CD30-Targeted Therapy with Brentuximab Vedotin Combined with Donor Lymphocyte Infusions Induce Sustained Clinical Remissions and Tumor Specific Immunity in a Series of Patients with Relapsed Hodgkin Lymphoma After Allogeneic Stem Cell Transplantation
Authors: Theurich Sebastian , Malcher Joke , Wennhold Kerstin , Shimabukuro-Vornhagen Alexander , Chemnitz Jens M. , Udo Holtick , Krause Anke , Kobe Carsten , Kahraman Deniz , Geothy Chakupurakal , Engert Andreas , Christof Scheid , Hallek Michael , von Bergwelt-Baildon Michael 
Published: October 2019

Abstract
Abstract 4213

Introduction
Hodgkin lymphoma (HL) is curable in a high proportion of patients. However, relapsed HL remains a therapeutic challenge especially if high-dose chemotherapy is not possible or the lymphoma has even relapsed after this salvage therapy. In such situations, allogeneic stem cell transplantation (alloSCT) is a potential curative option in which the graft-versus-lymphoma (GvL) effect can lead to immune mediated sustained tumor control. However, in the early phase after alloSCT, the risk of relapse is increased due to attenuated immune cell activity. In this situation, conventional systemic cytotoxic therapies are usually associated with a high mortality.
We hypothesized that treatment with brentuximab vedotin would be a promising approach for relapsed HL after alloSCT as it selectively targets the lymphoma cells via CD30 and might enhance a GvL response by the induction of immunogenic cell death. Moreover, the combination of this targeted therapy with donor lymphocyte infusions (DLI) would have the potential to further increase the GvL effect.

Methods
Four patients with relapsed HL after alloSCT were consecutively treated from March 2011 to March 2012 with brentuximab vedotin and DLI in an alternating regimen. All patients were included into a named-patient-program (Millenium, USA) and gave their written consent. Blood collection and immune cell in-vitro analyses were approved by the institutional review board. Evaluation of treatment response was performed clinically and with computed tomography scans following established criteria. Moreover, metabolic changes were analyzed by FDG-PET/CT scans.
To assess the induction of a GvL effect, we developed an in-vitro method using co-cultures of patient PBMCs (pre and post treatment) and well characterized CD30+ HL cell lines and controls as surrogate targets.

Results
Clinical evaluation showed that all four patients had marked clinical and metabolic responses with a median duration of disease control of at least 463 days (range 259–1189) after treatment initiation which is still ongoing in three patients. Sensory polyneuropathy and mild thrombopenia were the most common side effects.
Assessment of immunologic changes showed no significant tumor-specific T-cell reactivity prior to treatment. In contrast, a significant increase of HL-specific T cell activation could be observed in-vitro in all patients after treatment. Reactive HL-specific T cells mainly co-expressed CD161 and CD4 suggesting a TH17 like phenotype.

Conclusion
Taken together, we present evidence that CD30-targeted Hodgkin lymphoma therapy with brentuximab vedotin and DLI induces sustained clinical responses and tumor-specific immunity in an allogeneic setting which warrants further investigation in a larger population.

Disclosures:
Engert: Takeda Millenium: Consultancy, Honoraria, Research Funding.