FLIPI Score Research Articles

Revalidation of the Flipi Score in the Era of Immunotherapy.

The FLIPI prognosis score for follicular lymphoma (FL) was developed based on cases diagnosed between 1985 and 1992, and treated with different schemes that did not include rituximab (R). In the present study, we report the evolution of all FL treated in a single institution through the last decade and analize whether FLIPI mantains its effectiveness to identify different risk groups within patients treated with the new therapeutic alternatives available.Material and Methods: We identified sixty two patients with diagnosis of grade I-II-IIIa FL. Patients characteristics: median age 57.5 yr (r, 30–80); 36 males; 63% stages III–IV, and 37% with bone marrow infiltration at the time of diagnosis. Thirty eight percent had a low risk by FLIPI, 34% had an intermediate risk and 27.4% had a high risk. In 19 pts (30.6%) the initial decision was “watch and wait” but 82% received a form of treatment at some point. R was used in 36 pts (58%) with some of the following regimes: chemotherapy (chemo) + R and/or R as consolidation therapy and/or R as monotherapy and/or R as maintenance therapy. Of all prescribed treatments (excluding R as monotherapy and/or maintenance treatment), 52.8% were chemo alone, 20.2% chemo + R, 21.3% radiotherapy and 5.6% received a bone marrow transplant.Results: we considered the analysis of overall survival (OS) the most appropiate approach, since most treatments were seeking the control of the FL, and not the complete remission or cure. The follow up median time was 53.2 months ± 34.8 1SD. The 5-yr OS for the 62 pts was 81.8% ± 11.3 CI 95%. The 5-yr OS for those with a low, intermediate and high risk FLIPI was 100% −5, 84.2% ± 21 and 52% ±26.2, respectively. The difference in 5-yr OS was statistically significant between low and high risk, intermediate and high risk, but failed to prove a significant difference between low and intermediate risk. Among the different risk factors tested in a univariate analysis only age ≥ < 60 yr old demonstrated a significant difference, 60.7% vs 90%, respectively.Conclusions:1.The 5-yr OS in our series is higher than the one described in the original FLIPI study (Blood 2004; 104:1258–65) which was 81.8% vs 71% for the whole group; 90% vs 78.1% for pts <60 yr old; 60.7% vs 57.7% for ≥ 60 yr old; 100% vs 90.6% for low FLIPI and 84.2% vs 77.6% for intermediate FLIPI. The only group that failed to prove an improvement was the high risk FLIPI with 52% vs 52.5%.2.The impact of novel therapies was more evident in patients with a low or intermediate FLIPI and was even more evident in patients younger than 60 yr old.3.According to our results, FLIPI maintains its effectiveness in differentiating two risk groups, i.e., low-intermediate vs high.4.We believe that the OS curves will probably continue to improve as the treatments that are considered today as the most effective ones, were just included in our series in the last three years.

Patterns of Care in Follicular Lymphoma (FL): Are Minorities Being Treated Differently? Report from the National LymphoCare Study (NLCS).

FL, the most prevalent indolent lymphoma in the US, is less common in non-White populations including African Americans (AA) and Hispanics (H), limiting our knowledge about its natural history in these patients (pts). In addition, since minority pts are often under-represented in clinical trials, it is unclear whether our current treatment paradigm in FL applies to them. The NLCS is a prospective, longitudinal, multi-center, observational study that enrolls pts with newly diagnosed FL and collects data on their disease presentation, treatment patterns, and outcomes. Using NLCS, we evaluated demographics, disease presentations and patterns of care in FL amongst AA, H, and white (W) pts. As of 1/31/07, 87 AA, 118 H, and 2314 W pts were enrolled in the NLCS. AA accounted for 3.4% and H for 4.6% of total registered pts. Despite the small numbers, this represents the largest US-based database available for AA and H pts with FL. Data collection included information on grade, stage, B symptoms, FLIPI, and treatment choice. Either Chi-square or Fisher's exact test was used to assess the correlations depending on the sample size of the test. Below are the demographics and disease characterictics of analyzed pts:WhiteN=2314 (%)African-AmericanN=87 (%)HispanicN=118 (%)Age (yr)45216 ( 9.3)23 (26.4)24 (20.3)45–59774 (33.5)30 (34.5)39 (33.1)60–74856 (37.0)22 (25.3)41 (34.8)75+468 (20.2)12 (13.8)13 (11.9)SexMale1138 (49.2)37 (42.5)52 (44.1)StageI419 (18.1)12 (13.8)21 (18.0)II351 (15.2)12 (13.8)18 (15.4)III683 (29.6)25 (28.7)39 (33.3)IV840 (36.7)38 (43.7)37 (31.6)Grade1976 (42.3)46 (52.9)37 (31.6)2643 (27.8)19 (21.8)35 (29.9)3428 (18.5)10 (11.5)31 (26.5)Unknown216 ( 9.4)11 (12.6)11 ( 9.4)Mixed47 ( 2.0)1 ( 1.2)3 ( 2.6)FLIPIGood709 (36.1)22 (28.6)34 (37.8)Intermediate595 (30.3)17 (22.1)29 (32.2)Poor659 (33.6)38 (49.4)27 (30.0)B-symptomsYes584 (25.3)27 (31.0)34 (29.1)Two statistically significant differences in baseline characteristics were that AA pts were younger and had a poorer FLIPI at diagnosis compared to W pts. Looking at initial treatment patterns, the only difference was the use of anthracyclines among those receiving chemotherapy, with W pts more likely to receive an anthracycline-based regimen than AA pts (65.8% vs. 46.8%, p=0.01). The higher use of anthracyclines in W compared to AA pts persisted regardless of FLIPI score. Aside from anthracycline use, there were no major differences in treatment approaches and choices according to grade of disease between AA, H, or W pts. AA pts with grades 1 or 2 FL received less anthracyclines compared to W pts (37.5% vs. 56.4%, p=0.04). The small number of AA pts with grade 3 disease precluded a meaningful comparison with W pts in this subgroup. In conclusion, while the numbers are small, the NLCS provides the largest prospective registry information on AA and H pts. AA pts, who were younger and had a poorer FLIPI at diagnosis, also received less anthracycline-based therapies than W pts, whereas H and W pts were treated similarly. Further analyses are required to understand the underlying reasons for these observed differences. Long-term follow-up will determine if outcomes vary in these pt cohorts.

