Brentuximab Vedotin (Adcetris)

Number: 0823

Table Of Contents

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

Policy

Scope of Policy

This Clinical Policy Bulletin addresses brentuximab vedotin (Adcetris) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of brentuximab vedotin (Adcetris) is required of all Aetna participating providers and members in applicable plan designs. For precertification of brentuximab vedotin (Adcetris), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Site of Care Utilization Management Policy applies. For information on site of service for brentuximab vedotin (Adcetris), see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

  1. Criteria for Initial Approval

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

    1. Classic Hodgkin lymphoma (cHL)

      For treatment of CD30+ cHL when any of the following are met:

      1. The requested drug will be used as a single agent; or
      2. The requested drug will be used in combination with doxorubicin, vinblastine, and dacarbazine; or
      3. The requested drug will be used in combination with bendamustine for subsequent therapy; or
      4. The requested drug will be used in combination with dacarbazine; or
      5. The requested drug will be used in combination with nivolumab for subsequent therapy; or
      6. The requested drug will be used in combination with gemcitabine for subsequent therapy; or
      7. The requested drug will be used in combination with ifosfamide, carboplatin and etoposide for subsequent therapy, or
      8. The requested drug will be used in combination with etoposide, prednisone and doxorubicin, or
      9. The requested drug will be used in combination with cyclophosphamide, prednisone, and dacarbazine for subsequent therapy; or
      10. The requested drug will be used in combination with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide; or
      11. The requested drug will be used in combination with etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone.

    2. B-Cell lymphomas (a type of non-Hodgkin lymphoma)

      For treatment of CD30+ B-cell lymphomas with any of the following subtypes:

      1. Monomorphic post-transplant lymphoproliferative disorders (B-cell type) when both of the following are met:

        1. The requested drug will be used for subsequent therapy; and
        2. The member is not a candidate for transplant; or

      2. Diffuse large B-cell lymphoma when both of the following are met:

        1. The requested drug will be used as subsequent therapy; and
        2. The member is not a candidate for transplant; or

      3. HIV-related B-cell lymphomas (HIV-related diffuse large B-cell lymphoma, primary effusion lymphoma, and human herpesvirus-8 (HHV8)-positive diffuse large B-cell lymphoma) when both of the following are met:

        1. The requested drug will be used for subsequent therapy; and
        2. The member is not a candidate for transplant; or

      4. High-grade B-cell lymphomas when both of the following are met:

        1. The requested drug will be used for subsequent therapy; and
        2. The member is not a candidate for transplant;

      5. Pediatric primary mediastinal large B-cell lymphoma when both of the following are met:

        1. The requested drug will be used for relapsed or refractory disease, and
        2. The requested drug will be used in combination with nivolumab or pembrolizumab;

    3. Primary cutaneous lymphomas

      For treatment CD30+ primary cutaneous lymphomas with any of the following subtypes:

      1. Mycosis fungoides (MF)/Sezary syndrome (SS); or
      2. Lymphomatoid papulosis (LyP) when both of the following are met:

        1. The requested drug will be used as a single agent; and
        2. The disease is relapsed or refractory; or

      3. Cutaneous anaplastic large cell lymphoma when either of the following are met:

        1. The requested drug will be used as a single agent; or
        2. The requested drug will be used in combination with cyclophosphamide, doxorubicin, and prednisone (CHP);

    4. T-Cell lymphomas (a type of non-Hodgkin lymphoma)

      For treatment of CD30+ T-cell lymphomas with any of the following subtypes:

      1. Hepatosplenic T-cell lymphoma when the requested drug will be used as a single agent after two or more primary treatment regimens; or
      2. Adult T-cell leukemia/lymphoma when either of the following are met:

        1. The requested drug will be used as a single agent for subsequent therapy; or
        2. The requested drug will be used in combination with cyclophosphamide, doxorubicin, and prednisone; or

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

        1. The requested drug will be used as a single agent; or
        2. The requested drug will be used in combination with cyclophosphamide, doxorubicin, and prednisone; or

      4. 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 either of the following are met:

        1. The requested drug will be used as a single agent for subsequent or palliative therapy; or
        2. The requested drug will be used in combination with cyclophosphamide, doxorubicin, and prednisone; or

      5. Extranodal NK/T-cell lymphoma when all of the following are met:

        1. The requested drug will be used as a single agent; and
        2. The member has relapsed or refractory disease; and
        3. The member has had an inadequate response or contraindication to asparaginase-based therapy (e.g., pegaspargase); or

      6. Systemic anaplastic large cell lymphoma when either of the following are met:

        1. The requested drug will be used as a single agent; or
        2. The requested drug will be used in combination the cyclophosphamide, doxorubicin, and prednisone (CHP).

