pISSN 1598-2998, eISSN 2005-9256 Cancer Res Treat. 2020;52(2):374-387 https://doi.org/10.4143/crt.2019.198 Original Article Open Access Efficacy of Brentuximab Vedotin in Relapsed or Refractory High-CD30–Expressing Non-Hodgkin Lymphomas: Results of a Multicenter, Open-Labeled Phase II Trial Seok Jin Kim, MD, PhD1 Purpose Dok Hyun Yoon, MD, PhD2 The treatment outcome of brentuximab vedotin (BV) has not been related with CD30 expre- ssion in previous studies enrolling patients with a wide range of CD30 expression level. Jin Seok Kim, MD, PhD3 Thus, this study explored the efficacy of BV in high-CD30–expressing non-Hodgkin lym- MD, PhD4 Hye Jin Kang, phoma (NHL) patients most likely to benefit. Hye Won Lee, MD, PhD5 Hyeon-Seok Eom, MD, PhD5 Materials and Methods Jung Yong Hong, MD, PhD2 This phase II study (Clinicaltrials.gov: NCT02280785) enrolled relapsed or refractory high- CD30–expressing NHL, with BV administered intravenously at 1.8 mg/kg every 3 weeks. Junhun Cho, MD, PhD6 The primary endpoint was > 40% disease control rate, consisting of complete response MD, PhD6 Young Hyeh Ko, (CR), partial response (PR), or stable disease. We defined high CD30 expression as ! 30% 7 Jooryung Huh, MD, PhD tumor cells positive for CD30 by immunohistochemistry. Woo-Ick Yang, MD, PhD8 Weon Seo Park, MD, PhD9 Results High-CD30-expressing NHL patients (n=33) were enrolled except anaplastic large cell lym- Seung-Sook Lee, MD, PhD10 phoma. The disease control rate was 48.5% (16/33) including six CR and six PR; six patients MD, PhD2 Cheolwon Suh, (4CR, 2PR) maintained their response over 16 completed cycles. Response to BV and sur- 1 Won Seog Kim, MD, PhD vival were not associated with CD30 expression levels. Over a median of 29.2 months of follow-up, the median progression-free and overall survival rates were 1.9 months and 6.1 *A list of author’s a!liations appears at the months, respectively. The most common adverse events were fever (39%), neutropenia end of the paper. (30%), fatigue (24%), and peripheral sensory neuropathy (27%). In a post-hoc analysis for the association of multiple myeloma oncogene 1 (MUM1) on treatment outcome, MUM1- negative patients showed a higher response (55.6%, 5/9) than MUM1-positive patients + C +o r+re s+p o+n d+e n+c e +: W +o n+ S +e o +g K +i m +, M+ D +, P+h D+ + + + + + + + + + + + + + + + + + + + + + + (13.3%, 2/15). + D +i v +is i +on + o f + H e+m +a t o+l o +g y +-O +n c +ol o +g y +, + + + + + + D +e p+a r +tm +e n +t o +f M +e d+i c +in e+, S +a m +s u+n g+ M +e d+i c a+l + + Conclusion Center, Sungkyunkwan University School of + + + + + + + + + + + + + + + + + + + + BV performance as a single agent was acceptable in terms of disease control rates and tox- + M +e d+i c +in e+, 8 +1 I+rw +o n +- r o+, G+a n+g n+a m+ - g+u +, + + + + + S +e o +u l +06 3+5 1+, K +o r+e a + + + + + + + + + + + + icity profiles, especially MUM1-negative patients. + T +e l :+ 8 2+-2 -+3 4 +1 0 +-6 5 +4 8 + + + + + + + + + + + + + F +a x +: 8 2+- 2 +-3 4+1 0 +-1 7+5 4+ + + + + + + + + + + + + E +-m +a i l+: w +s k+i m +s m +c @+ s k+k u+. e +d u + + + + + + + + + + + + + + + + + + + + + + + + + + + + Key words + R +e c +ei v +e d + A +p r+il 1+2 ,+2 0 +1 9 + + + + + + + + + + Brentuximab vedotin, Non-Hodgkin lymphoma, CD30, + A +c c +e p +te d+ A+u +gu +st 1+2 ,+ 2 0 +1 9 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Multiple myeloma oncogene-1 + P +u b +li s +h e +d O+n +li n +e A+ u +g u +s t +13 ,+ 2 0+1 9 + + + + + + Introduction tory HL and systemic ALCL based on its high objective res- ponse rates of 75% and 86% in relapsed or refractory HL and systemic ALCL, respectively [2,3]. Subsequent to that appro- Brentuximab vedotin (BV) is an anti-CD30 monoclonal val, the efficacy of BV was evaluated in various subtypes of antibody conjugated with the microtubule-disrupting agent non-Hodgkin lymphoma (NHL), including diffuse large monomethyl auristatin E [1]. CD30, a transmembrane glyco- B-cell lymphoma (DLBCL), primary mediastinal B-cell lym- protein, is uniformly expressed in Hodgkin lymphoma (HL) phoma (PMBCL), peripheral T-cell lymphoma (PTCL), myco- and anaplastic large cell lymphoma (ALCL). BV has been sis fungoides (MF), and various cutaneous T-cell lymphomas previously approved for the treatment of relapsed or refrac- [4-8]. All of these studies enrolled patients with a wide range 374 Copyright ⓒ 2020 by the Korean Cancer Association │ https://www.e-crt.org │ This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Seok Jin Kim, Brentuximab Vedotin for CD30-High Lymphomas of CD30 expression levels, and their response rates were hoc analysis evaluating the associations of EBV positivity and unrelated to CD30 expression level of tumor cells. For exam- MUM1 expression with response to BV and survival out- ple, 70% of patients with cutaneous T-cell lymphomas, inclu- come to find biomarkers. We also re-evaluated the treatment ding MF, responded to BV, and the different cutoff values response to determine the interpatient heterogeneity of res- (< 10%, 10%-50%, and ! 