CVP alternating with fludarabine (CVP/F) chemotherapy prior to idiotype vaccination for follicular lymphoma (FL)

8065 Background: Reducing the tumor burden prior to vaccination facilitates an effective immune response (IR) against the idiotype in FL. In this context, we evaluated the efficacy and toxicity of a novel cytoreductive regimen, CVP/F. Methods: Newly diagnosed, advanced stage FL patients (pt) were treated with CVP (cyclophosphamide 400 mg/m2 PO d1–5, vincristine 2 mg d 1, prednisone 100 mg/m2 d1–5) alternating with F (25 mg/m2 IV d1–5) every 21 days for 2 cycles beyond best response (maximum 8). Pt judged to be cytoreduced adequately were vaccinated monthly × 5 with idiotype protein made from their FL. Results: Among 34 enrolled pt, median age was 45 years (yr), and FLIPI scores were: 18% low, 71% intermediate and 12% high. 38% pt had grade 1 and 62% had grade 2 FL. There were no toxic deaths or opportunistic infections. With 233 cycles (117 CVP and 116 F) given to 33 evaluable pt, neutropenic fever occurred in 7 cycles (3%). 20 cycles (17%) of CVP and 29 cycles (25%) of F were dose reduced for leukopenia. 18 pt (53%) achieved a CR (16) or CRu (2), and 13 pt (38%) had a PR. 22 pt (65%) treated with CVP/F proceeded to vaccination; 10 additional pt (29%) were vaccinated after secondary chemotherapy was given for further cytoreduction. At median follow-up of 11.2 yr, 15-yr overall survival (OS) was 85%. Two of 5 deaths occurred without lymphoma progression. TTF (time to treatment failure = second treatment, relapse, death) at 11 yr was 38%. Anti-idiotype antibody and T cell IR were seen in 44% and 31% pt, respectively. There were no differences in TTF or OS according to IR. Conclusions: CVP/ F was effective in advanced FL, comparing favorably with our historical experience with CVP in terms of CR rate, proportion proceeding to vaccination, TTF and OS after vaccination. This favorable outcome may have been due to the novel alternating CVP/F cytoreductive regimen, idiotype vaccination or both. The idiotype vaccine is now being tested in phase III trials. The CVP/F regimen also warrants further evaluation. No significant financial relationships to disclose.

I131-tositumomab monotherapy as frontline treatment for follicular lymphoma: Updated results after a median follow-up of 8 years

8033 Background: Monoclonal antibody-based therapies are improving the outcome for patients (pts) with follicular lymphoma (FL). Radioimmunotherapy has been found to be effective for pts with relapsed/refractory disease, but even more so when used as frontline treatment. Methods and Results. We previously reported the results of a phase II, single-institution, study of anti-CD20 I-131- Tositumomab (Bexxar) given as a single agent and as a single one-week treatment for 76 pts with Stage 3 or 4 FL (NEJM 352:441, 2005). An overall response (OR) rate and complete remission (CR) rate of 95% and 75%, respectively, were observed. With a median follow-up of 5.1 yrs, 5-yr overall survival (OS) and progression-free survival (PFS) were 89% and 59%, respectively, with a median PFS reached at 6.1 yrs. We now report on this pt cohort after a median follow-up of 7.93 yrs. The 8-year and 10-yr OS is estimated (by KM) now at 86% and 8-yr PFS is 50% (95% CI: 38.8 - 61.7%). Only 3 additional relapses have occurred in the additional follow-up period (at 8.0, 8.3, and 9.2 years) in those with CRs. The 8-yr PFS for the 57 pts who achieved CR is now 64%. The median for PFS has now being reached for CRs at 9.2 yrs. When the impact of baseline FLIPI scores were analyzed, only 8-yr OS was significantly affected when low-risk (LR) and intermediate-risk (IR) categories were combined and compared to the high-risk (HR) category (92% vs. 75%; p = 0.029). The 8-yr PFS for LR + IR pts was 56% vs. 35% for HR pts (p = 0.317). 27 of the 76 total pts (35%) had HR scores. Of additional importance, no cases of MDS or AML have yet been observed. Other longterm toxicities including thyroid status and second non-hematologic cancers will be updated at the meeting. Conclusions. These data underscore the high degree of effectiveness and durability of remissions achieved with a single, one-week course of frontline Bexxar and should serve as a benchmark for comparison to other studies using more prolonged and toxic treatments, including those combining unlabeled or radiolabeled antibodies with chemotherapy. No significant financial relationships to disclose.

Phase II study of short course CHOP-rituximab (R) followed by ibritumomab tiuxetan (IT) as first-line treatment for follicular lymphoma (FL)

8005 Background: Therapy with CHOP-R and radioimmunotherapy (RIT) is a promising treatment for untreated FL. Press reports complete responses (CR) of 69% in FL patients (pts.) with 6 cycles of CHOP followed by I-131 tositumomab. We report efficacy and safety using 3 cycles of CHOP-R followed by IT and extended R. Methods: Eligibility criteria include symptomatic or grade 3 untreated FL. 60 pts. have been accrued and 47 evaluated. The treatment consists of two phases: CHOP-R for 3 cycles followed by IT. One week after IT, pts receive R weekly × 4. Bone marrow (BM) biopsies and fusion PET-CT scans are obtained at baseline, after CHOP-R, and 12 weeks post RIT. The primary endpoint is CR rate. CR requires a neg. PET scan and conventional Working Group criteria. Results: Toxicity data are available for 47 pts of median age 56 (range, 39–78), 44 of whom completed both phases of therapy and are evaluated for response. Characteristics and CR rates after IT are shown: 3 pts. did not receive RIT (1 second malignancy, 1 non-compliance, 1 septic death). Of the 44, CR after CHOP-R is 41%. After IT, CR improved to 89%. Of the 5 pts who did not achieve CR, 3 had neg. PET scans (2 with PR, 1 with SD by CT), and 2 had residual disease by PET with PR by CT. At a mean follow-up of 16 months (range, 6–33 months), there are 4 relapses: 3 who achieved CR by PET-CT, 1 with PR by PET-CT. Toxicity was predominantly myelosuppression. There was 1 episode of febrile neutropenia after RIT. Conclusions: 3 cycles of CHOP-R followed by IT and R achieve a high CR in previously-untreated pts. with FL. Addition of RIT increased CR from 41% to 89%. Data will be presented on the affect of bulky disease, positive BM, grade 2 or 3 histology, and high FLIPI score on CR. Further follow-up is necessary to evaluate response duration and determine whether there is a correlation with early or late CR. [Table: see text] [Table: see text]

