Follicular Lymphoma Prognostic Index Research Articles

Prognostic and Immune-Related Factors for Response to Duvelisib in the Phase 2 DYNAMOTM Clinical Trial in iNHL

Prognostic and Immune-Related Factors for Response to Duvelisib in the Phase 2 DYNAMOTM Clinical Trial in iNHL

Prognostic Biomarkers Converge on a Germinal Centre Dark Zone Phenotype As a Determinant of Adverse Outcome in Follicular Lymphoma Patients Treated with Rituximab and Chemotherapy

Introduction: Follicular lymphoma (FL) is a clinically and genetically heterogeneous disease with highly variable patient outcomes. Recently, Huet et al. proposed a 23-gene expression-based risk score for predicting progression-free survival (PFS) in FL patients treated with rituximab and chemotherapy (Huet et al. Lancet Oncology 2018). The m7-FLIPI risk score has also been described as a clinico-genetic model predicting patient outcomes (Pastore et al. Lancet Oncology 2015). Moreover, EZH2 wild-type status and high expression of the FOXP1 transcription factor are associated with increased risk of lymphoma progression (Mottok et al. Blood 2018). This multitude of prognostic tools in FL raises the question whether they identify common biology. The aims of this study were to assess whether the 23-gene predictor score identifies a poor risk group of patients in our own gene expression dataset, and whether commonality exists between the 23-gene score, the m7-FLIPI, EZH2 mutation status and FOXP1 expression.Methods: In our previous work, we generated Illumina DASL microarray expression profiles for 137 FL patients who were treated with rituximab and CVP chemotherapy (cyclophosphamide, vincristine and prednisone). Using genes from the 23-gene linear risk predictor, we determined each patient's risk score by setting coefficients at -1 and +1 for genes associated with favorable and unfavorable PFS, respectively. We dichotomized the distribution of scores using the maximally selected log-rank statistic. We also performed unsupervised, hierarchical clustering to identify underlying subgroups in an unbiased fashion. Survival analyses were performed using the log-rank test and Cox regression analyses. We used gene set enrichment analysis to identify concordant differences of relevant gene signatures between specimens with either low or high expression of FOXP1.Results: Twenty genes from the 23-gene predictor (87%) were identified in the DASL gene expression dataset. The coefficients from univariate Cox regression analysis from our data were correlated with coefficients from Huet et al. (Pearson r = .7, P < .001; Spearman r = .44, P = .051). All poor-risk genes from the 23-gene predictor were associated with poor PFS in our data, and vice versa. Concordantly, calculated risk scores were significantly associated with PFS in the univariate Cox regression analysis (P = .007). Dichotomizing the distribution of risk scores identified 68% of cases with high risk score who had inferior PFS and OS compared to 32% of cases with low risk score (5-year PFS 54% vs. 77%, P = .004; 5-year OS 73% vs. 86%, P = .04). Hence, the risk score stratified patients into groups with diverging outcomes. This association was found to be independent of the Follicular Lymphoma Prognostic Index (FLIPI). In addition, the mean risk score was significantly higher in cases with high expression of FOXP1 (P < .001) and in cases with high m7-FLIPI risk score (P = .023). Unsupervised hierarchical clustering identified two main clusters (“cluster 1” and “cluster 2”) that were characterized by low and high expression of genes associated with poor outcome, respectively. Patients from “cluster 2” experienced worse PFS compared to patients in “cluster 1” (P = .046; 5-year PFS 54% vs. 68%). The 5-year OS was 72% for patients in “cluster 2”, vs. 81% in “cluster 1” (P = .13).We have previously reported that a germinal centre dark zone signature is enriched in cases with high FOXP1 expression, and the ICA13 signature reported by Huet et al. has been described as being highly expressed in centroblasts. Using gene set enrichment analysis, we found that genes with positive weight and coefficients in the ICA13 and the 23-gene predictor score, respectively, were enriched in the FOXP1-high phenotype (adjusted P = .009 and .005, respectively). GeneMANIA illustrated co-expression interconnectivity among ORAI2, TCF4, AFF3, FOXO1, CXCR4 and FOXP1, suggesting that genes with prognostic significance operate in tightly regulated networks.Conclusions: Our results exemplify the robustness of the predictor model by Huet et al. Further, we demonstrate biomarker convergence on a common phenotype: FOXP1 expression, EZH2 wild-type status and expression of dark zone-related genes, which characterize a subset of FL cases with adverse outcome following rituximab and chemotherapy. DisclosuresSarkozy:Roche/Genentech: Consultancy. Sehn:Roche/Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Weigert:Novartis: Research Funding; Roche: Research Funding. Steidl:Juno Therapeutics: Consultancy; Tioma: Research Funding; Bristol-Myers Squibb: Research Funding; Roche: Consultancy; Seattle Genetics: Consultancy; Nanostring: Patents & Royalties: patent holding.

