Three-year outcomes with brentuximab vedotin plus bendamustine as first salvage therapy in relapsed or refractory Hodgkin lymphoma

We report the final 3-year efficacy and safety outcomes from a trial of outpatient administration of brentuximab vedotin (BV) plus bendamustine as a first salvage regimen in relapsed/refractory Hodgkin lymphoma (HL). In this phase 1/2, open-label, single-arm study, 55 adult patients with relapsed or refractory HL received outpatient intravenous infusions of BV 1·8 mg/kg on Day 1 and bendustamine 90 mg/m2 on Days 1 and 2 of 3-week cycles for up to six cycles, followed by autologous stem cell transplantation (ASCT) and/or BV monotherapy for up to 16 cycles. Patients underwent computed tomography every 3 months for the first year and every 6 months thereafter until study closure, which occurred approximately 3 years after the last patient’s ASCT. Treatment response was assessed with the 2007 Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Of 53 efficacy evaluable patients, 40 (75·5%) underwent ASCT and 13 (24·5%) did not. Of 25 patients who underwent ASCT and six who did not continue BV monotherapy; 17 patients completed the maximum allowed 16 cycles of BV monotherapy. We previously reported 2-year outcomes, including a 92·5% objective response rate (ORR), a 73·6% complete remission (CR) rate, and estimated 2-year progression-free survival (PFS) of 62·6% overall and 69·8% for those who received ASCT (LaCasce et al., 2018). As reported, the regimen was generally well tolerated; notable adverse events included infusion-related reactions (largely manageable with premedication) in 56·4% of patients and peripheral neuropathy (PN) in 54·4% of patients, including 16·4% Grade 2, 3·6% Grade 3, and no Grade 4 or 5 PN events (LaCasce et al., 2018). The median (range) follow-up for the final overall survival (OS) evaluation was 44·5 (4–55) months from first dose and 41·8 (0–52) months from ASCT (Fig 1A). OS at 3 years was 92·0% [95% confidence interval (CI) 80·0–96·9%] with no difference between patients who did and did not undergo ASCT. Five patients died (none considered treatment-related), including three deaths reported previously (LaCasce et al., 2018), and two additional deaths in patients with disease progression after ASCT (one related to progressive HL and one of unknown cause). The median (range) follow-up for PFS evaluation was 38·7 (1–53) months from first dose and 36·6 (0–51) months from ASCT (Fig 1B). PFS at 3 years was 60·3% (95% CI 43·5–73·6%) overall, 67·1% (95% CI 47·9–80·5%) for patients who went on to ASCT, and 40·4% (95% CI 12·5–67·4%) for patients who did not undergo ASCT. A total of 19 PFS events (18 disease progressions and one death) occurred, including 17 events that were reported previously (LaCasce et al., 2018) and subsequent progressive disease reported in one patient who had undergone ASCT and one who had not. In all, 13 of 15 patients with >3 years of follow-up were progression-free at the last follow-up. Duration of CR was similar among patients who did and did not undergo ASCT (Fig 1C). These OS and PFS results with BV-bendamustine as first salvage therapy compare favourably with 2–4-year follow-up data reported for other pre-ASCT salvage regimens in relapsed/refractory HL. Among patients treated with bendamustine-gemcitabine-vinorelbine (BeGEV) before ASCT, the overall 2-year OS was 77·6% and 2-year PFS rates of 62·2% overall and 80·8% for transplanted patients were reported (Santoro et al., 2016). The 2-year OS and PFS were 88% and 46%, respectively, among patients treated with ofatumumab in combination with etoposide, steroids, cytarabine and cisplatin (O-ESHAP), most (80%) of whom underwent subsequent ASCT (Martinez et al., 2016). In a study of pre-ASCT augmented ifosfamide, carboplatin, and etoposide (ICE) followed by gemcitabine, vinorelbine, and liposomal doxorubicin (GVD) for non-CR patients, 4-year OS was 80% and 4-year event-free survival rates of 