survival rate (PFS), and OS. There were no pre-specified comparisons of the 2 treatment approaches. After sequential treatment, 11 (85 %) of 13 patients achieved an objective response (CR rate, 62 %; estimated 1-year PFS rate, 77 %). Grade 3/4 adverse events occurred in 8 (62 %) of 13 patients. At the end of combination treatment, all patients (n = 26) achieved an objective response (CR rate, 88 %; estimated 1-year PFS rate, 71 %). All 7 patients without ALCL achieved CR. Grade 3/4 adverse events (greater than or equal to 10 %) in the combination-treatment group were febrile neutropenia (31 %), neutropenia (23 %), anemia (15 %), and pulmonary embolism (12 %). The authors concluded that brentuximab vedotin, administered sequentially with CHOP or in combination with CHP, had a manageable safety profile and exhibited substantial anti-tumor activity in newly diagnosed patients with CD30(+) PTCL. Moreover, they stated that a phase III randomized controlled trial (RCT) is under way, comparing BV+CHP with CHOP.

Chen et al (2015) noted that brentuximab vedotin has recently become a promising therapeutic approach for CD30-positive hematological malignancies, but its role in other relapsed or refractory malignant lymphoma needs to be proven. Brentuximab vedotin was demonstrated effective, but no study has summarized the concrete effect of brentuximab vedotin in malignant lymphoma. To truly know the role of brentuximab vedotin, these researchers performed a systematic review of the literature and a meta-analysis of all known prospective trials, to assess the value of brentuximab vedotin for patients with relapsed and refractory malignant lymphoma. This was a systematic review of publications indexed in the PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ISI Web of Knowledge performed on February 10, 2015. A total of 6 studies, including 302 patients were identified. Meta-analyses were carried out to calculate the ORR, complete response rate (CRR), and partial response rate (PRR) of brentuximab vedotin for malignant lymphoma. In patients with malignant lymphoma, ORR was 0.61, CRR was 0.38, and PRR was 0.51. High heterogeneity between studies was observed, and funnel plots were not symmetrical, which meant that publication bias existed. Brentuximab vedotin was generally well-tolerated by patients reported in the included studies; adverse effects also occurred, but they were considered manageable. The authors concluded that the findings of this study showed that brentuximab vedotin is a safe and effective treatment for relapsed and refractory malignant lymphoma. They stated that in the future, brentuximab vedotin might become first-line therapy for relapsed/refractory CD30-positive malignancies, once more clinical trials with larger sample are carried out. The effectiveness of brentuximab vedotin combined with chemotherapy or radiotherapy, and strategies for decreasing the toxicity of brentuximab vedotin should also be studied.

Mesothelioma

Dabir et al (2015) stated that CD30 is a cytokine receptor belonging to the TNF super-family (TNFRSF8) that acts as a regulator of apoptosis. The presence of CD30 antigen is important in the diagnosis of HL and ALCL. There have been sporadic reports of CD30 expression in non-lymphoid tumors, including malignant mesothelioma. Given the remarkable success of brentuximab vedotin, an antibody-drug conjugate directed against CD30 antigen, in lymphoid malignancies, these researchers examined the incidence of CD30 in mesothelioma and investigated the ability to target CD30 antigen in mesothelioma. Mesothelioma tumor specimens (n = 83) were examined for CD30 expression by IHC. Positive CD30 expression was noted in 13 mesothelioma specimens, primarily those of epithelial histology. There was no significant correlation of CD30 positivity with tumor grade, stage, or survival. Examination of 4 mesothelioma cell lines (H28, H2052, H2452, and 211H) for CD30 expression by both FACS analysis and confocal microscopy showed that CD30 antigen localized to the cell membrane. Brentuximab vedotin treatment of cultured mesothelioma cells produced a dose-dependent decrease in cell growth and viability at clinically relevant concentrations. The authors concluded that the findings of this study validated the presence of CD30 antigen in a subgroup of epithelial-type mesothelioma tumors and indicated that selected mesothelioma patients may derive benefit from brentuximab vedotin treatment.

Also, the NCCN’s clinical practice guideline on “Malignant pleural mesothelioma” (Version 2.2019) does not mention brentuximab as a therapeutic option.

Multiple Myeloma

Sherbenou and colleagues (2015) stated that with optimal target antigen selection antibody-based therapeutics can be very effective agents for hematologic malignancies, but none has yet been approved for myeloma. Rituximab and brentuximab vedotin are examples of success for the naked antibody and antibody-drug conjugate classes, respectively. Plasma cell myeloma is an attractive disease for antibody-based targeting due to target cell accessibility and the complementary mechanism of action with approved therapies. Initial antibodies tested in myeloma were disappointing. However, recent results from targeting well-characterized antigens have been more encouraging. In particular, the CD38 and CD138 targeted therapies are showing single-agent activity in early phase clinical trials. These researchers reviewed the development pipeline for naked antibodies and antibody-drug conjugates for myeloma. The authors concluded that there is clear clinical need for new treatments, as myeloma inevitably becomes refractory to standard agents. The full impact is yet to be established, but these investigators are optimistic that the first FDA-approved antibody therapeutic(s) for this disease will emerge in the near future.

