Updated Results of the PRIMA Study Confirms the Benefit of 2-Years Rituximab Maintenance In Follicular Lymphoma Patients Responding to Immunochemotherapy.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1788-1788 ◽  
Author(s):  
Gilles Andre Salles ◽  
John Catalano ◽  
Pierre Feugier ◽  
Fritz C Offner ◽  
Reda Bouabdallah ◽  
...  
Keyword(s):  
Adverse Events ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Progression Free Survival ◽  
Induction Treatment ◽  
First Line ◽  
Free Survival ◽  
Rituximab Maintenance ◽  
Treatment Characteristics

Abstract Abstract 1788 The GELA-sponsored intergroup PRIMA Phase III study was designed to investigate the potential benefit of 2-years of rituximab maintenance in high tumour burden follicular lymphoma patients responding to one of three non-randomised first line immunochemotherapy treatments. The results of the pre-planned interim analysis with 24 months median follow-up were positive and demonstrated a significant reduction in the risk of progression for patients randomized to rituximab maintenance (Salles et al., ASCO 2010). We present here the updated efficacy and safety results after an additional year of follow-up, when all randomized patients had completed the observation/maintenance period. From December 2004 until April 2007, 1217 patients were enrolled from 223 centres. Complete data are available for 1193 patients who had the following pre-induction treatment characteristics: median age 56 years [range 22–87]; 52% male; 90% Ann Arbor stage III-IV; 33% B symptoms; 55% bone marrow involvement; 4% ECOG performance status >1; 34% elevated LDH; 32% β2-microglobulin≥3mg/L; FLIPI score 0–1 (21%), FLIPI 2 (36%), FLIPI 3–5 (43%). Most patients (74%) received R-CHOP induction (22% R-CVP, 4% R-FCM). Patients responding to induction therapy were stratified based on their immunochemotherapy regimen and response [CR/CRu versus PR], and randomized to observation or rituximab maintenance, 1 infusion (375 mg/m2) every 8 weeks for 2 years. A total of 1018 randomised patients were analyzed according to the ITT principle (513 observation/505 rituximab maintenance). All initial pre-treatment characteristics were well balanced between arms and the response status at time of randomization was CR=39%; CRu=31% and PR=29% (others 1%). After a median follow-up of 36 months, 3-year progression free survival was 60.3% (95% confidence interval [CI] 55.8 – 64.5%) in the observation arm and 78.6% (95% CI 74.7 – 82%) in the rituximab maintenance arm, respectively (stratified Log-Rank, P<.0001; hazard ratio [HR]=0.55, 95% CI 0.44 – 0.68). In pre-planned analyses of patient subgroups categorized by age, sex, FLIPI score, induction chemotherapy and response to induction, the effect of rituximab maintenance was found to be consistent with the overall study results. In a Cox regression multivariate analysis, older age (P=.0013), male sex (P=.013), higher FLIPI group (P<.0001), R-CVP induction treatment (P=.003) and rituximab maintenance (P<.0001) were all significant variables associated with inferior progression free survival. A significant reduction in the number of patients starting a new anti-lymphoma treatment (HR=0.60, 95% CI 0.47 – 0.76) or starting a new chemotherapy (HR=0.62, 95% CI 0.47 – 0.81) was also observed for rituximab maintenance. Regarding response to treatment, 52% of the patients that were in PR at the time of randomization converted to CR or CRu at the end of 2-year maintenance in the rituximab maintenance arm compared to 30% of patients in the observation arm (P=.0001). As a result, 361 out of 482 patients evaluated (75%) in the rituximab maintenance arm were in CR or CRu as compared to 268 out of 491 patients evaluated (55%) in the observation arm (P< .0001). At the time of the data cut-off, 30 patients (6%) had died in the observation arm compared to 26 patients (5%) in the rituximab maintenance arm (HR=0.87, 95% CI 0.51 – 1.47). The most common adverse events reported were infections, which occurred in 24% and 39% of the patients in the observation and rituximab maintenance arms respectively. Grade 3–4 adverse events were reported in 17% of patients in the observation arm and 24% in the rituximab maintenance arm (neutropenia 1% vs 4%; infections 1% vs 4%, respectively) but these lead to treatment discontinuation in only 8 and 19 patients, respectively. In conclusion, after an additional year of follow-up, these data demonstrate a sustained benefit of 2 years of rituximab maintenance therapy after immunochemotherapy, resulting in improved progression free survival and complete response rates. No additional or unexpected toxicities were observed. All randomized patients have an excellent survival to date and longer follow-up will explore factors affecting overall survival in these patients. The PRIMA results indicate that rituximab maintenance should be considered in all follicular lymphoma patients who have responded to first line immunochemotherapy. Disclosures: Salles: Roche: Consultancy, Honoraria. Off Label Use: The use of rituximab maintenance in follicular lymphoma patients. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants. Feugier:roche: Consultancy, Honoraria. Belada:Roche: Consultancy, Honoraria. Tilly:Amgen: Honoraria. Leppa:Roche: Honoraria. Soubeyran:Roche: Honoraria, Research Funding. Hagenbeek:roche: Consultancy. Lister:Allos: Consultancy; Bioconnections: Consultancy; Astra Zeneca: Consultancy; Tenet: Consultancy; GSK: Chairman of Safety Monitoring Committee. Lopez-Guillermo:Roche: Consultancy, Honoraria. Seymour:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel support; Bayer-Schering: Honoraria, Travel Support.

