Combining Brentuximab Vedotin with DHAP as Salvage Treatment in Relapsed/Refractory Hodgkin Lymphoma: The Phase II HOVON/LLPC Transplant BRaVE study

Abstract

Introduction Achieving a PET-negative metabolic (m)CR with salvage chemotherapy prior to autologous stem cell transplantation (ASCT) in relapsed/refractory Hodgkin lymphoma (R/R HL) is a strong predictive factor for long-term progression-free survival (PFS). In a phase I dose-escalation trial we have shown a favorable toxicity profile of 3 cycles of DHAP in combination with brentuximab vedotin (BV) with a high mCR rate (12/12 patients). A subsequent phase II study in 55 patients has been performed; the 6 patients treated at full dose of BV-DHAP in the phase I part were added to the current analysis. Methods BV was given at a fixed dose of 1.8 mg/kg on day (d) 1 of 3 cycles of DHAP q 3 weeks (dexamethasone 40 mg iv d 1-4, cisplatin 100 mg/m² iv d1 and cytarabine 2x2 g/m² iv d2). Cycle 2 was used for stem cell mobilization; after the 1st and 3rd cycle patients received pegylated G-CSF to prevent prolonged neutropenia and dose delays. The primary endpoint of the study was the mCR rate after 3 cycles of BV-DHAP based on central PET-review. Patients with a partial or complete response proceeded to high dose chemotherapy (BEAM) and ASCT. Results Twenty-three of the 61 patients (29 males; median age 29 yrs, range 19-71) had not achieved a CR to 1st line treatment (37%), which consisted of ABVD (n=45), (escalated) BEACOPP (n=11) or other regimens (n=5). The median time from response to 1st line treatment to relapse was 6 months (range 0-160 months); 38 patients (62%) had either primary refractory disease or early relapse (<1 year). All patients received the 1st cycle of BV-DHAP, 90% completed all 3 cycles and 87% underwent ASCT. G-CSF mobilized stem cells were harvested successfully after the 2nd cycle with 1 apheresis in all patients (median yield: 6x106 CD34+/kg; range: 2-23). Based on intention to treat analysis 48 patients achieved a metabolic CR after 3x BV-DHAP (mCR rate 79% (n=48/61)), 5 patients had a metabolic PR (8%) and 4 had PD (6.5%). Four patients went off study before the first evaluation (1 PD after cycle 1, 1 liver function abnormalities after cycle 2, 2 withdrew because of emotional problems). After ASCT 4 out of 5 patients with mPR converted to an mCR. At a median follow-up of 20.9 months the 2-year PFS is 76% (95% CI 65-89), and the OS projected at 2 years is 92% (95% CI 84-100). Hematologic toxicity after BV-DHAP consisted of neutropenia grade 3/4 in up to 63% of patients and thrombocytopenia grade 3/4 in up to 81% of patients. Only 3 patients had a bleeding event (epistaxis (n=2) and menorrhagia (n=1), all recovered without sequelae after platelet transfusion). Febrile neutropenia or infections after BV-DHAP occurred in 18 patients (15 grade 3 and 3 grade 4). A total of 21 SAE's other than fever/infections were reported, with kidney dysfunction (n=4; most likely related to cisplatin), malaise (n=3), nausea/vomiting (n=3) and liver function abnormalities (n=3) occurring in 3 or more patients. 11 patients had peripheral neuropathy (PN) already at baseline (10 grade 1, 1 grade 2); worsening of PN was not observed in those patients. New onset PN was seen in 19 patients (15 grade 1, 4 grade 2); no grade 3/4 PN was observed. Three deaths occurred during the study period, 1 encephalitis (exact cause unknown), 1 veno-occlusive disease, both after BEAM/ASCT and 1 trauma capitis (unrelated). One patient who refused further treatment after cycle 1 and went off study died of progressive disease. Conclusions Salvage immunochemotherapy with 3 cycles of BV-DHAP induces a high mCR rate of 79% in patients with R/R HL, which is an optimal starting point for consolidation with BEAM and ASCT and may contribute to a higher cure rate. The toxicity of combining BV and DHAP is acceptable and mainly consists of manageable hematologic toxicity and fever/infections. Figure. Figure. Disclosures Hagenbeek: Millennium/Takeda: Consultancy, Honoraria, Research Funding. Morschhauser:Janssen: Other: Scientific Lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lugtenburg:Millennium/Takeda: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Roche: Consultancy; BMS: Consultancy; Sandoz: Consultancy; Genmab: Consultancy. Gastinne:Millennium/Takeda: Honoraria. Tonino:Takeda: Consultancy, Honoraria. Kersten:Millennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; Kite Pharma: Honoraria; Novartis: Honoraria.

The role of transplantation in Hodgkin lymphoma

“…Primary refractory disease was documented in 45% of patients, and 31% had a disease relapse within 1 year. The ORR was 82% and the CR rate was 61%, higher than those observed with BV or nivolumab alone (Younes et al, 2012;Armand et al, 2018), and quite close to what was documented with sequential BV and chemotherapy (Moskowitz et al, 2015a;Cassaday et al, 2016;Garcia-Sanz et al, 2016;Hagenbeek et al, 2016).Stem cell mobilisation was possible in 44 patients within 9 days, with a median yield of 4Á7 9 10 6 CD34 + /kg. Importantly, this schedule was delivered on an outpatient basis, and the most relevant adverse events were nausea, fatigue and IRR.…”

“…A CR was obtained in all patients, with a negative PET scan in 11 cases (1 PET positive patient showed no disease upon mediastinal biopsy). All patients mobilised and harvested PBSC (median yield of 5Á3 9 10 6 CD34 + /kg) and proceeded to subsequent ASCT (Hagenbeek et al, 2016). Taken together, these trials indicate that BV may be favourably combined with conventional chemotherapy, producing significant CR rates without altering PBSC mobilisation or imparting significant toxicity.…”

“…Sixty‐four (97%) patients were able to mobilise and collect >2·0 × 10 6 CD34 + /kg with subcutaneous filgrastim, and could proceed to ASCT in 61 instances (Garcia‐Sanz et al , ). Another study applied BV‐DHAP in HL patients refractory to first‐line chemotherapy or at first relapse (Hagenbeek et al (). BV was given at the standard dose of 1·8 mg/kg on day 1, and the dose of cisplatin and cytarabine was modulated according to 3 dose levels in a classic 3 + 3 design.…”

Therapeutic Updates for Relapsed and Refractory Classical Hodgkin Lymphoma

“…Multiple trials have studied the combination of BV with chemotherapy such as DHAP, ICE or bendamustine with high response rates [ 27 , 28 , 29 ]. However, due to its excellent toxicity profile, the BV-bendamustine regimen is the most widely used in clinical practice.…”

Treatment of Hodgkin Lymphoma – New and Developing Therapies and Their Potential Role in Standard of Care

“…as single-agent or in combination with chemotherapy either sequentially or concurrently (with augmented ICE/ICE, DHAP, ESHAP), reported ORRs of 68-75% and CRs of 35-50% for single agent therapy,[60][61][62] as well as ORRs ranging from 87-100% and CRs ranging from 70-100% with combination therapy 59,[63][64][65][66][67]. In addition, several recent studies have evaluated the use of brentuximab vedotin as first-salvage therapy for relapsed or refractory Hodgkin lymphoma in combination with bendamustine (as a potentially less toxic alternative to platinum-or gemcitabine-based chemotherapy),…”