Results of Rituximab Plus ABVD in 65 Newly Diagnosed Patients with Classical Hodgkin Lymphoma: Improvement of Event Free Survival (EFS) in All International Prognostic Score (IPS) Groups.
Authors: Younes Anas , Fayad Luis Y. , Goy Andre , McLaughlin Peter , Pro Barbara , Romaguera Jorge , Hagemeister Fredrick , Rodriguez Maria A. , Samaniego Felipe , Kwak Larry , Neelapu Sattva , Medeiros L. Jeffrey , Wedgwood Amanda , Fanale Michelle 
Published: October 2019

Abstract
The malignant Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (HL) rarely survive outside their microenvironment, which is illustrated by the difficulty in establishing HRS-derived cell lines. Reactive B and T cells, monocytes, and eosinophils have been reported to express growth and survival factors such as CD30 ligand, CD40 ligand, RANK ligand, and BLyS that may support HRS cell survival. To examine the contribution of reactive B-cells to the survival of HRS cells in vivo, we hypothesized that depleting B-cells from the HL microenvironment by rituximab may deprive HRS cells from critical survival and resistance factors and thereby improving the efficacy of chemotherapy. To test this hypothesis, 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 HL irrespective of CD20 expression on HRS cells, bidimensionally measurable disease, adequate bone marrow reserve (ANC > 1,000/uL, Platelets > 100,000/uL) and adequate cardiac and renal functions. They were excluded if they had HIV infection, or were pregnant women. To date 70 newly diagnosed patients are enrolled, of whom 65 patients had at least 12 months of follow up and are evaluable for treatment response. The median age is 28 years (Range; 18–72 years). Patients had stage II (50%), stage III (31%), or stage IV (19%) disease. Using the IPS prognostic score model, 36 patients (55%) had a score of 2 or higher. With a median follow up of 32 months, the estimated event-free survival (EFS) for the entire group is 85% and the overall survival is 98%. EFS for patients with different IPS groups is shown in the table and is compared with the expected EFS for ABVD alone as reported by Hasenclever and Diehl (NEJM 1998). As shown, R-ABVD improved EFS in all IPS groups with the biggest impact seen in patients with IPS > 2. 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 CD20 and CD19 positive 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 or IPS category. A randomized phase-II study is planned to evaluate this strategy in patients with high IPS score.
IPS Score Group ABVD EFS (Hasenclever and Diehl) R-ABVD EFS (Current Study) 0–1 79% 95% 0–2 74% 87% 2 67% 76% 〉1 60% 76.5% 〉2 55% 77% 〉3 47% 71%