Brentuximab Vedotin Plus ESHAP (BRESHAP) Is a Highly Effective Combination for Inducing Remission in Refractory and Relapsed Hodgkin Lymphoma Patients Prior to Autologous Stem Cell Transplant: A Trial of the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO)

Abstract

Introduction: 30% of Hodgkin Lymphoma (HL) patients are refractory or relapse (RR) after first line therapy. Salvage chemotherapy followed by high-dose chemotherapy and with Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) can cure many patients, but those who are transplanted with active disease detectable by PET-CT have a very poor prognosis. Therefore, the current challenge in HL is to improve the results of the pre-transplant chemotherapy. We and others have demonstrated that the addition of Brentuximab Vedotin (BV) to chemotherapy can produce very good results. Objectives: We conducted a phase II trial to assess response rate with combined Brentuximab vedotin and ESHAP chemotherapy [BRESHAP] as 2nd line therapy for RRHL prior to APBSCT (ClinicalTrials.gov #NCT02243436). Methods: Primary efficacy endpoint was the proportion of complete responses (CR) pre-APBSCT. A prior phase I step was carried out to establish the appropriate dosis. Final treatment consisted of Brentuximab Vedotin (1.8 mg/m2/day IV, D1), Etoposide (40 mg/m2/day IV, D1-4), Solumedrol (250 mg/day IV, D1-4), High dose AraC (2 g/m2 IV, D5) and cisPlatin (25 mg/m2/day IV, D1-4). Results: Patients with relapsed or refractory classical HL (cHL) after one prior line of therapy were eligible. 66 patients were included in the trial. There were 35 females and 31 males, with a median age of 36 years (18-66). At inclusion, 40 patients were considered primary refractory, 16 as early relapses (complete remission -CR- shorter than 1 year) and 10 as late relapses. Currently, all patients have completed the pre-transplant therapy. During that period, there were 22 Severe Adverse Events (SAEs) reported in 15 patients: Fever in 13 occasions (neutropenic in seven, and non-neutropenic in six), hypomagnesemia and gastrointestinal alterations (n=2) and pneumothorax, skin lesions, left ventricular function reduction and pulmonary embolism [PE](n=1). There were 2 deaths: non-neutropenic abdominal sepsis and PE. Grade 3-4 hematologic toxicity presented in 22 cases: neutropenia (n=18), thrombocytopenia (n=12), and anemia (n=5). Grade 3-4 extrahematologic adverse events present in ≥5% of cases were non-neutropenic fever (n=8) and hypomagnesemia (n=3). All patients except three underwent stem cell mobilization after the 1st (n=15), 2nd (n=36) or 3rd (n=12) cycle using subcutaneous G-CSF 5 mcg/Kg/12 h. for 5 days. All patients collected >2·10e6/Kg peripheral blood CD34+ cells in all cases (median 5.75, range 2.12-33.4). The number of harvesting procedures was one in 47 patients, two in 13, three in 2 and four in 1. The transplant has been done in 61 patients, with data are available from 47: all engrafted with a median of 9&10 days for neutrophil and platelet recovery, respectively. No major events were registered during transplant period, except for one patient who died at day +110 due to pneumonia. Overall pre-transplant response was 96%, including a 70% and 26% complete and partial remission rates, respectively. Of these forty-seven patients, 37 (80%) were in metabolic CR after transplant and 3 (7%) in PR; six patients were considered as non-responders (13%) and went out of the trial. At a mean follow-up of 11 months, 7 patients have progressed, rendering a projected progression free survival of 87% at one year. Six patients have already died: three due to progression, and the three already mentioned above (PE, abdominal sepsis and pneumonia). With a mean follow-up of 11 months, the projected overall survival was 90% at one year (cause specific, 96%). Conclusions: BRESHAP is a highly effective regimen for remission induction prior to transplant in patients with refractory or relapsed Hodgkin lymphoma. The addition of BV to the conventional chemotherapy did not resulted in a higher toxicity for the pre- and post-transplant periods and it did not hamper the collection of PBSC. Disclosures No relevant conflicts of interest to declare.

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.…”

Brentuximab vedotin: clinical updates and practical guidance

“…For relapsed or refractory patients with HL, the combination of BV plus bendamustine or other drugs has been evaluated [ 76 77 78 ]. BV combined with nivolumab also demonstrated remarkable activity [ 79 80 ] ( Table 2 ).…”

Phase I dose-escalation study of brentuximab-vedotin combined with dexamethasone, high-dose cytarabine and cisplatin, as salvage treatment in relapsed/refractory classical Hodgkin lymphoma: The HOVON/LLPC Transplant BRaVE study

“…3 Combining BV and chemotherapy prior to high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) might lower the tumor burden and decrease the relapse rate after HDC-ASCT and thus contribute to cure. 4,5 Brentuximab vedotin has already been combined with standard therapy in a sequential strategy and concurrently with chemotherapy regimens such as ESHAP (etoposide, methylprednisolone, cytarabine and cisplatin) before HDC-ASCT, [6][7][8][9][10][11] and resulted in a CMR rate of more than 75% prior to HDC-ASCT. However, the combination of BV with multi-agent chemotherapy can be associated with significant toxicity.…”

“…However, the combination of BV with multi-agent chemotherapy can be associated with significant toxicity. 8,10 Tumor burden reduction by a combination of BV and DHAP treatment is attractive because DHAP by itself is well tolerated in patients with R/R cHL and results in 20% complete remission (CR) and 70% partial remission [PR; based on conventional computed tomography (CT) scanning] and 50-60% metabolic CR (CMR) while stem cell mobilization potential is maintained. 12 In this multicenter, openlabel, phase I dose-escalation study, patients aged 18 years or older with a histologically confirmed CD30 + R/R cHL were treated with three cycles of BV-DHAP, followed by HDC (BEAM regimen: carmustine, etoposide, cytarabine and melphalan) with an ASCT rescue.…”