    Aetna considers all other indications as experimental, investigational, or unproven. 

  2. Continuation of Therapy

    Aetna considers continuation of brentuximab vedotin (Adcetris) therapy medically necessary in 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.

  3. Related Policies

    1. CPB 0494 - Hematopoietic Cell Transplantation for Non-Hodgkin's Lymphoma
    2. CPB 0495 - Hematopoietic Cell Transplantation for Hodgkin's Disease
    3. CPB 0634 - Non-myeloablative Bone Marrow/Peripheral Stem Cell Transplantation (Mini-Allograft / Reduced Intensity Conditioning Transplant)

Dosage and Administration

Brentuximab vedotin (Adcetris) is available as a 50 mg lyophilized powder in a single-dose vail for intravenous infusion only.

The recommended Adcetris dosageFootnote1* is administered as a 30-minute intravenous infusion and is as follows for:

  • Adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma

    1.2 mg/kg up to a maximum of 120 mg in combination with chemotherapy. Administer every 2 weeks until a maximum of 12 doses, disease progression, or unacceptable toxicity.

  • Pediatric patients with previously untreated high risk classical Hodgkin lymphoma

    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 a maximum of 5 doses.

  • Adult patients with classical Hodgkin lymphoma consolidation

    1.8 mg/kg up to a maximum of 180 mg. Initiate Adcetris treatment within 4-6 weeks post-auto-HSCT or upon recovery from auto-HSCT. Administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity.

  • Adult patients with relapsed classical Hodgkin lymphoma

    1.8 mg/kg up to a maximum of 180 mg. Administer every 3 weeks until disease progression or unacceptable toxicity.

  • Adult patients with previously untreated systemic ALCL or other CD30-expressing 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.

  • Adult patients with relapsed systemic ALCL

    1.8 mg/kg up to a maximum of 180 mg. Administer every 3 weeks until disease progression or unacceptable toxicity.

  • Adult patients with relapsed primary cutaneous ALCL or CD30-expressing mycosis fungoides

    1.8 mg/kg up to a maximum of 180 mg. Administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity.

Footnote1* The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg.

Refer to full prescribing information for Adcetris for recommended dosage for individuals with renal or hepatic impairment.

Source: Seagen, 2022

Experimental, Investigational, or Unproven

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

  • Acute myeloid leukemia
  • Mesothelioma
  • Multiple myeloma
  • Renal cell cancer
  • Small cell lung cancer.
Table:

CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

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-cell administration, autologous
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
38225 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
38226      preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage)
38227      receipt and preparation of CAR-T cells for administration
38228      CAR-T cell administration, 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:
J1094 Injection, dexamethasone acetate, 1 mg
J1100 Injection, dexamethasone sodium phosphate, 1 mg
J2650 Injection, prednisolone acetate, up to 1 ml
J7512 Prednisone, immediate release or delayed release, oral, 1 mg
J8530 Cyclophosphamide; oral, 25 mg
J8540 Dexamethasone, oral, 0.25 mg
J8560 Etoposide; oral, 50 mg
J9000 Injection, doxorubicin hydrochloride, 10 mg
J9071 Injection, cyclophosphamide (auromedics), 5 mg
J9072 Injection, cyclophosphamide (dr. reddy's), 5 mg
J9073 Injection, cyclophosphamide (ingenus), 5 mg
J9074 Injection, cyclophosphamide (sandoz), 5 mg
J9075 Injection, cyclophosphamide, not otherwise specified, 5 mg
J9076 Injection, cyclophosphamide (baxter), 5 mg
J9130 Dacarbazine, 100 mg
J9181 Injection, etoposide, 10 mg
J9196 Injection, gemcitabine hydrochloride (accord), not therapeutically equivalent to j9201, 200 mg
J9201 Injection, gemcitabine hydrochloride, not otherwise specified, 200 mg
J9299 Injection, nivolumab, 1 mg
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
C82.90 - C82.99, C84.A0 - C84.99, C85010 - C85.99 Other malignant lymphomas
C83.00 - C83.09, C83.80 - C83.99, C86.50 -C86.51 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 - C83.3A 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]
C85.20 – C85.29 Mediastinal (thymic) large B-cell lymphoma [pediatric primary mediastinal large B-cell lymphoma]
C86.50 - C86.51 Angioimmunoblastic T-cell lymphoma [CD30+]
C86.00 - C86.01 Extranodal NK/T-cell lymphoma, nasal type
C86.10 Hepatosplenic T-cell lymphoma
C86.60 -C86.61 Primary cutaneous CD30-positive T-cell proliferations [Primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions or cutaneous ALCL with regional nodes]
C88.40 - C88.41 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):
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
C92.00 - C92.02 Acute myeloblastic leukemia
D47.Z9 Other specified neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue [[CD30-positive lympho-proliferative disorders]

