Abstract Recent clinical trials have underscored the value of repeated minimal residual disease (MRD) measurements as a highly sensitive method for detecting subclinical disease and enabling dynamic risk stratification in hematologic malignancies. Despite its clinical potential, the complex and heterogeneous nature of MRD kinetics presents significant challenges for interpreting and integrating it into routine clinical decision‐making. In this study, we present a comprehensive, model‐based workflow for the longitudinal analysis of MRD trajectories designed to improve relapse risk prediction. We applied this newly developed workflow to a cohort of patients with mantle cell lymphoma (MCL). MRD measurements were collected from both bone marrow (BM) and peripheral blood (PB) over time, stored in the Fondazione Italiana Linfomi MCL0208 clinical trial. Using our functional MRD workflow, we defined four MRD dynamics that collapsed into two clinically relevant groups: favorable (rapid, sustained negativization) and unfavorable (persistent or fluctuating MRD). Patients with unfavorable profiles showed significantly shorter time to progression (TTP), with hazard ratio (HR) = 4.18 (95% CI: 2.44–7.14) in BM and HR = 5.71 (95% CI: 2.86–11.42) in PB. External validation in the European MCL Network “Younger trial” confirmed the predictive power of this stratification, with Kaplan–Meier analyses demonstrating significant prognostic discrimination. The most informative temporal windows for patient clustering vary by tissue. Early‐phase BM assessments offer greater discriminatory power, whereas late‐phase assessments are most informative in PB. These findings indicate that longitudinal MRD assessment in PB represents a clinically actionable strategy that could reduce dependence on invasive BM procedures.

7074 Background: Bone marrow biopsy (BMB) is an invasive staging procedure for follicular lymphoma (FL) and its results are needed to calculate FLIPI2 and PRIMA-PI scores. Beyond conventional biopsy bone marrow can also be assessed through FDG-PET bone staging (PETb). We report preliminary data on a comparison of BMB and PETb in assessing BM involvement among FL patients enrolled in the FIL-FOLL12 trial. Methods: Untreated stage II–IV FL patients requiring therapy were included. Patients were balanced according to treatment received and arm. BMBs were assessed by morphology and immunohistochemistry. PET/CT scans were reviewed by two expert nuclear medicine physicians. Pathological bone uptake (PETb+) was defined as mono- or multifocal, or diffuse FDG uptake in bone segments higher than liver activity (SUVmax). Results: This analysis included 179 patients; no significant differences in disease characteristics were observed between the revised cohort and the remaining patients enrolled in the FOLL12 trial. High-risk FLIPI2 was noted in 35.4%, and β2-microglobulin was increased in 53% of patients. BMB involvement was present in 58.5% (median infiltration 30%, range 0.5–95%). PETb was positive in 38 cases (21%), including 14% with focal or multifocal involvement and 7% with diffuse increased uptake. Concordant results between BMB and PETb were observed in 53.6%: among 103 BMB+ patients, 30 were PETb+ (29%). PETb identified BM involvement in 8 cases missed by BMB. While BMB+ was not associated with a different risk of PFS compared to BMB-, we observed a significant impact of PETb+ on PFS: PETb+ had 41% 5-year PFS (CI 25-72, p=0.003), while BMB+/PETb- showed 74% (CI 62-83, p=0.27) and BMB-/PETb- 66%(CI 52-72, reference).We then calculated FLIPI2 and PRIMA-PI using either conventional BMB or PETb to define BM involvement. The agreement between BMB and PETb scores was 87% for FLIPI2 and 67% for PRIMA-PI and the main disagreement was due to reallocation to lower risk groups; FLIPI2 0-2 patients raised from 65% to 74.3% according to FLIPI2-PET. FLIPI2 was confirmed prognostic