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Mauro, F. R.1; Molica, S.2; Paoloni, F.3; Reda, G.4; Trentin, L.5; Marchetti, M.6; Pietrasanta, D.7; Coscia, M.8; Marasca, R.9; Sportoletti, P.10; Gaidano, G.11; Orsucci, L.12; Stelitano, C.13; Di Renzo, N.14; Liberati, A. M.15; Gottardi, D.16; Re, F.17; Ilariucci, F.18; Zinzani, P.19; Mannina, D.20; Gozzetti, A.21; Molinari, A. L.22; Gentile, M.23; Consoli, U.24; Laurenti, L.25; Arcaini, L.26; Ibatici, A.27; Murru, R.28; Tani, M.29; De Propris, M. S.1; Del Giudice, I.1; Della Starza, I.1; Raponi, S.1; Nanni, M.1; Fazi, P.3; Crea, E.3; Neri, A.4; Specchia, G.30; Guarini, A. R.1; Cuneo, A.31; Foà, R.1

doi: 10.1097/01.HS9.0000559712.15168.1d
Poster Session I: Chronic lymphocytic leukemia and related disorders - Clinical

1Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome

2Department of Hematology, Pugliese Ciaccio Hospital, Catanzaro

3Italian Group for Adult Hematologic Diseases (GIMEMA), Rome

4Department of Hematology-Transplant Unit, IRCCS Ospedale Maggiore, Milan

5Hematology, Department of Medicine, University of Padua, Padua

6S.O.C. di Medicina Interna, Ospedale Cardinal Massaia, Asti

7Department of Hematology, SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria

8Department of Hematology, University of Torino, AOU Città della Salute e della Scienza, Torino

9Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena

10Department of Oncology-Haematology, Santa Maria Hospital, University of Perugia, Perugia

11Division of Hematology, Dept. of Translational Medicine, Università del Piemonte Orientale, Novara

12Department of Haematology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Torino

13Department of Haematology, Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria

14Department of Hematology, P.O. V. Fazzi, Lecce

15Hematology, A.O.S. Maria, Università degli Studi di Perugia, Terni

16A.O.U. S. Giovanni Battista, A.O. Mauriziano-Umberto I, Turin

17Department of Hematology, CTMO University, Parma

18Department of Hematology, Arcispedale Santa Maria Nuova, Reggio Emilia

19Department of Hematology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna

20Division of Hematology, Azienda Ospedaliera Papardo, Messina

21Department of Hematology and Transplant, Le Scotte Hospital, Siena

22Department of Oncology and Hematology, Infermi Hospital, Rimini

23Hematology Section, Cosenza Hospital, Cosenza

24Division of Oncohematology, Azienda Ospedaliera - Garibaldi, Catania

25Institute of Hematology, Università Cattolica del Sacro Cuore, Rome

26Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia

27Hematology and Bone Marrow Transplantation Unit, IRCCS Ospedale Policlinico San Martino, Genova

28Division of Hematology and CTMO, Businco Hospital, Cagliari

29Division of of Haematology, Santa Maria delle Croci Hospital, Ravenna

30Department of Emergency and Transplantation, Hematology Section, University of Bari, Medical School, Bari

31Hematology Section, St. Anna University Hospital, Ferrara, Italy

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Single agent Ibrutinib (IBR), an inhibitor of Bruton's tyrosine kinase, is approved for the front-line treatment of patients with chronic lymphocytic leukemia (CLL).

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As in CLL patients, the addition of anti-CD20 monoclonal antibody provides superior efficacy to chemotherapy, in a prospective multicenter, study of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) group the potential for improved efficacy with the addition of rituximab (R) to IBR was investigated in previously untreated and unfit patients with CLL.

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Eligible patients were CLL patients requiring front-line treatment who showed a Cumulative Illness Rating Scale (CIRS) score >6 and/or creatinine clearance <70 mL/min. During the first phase of this study patients received IBR, 420 mg once daily continuously, and R, 375 mg/sqm, on day 1 of months 1-6. Then, IBR was given as a single agent until progression, or severe toxicity, or complete response (CR) with no evidence of minimal residual disease (MRD) or for a maximum duration of 6 years. The primary endpoint of this study was progression-free survival (PFS).

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Between March 2015 and April 2017 143 unfit patients with CLL were included in this study. The median follow-up was 22.4 months (range, 1-31.3). The median age of patients was 73 years, (range, 37-88), median CIRS score 6 with an ECOG 1-2 performance status in 37% of patients. Binet stage B/C was present in 81% of patients, increased beta-2 microglobulin in 71% and bulky nodes (size ≥ 5 cm) in 14%. The presence of del(17p) or del(11q) was recorded in 9% and 14% of cases respectively, TP53 mutations in 15% and 51% of patients were IGHV unmutated. Response to IBR+R combination was assessed in 141 patients. On an intention-to-treat basis, 114 (81%) patients achieved a response that was a CR in 20%, an L-PR in 13% and a PR in 52%. MRD was undetectable by flow cytometry (<10-4) in the peripheral blood and bone marrow of 3 patients and by PCR also in 2. Seven (5%) patients showed no response while a treatment failure was considered in 14% who experienced early discontinuation of treatment due to other reasons than no response. After the first phase of the study with IBR+R combination, 106 patients continued treatment with IBR as a single agent. PFS and OS rates at 24 months were 91% (95% CI, 85.45-97.16) and 93% (95% CI, 88.54-98.52) respectively. No significant differences in PFS and OS were observed according to the response to IBR+R combination (PFS and OS at 12 months from response, CR vs L-PR/PR: 100% vs 98.5%; p = 0.44); and the IGHV mutational status (mutated vs unmutated IGHV, PFS at 24 months: 92% vs 89%; p = 0.7; OS at 24 months: 93% vs 92%; p = 0.7), Patients with del(17p) and/or TP53 mutations showed a lower, though not significantly lower, survival (TP53 disruption, absent vs present, PFS at 24 months: 94% vs 77%; p = 0.08; OS at 24 months: 95% vs 87%; p = 0.2). Serious adverse events (AEs) were recorded in 18 (12%) patients. Most frequent severe AEs were infections (7 patients); cardiac disorders (7 patients, atrial fibrillation in 5); pyrexia/ neutropenic fever (5 patients), bleeding events (3, subdural hematoma in 2). Fatal AEs were recorded in 4 cases (leukoencephalopathy, 2; sepsis,1; myocardial infarction, 1).

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The addition of R to IBR resulted in a higher rate of CR than those seen with IBR given as a single agent. Front-line treatment with IBR+R given to old and unfit patients with CLL was relatively well tolerated and an effective treatment option with durable responses.

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