FLIPI Index Research Articles

Follicular lymphoma: first - line selection criteria of treatment

To analyze the clinical, laboratory, morphological parameters of patients with FL, who got R-B and R-CHOP therapy; determine the criteria for selecting induction therapy. The study included 203 patients with FL from 2000 to 2018. R-CHOP treatment was initiated in 126 patients, 14 of whom later received high - dose therapy (HDT) (R-DHAP: rituximab, dexamethasone, cisplatin, cytarabine) without autologous stem cell transplantation (autoSCT), 21 - HDT with autoSCT; treatment of 89 patients was limited to courses of R-CHOP and maintenance therapy with rituximab, two patients (in whom the disease progressed, despite R-CHOP therapy) were assigned the mNHL-BFM-90 program. The efficacy of treatment on various treatment regimens was evaluated primarily by overall survival. R-B. 77 patients received R-B therapy. Complete remission of the disease was achieved in 47/77 (61%) patients (3 of them later developed a relapse of the disease), partial remission was achieved in 15/77 (19%) patients, in 13/77 (17%) cases progression was recorded tumors. 70 patients had 1-2 cytological type of tumor, 6 patients - 3A cytological type. In cases of progression, 3 of 13 patients (46%) were diagnosed with 3A cytological type FL. Median observation (at the time of analysis) - 34 months. R-CHOP. 89 patients with FL received high - dose therapy with R-CHOP (6-8 courses) and maintenance therapy with rituximab. In 39 (44%) patients, the disease remained in remission, and in 50 (56%), a relapse of the disease developed. 50 patients had 1-2 cytological types, 39 - 3 cytological types. In cases of recurrence of FL, a 3A cytologic type (36%) was diagnosed in 18/50 patients. Median observation - 93 months. R-CHOP + HDT and autoSCT. 21 patients after the R-CHOP courses continued (due to insufficient antitumor response) high - dose chemotherapy (HDT) and auto-SCT were performed. In 18/21 (86%) cases, complete remission of the disease was achieved and maintained, in 3 (14%) cases relapse developed. 16 patients had 1-2 cytological types, 5 - 3 cytological types. Median observation - 81 months. R-CHOP + HDT without autoSCT. 14 patients started therapy under the R-CHOP program as induction therapy, but then (due to insufficient antitumor response), the treatment was continued according to the HDT without autoSCT. 11 (79%) patients are currently in remission of the disease, in 3 (21%) - there was a relapse. 10 patients had 2 cytological types of PL, 4 - 3 cytological types. 11 (79%) patients are currently in remission of the disease, in 3 (21%) - there was a relapse. Median observation - 80 months. 7-year OS of patients with FL on RB therapy was 89% (95% CI 75-99), on R-CHOP therapy - 85% (95% CI 73-90), on R-CHOP + HDT and autoSCT - 87% (95% CI 57-100), on R-CHOP + HDT without autoSCT - 82%. 7-year PFS of FL patients on RB therapy was 70% (95% CI 75-99), on R-CHOP therapy - 44% (95% CI 73-90), on R-CHOP + HDT and autoSCT - 74% (95% CI 57-100), on R-CHOP + HDT without autoSCT - 80%. The R-B is most effective in FL 1 and 2 cytological types. The cytological type does not correspond to the type of tumor growth: at 3A and 3A + 3B cytological types, nodular / nodular - diffuse and diffuse types of growth are found. When choosing an induction course, one should look at the cytological type of FL. A high proliferative activity index (according to Ki67) is a predictor of resistance to R-B therapy. The absence of an interfollicular T-cell reaction in tumor tissue FL is associated with tumor chemoresistance. The presence of the bulky factor is associated (in most patients) with the FLIPI index with values from 3 to 5, and is a predictor of a poor response to therapy. Patients with bulky, high (more than 35%) Ki67 index and FLIPI from 3 to 5 in the debut of the disease as the first line therapy, it is preferable to choose the R-CHOP mode, and in the absence of (after 4-6 courses) to complete or partial remission to continue conducting the HDT.

PS1257 LYMPHOCYTE TO MONOCYTE RATIO (LMR) PREDICTS PROGRESSION‐FREE SURVIVAL INDEPENDENTLY FROM FLIPI AND IS USEFUL IN IDENTIFYING PATIENTS WITH EARLY DISEASE PROGRESSION