Long-term complication in follicular lymphoma: assessing the risk of secondary neoplasm in 242 patients treated or not with 90-yttrium-ibritumomab-tiuxetan.

Non-Hodgkin lymphoma patients have a 25% increased risk of secondary primary neoplasms (SPNs). Regarding the controversy about the increased risk of SPN in patients exposed to radioimmunotherapy (RIT), we have analyzed this issue in a cohort of follicular lymphoma (FL) patients treated with/without RIT. A retrospective study including all consecutive FL patients diagnosed since 2001 was performed. Demographic, clinical data including the incidence of any kind of neoplasm (excluding basocellular skin carcinoma) were recorded. A total of 242 patients were registered, male/female: 103/139, mean age: 59.9 yr (15-86), stage IV (57.8%), and Follicular Lymphoma Prognostic Index (FLIPI) low-risk (62.15%) predominance. Ninety-six patients (39.7%) were treated with 90Y-IT. The median follow-up for patients treated or not with 90Y-IT was 61 (8-273) and 38 (1-171) months. With respect to SPN incidence, 38 (15.6%) patients have at least two cancers, in 17 (44.7%), FL was the SPN; for the rest (226), the global incidence of SPNs was 9.3% (21), but there were no differences related to the exposition or not to 90Y-IT (P = 0.26). In seven patients, more than two (2-6) different therapies were registered; four were exposed to fludarabine-based therapy, three to radiotherapy and two to autologous stem-cell transplantation, and in the RIT cohort, two patients developed myelodysplastic syndrome. This is one of the largest single institution reports assessing the risk of SPN in FL patients treated (96) or not (146) with 90Y-IT. It seems that 90Y-IT does not increase significantly the risk of SPN but avoiding its use after fludarabine and other intense cytotoxic schemes is recommended.

Soluble IL-2 Receptor α Is a More Sensitive Diagnostic Biomarker Than β2 Microglobulin and Predicts Survival in Follicular Lymphoma: Retrospective Analysis of 305 Cases