Management of Grade 3B Follicular Lymphoma (FL) Outside Clinical Trials: A Multicentric Retrospective Analysis on Behalf of Fondazione Italiana Linfomi (FIL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2716-2716
Author(s):  
Barbara Botto ◽  
Federica Cavallo ◽  
Manuela Zanni ◽  
Antonella Anastasia ◽  
Chiara Rusconi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Retrospective Analysis ◽  
Progression Free Survival ◽  
Line Treatment ◽  
First Line ◽  
Free Survival ◽  
Rituximab Maintenance ◽  
First Line Treatment

Abstract Introduction: Follicular lymphoma grade 3 is recognized as a distinct entity in the World Health Organization classification of lymphoma. It is further classified into grade 3a and 3b depending on percentage of centroblasts. There is no consensus about its clinical course because some studies indicate an indolent behavior but others describe a more aggressive. Large systematic studies are missing in particular for 3b follicular lymphoma which is often considered as a separate entity. Methods: We performed a retrospective multicentric study on a group of 3b FL patients diagnosed in nine Italian FIL centers between November 2002 and January 2015. Planned inclusion criteria at enrollment were first line Rituximab containing regimen treatment and diagnostic samples availability for central pathologic review. Aim of the study was to determine clinical response, OS and PFS. Tumor response was based on the International Working Group response criteria. Survival analysis was performed with Kaplan-Meier method. Results: We enrolled a total of 51 patients, 50 evaluable for response at the time of analysis; median age was 62 yrs (range 48-71), 29 (56%) in stage III-IV, 10 (20%) with B symptoms. First line treatment was R-CHOP in the majority of patients 47 (92%), R-Bendamustine and R-CVP in 2 (4%) respectively. Seven patients (14%) received Rituximab maintenance after first line, six (12%) underwent high dose chemotherapy and autologous stem cell transplant (ASCT) as consolidation therapy and 5 (10%) were treated with local radiotherapy on residual disease. We observed CR in 48 patients (96%), PR in 1 (2%), PD in 1(2%). Ten patients relapsed or progressed after first line treatment and four of them died, three for progressive disease and one due to senile dementia while in CR. No relapses were recorded in pts receiving Rituximab maintenance but the advantage was not statistically significant and the number of patients receiving maintenance was low. With a median follow up of 63 months from diagnosis (IQR 33-82), 3-yrs PFS and OS rates were 82% and 93% (fig 1 and 2) with the evidence of a plateau in both survival curves after 5 years observation. Central pathologic review is ongoing. Conclusion: With the limit of a retrospective analysis our study confirms the clinical benefit of a combined modality treatment with Rituximab plus antracycline-containing chemotherapy in patients with 3b FL. Our results compare favorably with those previously reported in studies without Rituximab, that failed to show a plateau with 3-yrs PFS ranging between 22% and 52%. This results need to be confirmed with a longer follow up and after the planned pathologic review. Figure 1. Progression-Free Survival. Median Follow-up 62 months (IQR 33-82). Figure 1. Progression-Free Survival. Median Follow-up 62 months (IQR 33-82). Figure 2. Overall Survival. Median Follow-up 63 months. Figure 2. Overall Survival. Median Follow-up 63 months. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study

2019 ◽  
Vol 37 (31) ◽  
pp. 2815-2824 ◽  
Author(s):  
Emmanuel Bachy ◽  
John F. Seymour ◽  
Pierre Feugier ◽  
Fritz Offner ◽  
Armando López-Guillermo ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Long Term Results ◽  
Induction Treatment ◽  
Free Survival ◽  
Rituximab Maintenance ◽  
To Receive