Background

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

  • Classical Hodgkin Lymphoma (cHL)

    • Treatment of adult patients with cHL after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates
    • Treatment of adult patients with cHL at high risk of relapse or progression as post-auto-HSCT consolidation
    • Treatment of adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine
    • Treatment of pediatric patients 2 years and older with previously untreated high risk classical Hodgkin lymphoma (cHL) in combination with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide

  • Systemic anaplastic large cell lymphoma (sALCL)

    • Treatment of adult patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen
    • Treatment of adult patients 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, in combination with cyclophosphamide, doxorubicin, and prednisone

  • Treatment of adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) in patients who have received prior systemic therapy

Compendial Uses

  • cHL stage I-II unfavorable 
  • CD30+ B-Cell Lymphomas

    • Monomorphic post-transplant lymphoproliferative disorders (B-cell type)
    • Diffuse large B-cell lymphoma
    • HIV-related B-cell lymphomas (CD30+ HIV-related diffuse large B-cell lymphoma, primary effusion lymphoma, and human herpesvirus-8 (HHV8)-positive diffuse large B-cell lymphoma)
    • High-grade B-Cell lymphomas
    • Pediatric primary mediastinal large B-cell lymphoma

  • CD30+ Primary Cutaneous Lymphomas

    • Mycosis Fungoides (MF)/Sezary Syndrome (SS)
    • Lymphomatoid papulosis (LyP)
    • Cutaneous anaplastic large cell lymphoma

  • CD30+ T-Cell Lymphomas

    • Hepatosplenic T-cell lymphoma
    • Adult T-cell leukemia/lymphoma
    • Breast implant-associated anaplastic large cell lymphoma (ALCL)
    • Peripheral T-cell lymphoma (PTCL)
    • Extranodal NK/T-cell Lymphoma
    • Angioimmunoblastic T-cell lymphoma

Brentuximab vedotin (Adcetris) carries black box warning of progressive multifocal leukoencephalopathy (PML). Fatal cases of John Cunningham (JC) virus infection resulting in PML have been noted in Adcetris-treated patients. The time for onset of symptoms vary and have occurred within 3 months of initial exposure to Adcetris therapy. Other contributory factors include prior therapies and underlying condition that may cause immunosuppression (Seagen, 2019).

Per the prescribing information, brentuximab vedotin (Adcetris) carries the following warnings and precautions:

  • Peripheral neuropathy: In trials of Adcetris monotherapy, 62% of patients experienced any grade of neuropathy
  • Anaphylaxis and infusion reactions
  • Hematologic toxicities: Fatal and serous cases of febrile neutropenia have been noted with Adcetris; prolonged (≥1 week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can occur with Adcetris
  • Serious infections and opportunistic infections: Pneumonia, bacteremia, sepsis or septic shock (including fatal outcomes), and other serious and opportunistic infections have been noted in patients treated with Adcetris
  • Tumor lysis syndrome
  • Hepatoxicity
  • Pulmonary toxicity: Fatal and serous events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), have been noted
  • Serious dermatology reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been noted with Adcetris
  • Gastrointestinal complications: Fatal and serious events of acute pancreatitis and other fatal and serious gastrointestinal (GI) complications including perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus have been noted
  • Hyperglycemia: In trials of Adcetris monotherapy, 8% of patients experienced any grade hyperglycemia, with 6% experiencing Grade 3 or 4 hyperglycemia
  • Embryo-fetal toxicity.