Furthermore, the NCCN’s clinical practice guideline on “Multiple myeloma” (Version 2.2019) does not mention brentuximab as a therapeutic option.

Appendix

Dosing Recommendations

Brentuximab vedotin is available as Adcetris in 50 mg vials, which contain powder for reconstitution.  For patients >100 kg, a weight of 100 kg should be used to calculate dose. The management of symptomatic adverse drug reactions, such as peripheral neuropathy and neutropenia, may require dose reduction, dose delay, or treatment discontinuation of Adcetris (brentuximab vedotin).

Previously Untreated Stage III or IV Classical Hodgkin Lymphoma: 1.2 mg/kg up to a maximum of 120 mg in combination with chemotherapy administered as an intravenous infusion over 30 minutes every 2 weeks until a maximum of 12 doses, disease progression, or unacceptable toxicity.

Classical Hodgkin Lymphoma Consolidation: Initiate treatment within 4-6 weeks post-auto-HSCT or upon recovery from auto-HSCT. 1.8 mg/kg up to a maximum of 180 mg administered as an intravenous infusion over 30 minutes every 30 minutes every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity.

Relapsed Classical Hodgkin Lymphoma: 1.8 mg/kg up to a maximum of 180 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

Relapsed Primary Cutaneous Anaplastic Large Cell Lymphoma or CD30-expressing Mycosis Fungoides: 1.8 mg/kg up to a maximum of 180 mg administered as an intravenous infusion over 30 minutes every 3 weeks until a maximum of 16 cycles,disease progression, or unacceptable toxicity.

Relapsed Systemic Anaplastic Large Cell Lymphoma: 1.8 mg/kg up to a maximum of 180 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

Previously untreated systemic ALCL or other CD30-expressiong peripheral T-cell lymphomas: 1.8 mg/kg up to a maximum of 180 mg in combination with chemotherapy. Administer every 3 weeks with each cycle of chemotherapy for 6 to 8 doses.

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:

38204 Management of recipient hematopoietic progenitor cell donor search and cell acquisition
38205 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogenic
38206     autologous
38230 Bone arrow harvesting for transplantation; allogeneic
38232     autologous
38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241     autologous transplantation
77261- 77295 Radiation therapy
96401 - 96450 Chemotherapy administration code range

HCPCS codes covered if selection criteria are met:

J9042 Injection, brentuximab vedotin, 1 mg

Other HCPCS codes related to the CPB:

J7510 Prednisone, oral, per 5 mg
J7512 Prednisone, immediate release or delayed release, oral, 1 mg
J8530 Cyclophosphamide; oral, 25 mg
J9000 - J9999 Chemotherapy drugs code range
Q0083 - Q0085 Chemotherapy administration
Q2049 Injection, doxorubicin hydrochloride, liposomal, imported lipodox, 10 mg
Q2050 Injection, doxorubicin hydrochloride, liposomal, not otherwise specified, 10 mg
S2150 Bone marrow or blood-derived peripheral stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including; pheresis and cell preparation/storage;marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition

ICD-10 codes covered if selection criteria are met:

C81.00 - C81.99 Hodgkin lymphoma
C82.00 - C82.09 Follicular lymphoma grade I
C82.10 - C82.19 Follicular lymphoma grade II
C82.50 - C82.59, C84.A0 - C84.99, C85,10 - C85.99 Other malignant lymphomas
C83.00 - C83.09, C83.80 - C83.99, C86.5 Other malignant lymphomas [single-agent therapy for primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions or cutaneous ALCL with regional nodes]
C83.30 - C83.39 Diffuse large B-cell lymphoma [HHV8-positive]
C84.00 - C84.09 Mycosis fungoides
C84.10 - C84.19 Sezary's disease
C84.40 - C84.49 Peripheral t-cell lymphoma
C84.60 - C84.79 Anaplastic large cell lymphoma, ALK positive or negative [single-agent therapy for primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions or cutaneous ALCL with regional nodes]
C86.5 Angioimmunoblastic T-cell lymphoma [CD30+]
C86.0 Extranodal NK/T-cell lymphoma, nasal type
C86.1 Hepatosplenic T-cell lymphoma
C86.6 Primary cutaneous CD30-positive T-cell proliferations [Primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions or cutaneous ALCL with regional nodes]
C88.4 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma].Lymphoma of skin-associated lymphoid tissue [SALT-lymphoma]; Lymphoma of bronchial-associated lymphoid tissue [BALT-lymphoma].
C91.50 - C91.52 Adult T-cell leukemia/lymphoma
D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)
R59.0 - R59.9 Enlarged lymph nodes [lymphoma associated with Castleman's disease in noncandidates for high-dose therapy]

ICD-10 codes not covered for indications listed in the CPB (not an all-inclusive list):

A81.2 Progressive multifocal leukoencephalopathy
C45.0 - C45.9 Mesothelioma
C64.1 - C65.9 Malignant neoplasm of kidney and renal pelvis [renal cell cancer]
C90.00 - C90.02 Multiple myeloma
D47.Z9 Other specified neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue [[CD30-positive lympho-proliferative disorders]

The above policy is based on the following references:

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