Safety and Early Efficacy in an Ongoing Pilot Study of Brentuximab Vedotin and AVD Chemotherapy Followed By 30 Gray Involved-Site Radiotherapy for Newly Diagnosed, Early Stage, Unfavorable Risk Hodgkin Lymphoma
Authors: Kumar Anita , Yahalom Joachim , Schoder Heiko , Caron Philip , Drullinsky Pamela , Gerecitano John F. , Hamilton Audrey , Hamlin Paul , Horwitz Steven M. , Jacob Alexandra G. , Matasar Matthew J. , McCall Susan , Moskowitz Alison J , Noy Ariela , Palomba Lia , Portlock Carol S , Straus David J. , Verwys Stephanie , Zelenetz Andrew D. , Zhang Zhigang , Younes Anas , Moskowitz Craig H. 
Published: November 2019

Abstract
Background: Brentuximab vedotin has not been previously studied in combination with combined modality therapy for the frontline treatment of early stage Hodgkin lymphoma. We designed a pilot study to assess the safety and early efficacy of four cycles of brentuximab vedotin (BV) + AVD chemotherapy followed by 30 Gray involved-site radiotherapy (ISRT) for the treatment for early stage, unfavorable risk HL.
Methods: Patients with newly diagnosed, stage I/II, classical HL with unfavorable risk profile (defined by the German Hodgkin Study Group (GHSG) with one of the following criteria: bulky mediastinal mass (≥1/3 maximum transverse thoracic diameter on PA-CXR or ≥10cm by CT imaging in transaxial plane), ESR≥50mm/h or ESR≥30mm/h in patients with “B” symptoms, extranodal involvement, or >2 involved lymph node sites) were eligible. Patients with stage IIB disease with disease bulk or extranodal involvement were included (conventionally classified as advanced stage per GHSG). Patients were treated with four cycles of brentuximab vedotin 1.2 mg/kg with AVD chemotherapy every 2 weeks followed by 30 Gray involved-site radiotherapy. The primary endpoint of the study was to evaluate the safety of this regimen, with particular attention to the development of pulmonary toxicity. A PET/CT was performed after 2 and 4 cycles of therapy. PET scans were interpreted using the Deauville 5-point scale and a negative scan was defined as Deauville 1-3.
Results: Interim data for the first 19 of a planned 30 patients enrolled are presented here. Median age was 32 (range, 18-50), 47% female, 100% stage II disease, 53% with disease bulk by GHSG criteria, 53% elevated ESR, 34% B-symptoms, 37% extranodal involvement, 42% >2 involved lymph node sites. All patients with disease bulk had large anterior mediastinal masses measuring >10cm by CT in transverse plane (range, 10-16.9 cm). There were eight patients enrolled who would be considered to have advanced stage disease by the GHSG classification: 3 with IIBX, 3 with IIBE, and 2 with IIBXE disease. To date, 79% (15/19) and 63% (12/19) have completed interim PET-2 and PET-4 imaging studies, respectively. Ninety-three percent of patients (14/15) achieved a negative PET scan after 2 cycles (6, 8, and 1 patients achieved Deauville score of 2, 3, 4, respectively). All patients with disease bulk were PET-2 negative (10/10). Ninety-two percent of patients achieved a negative PET scan after 4 cycles of therapy (1, 8, 2, and 1 patients achieved Deauville score of 1,2,3,4, respectively). The patient with a positive PET-4 scan had a subsequent positive biopsy and will be treated off study for primary refractory HL. The study treatment has been well-tolerated. No pulmonary toxicity has been observed. Serious adverse events have been documented in two patients: febrile neutropenia and grade 3 hypertension. One patient discontinued protocol treatment due to the development of grade 3 peripheral neuropathy after one treatment with BV+AVD. The four patients who have completed combined modality therapy and an end-of-treatment imaging assessment achieved complete responses and no relapses have occurred to date.
Conclusion: The combination of BV+AVD chemotherapy followed by ISRT appears well-tolerated with no early signal of increased pulmonary toxicity. In this interim analysis of 19 newly diagnosed patients with early stage, unfavorable risk HL, over ninety percent of the evaluable patients have achieved negative interim PET scans after 2 and 4 cycles of BV + AVD, suggesting this is a highly active treatment program even in patients with substantial disease bulk. Updated safety and response data will be presented at the meeting.

Disclosures
Hamlin: Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding; Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy. Horwitz:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Infinity: Research Funding; Kiowa Kirin: Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Research Funding; Amgen: Consultancy; Bristol Myers Squibb,: Consultancy; Jannsen: Consultancy. Matasar:Genentech: Consultancy; Spectrum: Consultancy. Younes:Novartis: Research Funding; J & J: Research Funding; Curis: Research Funding; Bayer; Bristol Meyer Squibb; Celgene; Incyte; Janssen R & D; Sanofi; Seattle Genetics; Takeda Millenium: Honoraria. Moskowitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Research Funding; Merck: Research Funding.