The most common adverse reactions (≥20% in any trial) were peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, and mucositis (Seagen, 2019).

Brentuximab vedotin (Adcetris) is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation) (Seagen, 2019).

Brentuximab vedotin is available as Adcetris (brentuximab vedotin) (Seagen Inc.) and 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 (Seagen, 2019).

Lymphomas

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).

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-label, 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.

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.

Bhatt et al (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, 2014) 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 et al (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.

On November 10, 2022, the U.S. Food and Drug Administration approved brentuximab vedotin (Adcetris) in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide for pediatric patients 2 years of age and older with previously untreated high risk classical Hodgkin lymphoma (cHL). The efficacy of Adcetris in combination with chemotherapy for the treatment of pediatric patients (2 to < 22 years of age) with previously untreated high risk cHL was studied in a randomized, open-label, actively controlled trial. High risk cHL was determined as Ann Arbor Stage IIB with bulk disease, Stage IIIB, Stage IVA, and Stage IVB. Of the 600 total patients randomized, 300 were randomized to brentuximab vedotin plus doxorubicin(A), vincristine (V), etoposide (E), prednisone (P), and cyclophosphamide (C) [brentuximab vedotin + AVEPC] arm, and 300 patients were randomized to A+bleomycin (B)+V+E+P+C [ABVE-PC] arm. Patients in each treatment arm received up to 5 cycles of the following: Brentuximab vedotin + AVEPC arm: brentuximab vedotin 1.8 mg/kg over 30 minutes (day 1), doxorubicin 25 mg/m2 (days 1 and 2), vincristine 1.4 mg/m2 (day 8), etoposide 125 mg/m2(days 1-3), prednisone 20 mg/m2 BID (days 1-7), cyclophosphamide 600 mg/m2 (days 1 and 2); or ABVE-PC arm: doxorubicin 25 mg/m2 (days 1 and 2), bleomycin 5 units/m2 (day1) and 10 units/m2 (day 8), vincristine 1.4 mg/m2 (days 1 and 8), etoposide 125 mg/m2 (days 1-3), prednisone 20 mg/m2 BID (days 1-7), cyclophosphamide 600 mg/m2 (days 1 and 2). The main efficacy outcome measure was event-free survival (EFS), identified as the time from randomization to the earliest of disease progression or relapse, second malignancy, or death due to any cause. Median EFS was not reached in either arm. There were 23 events (8%) in the brentuximab vedotin + AVEPC arm and 52 events (17%) in the ABVE-PC arm with a corresponding hazard ratio of 0.41 (95% CI: 0.25, 0.67; p=0.0002). The most frequent Grade ≥3 adverse reactions (≥5%) in pediatric patients treated with brentuximab vedotin in combination with AVEPC were neutropenia, anemia, thrombocytopenia, febrile neutropenia, stomatitis, and infection. The recommended brentuximab vedotin dose for pediatric patients 2 years of age and older is 1.8 mg/kg up to a maximum of 180 mg in combination with AVEPC every 3 weeks for a maximum of 5 doses (FDA, 2022; Seagen, 2022).

Brentuximab Vedotin and Lenalidomide for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Ward et al (2022) stated that new therapies are needed for patients with relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who do not benefit from or are ineligible for stem cell transplant (SCT) and chimeric antigen receptor therapy (CAR T). Brentuximab vedotin (BV) and lenalidomide (Len) have demonstrated promising activity as single agents in this population. These investigators reported the findings of a phase-I / dose expansion clinical trial examining the combination of BV/Len in rel/ref DLBCL. A total of 37 patients received BV every 21 days, with Len administered continuously for a maximum of 16 cycles. The MTD of the combination was 1.2 mg/kg BV with 20 mg/d Len; BV/Len was well-tolerated with a toxicity profile consistent with their use as single agents. Most patients required granulocyte colony-stimulating factor (G-CSF) support because of neutropenia. The ORR was 57 % (95 % CI: 39.6 to 72.5), CR rate, 35 % (95 % CI: 20.7 to 52.6); median duration of response, 13.1 months; median PFS, 10.2 months (95 % CI: 5.5 to 13.7); and median OS, 14.3 months (95 % CI: 10.2 to 35.6). Response rates were highest in patients with CD30+ DLBCL (73 %), but they did not differ according to cell of origin (p = 0.96). Natural killer (NK) cell expansion and phenotypic changes in CD8+ T-cell subsets in non-responders were identified by mass cytometry. The authors concluded that BV/Len represents a potential therapeutic option for patients with rel/ref DLBCL; and this combination is being further examined in a phase-III clinical trial.

