Brentuximab Vedotin in Combination with Multi-Agent Chemotherapy Is Well Tolerated and Shows Promising Activity As Frontline Treatment for Primary Mediastinal B-Cell Lymphoma
Authors: Svoboda Jakub , Strelec Lauren E. , Nasta Sunita Dwivedy , Landsburg Daniel J. , Mato Anthony R. , Pro Barbara , Barta Stefan Klaus , Shah Nirav N. , Nagle Sarah Jordan , Chong Elise A. , Napier Ellen , Garrett Samantha , Schuster Stephen J. 
Published: October 2019

Background: Primary mediastinal B-cell lymphoma (PMBL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) with distinctive clinical and immunophenotypic features. Most PMBL patients (pts) present at young age and with bulky mediastinal mass. Over 80% of PMBL cases are CD30 positive by immunohistochemistry (IHC). Standard frontline systemic therapy for PMBL remains controversial and the use of intensive regimens may be associated with increased toxicity. Brentuximab vedotin (BV) is a CD30-directed immunoconjugate with established efficacy in relapsed Hodgkin lymphoma and several other CD30 positive lymphoid malignancies, but this targeted agent has not been utilized in frontline combinations for PMBL.

Methods: We designed an open label phase I/II trial using BV administered concurrently with rituximab, cyclophosphamide, doxorubicin, and prednisone (standard R-CHOP with the omission of vincristine to minimize risk of neuropathy) as frontline treatment for PMBL, grey zone lymphoma (GZL), and other CD30-positive DLBCLs. Pts with any Ann Arbor stage and at least equivocal CD30 expression on IHC were eligible. Consolidative radiation was allowed after completion of therapy at discretion of the treating physician. Phase I utilized a 3+3 de-escalation design with starting dose of BV 1.8 mg/kg on Day 1 in combination with rituximab 375 mg/m2 on Day 1, cyclophosphamide 750 mg/m2 on Day 1, doxorubicin 50 mg/m2 on Day 1, and prednisone 100 mg daily on Days 1-5 every 3 weeks for 6 cycles. The primary objective of phase I was assessment of safety and dose limiting toxicity (DLT) defined as any grade 3/4 non-hematologic toxicity observed in Cycle 1 requiring dose delay >14 days from the planned Day 1 of Cycle 2. Secondary end points included overall response rate (ORR), progression free survival (PFS), and overall survival (OS). The primary phase II objective was ORR with secondary endpoints of PFS, OS, safety, and correlation with CD30 expression. Revised Response Criteria for Malignant Lymphoma was used for response assessment (Cheson, 2007). Enrollment began in January 2014 and is reported through July 27, 2015.

Results: Twelve pts including 9 PMBL (75%), 1 GZL (8%), and 2 DLBCL (17%) have been enrolled and treated; 11 patients are evaluable after completing protocol defined therapy. Median age was 37 years (range 25 - 58), 5 (45%) were female, 9 (82%) had elevated LDH, and 6 (55%) had stage III-IV disease. No DLT was observed during phase I and no BV dose de-escalation was required. There were no grade 3/4 non-hematologic adverse events (AEs). Hematologic grade 3/4 AEs included febrile neutropenia in 2 pts and afebrile neutropenia in 1 pt. Five pts had grade 2 non-hematologic AEs at least possibly related to BV including mucositis, nausea/vomiting, diarrhea, abdominal pain, anorexia, hypotension, and neuropathy. No study related deaths were observed. The ORR among evaluable pts was 100% (10 pts with CR, 1 pt with GZL with PR). The PFS and OS with median follow-up of 8 months (range: 4 -18 months) is 100%. Eight pts completed consolidative radiation therapy after systemic therapy.

Conclusions: We established safety of administrating BV 1.8 mg/kg in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline therapy for PMBL, GZL and CD30-positive DLBCL. This outpatient regimen was well tolerated. Clinical outcomes observed in this initial cohort are very encouraging and will be validated in the ongoing phase II part of the trial.

Disclosures

Svoboda: Celgene: Research Funding; Immunomedics: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding. Off Label Use: Brentuximab is not FDA approved for front-line therapy in PMBL and CD30+ DLBCL. Nasta:Seattle Genetics: Research Funding; BMS: Research Funding. Mato:Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy. Pro:Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses. Barta:Seattle Genetics: Research Funding. Schuster:Janssen: Research Funding; Celgene: Consultancy, Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Phamacyclics: Consultancy, Research Funding; Hoffman-LaRoche: Research Funding; Novartis: Research Funding; Gilead: Research Funding.