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Mazza, R.1; Spina, M.2; Califano, C.3; Gaudio, F.4; Carella, M.5; Consoli, U.6; Palombi, F.7; Musso, M.8; Pulsoni, A.9; Kovalchuk, S.10; Bonfichi, M.11; Ricci, F.1; Fabbri, A.12; Liberati, A. M.13; Rodari, M.14; Giordano, L.15; Balzarotti, M.1; Gallamini, A.16; Ricardi, U.17; Chauvie, S.18; Merli, F.19; Carlo-Stella, C.20; Santoro, A.20

doi: 10.1097/01.HS9.0000563228.79887.e0
Poster Session II: Hodgkin lymphoma - Clinical

1Medical Oncology and Hematology Department, Humanitas Research Hospital, Rozzano-Milano

2Medical Oncology department, Centro Riferimento Oncologico, Aviano

3Onco-Hematology Department, A. Tortora Hospital, Pagani

4Emergency and Transplantation Department, Hematology section, university of Bari, Bari

5Hematology Division, IRCCS S. Martino Hospital, Genova

6Hematology Department, Garibaldi Nesima Hospital, Catania

7Hematology Department, Regina Elena National Cancer Institute, Roma

8Onco-Hematology Unit, Casa di Cura La Maddalena, Palermo

9Department of Translational and Precision Medicine, Sapienza University, Roma

10Hematology Department, AOU Careggi, Firenze

11Hematology Division, IRCCS Policlinico S. Matteo, Pavia

12Hematology Unit, AOU Senese, Siena

13Onco-Hematology Division, S. Maria Hospital, Terni

14Nuclear Medicine Unit, Humanitas Research Hospital, Rozzano

15Biostatistic Unit, Humanitas Research Hospital, Rozzano-Milano, Italy

16Research, Innovation and Statistics Department, Centre Antoine-Lacassagne, Nice, France

17Oncology Department, Radiation Oncology, University of Torino, Torino

18Medical Physics Department, S. Croce e Carlo Hospital, Cuneo

19Hematology Department, Azienda Unità Sanitaria Locale IRCCS, Reggio Emilia

20Medical Oncology and Hematology Department, Humanitas University, Rozzano-Milano, Italy

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Four cycles of ABVD followed by 30 Gy involved site radiotherapy (ISRT) is the standard of care for patients with early unfavourable classical Hodgkin lymphoma (cHL). Since dose-density might represent an important factor to achieve complete remission and longterm survival, we designed a prospective, multicenter, phase II trial to investigate feasibility, safety and efficacy of dose-dense ABVD (dd-ABVD) in patients with early unfavourable HL. This prospective, multicentric, phase 2 study enrolled patients aged 18-70 years with newly diagnosed cHL, unfavourable stage I or II, according to EORTC prognostic criteria. Patients with stage IIB bulky were excluded.

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Aims of the study were to investigate feasibility, safety and efficacy of dd-ABVD in patients with early unfavorable cHL.

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Dd-ABVD consists of Doxorubicin, Bleomycin, Vinblastine and Dacarbazine used at the same doses of conventional ABVD but is administered on days 1 and 8 every 3 weeks instead of days 1 and 15 every 4 weeks. In the absence of progressive disease (PD) or unacceptable toxicity, 4 cycles of dd-ABVD followed by ISRT were administered. Interim PET was mandatory after 2 courses (PET-2). Patients experiencing PD were shifted to second-line salvage therapy. Feasibility and activity of dd-ABVD regimen were the primary endpoints of the study. By design, the study was considered feasible if ≤5 out of 52 patients required a dose reduction below 85% of the planned dose. The percentage of interim PET negativity was chosen as the parameter to evaluate its activity.

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Between February 2012 and June 2015, 96 patients were enrolled and evaluated. The feasibility endpoint was achieved with only 4 out of 52 patients requiring a dose reduction greater than 15%. The mean dose intensity in the 96 patients who started dd-ABVD treatment was 93.7% with only 3 patients unable to complete ddABVD chemotherapy due to toxicity. The activity analysis was performed in all 96 patients. PET-2 was available for 92/96 (95.8%) patients, of whom 79 were PET-2 negative (85.9%) and 13 PET-2 positive (14.1%). In 3 cases PET-2 was not performed due to logistic reasons and in 1 patient because of switch to standard ABVD following a SAE at cycle 1. Considering the global outcome of the 96 patients who received at least 1 dd-ABVD course: 90 patients achieved CR (93.8 %), 1 PR (1%), 4 PD (4.2 %) and 1 (1%) was without a known disease assessment. With a median follow-up of 39.9 months (range: 2.1- 57.6 months), median PFS and OS were not reached, at 24 months PFS and OS were 91.5% and 97.9%, respectively. No statistically significant differences were observed for PET-2 negative and PET-2 positive patients for both 2 years PFS (94.9% vs 84.6%, p: 0.260) and OS (98.7% vs 100% a, p: 0.560) (figure 1). Most frequent toxicities were haematological. The infection rate was low (infection 8.3% and febrile neutropenia 6.25%); no patient developed cardiac toxicity until now. There was one toxic death after cycle 4; 3 patients were discontinued from the study due to toxicity and were switched to standard ABVD or AVD



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The study demonstrates the feasibility of the dd-ABVD regimen in early unfavourable cHL which also allows a reduction in overall treatment duration without a significant increase in toxicity. Moreover, the dose-dense strategy translated in excellent data of outcome in term of CR rate, PFS, and OS with a low rate of progression at 2 years. Dd-ABVD deserves further comparison with conventional ABVD in early unfavourable as well in advanced cHL.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.