50%) were unrelated to response rate ponse as a post-hoc analysis, and updated the survival status in MF, although patients with < 5% CD30 expression had a on November 30, 2018. lower response likelihood compared with patients with ! 5% expression [4,5]. The response rate to BV was also unrelated with the level of CD30 expression in DLBCL (44%) and PTCL (41%), and these response rates were higher in PMBCL pati- Materials and Methods ents (13.3%) even though PMBCL is typically characterized by high CD30 expression [6-8]. Accordingly, these previous studies enrolling patients with a wide range of CD30 expres- 1. Study design sion levels may not provide sufficiently robust information on the association between CD30 expression and response to This phase 2, open-label, multicenter study was designed BV. Thus, we designed a phase II study to evaluate the effi- to evaluate the efficacy and safety of BV in patients with rela- cacy of BV as a salvage therapy in relapsed or refractory pati- psed or refractory high-CD30–expressing NHL other than ents with high-CD30–expressing NHL other than ALCL. ALCL. All subtypes of NHL including mature B-, T-, or NK- Although a precise definition of high CD30 expression has cell lymphomas except ALCL were eligible for enrollment. not been established, we defined cases having ! 30% of Because all patients were initially diagnosed with NHL CD30-positive tumor cells as high-CD30–expressing NHL before 2017, NHL subtype was classified based on the World considering previous studies have used 10% to 20% of CD30- Health Organization’s 2008 criteria. The primary study positive tumor cells as the cutoff values for CD30 expression objective was to determine the overall rate of disease control, across various subtypes of NHL [9-12]. defined as complete response (CR), partial response (PR), CD30, a member of the tumor necrosis factor receptor and stable disease (SD). Secondary objectives included deter- superfamily, is known to exert a variety of biological func- mining toxicity profiles, progression-free survival (PFS), and tions, including cell cycle regulation, apoptosis, and activa- overall survival (OS). Patients received 1.8 mg/kg BV intra- tion of nuclear factor !-light-chain-enhancer of activated B venously every 3 weeks. Those who achieved SD or better cells (NF-!B). CD30 is preferentially expressed in activated continued to receive treatments up to a maximum of 16 B cells; however, T and natural killer (NK) cells are also cycles. However, in the event of progressive disease (PD) or reported to express CD30 [13]. In addition, Epstein-Barr virus unacceptable toxicity, BV administration should be discon- (EBV) infection-associated lymphomas could express CD30 tinued; dose reduction to 1.2 mg/kg and treatment delay up because latent membrane protein 1, a critical element of EBV to 3 weeks was allowed, depending on the type and severity infection, may promote CD30 expression [14]. Accordingly, of toxicity, including peripheral neuropathy. Blood transfu- previous studies have shown approximately 40% of CD30 sion or granulocyte colony-stimulating factors were allowed expression in extranodal natural killer/T-cell lymphoma for patients with anemia, thrombocytopenia, and neutrope- (ENKTL), in which latent membrane protein 1 is commonly nia. Response evaluation was completed by the investigator expressed [15,16]. CD30 expression is also associated with according to the 2007 Revised International Working Group activation of interferon regulatory factor 4, also known as Response Criteria for Malignant Lymphoma [21]. Baseline multiple myeloma oncogene 1 (MUM1), because CD30 acti- assessment was performed by using computed tomography vation may promote activities of the NF-!B leading to MUM1 (CT) and fluorine-18 deoxyglucose (FDG) positron emission expression [17]. This positive feedback signaling from CD30 tomography/computed tomography (PET/CT) of the neck, to MUM1 might contribute to tumor aggressiveness, because chest, abdomen, and pelvis prior to the first treatment cycle. MUM1 binds directly to the MYC promoter region leading Restaging assessment was performed by CT and PET/CT to cell proliferation [18,19]. Thus, EBV positivity and MUM1 after the second cycle.