Background:Despite the overall good prognosis of follicular lymphoma (FL), approximately 20 to 30% of the cases experience early progression after first line therapy and suffer adverse survival (Casulo et al., 2015; Shi et al., 2017). Several efforts have been made to identify pre‐treatment factors useful to assess prognosis, however currently available parameters do not allow to accurately stratify patients before treatment. Lymphocyte to monocyte ratio (LMR) has been previously identified as an useful prognostic markers in diffuse large B‐cell lymphoma treated with Rituximab‐based chemotherapy (Rambaldi et al., 2013).Aims:In this study we aimed to evaluate the potential role of LMR in identifying patients with FL experiencing early progression after first line therapy.Methods:831 patients with a diagnosis of grade 1–3a FL were identified in the Bergamo Lymphoid Cancer Registry (NCT03131531) between 1983 to 2017. Cases managed with watchful observation after diagnosis (N = 145) or receiving local therapy (N = 121) or without adequate clinical information or follow‐up data (N = 117) were excluded from the analysis. The remaining patients (N = 448) with stage II‐IV disease and receiving first line chemotherapy at diagnosis were included in the study. The majority of the patients were treated with Rituximab‐based therapy (72%). Chemotherapy regimens included CHOP (N = 298), CVP (N = 76), Bendamustine (N = 22), Chlorambucil (N = 34) or others (N = 18). Rituximab maintenance was administered to 61 patients.Patients with early progression were defined as those with a PFS event before 30 months from first‐line treatment start (PFS30). Receiver operating characteristic (ROC) analysis was performed to assess the optimal cut‐off of LMR to predict PFS30. Kaplan‐Meyer curves, log‐rank tests and Cox models were used for survival analyses.Results:In the study population, 26% of the patients experienced early progression and were characterized by a shorter median OS compared to the other group (6.3 vs 17 years, P < 0.0001, Figure 1A). The optimal cut‐off of LMR to predict PFS30 was identified, with patients with LMR ≤2 or >5.2 (N = 176) being at higher risk for a PFS event compared to those with LMR >2 and ≤5.2 (N = 272) (Figure 1B). In multivariate analysis for PFS, LMR retained its significance independently from FLIPI (P = 0.0001). The simple addition of LMR to standard FLIPI permitted to refine patient prognosis in terms of PFS (Figure 1C) and OS (Figure 1D), with three groups identified i.e. low risk (FLIPI low and favorable LMR), intermediate risk (FLIPI low and unfavorable LMR; FLIPI int or high and favorable LMR) and high risk (FLIPI int or high and unfavorable LMR). Specifically, 57 (36%) patients with intermediate FLIPI were upgraded in the high risk category and 80 (54%) high risk FLIPI were downgraded into the intermediate one. Patients in the new high risk category were characterized by a 42% probability to have a PFS event before 30 months, compared to the 22% and 10% of the intermediate and low risk group, respectively. LMR was significantly associated with OS in univariate analysis (P = 0.047), but not in multivariate analysis with FLIPI (P = 0.11). The combined LMR and FLIPI index predicted survival with a 30‐months OS of 96%, 94% and 85% in the low, intermediate and high risk category, respectively (P = 0.0032).Summary/Conclusion:LMR is a significant prognostic factor for PFS in FL, independent from FLIPI and closely related to the use of Rituximab. The combination of LMR with currently available prognostic markers can be useful in identifying high patient before the start of first line treatment.image

Follicular lymphoma: results of multicenter study of first-line therapy with bendamustine and rituximab, risk factors for adverse events (fl-rus-2013 protocol)

Follicular lymphoma: results of multicenter study of first-line therapy with bendamustine and rituximab, risk factors for adverse events (fl-rus-2013 protocol)

Rituximab Maintenance after First Line Immunochemotherapy Improves Overall Survival in Patients with Follicular Lymphoma

IntroductionPatients with follicular lymphomas (FL) often follow an indolent disease course initiated with the wait-and-watch approach. Chemotherapy, including rituximab (R), is inevitably required in most patients though. R-maintenance is indicated for patients achieving a partial or complete remission based results from randomized clinical trials and confirmed by meta-analyses demonstrating a prolonged progression free survival. A benefit in overall survival (OS), however, has yet to be established in the first line setting.Patients and methodsWe completed a retrospective analysis in patients extracted from the Danish National Lymphoma Register. Eligible patient data included histopathological confirmation of FL diagnosed in the period 2000-2014 who received R-Chemotherapy as first line treatment and surviving a minimum 1 year after treatment initiation. A Cox regression model was performed, adjusted for age, gender, stage, response rates and treatment period (pre-maintenance era (year 2000-2010) vs. maintenance era (year 2011-2014)) with hazard ratio (HR) of OS as the primary endpoint. All patients were followed until June 2016.Results1037 patients were extracted from the register. 481 patients received R-maintenance (RM-group) and 556 patients did not. The median age was 62 (26-90), 526 (51%) were male, LDH was elevated in 325 (31%) and 436 (42%) had a high FLIPI index. The median follow-up time was 6.3 years. The five year OS for all patients was 86%. A significant change in the chemotherapy regimens was observed between the two groups, since Bendamustine was more frequently used in the maintenance group. A significant lower HR was observed in the RM group with a HR of 0.63 (95% CI 0.44 - 0.88, P = 0.008). Furthermore, gender proved of significance, with a HR for men of 1.78 (95% CI 1.32-2.40, P < 0.001).ConclusionsRituximab maintenance treatment following first line immunochemotherapy in patients with follicular lymphoma improved survival in a large population based cohort of patients and consolidates this strategy as part of the standard of care in this patient group. DisclosuresNo relevant conflicts of interest to declare.

Frontline Intensive Chemotherapy Brings Survival Benefit In Young, Risky Patients With Follicular Lymphoma: Pair-Matched Analysis From The Czech Lymphoma Study Group (CLSG) Database

