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. Author manuscript; available in PMC: 2018 Jan 1.
Published in final edited form as: Crit Rev Oncol Hematol. 2016 Nov 21;109:42–50. doi: 10.1016/j.critrevonc.2016.11.009

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

Garrett K Berger a,1, Ali McBride a,1, Stephanie Lawson a, Kelsey Royball a, Seongseok Yun b, Kevin Gee c, Irbaz Bin Riaz b, Ahlam A Saleh d, Soham Puvvada b,2, Faiz Anwer e,*,2
PMCID: PMC5218629  NIHMSID: NIHMS834426  PMID: 28010897

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.

Keywords: Brentuximab vedotin, Relapse or refractory NHL, CD30

1. 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.

2. Materials and methods

2.1. 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).

Fig. 1.

Fig. 1

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Trials selection process for the systematic review.

*Two additional studies included after initial screening

2.2. 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 (1900–2015); Thompson Reuters Web of Science-Conference Proceedings Citation Index-Science (1990–2015); Scopus (1823–2015). Additionally, the following clinical trial registers were searched: ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP). The search strategies included various combinations of text-words, and controlled vocabulary when available. There were no language or year limits placed on the search. Database and trial register searches were conducted on 5/22/2015. The detailed search strategy is provided in the Appendix 1. The following conference proceedings were searched for relevant abstracts: the American Society of Hematology (from 2000), the American Society of Clinical Oncology (from 2000), the European Hematology Association (from 2000), the American Society of Bone Marrow Transplantation (from 2000), and the European Society of Medical Oncology (from 2000) last assessed 6/30/2015. Also, the references from all identified studies were investigated manually to identify relevant trials.

2.3. Study selection

The titles and abstracts of screened articles were reviewed independently by three reviewers (G.K.B., S.L., K.R.). Full articles that were potentially relevant to study were reviewed with the original three reviewers in addition to the fourth reviewer (K.G.) to confirm the eligibility. Any discrepancies were resolved after group discussion with the four aforementioned reviewers.

2.4. Data abstraction and analysis

Studies were identified by the first author and year of first full publication (if available) or published abstract or letter. Outcomes and timing of reported outcomes were recorded as specified in each study. When not explicitly stated, outcomes were calculated on the basis of information included within the published record; if this was not possible, ‘not reported’ was recorded in the results tables. Data are presented as the mean (+/− standard deviation) or median (range), and all values are expressed to one decimal place unless the original article did not provide this degree of accuracy. Primary study outcomes focus on therapeutic efficacy of BV in the treatment of NHLs using objective response rate (ORR) as a measure.

3. Results

3.1. 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 = 6), and not focused on BV (n = 1). A total 27 articles met our inclusion criteria: phase II (n = 7), phase I (n = 6), phase I/II (n = 1) and case reports (n = 13). The summary of the selection process is depicted in the flow diagram (Fig. 1). At a later date, we decided to include mastocytosis and germ cell tumor data yielding one additional case study and one additional phase II study.

3.2. Study demographics

All selected studies included patients with pathologically proven NHLs and our systematic review included a total 359 patients of sALCL (n = 124), primary cutaneous ALCL (n = 6), DLBCL (n = 61), PMBL (n = 6), grey zone lymphoma (GZL) (n = 7), follicular lymphoma (FL) (n = 3), plasmablastic lymphoma (n = 2), peripheral TCL (n = 45), PTLD (n = 10), MF (n = 79), SS (n = 13), LyP (n = 9), germ cell tumors (GCT) (n = 3) and mastocytosis (MC) (n = 4).

4. 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 weeks) and 27% (n = 13) achieved a partial response (PR). Stable disease (SD) was maintained in 22% (n = 11) and 33% (n = 16) experienced disease progression (PD). Sixteen additional patients were given BV with rituximab and displayed favorable tolerance for this therapy (Jacobsen et al., 2015). The Yasenchak et al. phase II study utilized BV in combination with standard R-CHOP chemotherapy for the front-line treatment of patients with CD30-unselected high-intermediate/high-risk DLBCL. Twelve patients reached end of therapy (33 enrolled). The median age was 66 years. An OR was shown in 92% (n = 11) (Yasenchak et al., 2014). Complete remission was achieved by 58% (n = 7) and 33% (n = 4) achieved PR. Progressive disease was experienced by 9% (n = 1). Duration of response data not available at this time.

2. Post-Transplant Lymphoproliferative Disorder (PTLD)

There is one phase I and one phase II study for patients with PTLD, along with one case report for a total of ten patients.

2.1 Phase I studies

Gandhi et al. published a phase I/II trial looking at BV in adult PTLD patients with previously untreated CD20+ NHL, with co-expression of EBV and/or CD30 (all at any level) (Gandhi et al., 2014). Of the six patients, one was polymorphic (CD30+, EBV+), four were monomorphic B-cell like (all CD30+) and one was TCL (CD30−, EBV+). Median age was 61 years, 33% (n = 2) were male, and median follow-up was nine months. Five patients (71%) had a CR and none of them showed PD. One patient with SD achieved CR after discontinuing protocol chemoimmunotherapy (CIT). One patient who achieved SD declined further therapy, but had not progressed at his last follow up (Gandhi et al., 2014).

2.2 Phase II studies

In the Jacobsen et al. phase II study of relapsed/refractory DLBCL, three of study subjects had CD30+ PTLD (Jacobsen et al., 2015). Age and gender data are not available for these patients. An OR was experienced by 33% (n = 1), 33% (n = 1) achieved CR, and 33% (n = 1) experienced PD (Jacobsen et al., 2015).

2.3 Case reports

Hill et al. described a PTLD in a 62-year-old female with CD30+ DLBCL, who achieved CR for a duration of 20 weeks follow-up (Hill et al., 2014)

3. Grey Zone Lymphoma (GZL)

There is one phase II study and one case report totaling seven patients with GZL.

3.1 Phase II studies

The Jacobsen et al. phase II study included a total of six GZL patients (Jacobsen et al., 2015). All patients (n = 6) were CD30+. Gender and age data are not available for this subset of patients. An OR was shown in 50% (n = 3). Seventeen percent (n = 1) attained CR and 33% (n = 2) experienced PR. Stable disease was maintained by 33% (n = 2) and 17% (n = 1) experienced PD to single agent BV (Jacobsen et al., 2015).

3.2 Case reports

Ponugupati et al. detailed a case report of a 62-year-old male with relapsed CD30+, CD20+, ALK− GZL (Ponugupati and Haddad, 2012). He was treated with rituximab followed by BV along with bendamustin, and achieved CR after three cycles (nine weeks) (Ponugupati and Haddad, 2012).

4. Primary Mediastinal B-Cell Lymphoma (PMBL)

There is one phase II study totaling six patients with PMBL.

