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

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.

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Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation

Blood ◽

10.1182/blood-2011-12-397893 ◽

2012 ◽

Vol 120 (3) ◽

pp. 560-568 ◽

Cited By ~ 115

Author(s):

Ajay K. Gopal ◽

Radhakrishnan Ramchandren ◽

Owen A. O'Connor ◽

Robert B. Berryman ◽

Ranjana H. Advani ◽

...

Keyword(s):

Stem Cell ◽

Adverse Events ◽

Stem Cell Transplantation ◽

Hodgkin Lymphoma ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Sensory Neuropathy ◽

Progression Free Survival ◽

Complete Response ◽

Brentuximab Vedotin

Abstract Hodgkin lymphoma (HL) relapsing after allogeneic stem cell transplantation (alloSCT) presents a major clinical challenge. In the present investigation, we evaluated brentuximab vedotin, a CD30-directed Ab-drug conjugate, in 25 HL patients (median age, 32 years; range, 20-56) with recurrent disease after alloSCT (11 unrelated donors). Patients were > 100 days after alloSCT, had no active GVHD, and received a median of 9 (range, 5-19) prior regimens. Nineteen (76%) had refractory disease immediately before enrollment. Patients received 1.2 or 1.8 mg/kg of brentuximab vedotin IV every 3 weeks (median, 8 cycles; range, 1-16). Overall and complete response rates were 50% and 38%, respectively, among 24 evaluable patients. Median time to response was 8.1 weeks, median progression-free survival was 7.8 months, and the median overall survival was not reached. Cough, fatigue, and pyrexia (52% each), nausea and peripheral sensory neuropathy (48% each), and dyspnea (40%) were the most frequent adverse events. The most common adverse events ≥ grade 3 were neutropenia (24%), anemia (20%), thrombocytopenia (16%), and hyperglycemia (12%). Cytomegalovirus was detected in 5 patients (potentially clinically significant in 1). These results support the potential utility of brentuximab vedotin for selected patients with HL relapsing after alloSCT. These trials are registered with www.clinicaltrials.gov as NCT01026233, NCT01026415, and NCT00947856.

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