Restrospective analysis of non-Hodgkin lymphoma (NHL) patients (p) treated with 90Y ibritumomab tiuxetan (90Y- IT): Iberia RIT database

18526 Background: 90Y-IT is approved for the treatment of refractory NHL. The aim of this study was to collect data of NHL p treated with 90Y-IT within the clinical practice setting, to retrospectively analyze treatment effectiveness and tolerability, in order to provide a pragmatic approach to experimental data. Methods: Multicenter, retrospective study. NHL p treated during last year with 90Y-IT, were registered. Effectiveness endpoints retrospectively studied were: objective response rate (ORR), time to progression (TTP) and overall survival (OS). Clinical prognostic factors were collected to asses their possible influence upon treatment effectiveness, by multivariate analyses. Results: 65 p were registered: M/F, 58.5%/41.5%; median age, 59 years (22–83); ECOG 0–1, 73.3%. Median time since lymphoma diagnosis was 3.6 years. At diagnosis, 84.6% had follicular lymphoma (grade 1, 44.9%; grade 2, 40.8%) and 15.4% non- follicular lymphoma. Most of the cases were refractory to previous treatments (78.1%). Median number of previous treatments was 3 (range 1–8) Median administered dose of 90Y-IT was 0.4 mCi/Kg. ORR was 70.8% (95% CI: 59.8, 81.9). With a median follow-up time of 6 months, median TTP was 16.1 months (95% CI: 11.2, 21.1) and median OS has not been achieved. Within the group of follicular lymphoma, ORR was 74.6% (95% CI: 63.1–86.1) and TTP 17.7 months (95% CI: 14.3, 21.1). Bone marrow involvement and high FLIPI score were significantly associated with higher risk of progression disease: hazard ratio 3.71 (95% CI: 1.00, 13.68) and 21.12 (95% CI: 2.37, 187.91), respectively. Median time to G3–4 haematological toxicity ranged between 27–38.5 days, being the most frequent thrombocitopenia (46.2%) and neutropenia (33.8%). 17 p required red blood cell transfusions (median, 4 U) and 19 required platelet transfusions (median, 7 U). The most frequent G3–4 non haematological toxicity was asthenia (10.8%). Updated survival data will be presented at the meeting. Conclusions: These results obtained with 90Y-IT for NHL treatment within the clinical practice setting are concordant with published experimental data, despite the limitations of the retrospective design. [Table: see text]

Risk and Clinical Implications of Transformation of Follicular Lymphoma to Diffuse Large B-Cell Lymphoma

To study the clinical significance of transformation to diffuse large B-cell lymphoma (DLBCL) in patients with follicular lymphoma (FL). From 1972 to 1999, 325 patients were diagnosed with FL at St Bartholomew's Hospital (London, United Kingdom). With a median follow-up of 15 years, progression occurred in 186 patients and biopsy-proven transformation in 88 of the 325. The overall repeat biopsy rate was 70%. The risk of histologic transformation (HT) by 10 years was 28%, HT not yet having been observed after 16.2 years. The risk was higher in patients with advanced stage (P = .02), high-risk Follicular Lymphoma International Prognostic Index (FLIPI; P = .01), and International Prognostic Index (IPI; P = .04) scores at diagnosis. Expectant management (as opposed to treatment being initiated at diagnosis) also predicted for a higher risk of HT (P = .008). Older age (P = .005), low hemoglobin level (P = .03), high lactate dehydrogenase (P < .0001), and high-risk FLIPI (P = .01) or IPI (P = .003) score at the time of first recurrence were associated with the diagnosis of HT in a biopsy performed at that time. The median survival from transformation was 1.2 years. Patients with HT had a shorter overall survival (P < .0001) and a shorter survival from progression (P < .0001) than did those in whom it was not diagnosed. Advanced stage and high-risk FLIPI and IPI scores at diagnosis correlate with an increased risk of HT. This event strongly influences the outcome of patients with FL by shortening their survival. There may be a subgroup of patients in whom HT does not occur.

Non-Hodgkin lymphoma with t(14;18): clonal evolution patterns and cytogenetic–pathologic–clinical correlations

The pattern and frequency of secondary chromosome abnormalities in t(14;18)-carrying non-Hodgkin lymphomas (NHL) were evaluated for differences in relation to histologic NHL subtype and patients' outcome. One hundred and forty-nine NHL patients with t(14;18) and complete cytogenetic, morphologic, and clinical information were selected. One hundred and twelve cases were follicular lymphoma (FL) and 37 were diffuse large B-cell lymphoma (DLBCL). One hundred and forty cases showed secondary aberrations (94%, median = 6.0). The most frequent were losses from chromosome arms 1p and 6q and +7 (26%). Loss from 1q, +7, and +12 were more frequent in DLBCL than in FL. Loss from 1p, Xp, and -16 were more frequent in FL grade 3 than in FL grades 1 and 2. Patients with <6.0 secondary cytogenetic aberrations had better prognosis than did those with a higher number of aberrations. Trisomy 21 was associated with shorter patient survival. FLIPI score, the number of secondary chromosomal aberrations, and +21 were all of independent prognostic value in Cox multivariate analysis. FL grade 1-3a patients that had received chemotherapy, showed a higher frequency of i(6p) and loss from 6q. Secondary chromosomal aberrations showed some correlation with the morphologic subgroups of t(14;18)-NHL. Trisomy 21 and the presence of >6.0 secondary cytogenetic aberrations both correlated with shorter overall survival.

Tumor-Infiltrating T Cells Are Not Predictive of Clinical Outcome in Follicular Lymphoma.