4.1 Phase II studies

A total of six relapsed CD30+ PMBL patients were included in Jacobsen et al. phase II study. Age and gender data are not available for this subset. Seventeen percent (n = 1) experienced an OR. CR was achieved by 17% (n = 1). SD was maintained by 50% (n = 3) and 33% (n = 2) experienced PD (Jacobsen et al., 2015).

5. Follicular Lymphoma (FL)

There is one phase II study totaling three patients with FL.

5.1 Phase II studies

In the Jacobsen et al. phase II study, three patients had a diagnosis of CD30+ FL. Age and gender data are not reported for this subset. 0% (n = 0) showed an OR. SD was maintained by 66% (n = 2) and 33% (n = 1) experienced PD (Jacobsen et al., 2015).

5. 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 duration 36 weeks) (Younes et al., 2010). In the Gibb et al. phase I study, refractory CD30+ lymphoma patients were treated with BV as a bridge to allogeneic SCT (Gibb et al., 2013). Of the 24 patients in this study, 18 had HL, five had sALCL and one had TCL. Gender and age data are not specified for this subset of patients. CD30 positivity was seen in 100% (n = 5), 40% (n = 2) were ALK−, and 60% (n = 3) had unknown ALK status. Complete remission leading to transplant was achieved by 60% (n = 3). Data is not available for the remaining two patients regarding SD versus PD (Gibb et al., 2013). The Fanale et al. phase I trial studied the efficacy of BV as a front-line treatment in peripheral TCL patients including sALCL (n = 32) (Fanale et al., 2014). Of the 32 patients, 50% (n = 16) were male (median age of 35 years). CD30 positivity was seen in 100% (n = 32) and 19% (n = 6) were ALK+. An OR was experienced by 94% (n = 30) (median duration 52·8 weeks). Of these patients, 75% (n = 24) achieved CR (median duration 105.2 weeks) and 19% (n = 6) experienced a PR. Progressive disease was suffered by 6% (n = 2) (Fanale et al., 2014). Bartlett et al. published a phase I dose-escalation study (Bartlett et al., 2009). Four patients had sALCL. There are no available data separating the gender and age for this subset of patients. CD30 positivity was seen in 100% (n = 4). There were no available ALK expression data. Complete remission was achieved by 75% (n = 3) (median duration N/A). The remaining 25% (n = 1) experienced SD (Bartlett et al., 2009). Fanale et al. published a phase I dose-escalation study with refractory HL (n = 38), sALCL (n = 5) and peripheral T-cell lymphoma (PTCL) (n = 1) (Fanale et al., 2012). There are no available data separating the gender and age for this subset of patients. CD30 positivity was seen in 100% (n = 5) and 20% (n = 1) were ALK+. An OR was experienced by 80% (n = 4) (median duration N/A). Complete remission was achieved by 80% (n = 4) (median duration N/A) and 20% (n = 1) experienced SD (Fanale et al., 2012).

1.2. Phase II studies

The Pro et al. phase II study included 58 relapsed/refractory sALCL patients of which 57% (n = 33) were male and the median age was 52 years (Pro et al., 2012). CD30 positivity was seen in 100% (n = 58) and 72% (n = 42) were ALK+. An OR was experienced by 86% (n = 50) (median duration 50.4 weeks). Fifty seven percent (n = 33) achieved CR (median duration 52.8 weeks) and 29% (n = 17) experienced a PR. Stable disease was maintained by 3% (n = 2) and 5% (n = 3) experienced PD (Pro et al., 2012). In the Ogura et al. phase I/II study looking at CD30+ patients with HL (n = 14) or sALCL (n = 5), 100% (n = 5) were male (median age 41 years) (Ogura et al., 2014). The CD30 biomarker was expressed in 100% (n = 5) and 20% (n = 1) were ALK+. Of these patients, 100% (n = 5) experienced an OR (median duration 38·80 weeks). Eighty percent (n = 4) achieved CR (median duration N/A) and 20% (n = 1) achieved a PR (Ogura et al., 2014). In the Bartlett et al. phase II study looking at retreatment of CD30+ patients with HL (n = 21) or sALCL (n = 8) who initially achieved an OR with BV, the median age of sALCL patients was 51.5 years and male patients made up 50% (n = 4) (Bartlett et al., 2014a). All sALCL patients were CD30+ (n = 8) and 38% (n = 3) of them were ALK+. An OR was experienced by 88% (n = 7) (median duration 28 weeks). Five patients (63%) achieved CR (median duration 20 weeks) and 25% (n = 2) experienced PR (Bartlett et al., 2014a).

1.3 Case reports

Sampson et al. reported a 17-year-old male patient with CD30+ sALCL (no ALK data is available) who relapsed after autologous transplant (Sampson et al., 2012). The patient obtained CR immediately, which lasted up to 69 weeks of follow-up. Heidegger et al. reported a case of 24-year-old male with CD30+ and ALK+ sALCL relapsed/refractory after CHOP therapy (Heidegger et al., 2014). A combination of BV and DHAP was administered as a salvage regimen. The patient achieved CR for three consecutive weeks leading to HSCT (Heidegger et al., 2014). Broccoli et al. detailed two cases of sALCL (Broccoli et al., 2013). A 65-year-old male with CD30+ and ALK− relapsed sALCL achieved PR after first treatment and CR after third cycle (nine weeks). At last follow-up, the patient was still in CR (duration 36 weeks). The second case was a 73-year-old female with CD30+ ALK− relapsed/refractory sALCL. After three cycles of BV (12 weeks), the patient experienced notable drug-induced peripheral neuropathy and BV was discontinued. At a follow-up of 40 weeks, the patient was in CR (Broccoli et al., 2013).

2. Sézary Syndrome (SS)/Mycosis Fungoides (MF)

There are three phase II studies and four case reports totaling 91 patients with MF (n = 79) and SS (n = 13).

2.1 Phase II studies

Bashey et al. published a phase II abstract detailing BV in the treatment of MF (n = 14) and SS (n = 1) with variable CD30 expression (Bashey et al., 2012). Median age was 64 years. Gender data are not available. An OR was observed in 60% (n = 9) (not specified CR versus PR). Median duration is unknown. Of the patients who did not experience an OR, the data do not specify SD versus PD. Kim et al. published a phase II study observing BV in 22 patients with MF and 10 patients with SS (Kim et al., 2014). CD30 expression was variable. Gender differentiating data are not available. The median age was 62-years-old. An OR was experienced by 70% (n = 21) in which CR was achieved by 3% (n = 1; SS) and 66% (n = 20) experienced PR. Stable disease was maintained by 13% (n = 4) and 17% (n = 5) experienced PD. Duvic et al. published a phase II study observing BV activity in CD30+ cutaneous TCL and lymphoproliferative disorders (Duvic et al., 2013). Of the 48 total patients, there were 28 with CD30+ MF and seven with CD30+ MF with LyP. Gender and age information are not specified for these subpopulations. Of these patients, 60% (n = 21) achieved an OR (median duration 14·4 weeks). Eight patients (23%) achieved CR (median duration not reported) and 37% (n = 13) experienced a PR.