BackgroundFollicular lymphoma (FL) is a disease with very heterogeneous course ranging from the indolent forms to rapidly progressive cases with poor outcome. Optimal therapy in FL patients with high tumor burden is immunochemotherapy (R-CHOP is the most frequent regimen used), followed by maintenance treatment. Data from randomized prospective studies (PRIMA) showed poorer outcome in those with high risk disease in terms of lower CR rate, higher risk of relapse and lower efficacy of maintenance therapy. Data comparing up-front intensive approach in younger fit patients and R-CHOP are limited. AimTo analyze long term results of intensive treatment protocol (R-sequential chemotherapy) in comparison with age, FLIPI and maintenance delivery matched (R-CHOP) controls. MethodsHere we analyzed data of 48 prospectively enrolled FL patients who were treated by sequential (R-SQ) chemotherapy with or without up-front autologous stem cell transplant (ASCT) as a part of stratified risk adapted treatment in one institution. For R-SQ regimen were indicated patients<65 years with INT-FLIPI (with at least 2 additional risk factors: bulk and/or elevated B2M>3mg/L and/or thymidine kinase>15 IU/L) or HIGH-FLIPI patients (irrespective of additional risk factors). R-SQ protocol consists of alternating three cycles of etoposide-doxorubicine regimen (PACEBO), one methotrexate-ifosfamide regimen (IVAM), and one cycle of high dose cytarabine regimen (HAM). Remission was consolidated with 6th cycle of chemotherapy (PACEBO) in INT-FLIPI patients (n=22, 46%) or with ASCT with BEAM-200 conditioning (n=26, 54%) in HIGH-FLIPI patients. Maintenance immunotherapy was applied for historical reasons in 24 patients (50%). Controls were randomly selected from the Czech Lymphoma Study Group (CLSG) database from 626 cases with confirmed FL grade I to IIIa, treated with R-CHOP. Pair matching was performed on 1:3 basis, controls were matched by age, FLIPI and rituximab maintenance application. In the end, we analyzed intensive SQ-group (n=44) and standard control R-CHOP-group (n=144). Maintenance therapy was delivered to 24 patients (50%) in R-SQ group and to 72 patients (50%) in R-CHOP-group (P=1.00). ResultsMedian age of SQ-group was 47.6 years compared to 48.7 years in R-CHOP (P=0.44), FLIPI index was equally distributed: INT-FLIPI (43% vs 43%), HIGH-FLIPI (57% vs 57%, P=1.00). Treatment response quality was higher in SQ-group than in R-CHOP-group: CR/CRu 93.8% vs 70%, PR 6.2% vs 23% and SD/PD 0% vs 8% respectively (P=0.01). During the follow-up, (median 3.5 and 6.1 years in R-CHOP and SQ-group respectively, P<0.01) 10 patients (20.8%) relapsed or progressed in the R-SQ-group, and 41 (29%) in the R-CHOP-group (P=0.01). Only two of 48 patients (4.2%) died in the R-SQ-group, whereas twelve (8.7%) died in the R-CHOP-group (P=0.03). Five-year progression-free survival (PFS) was superior in the R-SQ-group with 78.5% (95% CI 0.66-0.91) survival compared to 53.8% (95% CI 0.43-0.65, P=0.005, HR=0.37) in the R-CHOP-group. Five-year overall survival (OS) was 100% in the R-SQ-group and 91.9% (95% CI 0.86-0.97, P=0.027, HR=0.18) in the R-CHOP group. When analyzing patients who received maintenance therapy, we found no difference in OS (P=0.13), but there was still significant difference in 5-year PFS in favor of the R-SQ-arm (88.4% and 58.2%, P=0.034). ConclusionsIn risky FL patients, intensive front-line therapy brings about 24% advantage in CR rate, about 25% higher 5-year PFS (reduces risk of relapse/progression by 62%) and about 10% advantage in 5-year OS (reduces risk of death by 82%). Maintenance immunotherapy application overshadows OS but not PFS advantage of intensive chemotherapy. Finally, in younger physically fit risky patients, more intensive induction regimen leads to superior disease control a remission duration compared to standard R-CHOP. AcknowledgmentSupported by grants: LF-2013-004, IGA NT12193-5/2011 and PRVOUK-27/LF1/1. We would like to thank to all referring physicians: Jan Pirnos (Ceske Budejovice), Katerina Kubackova (FN Motol), Lucie Barsova (Liberec), Petr Kessler (Pelhrimov), Jitka Jakesova (Pribram), Milan Lysy (Usti n. Labem), Jindra Ciberova (Znojmo), Dagmar Adamova (Opava), Milan Matuska (Ostrava), Martin Brejcha (Novy Jicin). [Display omitted] Disclosures:Trneny:Roche: Honoraria, Research Funding.

A phase III randomized intergroup trial (S0016) comparing CHOP plus rituximab with CHOP plus iodine-131-tositumomab for front-line treatment of follicular lymphoma: Results of subset analyses and a comparison of prognostic models.

8001 Background: Advanced follicular lymphomas (FL) are considered incurable with chemotherapy and there is no consensus on the best treatment. Outcomes are variable, but can be partially predicted by defined prognostic factors. SWOG and CALGB compared the safety and efficacy of 2 immunochemotherapy regimens in a Phase III trial enrolling 554 patients between 3/1/2001 and 9/15/2008. Methods: Patients were eligible if they had bulky stage II, III or IV FL and had not received prior therapy. Patients randomized to CHOP-R received 6 cycles of CHOP every 21 days + 6 doses of rituximab. Patients randomized to CHOP-RIT received 6 cycles of CHOP, followed by consolidative radioimmunotherapy with tositumomab/iodine I-131 tositumomab. A Cox proportional hazards multi-variable regression analysis assessed the prognostic impact of age, stage, LDH, LN size and number, performance status, hemoglobin, β2 microglobulin, BM involvement, and B symptoms. The prognostic value of 3 multi-variable models were compared. Results: Outcomes were outstanding with either CHOP-R or CHOP-RIT (2 yr PFS: 76% vs 80% [ p =0.11]; 2 yr OS: 97% vs 93% [p =0.08], respectively). Subset analyses so far have not identified any subgroups clearly benefitting to a greater degree from CHOP-R or CHOP-RIT in terms of both PFS and OS. Cox multivariable regression analysis identified serum-β2M, LDH level, and FLIPI index as the strongest prognostic factors associated with worse PFS and OS. Conclusions: Both regimens produced outstanding PFS and OS, and no statistically significant differences between them were observed. FLIPI, FLIPI2, and LDH + β2M models were all strong predictors of patient outcomes. A combination of LDH + β2M was as good as the FLIPI index, and was simpler to apply. (Supported in part by NCI grants CA32102 and CA38926 from the NCI and GlaxoSmithKline.) [Table: see text]

The Use of FDG-PET in the Initial Staging of Patients with Follicular Lymphoma (FL). A Retrospective Study From the Fondazione Italiana Linfomi