Background: Follicular lymphoma (FL) has variable clinical outcomes. It has been suspected that tumor-infiltrating immune cells affect the biology and outcome of this disease. Using gene expression profiling and immunoperoxide tissue staining techniques, T cells and macrophages have been related to the survival outcome in some studies, but not others. In the current study, we used flow cytometry to analyze T cells and their subsets in follicular lymphoma biopsy specimens and determined whether these cell populations correlated with clinical features and outcomes.Methods: Two hundred and eighty-nine follicular lymphoma patients (pt) presented from 1997 to 2003 underwent an excisional lymph node biopsy prior to any treatment. The median age of pt at diagnosis was 45.7 yrs, median follow-up was 8.6 yrs for living pts, and median survival was 15.7 yrs. All but 8 patients had stage III/IV disease, 5 had stage I/II, and 3 were unknown. The histological grades were: 162 (56%) grade 1, 112 (39%) grade 2, 13 (4.5%) grade 3 and 2 (0.5%) unknown. Among the 289 patients, 41(17%) had low FLIPI score, 150 (63%) intermediate, 48 (20%) high and 50 unknown. All biopsies were analyzed for CD20, CD3, CD4, CD8 and HLA-DR expression by single-parameter flow cytometry. The 289 pts were divided into a training set of 147 and a validation set of 142, stratified by age and era of diagnosis. We used these two factors to stratify the pts because age at diagnosis is the most important prognostic factor for survival, and, in our data set, the era of diagnosis had an impact on survival and on the time from diagnosis to first treatment. For our analysis, we began with the training set and used the percentages of each immune cell population as a continuous variable in a univariate analysis in relation to clinical features and outcomes. We chose 8 phenotypic variables: CD20, CD3, CD4, CD8, HLA-DR, CD4/CD3 ratio, CD8/CD3 ratio, and activated T cells [defined as (HLA-DR-CD20)/CD3]. Five parameters were used as clinical endpoints: overall survival, FLIPI score at diagnosis, the time from diagnosis to first treatment (defined as the time from the first treatment to second treatment), response to CVP as the first treatment and the duration of the benefit from the first treatment (defined as the time interval between initiation of first treatment and initiation of second treatment).Results: The number of pt evaluable for each of the outcome parameters was as follows: 289 for time to first treatment and for overall survival, 239 for FLIPI scores, 164 for response to CVP and 129 for duration of the benefit from the first treatment., Of the 8 variables tested in the training set, only CD4/CD3 ratio and CD8/CD3 ratio were marginally significant for the survival endpoint, with p 0.034 and 0.088, respectively. None of the variables was significant for any of the other endpoints. A multivariate analysis yielded CD4/CD3 as the only significant predictor for survival. When CD4/CD3 was tested in the validation set, it yielded a p value of 0.48.Conclusion: We find no evidence that the percentage of tumor-infiltrating T cells or their subsets is predictive of clinical outcome in follicular lymphoma. Any gene expression signature involving T cells that does relate to clinical outcome could therefore be a property of the activity of the cells rather than a simple reflection of their numbers.

Phase 2 Study of Bortezomib Weekly or Twice Weekly Plus Rituximab in Patients with Follicular (FL) or Marginal Zone (MZL) Lymphoma: Final Results.

Background: Bortezomib (btz, VELCADE®) has single-agent activity in relapsed/refractory non-Hodgkin's lymphoma (NHL), including FL and MZL, on a twice-weekly schedule. Rituximab (R) is approved for relapsed/refractory CD20+ B-cell NHL. Preclinical studies show additive activity in lymphoma cell lines and lymphoma-bearing SCID mice. Btz and R have no overlapping toxicity. Weekly btz is active and safe in multiple myeloma trials.Methods: Patients (pts) with measurable CD20+ FL or MZL, KPS ≥50%, and a response with TTP ≥4 months to any prior R-containing regimen, were randomized to btz 1.3mg/m2 twice weekly (d 1, 4, 8, 11 of 21-d cycle, 5 cycles, Arm A) or btz 1.6mg/m2 weekly (d 1, 8, 15, 22 of 35-d cycle, 3 cycles, Arm B). R 375mg/m2 was given weekly for 4 weeks from d 1, cycle 1, in both arms. Response was evaluated by independent radiology review (IRR) and by investigators using the IWRC.Results: 81 pts (41 Arm A, 40 Arm B) were enrolled; median age: 64 yrs (63.0, 64.5); FL: 86% (80%, 93%); Stage IV: 47% (44%, 50%); KPS <90%: 20% (17%, 23%); LDH >ULN: 27% (32%, 23%); ≥1 extranodal site: 43% (41%, 45%); FLIPI score ≥2: 69% (71%, 68%). In total, 56% (54%, 58%) had ≥2 prior lines of therapy, 81% (80%, 82%) had prior CHOP/CVP ±R, 84% (78%, 90%) had prior R (alone or combination), and 8% (7%, 8%) had prior SCT. Median % of planned cumulative btz dose received: 75% (Arm A) and 99% (Arm B); median total btz: 19.5 and 19.0mg/m2; median dosing intensities per week: 1.6 and 1.3mg/m2. Response rates and TTP in evaluable pts are shown in Table 1. TTP curves by IRR are broadly overlapping between the arms (Figure). Most common AEs were fatigue, GI events, and peripheral neuropathy. Grade ≥3 AEs were more common in Arm A (54%) vs Arm B (35%), notably thrombocytopenia (10% vs 0%) and neutropenia (10% vs 3%), as were grade ≥4 AEs and serious AEs.Conclusion: Weekly and twice weekly btz + R are active and well tolerated in relapsed/refractory CD20+ indolent NHL. The more convenient weekly regimen appears to offer similar efficacy with less toxicity. Weekly btz 1.6mg/m2 + R is being compared with R in a phase 3 study.Response rates and time to events dataBy investigatorBy IRRArm A, N=37Arm B, N=40*Arm A, N=37*Arm B, N=40*Response rate (CR+CRu+PR), n (%)21 (57)21 (53)17 (46)15 (38)CR+CRu7 (19)6 (15)4 (11)1 (3)PR14 (38)15 (38)13 (35)14 (35)SD9 (24)13 (33)8 (22)17 (43)PD7 (19)5 (13)11 (30)7 (18)Median TTP, mo9.99.05.29.7*1 pt with no post-baseline assessment [Display omitted]

A Study on the Prognosis of Patients Relapsing after Autologous Stem Cell Transplantation (auto-SCT) for Follicular Lymphoma (FL): The Impact of Remission Duration.