PURPOSE The PRIMA study (ClinicalTrials.gov identifier: NCT00140582 ) established that 2 years of rituximab maintenance after first-line immunochemotherapy significantly improved progression-free survival (PFS) in patients with follicular lymphoma compared with observation. Here, we report the final PFS and overall survival (OS) results from the PRIMA study after 9 years of follow-up and provide a final overview of safety. METHODS Patients (> 18 years of age) with previously untreated high–tumor-burden follicular lymphoma were nonrandomly assigned to receive one of three immunochemotherapy induction regimens. Responding patients were randomly assigned (stratified by induction regimen, response to induction treatment, treatment center, and geographic region) 1:1 to receive 2 years of rituximab maintenance (375 mg/m2, once every 8 weeks), starting 8 weeks after the last induction treatment, or observation (no additional treatment). All patients in the extended follow-up provided their written informed consent (data cutoff: December 31, 2016). RESULTS In total, 1,018 patients completed induction treatment and were randomly assigned to rituximab maintenance (n = 505) or observation (n = 513). Consent for the extended follow-up was provided by 607 patients (59.6%) of 1,018 (rituximab maintenance, n = 309; observation, n = 298). After data cutoff, median PFS was 10.5 years in the rituximab maintenance arm compared with 4.1 years in the observation arm (hazard ratio, 0.61; 95% CI, 0.52 to 0.73; P < .001). No OS difference was seen in patients randomly assigned to rituximab maintenance or observation (hazard ratio, 1.04; 95% CI, 0.77 to 1.40; P = .7948); 10-year OS estimates were approximately 80% in both study arms. No new safety signals were observed. CONCLUSION Rituximab maintenance after induction immunochemotherapy provides a significant long-term PFS, but not OS, benefit over observation.

Comparing The Cost-Effectiveness Of Rituximab Maintenance (MR) and Radioimmunotherapy (RIT) Consolidation Therapy Following First-Line Chemo/Immunochemotherapies For Follicular Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2923-2923
Author(s):  
Qiushi Chen ◽  
Turgay Ayer ◽  
Adam C Rose ◽  
Loretta J. Nastoupil ◽  
Christopher R. Flowers
Keyword(s):  
Cost Effectiveness ◽  
Adverse Events ◽  
Follicular Lymphoma ◽  
Progression Free Survival ◽  
Consolidation Therapy ◽  
Line Treatment ◽  
First Line ◽  
Free Survival ◽  
Frontline Treatment ◽  
The Cost

Abstract Background Follicular lymphoma (FL), the most common indolent non-Hodgkin's lymphoma, has been regarded incurable and no consensus in management strategy has existed so far. In current clinical practice, the most commonly used frontline therapy is the immunochemotherapy (R-chemotherapy). Several phase III randomized trials - ECOG1496(Hochster, JCO2009), PRIMA(Salles, Lancet2011), and FIT(Morschhauser, JCO2008) - have shown that rituximab maintenance (MR) therapy and radioimmunotherapy (RIT) consolidation in addition to the frontline R-chemotherapy can improve progression-free survival (PFS) and help achieve a higher response quality. We conducted a cost-effectiveness analysis of maintenance or consolidation therapy versus observation after frontline treatment from the US payer's perspective. Methods We developed separate Markov models over patients' lifetime for PRIMA, ECOG, and FIT trial to compare the cost and effectiveness of observation with MR/RIT after completion of frontline treatment. Published progression free survival (PFS) and overall survival (OS) curves were extracted and fitted with Log-logistic regression survival model. Progression risks and cause-specific mortality after first-line treatment were extrapolated from the corresponding fitted PFS and OS model for each arm. Risk estimates after second-line treatment were identical for different models, estimated from the published survivals of observation arm in EORTC20981 trial. Costs for administration, monitoring, and management of adverse events were based on Medicare reimbursement rates for physician services, and drug costs were the wholesale acquisition cost, all valued in 2013 US dollars. In the microsimulation, initial age at diagnosis was sampled from the age distribution according to Surveillance Epidemiology and End Result (SEER) database. All costs and effectiveness were discounted at 3% per year. Primary outcomes were incremental cost per life-year gained (LY) and cost per quality adjusted life-year (QALY) gained. Model robustness in parameter uncertainties were addressed by one-way and probabilistic sensitivity analysis. Results Compared with observation, MR therapy provided 0.998 QALYs (0.901 LYs) at a cost of $43234 in PRIMA study, 1.070 QALYs (0.866 LYs) at a cost of $50146 in ECOG study, while RIT consolidation provided 0.795 QALYs (0.653 LYs) at a cost of $46085 in FIT trial. The incremental cost per QALY gained for RIT in FIT, and MR in PRIMA and ECOG were $57975, $43301, and $46844, respectively. From the table summarizing effectiveness and cost results, RIT and MR had comparable incremental QALYs before first progression, while RIT had higher incremental costs of adverse events due to relatively high incidence of adverse events in the RIT arm. Conclusions We used the same modeling framework and consistent parameter estimates to evaluate the cost-effectiveness of MR and RIT compared to observation after frontline treatment for FL patients. All strategies showed favorable cost-effectiveness profile with ICER below $100,000/QALY willingness-to-pay. Differences in induction therapies in three trials should also be noted when the ICERs of three models are compared. Disclosures: Flowers: Abbott, Celgene, Millennium/Takeda, Sanofi, Spectrum, Janssen: Research Funding; Celgene, Genentech Bio-oncology : Consultancy.