Abstract 2651 Background and objectives[18F]fluorodeoxyglucose - Positron Emission Tomography (FDG-PET) is confirmed as a useful functional imaging tool for staging and response assessment in Hodgkin lymphoma and Diffuse Large B-Cell Lymphoma. Despite FL is accounted among FDG-avid lymphomas few studies have been performed to investigate how FDG-PET can be used in initial staging of FL patients. We conducted a retrospective analysis to investigate the role of FDG-PET in the initial staging of FL. Patients and methodsThe study was designed as a retrospective unplanned analysis of patients with newly diagnosed FL enrolled in the FOLL05 phase III trial (NCT00774826) and randomized to one of the three study arms (R-CVP. R-CHOP, R-FM). To be included in the study patients should have confirmed eligibility for the FOLL05 trial, have available data on clinical presentation, treatment details and results, and on follow-up. Baseline staging had to be performed with contrast-enhanced Computed Tomography (CT), with CT-PET, and with Bone Marrow (BM) biopsy. For study purposes disease extension at baseline was defined independently for both CT and PET using on local report and interpretation; only for difficult cases images were centralized and reviewed. For each exam nodal sites (NS) were counted according to the FLIPI schema. NS were considered as positive if greater than 1.5 cm in their maximum transverse diameter at CT or, using PET, if FDG avid or if they had disappeared at the end of treatment. Extranodal sites (ENS) were counted on an organ basis and were considered positive at CT in case of nodular involvement or in case of organ enlargement not otherwise justified. Extranodal involvement at PET was considered for sites showing avidity for FDG not justified by conditions other than FL. Conventional Ann Arbor (AA) staging was based on CT scan assessment only. PET and CT scan results were compared using the kappa-statistic measure of interrater agreement (IR), and the level of agreement was defined by the Koch Landis scale. ResultsAmong 534 patients enrolled in the FOLL05 trial, 122 cases fulfilled eligibility criteria for this study. All but 2 cases were confirmed as FDG avid at PET scan; these two cases were not used for staging comparison. Median age of patients was 57 years (range 33–74), 33% were older than 60 years, 48% were males. Bone marrow biopsy was positive in 52%. Using CT, AA stage was III-IV in 77% of cases. Fifty-two percent, 36%, and 12% of cases had less 0–4, 5–8, and >8 NS, at CT, respectively. Overall CT scan allowed the identification of 48 ENS in 36 patients (30%); 2 or more ENS were described in 8 patients (6%); most frequent ENS were spleen (52%), liver (10%), skin/soft tissue (8%) and GI tract (6%). Using PET 38%, 37%, and 25% of cases had 0–4, 5–8, >8 NS, respectively. PET allowed the identification of 88 ENS in 55 patients (46%) and 2 or more ENS were found in 17 patients (14%). Most frequent ENS at PET were bone (35%), spleen (30%), GI tract (10%), and skin/soft tissue (7%). Classifying patients according to the number of NS (0–4, 5–8, >8) agreement between CT and PET was fair (IR= 61%, Kappa=0.39). Agreement between CT and PET for ENS (grouped as 0, 1, and >1) was also fair (IR= 63%, Kappa=0.31) and improved to moderate when also details on BM histology were considered (IR 82% K=0.4). When PET was used independently of CT to define AA stage a moderate agreement was achieved with CT (IR=76%, kappa= 0.58): in particular 22 cases (18%) were upstaged with PET while only 6 (5%) were downstaged; seventeen out of 25 (68%) patients were reclassified by PET as stage III-IV from a previous localized stage. Looking at FLIPI, 22%, 41%, and 37% were classified by CT as having score of 0–1, 2, and 3–5, respectively. The use of PET modified CT based FLIPI index in 26% of cases, with a substantial agreement between PET and CT (IR=74%, kappa=0.61). FLIPI2 index is not affected by the use of PET. ConclusionsThe results of this study confirm FL as a FDG-avid disease. The use of PET for the initial staging of patients with FL seems to provide a more accurate definition of disease extent compared with CT. The clinical usefulness of adding PET to the initial staging of FL needs to be further investigated. Disclosures:Di Raimondo:Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

PROGNOSTIC FACTORS IN FOLLICULAR LYMPHOMA IN THE RITUXIMAB ERA: HOW TO IDENTIFY A HIGH-RISK PATIENT?

Follicular lymphoma accounts for about 20-30% of non-Hodgkin's lymphomas. Clinical behaviour and overall prognosis are highly variable, ranging from indolent forms with occasional spontaneous remissions to rapidly progressive disease. Modern treatment strategies have shifted from a primarily "palliative" approach to more intensive risk-adapted therapy with the intention of achieving complete long-term remission. New targeted treatment with monoclonal antibodies (MoAb) and radioimmunoconjugates (RIT) has resulted in unprecedented improvements in treatment outcome. At the same time, a large amount of information is now available on lymphomagenesis, the role of the microenvironment of lymphomatous follicles and cytogenetic abnormalities. We can better understand the role of the patient's innate anti-lymphoma immunity. Although no standard front-line therapy has been established, increasingly more data show that risk-adapted treatment strategy have survival benefits for high-risk patients. For this reason, accurate prognostic indices are urgently needed to find optimal therapies for particular lymphoma patients. Whereas the currently used FLIPI index was established in the pre-rituximab era, the newly designed FLIPI 2 index still needs to be confirmed in prospective trials. New therapeutic approaches with MoAb, RIT and other biological agents allow the population to be divided into increasing numbers of groups with different outcomes. All in all, in the near future, we will probably not use only one basic prognostic index for all populations of FL patients. New prognostic schemes should analyze patients separately and include both disease- and patient/host-related parameters.