Although auto-SCT has been in use for treatment of advanced FL since many years, little is known about the course of those who relapse after this procedure. Because these patients may be candidates for aggressive salvage approaches, we sought to study the outcome of patients with FL relapsing after auto-SCT with particular focus on factors predicting for survival.Methods: Relapse cases were identified retrospectively from 244 patients autografted for FL between August 1990 and November 2002 in 3 institutions. Overall survival after relapse (OS) was calculated according to Kaplan-Meier and analyzed for the prognostic impact of pre-relapse variables as well as of post-relapse salvage treatment by univariate log rank comparisons and Cox regression analyses.Results: With a median follow-up of 88 (5–186) months post auto-SCT, 104 relapses occurred, corresponding to a 10-year relapse probability of 0.47 (95%CI 0.4–0.53). Median age of relapsed patients was 48 (22–65) years. FLIPI score at diagnosis was low in 18%, intermediate in 58%, and high in 24%. In 51%, auto-SCT had been given as part of first-line treatment, and 45% had been in complete remission at auto-SCT. Myeloablation included total body irradiation (TBI) in 57% of the cases. Median time from auto-SCT to relapse was 19 (2–128) months, with only 2 relapses occurring later than 6 years post transplant. Transformed FL was present in 14% of those 87 patients who had relapse histology available. Rituximab-containing salvage therapy was given to 50% of the patients after relapse. With 45 (1–139) months of follow-up, median OS after relapse was 100 months. Log rank comparisons identified auto-SCT as part of salvage treatment, time to relapse <12 months, and salvage without rituximab as factors adversely influencing OS, while all other variables listed above had no impact. Cox analysis considering sex, age, salvage auto-SCT, TBI, time to relapse, and rituximab salvage confirmed a possible adverse impact of time to relapse <12 months (hazard ratio 2.58 (95%CI 0.99–6.82); p 0.055) but none of the other covariates on OS.Conclusions: The prognosis of patients relapsing after auto-SCT for FL is surprisingly good. However, those whose disease recurs within the first post-transplant year tend to have a dismal outcome and might benefit from experimental salvage approaches, such as allogeneic SCT.

Maintenance Treatment with Rituximab in Follicular NHL.

Introduction: Preceding studies have shown that Rituximab ® prolongs relapsed free time (TFR) and response duration (RD) in follicular NHL (FNHL) when given either together with chemotherapy or alone as maintenance after therapy. The best schedule of maintenance with R still remains unknown.Aim of study: to evaluate the relapsed free time in FNHL patients using R as maintenance after being treated with an induction schedule that included R.Design: observational, prospective trial in previously patients with FL treated with chemotherapy + R in complete remission (CR).Patients and methods: Since January 2002 to December 2005, 23 previously treated FL grade I or II patients with one R-chemotherapy line were included. At diagnosis baseline assessment: age, gender, clinical and physical exam, blood counts, serum and urine biochemistry, albumin, β2-microglobuline and LDH level, body scan, bone marrow biopsy. Patients were classified according to ECOG, clinical stage and FLIPI. Patients in complete remission (CR) after chemotherapy received R 375 mg/m2 × 4 weekly every 6 months for 2 years. Re-staging studies were performed at every cycle: CR, partial remission (PR) and relapse ®. Toxicity events have been noted.Statistical analysis: Overall survival (OS), relapsed free survival (RFS). Survival analysis was performed using Kaplan-Meier and Cox regression.Results: Mean age 53.1 (35–75), 12 F/11M; ECOG 0(14), 1(8), 2(1); B symptoms 10; FLIPI score 0(2 patients), 1(10), 2(7), 3(4); stage I (2 patients), II(4), III(9), IV(8); grade I(10), II(13).Therapy schedules: R-CHOP (69.5%), R-CHOP+RTP (8,7%), R-CMF (17,3%), R-CF (4.3%). At present 21,7% of patients have completed maintenance for two years, 30,4% have received 3 courses, 60,8% two and 1 100%. None of them have relapsed.Adverse events: two patients were excluded because of grade 3–4 neutropenia and two referred erythema while infusion of R. OS: mean 28.2 months (10–61); RFS: mean 22 months (4–53).Conclusions: R maintenance seems to be effective in FL. The tolerance has been good in most of the patients and only two cases presented severe adverse events, neutropenia, in those patients who had received QTP with fludarabine+R. It is necessary a longer follow-up to consider the magnitude of the effect obtained with R maintenance.

Long-Term Follow-Up of Autologous Bone Marrow Transplantation for Follicular Lymphoma in First Remission: Bone Marrow Involvement at Harvest and PCR Detectable Disease after Ex Vivo Purging Predict Relapse.

ASCT improves progression-free and likely overall survival in patients with relapsed follicular lymphoma. Randomized trials of ASCT as upfront therapy have generally also found an improvement in progression-free survival, but this benefit has been counterbalanced by an increase in second malignancies. We report the long-term outcome of two sequential prospective clinical trials of autologous bone marrow transplantation for advanced stage follicular lymphoma patients under 60 in first remission. In the 1st study 83 previously untreated patients received 6–8 cycles of CHOP induction and in the 2nd study 20 patients received 4 cycles of high-dose CHOP induction (cyclophosphamide 1.5 g/m2 d1–2 with g-csf support). The median age of the patients was 42 (range 19–57). 17% had high FLIPI scores, 58% intermediate and 25% low; all patients were under 60 and 21% had missing data required in the FLIPI. 96% had stage III or IV disease. 77 of 83 patients on the 1st study, and 19 of 20 on the 2nd study (N=96 total), achieved a protocol-defined minimal disease state after CHOP induction (< 2 cm masses, <20% bone marrow involvement). 35% of patients achieved CR after induction. Nine patients required IFRT to achieve protocol eligibility. Marrow was purged in vitro with anti-B1 (CD20), B5 and J5 (CD10) monoclonal antibodies and complement. Subjects were conditioned with cyclophosphamide and total body irradiation prior to re-infusion of purged bone marrow. Two early treatment-related deaths were observed. The 12 year relapse-free survival is 42.7% (95% CI 32.3–52.7%) and overall survival 60.7% (95% CI 49.5–70.1%). 44 patients (45.8%) have relapsed with follicular lymphoma of whom 24 have died of disease and 15 are alive. The median survival following relapse is 6.1 years (95% CI 4.1–9.0). 27 patients (28%) have developed a second malignancy, at a median 8.7 years following ABMT, including 10 cases of MDS/AML, 2 non-MDS hematologic malignancies, 8 solid tumors and 10 non-melanoma skin cancers. 9 patients (9.4%) have died of a secondary malignancy. Age, stage, FLIPI, hemoglobin, LDH, number of nodal sites, IFRT, and induction therapy were not predictive of PFS or OS. Histologic evidence of residual bone marrow disease at harvest was associated with a 12 year PFS 33.9% (95% CI 20.5–47.9%), compared to 50% (95% CI 34.8–63.5%) for those without marrow involvement (p= 0.02, log-rank test). 70 patients with known detectable bcl-2/IgH translocations prior to therapy had post-purging bone marrow samples analyzed by PCR; 30 of these 70 were negative. The 12 year RFS for PCR negative patients is 66.7% (95% CI 47–81%), compared to 26.3% (95% CI 14–41%) for those with PCR detectable disease (p= 0.001, log-rank test). In Cox proportional hazards regression analysis evaluating the impact of pre-transplant factors on PFS, only histologic bone marrow involvement at harvest (HR 2.27, 95% CI 1.31–3.93, p<0.004) and PCR positivity after ex vivo purging (HR 4.18, 95% CI 1.99–8.80, p= 0.0002) were independent predictors of outcome. These results, showing that 42.7% of patients are in ongoing complete remission and 60.7% are alive at twelve years following ABMT, suggest that a subset of follicular lymphoma patients can experience prolonged survival with ABMT in first remission.