for PFS and its c-Harrel increased from 0.582 to 0.602 when BMB was substituted with PETb (Table 1), with a 52% (CI 39-64) 5-Year PFS for conventional high risk FLIPI2 shifting to 41% (CI26-56) for high risk FLIPI2-PET. Conclusions: Although BMB detects marrow involvement in most patients, this does not uniformly translate into adverse prognosis. PETb, while less sensitive, identifies metabolically active and prognostically relevant bone disease. A FDG-PET-based assessment of bone involvement could refine risk stratification in FL and spare BMB in most patients Score HR for High risk CI c-Harrell FLIPI2 2.03 1.25-3.31 0.582 FLIPI2-PET 2.58 1.57-4.26 0.602 PRIMA-PI 1.23 0.67-2.23 0.537 PRIMA-PI-PET 1.47 0.85-2.54 0.550

Maintenance treatment in elderly patients with relapsed or refractory (R/R) follicular lymphoma (FL) remains an area of investigation. RENOIR was a multicenter, phase III, open-label randomized trial conducted by the Fondazione Italiana Linfomi (FIL) in elderly patients with R/R FL after one or two prior therapies. Patients achieving partial or complete response (PR/CR) after 4-6 cycles of standard rituximab-based chemotherapy were randomized 1:1 to maintenance with rituximab alone (R, standard arm) or rituximab plus lenalidomide (R2, experimental arm). The primary endpoint was 2-year progression-free survival (PFS) from randomization with an expected HR =0.5. A total of 152 patients (median age 71 years) were enrolled. After induction, 129 (85%) achieved an overall response (CR 58%) and were randomized to R (n=65) or R2 (n=64). At a median follow-up of 68 months, the 2-year PFS was 73% in the R2 arm and 64% in the R arm (HR 0.73, 95% CI 0.46-1.16, p=.183). An unplanned hypothesis- generating subgroup analysis showed a greater 2-year PFS benefit with R2 in patients aged <70y (HR=0.35): R2 96% vs R 69%. Two-year overall survival (OS) rates were similar (R2 80% vs R 89%; HR 1.12). Grade 3/4 adverse events were more frequent in R2, mainly neutropenia and gastrointestinal disorders. In conclusion, the primary endpoint of the study was not met and R2 maintenance did not significantly improve 2-year PFS in elderly patients with R/R FL, though a numerically benefit was observed. R2 showed a more favorable benefit/risk profile in patients <70 years whereas in older patients careful consideration of individual tolerability is warranted. Trial registration: RENOIR study (NCT02390869) clinicaltrial.gov.

Mantle cell lymphoma (MCL) is a clinically heterogeneous disease with varying treatment responses and outcomes. Despite the utility of the Mantle Cell Lymphoma International Prognostic Index (MIPI), its predictive capacity can be enhanced by integrating genetic markers such as TP53 mutations. We analysed 143 newly diagnosed MCL patients from a real-world cohort, assessing TP53 mutational status, clinical and biological markers. We developed the MIPI53 index by incorporating TP53 mutations, lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) status and age. Internal validation was performed via bootstrapping, and external validation was conducted with data from the fondazione Italiana Linfomi (FIL) MCL0208 trial. Patients were stratified into low-, intermediate- and high-risk groups, showing significant differences in 5-year progression-free survival (PFS) (83.1%, 35.4% and 12.0%, respectively; p < 0.0001) and 5-year overall survival (OS) (92.1%, 80.5% and 33.8%, respectively; p < 0.0001). External validation confirmed the robustness of the model (c-index: 0.732; akaike information criterion, AIC: 296.2 according to OS). A simplified version (sMIPI53) was developed, maintaining high predictive accuracy in both training (c-index: 0.819; AIC: 404.5) and external cohort (c-index: 0.730; AIC: 296.7). The MIPI53 index effectively stratifies MCL patients into prognostic groups by integrating genetic and clinical variables to enhance outcome prediction.