Brentuximab Vedotin 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.

Forlenza et al (2023) noted that outcomes for children and adolescents with relapsed and refractory HL are poor, with approximately 50 % of patients experiencing a subsequent relapse. The anti-CD30 antibody-drug conjugate BV improved PFS when used as consolidation after ASCT in adults with high-risk relapsed/refractory HL. Data on BV as consolidative therapy following ASCT in pediatric patients with HL are extremely limited, with only 11 patients reported in the literature. These researchers carried out a retrospective analysis of 67 pediatric patients who received BV as consolidation therapy following ASCT for the treatment of relapsed/refractory HL to describe the experience of this regimen in the pediatric population. This was the largest cohort reported to-date. These investigators found that BV was well-tolerated with a safety profile similar to adult patients. With a median follow-up of 37 months, the 3-year PFS was 85 %. The authors concluded that these findings suggested a potential role for the use of BV as consolidation therapy following ASCT for children with relapsed/refractory HL.

Brentuximab plus AVD (Doxorubicin, Vinblastine, and Dacarbazine) Followed by Radiotherapy for the Treatment of Classic Hodgkin Lymphoma

Ueda et al (2023) stated that no consensus has been reached yet concerning treatment strategies for a sequential cHL following gray zone lymphoma (GZL). Prognosis of GZL following a failed autologous hematopoietic stem-cell transplantation (auto-HCT) is poor and treatment strategy is very limited. As yet there are limited data showing clinical outcomes of BV for GZL, especially for sequential CHL following GZL. These investigators reported a case of cHL following primary refractory GZL following a failed auto-HCT and showed favorable response to 1st-line cHL-directed chemoradiotherapy consisting of BV plus doxorubicin, vinblastine, and dacarbazin (AVD) followed by irradiation. The sequential cases with an early evolution, whose diagnosis of 2nd lymphoma was made within 1 year, have been recently reported very poor survival shorter than 1 year. Whether a sequential cHL following GZL should be treated as a primary or relapsed disease has not been clearly elucidated. This patient showed favorable response to 1st-line cHL-directed chemoradiotherapy without allogenic HCT (allo-HCT) and has in continuous remission for 2 years. The authors concluded that the management of this case could aid physicians in making better treatment-decisions and provide insights for further exploration in future studies.

Brentuximab plus Doxorubicin and Dacarbazine for the Treatment of Classic Hodgkin Lymphoma

Abramson et al (2023) noted that ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) with or without radiation has been the standard treatment for limited-stage HL but carries risks of bleomycin lung injury and radiation toxicity.  Brentuximab vedotin is approved with AVD for stage III to IV HL; but carries increased risks of peripheral neuropathy (PN) and neutropenic fever, likely due to overlapping toxicity between BV and vinblastine.  These researchers examined the use of BV in combination with AD for 4 or 6 cycles based on interim positron emission tomography (PET) response.  A total of 34 patients with non-bulky stage I to II HL were enrolled.  Risk was early favorable in 53 % and unfavorable in 47 %.  The overall and complete response rates (CRRs) were 100 % and 97 %, respectively, with a 5-year PFS of 91 %.  No differences in outcome were observed based on stage (I versus II) or risk status (early favorable versus unfavorable).  The most common AEs were nausea (85 %), peripheral sensory neuropathy (59 %), and fatigue (56 %).  There were no cases of grade-IV neutropenia or neutropenic fever, and no patient received granulocyte-colony stimulating factor (GCSF).  Most cases of PN were grade-I, and no patient experienced grade-III or higher PN.  BV-AD produced a high CRR and durable PFS with most patients requiring 4 cycles of therapy.  Compared with BV-AVD, the toxicity profile appeared improved, with predominantly grade-I reversible PN and no case of grade-IV neutropenia or neutropenic fever.  The authors concluded that this regimen warrants further study in HL and may serve as a backbone for the addition of targeted therapies in future trials of initial therapy in cHL, with one such study already underway.

