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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2025
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