2.2 Case reports

Devarakonda et al. detailed a case report regarding a male (age not reported) with relapsed CD30+ MF (Devarakonda and Haddad, 2012). This patient achieved CR after three cycles (nine weeks) and continued for two more cycles at time of publication. Mehra et al. detailed a case report of four patients with MF/SS (Mehra et al., 2015). Three patients had MF and one had SS. Three-quarters (n = 3) were male (median age 50.5 years). All patients (n = 4) were CD30+. An OR was observed in 50% (n = 2). Twenty-five percent (n = 1) achieved CR and 25% (n = 1) experienced a PR. These patients promptly received allogenic HSCT. The patient who experienced the CR was still in CR 32 weeks after transplantation. The patient who experienced PR relapsed after transplantation and eventually expired. One patient (25%) experienced PD and later expired. Mody et al. detailed two case reports of male patients with CD30+ MF (Mody et al., 2013). Both patients were male (75 years and 87 years). Both patients achieved CR for a median duration of 27 weeks. Saintes et al. detailed two case reports of BV use in relapsed/refractory MF/SS (Saintes et al., 2015). One of a male patient with CD30+ MF and one of a male patient with CD30+ SS. Age data were not available. Both patients experienced a PR for a median duration of 31.5 weeks.

3. Peripheral T-cell lymphoma/Angioimmunoblastic T-cell lymphoma

3.1 Phase I studies

There are four phase I studies totaling 10 patients with PTCL. Younes et al. published a phase I study and one patient in this study had a diagnosis of CD30+ angioimmunoblas-tic TCL (Younes et al., 2010). Age and gender of this patient are not detailed separately. This patient experienced PD. Of note, this patient had the best response of those in the low dose cohort. Gibb et al. published a phase I study looking at BV as bridge therapy for allogenic SCT in patients with HL, ALCL or CD30+ TCL (Gibb et al., 2013). One patient in this study had CD30+ TCL. The age and gender of this patient are not detailed separately. This patient experienced either PD or death prior to follow-up PET after 4 cycles (1 of 4 in this category; results not specific to TCL). Fanale et al. published a phase I study looking at BV as front-line therapy for patients with TCL (Fanale et al., 2014). Seven patients fall into the category of PTCL [PTCL-NOS (n = 2), angioimmunoblastic TCL (n = 2); enteropathy associated TCL (n = 1), TCL (n = 2)]. Of these patients, 14% (n = 1) were male (median age 55 years). All patients (n = 7) were CD30+. An OR was observed in 100% (n = 7) of patients (median duration 56·7 weeks). All patients (n = 7) achieved CR as well (median duration 56·7 weeks). An additional phase I study performed by Fanale et al. details one patient, diagnosed with CD30+ TCL, who experienced a PR for an unknown duration (Fanale et al., 2012).

3.2. Phase II studies

Horwitz et al. published a phase II study observing BV efficacy in relapsed TCL (Horwitz et al., 2014). This study included a total of 35 patients with PTCL (PTCL-NOS [n = 22], angioimmunoblastic TCL [n = 13]). Males comprised 77% (n = 27) (median age 64 years). All of these patients were CD30+. An OR was observed in 41% (n = 14) (median duration 30.4 weeks). Complete remission was achieved in 24% (n = 8) (median duration 30.4 weeks) and 18% (n = 6) experienced a PR. Stable disease was maintained in 18% (n = 6) and 41% (n = 14) experienced PD.

4. Lymphatoid Papulosis (LyP)

4.1 Phase II studies

Duvic et al. published a phase II study observing BV activity in CD30+ cutaneous TCL and lymproliferative disorders (Duvic et al., 2013). Of the 48 total patients, there were nine with CD30+ LyP alone. Gender and age information are not specified for this subpopulation. All of these patients (n = 9) achieved an OR (median duration 23 weeks). Complete remission was achieved by 56% (n = 5) and 44% (n = 4) experienced a PR.

5. Primary Cutaneous ALCL

There is one phase II study and two case reports totaling six patients with primary cutaneous ALCL (pc-ALCL).

5.1. Phase II studies

Duvic et al. published a phase II study observing BV activity in CD30+ cutaneous TCL and lymphoproliferative disorders (Duvic et al., 2013). Of the 48 total patients, there were two with CD30+ pc-ALCL and two with CD30+ pc-ALCL and LyP. Gender and age information are not specified for these sub-populations. All of these patients (n = 4) achieved an OR (median duration 18 weeks). All four patients achieved CR (median duration 10 weeks).

5.2. Case reports

Patsinakidis et al. detailed a case report of a 56-year-old male with CD30+ and ALK− pc-ALCL (Patsinakidis et al., 2015). The patient achieved PR after four weeks and CR after another four weeks. No follow-up data is available. Kaffenberger et al. detailed a case report of a 60-year-old male with CD30+, ALK− refractory pc-ALCL (Kaffenberger et al., 2013). After two cycles (six weeks) the patient experienced CR, which continued through follow-up at 56 weeks.

6. 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 size of the suprclavicular lesion over the following 72 h, although the patient expired from a significant GI bleed (Holderness et al., 2013).

2. Germ Cell Tumors (GCT)

CD30 positivity is seen in germ cell tumors 5 (Dürkop et al., 2000; Pallesen and Hamilton-Dutoit, 1988; Hittmair et al., 1996; Chiarle et al., 1999; Leroy et al., 2002). There is one phase II study totaling three patients with germ cell tumors. There is a need for studies both in the pre-clinical and clinical settings (Sharman et al., 2012).

2.1 Phase II studies

Albany et al. published a phase II abstract evaluating BV activity in CD30+ non-lymphomatous malignancies (Albany et al., 2013). Of the 84 total enrolled patients, there were three with CD30+ relapsed or refractory testicular cancer. All three patients were male with a median age of 26 years. Two of these patients (66%) achieved an OR (median duration NR), both of which were PRs. One patient (33%) experienced SD (median duration NR).

3. Mastocytosis

3.1 Case reports

Borate et al. details four patients with aggressive or indolent systemic mastocytosis (SM) (Borate et al., 2016). All patients (n = 4) were CD30 positive, and 75% (n = 3) were male (median age 63 years). One patient (25%) experienced PR (median duration 144 weeks), one patient showed SD (25%), and two patients (50%) had no response. There is a need for further studies in both the pre-clinical and clinical settings.

