Brentuximab vedotin for treatment of non-Hodgkin lymphomas: A systematic review

Abstract

Background

Brentuximab vedotin (BV) is an antibody-drug conjucate (ADC) comprising a CD30-directed antibody, conjugated to the microtubule-disrupting agent MMAE via a protease cleavable linker. BV is FDA approved for use in relapsed classical Hodgkin lymphoma (HL) and relapsed systemic anaplastic large cell lymphoma (sALCL). There are multiple publications for its utility in other malignancies such as diffuse large B-cell lymphoma (DLBCL), mycosis fungoides (MF), Sézary syndrome (SS), T-cell lymphomas (TCL), primary mediastinal lymphoma (PMBL), and post-transplant lymphoproliferative disorders (PTLD). We believe that BV could potentially provide a strong additional treatment option for patients suffering from NHL.

Objective

Perform a systematic review on the use of BV in non-Hodgkin lymphoma (NHL) and other CD30⁺ malignancies in humans.

Data sources

We searched various databases including PubMed (1946–2015), EMBASE (1947–2015), and Cochrane Central Register of Controlled Trials (1898–2015).

Eligibility criteria

Inclusion criteria specified all studies and case reports of NHLs in which BV therapy was administered.

Included studies

A total of 28 articles met these criteria and are summarized in this manuscript.

Conclusion

Our findings indicate that BV induces a variety of responses, largely positive in nature and variable between NHL subtypes. With additional, properly powered prospective studies, BV may prove to be a strong candidate in the treatment of various CD30⁺ malignancies.

Introduction

CD30 (Ki-1) is a cell membrane protein deriving from the tumor necrosis factor (TNF) receptor family. Expression of CD30 is correlated with B and T cell activation. Since its initial description in the early 1980′s, the CD30 antigen has been associated primarily with Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) (Stein et al., 1982). CD30 expression is restricted to a small population of activated B and T lymphocytes, NK cells, and lower levels in activated monocytes and eosinophils (Argrawal et al., 1996). In addition to sALCL, the CD30 antigen has been identified in various other non-Hodgkin lymphomas (NHL) including hematological malignancies such as diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas (TCL), primary mediastinal lymphoma (PMBL), post-transplant lymphoproliferative disorders (PTLD), enteropathy associated PTCL,cutaneous malignancies such as mycosis fungoides (MF), Sézary syndrome (SS), and lymphatoid papulosis (LyP) (Stein et al., 1982, Jacobsen et al., 2015, Kim et al., 2014, Schwarting et al., 1989). The CD30 antigen also has been identified in non-lymphomatous malignancies like germ cell tumors such as embryonal carcinoma, seminomas, malignant melanomas, neoplasms of mesenchymal origins including leiomyomas, leiomysarcomas, rhabdomyosarcomas, aggressive fibromatoses, fibrosarcomas, synovial sarcomas, giant cell tumors of tendon sheaths, malignant fibrous histiocytomas, osteosarcomas, Ewing's sarcomas, in a tumor cell subpopulation of malignant schwannomas, in the Schwann cell compartment of ganglioneuromas, and in the myoepithelial compartment of fibroadenomas, inflammatory myofibroblastic tumors, ovarian cancer, mesothelioma, squamous cell carcinoma, triple negative breast cancer, pancreatic cancer, small cell lung cancer, anal cancer, thyroid carcinoma, cutaneous angiosarcoma, and a small subset of undifferentiated nasopharyngeal non-keratinizing carcinoma (Latza et al., 1995, Gopalan et al., 2009, Dürkop et al., 2000, Pallesen and Hamilton-Dutoit, 1988, Polski and Janney, 1999, Lau et al., 2007, Suster et al., 1998, Bode et al., 2011, Hittmair et al., 1996, Sharman et al., 2012, Garcia-Prats et al., 1998, Dunphy, 2000, Aggerholm-Pedersen et al., 2011, Weed and Folpe, 2008, Kneile et al., 2006, Menasce and Eyden, 2005, Mechtersheimer and Moller, 1990, Mariño-Enríquez et al., 2016). Moreover, systemic mastocytosis, which is classified as a myeloid neoplasm, is also known to express CD30 although the clinical data is limited (Borate et al., 2016).

In NHL, CD30 has been utilized as a therapeutic target (Ferri, 2015, Terada and Sugiura, 2010, Muta and Podack, 2013). Brentuximab vedotin is an ADC comprising a CD30-directed antibody, conjugated to the microtubule-disrupting agent MMAE via a protease cleavable linker. It received accelerated approval from the federal drug administration (FDA) in 2011 for the treatment of relapsed classical HL and sALCL (Brentuximab vedotin, 2011).

Based on clinical benefit observed in HL and sALCL, the efficacy of BV also has been tested in many other NHLs that express CD30. In this systematic review, our objective is to summarize data from phase I/II trials along with case reports, case series and meeting abstracts that focus on the use of BV in treatment of CD30⁺ NHLs.