Clinical Features and Prognostic Assessment of Nodal Marginal Zone B-Cell Lymphoma, a Rare Disease with Follicular-Like Behaviour.

Background. Primary nodal marginal zone B-cell lymphoma (MZL) is a rare entity recognized by the WHO classification. Diagnosis requires a lymph node localization in the absence of prior or concurrent involvement of extranodal sites. Most studies reported so far focus mainly on histopathology, while the clinical features and outcome of this uncommon lymphoma remains less defined.Aim. To define the clinical features and to assess prognosis of primary nodal marginal zone B-cell lymphoma. Methods. We studied a series of 47 newly diagnosed patients with primary nodal marginal zone B-cell lymphoma. Diagnosis was made on histologic examination of lesional tissues integrated with immunohistochemical data. No patient showed MALT or splenic localisation of lymphoma at diagnosis.Results. Patients: 17 males and 30 females, median age 63 years (25–79) with 64% aged more than 60 years. 13% of patients had stage I disease, 10% stage II, 32% stage III, 45% stage IV (bone marrow involvement). 11% had peripheral blood involvement, 11% had bulky disease, 15% B symptoms, 6% ECOG score ≥ 2. 23% had hemoglobin <12 g/dl. LDH was above normal in 15% and β2-microglobulin in 45%. 11% had an autoimmune background. HCV serology was positive in 24% (9/38). With the IPI score 37% ranked in the low risk, 22% in the low-intermediate, 35% in the intermediate-high, and 7% in the high risk category. Using the FLIPI score, 33% were classified as low risk, 34% as intermediate risk, and 33% as high risk. After treatment, 57% achieved a complete response and 24% a partial response, for an overall response rate of 81%. At a median follow-up of 2.6 years, no patient developed splenic or MALT involvement. 5-years and 10-years OS is 69% (95% CI 52–86%). Death occurred in 10 pts (related to NHL in 9, to another neoplasm in one). In univariate analysis the following factors were associated with shorter event-free survival (EFS): B symptoms (p=0.001), high vs intermediate vs low risk FLIPI score (p=0.009). The following factors were associated with worse overall survival: high vs intermediate vs low risk FLIPI score (p=0.02), age > 60 years (p=0.05), LDH above normal (p=0.05). HCV positivity was of borderline significance (p=0.06). In multivariate analysis hemoglobin < 12 g/dl (p=0.02, HR 14.3) was predictive of shorter EFS. Concerning overall survival, only the FLIPI retained statistical significance in predicting a worse outcome (p=0.02, HR 3.5). Positive HCV serology was of borderline significance (p=0.06, HR 4.4).Conclusions: among marginal zone neoplasms, primary nodal marginal zone lymphoma appears a distinct disorder with an indolent behaviour. The association with HCV infection (25%) is particularly high in comparison with non-marginal zone lymphomas. Considering the prognostic assessment of this rare disease, the FLIPI score is effective in detecting patients at worse prognosis with the same power as in follicular lymphoma. Thus, the application of the FLIPI may be of clinical value for treatment decision also in primary nodal marginal zone lymphoma.

Primary Extranodal Follicular Lymphoma: Clinicobiological Features and Outcome.

Follicular lymphoma (FL) is typically a nodal disease. Primary extranodal FLs, that represent less than 10% of the cases, might have differentiated clinicobiological features. The aim of the present study was to analyze the main clinicobiological characteristics, response to therapy and outcome of a series of patients with FL primarily extranodal in origin, and compare them with nodal FLs. Twenty two patients (12M/10F; median age, 59 years) with FL with primary origin in extranodal location diagnosed in a single institution during a 24-year period, with primary origin in extranodal location were the subject of the study. The control group was constituted by 212 patients with nodal FL diagnosed during the same period of time. Main clinicobiological features were recorded and analyzed. The sites of the primary disease were: skin, 5 cases; Waldeyer's ring, 4; GI tract, 3; bone marrow, CNS and parotid (two cases each); and pancreas, thyroid, kidney and orbit (one case each). Main histological and clinical features are listed in the table. Treatment was given without considering the nodal or extranodal origin of the disease and consisted of: monotherapy with alkylating agents (38 cases), polychemotherapy (149), and fludarabine alone or with other drugs (14) and others, including surgery and observation (33). CR rate was higher in extranodal than in nodal FL (82% vs. 53%, respectively; p=0.02), but no differences were found in overall survival. FLIPI score was the most significant variable predicting overall survival in the global series as well as in either in nodal or extranodal FL.In conclusion, extranodal FL had some peculiar clinicobiological features with respect to nodal cases. Regarding the outcome, although patients with extranodal FL showed a higher CR rate, the overall survival was similar in both groups.Extranodal FL (N=22)Nodal FL (N=212)pAge (median, range)59 (28–82) years55 (24–93) yearsNSSex (M/F)12/10100/112NSHistological grade 3 (%)1210NSCD10+(%)8590NSBcl2+ (%)6791NSBcl2/JH (%)37650.03Stage IV (%)5064NSBone marrow + (%)36620.02LDH > 450 IU/L (%)1524NSB2-microglobulin > 2.3 mg/L (%)7410.058High-risk FLIPI (%)1935NSCR rate (%)82530.025-year OS (%)7574NS5-year FFS (%)6727<0.02

The impact of FLIPI on outcome of frontline treatment with single-agent I-131 tositumomab for follicular lymphoma (FL)