The authors stated that the main drawback of this trial was the small sample size of 34 patients and the non-comparative nature of this phase-II clinical trial.  These investigators did include similar numbers of early favorable and unfavorable patients, although only 1 patient had stage IIB disease, and no patient had bulky mediastinal disease due to the eligibility criteria; thus, the findings in this subset could not be directly compared with other studies which included patients with all early unfavorable risk characteristics.  This trial also included very few older patients with HL; therefore, a larger study would be needed to understand generalizability of these findings.  Nonetheless, this study did report encouraging safety and effectiveness of BV-AD in non-bulky limited-stage cHL and allowed omission of historic and potentially toxic standards of bleomycin, vinblastine, and radiation therapy.  These data also questioned the role of vinblastine in the BV-AVD regimen, in which dual targeting of the microtubule resulted in excess neuropathy and neutropenia, which appeared to be mitigated by eliminating vinblastine in favor of BV.  With a 5-year PFS of approximately 91 % for this and other radiation-sparing approaches, there is still room to optimize effectiveness of initial therapy in patients with non-bulky limited-stage cHL.

Brentuximab plus Nivolumab with or without Bendamustine for the Treatment of Relapsed/Refractory Hodgkin Lymphoma

Harker-Murray et al (2023) stated that children, adolescents, and young adults (CAYA) with relapsed/refractory (R/R) cHL without complete metabolic response (CMR) before auto-HCT have poor survival outcomes. CheckMate 744, a phase-II clinical trial for CAYA (aged 5 to 30 years) with R/R cHL, examined a risk-stratified, response-adapted approach with BV plus nivolumab followed by BV plus bendamustine for patients with suboptimal response. Risk stratification was primarily based on time to relapse, prior treatment, and presence of B symptoms. These investigators presented the primary analysis of the standard-risk cohort. Data from the low-risk cohort were reported separately. Patients received 4 induction cycles with BV plus nivolumab; those without CMR (Deauville score of greater than 3) received BV plus bendamustine intensification. Patients with CMR after induction or intensification proceeded to consolidation (high-dose chemotherapy/auto-HCT per protocol). Primary endpoint was CMR any time before consolidation. A total of 44 patients were treated; median age was 16 years. At a minimum follow-up of 15.6 months, 43 patients received 4 induction cycles (1 discontinued), 11 of whom received intensification; 32 proceeded to consolidation. CMR rate was 59 % after induction with BV plus nivolumab; and 94 % any time before consolidation (BV plus nivolumab ± BV plus bendamustine); the 1-year PFS rate was 91 %. During induction, 18 % of patients experienced grade-III/IV treatment-related AEs. This risk-stratified, response-adapted salvage strategy had high CMR rates with limited toxicities in CAYA with R/R cHL. Most patients did not require additional chemotherapy (bendamustine intensification). These researchers stated that additional follow-up is needed to confirm durability of disease control.

In a multi-center, phase-II clinical trial, Herrera et al (2023) examined the safety and activity of BV plus nivolumab combination following auto-HCT consolidation in patients with high-risk R/R cHL. This study was carried out at 5 centers in the U.S. Eligible patients were aged 18 years or older with high-risk R/R cHL, had an ECOG performance status of 0 to 2, and had adequate organ and bone marrow function. Enrolled patients received BV (1.8 mg/kg) and nivolumab (3 mg/kg) intravenously starting 30 to 60 days following auto-HCT on day 1 of each 21-day cycle for up to 8 cycles. Nivolumab dose reduction was not allowed; BV dose reduction to 1.2 mg/kg was permitted. If one drug was discontinued because of a toxic effect, the other could be continued. The primary endpoint was 18-month PFS in all treated patients. Between May 3, 2017, and July 13, 2019, a total of 59 patients were enrolled and received the study therapy. Patients initiated BV plus nivolumab for a median of 54 days (inter-quartile range [IQR] 46 to 58) following auto-HCT and received a median of 8 cycles (8 to 8); 34 (58% ) of 59 patients were male, 29 (49 %) completed 8 cycles of BV plus nivolumab, and 45 (76 %) completed 8 cycles of at least one drug. The median follow-up time was 29.9 months (IQR 24.6 to 34.8). The 18-month PFS in all 59 patients was 94 % (95 % CI: 84 to 98). The most common AEs were sensory peripheral neuropathy (31 [53 %] of 59) and neutropenia (25 [42 %]), and immune-related AEs requiring corticosteroids occurred in 17 (29 %) of 59 patients. No treatment-related deaths were observed. The authors concluded that BV plus nivolumab was highly active following auto-HCT consolidation for patients with high-risk R/R cHL, most of whom had previous exposure to either BV or PD-1 blockade. These researchers stated that combination immunotherapy in this setting should be further studied in patients with cHL with further refinement of the regimen to mitigate toxic effects, especially in high-risk patients in whom more intensive therapy to prevent relapse is needed.