The TRIANGLE trial established an ibrutinib-containing therapy without autologous stem-cell transplantation (ASCT) as the new standard for younger, treatment-naïve patients with mantle cell lymphoma (MCL). However, the benefit of rituximab maintenance (RM) within this novel standard is unclear. We investigated whether RM improves progression-free survival (PFS) and overall survival (OS) with acceptable toxicity when added to the experimental arms of TRIANGLE. This secondary analysis of TRIANGLE included patients randomly assigned to ibrutinib-containing therapy without (I) or with (A + I) ASCT who responded to induction/ASCT. RM was given per national and center practice. PFS and OS of patients with and without RM were compared with inverse probability of treatment weighted Kaplan-Meier curves and log-rank tests. Among responders after induction/ASCT (I: 274; A + I: 237), RM was given to 61% (I) and 64% (A + I). RM prolonged PFS in ibrutinib-containing treatment arms (I: log-rank test: P = .003, 4-year PFS probability RM v no RM, 85% v 73%; A + I: P < .001, 90% v 75%). There were trends toward prolonged OS in RM groups. RM groups were at higher risk of grade 3 to 5 infectious toxicity (I: 34% v 11%; A + I: 41% v 18%). Our findings support adding RM to BTK inhibitor treatments in younger, untreated patients with MCL to achieve prolonged remission.

Background. The FOLL12 study demonstrated that in High tumor burden patients with Follicular lymphoma (FL) treated with immunochemotherapy (ICT), standard rituximab maintenance (RM) was associated with improved Progression Free Survival (PFS) compared with a response-adapted post-induction approachbased on metabolic response and molecular assessment of minimal residual disease (MRD). We here present updated results of study endpoints after a median follow up of 7.9 years. Methods. The FOLL12 study enrolled adult patients with gr1-3a FL, advanced stage and high tumor burden. Eligible patients were randomly assigned to receive ICT with either R-CHOP or R-Bendamustine followed by standard RM or a response-adapted post-induction approachbased on metabolic response and molecular assessment of minimal residual disease (MRD).End of Induction (EOI) metabolic response was centrally defined applying the 5-point Deauville scale (DS) that defined Complete metabolic response (CMR) in case of DS 1-3. MRD was defined according to nested PCR assessment of IGH::BCL2 rearrangement on bone marrow and peripheral blood and was evaluated only for patients with a molecular marker (MM) at baseline assessment. Post induction therapy in the experimental arm consisted of: CMR and MRD- patients, observation; CMR and MRD+ (EOI or Follow up) 4 weekly rituximab until MRD- for up to 3 courses; no CMR, one dose of ibritumomab tiuxetan followed by standard RM. The primary study endpoint was Progression Free Survival (PFS). Results. A total of 807 patients were randomized and 786 were eligible for this updated analysis. After a median follow-up of 7.9 years (range 0.1 to 12.3 years), median PFS was not achieved and 5 and 10-year PFS rates were 67% (95%IC 63-70%) and 54% (49-58). Also with this updated follow up the standard RM arm was associated with improved PFS rates vs the response adapted arm (Exp. vs STD HR 1.54, 95%CI 1.23-1.93). After first progression 270 patients received a second line therapy mainly represented by an alternative ICT combination. PFS and OS rates after first relapse were 41% and 78% at 5 years respectively without difference comparing the main therapeutic options. Overall, after the induction 85 second malignancies were reported, including 37 hematologic malignancies and 48 solid cancers out of 744 patients. The cumulative risk of 2nd malignancy at 5 year was 13.2%, with a trend for higher risk for patients treated with RB vs R-CHOP (HR adjusted for age, sex, FLIPI2, study arm 1.48 (CI95% 0.96– 2.28). The 5-year cumulative risk of tFL from start of induction was 4.2%. with significant higher risk associated with the use of RB vs R-CHOP (HR adjusted for age, sex, FLIPI2 and Arm 2.26, CI95% 1.10 – 4.63). Overall 15 late infections were reported starting from the end of induction therapy, corresponding to a rate of 1.4% and 2.9% in RCHOP and RB, respectively (logrank p=0.022). Out of 101 deaths, 33 were due to progressive disease, 13 infections, 12 second malignancy 28 for other non lymphoma related causes and 15 for unknown reasons, resulting in 5 and 10-year Overall Survival (OS) rates of 92% (90-94) and 82% (78-86), respectively. Comparing study arms no differences were observed in terms of OS rates (HR 1.20, 95%CI 0.81–1.77). Conclusions. This long term updated analysis of the FOLL12 study demonstrated that high tumor burden FL patients initially treated with ICT are offered excellent outcomes with more than half of the patients who don't relapse after first line therapy and with very high survival rates. Also with the longer follow up standard RM was associated with improved PFS vs the response adapted approach but still no difference in term of OS was observed. While similar excellent results are achieved in terms of long term outcomes the choice of initial ICT may result in different risks in terms of late events mainly represented by second malignancies, tFL and infections.

