Evaluation of the Regimen Brentuximab Vedotin Plus ESHAP (BRESHAP) in Refractory or Relapsed Hodgkin Lymphoma Patients: Preliminary Results of a Phase I-II Trial from the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO)
Authors: Garcia-Sanz Ramon , Sureda Anna , Alonso-Alvarez Sara , Gonzalez Ana Pilar , Rodriguez Antonia , Salar Antonio , de la Cruz Fatima , Domingo Eva , Moreno Miriam , Lopez Javier , Piñana Jose Luis , Rodriguez Gabriela , Canales Miguel , Gurierrez Antonio Manuel , López-Guillermo Armando , Caballero María Dolores , Jimenez Silvia , Martinez Carmen 
Published: October 2019

Abstract
Introduction: Around 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. Phase 2 single agent trials with Brentuximab Vedotin (BV) in highly RRHL patients have demonstrated overall and complete response rates of 75% and 34%, respectively (Younes, JCO 2012; 30:2183); as 2nd line, BV has provided very promising results in combination with chemotherapy (LaCasce, Blood 2014; 124(21):3099)
Objectives: We conducted a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and response rate with combined Brentuximab vedotin with ESHAP chemotherapy [BRESHAP] as 2nd line therapy for RRHL prior to APBSCT (ClinicalTrials.gov #NCT02243436).
Methods: The primary efficacy endpoint was the proportion of complete responses (CR) pre-APBSCT. It is a phase I-II trial with dose escalation followed by expansion. Treatment consisted of 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). BV was administered at three dose levels: 0.9, 1.2 or 1.8 mg/kg IV on day 1 to each cohort of patients, following the scheme of cohorts of 3 patients each, to assess the maximum tolerable dose (MTD). The dose limiting toxicity (DLT) was defined as Grade 4 hematologic toxicity extended over 3 weeks or non-hematologic toxicity grade ≥3 during the first treatment cycle. Patients were evaluated weekly.
Results: Patients with relapsed or refractory classical HL (cHL) after one prior line of therapy were eligible. To date, 27 patients have been included in the trial. The first 9 have completed the three courses as scheduled, without TLD doses. Fifteen patients have received the first full cycle, presenting 4 episodes of severe adverse reactions: non-neutropenic fever due to IV AraC and to complicated catheter insertion; one pneumothorax after catheter insertion; and one febrile neutropenia recovered with antibiotic treatment. Grade 4 hematologic toxicity presented in three of these nine patients: 2 neutropenia and thrombocytopenia 1. All nine patients underwent stem cell mobilization after the 1st or the 2nd treatment cycle with subcutaneous G-CSF 5 mcg/Kg days +7 to +14, collecting >2·10e6/Kg peripheral blood CD34+ cells in all cases, with no grade 3-4 toxicity. The number of harvesting procedures was one & two in seven & two patients, respectively. The transplant has been done in 6 patients, with a median of 9 days and 10 days for neutrophil and platelet recovery, respectively. All nine patients had no evidence of disease before the transplant by PET-CT, although one patient had residual FGD uptaking areas without underlying anatomical lesions on CT (metabolic complete response: 89%). Six patients have been evaluated after the APBSCT and they are all in metabolic CR. The phase II of the trial was open on April the 12th 2015, with BV at the recommended dose of 1.8 mg/kg per course. At the submission of this report, there were 28 patients recruited, and 17 evaluated pre-transplant, achieving 16 CR. The complete results will be presented during the meeting; the projected recruitment by the meeting is 45 (65% of the total planned recruitment).
Conclusions: BRESHAP is a tolerable treatment scheme as remission induction prior to transplant in patients with refractory or relapsed Hodgkin lymphoma, and it offers very promising results.

Disclosures
Off Label Use: Brentuximab Vedotin in Resistant or Relapsed Hodgkin Lymphoma patients who are candidates to Autologous Stem Cell Transplant. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau. Caballero:Takeda: Honoraria, Research Funding.