70% overall and 79% for transplanted patients were reported (Moskowitz et al., 2012). Peripheral neuropathy is a well-described side-effect of BV therapy that is largely reversible (Siddiqi, Thomas, & Chen, 2014). With a median 31·3 months follow-up from the end of BV treatment, no new PN events were reported and 19 of the 30 patients (63%) who previously reported PN had resolution or improvement of all or some PN symptoms (Table 1). The median time to resolution or improvement was 3 weeks. At the end of follow-up, 25 patients (83·3%) had no residual PN or Grade 1 PN, four patients had ongoing Grade 2 PN, and one patient had ongoing Grade 3 PN. The frequency and reversibility of PN in our present study are consistent with previous reports of BV therapy. In phase 2 and 3 trials of BV monotherapy for HL and anaplastic large-cell lymphoma, PN was reported in 53–67% of BV-treated patients (Pro et al., 2012; Younes et al., 2012; Moskowitz et al., 2015), with 20% Grade 2 and 11% Grade 3 events reported in one study (Younes et al., 2012), and 14% Grade 3 events in another study (Pro et al., 2012). In those studies, complete resolution of PN was reported in 48–50% of patients (Pro et al., 2012; Younes et al., 2012), and resolution or improvement was reported in 80–85% (Pro et al., 2012; Younes et al., 2012; Moskowitz et al., 2015). In conclusion, the combination of BV and bendamustine administered in the outpatient setting as first salvage therapy for relapsed or refractory HL produced a high ORR and CR rate, and 75% of patients were able to undergo ASCT. Patients proceeding to ASCT demonstrated a favourable 3-year PFS and all patients showed a favourable 3-year OS. Consistent with earlier studies, about half of BV-treated patients experienced PN, most of which was mild and reversed after treatment ended. The authors thank the patients and clinical study teams who participated in this research. Medical writing and editorial support were provided by Laurie LaRusso, Chestnut Medical Communications, and Eric Bertelsen, Seattle Genetics, Inc., and paid for by Seattle Genetics. This work was supported by research funding from Seattle Genetics, Inc. Contribution: Ann S. LaCasce and Ranjana Advani contributed to the conception and design of the study, data collection and interpretation, and writing of the report; Julie Vose and Owen A. O’Connor contributed to the conception and design of the study, data interpretation, and critical review of the report; R. Gregory Bociek, Ahmed Sawas, Paolo Caimi, Edward Agura, Jeffrey Matous, Stephen M. Ansell, Howland E. Crosswell, Miguel Islas-Ohlmayer, Caroline Behler, Eric Cheung, and Andres Forero-Torres contributed to the data and interpretation and critical review of the report; Neil Josephson contributed to the study design, data interpretation, and writing of the report; Yinghui Wang contributed to the study design, data interpretation, and critical review of the report. The institutions of Ann S. LaCasce, R. Gregory Bociek, Ahmed Sawas, Paolo Caimi, Edward Agura, Jeffrey Matous, Stephen M. Ansell, Howland E. Crosswell, Miguel Islas-Ohlmayer, Caroline Behler, Eric Cheung, Andres Forero-Torres, Julie Vose, Owen A. O’Connor, and Ranjana Advani received funding from Seattle Genetics, Inc. to conduct the trial. Howland E. Crosswell, Neil Josephson, and Yinghui Wang, have equity ownership in Seattle Genetics, Inc. Julie Vose and Ahmed Sawas have received honoraria from Seattle Genetics, Inc. Jeffrey Matous and Caroline Behler have participated in a speakers’ bureau for Seattle Genetics, Inc and Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceuticals Limited. Owen A. O’Connor has received research funding from Seattle Genetics, Inc. Howland E. Crosswell has acted as a consultant for and has received travel expenses from Seattle Genetics, Inc. Neil Josephson was employed by Seattle Genetics, Inc. at the time this research was conducted. Yinghui Wang is employed by Seattle Genetics, Inc.