Efficacy of Brentuximab Vedotin in Relapsed or Refractory High-CD30–Expressing Non-Hodgkin Lymphomas: Results of a Multicenter, Open-Labeled Phase II Trial
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Purpose The treatment outcome of brentuximab vedotin (BV) has not been related with CD30 expression in previous studies enrolling patients with a wide range of CD30 expression level. Thus, this study explored the efficacy of BV in high-CD30–expressing non-Hodgkin lymphoma (NHL) patients most likely to benefit. Materials and Methods 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. The primary endpoint was > 40% disease control rate, consisting of complete response (CR), partial response (PR), or stable disease. We defined high CD30 expression as ! 30% tumor cells positive for CD30 by immunohistochemistry. Results High-CD30-expressing NHL patients (n=33) were enrolled except anaplastic large cell lymphoma. The disease control rate was 48.5% (16/33) including six CR and six PR; six patients (4CR, 2PR) maintained their response over 16 completed cycles. Response to BV and survival 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 months, respectively. The most common adverse events were fever (39%), neutropenia (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 (13.3%, 2/15). Conclusion BV performance as a single agent was acceptable in terms of disease control rates and toxicity profiles, especially MUM1-negative patients.
Abstract
Purpose The treatment outcome of brentuximab vedotin (BV) has not been related with CD30 expression in previous studies enrolling patients with a wide range of CD30 expression level. Thus, this study explored the efficacy of BV in high-CD30–expressing non-Hodgkin lymphoma (NHL) patients most likely to benefit. Materials and Methods 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. The primary endpoint was > 40% disease control rate, consisting of complete response (CR), partial response (PR), or stable disease. We defined high CD30 expression as ! 30% tumor cells positive for CD30 by immunohistochemistry. Results High-CD30-expressing NHL patients (n=33) were enrolled except anaplastic large cell lymphoma. The disease control rate was 48.5% (16/33) including six CR and six PR; six patients (4CR, 2PR) maintained their response over 16 completed cycles. Response to BV and survival 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 months, respectively. The most common adverse events were fever (39%), neutropenia (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 (13.3%, 2/15). Conclusion BV performance as a single agent was acceptable in terms of disease control rates and toxicity profiles, especially MUM1-negative patients.
참고문헌 (33)
- Francisco JA, "cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity", Blood, 102, pp.1458~1465 (2003)
- Younes A, "Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma", J Clin Oncol, 30, pp.2183~2189 (2012)
- Pro B, "Brentuximab vedotin(SGN-35)in patients with relapsed or refractory systemic anaplastic large-cell lymphoma : results of a phase II study", J Clin Oncol, 30, pp.2190~2196 (2012)
- Duvic M, "Results of a phase II trial of brentuximab vedotin for CD30+cutaneous T-cell lymphoma and lymphomatoid papulosis", J Clin Oncol, 33, pp.3759~3765 (2015)
- Kim YH, "Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sezary syndrome with variable CD30 expression level : a multi-institution collaborative project", J Clin Oncol, 33, pp.3750~3758 (2015)
- Jacobsen ED, "Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed", refractory DLBCL with variable CD30 expression, 2015, pp.125, 1394~1402
- Horwitz SM, "Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin", Blood, 123, pp.3095~3100 (2014)
- Zinzani PL, "Brentuximab vedotin in relapsed primary mediastinal large B-cell lymphoma : results from a phase 2 clinical trial", Blood, 129, pp.2328~2330 (2017)