Result of FDG PET-CT Imaging After Immunochemotherapy Induction Is a Powerful and Independent Prognostic Indicator of Outcome for Patients with Follicular Lymphoma: An Analysis From the PRIMA Study

AbstractAbstract 855 Aim:Despite its often indolent clinical course, follicular lymphoma (FL) is a heterogeneous disease. Current criteria for early identification of patients with a poor prognosis are suboptimal - the FLIPI and F2 index are insufficient prognostic markers for individual patients and the limitations of post-treatment conventional response criteria have long been acknowledged. FL shows increased FDG uptake, but unlike DLBCL, minimal data exist about the role of PET-CT in response assessment. We have used the prospective conventional response assessment and 42 month patient follow-up in the PRIMA (Primary Rituximab and Maintenance, Salles et al., ASCO 2010, Abstr#8004) study as a platform for analysis of the utility of PET-CT in FL. Methods:The PRIMA database was interrogated and investigators surveyed to identify PET-CT scans performed during staging and induction response assessment. Single modality PET-only scans were not eligible for inclusion. Local PET interpretation (positive + or negative -) was used to explore associations with patient outcomes. The primary endpoint was PFS from PRIMA registration. Results:277 PET-CT scans on 160 patients from 40 centres were identified. Baseline patient characteristics did not differ from the overall PRIMA patient population. Positive PET-CT scans were recorded in 119/120 (99%) at diagnosis, 11/33 (33%) interim restaging scans and 32/124 (26%) post induction treatment (R-CHOP or R-CVP).There was significant correlation between PET-CT result and conventional response assessment at the end of immunochemotherapy (p<0.0005). The incidence of post-treatment PET+ increased across the categories of lesser conventional responses, occurring in 8% (4/50) CR, 31% (12/39) CRu, 41% (11/37) PR, 67% (2/3) SD, and 80% (4/5) PD. While 73/91 (80%) of PET- patients were in CR/CRu, given the very high overall response rate on study, 16/33 (48%) of the PET+ population were also in CR/CRu.With a median follow-up of 42 months, a significantly inferior actuarial 3yr PFS was observed in post-treatment PET+ vs. PET- patients (Figure 1): 32% (95% CI 17–48%) vs. 74% (95% CI 63–82%) (log rank p<0.0001, HR 3.5, 95% CI 2.0–6.1), median PFS 19 months (13-35) vs. not reached, (52-NR).Using proportional hazard regression analysis, both conventional response (overall p=0.0002) and PET+ status (HR 2.8 p=0.0007) were significant predictors of inferior PFS. However, the predictive power of conventional response assessment was limited to non-responders: SD/PD vs. CR/CRu (HR 6.5, p<0.0001), and SD/PD vs. PR (HR 5.2, p=0.0009). Comparison of PR vs. CR/CRu was not different (HR 1.2, p=0.5). While PET+ status had a significant negative impact on PFS in both the CR/CRu (HR 2.6, p=0.015) and PR (HR 4.3 p=0.018) patient groups, there was no difference in outcome between CR/CRu vs. PR patients within the PET+ (HR 1.5 p=0.42) and PET- (HR 1.0 p=0.98) subgroups.When only patients randomised for the maintenance element of the PRIMA study were considered, post-treatment PET+ (15/59) remained predictive of 3yr PFS (27 vs. 69%, HR 3.1, p=0.005) in the observation arm, but post-treatment PET+ (9/47) was not significantly associated with an adverse outcome in patients receiving rituximab maintenance (3-year PFS 56 vs. 81%, HR 2.2, p= 0.18).In a multivariate Cox model including responding patients the following factors were negative predictors of PFS: post-treatment PET+ (HR 3.1 p<0.0014); R-CVP induction therapy (HR 2.8, p<0.014); and baseline β2M ≥3 (HR 2.6 p<0.0042), while conventional PR and FLIPI were not. Conclusion:This PRIMA sub-study demonstrates that post-treatment PET-CT is a powerful predictor of PFS that complements conventional response evaluation after first line immunochemotherapy for FL. Patients who are PET- can expect a prolonged PFS whether in conventional CR or PR, but for those remaining PET+, with a median 19 month PFS, the disease cannot be characterized as indolent. Future clinical trials should evaluate an FDG PET-CT response adapted approach focused on improving outcomes for this group. [Display omitted] Disclosures:Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shpilberg:Roche: Consultancy, Honoraria.

High ratio of interfollicular CD8/FOXP3-positive regulatory T cells is associated with a high FLIPI index and poor overall survival in follicular lymphoma.

Several studies have highlighted the importance of the microenvironment in the behaviour of follicular lymphoma (FL). We conducted an immunohistochemical analysis to assess the role of different cell subpopulations, i.e. CD8, CD68 and forkhead box protein P3 (FOXP3)-positive regulatory T cells (Treg cells) in 84 lymph nodes of 58 patients with FL (58 at diagnosis, 26 at relapse). Since the overall effect of Tregs is considered to depend on their number in relation to CD8(+) effector T cells, we determined the corresponding ratio for each patient and correlated the results with clinical parameters. The interfollicular CD8/FOXP3(+) cell ratio was significantly higher in patients with histological grade 3 tumours (2.04 vs. 1.63) and with a high risk FLIPI index (2.99 vs. 1.53) compared to those with grade 1-2 tumours or a low-intermediate FLIPI index. Similar results were obtained for the follicular CD8(+)/FOXP3(+) cell ratio. The interfollicular CD8/FOXP3 ratio was found to have prognostic value [a 5-year overall survival (OS) of 82 vs. 59% for a ratio of ±1.68]. In addition, an interfollicular FOXP3(+) cell number of more than 86 cells/mm(2) was correlated with a more favourable outcome (p=0.03). When patients at diagnosis and relapse were compared, a significant difference (p=0.05) in the localization (interfollicular vs. intrafollicular) of FOXP3(+) cells was observed. The CD8/FOXP3 ratio in the interfollicular areas was significantly different (1.66 at diagnosis vs. 2.2 at relapse, p=0.05). The presence of a small number of FOXP3(+) cells with a high CD8/FOXP3 ratio is probably the indicator of an active immune response during tumour development, with lymphoma cells acting as targets or bystanders.