Introduction: Soluble-form IL-2 receptor α (sIL-2Rα) has been identified as a significant prognostic biomarker in patients with non-Hodgkin’s lymphoma (NHL) treated using rituximab-containing regimens. However, the clinical significance of sIL-2R is not fully understood, especially in subtypes of NHL, such as follicular lymphoma (FL). In addition to sIL-2Rα, β2-microglobulin (B2M) has been used as a prognostic and diagnostic biomarker of FL. We compared the predictive and diagnostic abilities of sIL-2Rα and B2M for FL.Patients and Methods: We analyzed 305 patients newly diagnosed with FL (Grade1-3a) between January 2001 and July 2012. Levels of sIL-2Rα and B2M were evaluated at diagnosis. The optimal cut-off values of sIL-2Rα and B2M were calculated from receiver operating characteristic (ROC) curves. Overall survival (OS) and progression-free survival (PFS, death from any cause, relapse and refractory disease) were analyzed using Kaplan-Meier methods and survival was compared using log-rank tests. To estimate the survival impact of several factors including sIL-2Rα, B2M, Hb<12g/dl, B symptoms, LDH, bone marrow involvement, bulky disease, extranodal disease and age, we performed multivariate analysis using the Cox proportional hazards model.Results: Median age was 59 years (range: 28-86 years) and the male: female ratio was 1:1. Most (245/305) patients were treated with chemotherapy regimens. Rituximab was concomitantly administered to 227 of these patients (R-Chemo) and 52 of these patients received rituximab maintenance for 2 years. In the 305patients, clinical stage was I in 12.3%, II in 15.1%, III in 24.9%, and IV in 45.9% and the Follicular Lymphoma Prognostic Index was low in 35.7%, intermediate in 27.2% and high in 36.7%. The median follow-up period was 1,516 days (range: 7 - 4,776 days). The median sIL-2Rα value was 1,107.5 U/L (range: 127-20,800 U/L) and the median B2M value was 2.2 mg/L (range: 1.0-10.29). The 3-year OS of the entire population was 87.8% and the 3-year PFS was 65.1%. The percentage of patients whose sIL-2Rα or B2M level was higher than the upper normal limit (520 U/L for sIL-2Rα, 2.0 mg/L for B2M) at diagnosis was higher for sIL-2R (76.8%) than for B2M (54.2%) patients (p<0.0001), indicating that sIL2Rα is more sensitive diagnostic marker for FL than B2M. To estimate the predictive value of sIL-2Rα and B2M for survival, we determined the optimal cut-off levels of sIL-2Rα and B2M using ROC analysis. This analysis showed that sIL-2Rα and B2M values of 1,700 U/L and 2.2mg/Lrespectivelywere the most sensitive and specific values for prediction of a 3-year PFS. Using these values, patients were separated into two significantly different groups of sIL-2Rα values (>1,700 U/L and ≤1,700 (p<0.0001)) and of B2M values (>2.2 mg/L and ≤ 2.2 mg/L (p=0.0017)). Further, PFS differed significantly between patients with sIL-2Rα values of >520 U/L and ≤520 U/L, >1,000 U/L and ≤1,000 U/L ,and >2,000 U/L and ≤2,000 U/L (p=0.03, 0.0003 and <0.0001, respectively) and also between patients with B2M values of >2.0 mg/L and ≤2.0 mg/L, >2.5 mg/L and ≤2.5 mg/L, >3.0 mg/L and ≤3.0 mg/L (p=0.011, 0.0016 and 0.0184, respectively). Univariate analysis identified several reported prognostic factors, such as clinical stage3-4, B2M>2.2 mg/L, number of nodal site>5, bone marrow involvement, Hb<12 g/dl, performance status<2, number of extranodal site>1, longest diameter>6 cm (<0.0001, 0.002, 0.0002, 0.0204, 0.0345, 0.0089, 0.0004 and 0.0053, respectively) in addition to sIL-2Rα (p<0.0001). Cox multivariate analysis indicated sIL-2Rα as a significant prognostic factor (p=0.0361), in addition to several other factors (bone marrow involvement, number of extranodal site<2, number of nodal site>5). In the group treated with the R-chemo regimen, the 3-year OS was 86.9% and the 3-year PFS was 64.9%. Within this group, PFS significantly differed between the two groups of sIL-2Rα; >1,700 U/L and ≤1,700 (p<0.0001), and between two groups with different B2M values >2.2 mg/L and ≤ 2.2 mg/L (p=0.0056). Again, multivariate analysis showed that sIL-2Rα (>1,700 U/L), in addition to several other factors, was associated with poorer prognosis. Conclusion: This study showed that sIL-2Rα is a more sensitive diagnostic biomarker of FL than B2M. In terms of survival, sIL-2R is an important risk factor of FL, not only for all patients with FL, but also in the R-Chemo era. DisclosuresHanda:Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding.

Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy.

Loss of cell cycle controls is a hallmark of cancer and has a well-established role in aggressive B cell malignancies. However, the role of such lesions in indolent follicular lymphoma (FL) is unclear and individual lesions have been observed with low frequency. By analyzing genomic data from two large cohorts of indolent FLs, we identify a pattern of mutually exclusive (P = 0.003) genomic lesions that impair the retinoblastoma (RB) pathway in nearly 50% of FLs. These alterations include homozygous and heterozygous deletions of the p16/CDKN2a/b (7%) and RB1 (12%) loci, and more frequent gains of chromosome 12 that include CDK4 (29%). These aberrations are associated with high-risk disease by the FL prognostic index (FLIPI), and studies in a murine FL model confirm their pathogenic role in indolent FL. Increased CDK4 kinase activity toward RB1 is readily measured in tumor samples and indicates an opportunity for CDK4 inhibition. We find that dual CDK4 and BCL2 inhibitor treatment is safe and effective against available models of FL. In summary, frequent RB pathway lesions in indolent, high-risk FLs indicate an untapped therapeutic opportunity.