7509 Background: The FLIPI is potentially useful in predicting clinical outcome and comparing treatment results among clinical studies in FL. We recently reported the results of I-131 tositumomab as frontline treatment in 76 pts with advanced-stage FL (NEJM 325:441, 2005). A single 1-week course resulted in a 95% and a 75% overall and complete response (CR) rate, respectively, and at a median follow-up of 5.1 years median progression-free survival (PFS) was 6.1 yrs. In multivariate analyses, bone marrow involvement was the only baseline variable that had a significant effect on PFS. Methods: To evaluate whether baseline FLIPI scores in this study could predict outcome and to compare this pt population with that in other frontline studies, the records of all 76 patients were reviewed. Results: FLIPI scores were available for 74 of the 76 pts: 11 pts (15%) low risk, 37 (50%) intermediate risk, and 26 (35%) high risk. CR rates for each risk group were 82%, 73%, and 73%, respectively. 5-yr PFS were 63% (35–92%, 95% CI), 63% (47–78%), and 52% (33–71%), respectively, p = 0.322. Grouping low + intermediate risk vs. high for PFS: p = 0.134. 5-yr overall survival (OS) rates were 100%, 95% (87–100%), 78% (62– 93%), respectively, p = 0.072, but grouping low + intermediate risk vs. high p = 0.028. A comparison to other frontline studies is below. Conclusions: The FLIPI did not predict for PFS or OS in FL pts treated with single-agent I-131 Tositumomab. However, an OS difference was seen when low + intermediate risk pts were grouped and compared with high risk pts. The distribution of FLIPI scores amongst pts in this study is similar to that observed in other front-line FL studies. Further studies exploring single-agent radioimmunotherapy vs. chemo/radioimmunotherapy combinations are warranted. [Table: see text] [Table: see text]

Update of the FL2000 randomized trial combining rituximab to CHVP-Interferon in follicular lymphoma (FL) patients (pts)

7508 Background: The GELA-GOELAMS FL2000 trial investigated the role of rituximab in the first line treatment of FL pts. Methods: This prospective randomized study compared the CHVP regimen (12 courses) +18 months α2b-IFN (CHVP-I) to 6 CHVP courses combined with 6 rituximab infusions + 18 months IFN (R-CHVP-I). The primary endpoint was event-free survival (EFS). Inclusion criteria consisted in untreated stage II-IV FL pts; 18–75 years old; with a high tumor burden defined by at least one of the following criteria: B symptoms, ECOG PS&gt;1, LDH&gt;normal value, β2-microglobulin ≥3 mg/L, largest tumor ≥7 cm, 3 distinct nodes ≥3 cm, serous effusion, compression or symptomatic spleen enlargement. Results: From 05/00 until 05/02, 358 eligible pts were randomized (CHVP-I 183 pts and R-CHVP-I 175 pts) with the following characteristics: M/F = 1; median age = 60 years [25–75]; ECOG &gt; 1 = 8%; B symptoms = 27%; AA stage &gt; II = 87%; bone marrow involvement = 58%; β2-m ≥3 mg/L = 31%; LDH &gt; N = 37%; Hb &lt;12 g/dL = 18%; FLIPI score ≥3 in 57% of the pts. The first analysis [ASH 2004] showed a significant better treatment response in R-CHVP-I as compared to CHVP-I and a improvement of event free survival (EFS) in the R-CHVP-I arm (Log-Rang, P = .003). As initially planned, a second analysis on all pts has now been performed with a median follow-up of 3½ years, all pts with data &gt;01/01/05. The median EFS for the whole population has not yet been reached. In the CHVP-I arm, median EFS was 3 years and 46% of the pts are event-free at 42 months (mo.). In contrast, the median has not been reached in the R-CHVP-I arm and the EFS is 67% at 42 mo. (P &lt; .0001). This improvement in EFS was found both in the 150 pts with a low or intermediate FLIPI score (P = .019) and in those (n = 201) with a high score (P = .0005). When considering the 230 pts responders at the end of 18 mo. of therapy, 42 mo. EFS is 62% in CHVP-I arm versus 81% in R-CHVP-I arm (P = .002). Finally, the overall survival at 42 mo. of patients in the CHVP-I arm is of 84% versus to 91% in the R-CHVP-I arm (P = .029) with a reduction of death risk by approximately 2 (RR = 0.55). Conclusions: These results demonstrate that rituximab combined with CHVP-I has a durable benefit, in all FLIPI risk groups, allows to reduce the duration of chemotherapy and improves overall survival in high-tumor burden FL pts. [Table: see text]

Prospective Validation of the FLIPI: Baseline Distribution and Correlates in Newly Diagnosed Follicular Lymphoma (FL) Patients from the US: First Report of the National LymphoCare Study.

Background: FL comprises one quarter of lymphoma in the United States, presents in a heterogeneous fashion, and generates substantial debate regarding optimal management strategies. The recently published clinical prognostic index (FLIPI, BLOOD 104:1258) facilitates outcome evaluation and may guide therapeutic strategy. The National LymphoCare Study (NLCS) is an ongoing disease-based longitudinal observational study designed to assess patterns of initial disease presentation including prognosis, long term treatment choices, and clinical outcomes in FL patients.Methods: Beginning March, 2004, pts were recruited from U.S. community practices and academic centers. Pts with FL diagnosed within 6 months with no prior lymphoma history are eligible for enrollment. Collected data includes histology, staging and prognostic evaluation, serial management strategies including drug choices but not doses, response to treatment, and events including relapses and death. There is no study-specific prescribed treatment regimen or intervention. The treating physician determines management for FL according to clinical judgment.Results: 992 pts were enrolled from 207 sites through April, 2005. 182 community sites enrolled 86% of subjects. Pt characteristics include median age 62y, 52.5% female, 90.6% Caucasian, 40% Gr1, 26% Gr2, 19% Gr3, 13% NOS, with highest determined Ann Arbor stage = 17% I, 15%II, 26% III, 33%IV, 8% Unk. The demographic characteristics are similar to pts in the national SEER registry (median age 64, 51% F, 91.3% Caucasian) but clinical characteristics are notable for a higher fraction of advanced stage disease. 686/992 (69%) patients had calculable FLIPI scores based on initial investigator workup. Of factors contributing to FLIPI scores, LDH was collected by investigators in 78% of pts. When correlated with age, geography, and academic/community sites, LDH collection rates differ with 90% in academic sites vs 76% in community sites (p = .0002). Distribution of FLIPI among 686 pts with complete scores are shown in Table1, and show remarkable consistency across grades.Summary: The NLCS is an ongoing study with a large and rapidly growing database combining clinical and treatment data and is the first database investigating initial workup, prognosis, and outcomes of pts in a predominantly community based U.S. population. FL pts enrolled in NLCS are similar to those in the SEER database, and should be widely generalizable to the US population. FLIPI continues to define three distinct groups in the NLCS and is independent of histologic grade. Current evaluation patterns result in 31% incomplete FLIPI scores, suggesting this useful prognostic index is underutilized.FLIPI distribution (%)Low36373738348114Intermed37313228371440High2732313429546Solal Celigny n=1795NLCS n=686NLCS Gr1 n=276NLCS Gr2 n=188NLCS Gr3 n=136Stage I/II n=234Stage III/IV n=452

Serum BLyS Level as a Prognostic Marker in Patients with Lymphoma.

