Six Weekly Doses of Rituximab Plus ABVD for Newly Diagnosed Patients with Advanced Stage Classical Hodgkin Lymphoma: Depletion of Reactive B-Cells from the Microenvironment by Rituximab.
Authors: Younes Anas , McLaughlin Peter , Fayad Luis E. , Goy Andre , Romaguera Jorge E. , Pro Barbara , Rodriguez Maria A. , Samaniego Felipe , Kwak Larry , Neelapu Sattva , Medeiros Jeffrey 
Published: April 2020

Abstract
The malignant Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL) rarely survive outside their microenvironment, which is illustrated by the difficulty in establishing HRS-derived cell lines. Thus, we hypothesized that destroying the HL microenvironment may deprive HRS cells from critical survival factors leading to their death. The majority of the cells in this microenvironment are benign T and B lymphocytes. Both B and T cells have been reported to express growth and survival factors such as CD30 ligand, CD40 ligand, and RANK ligand that may support HRS cell survival. To determine the contribution of benign B-cells to the survival of HRS cells in vivo, we recently conducted a pilot study using rituximab alone in patients with relapsed classical HL. Rituximab produced an overall response rate of 23% in heavily pretreated patients with relapsed classical HL, presumably by depleting benign B cells from HL lesions. In this study, we evaluated the safety and efficacy of the novel combination of rituximab and ABVD (R-ABVD) chemotherapy in newly diagnosed patients with classical HL. Rituximab was given at 375 mg/m2 weekly for 6 weeks to rapidly deplete B lymphocytes, while ABVD was given at a standard dose and schedule. The first dose of rituximab was given concurrently with the first dose of ABVD (schedule A) or 3 weeks before the first dose of ABVD (schedule B). Patients with lesions larger than 5 cm received involved field radiation therapy at the end of R-ABVD. Patients were eligible if they were older than 16 years of age and had biopsy-confirmed classical HD irrespective of CD20 expression on RS cells, bidimensionally measurable disease, adequate bone marrow reserve (ANC &gt; 1,000/uL, Platelet &gt; 100,000/uL) and adequate cardiac and renal functions. They were excluded if they had HIV infection, or were pregnant women. To date 72 newly diagnosed pts are enrolled. Analysis of the first 52 pts is provided. Analysis of the entire 72 patients will be presented at the meeting. The median age was 30 years (range; 18–63 years). Patients had stage II (50%), stage III (31%), stage IV (19%) disease. Using the German prognostic score model, 32 patients (62%) had a score of 2 or higher. With a median follow up of 32 months, the estimated event-free survival (EFS) is 82% and overall survival 100%. EFS for patients with a prognostic score of 0–1 is 92%, score 0–2 is 86%, and score 3–5 is 73%. Treatment was reasonably well tolerated with the majority of toxicities being grade 1 and 2. One patient developed PCP pneumonia proven by bronchalveolar lavage. In two patients, fine needle aspiration of a peripheral lymph node was performed before the first and after the third dose of rituximab (schedule B-before starting ABVD). Rituximab induced complete depletion of B cells from HL node. We conclude that in patients with classical HL, the addition of 6 weekly doses of rituximab to standard dose and schedule of ABVD chemotherapy is effective in terms of remission rate and remission duration irrespective of CD20 expression on HRS cells. Furthermore, patients with prognostic score of 3 or higher had a 73% EFS suggesting that this strategy may improve treatment outcome in this patient population.