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 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.

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Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-5364
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Lymphoma Diagnosis and Treatment
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article

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

Salvatore Leotta, Umberto Vitolo, Elsa Pennese, Samantha Pozzi et al.
Blood
Lymphoma Diagnosis and Treatment
article

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

Salvatore Leotta, Umberto Vitolo, Elsa Pennese, Samantha Pozzi, Pietro Lauzzana, Filíppo Gherlinzoni, Simone Ferrero, Elisa Bossi, Monica Tani, Giuseppe Pietrantuono, Luca Arcaini, Rita Tavarozzi, Donato Mannina, Attilio Olivieri, Vittorio Ruggero Zilioli, Antonio Pinto, Andrea Evangelista, Ilaria Del Giudice, Lucia Farina, Gianluca Gaïdano, Francesca Re, Benedetta Puccini, Giovannino Ciccone, Sara Veronica Usai, Giorgina Specchia, Fabio Benedetti, Carola Boccomini, Jacopo Olivieri, Chiara Bottelli, Vincenzo Pavone, Caterina Patti, Barbara Botto, Silvia Bolis, Domenico Pastore, Manuela Zanni, Alessandra Tucci, Marco Ladetto, Chiara Ghiggi, Fabrizio Pomponi, Catello Califano, Andrés J.M. Ferreri, Annalisa Arcari, Angelo Palmas, Federica Cavallo, Flavio Falcinelli, Antonella Anastasia, Stefano Luminari
article en

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.

BloodVol. 146(Supplement 1)
University of Verona (IT), University of Modena and Reggio Emilia (IT), Marche Polytechnic University (IT), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), University of Parma (IT), Vita-Salute San Raffaele University (IT), University of Pavia (IT), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Azienda Ospedaliera di Perugia (IT), Azienda Sanitaria Unità Locale di Reggio Emilia (IT), Ospedale "Santa Maria delle Croci" di Ravenna (IT), Centro di Riferimento Oncologico della Basilicata (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Ospedale Vincenzo Cervello (IT), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Ospedale A. Perrino (IT), Azienda Ospedaliera San Gerardo (IT), CTO Andrea Alesini (IT), Azienda Ospedaliera S.Maria (IT), Ospedale Santa Maria della Misericordia di Udine (IT), I.R.C.C.S. Oasi Maria SS (IT), Ospedale di Parma (IT), Guglielmo da Saliceto Hospital (IT), Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT), Azienda Ospedaliera Ospedale Maggiore (IT), Ca' Foncello Hospital (IT), Ospedale Policlinico San Martino (IT), Azienda USL di Pescara (IT), Mylan (Italy) (IT), Candiolo Cancer Institute (IT), Policlinico San Matteo Fondazione (IT), Ospedale San Bortolo (IT), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), Piedmont University (US), Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo (IT), Gruppo Italiano per il Trapianto di Midollo Osseo (IT), Azienda Ospedaliero Universitaria Policlinico "G.Rodolico - San Marco" (IT), Alleanza Contro il Cancro (IT), Azienda Ospedaliera Ospedali Riuniti Papardo Piemonte (IT), Azienda Ospedaliera G. Brotzu (IT), University of Florence (IT), University of Turin (IT), University of Bari Aldo Moro (IT), Sapienza University of Rome (IT)
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