TY - JOUR
T1 - Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial
AU - Ladetto, Marco
AU - Cortelazzo, Sergio
AU - Ferrero, Simone
AU - Evangelista, Andrea
AU - Mian, Michael
AU - Tavarozzi, Rita
AU - Zanni, Manuela
AU - Cavallo, Federica
AU - Di Rocco, Alice
AU - Stefoni, Vittorio
AU - Pagani, Chiara
AU - Re, Alessandro
AU - Chiappella, Annalisa
AU - Balzarotti, Monica
AU - Zilioli, Vittorio R.
AU - Gomes da Silva, Maria
AU - Arcaini, Luca
AU - Molinari, Anna L.
AU - Ballerini, Filippo
AU - Ferreri, Andrés J.M.
AU - Puccini, Benedetta
AU - Benedetti, Fabio
AU - Stefani, Piero M.
AU - Narni, Franco
AU - Casaroli, Ivana
AU - Stelitano, Caterina
AU - Ciccone, Giovannino
AU - Vitolo, Umberto
AU - Martelli, Maurizio
N1 - Funding Information:
ML has received invitations to scientific meetings, institutional research support, and contracts with AbbVie, Acerta, Amgen, Archigen, ADC Therapeutics, BeiGene Celgene, Gilead, J&J, Jazz, Roche, Sandoz, and Takeda. SF has done consultancy work for Janssen; advisory board work for Janssen and EUSA Pharma; has received speaker honoraria from Janssen, EUSA Pharma, and Servier; and research funding from Gilead. AC has served on advisory boards for Celgene, Iqone, Janssen, and Takeda; and received lecture fees from Celgene, Gilead-Kite, Janssen, Roche, and Servier. VRZ has acted as an adviser for Janssen and MSD, and received honoraria from Italfarmaco and Roche. MGdS has received research grants from Gilead; has served on advisory boards member for Janssen, AbbVie, Roche, Celgene, Gilead, and AstraZeneca; has been a speaker for Janssen, BMS, AbbVie, Gilead, and Takeda; and has received travel support from Janssen, Roche, AbbVie, Celgene, and Gilead. AJMF has served on advisory boards for Gilead, Juno, Novartis, and PletixaPharm; has received research grants from BMS, Beigene, Pharmacyclics, Hutchison Medipharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis, and Pfizer; and has patents on NGR-hTNF/RCHOP in relapsed or refractory PCNSL and SNGR-hTNF in brain tumours with San Raffaele Scientific Institute. UV has served on advisory boards for Celgene, Janssen, and Gilead; and received honoraria for lectures from Celgene, AbbVie, Roche, Janssen, and Gilead. MMa has acted as a consultant for and received honoraria from Roche, Celgene, Janssen, Sandoz, Novartis, and Gilead; and has served as a member of the advisory board for Roche, Celgene, Janssen, Sandoz, Novartis, and Gilead. All other authors declare no competing interests.
Funding Information:
The study was sponsored by Fondazione Italiana Linfomi and endorsed by the European Mantle Cell Lymphoma network. We are grateful to the Fondazione Italiana Linfomi personnel for their management of the study, particularly Antonella Ferranti, Daniela Gioia, and Alessandro Levis. We are grateful to the European Mantle Cell Lymphoma Network for scientific support and useful discussions during study design and conduct. We are indebited to Alberto Zamò, Domenico Novero, and Marco Paulli for the histological revision of patient specimens.
Publisher Copyright:
© 2021 Elsevier Ltd
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/1
Y1 - 2021/1
N2 - Background: Fit patients with mantle cell lymphoma aged 18–65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population. Methods: This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18–59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0–3, or aged 60–65 years with ECOG 0–2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m2 on day 1, oral prednisone 100 mg [total dose] on days 1–5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m2 on day 1; intravenous doxorubicin 50 mg/m2, vincristine 1·4 mg/m2, and cyclophosphamide 750 mg/m2 on day 2; oral prednisone 100 mg/m2 on day 2–6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m2 on day 1, intravenous rituximab 375 mg/m2 on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m2 every 12 h on days 1–3, intravenous rituximab 375 mg/m2 on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 109 cells per L or 10 mg per day for platelets 60–100 × 109 cells per L, days 1–21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009–012807–25) and ClinicalTrials.gov (NCT02354313). Findings: Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51–62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24–50), 3-year progression-free survival was 80% (95% CI 70–87) in the lenalidomide group versus 64% (53–73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30–0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3–4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3–4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events. Interpretation: Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma. Funding: Fondazione Italiana Linfomi and Celgene.
AB - Background: Fit patients with mantle cell lymphoma aged 18–65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population. Methods: This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18–59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0–3, or aged 60–65 years with ECOG 0–2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m2 on day 1, oral prednisone 100 mg [total dose] on days 1–5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m2 on day 1; intravenous doxorubicin 50 mg/m2, vincristine 1·4 mg/m2, and cyclophosphamide 750 mg/m2 on day 2; oral prednisone 100 mg/m2 on day 2–6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m2 on day 1, intravenous rituximab 375 mg/m2 on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m2 every 12 h on days 1–3, intravenous rituximab 375 mg/m2 on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 109 cells per L or 10 mg per day for platelets 60–100 × 109 cells per L, days 1–21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009–012807–25) and ClinicalTrials.gov (NCT02354313). Findings: Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51–62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24–50), 3-year progression-free survival was 80% (95% CI 70–87) in the lenalidomide group versus 64% (53–73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30–0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3–4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3–4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events. Interpretation: Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma. Funding: Fondazione Italiana Linfomi and Celgene.
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U2 - 10.1016/S2352-3026(20)30358-6
DO - 10.1016/S2352-3026(20)30358-6
M3 - Article
AN - SCOPUS:85098158181
VL - 8
SP - e34-e44
JO - The Lancet Haematology
JF - The Lancet Haematology
SN - 2352-3026
IS - 1
ER -