7. 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) maintained SD and 11% (n = 11) experienced PD.

GZL

There are seven patients over one phase II study and one case report. All patients (n = 7) were CD30+. Of these, 57% (n = 4) experienced an OR (median duration not segregated for these respective studies). Complete remission was achieved by 29% (n = 2), 29% (n = 2) experienced PR, 29% (n = 2) maintained SD and 14% (n = 1) experienced PD.

PMBL

There is one phase II study totaling six patients. CD30 positivity was seen in 100% (n = 6). Of these, 17% (n = 1) experienced an OR. Complete remission was achieved in 17% (n = 1), 50% (n = 3) maintained SD and 33% (n = 2) experienced PD.

FL

There is one phase II study totaling three patients with FL (Jacobsen et al., 2015). All of these patients (n = 3) were CD30+. No patients experienced an OR, 66% (n = 2) maintained SD and 33% (n = 1) experienced PD.

ALCL

There are 123 patients over eight phase I and phase II studies, in addition to three case reports. CD30 positivity was seen in 100% (n = 123) with variable expression while 48% (n = 56) were ALK+. An OR was seen in 87% (n = 108) of these patients (median duration 41.31 weeks). Complete remission achieved in 65% (n = 80) (median duration 53.50 weeks), 23% (n = 28) experienced PR, SD was maintained in 3% (n = 4) and 4% (n = 5) experienced PD.

SS/MF

There are 91 patients over three phase I/phase II studies and four case reports (79 MF, 13 SS). All patients (n = 91) were CD30+ with variable expression. Sixty five percent (n = 58) experienced an OR (median duration 14.4 weeks). Complete remission was achieved in 17% (n = 13), 46% (n = 35) experienced a PR, SD was maintained in 5% (n = 4) and 7% (n = 5) experienced PD.

TCL

There are four phase I and one phase II study totaling 45 patients with PTCL. Of the available gender data, 67% (n = 28) were male (median age 58 years). All patients (n = 45) were CD30+ with variable expression. Of these, 48% (n = 22) experienced an OR (median duration 43.55 weeks). Complete remission was achieved in 35% (n = 15) (median duration 43.55 weeks), 16% (n = 7) experienced a PR, SD was maintained in 13% (n = 6) and 36% (n = 16) experienced PD.

LyP

There are nine total patients within one phase II study. All patients (n = 9) were CD30+. Of these, 100% (n = 9) achieved an OR (median duration 23 weeks). Complete remission was achieved by 56% (n = 5) and 44% (n = 4) experienced a PR.

pc-ALCL

There are six total patients over one phase II study and two case reports. All patients (n = 6) were CD30+. Of these, 100% (n = 6) experienced an OR (median duration 26 weeks) all of which were classified as CR (median duration 17 weeks).

PBL

There are two total patients over one phase II study and one case report. All patients (n = 2) were CD30+. An OR was experienced by 50% (n = 1) (median duration three days). A PR was experienced by 50% (n = 1) (median duration three days) and 50% (n = 1) experienced PD.

8. 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 correlation between surface expression of CD30 and expression of cytoplasmic CD30 remains unclear (Blatt et al., 2015). CD30 targeting has shown to produce growth inhibition (G2/M cell cycle arrest) and apoptosis in neoplastic cells. The bystander effect and Fc portion mediated antibody dependent phagocytosis are also postulated as possible mechanisms for activity. CD30 expression is possibly regulated in many ways, one of which is the RAS-MEK-dependent pathway as described in MCs. Other proposed mechanisms include the nuclear factor-kB (NF-kB) pathway, MAPKs (i.e. extracellular-regulated kinase [ERK], Jun N-terminal kinase [JNK]) and p38 (Al-Shamkhani, 2004).

Understanding about laboratory methods to define and determine CD30 expression (cytoplasmic, serum and surface), its correlation with targeted drug therapy and clinical outcome is evolving. CD30 determination is commonly done by routine immunohistochemistry (IHC) staining using the antibody like anti-CD30 BerH2. CD30 positivity is defined as >1% surface expression on neoplastic cells. CD30 surface expression can be determined by computer-assisted methods using pixel-based image processing techniques. Soluble CD30 (sCD30) concentrations can be measured with commercial bead-based sandwich fluoroimmunoassay. Studies have shown that it is possible to have elevated sCD30 at baseline and quantifiable level of CD30 expression by computer-assisted methods, even if the visual assessment of IHC is negative for CD30 expression. Data reveal that there is a lack of clear correlation between the level of surface CD30 or sCD30 and response to BV. Many hypotheses are postulated to explain this discrepancy such as heterogeneous CD30 expression within the tumor with the possibility of a minimum threshold of CD30 required for clinical response (Jacobsen et al., 2015).

After excluding the data from studies in HL, we summarized data for NHLs and included results of phase I/II clinical trials (n = 14). Data from case reports (n = 14) was included due to the paucity of data on the subject and lack of randomized trials. There is no available phase III data on the subject. We stratify the study populations into three specific groups: B-cell malignancies (group A), T-cell malignancies (group B), and non-B or non-T-cell hematological malignancies (group C). We found clinical evidence for the efficacy of BV in twelve non-Hodgkin hematological malignancy subtypes.

Among B-cell lymphomas including DLBCL, FL, PMBL, PTLD, and GZL studies, 51% (n = 44) of patients achieved an OR and 29% (n = 25) achieved CR with BV treatment. In a small study by Bartlett et al., it was observed that in DLBCL patients even with undetectable CD30 by traditional IHC staining, an OR was observed in 27% (n = 6) of patients. Only three patients were treated with advanced FL and two of these showed SD at best. Out of six patients with relapsed/refractory PMBL, three patients had SD and one CR was seen. Among less than ten PTLD patients, almost half showed an OR (Bartlett et al., 2014b). Among patients with T-cell lymphomas with evidence of CD30 expression by IHC, 48% (n = 22) of these patients experienced an OR and 35% (n = 15) achieved CR. Additionally, ALCL patients showed objective responses in 87% of cases. Similarly, objective responses were noted in other subtypes such as LyP patients in which experience is limited (n = 9) but 100% positive responses were observed.

We recognize that limitations of this review are heterogeneity in disease subtypes and study design. Publication results are confounded by unmatched variable prognostic factors such as age, gender, prognostics score, molecular and genetic subtype, IPI score, grade and lymphoma stage, type, number of prior chemo- or immunotherapies, variable CD30 expression all of these are important factors to consider but have not been elaborated in many trials.

