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J. Svoboda et al.
of central lines to thrombosis, and any possible role for prophylactic anticoagulation in PMBCL patients.
We also attempted to define clinical and pathological factors which would correlate with outcomes of patients receiving BV-R-CHP therapy for CD30+ B-cell lym- phomas. IPI risk group, which is well-established as a prognostic factor for outcomes of frontline treatments in DLBCL, did not clearly correlate with complete response rate, progression-free survival or overall survival in our study. This could be due to the small number of patients in the high or high-intermediate IPI risk category. Furthermore, the majority of our patients had PMBCL and the utility of the IPI has some limitations as most patients are young and present with limited stage disease. For our ancillary studies, we planned an analysis of CD30 expression by immunohistochemistry and correlation with outcomes as there is controversy over the impact of CD30 status on the efficacy of BV.33,36,37 However, this proved difficult because of the very low number of relapses and heterogeneity of CD30 staining patterns in neoplastic cells (Figure 3). Additional studies beyond a simple determination of the percentage of CD30+ cells by immunohistochemistry and visual assessment will need to be applied and other groups have attempted this with some success.37,38
Among 21 patients who had pre-treatment tissue ana- lyzed by LymphC3x, we found that there was discor- dance between the protocol-specified standard clinico- pathological diagnosis of PMBCL and the gene expres- sion-based method. These findings are thought-provok- ing since, in small trials of PMBCL, even a few misclassi- fied patients may have a great impact on interpretation of the results. We believe that developing objective diagnos- tic criteria based on quantitative methods, such as gene expression signatures, will be an important step in design- ing treatment strategies for B-cell lymphoma patients with mediastinal lesions and for comparing results across PMBCL trials.
This trial is limited by the small number of evaluable patients and diagnostic heterogeneity. However, the enti- ties included are rare, and we involved three institutions to enroll 32 patients. One of the challenges when inter- preting the clinical efficacy and progression-free/overall survival data of patients treated with the BV-R-CHP regi- men is the fact that consolidative radiation was used in about 50% of all patients enrolled on this trial. The pro- tocol was designed in 2011-2012 when R-CHOP fol- lowed by consolidative radiation therapy was utilized by most centers for PMBCL patients. Therefore, the protocol allowed investigators to use consolidative radiotherapy after completion of BV-R-CHP. It is important to note that the end-of-treatment response assessment was per- formed before radiation. Interestingly, there were no sta- tistically significant differences in progression-free or overall survival between patients who received consol- idative radiation and those who did not. There were no clear differences in patients’ characteristics between those who received consolidative radiotherapy and those who did not other than institutional practice differences. Of the four patients who did not achieve metabolic com- plete response on end-of-treatment imaging, two received consolidative radiation therapy and two did not. Longer follow-up will be necessary to determine whether
there are any long-term toxicities of radiation in the study participants (with the majority of patients having received proton radiation). Of note, an ongoing random- ized trial in patients with PMBCL may allow us to deter- mine whether consolidative radiation therapy after front- line chemoimmunotherapy is necessary in patients who achieve metabolic complete response after systemic treat- ment (ClinicalTrial.gov identifier: NCT01599559).
BV in combination with R-CHP with or without consol- idative radiation therapy is a feasible and active frontline treatment in patients with CD30+ B-cell lymphomas. The safety profile of this regimen, ease of administration and preliminary efficacy data appear promising. The next gen- eration of trials in CD30+ B-cell lymphomas and PMBCL should take into consideration the clinical and biological heterogeneity of these lymphomas. Ultimately, developing treatment regimens that will be tailored to unique tumor and patient characteristics will result in improved out- comes and will minimize treatment-related toxicities.
Disclosures
JS has received research funding from Seattle Genetics, BMS, Merck, Celgene, Incyte, and Pharmacyclics and honoraria for consultancy from Seattle Genetics, BMS, Kite, Kyowa, and Astra-Zeneca. DL has received research funding from Curis, Takeda, and Triphase and honoraria for consultancy from Curis and Celgene and for participation in a speakers’ bureau from Seattle Genetics. SDN has received research funding from Roche, Incyte, Rafael, Aileron, Takeda/Millenium, Debiopharm, and Atara and honoraria for consultancy from Merck. SKB has received research funding from Seattle Genetics, Merck, Celgene, Takeda, and Bayer, and honoraria for consultancy from Janssen, for educational activity from Mundipharma, and for advisory board work from Seattle Genetics. NK has received research funding from BMS and Janssen and honoraria for consultancy from Seattle Genetics and for participation in a speakers’ bureau from Genentech. EAC has received honoraria for consultancy from Novarti. JG has received honoraria for consultancy from Seattle Genetics. CS has received research funding from BMS and Tioma and honoraria for consultancy from Seattle Genetics, Roche, Bayer, and Curis; CS is also named as an inventor on a patent filed by the National Cancer Institute "Methods for determining lymphoma type". SJS has received research funding from Celgene, Genentech, Merck, and Novartis and honoraria for consultancy from Celgene, Dava Oncology, Merck, Nordic Nanovector, Novartis, Genentech, Gilead, and Pfizer. AM has received research funding from Merck. MSL has received honoraria for consultancy from Seattle Genetics. SMB, SJN, JEF, SG, LS, SM, TSW, CK, HJB, MY, JPP, AMB, SSH, HK, RN, and MR have no conflicts of interest to disclose.
Contributions
JS and SJS designed the study; JS analyzed the data and wrote the manuscript; SMB, SJN, LS, HJB, MY and SM per- formed research and analyzed the data; DL, SDN, SKB, NK, JEF, SG, EAC, JG, TSW, CK, JPP and AM provided treatment and follow-up for patients on the study; AMB, SSH, RN, CS, MSL and MR were involved in research design and analysis of the correlative studies. All authors read, critically reviewed and approved the manuscript. The authors would like to thank Dr. Elena Gitelson, in memoriam, who was involved with the initial trial conception and protocol discussions.
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