Discordant results have been generated regarding the prognostic role of Total Metabolic Tumor Volume (TMTV) in Follicular Lymphoma (FL). The use of prospective data and the adoption of the newly defined standardized SUV4 method for calculating TMTV may generate stronger evidence. We conducted a pre-planned post hoc analysis of the prospective multicenter randomized phase III FOLL12 trial for newly diagnosed high tumor burden FL (grade 1-3a), which mandated baseline staging with PET. Baseline PET/CT scans were reviewed centrally, and TMTV was calculated using the fixed threshold of SUV4. Kaplan-Meier and Cox regression were used for survival analysis. The primary study endpoint was Progression free Survival (PFS). A total of 689 FL patients were available for TMTV definition. Median TMTV was 161 mL (IQR 50 to 388 mL) and the best cutoff value was set at 180 mL. Patients with high TMTV had a significantly lower 5-year PFS compared to those with low TMTV: 59% (95% CI, 53-65%) vs. 74% (95% CI, 69-78%) HR 1.61 (95% CI, 1.24-2.09). Prognostic role of TMTV was independent of study arm, chemotherapy regimen, and FLIPI2. Combined with FLIPI-2, we identified three groups with different 5-yr PFS rates, with the lowest rates (51%) for patients with high TMTV and high FLIPI2. Combined TMTV and FLIPI model was also prognostic to predict the risk of early progression and of death. Applying the SUV4 standard method pre-treatment TMTV is confirmed as a strong and independent predictor of PFS in FL patients. Integrating TMTV with FLIPI-2 improves risk assessment.

Introduction: Novel immunotherapies (including antiCD19 CAR-T cells, bispecific antiCD20/antiCD3 Monoclonal Antibodies (MoAbs), AntiCD19 Antibodies Drug-Conjugated (ADC)) completely changed the outcome of relapsed/refractory lymphomas. Patients undergoing these therapies showed increased risk of infection due to prior immunosuppression, deep B-cell depletion, treatment of unique toxicities with anti-interleukins and steroids, on-target effects of hypogammaglobulinemia and prolonged cytopenia. On these bases, we conducted this observational retrospective multicenter study to evaluate pattern of infections and impact on outcome in a cohort of non-Hodgkin's lymphomas (NHL) patients. Methods: This is an observational retrospective multicenter study, aimed to evaluate infections incidence, type and timing, and the outcome of NHL patients, treated with novel immunotherapies in the first two years from treatment start. All patients diagnosed with NHL in three Italian centers, who started the treatment from Dec 1st, 2019 to Apr 30th, 2025 were consecutively included in the analysis. Results: 110 NHL patients were treated with 131 lines of immunotherapies, including 91 with antiCD19 CAR-T cells (46 Axi-cel, 29 Tisa-cel, 16 Brexu-cel), 30 with antiCD20/antiCD3 bispecific MoAbs (10 glofitamab, 14 epcoritamab and 6 mosunetuzumab), and 10 with AntiCD19 ADC (loncastuximab). Among 110 patients, 13 cases received 2 and 4 patients 3 consecutive lines of