Further research, with appropriately powered prospective studies and strict diagnosis with clear identification of CD30 expression by IHC, sCD30 and computer assisted techniques along with other variables like prognostic factors, IPI score, grade, stage, prior therapies and outcome ascertainment, are needed to understand the BV efficacy in various CD30 positive malignancies. Ongoing studies with BV in CD30 positive hematological malignancies are summarized in Table 1. BV is being tested in various combinations with immunomodulatory agents such as lenalidomide, rituximab, single agent bendamustine and multi-agent chemotherapy, which may exhibit synergistic growth-inhibitory effects. Such combinations need to be tested based on pathologically active intracellular mechanism in each disease subtype. BV needs to be further studied in the setting of autologous and allogenic HSCT for CD30+ malignancies to prevent post-HSCT relapse (Taverna et al., 2016; Gopal et al., 2012).

Table 1.

Ongoing Clinical Trials.

Study Pathology Interventions Outcomes
Phase I/II
NCT01657331 		HL, ALCL BV+ Bendamustine Safety and Efficacy
Phase II
NCT02388490 		Relapsed/refractory EBV and CD30 positive lymphomas BV ORR
Phase II
NCT01393717 		Relapse/refractory HL BV prior to Auto SCT Efficacy
Phase I/II
NCT01805037 		EBV and CD30 positive lymphomas BV+ Rituximab as a first treatment Safety and Efficacy
Phase I/II
NCT02096042 		AML BV + 5-Azacytidine Safety and Efficacy
Phase I/II
NCT01771107 		Stage II–IV HIV associated HL BV + AVD Safety and Efficacy
Phase II
NCT02567851 		HL BV Efficacy
Phase II
NCT02423291 		Relapse/refractory PMLBCL BV Safety and Efficacy
Phase I/II
NCT01492088 		Pediatric relapsed/refractory HL and ALCL BV Safety and Efficacy
Phase0
NCT01900496 		Relapsed/refractory HL BV+ Rituximab Efficacy
Phase I
NCT02254239 		Relapsed/refractory HL BV+ Everolimus Safety
Phase I/II
NCT02462538 		Relapsed/refractory ALK positive ALCL BV+ Imatinib Safety and Efficacy
Phase IV
NCT01990534 		Relapsed/refractory HL BV Efficacy
Phase II
NCT02298257		 Stage III–IV HIV associated HL BV Safety and Efficacy
Phase I
NCT01896999 		Relapsed/refractory HL BV+ Ipilimumab/nivolumab Safety and Efficacy
Phase II
NCT02169505 		High risk CD30 positive lymphoma BV post allogeneic SCT Safety and Efficacy
Phase I
NCT02164006 		HL BV + PI3 K inhibitor (TGR-1202) Safety and Efficacy
Phase I/II
NCT02227199 		Relapsed/refractory HL BV + ICE Safety and Efficacy
Phase III
NCT01578499 		CD30 positive cutaneous T-cell lymphoma BV vs. Physician’s choice (methotrexate or bexarotene) Efficacy
Phase II
NCT01979536 		Stage II–IV ALCL BV vs. Crizotinib in combination with chemotherapy as a first treatment Safety and Efficacy
Phase I
NCT01979536 		Relapse/refractory DLBCL BV+ Lenalidomide Safety
Phase II
NCT01925612 		DLBCL BV + RCHOP or RCHP Safety and Efficacy
Phase II
NCT01716806 		Newly diagnosed HL in adults age 60 and above BV single agent
BV + Dacarbazine
BV + Bendamustine		 Efficacy
Phase II
NCT02588651 		Relapsed/refractory CD30 low (< 10%) mature T-cell lymphoma BV Efficacy
Phase I/II
NCT01874054 		HL BV + Bendamustine Safety and Efficacy
Phase II
NCT02280785 		Relapsed/refractory CD30 positive NHL other than ALCL BV Efficacy
Phase II
NCT02505269 		Non-bulky limited stage HL BV + Adriamycin + Dacarbazine Efficacy
Phase I/II
NCT02429375 		Relapsed/refractory HL BV + Mocetinostat (MGCD0103) Safety and Efficacy
Phase I/II
NCT02581631 		NHL BV + Nivolumab Safety and Efficacy
Phase III
NCT02684292 		Relapsed/refractory HL BV vs. Pembrolizumab Safety and Efficacy
Phase IV
NCT01909934 		Relapsed/refractory systemic ALCL BV Safety and Efficacy
Phase I/II
NCT02572167 		Relapsed/refractory HL BV + Nivolumab Safety and Efficacy
Phase II
NCT02227433 		First relapse or primary refractory elderly HL BV Efficacy
Phase II
NCT02594163 		CD30 positive DLBCL Rituximab and Bendamustine ± BV Safety and Efficacy
Phase I
NCT01309789 		CD30 positive mature T-cell and NK neoplasms BV + Chemotherapy Safety
Phase II
NCT02497131 		Relapsed/refractory CD30 positive PTCL BV Safety and Efficacy
Phase II
NCT02623920 		Relapsed/refractory B-cell NHL BV + Rituximab + Bendamustine Efficacy
Phase II
NCT02275598 		Previously untreated HL BV followed by AVBD Safety and Efficacy
Phase II
NCT02191930 		Older patients with newly diagnosed HL BV + CAP Safety and Efficacy
Phase I
NCT02616965 		Cutaneous T-cell lymphoma BV + Romidepsin Safety and Efficacy
Phase II
NCT02292979 		Untreated HL BV + ABVD Safety and Efficacy
Phase I/II
NCT01994850 		CD30 positive PMLBCL, DLBCL, GZL BV + Chemotherapy Safety and Efficacy
Phase II
NCT01476410 		Older patient with previously untreated Stage II–IV HL BV + Chemotherapy Efficacy
Phase II
NCT01352520 		CD30 positive ALCL, MF, LyP BV Safety and Efficacy
Open in a new tab

Abbreviation: HL (Hodgkin lymphoma), NHL (non-Hodgkin lymphoma), Primary mediastinal large B-cell lymphoma (PMLBCL), ALCL (anaplastic large cell lymphoma), DLBCL (diffuse large B-cell lymphoma), GZL (gray zone lymphoma), MF (mycosis fungoides), LyP (lymphomatoid papulosis), BV (brentuximab vedotin), ICE (ifosfamide + carboplatin + etoposide), RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), RCHP (rituximab, cyclophosphamide, doxorubicin, and prednisone), CAP (cyclophosphomaide, doxorubicin, prednisone).

In conclusion, these studies have shown that the antibody-drug conjugate brentuximab vedotin induced positive responses in a variety of relapse and refractory NHL.

Acknowledgments

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 design, data collection, data analysis, data interpretation

IBR: data interpretation, writing, editing

AAS: literature search, study design, writing, editing

SP: data interpretation, writing, editing

FA (corresponding author): literature search, study design, data analysis, data interpretation, writing, editing

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.