Increased Dose Rituximab Followed by Maintenance Rituximab As Initial Therapy for Indolent B Cell Lymphomas: A Phase II Trial,

Abstract 3716 Background:Rituximab monotherapy as initial treatment for low-grade B-cell lymphomas produces responses in approximately 70% of patients with one third achieving a complete response, and progression-free survival (PFS) of approximately 2 years. Maintenance rituximab appears to prolong initial remissions after rituximab alone. Current dosing for rituximab is largely empiric, so we sought to investigate whether increased doses of rituximab induction would increase the complete response rate (CRR) over that expected from standard dose rituximab. We also sought to assess whether high-dose induction followed by standard maintenance would produce a PFS comparable with that of combination chemoimmunotherapy strategies. Methods:We conducted a phase II trial of increased-dose rituximab monotherapy induction, followed by a standard maintenance schedule. Eligible patients were adults with previously untreated low-grade B-cell lymphomas with measurable disease >2cm and were not candidates for potentially curative radiotherapy to localized disease. Subjects were treated with induction rituximab at a dose of 750 mg/m2 on days 1,8,15, and 22. Patients without progressive disease were then treated with maintenance rituximab at 375mg/m2 every 3 months for 8 doses or until disease progression. The primary end point was CRR as defined by the International Workshop Response Criteria (1999). Secondary endpoints included overall response rate (ORR), PFS, and toxicity. The study was designed with 90% power to show a 50% CRR, with a 30% CRR considered unworthy of further study. Results:Between August 2009 and August 2010, 40 eligible subjects were enrolled (31 grade 1–2 follicular lymphomas, 4 marginal zone lymphomas, 3 small lymphocytic lymphomas, and 2 indolent B cell lymphoma not otherwise specified). The median age was 60 (range 36–88) All subjects had advanced Ann Arbor stage disease. Twenty-two subjects (55%) had involvement of >4 nodal sites, 6 (15%) had a Hgb <12 and 9 (23%) had an elevated LDH. Six subjects (15%) were low risk by the follicular lymphoma prognostic index(FLIPI), 15 (38%) were intermediate risk, and 17 (43%) were high risk. The FLIPI was not available for 2 patients. One patient was not evaluable for the 4 week response assessment in induction due to withdrawal of consent after 3 weeks of therapy. After induction therapy, 1 subject had a CR (3%), 18 had a PR (46%), and 20 had SD (51%). No subjects had progressive disease after induction and all evaluable patients had a reduction in tumor size. With a median number of 4 (range 1–6) maintenance cycles, the CRR increased to 30%, with PRR of 38% and SD in 15% (fig. 1). The PFS at 12 months was 89% [95% CI, 73– 96]. A total of 5 subjects progressed during maintenance therapy, 2 subjects after 3 cycles, 1 after 2 cycles and 2 after 1 cycle. Treatment was well tolerated with only 3 cases (7.5%) of grade 3/4 neutropenia. Twenty three (58%) subjects had allergic reactions with infusions but only 2 (5%) were grade 3 reactions. [Display omitted] Conclusions:Increased dose rituximab monotherapy is well tolerated, but does not improve the CRR compared to what would be expected from rituximab at standard doses. Significant improvement in the CRR occurred with ongoing maintenance therapy, and the vast majority of patients remain in remission after 1 year. Ongoing follow-up will determine whether this approach produces a PFS comparable to a chemoimmunotherapy treatment program. Disclosures:Hochberg:Genentech: Consultancy. Fisher:Genentech: Consultancy. Abramson:Genentech: Consultancy.

