Transplant BRaVE trial | Brentuximab vedotin in combination with DHAP for patients with relapsed/refractory classical Hodgkin lymphoma

Patients with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) are generally treated with salvage chemotherapy to achieve the best possible response (metabolic complete response, mCR) before proceeding to high-dose chemotherapy followed by an autologous peripheral blood stem cell transplant (auto-PBSCT). If patients can tolerate and complete this treatment, there is a 40–60% chance of cure, but these rates improve amongst patients who achieve a mCR before transplantation.

 One of the conventional regimens used as salvage chemotherapy is DHAP: a combination of dexamethasone, high-dose cytarabine, and cisplatin. With DHAP treatment, only about 25% of patients achieve a mCR confirmed by ¹⁸F-fluorodeoxyglucose positron emission tomography-computed tomography (¹⁸FDG PET-CT). Other chemotherapy regimens have reported between 50–60% mCR rates.

 Marie José Kersten and colleagues published in Haematologica the results of the phase II Transplant BRaVE study (NCT02280993).¹ The initial results of the study from the phase I or dose escalation part were reported at the end of 2018. Click here to read the briefing on Lymphoma Hub. The investigators of the Transplant BRaVE study aimed to improve the efficacy/mCR rates of conventional regimens by adding brentuximab vedotin (BV) to DHAP and, consequently, improve the survival outcomes of patients with R/R cHL.

Study design

• Prospective, open-label, phase II study
• Patients: aged ≥ 18 years with histologically confirmed CD30-positive cHL, with primary refractory disease or a first relapse after first-line chemotherapy
• Treatment:
  • Three 21-day cycles of BV (1.8 mg/kg, intravenous [IV], Day 1), dexamethasone (40 mg orally or IV, Days 1–4), cisplatin (100 mg/m², 24 hours continuous IV, Day 1), and cytarabine (2×2 g/m² every 12 hours, 3 hours for each infusion, Day 2)
  • After Cycle 2, stem cells were mobilized and harvested
  • Patients with progressive disease (PD) went off study; patients with a metabolic partial response (mPR) or mCR proceeded to BEAM (carmustine, 300 mg/m², Day -7; etoposide, 100 mg/m²; cytarabine, 100 mg/m², twice daily, Days -6, -5, -4, and -3; and melphalan, 140 mg/m², Day -2), followed by auto-PBSCT on Day 0
  • A PET-CT scan was performed after Cycle 3 and 6 weeks after auto-PBSCT
• Primary outcome: rate of patients with severe toxicity (Grade 4) during Cycle 1–3 of the combination treatment (BV + DHAP)
• Secondary outcomes: incidence of severe adverse events (AEs) during the combination treatment and mCR by PET-CT after the third cycle of BV-DHAP reinduction therapy

 Patients and treatment

• Fifty-five patients were enrolled in the phase II study
• Median age was 29 years and relevant baseline patient characteristics can be found in Table 1
• Of all patients, 49 (89%) completed all three cycles of BV-DHAP, and those with a mPR or mCR proceeded to BEAM, followed by auto-PBSCT (85%)

 Table 1. Patient characteristics at baseline¹

Efficacy

According to the independent review of FDG-PET-CT scans obtained after the third cycle and 6 weeks after transplant, the overall response rate of BV-DHAP treatment was 90% (95% CI, 79–97):

• 42/52 evaluable patients (81%) achieved an mCR before transplant
• Five (10%) patients had a mPR, with four of them converting to mCR after auto-PBSCT, and the remaining patient achieved a mCR with additional radiotherapy
• Five patients progressed during treatment

 Baseline characteristics (i.e. age, time to relapse and first-line treatment) did not differ significantly between patients with mCR or mPR.

 After a median follow-up of 27 months, 2-year progression-free survival (PFS) for all 55 patients was 73.5% (95% CI, 62.6–86.4), and the 2-year overall survival (OS) was 94.9% (95% CI, 89.5–100.0).

 Regarding some of the subgroup exploratory analyses, patients with mPR after three cycles of BV-DHAP had a lower PFS compared with patients with mCR. This translated into a higher risk of progression, regardless of their conversion to mCR after the transplant or their refractory status. However, primary refractory status had an effect on PFS rates, and more patients progressed at 2 years compared to patients with relapsed disease: 63% (95% CI, 46–85) versus 86% (95% CI, 75–98), with a hazard ratio of 0.33 (95% CI, 0.11–0.98), p = 0.046.

 Safety

During BV-DHAP treatment, 20 patients (36%) experienced one or more AE that met the dose-limiting toxicity criteria (considered significant toxicity). In total, 33% of patients experienced one or more serious AEs during treatment. The most common AEs, regardless of grade, were neutropenia, thrombocytopenia, fever, nausea/vomiting, ototoxicity (leading to a switch from cisplatin to carboplatin in seven patients), and nephrotoxicity. Frequent Grade 3–4 AEs are summarized in Table 2.

 Table 2. Grade 3-4 AEs experienced by more than one patient¹

Other AEs related to BV were also registered, particularly peripheral neuropathy (PN). A total of 18 patients developed a new-onset PN. All were Grade 1–2, and all recovered. Those patients presenting PN at baseline did not worsen during BV-DHAP treatment. 

 Conclusion

The authors conclude that adding BV to DHAP as salvage regimen leads to a higher mCR, and an improvement in 2-year PFS and OS rates compared with historical studies (2-year PFS between 50–70%). A longer follow-up is needed to be able to confirm if patients who are in remission after 2 years will be ultimately cured.

 The Transplant BRaVE study is the first clinical trial to explore the BV-DHAP combination. Toxicity was manageable, however the authors noted that patients should be monitored closely, especially for hematological toxicity, nephrotoxicity, and liver toxicity. Although other salvage chemotherapy regimens are associated with less toxicity than BV-DHAP, the benefit on survival outcomes, resulting from achieving better responses, needs to be considered.

 With the data currently available, the investigators cannot be sure if the risk-benefit balance of BV will favor it remaining in the consolidation setting or moving prior to auto-PBSCT since it achieved higher responses with lower total dose and, therefore, less toxicity.