Appendix 1. : Example Search Strategy

PubMed (1946–2015)Date searched: May 22, 2015

(((((“Hematologic Neoplasms” [Mesh:NoExp] OR “Lymphoma” [Mesh:NoExp] OR “Lymphoma, Non-Hodgkin” [Mesh] OR NHL [tw] OR (non [tw] AND hodgkin* [tw]) OR nonhodgkin* [tw] OR ((“b cell” [tw] OR “t cell” [tw] OR burkitt* [tw] OR “primary effusion” [tw] OR granulomatosis [tw] OR follicular [tw] OR immunoblastic [tw] OR lymphoblastic [tw] OR “mantle cell” [tw] OR anaplastic [tw] OR cutaneous* [tw] OR malt [tw] OR “mucosa associated lymphoid tissue” [tw] OR aggressive [tw] OR indolent [tw]) AND (lymphoma* [tw] OR malignan* [tw])) OR Dlbcl [tw] OR dlbl [tw] OR “papulosislymphomatoid” [tw] OR “mycosis fungoides” [tw] OR “pagetoidreticulosis” [tw] OR “sezary syndrome” [tw] OR ((cd30 [tw] OR cd30+ [tw] OR “cd 30” [tw] OR “cd 30+” [tw]) AND (lymphoma* [tw] OR malignan* OR neoplasm* [tw])))) AND ((“cAC10-vcMMAE” [Supplementary Concept] OR “Immunoconju-gates”[Mesh:NoExp] OR Brentuximab [tw] OR Adcetris [tw] OR Anti-cd30 [tw] OR “Antibody drug conjugate” [tw] OR SGN-35 [tw] OR SGN35 [tw] OR cAC10-vcMMAE [tw]))))) NOT (animals [mh] NOT humans [mh])

Footnotes

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 other authors have nothing to disclose.

