Brentuximab vedotin for treatment of non-Hodgkin lymphomas: A systematic review
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.
Section snippets
Eligibility criteria
Inclusion criteria specified all studies and case reports of NHLs in which BV therapy was administered. Studies with HL, non-human populations, and no reported objective response outcome were excluded from the systematic review (Fig. 1).
Literature search
A literature search was performed in the following resources: PubMed (1946–2015); Embase.com EMBASE (1947–2015); Wiley Cochrane Library- Central Register of Controlled Trials (1898–2015); Thompson Reuters Web of Science- Science Citation Index Expanded
Search results
The systematic search identified a total of 2753 records. Additionally, 43 records were screened from the WHO ICTRP search. After excluding 1110 duplicates, the remaining 1686 records were screened for relevance based on their titles and abstracts. Of these 1686, 73 were deemed potentially eligible and retrieved for full text review. After detailed review, a total of 46 records were further excluded for the following reasons: duplicate study data (n = 39), ongoing trials with no available data (n =
Group A: B-cell malignancies
1. DLBCL
There are two phase II studies totaling 61 patients with DLBCL.
1.1 Phase II studies: Jacobsen et al. performed a phase II study with relapsed/refractory DLBCL(Jacobsen et al., 2015). Of the 49 patients in this study, 57% were male (n = 28) (median age 62 years). These patients displayed variable levels of CD30 expression. An objective response (OR) to BV was shown in 43% (n = 21) with a median duration of 22·4 weeks. Complete remission (CR) was obtained by 17% (n = 8) (median duration, 66·4
Group B: T-cell malignancies
1. Systemic Anaplastic Large Cell Lymphoma (sALCL)
There are five phase I, three phase II studies, and three case reports totaling 124 patients with sALCL.
1.1 Phase I studies: The Younes et al. phase I study looked at CD30+ relapsed HL (n = 42), angioimmunoblastic TCL (n = 1) and sALCL (n = 2) patients treated with BV (Younes et al., 2010). No gender or age data are specified for these patients. CD30 positivity was seen in 100% (n = 2) and 100% (n = 2) were ALK+. All patients (n = 2) achieved CR (median
Group C: other malignancies
1. Plasmablastic Lymphoma
There is one phase II study and one case report totaling two patients with plasmablastic lymphoma (PBL).
1.1. Phase II studies: A phase II study reported one patient with CD30+ PBL, who achieved PD upon BV treatment (Jacobsen et al., 2015)
1.2 Case reports: Holderness et al. detailed a case report of a 48-year-old male with transformed CLL (PBL) with a CD30 positive immunophenotype, After failure of two intensive regimens, BV therapy induced a significant decrease in the
Summary
DLBCL: There are 61 CD30+ patients in two phase II studies. An OR was experienced by 52% (n = 32), and 25% (n = 15) achieved CR. A PR was experienced by 28% (n = 17), 18% (n = 11) maintained SD and 28% (n = 17) experienced PD.
PTLD: There are ten patients over one phase I study, one phase II study and one case report. All patients (n = 9) were CD30+. Of these patients, 56% (n = 5) experienced an OR (median duration 36 weeks). Complete remission was achieved by 56% (n = 5) (median duration 36 weeks), 22% (n = 2)
Discussion
The CD30 antibody is targeted by BV as an ADC comprising a CD30-directed antibody, conjugated to the microtubule-disrupting agent MMAE via a protease cleavable linker (Younes et al., 2012). CD30+ hematological malignancies in the relapsed and refractory setting have significantly worse outcomes compared to those with newly diagnosed disease. CD30 has been targeted with some success for relapsed hematological malignancies. CD30 can be expressed on the cell surface and in the cytoplasm but
Funding
This work was supported in part by grant no. R25CA078447(J.A.T.), P30 CA023074 from the National Cancer Institute, National Institutes of Health, Bethesda, MD.
Declaration of interests
Dr. McBride discloses financial interest from Seattle Genetics in the form of advisory board membership.
Dr. Puvvada discloses financial interest from Genentech, Abbvie, Spectrum, Jannsen, Takeda and Seattle Genetics in the form of institutional research funding, travel for investigators’ meetings and advisory board memberships.
Dr. Anwer discloses financial interest from Seattle Genetics and Incyte Corporation in the form of advisory board membership and participation in speakers’ program.
All
Acknowledgements
GKB (co-first author): literature search, figures, study design, data collection, data analysis, data interpretation, writing, editing
AM (co-first author): study design, data analysis, data interpretation, writing, editing
SL: literature search, figures, study design, data collection, data analysis, data interpretation
KR: literature search, figures, study design, data collection, data analysis, data interpretation
SY: data interpretation, writing, editing
KG: literature search, figures, study
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G.K.B and A.M. equally contributed as first co-authors.
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FA and SP equally contributed as last co-authors.