Brentuximab Vedotin in Combination with Donor Lymphocyte Infusion for Patients with Hodgkin Lymphoma Relapsing after Allogeneic Stem Cell Transplantation
Authors: Tsirigotis Panagiotis , Yerushalmi Ronit , Gkirkas Kostantinos , Shentov Noga , Danylesko Ivetta , Stamouli Maria , Avigdor Abraham , Mohty Mohamad , Shimoni Avichai , Nagler Arnon 
Published: October 2019

Abstract

Introduction
Brentuximab Vedotin (BV) has recently received approval for treatment of Hodgkin lymphoma (HL) relapse after auto-SCT. Although BV is very effective in treating relapse of HL post auto-SCT, response is usually transient. In contrast, there is a paucity of data regarding the efficacy and safety of BV, combined or not with donor lymphocyte infusion (DLI), for the treatment of relapse occurring after allo-SCT.
Methods
Search for patients (pts) with relapsed HL post allo-SCT was performed in our transplant data set with the aim to evaluate the efficacy and safety of BV in combination with DLI for the treatment of relapsing HL post allo-SCT. Eight pts with relapsed HL after allo-SCT that were treated with BV were included in this report.
Results
Patients and treatment: There were 6 males and 2 females, with a median age of 31 years (range, 23 - 40), who had previously failed an auto-SCT. Five pts had previously received BV after auto-SCT and all but one responded to treatment. All pts had chemosensitive disease before allo-SCT and were transplanted in a state of partial remission (PR). The graft source was unmanipulated peripheral blood stem cells from a matched related or an unrelated donor in 5 and 2 pts, respectively, while 1 pt received a double umbilical cord blood graft (DUCB). Five pts achieved complete remission (CR) and one PR after allo-SCT, while 2 pts had progressive disease (PD). Disease progression occurred in a median of 11 months (range, 4 - 17) after allo-SCT. All pts received BV at a dose of 1.8mg/kg every 3 weeks for a maximum of 16 doses, till disease progression or toxicity. In two pts chemotherapy was administered before BV. A median of 4.5 (range, 3 -12) BV cycles was administered. DLI was co-administered in 5 out of 7 pts (excluding one patient who received DUCB). Decision for DLI was at the discretion of the treating physician. One pt received 4 DLIs at escalating doses (5x106, 107, 5x107, 108/kg), while another one received 2 escalating DLIs (107, 108/kg) at 3 months interval. Three pts received a single DLI (107/kg).
Treatment outcome: Three and two pts achieved CR and PR respectively after treatment with BV in combination with DLI. None of the pts treated only with BV responded. Four out of 5 pts developed GVHD (3 chronic, 1 acute) post DLI administration, that resolved in all cases after a short course of low dose steroids. Disease progression was observed in 3 out of 5 responders in 4, 7 and 9 months, while 2 pts remain progression free with a median follow up of 14,5 (range, 4 - 22) months. Six out of 8 pts are alive, while 2 pts died from HL. BV/DLI treatment was well tolerated and no serious adverse effects were observed in any of the patients.
Conclusions
In our study, we observed that administration of BV with DLI for HL relapsing post allo-SCT in pts with prior failure to auto-SCT was effective while toxicity was minimal. Notably, re-administration of BV to pts previously treated for post auto-SCT relapse did not result in additional toxicity or resistance. Furthermore, BV combined with DLI, but not BV alone, yielded anti-tumor response in 5/7 of these very high risk pts suggesting a possible synergistic effect. Of notice is the observation that one pt who was refractory to BV post auto-SCT, had a PR after re-administration of BV post allo-SCT. Our observations are in accordance with the results of a previous report, showing that BV plus DLI after allo-SCT creates a vaccination like-effect against HL [1]. Finally, in our study we observed lower than expected frequency of GVHD post DLI that was of transient duration and easily manageable with low dose steroids. We assume that this may be due to an immune-modulating effect produced by BV. Indeed previous studies have shown that CD30 is expressed on the surface of activated T-cells present in inflammatory infiltrates of GVHD lesions [2]. Administration of BV plus DLI should be tested in larger group of patients at high risk of relapse after allo-SCT.
References Theurich S, Malcher J, Wennhold K, et al. Brentuximab Vedotin Combined With Donor Lymphocyte Infusions for Early Relapse of Hodgkin Lymphoma After Allogeneic Stem-Cell Transplantation Induces Tumor-Specific Immunity and Sustained Clinical Remission. J Clin Oncol. 2013; 31: 59-63. Chen Y, McDonough S, Hasserjian R, et al. Expression of CD30 in patients with acute graft-versus-host disease. Blood. 2012; 120: 691-696.

Disclosures
Tsirigotis: CELLTRION, Inc.: Research Funding.