Increased incidence of secondary malignancies after autologous stem cell transplantation in follicular lymphoma patients: Long-term results of the FIL-FLAZ12 Phase III randomized trial
Abstract
Abstract Introduction Registry data, including European Society for Blood and Marrow Transplantation (EBMT) data (Pettengell, BMT 2021), show that Autologous Stem Cell Transplant (ASCT) is commonly used as consolidation in relapsed/refractory (R/R) follicular lymphoma (FL), particularly after response to salvage chemoimmunotherapy (CIT), despite a lack of randomized evidence supporting its superiority in the rituximab era. The phase III FIL-FLAZ12 (NCT01827605) trial is the only study comparing ASCT to anti-CD20 radioimmunotherapy (RIT). At the primary analysis with a median follow-up (mFU) of 77 months (M), ASCT showed no benefit over RIT and higher acute toxicity (Ladetto, Ann Oncol 2023). We now report updated long-term results with a median follow-up (mFU) of 103 months (M) from enrollment and randomization. Methods Adult patients (pts) (18-65 yrs) with R/R FL and without clinically significant comorbidities were enrolled. All pts received three conventional, investigator-chosen CIT, and those achieving at least a PR were randomized 1:1 to undergo either ASCT or RIT prior to CD34+ stem cell collection. All patients received rituximab maintenance following consolidation. The primary endpoint was progression-free survival (PFS). Study schema, statistical plan and other details were described elsewhere (Ladetto, Ann Oncol 2023) Results From 30 August 2012 to 19 September 2019, 164 pts were enrolled (all Caucasians, median age 57 yrs; 55% Male). 141 responding pts were randomly assigned to ASCT (70 pts) and to RIT (71 pts). Early results in terms of efficacy and toxicity have been described elsewhere (Ladetto, Ann Oncol 2023). At a mFU of 103 M from enrollment, 84M-PFS and OS for the total study population were 44% (95% CI: 36–52) and 77% (95% CI: 69–83), respectively. In the randomized cohort, 84M-PFS was comparable between arms: 46% (33–57) in the ASCT group vs 49% (37–60) in the RIT group (HR=0.98, 95% CI: 0.62–1.55; p=0.92). Similarly, 84M-OS was nearly identical: 78% ASCT, 77% RIT (HR=0.92; p=0.80). Exploratory multivariable analysis identified male sex (HR=2.35), elevated LDH (HR=1.71), extranodal disease (HR=1.79), and Progression of Disease within 24 months (POD24) (HR=2.13) as independent predictors of inferior PFS (all p<0.05). Subgroup analysis suggested a possible benefit of ASCT in a small subset of pts with refractory disease (N=16; p=0.002), whereas pts with limited-stage disease appeared to benefit more from RIT (p=0.006). Patients with POD24 showed no benefit if treated with ASCT. Importantly, Secondary Malignancies (SMs) occured more frequently after ASCT: 16 cases in ASCT arm (4 urothelial, 3 cutaneous, 1 hepatic, 1 gastrointestinal, 1 breast, 1 pulmonary, 1 prostate, 1 lymphoma, 3 Myelodysplastic Syndromes) vs 4 in the RIT arm (1 breast, 1 Myelodysplastic Syndrome, 2 Acute Myeloid Leukemia). The 5-year cumulative incidence of SMs was significantly higher in the ASCT group (12.0% vs 6.8%; HR=3.23, 95% CI: 1.03–10.2; p=0.045), with 8 fatal events—6 of which occurred in the ASCT arm. Conclusion Our long-term data conclusively indicates the lack of benefit of ASCT vs RIT as consolidation in R/R FL. Notably, a significantly higher incidence of SMs was observed in the ASCT arm, including fatal events, highlighting a substantial long-term toxicity burden associated with this strategy. These findings underscore the need to carefully weigh the risks of ASCT, particularly in the context of emerging chemo-free and less intensive strategies that may offer similar efficacy with improved safety profiles.