immunotherapies, respectively. Median age was 63 years (range 18- 84), with significantly older age in patients receiving bispecific MoAbs (72 years, range 40- 84), if compared with those receiving CAR-T and ADC (p < 0.001). Seventy-one (65%) were male, while NHL histology was: Diffuse Large B-cell (DLBCL) in 67 (61%), High grade B-cell (HGBCL) in 9 (8%), Primary mediastinal (PMBCL) in 5 (5%), Mantle (MCL) in 16 (14%) and Follicular lymphoma (FL) in 13 (12%) cases, respectively. Median number of previous lines of treatment was 2 (range 1- 7), with 1 previous therapy in 13 (10%), 2 in 76 (58%), 3 in 26 (20%), > 3 in 16 (12%) cases, respectively. Response to the last prior line of treatment was refractory in 70 (53%), early relapse (3- 12 months) in 30 (23%), late relapse (>12 months) in 31 (24%) cases. Thirty-two patients had previously received autologous stem cell transplantation, in one case both auto and allogeneic transplantation. Total infective events recorded in the first two years from treatment were 112 (72 (64%) bacterial, 30 (28%) viral, 4 cases of concomitant viral + bacterial, 4 cases of fever with unknown origin (FUO) and 2 fungal infections). COVID19 still represented 16% of whole infections, while the most frequent site was pneumonia, followed by colitis. Infection grade was: 1-2 in 62%, 3-4 in 33%, 5 in 5% of cases. Hospitalization was required in 42% of cases. Median time from starting of immunotherapy to first infection was 15 days (range 1- 420), with 82% of infections occurring in the first 100 days and 71% in the first 30 days. Among 131 lines of immunotherapies administered: 70 (53%) had no infective complications, while 61 (47%) showed at least 1 (range per treatment 1- 6). We observed one infective event in 40 cases (31%), two infective events in 12 cases (9%), three infective events in 3 cases (2%) and more than 3 episodes in 6 (5%) cases. Very Early infections (< 30 days) were more frequently of bacterial origin (69%), while late infections (> 100 days) were more often viral (60%). Only 2 mycoses were recorded: one early (21 days) fungal and bacterial pneumonia, one late onset (more than one year after starting therapy) aspergillosis, both in DLBCL patients treated with bispecific MoAbs. Mantle cell and follicular lymphomas histology were associated to relative higher risk of infections (HR 1.45, 95% CI 1.25- 1.78, p 0.045), along with higher number of previous lines of treatment (p 0.032), while no differences were seen according to IgG level, Hb, plts, GN level, or support with IGIV or G-CSF. Fifty-five deaths occurred, caused by: lymphoma progression in 43 (78%), grade 5 infections in 3 (5%), other causes in 9 (16%) patients. Conclusions: Infections are common complications during novel immunotherapy treatments in NHL: nonetheless, in our real-life cohort most of cases occurred early (< 100 days) and showed manageable mild-moderate severity. Overall, in this setting of relapsed/refractory NHL patients the main cause of death remains lymphoma progression.

