Combining brentuximab vedotin with dexamethasone, high-dose cytarabine and cisplatin as salvage treatment in relapsed or refractory Hodgkin lymphoma: the phase II HOVON/LLPC Transplant BRaVE study

Abstract

Achieving a metabolic complete response (mCR) before high-dose chemotherapy (HDC) and autologous peripheral blood stem-cell transplant (auto-PBSCT) predicts progression free survival (PFS) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL). We added brentuximab vedotin (BV) to DHAP to improve the mCR rate. In a Phase I dose-escalation part in 12 patients, we showed that BV-DHAP is feasible. This Phase II study included 55 R/R cHL patients (23 primary refractory). Treatment consisted of three 21-day cycles of BV 1.8 mg/kg on day 1, and DHAP (dexamethasone 40mg days 1-4, cisplatin 100mg/m2; day 1 and cytarabine 2x2g/m2; day 2). Patients with a metabolic partial response (mPR) or mCR proceeded to HDC/auto-PBSCT. Based on independent central FDG-PET-CT review, 42 of 52 evaluable patients (81% [95% CI: 67-90]) achieved an mCR before HDC/auto-PBSCT, five had an mPR and five had progressive disease (three were not evaluable). After HDC/auto-PBSCT, four patients with an mPR converted to an mCR. The 2-year PFS was 74% [95% CI: 63-86], and the overall survival 95% [95% CI: 90-100]. Toxicity was manageable and mainly consisted of grade 3/4 hematological toxicity, fever, nephrotoxicity, ototoxicity (grade 1/2) and transiently elevated liver enzymes during BV-DHAP. Eighteen patients developed new onset peripheral neuropathy (maximum grade 1/2) and all recovered. In conclusion, BV-DHAP is a very effective salvage regimen in R/R cHL patients, but patients should be monitored closely for toxicity. ClinicalTrials.gov identifier: NCT02280993.

Figure 1.

Consort diagram. Number of patients in the full analysis set going through the protocol treatment including reasons for exclusion. BV: brentuximab vedotin; DHAP: dexamethasone, high-dose cytarabine, cisplatin; C: cycle; N: number; CT: computed tomography; SC: stem cell; PD: progressive disease; VIM: ifosfamide, mitoxantrone, etoposide; PET: positron emission tomography; mCR: metabolic complete response; BEAM: carmustine, etoposide, cytarabine, melphalan; auto-PBSCT: autologous peripheral blood stem-cell transplant.

Figure 2.

Kaplan-Meier survival analysis. Kaplan-Meier survival analysis for all 55 phase II patients by intention-to-treat, including the number of patients at risk at 1, 2 and 3 years with regard to (A) progression-free survival and (B) overall survival, measured from enrollment.

Figure 3.

Kaplan-Meier exploratory analysis. Kaplan-Meier exploratory analysis for all 55 phase II patients and six patients from phase I who were treated at the same dose level, including the number of patients at risk at 1, 2 and 3 years with regard to (A) progression-free survival (PFS) stratified for patients with a metabolic complete response (mCR; n=48) or partial response (mPR; n=5) on the positron emission tomography-computed tomography (PET-CT) scan after three cycles of BVDHAP, measured from the time of that PET-CT scan, and (B) PFS stratified for relapsed patients (n=37; defined as recurrent disease after having reached a complete response on first-line treatment) versus patients with primary refractory disease (n=24; no complete response on first-line treatment), measured from enrollment. BV: brentuximab vedotin; DHAP: dexamethasone, high-dose cytarabine, cisplatin.