References

  1. Aggerholm-Pedersen N, Bærentzen S, Holmberg Jørgensen JP, Safwat A. A rare case of CD30+, radiation-induced cutaneous angiosarcoma misdiagnosed as T-cell lymphoma. J Clin Oncol. 2011;29(13):e362–e364. doi: 10.1200/JCO.2010.33.3641. [DOI] [PubMed] [Google Scholar]
  2. Al-Shamkhani A. The role of CD30 in the pathogenesis of haematopoietic malignancies. Curr Opin Pharmacol. 2004;4(4):355–359. doi: 10.1016/j.coph.2004.02.007. [DOI] [PubMed] [Google Scholar]
  3. Albany C, Feldman DR, Garbo LE, Einhorn LH. Antitumor activity of brentuximab vedotin in CD30 positive refractory germ cell tumors. J Clin Oncol. 2013;31(6) [Google Scholar]
  4. Argrawal B, Reddish M, Longenecker BM. CD30 expression on human CD8+ T cells isolated from peripheral blood lymphocytes of normal donors. J Immunol (Baltimore, Md: 1950) 1996;157(8):3229–3234. [PubMed] [Google Scholar]
  5. Bartlett N, Forero-Torres A, Rosenblatt J, Fanale M, Horning SJ, Thompson S, et al. Complete remissions with weekly dosing of SGN-35, a novel antibody-drug conjugate (ADC) targeting CD30, in a phase I dose-escalation study in patients with relapsed or refractory Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL) J Clin Oncol. 2009;27(15):8500. [Google Scholar]
  6. Bartlett NL, Chen R, Fanale MA, Brice P, Gopal A, Smith SE, et al. Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies. J Hematol Oncol. 2014a;7:24. doi: 10.1186/1756-8722-7-24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bartlett NL, Smith MR, Advani R, Feldman T, Savage KJ, Palanca-Wessels MC, et al. Brentuximab vedotin monotherapy in DLBCL patients with undetectable CD30: preliminary results from a phase 2 study. Blood. 2014b;124(21) [Google Scholar]
  8. Bashey S, Krathen M, Sutherland K, Sundram U, Lingala B, Horwitz S, et al. Exploratory study of brentuximab vedotin (SGN-35), a novel monoclonal antibody-drugconjugate against CD30, in mycosis fungoides (MF) and Sézary syndrome (SS) demonstrates clinical responses regardless of CD30 expression levels. J Invest Dermatol. 2012;132:S95. [Google Scholar]
  9. Blatt K, Cerny-Reiterer S, Schwaab J, Sotlar K, Eisenwort G, Stefanzl G, et al. Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis. Blood. 2015;126(26):2832–2841. doi: 10.1182/blood-2015-03-637728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bode PK, Barghorn A, Fritzsche FR, Reiner MO, Kristiansen G, Knuth A, et al. MAGEC2 is a sensitive and novel marker for seminoma: a tissue microarray analysis of 325 testicular germ cell tumors. Mod Pathol. 2011;24(6):829–835. doi: 10.1038/modpathol.2011.6. [DOI] [PubMed] [Google Scholar]
  11. Brentuximab vedotin [package insert] Seattle Genetics, I; Bothell, WA: 2011. < http://www.seattlegenetics.com/pdf/adcetris_USPI.pdf>(Accessed 04/21/2016. [Google Scholar]
  12. Broccoli A, Derenzini E, Pellegrini C, Narducci R, Stefani G, Casadei B, et al. Complete response of relapsed systemic and cutaneous anaplastic large cell lymphoma using brentuximab vedotin: 2 case reports. Clin Lymph Myeloma Leuk. 2013;13(4):493–495. doi: 10.1016/j.clml.2013.03.008. [DOI] [PubMed] [Google Scholar]
  13. Chiarle R, Podda A, Prolla G, Gong J, Thorbecke GJ, Inghirami G. CD30 in normal and neoplastic cells. Clin Immunol. 1999;90(2):157–164. doi: 10.1006/clim.1998.4636. [DOI] [PubMed] [Google Scholar]
  14. Dürkop H, Foss HD, Eitelbach F, Anagnostopoulos I, Latza U, Pileri S, et al. Expression of the CD30 antigen in non-lymphoid tissues and cells. J Pathol. 2000;190(5):613–618. doi: 10.1002/(SICI)1096-9896(200004)190:5<613::AID-PATH559>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
  15. Devarakonda SS, Haddad PA. Activity of brentuximab vedotin (adcetris TM) in replaced progressive CD30+ transformed mycosis fungoides (TMF) J Immunother. 2012;35(9):781. [Google Scholar]
  16. Dunphy CH. Malignant mesothelioma with CD30-positivity: a case report and review of the literature. Arch Pathol Lab Med. 2000;124(7):1077–1079. doi: 10.5858/2000-124-1077-MMWCP. [DOI] [PubMed] [Google Scholar]
  17. Duvic M, Tetzlaff M, Clos AL, Gangar P, Talpur R. Phase II trial of brentuximab vedotin for CD30+ cutaneous T-Cell lymphomas and lymphoproliferative disorders. Blood. 2013;122(21) [45] [Google Scholar]
  18. Fanale MA, Forero-Torres A, Rosenblatt JD, Advani RH, Franklin AR, Kennedy DA, et al. A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies. Clin Cancer Res. 2012;18(1):248–255. doi: 10.1158/1078-0432.CCR-11-1425. [DOI] [PubMed] [Google Scholar]
  19. Fanale MA, Horwitz SM, Forero-Torres A, Bartlett NL, Advani RH, Pro B, et al. Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a phase I study. J Clin Oncol. 2014;32(28):3137–3143. doi: 10.1200/JCO.2013.54.2456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ferri FF. Lymphoma, Non-Hodgkin. 2015. Elsevier Mosby; Philadelphia, PA: 2015. pp. 716–718. [Google Scholar]
  21. Gandhi M, Ma S, Smith SM, Nabhan C, Evens AM, Winter JN, et al. Brentuximab vedotin (BV) plus rituximab (R) as frontline therapy for patients (pts) with epstein barr virus (EBV)+ and/or CD30+ lymphoma: phase I results of an ongoing phase I–II study. Blood. 2014;124(21) [Google Scholar]
  22. Garcia-Prats MD, Ballestin C, Sotelo T, Lopez-Encuentra A, Mayordomo JI. A comparative evaluation of immunohistochemical markers for the differential diagnosis of malignant pleural tumours. Histopathology. 1998;32(5):462–472. doi: 10.1046/j.1365-2559.1998.00405.x. [DOI] [PubMed] [Google Scholar]
  23. Gibb A, Jones C, Bloor A, Kulkarni S, Illidge T, Linton K, et al. Brentuximab vedotin in refractory CD30+ lymphomas: a bridge to allogeneic transplantation in approximately one quarter of patients treated on a Named Patient Programme at a single UK center. Haematologica. 2013;98(4):611–614. doi: 10.3324/haematol.2012.069393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gopal AK, Ramchandren R, O’Connor OA, Berryman RB, Advani RH, Chen R, et al. Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood. 2012;120(3):560–568. doi: 10.1182/blood-2011-12-397893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Gopalan A, Dhall D, Olgac S, Fine SW, Korkola JE, Houldsworth J, et al. Testicular mixed germ cell tumors: a morphological and immunohistochemical study using stem cell markers, OCT3/4, SOX2 and GDF3, with emphasis on morphologically difficult-to-classify areas. Mod Pathol. 2009;22(8):1066–1074. doi: 10.1038/modpathol.2009.66. [DOI] [PubMed] [Google Scholar]
  26. Heidegger S, Beer AJ, Geissinger E, Rosenwald A, Peschel C, Ringshausen I, et al. Combination therapy with brentuximab vedotin and cisplatin/cytarabine in a patient with primarily refractory anaplastic lymphoma kinase positive anaplastic large cell lymphoma. Onco Targets Ther. 2014;7:1123–1127. doi: 10.2147/OTT.S59795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hill BT, Tubbs Do RR, Smith MR. Complete remission of CD30 positive diffuse large B-cell lymphoma (DLBCL) in a patient with post-transplant lymphoproliferative disorder (PTLD) and end-stage renal disease treated with single agent brentuximab vedotin. Leukemia Lymphoma. 2014 doi: 10.3109/10428194.2014.911865. [DOI] [PubMed] [Google Scholar]
  28. Hittmair A, Rogatsch H, Hobisch A, Mikuz G, Feichtinger H. CD30 expression in seminoma. Hum Pathol. 1996;27(11):1166–1171. doi: 10.1016/s0046-8177(96)90310-x. [DOI] [PubMed] [Google Scholar]
  29. Holderness BM, Malhotra S, Levy NB, Danilov AV. Brentuximab vedotin demonstrates activity in a patient with plasmablastic lymphoma arising from a background of chronic lymphocytic leukemia. J Clin Oncol. 2013;31(12):e197–e199. doi: 10.1200/JCO.2012.46.9593. [DOI] [PubMed] [Google Scholar]