Follicular lymphoma (FL) has a heterogeneous clinical course, and despite advances in therapy, a significant proportion of patients experiences relapse. Existing prognostic models do not fully capture the biological heterogeneity of disease. PET/CT-derived biomarkers such as total metabolic tumor volume (TMTV) and the maximum lesion distance (Dmax) have emerged as prognostic tools, though their combined utility in FL remains underexplored. This study aimed to develop a composite prognostic score incorporating clinical and imaging metrics to improve baseline risk stratification in patients with newly diagnosed FL. This is a post hoc analysis of patients enrolled in the FOLL12 trial which had avalaible baseline TMTV calculated. TMTV was calculated using the SUV4 threshold method, and the cut-off of 180 mL based on previously published study (Durmo et al., Am J Hematol) was used for analysis. Dmax was derived from lesion coordinates of TMTV and normalized by body surface area (SDmax). The optimal SDmax cut-point for progression-free survival (PFS) was determined using maximally selected log-rank test. A composite score was derived assigning weighted points to features that were indipendend in multivariable analysis. Model performance was assessed using Harrell's c-index. Internal validation for Sdmax and model through 1000 bootstrap resamples was used. Study primary endpoint was PFS and overall survival (OS) was a secondary endpoint. This analysis included 682 treatment-naïve patients with grade 1-3a FL. 336 (50%) was older than 60 years and 315 (46%) was male. The cohort was balanced across treatment arms (experimental arm n=351). A total 286 (42%) patients had R-Bendamustine as induction treatment. Median SDmax was 284 mm/m² (IQR: 247; range: 4–1037 mm/m²). An optimal SDmax cut-point of 400 mm/m² was identified, stratifying patients into low (SDmax ≤400 mm/m², n=538, 79%) and high (SDmax >400 mm/m², n=144, 21%) dissemination groups. SDmax >400 mm/m² and TMTV >180 mL were independently associated with inferior PFS (HR of 1.50, 95% CI: 1.12–2.02 and 1.32 95% CI: 1.01–1.73, respectively). FLIPI-2 and male sex also were independent prognostic factors. These variables were consistently selected in bootstrap resampling and used to derive a combined prognostic score ranging from 0 to 6 points, 1 point each for high TMTV, high SDmax, male sex and 3 points for high FLIPI2. The composite score effectively stratified our cohort into three risk groups: 307 (45%) patients into low-risk (score 0–1) with a 5-year PFS of 79% (95% CI, 73-83%), 140 (21%) of patients into intermediate-risk (score 2–3): 5-year PFS 65% (95% CI 56-72%, HR=1.86) and 235 patients (34%) into a high-risk (score 4–6) with a 5-year PFS 52% (95% CI 45-59% , HR=2.93). The prognostic role of the composite score was confirmed by treatment arm. Incorporating PET metrics improved model discrimination over FLIPI-2 alone (c-index: 0.636 vs. 0.600; p=0.015). Internal validation demonstrated excellent reproducibility of the model (bootstrap-corrected c index of 0.632) and a shrinkage factor of 0.995, indicating minimal overfitting and stable predictive performance. 5-year OS rates was 97% for score 0–1 (n=307), 94% for score 2–3 (n=140; HR = 2.44, 95% CI: 1.05–5.67), and 88% for score 4–6 (n=235; HR = 4.96, 95% CI: 2.45–10.0). A composite prognostic score integrating FLIPI-2 with baseline TMTV, SDmax, and sex improves risk stratification in FL. This integrated model identifies patients at highest risk of progression and may support personalized therapeutic strategies in future trials.

The SARS-CoV2 pandemic has posed unprecedented challenges between temporary or permanent discontinuation of immunosuppressive treatment to protect patients, or disease control prioritization by not interrupting treatment. Maintenance treatment with anti-CD20 monoclonal antibodies (MoAbs) improves progression-free survival (PFS) in follicular lymphoma (FL), but also impairs anti-SARS-CoV2 immune response. This challenge has been addressed in Italy by temporary, definitive or no discontinuation of anti-CD20 treatment. We report the outcome of 539 FL patients receiving anti-CD20 MoAbs (rituximab in 431, obinutuzumab in 108), which were temporarily discontinued in 150 patients (group A), definitively discontinued in 166 (group B), or uninterrupted in 223 (group C). In the overall cohort, the 3-year progression-free survival (3y PFS) and 3-year overall survival (3y OS) rates were 80% and 88%. PFS and OS were significantly better in group A compared to group B and C (p = 0.01). Induction chemoimmunotherapy significantly influenced OS: the 3y OS was 91% vs 85% in CHOP vs bendamustine treated patients (p = 0.04), while the 3y OS was 90% vs 77% in rituximab vs obinutuzumab treated patients (p = 0.002). SARS-Cov2 infection was the main cause of death (67% of cases). Vaccination with multiple doses demonstrated to be clinically helpful, with impact on OS.

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.