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M.J. Kersten et al.
Introduction
Salvage chemotherapy followed by high-dose chemother- apy (HDC) and autologous peripheral blood stem cell trans- plant (auto-PBSCT) has been the standard of care for patients with relapsed or refractory classical Hodgkin lymphoma (R/R cHL) for decades.1,2 With this treatment, cure rates of 40- 60% can be achieved. Patients failing this treatment and those relapsing after second-line treatment generally have a very poor prognosis.3-5
Response to salvage treatment is one of the most impor- tant predictors of outcome after auto-PBSCT, with metabolic active residual disease, as assessed by [18F]fluorodeoxyglu- cose (FDG) - positron emission tomography (PET) - comput- ed tomography (CT) scan, before HDC/auto-PBSCT confer- ring an inferior prognosis.6-8 Therefore, higher cure rates may be achieved by improving the metabolic complete response (mCR) rate before HDC/auto-PBSCT. Conventional salvage chemotherapy regimens result in mCR rates of about 50- 60%.6,9-11 DHAP (dexamethasone, high-dose cytarabine, cis- platin) is one of the most commonly used salvage regimens for R/R cHL in Europe.12
Brentuximab vedotin (BV) is targeted high-dose intracellu- lar chemotherapy, consisting of an anti-CD30 antibody con- jugated to the potent anti-microtubule agent monomethyl auristatin-E.13,14 Several phase II studies have shown promis- ing clinical activity of BV in R/R cHL, both as monotherapy and combined with chemotherapy.15-20 Toxicities of BV include infusion-related reaction (IRR), myelosuppression, and peripheral neuropathy, the latter being reversible in the majority of patients.15,16,18,20,21
In the current prospective, multicenter, international phase I/II Transplant BRaVE study we investigated the efficacy and safety of BV-DHAP followed by HDC (BEAM: carmustine, etoposide, cytarabine, melphalan) and auto-PBSCT in R/R cHL patients.
Results of the phase I part of this study in 12 patients have been published previously and showed that the combination of BV-DHAP is feasible with acceptable toxicity.22 The rec- ommended dose level was established at full dose of all drugs with BV dosed at 1.8 mg/kg.22 The primary endpoints for the phase II single arm part were the fraction of patients achiev- ing an mCR as judged by independent review of PET-CT scan after the third cycle of BV-DHAP, and the rate of grade 3/4 non-hematologic adverse events (AE), including neuro- toxicity, during BV-DHAP.
Methods
Patients
All patients provided written informed consent. The study protocol was approved by the Ethical Review Committee (ERC) of all participating centers. The study was carried out in accor- dance with the principles of the Declaration of Helsinki.
Study design and treatment
Transplant BRaVE (clinicaltrials.gov identifier: NCT02280993) is
a prospective, open-label study conducted at eight centers in the Netherlands (n=5), France (n=3) and Denmark (n=1). An inde- pendent Data Safety Monitoring Board (DSMB) evaluated the general progress and safety aspects of the study at predefined intervals.
Baseline assessment included a lymph node and bone marrow biopsy, and a PET-CT scan. Patients filled in a neurotoxicity questionnaire at study entry, prior to each cycle, and at three months after auto-PBSCT.
Patients were treated with three 21-day cycles of BV (1.8 mg/kg, i.v., day 1), dexamethasone (40 mg orally or intravenous [i.v.], days 1-4), cisplatin (100 mg/m2, continuous i.v. [24 hours], day 1) and cytarabine (2x2 g/m2 q12 hours, 3 hours for each infusion, day 2). After cycle 2, stem cells were mobilized and harvested using gran- ulocyte colony-stimulating factor (G-CSF). A PET-CT scan was performed after cycle 3. Patients with progressive disease (PD) went off study, whereas patients with a partial response (mPR) or mCR proceeded to BEAM (carmustine, 300 mg/m2, day -7; etopo- side, 100 mg/m2 and cytarabine, 100 mg/m2, 2x/day, days -6, -5, -4 and -3; and melphalan, 140 mg/m2, day -2), followed by auto- PBSCT (on day 0). Six weeks after auto-PBSCT, response evalua- tion was performed by PET-CT. G-CSF was recommended to pre- vent long-lasting neutropenia.
Endpoints
All endpoints and their definitions are described in Online Supplementary Table S2. Responses were determined according to the 2014 Lugano criteria.23 All PET-CT scans were centrally reviewed by two independent nuclear medicine physicians (AA, RV) and a third adjudicator (OH) in case of discrepancies. Visual assessment was performed using the Deauville score (DS), assessing DS1-3 as mCR. Toxicity was reported according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Statistical analysis
Details about the study design and statistical analysis are pro- vided in Online Supplementary Appendix 1. Efficacy analysis was performed among all evaluable patients. Primary safety analysis was performed among all patients who received at least one dose of study medication. Response rates and their correspon- ding 95% two-sided exact confidence intervals (CI) were calcu- lated. AE were analyzed descriptively. The Kaplan-Meier method was used for time-to-event analysis. An exploratory analysis with a Cox proportional hazards regression was per- formed on all phase II patients, and six patients from the phase I part of the study who were treated at the recommended dose level. The Kaplan-Meier method and log-rank test were used to analyze univariable associations with progression-free survival (PFS). All statistical analyses were performed using R software version 3.6.1 and SAS software version 9.4.
Results
Patients and treatment
Between May 2014 and July 2017, a total of 67 patients with R/R cHL were enrolled for the entire Transplant BRaVE phase I/II study (n=12 in phase I and n=55 in phase II). Due to withdrawal of consent of two patients after one cycle of BV-DHAP and three patients not completing all BV-DHAP cycles, five more patients were enrolled in phase II than planned according to the sample size calcu- lations (n=50) to ensure a sufficient number of evaluable patients in the primary analysis.
The study enrolled patients aged ≥18 years with histologically confirmed CD30 positive cHL by local pathology assessment, either having primary refractory disease or a first relapse after first-line chemotherapy. Online Supplementary Table S1 shows the complete list of inclusion and exclusion criteria. Central pathology review was performed by two experienced hematopathologists (DDJ, AD).
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