A Pilot Study of Brentuximab Vedotin and AVD Chemotherapy Followed By 20 Gy Involved-Site Radiotherapy in Early Stage, Unfavorable Risk Hodgkin Lymphoma
Authors: Kumar Anita , Casulo Carla , Advani Ranjana H. , Budde Lihua , Barr Paul M. , Batlevi Connie L. , Caron Philip , Chen Robert W. , Constine Louis S. , Courtien Amanda , Dandapani Savita , Drullinsky Pamela , Friedberg Jonathan W. , Gerecitano John , Hamilton Audrey , Hamlin Paul A. , Hoppe Richard T. , Horwitz Steven M. , Matasar Matthew J. , Miller Shoshana T. , Moskowitz Alison J. , Noy Ariela , Palomba Maria L. , Portlock Carol S. , Schoder Heiko , Straus David J. , Yang Joanna C. , Younes Anas , Zelenetz Andrew D. , Zhang Zhigang , Yahalom Joachim , Moskowitz Craig H. 
Published: April 2021

Abstract
Introduction:The combination of brentuximab vedotin (BV) with AVD chemotherapy followed by 30Gy involved-site radiotherapy (ISRT) for the treatment of early stage, unfavorable risk Hodgkin lymphoma (HL) has demonstrated promising efficacy and an acceptable safety profile in the first cohort of this pilot study (Kumar et al, Blood, 2016). In cohort 2, we tested whether the ISRT dose could be reduced to 20Gy to minimize RT-related toxicity while maintaining efficacy.
Methods: Patients received 4 cycles of BV 1.2 mg/kg with AVD chemotherapy every 2 weeks, followed by 30 Gy ISRT in cohort 1 and 20Gy ISRT in cohort 2. Eligible patients were untreated stage I/II, classical HL with any of the following unfavorable risk factors: bulky disease (maximal transverse or coronal diameter &gt;7 cm on CT), elevated ESR, extranodal involvement, &gt;2 lymph node sites, or infradiaphragmatic disease. Patients with stage IIB disease with disease bulk or extranodal involvement were eligible. PET/CT after 2 and 4 cycles and after ISRT were interpreted with the 5-point Deauville scale (negative=1-3). The primary endpoint of cohort 2 was to evaluate preliminary efficacy with the rate of complete responses (CRs).
Results: In cohort 2, 29 patients were enrolled with median age of 33 (range 19-55), 100% stage II, 69% with disease bulk (&gt;7cm), 41% elevated ESR, 38% B-symptoms, 21% extranodal involvement, 72% &gt;2 involved lymph node sites, and 3% infradiaphragmatic disease. Twenty patients (69%) had bulky anterior mediastinal masses, ranging from 7 to 17.3cm. Nine patients (31%) had advanced stage disease by the GHSG criteria: IIBX (n=7) and IIBXE (n=2) disease.
In cohort 2, 90% and 93% of patients achieved a negative PET scan after 2 and 4 cycles of therapy, respectively (Figure 1). Of the 2 patients with positive PET-4 scans, one underwent a biopsy that was negative for HL and the other was not biopsied due to the inaccessible location of residual FDG-uptake. Both patients received ISRT. The 28 patients who have completed combined modality therapy (CMT) all have achieved CRs. One additional patient chose to forego ISRT, received 2 additional cycles of ABVD off study, and achieved a CR. To date, the median duration of remission is 8.5 months, with a range of less than 1 month to 17 months. No relapses have occurred. The efficacy is similar across cohorts 1 and 2 with interim PET negative rates of ≥90% and all patients who completed CMT have achieved a CR (Figure 1). In cohort 1, two patients had biopsy-proven primary refractory HL after 4 cycles of chemotherapy and in cohort 2, there have been no treatment failures.
Conclusion: BV+AVD x 4 cycles followed by 20Gy ISRT is an effective treatment program for early stage, unfavorable risk HL, including a high proportion of patients with bulky disease. As with 4 cycles of escalated BEACOPP tested in the GHSG HD11 clinical trial, 20Gy ISRT appears to be adequate consolidation after BV+AVD x 4 cycles. A third cohort of this pilot study is currently accruing in which patients receive BV+AVD x 4 cycles followed by 30Gy consolidation volume radiation. There is also a planned 4th cohort with no radiotherapy for PET-negative patients after 4 cycles of BV+AVD. After completion of the 4 cohorts, we plan to recommend the therapeutic strategy with the greatest efficacy and least toxicity to be further studied in a larger, randomized prospective study for early stage, bulky HL. Updated response data for all patients will be presented at the meeting.

Disclosures
Kumar: Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Casulo: Gilead: Honoraria, Other: travel support; Celgene: Research Funding; Infinity: Consultancy. Advani: Sutro: Consultancy; Nanostring: Consultancy; Celgene: Research Funding; Agensys: Research Funding; Spectrum: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Juno Therapeutics: Consultancy; Gilead: Consultancy; Regeneron: Research Funding; Millennium: Research Funding; Bayer Healthcare Pharmaceuticals: Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Merck: Research Funding; Infinity: Research Funding; Kura: Research Funding; Cell Medica: Research Funding; Pharmacyclics: Consultancy. Barr: Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Infinity: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Celgene: Consultancy; AbbVie: Consultancy, Research Funding. Chen: Affimed: Research Funding; Pfizer: Consultancy; Merck: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Drullinsky: Seattle Genetics: Honoraria, Other: Ad Board. Friedberg: Bayer HealthCare Pharmaceuticals.: Other: Data and Safety Monitoring Board: Bayer HealthCare Pharmaceuticals.. Gerecitano: Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aratana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Royal Bank of Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Arcus Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orexo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mass Medical International: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamlin: Gilead: Consultancy, Honoraria; Seattle Geneitcs: Other: research support; Incyte: Other: research support; Novartis: Other: research support; Celgene: Consultancy, Honoraria; Portola: Consultancy, Honoraria, Other: research support. Horwitz: Kyowa Hakko Kirin: Consultancy, Research Funding; BMS: Consultancy; Mundipharma: Consultancy; Aileron Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; HUYA: Consultancy; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Spectrum Pharmaceuticals: Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding. Moskowitz: ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Incyte: Research Funding; Takeda: Honoraria; Seattle Genetics: Honoraria, Research Funding. Noy: Pharmacyclics LLC, an AbbVie Company: Honoraria, Other: Travel, Accommodation, Expenses, Research Funding, Speakers Bureau. Palomba: Merck: Consultancy. Straus: Received consulting fee from Seattle Genetics for involvement in the research: Consultancy. Younes: Takeda Millenium: Honoraria; Johnson & Johnson: Research Funding; Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Curis: Research Funding; Seattle Genetics: Honoraria; Sanofi: Honoraria; Merck: Honoraria; Janssen: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Bayer: Honoraria; Novartis: Research Funding. Zelenetz: Celgene: Consultancy; Amgen: Consultancy. Moskowitz: Genentech BioOncology: Consultancy; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Celgene: Consultancy.