Background: BLyS is a TNF family member which was recently shown to play a critical role for survival of normal and malignant B cells. BLyS is expressed by monocytes, macrophages, dendritic cells as well as lymphoma cells, where its expression levels increase as tumors transform to a more aggressive phenotype. Previous small studies suggested that serum BLyS level is elevated in some proportion of patients with aggressive non-Hodgkin lymphoma (NHL). Little is known if serum BLyS level has prognostic value in patients with lymphoma. Thus, we determined serum soluble BLyS levels in 191 samples obtained from patients with various forms of lymphoma, and correlated them with the clinical characteristics and the prognosis.Materials and Methods: We analyzed serum BLyS level with ELISA in normal individuals and patients with newly diagnosed or relapsed lymphoma. Patients' histopathological diagnosis, stage, presence of bulky disease, serum LDH, serum beta-2 microglobulin (b2m), IPI score, FLIPI score, progression free survival (PFS) and overall survival (OS) were correlated with serum BLyS levels. For survival analysis.Results: The sensitivity of the ELISA assay was 0.4 ng/ml. Serum samples from 93 normal individuals,135 newly diagnosed patients with lymphoma, and 56 patients with relapsed lymphoma were examined for serum soluble BLyS levels. Median serum BLyS levels were <0.4ng/ml (range 0–0.5) in normal individuals, 1.8ng/ml (0–60.0) in Hodgkin lymphoma (HL), <0.4ng/ml (0–28.5) in small lymphocytic lymphoma, <0.4ng/ml (0–0.94) in marginal zone lymphoma, 1.43ng/ml (0–26.2) in follicular grade 1/2, 1.3ng/ml (0–32.1) in follicular grade 3, 1.9ng/ml (0–6.9) in diffuse large B cell lymphoma, 1.4ng/ml (0–2.8) in immunoblastic lymphoma, <0.4ng/ml (0–14.7) in mantle cell lymphoma. BLyS levels did not correlate with stage, presence of bulky disease, serum LDH, serum b2m, IPI score, FLIPI score. Elevated BLyS levels (>=2ng/ml) were observed more frequently in patients with relapsed lymphomas (42/56, 75%) than in patients with newly diagnosed lymphomas (46/136, 45%, p<0.0001) (Table). BLyS levels were more frequently elevated in relapsed HL than relapsed NHL (p=0.02). Elevated serum BLyS levels were associated with shorter PFS in all patients with relapsed lymphoma (median 2.4 vs 13.4 month, p=0.03, by Wilcoxon), and in patients with relapsed aggressive NHL (1.1 month vs 40.5 months, p=0.02). Patients with elevated BLyS levels had shorter OS in all patients with relapsed lymphoma (median 14.8 vs 49.3 months, p=0.01). Elevated BLyS levels in patients with newly diagnosed lymphoma had no significant impact on PFS or OS in our study.Conclusion: Serum BLyS levels are frequently elevated in patients with lymphoma, especially HL. Serum BLyS level is particularly higher in patients with relapsed disease, and is associated with poor prognosis in those patients group. Our study suggests the promising role of BLyS in the prognostication of patients with lymphoma, particularly aggressive NHL and HL.

Benefit of the Adjunction of Rituximab in Salvage Regimen before Autologous Stem-Cell Transplantation (ASCT) in Follicular Lymphoma at Relapse. A Single Institution Study.

Follicular lymphomas have an indolent evolution with a median survival ranging between 8–10 years. At relapse, high-dose therapy followed by autologous stem-cell transplantation (ASCT) can be considered as an alternative to conventional chemotherapy. However, efficacy of this strategy remains controversial.The purpose of our retrospective study is to evaluate ASCT in the pre and post rituximab era as consolidation after 2nd or 3rd remission (at least PR).Between March 1989 and Apr 2004, 54 pts were treated at relapse with ASCT in our institution. At initial diagnosis, median age was 47 yrs (range 24–61) and FLIPI score was ≥ 3 in 18%. ASCT was performed in 2nd remission in 43 cases and in 3rd remission in 11 [median delay diagnosis-ASCT=44 months (range 7–139) and 53 months (range 21–227), respectively]. The conditioning regimens used were: VP16/cyclophosphamide/TBI in 33 cases, cyclophosphamide/TBI in 9, BEAM in 10 and cyclophosphamide/busulfan in 2. After ASCT, 49 pts achieved CR, 4 achieved PR and one pt progressed. In Dec 2004, with a median follow-up of 4.7 yrs, 27 pts (50%) had relapsed after ASCT with a median time to relapse of 12 months (range 2–95) and 18 pts have died. Causes of death were: lymphoma recurrence in 8 cases, secondary malignancy in 6 cases (3 MDS/AML, 2 radiation-associated solid tumors, 1 EBV associated lymphoma after a new salvage treatment including allogenic transplantation), and late infection in 4 cases, 2 of them occurring in remission (varicella and septicaemia) and 2 others after a new salvage therapy (cellulitis during chemotherapy-induced neutropenia and HHV6 encephalitis after allogenic transplantation). Ten-year overall survival (OS) from initial diagnosis was 68%. Five-year OS and event-free survival after ASCT were 74 and 52%, respectively.Patients treated at relapse before 1998 did not receive rituximab (rituximab-naive pts: n=29) and those treated after 1998 received a rituximab-based salvage regimen before ASCT (rituximab-treated pts: n=25). The main characteristics of the two populations were as indicated in the table below:rituximab-naive grouprituximab-treated groupN2925FLIPI at initial diagnosis (Low/Intermediate/High) %41/48/1127/46/27Median age at ASCT (yrs)50 (range35–60)52 (range 30–62)ASCT performed in 2nd remission2320ASCT performed in 3rd remission65Median duration of response following last treatment line prior to ASCT (months)21 (range 1–91)11 (range1–49)After adjusting for the follow-up (median follow-up of the rituximab-treated group: 3.8 yrs), comparison between the two groups of pts treated with ASCT at relapse shows a significantly better OS of the rituximab-treated group as compared to that of the rituximab-naïve group (100 vs 61% at 4 years, p=0.01). These data suggest that the well-established efficacy of rituximab in FL is not abrogated by consolidative ASCT delivered at relapse in pts not previously treated with rituximab and further emphasize the superiority of immunochemotherapy over chemotherapy alone.