Prognostic impact of CD31-positive microvessel density in follicular lymphoma patients treated with immunochemotherapy

Background Tumour-infiltrating mast cells (MCs) can remodel tumour microenvironment and growth by suppressing immune responses and potentiating angiogenesis. Furthermore, accumulation of MCs in follicular lymphoma (FL) correlates with unfavourable prognosis after immunochemotherapy. Here we investigated whether tumour vascularity is associated with MC content and outcome in FL patients treated with immunochemotherapy. Patients and methods Microvessel density (MVD) and MC content were determined immunohistochemically from pretreatment samples of 95 FL patients using CD31, CD34 and mast cell tryptase antibodies. Gene expression data from a separate set of 24 FL patients were analysed for comparison. All patients were treated with the combination of rituximab (R) and cyclophoshamide-doxorubicin–vincristine–prednisone (CHOP) chemotherapy. Results Increased CD31+ MVD correlated positively with the number of tumour infiltrating MCs and CD34+ vessels, and negatively with the outcome. Overall survival and progression-free survival were significantly better among patients with low CD31+ MVDs. In multivariate analyses, CD31+ MVD had prognostic value independently of Follicular Lymphoma Prognostic Index but not of MC content. Consistent with the immunohistochemical data, high CD31/ PECAM1 mRNA levels were associated with adverse outcome. Conversely, a positive prognostic impact of VEGF mRNA expression on the outcome was found. Conclusion Vascularity is associated with MC content and outcome in R-CHOP-treated FL patients.

Nongastric Marginal Zone B-Cell Lymphoma: A Prognostic Model from a Retrospective Multicenter Study.

Purpose: The International Prognostic Index (IPI) and Follicular Lymphoma Prognostic Index (FLIPI) are used as prognostic indices for NHL and indolent lymphoma. However, marginal zone B-cell Lymphoma (MZL) evidences a distinctive clinical presentation and a natural course; thus, in this study, we attempted to devise an adequate prognostic index for MZL.Patients and method: From 1990 to 2005, 205 patients diagnosed with MZL were retrospectively reviewed. After analysis of the prognostic factors, progression free survival (PFS) and overall survival (OS), we constructed a prognostic index of MZL (MZLPI) via the summation of each factor. We then compared PFS and OS with IPI, FLIPI, and MZLPI.Results: According to our multivariate analysis of PFS and OS of MZL, nodal MZL, ECOG performance ≥ 2 and advanced stage were composed of MZLPI. MZLPI was grouped as follows: score 0 as a low risk group, score 1 as an intermediate risk group, and score ≥2 as a high risk group. The PFS curve, according to MZLPI results, evidenced a more discriminated pattern than IPI and FLIPI, and this was especially true in the intermediate risk group. In OS, MZLPI (P=0.0007) evidenced a more discriminated pattern than IPI (P=NS) or FLIPI (P=0.0044).Conclusion: MZLPI, which is constructed of relatively simple factors, may represent a useful prognostic index for the prediction of PFS and OS in MZL, and may also be used as a substitute for IPI or FLIPI.

Nongastric marginal zone B-cell lymphoma: A prognostic model from a retrospective multicenter study

The International Prognostic Index (IPI) and Follicular Lymphoma Prognostic Index (FLIPI) are used as prognostic indices for NHL and indolent lymphoma. However, marginal zone B-cell lymphoma (MZL) evidences a distinctive clinical presentation and a natural course; thus, in this study, we attempted to devise an adequate prognostic index for MZL. Two-hundred and five patients diagnosed with MZL were retrospectively reviewed. After analysis of the prognostic factors, progression-free survival (PFS), and overall survival (OS), we constructed a prognostic index of MZL (MZLPI) via the summation of each factor. We then compared PFS and OS with IPI, FLIPI, and MZLPI. According to our multivariate analysis, nodal MZL, ECOG performance ⩾2, and advanced stage were composed of MZLPI. MZLPI was grouped as follows: score 0 as a low-risk group, score 1 as an intermediate risk group, and score ⩾2 as a high-risk group. The PFS curve, according to MZLPI results, evidenced a more discriminated pattern than IPI and FLIPI, and this was especially true in the intermediate risk group. In OS, MZLPI ( P = 0.0007) evidenced a more discriminated pattern than IPI ( P = NS) or FLIPI ( P = 0.0044). MZLPI, which is constructed of relatively simple factors, may represent a useful prognostic index for the prediction of PFS and OS in MZL, and may also be used as a substitute for IPI or FLIPI.

Maintenance Rituximab after CVP Results in Superior Clinical Outcome in Advanced Follicular Lymphoma (FL): Results of the E1496 Phase III Trial from the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B.