  30. Horwitz SM, Advani RH, Bartlett NL, Jacobsen ED, Sharman JP, O’Connor OA, et al. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood. 2014;123(20):3095–3100. doi: 10.1182/blood-2013-12-542142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Jacobsen ED, Sharman JP, Oki Y, Advani RH, Winter JN, Bello CM, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015;125(9):1394–1402. doi: 10.1182/blood-2014-09-598763. [DOI] [PubMed] [Google Scholar]
  32. Kaffenberger BH, Kartono Winardi F, Frederickson J, Porcu P, Wong HK. Periocular cutaneous anaplastic large cell lymphoma clearance with brentuximab vedotin. J Clin Aesthet Dermatol. 2013;6(8):29–31. [PMC free article] [PubMed] [Google Scholar]
  33. Kim YH, Tavallaee M, Rozati S, Sundram U, Salva K, Wood GS, et al. Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides or sezary syndrome: final results show significant clinical activity and suggest correlation with CD30 expression. Blood. 2014;124(21) [Google Scholar]
  34. Kneile JR, Tan G, Suster S, Wakely PEJ. Expression of CD30 (Ber-H2) in nasopharyngeal carcinoma, undifferentiated type and lymphoepithelioma-like carcinoma: a comparison study with anaplastic large cell lymphoma. Histopathology. 2006;48(7):855–861. doi: 10.1111/j.1365-2559.2006.02449.x. [DOI] [PubMed] [Google Scholar]
  35. Latza U, Foss HD, Dürkop H, Eitelbach F, Dieckmann KP, Loy V, et al. CD30 antigen in embryonal carcinoma and embryogenesis and release of the soluble molecule. Am J Pathol. 1995;146(2):463–471. [PMC free article] [PubMed] [Google Scholar]
  36. Lau SK, Weiss LM, Chu PG. D2–40 immunohistochemistry in the differential diagnosis of seminoma and embryonal carcinoma: a comparative immunohistochemical study with KIT (CD117) and CD30. Mod Pathol. 2007;20(3):320–325. doi: 10.1038/modpathol.3800749. [DOI] [PubMed] [Google Scholar]
  37. Leroy X, Augusto D, Leteurtre E, Gosselin B. CD30 and CD117 (c-kit) used in combination are useful for distinguishing embryonal carcinoma from seminoma. J Histochem Cytochem. 2002;50(2):283–285. doi: 10.1177/002215540205000216. [DOI] [PubMed] [Google Scholar]
  38. Mariño-Enríquez A, Wang WL, Roy A, Lopez-Terrada D, Lazar AJ, Fletcher CD, et al. Epithelioid inflammatory myofibroblastic sarcoma: an aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK. Am J Surg Pathol. 2016;35(1):135–144. doi: 10.1097/PAS.0b013e318200cfd5. [DOI] [PubMed] [Google Scholar]
  39. Mechtersheimer G, Moller P. Expression of Ki-1 antigen (CD30) in mesenchymal tumors. Cancer. 1990;66(8):1732–1737. doi: 10.1002/1097-0142(19901015)66:8<1732::aid-cncr2820660815>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  40. Mehra T, Ikenberg K, Moos RM, Benz R, Nair G, Schanz U, et al. Brentuximab as a treatment for CD30+ mycosis fungoides and Sezary syndrome. JAMA Dermatol. 2015;151(1):73–77. doi: 10.1001/jamadermatol.2014.1629. [DOI] [PubMed] [Google Scholar]
  41. Menasce LP, Eyden B. Nasopharyngeal carcinoma mimicking large-cell anaplastic lymphoma. Histopathology. 2005;46(3):342–344. doi: 10.1111/j.1365-2559.2004.02007.x. [DOI] [PubMed] [Google Scholar]
  42. Mody K, Wallace JS, Stearns DM, Bowers G, Lacy SR, Levy NB, et al. CD30-positive cutaneous T-cell lymphoma and response to Brentuximab Vedotin: 2 illustrative cases. Clin Lymph Myeloma Leuk. 2013;13(3):319–323. doi: 10.1016/j.clml.2012.12.008. [DOI] [PubMed] [Google Scholar]
  43. Muta H, Podack ER. CD30: from basic research to cancer therapy. Immunol Res. 2013;57(1–3):151–158. doi: 10.1007/s12026-013-8464-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Ogura M, Tobinai K, Hatake K, Ishizawa K, Uike N, Uchida T, et al. Phase I/II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30-positive Hodgkin’s lymphoma or systemic anaplastic large-cell lymphoma. Cancer Sci. 2014;105(7):840–846. doi: 10.1111/cas.12435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Pallesen G, Hamilton-Dutoit S. Ki-1 (CD30) antigen is regularly expressed by tumor cells of embryonal carcinoma. Am J Pathol. 1988;133(3):446–450. [PMC free article] [PubMed] [Google Scholar]
  46. Patsinakidis N, Kreuter A, Moritz RK, Stucker M, Altmeyer P, Mollenhoff K. Complete remission of refractory, ulcerated, primary cutaneous CD30+ anaplastic large cell lymphoma following brentuximab vedotin therapy. Acta Derm Venereol. 2015;95(2):233–234. doi: 10.2340/00015555-1874. [DOI] [PubMed] [Google Scholar]
  47. Polski JM, Janney CG. Ber-H2 (CD30) immunohistochemical staining in malignant melanoma. Mod Pathol. 1999;12(9):903–906. [PubMed] [Google Scholar]
  48. Ponugupati JP, Haddad PA. Activity of rituximab-bendamustine (RB) in sequence with brentuximab vedotin (adcetris TM, BV) in gray zone lymphoma (GZL) between hodgkins lymphoma (HL) and diffuse large B cell lymphoma (DLBCL) J Immunother. 2012;35(9):782. [Google Scholar]
  49. Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–2196. doi: 10.1200/JCO.2011.38.0402. [DOI] [PubMed] [Google Scholar]
  50. Saintes C, Saint-Jean M, Renaut JJ, Dreno B, Quereux G. Dramatic efficacy of brentuximab vedotin in two patients with epidermotropic cutaneous T-cell lymphomas after treatment failure despite variable CD30 expression. Br J Dermatol. 2015;172(3):819–821. doi: 10.1111/bjd.13337. [DOI] [PubMed] [Google Scholar]
  51. Sampson B, Triche L, Rytting M. Brentuximab vedotin (SGN 35): prolonged remission in a teen-ager with multiply relapsed anaplastic large cell lymphoma. Br J Haematol. 2012;159:62. [Google Scholar]
  52. Schwarting R, Gerdes J, Durkop H, Falini B, Pileri S, Stein H. BER-H2: a new anti-Ki-1 (CD30) monoclonal antibody directed at a formol-resistant epitope. Blood. 1989;74(5):1678–1689. [PubMed] [Google Scholar]
  53. Sharman JP, Goldschmidt JH, Burke JM, Hellerstedt BA, McIntyre K, Yasenchak CA, et al. CD30 expression in nonlymphomatous malignancies. J Clin Oncol. 2012;30(15) [15] [Google Scholar]
  54. Stein H, Gerdes J, Schwab U, Lemke H, Mason DY, Ziegler A, et al. Identification of Hodgkin and Sternberg-reed cells as a unique cell type derived from a newly-detected small-cell population. Int J Cancer. 1982;30(4):445–459. doi: 10.1002/ijc.2910300411. [DOI] [PubMed] [Google Scholar]
  55. Suster S, Moran CA, Dominguez-Malagon H, Quevedo-Blanco P. Germ cell tumors of the mediastinum and testis: a comparative immunohistochemical study of 120 cases. Hum Pathol. 1998;29(7):737–742. doi: 10.1016/s0046-8177(98)90284-2. [DOI] [PubMed] [Google Scholar]
  56. Taverna J, Yun S, Jonnaula J, Saleh A, Riaz I, Abraham I, et al. Role of maintenance therapy following high-Dose chemotherapy and autologous hematopoietic cell transplantation in aggressive lymphomas: a systematic review. Biol Blood Marrow Transplant. 2016 doi: 10.1016/j.bbmt.2016.02.007. in press. [DOI] [PubMed] [Google Scholar]
  57. Terada T, Sugiura M. Metastatic hepatocellular carcinoma of skin diagnosed with hepatocyte paraffin 1 and a-fetoprotein immunostainings. Int J Surg Pathol. 2010;18(5):433–436. doi: 10.1177/1066896908318743. [DOI] [PubMed] [Google Scholar]
  58. Weed BR, Folpe AL. Cutaneous CD30-positive epithelioid angiosarcoma following breast-conserving therapy and irradiation: a potential diagnostic pitfall. Am J Dermatopathol. 2008;30(4):370–372. doi: 10.1097/DAD.0b013e31817330ff. [DOI] [PubMed] [Google Scholar]
  59. Yasenchak CA, Farber CM, Budde LE, Ansell SM, Advani R, Holkova B, et al. Brentuximab vedotin in combination with RCHOP as front-line therapy in patients with DLBCL: interim results from a phase 2 study. Blood. 2014;124(21) [Google Scholar]
  60. Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363(19):1812–1821. doi: 10.1056/NEJMoa1002965. [DOI] [PubMed] [Google Scholar]
  61. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183–2189. doi: 10.1200/JCO.2011.38.0410. [DOI] [PMC free article] [PubMed] [Google Scholar]

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