Effect of t(11;14) on outcomes of patients (pts) with newly diagnosed multiple myeloma (NDMM) in the connect MM registry.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8032-8032 ◽  
Author(s):  
Cristina Gasparetto ◽  
Sundar Jagannath ◽  
Robert M. Rifkin ◽  
Brian G. Durie ◽  
Mohit Narang ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
First Line ◽  
Free Survival ◽  
Loss To Follow Up ◽  
Observational Cohort ◽  
The Impact ◽  
Clinical Trial Information

8032 Background: The impact of t(11;14) (16%–24% of MM pts) on prognosis is not fully understood. Consensus is lacking on the effects of induction treatment (tx) on outcomes with t(11;14). The Connect MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with NDMM designed to examine real-world diagnostic patterns, treatment (tx) patterns, clinical outcomes, and HRQoL pt-reported outcomes in pts with NDMM. The impact of t(11;14) on tx outcomes are reported. Methods: Analysis included data from pts from 250 community, academic, and government sites in cohort (C) 1 (9/2009–12/2011) and C2 (12/2012–4/2016), who completed first-line (1L; induction) tx and were tested for t(11;14) by FISH or cytogenetics. Primary end points (progression-free survival [PFS] and overall survival [OS]) were measured from start of 1L tx to earliest event (PFS, death or progression; OS, death), loss to follow-up, or data cutoff, adjusted for baseline (BL) risk factors. A sensitivity analysis excluding pts with concomitant cytogenetic abnormalities [del 17p, t(4;14), t(14;16), 1q+] was also performed. Results: By 1/2018, 3011 pts were enrolled; 2938 were treated. Of 1574 enrolled pts tested for t(11;14), 378 were t(11;14)+ and 1196 were t(11;14)−. More pts in C2 vs C1 were t(11;14)+ (60% vs 40%). BL characteristics were similar between groups. t(11;14) status did not affect PFS ( P= NS) or OS ( P= NS; Table). Pts in C1 and C2 received similar 1L txs (IMiD agent + proteasome inhibitor [PI], 30% vs 42%; PI only, 42% vs 43%; IMiD agent only, 17% vs 11%). Results were similar when pts with concomitant abnormalities were excluded. Conclusions: Results of this analysis suggest that t(11;14) does not affect PFS and OS outcomes in NDMM pts. Clinical trial information: NCT01081028. [Table: see text]

Impact Of Rituximab Maintenance Schedule On Prognosis In First Line Treatment Of Follicular Lymphoma. Retrospective Analysis From Czech Lymphoma Group (CLG) Database

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4387-4387
Author(s):  
Andrea Janikova ◽  
Zbynek Bortlicek ◽  
Vit Campr ◽  
Leos Kren ◽  
David Belada ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Retrospective Analysis ◽  
Research Funding ◽  
Statistical Significance ◽  
Induction Treatment ◽  
Line Treatment ◽  
First Line ◽  
Rituximab Maintenance ◽  
First Line Treatment

Abstract Introduction Results of randomized studies showed benefit of maintenance therapy with monoclonal anti-CD20 antibody (rituximab) in terms of time to progression (PFS) and overall survival (OS) in follicular lymphoma (FL). General recommendation, based on large clinical trial, is to give 2 years of rituximab maintenance á 375mg/m2every 2 months (12 doses) in first line setting. On the other hand, there are various rituximab maintenance schedules; however, the clear comparison of clinical efficacy is missing. Our retrospective analysis compared two different schedule of rituximab maintenance in first-line treatment of FL used in university centers participating on CLG registry. Methods Data were recruited from 1702 FL patients registered in the prospectively maintained multicentric database (Czech Lymphoma Group; CLG). For the analysis, patients with stage II-IV of new diagnosed FL (grade 1-3a) responding (complete or partial remission) to 6-8 cycles first-line RCHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) followed with rituximab maintenance (RM) were included. Completed planned maintenance was inclusion criterion. Patients with previous watch and wait or additional first line therapy (radiotherapy, other chemotherapy, transplant therapy) were excluded. Results Totally, 168 evaluable FL patients with median age 57ys (range 28-82) including 70 (41.7%) men treated with RCHOP + RM were found in CLG database. 52/168 patients received totaly 8 doses of rituximab maintenance every 3 months for 2 years (RM8 arm), whereas 47/168 patients were treated with totaly 12 doses (RM12 arm) of rituximab maintenance every 2 months for 2 years. All patients in both subgroups completed planned RM therapy. There was no difference in distribution of age, gender, FLIPI, grade, B-symptoms, bone marrow involvement, performance status, LDH and beta2microglobuline level between both arms. Induction treatment in terms of administered cycles CHOP (6xCHOP in 41/52 and 35/45 pts., for RM8 and RM12 arm) and rituximab doses (8xR in 48/52 and 41/45 pts., for RM8 and RM12 arm) was similar between arms (ns). There were 4/52 (7.7%) and 5/47 (10.6%) relapses in subgroups RM8 and RM12, with no statistical significance. Median PFS was 3.8 (2.1-5.8) years vs. 3.9 (2.4-7.8) years in RM8 and RM12 arms (not significant), and median OS 3.91 (2.2-6.94) years vs. 3.1 (2.48-8.6) years also with no statistical significance. Conclusion Our results show, that rituximab maintenance given every 2 or every 3 months for two years in first line treatment brings similar benefit to the FL patients in terms of remission duration and overall survival. Despite the fact, that presented data are retrospective observation, this is the first report comparing two different rituximab maintenance regimens in FL. Further prospective study and longer follow up are needed to confirm our preliminary data. This work was supported by grant NT/12193-5 and MHCZ-DRO (FNBr 65269705) Disclosures: Mayer: Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding. Trneny:Roche: Honoraria, Research Funding.