Low Ratio of Inter-Follicular CD8/FOXP3-Positive Regulatory T-Cells Is Associated with a favourable Overall Survival in Follicular lymphoma (FL).

Background: By using gene expression profiling, a major role for T-lymphocytes and macrophages (M) have been observed, defining 2 prognostic subgroups. Then, conflicting results were published with both positive and negative impacts of different T-cells subpopulations, particularly for T-regulatory (Tregs) cells. In addition, CD8 and CD4 T-cells were mentioned as key cells in progression and/or transformation process and CD68+ M associated with a poor outcome. Functional studies have suggested that follicular dendritic cells have to be considered as important cells in comprehensive biology of FL, and that the function is probably associated with the proximity of tumour cells, different in intra-or inter-follicular location. We investigate the role CD8+ T cells, FOXP3+ Tregs and M, and calculate in large fields the different numbers of these cells, particularly focusing on their intra-versus inter-follicular localisation. To approach a more dynamical view of the immune response we correlate the ratio CD8+/Treg in these 2 compartments and correlated results with clinical parameters and outcome.Patients and Methods: Immunochemistry was used to study numbers and distribution of CD8, CD68, and Tregs cells in 89 patients with FL (65 at diagnosis and 24 at relapse). Since it can be expected that overall effect of Tregs depends on their number in relation to CD8+ effectors T cells, we determined the corresponding ratio for each patient and correlated the results with clinical parameters.Results: The median age of the patients was 58 years (range 23–91 years), and the male/ female ratio was 1.2. There were 67 % of the patients with grade1, 17 % grade 2 and 16 % grade 3a. Advanced stage (Ann Arbor IV) was observed in 24 %. The distribution of the population according to the FLIPI was the following: low risk 36 %, intermediate risk 45 % and high risk, 19 %. The interfollicular CD8/FOXP3+ cell ratio was significantly higher in patients with grade 3 tumours (2.04 versus 1.63) and with a high risk FLIPI index (2.99 versus 1.53) compared with those with grade 1–2 tumours or a low–intermediate FLIPI index. The same results were obtained with the intra-follicular CD8+/FOXP3 + cell ratio. The inter-follicular CD8/FOXP3 ratio was found to have prognostic value for overall survival with a 5-years OS of 82% versus 59% for a ratio of less or more than 1.68. Moreover, an inter-follicular FOXP3+ cell number of more than 86 cells/mm2 was correlated with a more favourable outcome (p = 0.03). When comparing the 2 groups at diagnosis and relapse, we observed a significant difference between the number of CD68 cells both in intra-follicular locations (39.23 at diagnosis versus 32 at relapse, p= 0.07) and inter-follicular locations (96 at diagnosis versus 62 at relapse, p=0.05). The CD8/FOXP3 ratio in inter-follicular locations was significantly different (1 .66 at diagnosis versus 2.2 at relapse, p=0.05).Conclusion: The presence of abundant FOXP3+ cells with a low CD8/FOXP3 ratio is probably the mark of an active immune response during tumour development, with lymphoma cells acting as targets or bystanders.

Induction with Fludarabine, Cyclophosphamide and Rituximab as Front-Line Therapy Against Follicular Lymphoma: Results from a Cooperative Spanish Trial

Background and objective Fludarabine in combination with cyclophosphamide (FC) plus rituximab (R) is an effective treatment for newly diagnosed as well as relapsed follicular lymphoma (Tam 2004; Keating 2005; Sacchi 2007). Maintenance treatment with R, after different induction treatments, improves overall and progression-free survival (Forstpointner 2006; van Oers 2006). Therefore, we aimed to evaluate the efficacy and safety of the FC-R regime followed by maintenance doses of R.Patients and Methods We present an intermediate report of the one-arm study in which 75 previously untreated patients with a diagnosis of follicular non-Hodgkin's lymphoma in Ann Arbor stage II–IV were included between October 2004–2006. Seventy four were assessed for safety after receiving at least one FC-R dose (F: 3x25 mg/m2 and C: 1 g/m2; R: 375mg/m2), and 72 for response to treatment. Patients aged 53.4 years in average, one in five showed bulky disease and 72.2% Ann Arbor IV staging. FLIPI index determined 23.9% patients with low (0–1) score, 38% with intermediate (2) and 38% with poor score (3). A total of 47 patients presented some molecular alteration in PB or BM.Results Induction therapy was delivered throughout 4–6 courses, resulting in 91% complete responses (CR) and 9% partial responses (PR) (Table 1). From the patients who presented monoclonal population at diagnosis, 40 were evaluated for molecular response after induction and only 1 remained MDR positive for bcl2/IgH. Overall survival (OS) at 24 months was 87.5%, and two patients presented progressive disease within this period. The median OS has not been reached at this evaluation. To the date, 262 adverse effects grade 3–4 (32.6%) have been documented (80.9% neutropenias) and 80 infectious complications were recorded (23.8% grade 3–4). Three patients died from respiratory diseases, two from acute leukemia, and six from other causes.Table 1EVOLUTION OF RESPONSEEvaluated Response at End of Induction TherapyEvaluated Response Post-Course 3Assesable End Ind. (n=67)Missing End Ind. (n=5)Assesable PC3 (n=70)CRITERIACRPRNEWDEX14CR12-11-32uCR31-1--24PR166--22Missing PC3 (NE)2----72Total616212CR: complete response; uCR: unconfirmed CR; PR: partial response; NE: not evaluated; WD: withdrawn; EX: exitus.Conclusions The FC-R has proven a potent antitumoral activity in untreated follicular lymphoma patients, rendering very high clinical and molecular responses. However, as reported in similar studies (Hochster 2007 ASCO), the high incidence of prolonged neutropenias and lymphopenias developed as consequence of the chemotherapy regime, questions the safety of the induction treatment.