Article Details
Authors (47)
Rita Tavarozzi
4Memorial Sloan Kettering Cancer Center, New York, NY
Andrea Evangelista
2Unit of Clinical Epidemiology, AOU Città Della Salute E Della Scienza Di Torino and CPO Piemonte, Turin, Italy
Manuela Zanni
3AOU SS Antonio e Biagio e Cesare Arrigo, SCDU of Hematology, Alessandria, Italy
Simone Ferrero
University of Turin, Turin, Italy
Alessandra Tucci
10Department of Haematology, Azienda Socio Sanitaria Territoriale Spedali Civili, Brescia, Italy
Barbara Botto
8Department of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy
Silvia Bolis
7SC Ematologia ASST-Monza, Monza, Italy
Pietro Lauzzana
8Division of Hematology, Clinica Ematologica, Centro Trapianti e Terapie Cellulari Carlo Melzi, DISM, Azienda Ospedaliero Universitaria S. M. Misericordia, Udine, Italy
Vittorio Ruggero Zilioli
12Division of Hematology, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Milan, Italy
Benedetta Puccini
10Department of Haematology, University of Florence, Florence, Italy
Annalisa Arcari
11Hematology Unit, Ospedale Guglielmo da Saliceto, Piacenza, Italy
Vincenzo Pavone
28Cardinal Panico Hospital, Tricase, Italy
Gianluca Gaidano
13Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
Monica Tani
14Hematology Unit, Department of Oncology and Hematology, “Santa Maria delle Croci” Hospital, Ravenna, Italy
Federica Cavallo
10University of Torino, Torino, Italy
Antonio Pinto
15Department of Hematology, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico “Fondazione G Pascale”, Naples, Italy
Chiara Ghiggi
Domenico Pastore
24A. Perrino Hospital, Brindisi, Italy
Lucia Farina
1Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
Andrés José María Ferreri
19IUniversity Vita-Salute San Raffaele, Milano, Italy Strategic Program on Lymphomas, IRCCS San Raffaele Scientific Institute, Milano, Italy, Milan, Italy
Angelo Palmas
23Ospedale “San Francesco”, Nuoro, Italy
Caterina Patti
21“Villa Sofia – Cervello” Hospital, Palermo, Italy
Francesca Re
Fabio Benedetti
Salvatore Leotta
24Division of Hematology and Program for Hematopoietic Transplantation, Azienda Ospedaliera Policlinico Vittorio Emanuele, Catania, Italy
Stefano Luminari
Azienda Unita Sanitaria Locale IRCCS of Reggio Emilia, Reggio Emilia, Italy
Elsa Pennese
13Unità Operativa Semplice Dipartimentale Centro Diagnosi e Terapia Linfomi, Presidio Ospedaliero Pescara, Pescara, Italy
Elisa Bossi
7SC Ematologia ASST-Monza, Monza, Italy
Carola Boccomini
Azienda Ospedaliero–Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
Antonella Anastasia
6ASST Spedali Civili, Department of Hematology, Brescia, Italy
Chiara Bottelli
5Department of Hematology, Spedali Civili, Brescia, Italy
Donato Mannina
27Hematology Unit, Papardo Hospital Messina, Messina, Italy
Samantha Pozzi
28Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto, Università di Modena e Reggio Emilia, Modena, Italy
Catello Califano
29Hematology, Hospital “Andrea Tortora”, Pagani, Pagani, Italy
Luca Arcaini
Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Flavio Falcinelli
31Hematology and Bone Marrow Transplantation, Azienda Ospedaliera Di Perugia, Perugia, Italy
Giuseppe Pietrantuono
32IRCCS CROB, Referral Cancer Center of Basilicata, Rionero In Vulture, Italy
Ilaria Del Giudice
Sapienza University of Rome, Rome
Sara Usai
34AO Brotzu - Ospedale Oncologico Businco, Unit of Hematology and Bone Marrow Transplant, Cagliari, Italy
Jacopo Olivieri
9Azienda Ospedaliera di Udine, Udine, Italy
Filippo Gherlinzoni
36Division of Hematology, Ca' Foncello Hospital, Treviso, Italy
Attilio Olivieri
37Ospedale Regionale delle Marche, Ancona, Italy
Giorgina Specchia
38Department of Emergency and Organ Transplantation D. E. T. O., Hematology Section, University of Bari, Bari, Italy
Fabrizio Pomponi
39Hematology, San Bortolo Hospital, Vicenza, Treviso, Italy
Giovannino Ciccone
5Clinical Epidemiology Unit, Oncology Department, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino and Centro di Riferimento Regionale per l’Epidemiologia e la Prevenzione Oncologia Piemonte Piemonte, Turin, Italy
Umberto Vitolo
Candiolo Cancer Institute
Marco Ladetto
1University of Eastern Piedmont, Department of Translational Medicine, Novara, Italy