scholarly journals Prognostic Value of Circulating Bcl-2/Igh Levels before and after Treatment in 415 Patients with Advanced Follicular Lymphoma Receiving First-Line Immuno-Chemotherapy in 2 Prospective StiL Trials - the Effect of Rituximab Maintenance

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4149-4149
Author(s):  
Guido Kobbe ◽  
Sabrina Pechtel ◽  
Fabian Zohren ◽  
Jürgen Barth ◽  
Alexander Christoph Burchardt ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Maintenance Therapy ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
The Other ◽  
First Line ◽  
Advisory Committees ◽  
Rituximab Maintenance

Abstract Introduction. The prognosis of patients with follicular lymphoma (FL) has improved during recent years following the introduction of immuno-chemotherapy and Rituximab maintenance. Nevertheless, some patients still relapse early and have a poor prognosis. Several prognostic scoring systems have been developed using clinical, laboratory as well as molecular data, while the early identification of high-risk patients remains a challenge. In this context, the relevance of circulating bcl2/IgH levels for patient stratification is not clear. We could show that high circulating bcl2/IgH levels in the peripheral blood (PB) before therapy were an independent adverse prognostic factor for progression free survival (PFS) in patients receiving R-CHOP or Bendamustine-Rituximab (B-R) in the NHL1 study of the German StiL group (Zohren et al, Blood 2015). Methods. Using a sensitive quantitative PCR method as previously described (Zohren et al, Blood 2015), a total of 2,491 circulating bcl-2/IgH level analyses were performed on PB samples before (n=415) and after (n=305) 6 cycles first-line immuno-chemotherapy and during follow-up (n=1,771). Results of these molecular studies were correlated with clinical outcome. We first present a 10-year update of the 107 bcl2/IgHpositive patients from the StiL-NHL1-trial. Secondly, we report the results from the StiL-NHL7-trial including bcl2/IgH analyses of 308 bcl2/IgHpositive patients who received B-R and Rituximab maintenance. Results. With a median follow-up of 10 years in the 107 bcl2/IgHpositive patients from the StiL-NHL1-trial, high PB bcl-2/IgH levels (bcl-2/IgH to reference gene (tPA) ratio >1) before treatment as compared to low (ratio <1) levels remained a major independent prognostic factor for PFS (median 22 vs 71 months, HR 2.27, 95% CI 1.37-3.75; p=0.001). We also confirm that patients who were still bcl-2/IgHpositive after six cycles of immuno-chemotherapy had significantly inferior PFS (13 vs 79 months, Hazard Ratio (HR) 2.97, 95% CI 1.53-5.78; p=0.001) and overall survival (OS, 128 months vs not reached , HR 3.90, 95% CI 1.39-11.00; p=0.010). In contrast, among the 308 bcl-2/IgHpositive patients of the StiL-NHL7-trial, who all received B-R and Rituximab maintenance, PB bcl-2/IgH levels (ratio >1 vs <1) before therapy were no longer prognostic for PFS (99 months vs not reached, HR 1.06, 95% CI 0.66 - 1.69; p=0.814) or OS. On the other hand, being bcl-2/IgHpositive after 6x B-R remained a poor prognostic factor for PFS (43 months vs not reached, HR 2.44, 95% CI 1.18-5.04; p=0.016 ) and OS (72 months vs not reached, HR 4.03, 95% CI 1.82-8.96; p=0.001) despite Rituximab maintenance. When comparing StiL-NHL1 and StiL-NHL7 patients with respect to bcl-2/IgH levels and the effect of Rituximab maintenance, we found that Rituximab maintenance led to a significantly better PFS. In patients with low (ratio <1) bcl-2/IgH levels before therapy the hazard ratio of 1.7 was modest (71 months vs not reached, HR 1.70, 95% CI 1.16-2.50; p=0.006) in comparison to 3.46 as observed in patients with high (ratio >1) bcl-2/IgH levels (22 vs 99 months, HR 3.46, 95% CI 1.93-6.20; p<0.000). These findings suggest that patients with high bcl-2/IgH levels before therapy have a greater benefit from Rituximab maintenance therapy. There was no difference with regard to OS between StiL-NHL1 and StiL-NHL7 patients who were still bcl-2/IgHpositive after 6 cycles of immuno-chemotherapy implying that these patients may not benefit from Rituximab maintenance. Conclusion. High circulating bcl-2/IgH levels in the PB before first line therapy identify a subgroup of patients with advanced FL who have significantly shorter PFS after standard immuno-chemotherapy. These patients greatly benefit from the addition of Rituximab maintenance, because pre-treatment bcl-2/IgH levels lose their predictive value with Rituximab maintenance therapy. On the other hand, patients who remain bcl-2/IgHpositive after standard immuno-chemotherapy have short PFS and OS despite treatment with Rituximab maintenance and therefore are candidates for experimental treatment approaches. Disclosures Kobbe: Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Zohren:Pfizer Inc.: Employment. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Greil:Sandoz: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Schroeder:Celgene: Consultancy, Honoraria, Research Funding. Rummel:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Astellas: Honoraria; Eisai: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Symbio: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 509-509 ◽  
Author(s):  
Gilles Andre Salles ◽  
John Francis Seymour ◽  
Pierre Feugier ◽  
Fritz Offner ◽  
Armando Lopez-Guillermo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Second Line ◽  
Second Line Therapy ◽  
Advisory Committees ◽  
Free Survival ◽  
Rituximab Maintenance ◽  
Line Therapy