Non Hodgkin Lymphoma (NHL) Distribution and Clinical Characteristics in a Mexican Registry with High Frequency of T Cell NHL: A Descriptive Study on Behalf of Mexican Hematology Study Group (MHSG).

Background: Among the NHL, B Cells NHL are more frequent than T Cells NHL (6%) as described in USA & European reports. The highest frequencies of T Cell NHL have been reported in Japan with 9% and India with 12%. In a Mexican retrospective study we found a T Cell NHL frequency of 13%.Objective: To corroborate the patterns and frequency of B and T cell lymphomas in Mexico.Methods: The registry of lymphoid neoplasms was created based on the WHO classification. The Lymphoma subtype analysis was prepared in two periods: retrospectively from 2002 to December 2005 and prospectively from January to December 2006. The data recorded were: age, sex, cell type (B o T), NHL frequency, primary site, stage and prognostic index (IPI and FLIPI).Results: In the first group 2375 Lymphomas were included: 2122 B Cell NHL (89.34%) and 253 T-cell lymphomas 253 (10.6%). B-cell NHL: gender 55.17% male and 44.66 female, median age of 55.21 years Age >60 years 45.7%; 62% III–IV stage. After applying the FLIPI index, the patients were divided into three risk groups: low (8.4% of cases), intermediate (81%), and high (10.6%). The distribution of patients in IPI risk groups was 15.7%, 76%, and 8.3% of cases classified as low, intermediate, and high risk The frequencies of B cell lymphoma were: 49% DLBCL, 15% Follicular Lymphoma, 5.35% CLL/SLL, 1.6% Mantle cell Lymphoma, 0.9% Follicular Center Lymphoma, 1.6% Marginal Zone B Lymphoma, 6.1% MALT, 1.6% Burkitt Lymphoma. T cell lymphomas were distributed in: Peripheral T Cell 253 (46.36%), Cutaneous Anaplastic 42 (16.09%), T/NKcell 35 (13.40%), Lymphoblastic 28 (6.16%), T non classifiable 10 (3.83%). The second group included 344 lymphomas; 309 (89.82%) B Cell NHL and 31 (10.01%) T cell Lymphomas. Gender 51.7 male and 48.3 female, medium age 57.79 years (SD 16.09); . >60 years 44%. After applying the FLIPI index the distribution of patients was 24.5% with intermedium risk and 9.5.8% high risk. Patients were divided into three IPI risk groups: Low 69.2% Intermediate 23% and high risk 7.8%. The frequencies of B cell lymphomas subtype were: DLBCL 168 (52.3%), Follicular 58(18.4%), CLL/SLL 19 (6.14%), Mantle Cell 10 (3.2%), Follicle Center Lymphoma (0.9%), Marginal Zone B 4 (1.2%), MALT 14 (4.5%), Burkitt's Lymphoma 5 (1.6%). The T Cell Lymphoma subgroup frequencies were: T Cell Peripheral 7 (22.5%), Cutaneous Anaplastic 5 (16.1%), N/K cell 4 (12.9), Lymphoblastic 3 (9.6%), T lymphoma non classifiable 6 (19%).Conclusions: We confirmed a high incidence of T cell NHL in consecutive registries in Mexico. In the B cell subgroup it seems to be a difference where the DLBCL has a higher frequency and the CLL/SLL subgroup the lowest compared with other series. These differences in frequency might be explained by ethnic characteristics, however we need more epidemiological and viral studies, looking for Epstein Barr virus.

Induction with Fludarabine, Cyclophosphamide and Rituximab Followed by Maintenance with Rituximab: Results of a Prospective Study in 75 Patients (LNHF-03).

Objectives. To evaluate clinical efficacy, molecular response and safety following the use of a regimen of fludarabine (25 mg/m2 x 3 days) Cy (1g/m2 x 1 day) and Rituximab (375 mg/m2/ x 1 day) (FCR)x 6 cycles, followed by maintenance with rituximab (375 mg/m2/week/x 4 weeks every 6 months x 2 years). (LNHF-03 Study).Patients and methods. Seventy-five (75) patients with a diagnosis of follicular NHL were included in the study between October 2004 and January 2006. The median age was 54 years (30–75). Twenty-one per cent (21%) of the patients had bulky disease. According to the FLIPI index: (0–1): 22.6%; 2: 40,3%; 3: 37,1%. Minimal residual disease (MRD): A clonal population on diagnosis was identified by means of the bcl–2/IgH major and minor rearrangement study by means of quantitative PCR rearrangements of the Igs by means of fluorescent PCR. Subsequently, samples were studied following the induction treatment and during the maintenance treatment. The analysis is performed in the 70 patients that completed the six induction regimens and were evaluated.Results. 64/70 patients were given the six cycles planned (91%). The presence of persistent cytopenia limited the cycles given in the other 6 patients to 4 or 5. Three hundred and thirty-eight (338) adverse effects were documented in the 414 cycles given to the 70 patients evaluated, almost all of them being mild, and 26 severe (degree 3–4), and almost all the cases were neutropenias. Infectious complications were frequent and many were severe: herpes zoster (5), pneumonia (5), cerebral toxoplasmosis (1), aspergillosis (1), infection by CMV (2). One patient developed erythroleukaemia within the first year following completion of the treatment. Three patients died ( CMV + aspergillosis, pneumonia, erythroleukaemia). 86% of the patients reached CR following induction, 6% unconfirmed CR and 8% partial response. On diagnosis, a clonal population was identified in 63% (45/71) of the cases. Of these 45 patients, samples are available following induction treatment in 35 cases. The molecular disease was negativised in all the cases, except one case with persistence of positive bcl2/IgH (0.3% as opposed to diagnosis) and is in uncertain CR. Of the 34 cases with negative ER, 32 are in CR or uncertain CR and 2 PR.Conclusions. The FCR regimen has proven to have a potent antitumoral activity in recently diagnosed follicular lymphoma patients with very high clinical (86% CR) and molecular (95%) responses. The immunosuppression caused is profound, with the appearance of opportunistic infections, and in some cases prolonged lymphopenias and neutropenias that call for future assessment and follow-up.