E1496 is a phase III trial designed to evaluate the ability of 2 years (yr) of maintenance rituximab (MR) to prolong progression-free survival (PFS) after CVP (cyclophosphamide 1 G/m2 day [d] 1, vincristine 1.4 mg/m2 [max = 2 mg] d 1, prednisone 100 mg/m2 d 1–5) chemotherapy in stage III–IV follicular grade 1 and 2 and small lymphocytic lymphoma. After CVP treatment to maximum response, (6–8 cycles), stable and responding patients (pt) were randomized to MR (375 mg/m2 weekly x 4) every 6 months x 4 or observation (OBS). Stratification factors included histology, response and residual disease after CVP. With 3-yr median follow-up, survivals (from time of randomization, one-sided logrank p values) for all pt (n=304) favored MR for PFS (p = 3 x 10–8; hazard rate {HR} = 0.38 [0.28;0.54, 95% confidence intervals]) and OS (p = 0.09; HR = 0.66 [0.36–1.22]). Because the large majority of pt have FL and because rituximab efficacy is notably greater in FL, we focused in this report on the 237 FL pt. Median age was 58 yr, 65% were stage IV, 64% had marrow disease, 64% had high tumor burden and 37% had high-risk disease by the follicular lymphoma prognostic index. PFS after randomization was significantly longer for MR vs OBS (p = 3 x 10-7; HR = 0.39 [0.27;0.57]). The estimated PFS at 4 yr (~4.5 yr after start of treatment) was 56% for MR vs 33% for OBS. Differences in PFS were significant within the predefined strata and the differences were most significant in favor of MR for pt with high initial tumor burden and minimal residual disease after CVP. Overall survival was superior for MR (p = 0.03; HR = 0.51 [0.25;1.04]. Estimated OS at 4 yr (~4.5 years after start of treatment) was 88% for MR vs 72% for OBS. Of 33 deaths, 21 occurred on the OBS arm. These data demonstrate that maintenance rituximab not only significantly delays disease progression in FL compared with OBS but that a substantial proportion of patients treated with MR remain disease-free at 4 years after the completion of CVP. These are the first data to strongly suggest a survival benefit with a therapy that includes rituximab and CVP and the first to strongly suggest a survival benefit with maintenance rituximab in FL.

Follicular lymphoma: Management options in the era of targeted therapy

For the vast majority of patients diagnosed with follicular lymphoma, the disease is never cured. As a result, it becomes a "chronic disease" that must be managed over many years. A wide array of management options exist, and it is difficult to claim that one strategy is better than another. It remains to be proven that a particular initial therapy or a particular sequence of therapies is superior, if one defines "superior" as affecting survival. It also remains to be proven that immediate treatment is superior to a "watch and wait" approach in patients with low tumor burden. However, newer targeted approaches to treatment are providing additional treatment options, and they generally have more favorable side-effect profiles than traditional cytotoxic therapies. The challenge is determining how to best incorporate such targeted therapies into traditional treatment. Additionally, determining the true impact of newer therapies is not entirely straightforward, as selection bias often confounds trial results in follicular lymphoma. A new follicular lymphoma prognostic index should aid in the interpretation of future clinical trials.

High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS

AbstractDoxorubicin-based immunochemotherapy, with interferon, has been shown to improve survival in patients with advanced follicular lymphoma. High-dose chemotherapy with stem-cell support is effective in follicular lymphoma in relapse but remains controversial as a first-line therapy. In a randomized study using a purged autologous stem-cell support, we compared these 2 approaches in patients with advanced follicular lymphoma. Newly diagnosed advanced follicular lymphoma patients (172 patients) were randomly assigned either to an immunochemotherapy regimen (cyclophosphamide, doxorubicin, teniposide, prednisone, and interferon) or to a high-dose therapy followed by purged autologous stem-cell transplantation. Compared with the patients who received chemotherapy and interferon, patients treated with high-dose therapy had a higher response rate (69% vs 81%, P = .045) and a longer median event-free survival (not reached vs 45 months). This did not translate into a better survival rate due to an excess of secondary malignancies after transplantation. The Follicular Lymphoma Prognostic Index identified a subgroup of patients with a significantly higher event-free survival rate after high-dose therapy. Autologous stem-cell transplantation cannot be considered as the standard first-line treatment of follicular lymphoma for patients younger than 60 years old with a high tumor burden.