Abstract The intergroup PRIMA Phase III study was designed to investigate the potential benefit of 2-years of rituximab maintenance in patients with follicular lymphoma (FL) responding to one of three non-randomised first line immunochemotherapy treatments. The results of the final analysis with 36 months follow-up (Salles et al., Lancet 2011) demonstrated a significant reduction of the risk of progression or death with a hazard ratio (HR) of 0.55 in favour of patients randomized to rituximab maintenance. We present here the updated results with 3 additional years of follow-up. From December 2004 until April 2007, 1217 patients were enrolled from 223 centres and complete data were available for 1193 patients who had the following pre-induction treatment characteristics: median age 56 years [range 22–87]; 52% male; 90% Ann Arbor stage III-IV; 33% B symptoms; 56% bone marrow involvement; 4% ECOG performance status >1; 34% elevated LDH; 32% β2-microglobulin >3mg/L; FLIPI score 0-1 (21%), FLIPI 2 (36%), FLIPI 3-5 (43%). Most patients (75%) received R-CHOP induction (22% R-CVP, 3% R-FCM). Patients responding to induction therapy were stratified based on their immunochemotherapy regimen and response [CR/CRu versus PR] and randomized to observation or rituximab maintenance, 1 infusion (375 mg/m2) every 8 weeks for 2 years. A total of 1018 randomised patients were analyzed according to the ITT principle (513 observation / 505 rituximab maintenance). All initial pre-treatment characteristics were well balanced between arms and the response status at time of randomization was CR=39%; CRu=32% and PR=28% (others 1%). With a median follow-up of 73 months from randomization, 6-year progression free survival estimate was 42.7% (95% CI 38 – 46.9%) in the observation arm (284 events, median=48 months) and 59.2% (95% CI 54.7 – 63.7%) in the rituximab maintenance arm (194 events, median not reached), respectively (stratified Log-Rank, P<. 0001; HR = 0.58 ; 95% CI 0.48 - 0.69). In pre-planned analyses of patients subgroups categorized by age, sex, FLIPI score category, induction chemotherapy and response to induction, the effect of rituximab maintenance was examined and found to be consistent among these different subgroups. In a Cox regression multivariate analysis, rituximab maintenance (HR=0.57; P<.0001) as well as older age (HR=0.79; P=.015), female sex (HR=0.72; P=.0003) and low or intermediate FLIPI groups (HR=0.67; P<.0001) were all significant variables associated with superior progression free survival. A significant reduction in the risk of starting a new anti-lymphoma treatment (HR=0.63, 95% CI 0.52 - 0.76) or starting a new chemotherapy (HR=0.70, 95% CI 0.57 - 0.86) were also observed for rituximab maintenance. The rate of histological transformation did not appear to differ between the 2 treatment arms: in the observation arm, transformation was documented in 24 patients (114 cases with morphological documentation out of 278 progressions) versus 16 patients in the rituximab maintenance arm (80 out of 186) respectively. Overall response rate to second-line therapy was reported by investigators to be 180/227 (79%) in patients from the observation arm (CR/CRu=61%; PR=19%) versus 109/144 (76%) in patients from the rituximab maintenance arm (CR/CRu =51%; PR=22%) (P=NS). At the time of the data cut-off, overall survival (OS) remains favourable in both study arms: 58 patients (11.3%) have died in the observation arm (6-years OS estimate 88.7%) compared to 59 patients (11.7%) in the rituximab maintenance arm (6-year OS estimate 87,4%). Main causes documented for death in the observation and rituximab maintenance arm respectively were lymphoma (28 ; 28), other malignancy (19 ; 5) and infections (4 ; 7). No new significant safety data were captured with this additional follow-up period. In conclusion, with 3 additional years of follow-up, these data demonstrate a sustained and persistent benefit of 2 years of rituximab maintenance therapy after immunochemotherapy, resulting in improved progression free survival. No additional or unexpected long term toxicities were observed and second line therapy efficacy results did not significantly differ between the 2 study arms. Overall survival appears very favourable for these randomized patients. Disclosures: Salles: Roche: Consultancy, Honoraria, Research Funding. Seymour:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau, Travel support Other; Genetech: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Feugier:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Offner:Lilly: Membership on an entity’s Board of Directors or advisory committees. Lopez-Guillermo:Roche: Membership on an entity’s Board of Directors or advisory committees. Belada:Roche: Consultancy. Catalano:Roche: Membership on an entity’s Board of Directors or advisory committees. Haioun:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Simpson:Janssen Research & Development: Honoraria. Leppa:Roche: Consultancy, Honoraria, Research Funding, Travel support Other. Soubeyran:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Hagenbeek:Takeda/Millennium: Consultancy. Casasnovas:ROCHE: Consultancy, Honoraria, Research Funding. Coiffier:Millennium Pharmaceuticals : Consultancy. Tilly:Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding.