Evaluation of three prognostic indexes in follicular lymphoma

6595 Background: Three validated prognostic models have been proposed for use in patients with follicular lymphoma (FL), the International Non-Hodgkin’s Lymphoma Prognostic Index (IPI), the ILI model from the Italian intergroup, and recently the FLIPI model from the French International Lymphoma Prognostic Index. The aim of this study was to apply these three models to a group of FL patients to determine the concordance between them and their usefulness in predicting clinical outcome, including rate of transformation. Methods: The IPI index (age >60 years, extranodal involvement ≥2 sites, elevated lactate dehydrogenase (LDH), ECOG performance status ≥2, stage ≥3), the ILI index (age >60, extranodal involvement ≥ 2 sites, elevated LDH, male sex, B symptoms and erythrocyte sedimentation rate ≥ 30) and the FLIPI index (age > 60, stage ≥ 3, elevated LDH, number of nodal sites > 4, hemoglobin < 120 g/L), respectively were calculated and applied to 100 patients diagnosed with FL (grade I-III) between 1994 and 2001. Overall survival (OS) and progression free survival (PFS) were calculated for each prognostic group (low, intermediate and high risk) by the Kaplan-Meier method. Results: The median follow-up of our series was 31 months (mo) (range 1–340). Median OS was 24 mo (range 1–226). The median PFS was 41 mo (range 4–145). Concordance between the three indexes was 40%. The index that best predicted mortality was the ILI (p=0.027). The distribution of patients and mean overall survival according to risk group were similar for each index. Patients who went on to transform to aggressive NHL were rarely classified as high risk at diagnosis of FL by any index. Conclusions: Although the concordance between the three models was low, each is useful for classifying FL patients into risk groups and in predicting outcome in this group of patients. Transformation was not well predicted by any of the models. This information will be combined with cytogenetic, immunohistochemical, and DNA microarray data from frozen tumor tissue (currently proceeding) to develop a combined molecular and clinical prognostic index. A combined index may help select appropriate treatment for individual patients. No significant financial relationships to disclose.

Manteinance Treatment with Interferon (IFN) Is Not Necessary to Achieve Prolonged Progression Free Survival (PFS) in Patients with Indolent Non Hodgkin's Lymphoma (NHL). Results from a Prospective Randomized Trial on 165 Patients.

INTRODUCTION. Treatment with IFN and chemotherapy induces a significant improvement of PFS in patients with low-grade NHL, specially in patients with responsive disease. However, the best IFN schedule is still pending as benefits are observed when IFN is administered associated to the induction therapy or, as maintenance treatment or, in both treatment phases.OBJETIVE. To evaluate the additional benefit or not of one year maintenance treatment with IFN in patients who achieve response after an induction treatment with CVP and IFN for 3 months.PATIENTS & METHODS. From February 1990- October 2002, 165 patients with low-grade NHL were recruited. Patients received treatment with CVP (median number 6 cycles) and IFN, 3MU/m2 three times a week during 3 months. Patients with complete or partial responses were then randomized to receive treatment with 12 months of IFN, 3MU/m2 three times a week vs observation. With a median of 4,7 years (range 0.3 to 11.7 years) for surviving patients, we analysed response, PFS and overall survival.RESULTS. Patients median age was 63 years (range 28–89 years), with 65.5% having follicular (FL), 20% small lymphocyte and 14% marginal zone lymphoma. Most patients (83%) were in advance stage and 75% had extranodal involvement. Thirty-three percent of FL patients had a FLIPI index score > 3. Dose-intensity for cyclophosphamide and IFN in the induction treatment was 71% and 69%, respectively. Ten patients withdraw the study due to grade 3–4 toxicity events (6.5%).Response: 86% of patients achieved a response, 80% complete. One hundred and twelve out of the 143 responding patients were randomised to receive IFN for 12 months (56 patients) vs observation (56 patients). Patients and disease characteristics for each group were similar. Median dose of maintenance IFN treatment was 67% (range 8%–113%). Fourteen patients (25%) withdraw the study, 7 due to IFN toxicity.PFS: Median PFS of the whole series was 6.76 years, 6.6 years for patients in the maintenance IFN group vs 7.8 years for the observation group, p=0.7.Overall survival at 12 years is 81% for both groups. Interestingly, 31 patients who achieved a good response but were not randomised showed a significantly shorter OS, p=0.001.CONCLUSION. No additional increase on PFS has been observed when maintenance IFN is administered to patients responding to CVP and short term IFN induction therapy. With our data, very good response rates and long lasting remission are achieved with only 3 months IFN treatment. Treatment tolerance is therefore significantly better.