- Hu S, "CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature : a report from the International DLBCL Rituximab-CHOP Consortium Program Study", Blood, 121, pp.2715~2724 (2013)
- Hao X, "The expression of CD30 based on immunohistochemistry predicts inferior outcome in patients with diffuse large B-cell lymphoma", PLoS One, 10, pp.e0126615~ (2015)
- Schwartz EJ, "Immunohistochemical characterization of nasal-type extranodal NK", T-cell lymphoma using a tissue microarray : an analysis of 84 cases, 2008, pp.130, 343~351
- Li P, "CD30 expression is a novel prognostic indicator in extranodal natural killer", T-cell lymphoma, nasal type, 2014, pp.14, 890~
- Wright CW, "CD30 activates both the canonical and alternative NF-kappaB pathways in anaplastic large cell lymphoma cells", J Biol Chem, 282, pp.10252~10262 (2007)
- Cao M, "Nuclear factor !B represses the expression of latent membrane protein 1 in Epstein-Barr virus transformed cells", World J Virol, 3, pp.22~29 (2014)
- Kim WY, "Prognostic implications of CD30 expression in extranodal natural killer", T-cell lymphoma according to treatment modali-ties, 2015, pp.56, 1778~1786
- Feng Y, "CD30expression in extranodal natural killer", T-cell lymphoma, nasal type among 622 cases of mature T-cell and natural killercell lymphoma at a single institution in South China, 2017, pp.36, 43~
- Boddicker RL, "The oncogenic transcription factor IRF4 is regulated by a novel CD30", NF-!B positive feedback loop in peripheral T-cell lymphoma, 2015, pp.125, 3118~3127
- Shaffer AL, "IRF4 addiction in multiple myeloma", Nature, 454, pp.226~231 (2008)
- Shaffer AL, "IRF4: immunity. Malignancy! Therapy?", Clin Cancer Res, 15, pp.2954~2961 (2009)
- Park S, "A phase II study of brentuximab vedotin for relapsed or refractory CD30-positive non-Hodgkin lymphomas other than anaplastic large cell lymphoma", Blood, 130, pp.4077~ (2017)
- Cheson BD, "Revised response criteria for malignant lymphoma", J Clin Oncol, 25, pp.579~586 (2007)
- Simon R, "Optimal two-stage designs for phase II clinical trials", Control Clin Trials, 10, pp.1~10 (1989)
- Schemper M, "A note on quantifying follow-up in studies of failure time", Control Clin Trials, 17, pp.343~346 (1996)
- Prince HM, "Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma(ALCANZA) : an international, open-label, randomised, phase 3, multicentre trial", Lancet, 390, pp.555~566 (2017)
- Chen R, "CD30 downregulation, MMAE resistance, and MDR1 upregulation are all associated with resistance to brentuximab vedotin", Mol Cancer Ther, 14, pp.1376~1384 (2015)
- Chen RW, "Inhibition of MDR1 overcomes brentuximab vedotin resistance in Hodgkin lymphoma cell line model and is synergistic with brentuximab vedotin in mouse xenograft model", Blood, 128, pp.752~ (2016)
- Chen RW, "Phase 1 study of MDR1 inhibitor plus brentuximab vedotin in relapsed", refractory Hodgkin lymphoma, 2018, pp.132, 1636~
- Yamaguchi M, "Frequent expression of P-glycoprotein", MDR1 by nasal T-cell lymphoma cells, 1995, pp.76, 2351~2356
- Heo MH, "IRF4", MUM1expression is associated with poor survival outcomes in patients with peripheral T-cell lymphoma, 2017, pp.8, 1018~1024
- Yoshimori M, "P-glycoprotein is expressed and causes resistance to chemotherapy in EBV-positive T-cell lymphoproliferative diseases", Cancer Med, 4, pp.1494~1504 (2015)
- 이준호, "Brentuximab vedotin: clinical updates and practical guidance", Blood Research, 52(4), pp.243~253 (2017), 대한혈액학회
- Oak E, "A safety evaluation of brentuximab vedotin for the treatment of Hodgkin lymphoma", Expert Opin Drug Saf, 15, pp.875~882 (2016)
- Horwitz S, "Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma(ECHELON-2) : a global, double-blind, randomised, phase 3 trial", Lancet, 393, pp.229~240 (2019)