Is Stem Cell Transplantation for Transformed Follicular Lymphoma Required in the Rituximab Era?: The Royal Marsden Experience 2003-2013

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1719-1719 ◽  
Author(s):  
Mary Gleeson ◽  
Eliza A Hawkes ◽  
Clare Peckitt ◽  
Andrew Wotherspoon ◽  
Ayoma Attygalle ◽  
...  
Keyword(s):  
Stem Cell ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Poor Prognosis ◽  
Induction Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Transformed Follicular Lymphoma

Abstract Background: High-grade transformation (HT) of follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL) occurs at a rate of 3% per year and has been associated with a very poor prognosis, with a median overall survival (OS) of 1 year reported by Montoto et al in the pre-rituximab era. Treatment often includes upfront autologous or allogeneic stem cell transplantation (SCT) due to the poor prognosis, but rarely maintenance rituximab despite evidence in FL. These patients are excluded from the majority of clinical trials and hence the role of SCT in the rituximab era and maintenance rituximab are not well evaluated. Methods: We performed a retrospective analysis of all patients aged ≥18 years with histologically proven transformed follicular lymphoma (TFL) diagnosed and treated (≥1 cycle of chemotherapy) at our institute in the 10-year period 2003-2013. Histopathology databases were searched to identify patients diagnosed with DLBCL and FL (grade 1-3a). Clinical data were collated from electronic patient records. Patients with grade 3b FL were excluded. A minimum interval of 6 months between the diagnosis of FL and development of HT was required for inclusion to outrule a discordant lymphoma. All histological specimens were reviewed by an expert haematopathologist. The study was approved by our institutional review board. Results: Between March 2003 and May 2013, a total of 56 patients were diagnosed with TFL (to DLBCL) and received first-line induction treatment +/- autologous/allogeneic SCT. The median follow-up was 5.6 years. The median time from diagnosis of FL to HT was 5.3 (range 0.6-29.3) years with a median age at diagnosis of TFL of 61 years (range 34-85). 59% (n=33) had received prior chemotherapy for FL. At diagnosis of TFL 89% (n=50/56) of patients received chemotherapy +/- radiotherapy (IFRT) without subsequent SCT. Upfront autologous or allogeneic SCT post induction was performed for 4 (7%) and 2 (3.5%) patients respectively. 91% of patients (n=51/56) received rituximab containing (R) chemotherapy and 68% (n=38/56) were treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). 16.1% (9/56) received IFRT post induction. 14.3% (8/56) patients received R-maintenance following first-line treatment for TFL. For patients treated with R-chemotherapy alone (n=46) the 2 and 5-year OS and PFS (for TFL) were 84.5% and 70.9% and 58.7% and 49.3% respectively. In patients aged >65 years (n=17) 5-year OS was similarly 71.6%. Patients treated with R-CHOP had 2 and 5-year OS of 89% and 76% and PFS (TFL) rates of 59.5% and 51.7% respectively. Patients who received R-chemotherapy induction followed by R-maintenance (n=8) had both 2-year OS and PFS (TFL) of 100%. 82% of all patients (46/56) underwent FDG-PET on completion of induction treatment +/- SCT. A negative PET (n=30) was associated with 2 and 5-year OS rates of 90% and 74.1% and PFS (TFL) of 60% and 49.2%. Conclusion: The outcome for TFL has significantly improved with the advent of rituximab. In our analysis the 2 and 5-year OS rates of 84.5% and 70.9% with R-chemotherapy alone are superior to reported OS for patients undergoing upfront autologous/allogeneic SCT, while PFS rates are comparable to those quoted for upfront autologous SCT. Although the numbers are small (n=8) and follow-up shorter, the outcomes for patients treated with R-chemotherapy followed by R-maintenance (2-yr OS and PFS of 100% and 100%) are particularly encouraging while offering minimal additional toxicity. In conclusion our data indicate that upfront SCT may no longer be required for TFL in the rituximab era. Rituximab maintenance should be considered in the management of these patients. Disclosures Hawkes: Roche: Travel grant Other. Peckitt:Sanofi: Membership on an entity's Board of Directors or advisory committees. Dearden:Roche: Membership on an entity's Board of Directors or advisory committees. Cunningham:Astra Zeneca: Research Funding; Novartis: Research Funding; Merck Serono: Research Funding; Sanofi: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Roche: Research Funding.