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.

Multiple Myeloma

Sherbenou et al (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.

Combination of Brentuximab Vedotin and Bendamustine for the Treatment of CD30+ Peripheral T-Cell Lymphoma

Wagner et al (2020) noted that a treatment regimen consisting of brentuximab vedotin (Bv) and bendamustine (B) has been described as a highly potent salvage therapy and as an effective induction therapy leading to high response rates before ASCT in patients with cHL.  In a retrospective study, these researchers examined this therapy's efficacy in unselected patients with cHL and CD30+ PTCL.  Data of 28 patients with cHL and 5 patients with PTCL treated with a combination of Bv and B at 3 Austrian tertiary cancer centers were analyzed.  In patients with cHL, the ORR was 100 % (78.6 % CR, 21.4 % PR).  After 17 months median follow-up, median survival times were not reached; 1-year PFS was 81.9 %, and 1-year OS was 95.7 %; 13 eligible patients (46.4 %) successfully underwent planned ASCT after salvage therapy with BvB and subsequent HDC; 3 of the 5 PTCL patients achieved CR, while 2 did not respond and died during or shortly after therapy.  The authors concluded that a combination of Bv and B was an effective salvage and induction therapy before ASCT in patients with RR-cHL.  Moreover, these researchers stated that further studies with a higher number of patients are needed to directly compare the efficacy of this treatment to other options for salvage therapy; and further studies are also needed to evaluate the possible use and efficiency of BvB in patients with PTCL compared to other therapeutic regimens.

The authors stated that drawbacks of this study included the retrospective nature of the study design, the not standardized and possibly incomplete documentation of adverse events (AEs) in some patients and the relatively small number of patients (cHL, n = 28; PTCL, n = 5).  One major drawback of this study was the lack of long-term follow-up.  The heterogeneity of the patient population regarding number and type of previous therapy and other patient characteristics complicated the comparison to other data, but resembled clinical practice.

Combination of Brentuximab Vedotin and Re-Induction Chemotherapy (Mitoxantrone, Etoposide, and Cytarabine) for the Treatment of Acute Myeloid Leukemia

Narayan et al (2020) noted that outcomes for patients with RR-acute myeloid leukemia (RR-AML) remain poor.  Novel therapies specifically targeting AML are of high interest; Brentuximab vedotin (Bv) is an antibody-drug conjugate that is specific for human CD30.  In a phase-I, dose escalation clinical trial, these researchers examined the safety of Bv combined with mitoxantrone, etoposide, and cytarabine (MEC) re-induction chemotherapy for patients with CD30-expressing RR-AML.  Using a standard dose escalation design, these investigators evaluated 3 dose levels of Bv (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7.  There were no dose-limiting toxicities (DLTs) noted and the maximum tolerated dose (MTD) was not reached.  The recommended phase-II dose of Bv was determined to be 1.8 mg/kg when combined with MEC.  The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade greater than or equal to 3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]).  Among the 22 patients enrolled in the trial, the composite response rate was 36 %, with a composite response rate of 42 % noted among those who received the highest dose of Bv.  The median OS was 9.5 months, with a median disease-free survival (DFS) of 6.8 months observed among responders.  Approximately 55 % of patients were able to proceed with either allogeneic hematopoietic SCT or donor lymphocyte infusion (DLI).  The authors concluded that the combination of Bv with MEC was found to be safe in patients with CD30-expressing RR-AML and warrants further study comparing this combination with the use of MEC alone in this population.

References

The above policy is based on the following references:

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