scholarly journals Hypogammaglobulinaemia and Infectious Toxicity Related with the Use of Maintenance Strategies with Rituximab in B Lymphomas

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5100-5100
Author(s):  
Lucia García Mañó ◽  
Leyre Bento ◽  
Jordi Martinez-Serra ◽  
Antonio Salar ◽  
Jose Maria Sanchez Raga ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Intravenous Immunoglobulins ◽  
Induction Treatment ◽  
Low Grade ◽  
First Line ◽  
Rituximab Maintenance ◽  
Diagnostic Characteristics ◽  
Grade 3

Abstract Introduction The use of maintenance treatment with rituximab in B lymphomas has improved the results in terms of progression free survival in follicular lymphoma (PRIMA trial). This improvement has been seen in other types of indolent lymphomas including chronic lymphatic leukemia or specific cases of aggressive lymphomas with or without low grade associated component. However, the rituximab maintenance, even though is a well-tolerated strategy, is not free of toxicity. Our objective is reporting the rituximab toxicity associated to the maintenance with rituximab in a series of B-cell lymphomas treated with immunochemotherapy in first line in Hospital Son Espases (HUSE) and Hospital del Mar (HM). Methods and materials To avoid selection bias, we retrospectively identified from the Pharmacy registries of HUSE and HM those patients who had been treated with rituximab maintenance between 2002 and 2014 in first line of induction treatment with conventional immunotherapy or immunochemotherapy. Second lines or more intensive treatments were excluded. We obtained information about diagnosis, prognostic and outcome in all the patients, including levels of immunoglobulins as well as the seriousness of infections or other related side effects. Polymorphisms FcgRIIIa were analyzed using RT-PCR and sequencing. Results With the previous criteria 82 patients were included. Table 1 shows the diagnostic characteristics and the treatment of the patients. The median of age was 65 years; most cases were follicular lymphoma treated with R-CHOP or R-B and receiving maintenance with rituximab every 2 months (66%). Table 2 describes toxicity related to rituximab maintenance: hypogammaglobulinaemia IgG, IgA or both in the 27%, 21% and 11% of the cases respectively. When we analyzed the role of polymorphisms of FcgRIIIa we found that the patients with homozigous polymorphism VV were exempt of hypogammaglobulinaemia IgG or IgA. Moreover the polymorphism FF was associated meaningfully with a greater incidence of hypogammaglobulinaemia IgA (p=0.022). Only the 8% of the cases of hypogammaglobulinaemia needed treatment with intravenous immunoglobulins and only 6% had grade 3-4 infections. 21% of the patients treated with rituximab maintenance developed grade 3-4 neutropenia, generally reversible with the administration of G-CSF and without serious infections. Increase of mortality was not observed related with the presence of hypogamaglobulinaemia IgG (p=0.34), IgA (p=0.59) or both (p=0.59) or grade 3-4 neutropenia secondary to rituximab (p=0.38). Conclusions Between one-quarter or one-fifth of the patients who received maintenance therapy with rituximab during 2 years associate hypogammaglobulinaemia IgG, IgA and/or neutropenia as toxicity. Nevertheless these complications are generally mild, without related severe infections or increase of mortality. Table 1. Clinical characteristics of the series Median of age 65 (27-85) Sex 41 (50%) / 41 (50%) ECOG PS >1 7 (9%) Type of lymphoma:- Folicular lymphoma- DLBCL- CLL/SLL- Marginal lymphoma- Mantel cell lymphoma- Other 46 (56%)13 (16%)8 (10%)6 (7%)5 (6%)4 (5%) Stage III-IV 71 (87%) B symptoms 29 (35%) Induction treatment:- R-CHOP/R-CVP- R-B- Rituximab alone- Schema with Fludarabine-R- Intensive schemas- Others 50 (61%)13 (16%)9 (11%)4 (5%)3 (4%)3 (4%) Type of maintenance (2 years):- Every 2 months- Every 3 months- Every 6 months (4 weeks) 54 (66%)15 (18%)1 3 (16%) Table 2. Rituximab maintenance attributable toxicity Polimorphism FcgRIIIA Type of toxicity Total FF FV VV p Hypogammaglobulinaemia- IgG- IgA- Double IgG + IgA 22 (27%)17 (21%)9 (11%) 7 (23%)11 (37%)3 (10%) 15 (31%)6 (12%)6 (12%) 0 (0%)0 (0%)0 (0%) 0.340.0220.74 Treatment with immunoglobulins iv 7 (8%) 3 (10%) 4 (8%) 0 (0%) 0.79 Grade 3-4 infections: 5 (6%) 2 (7%) 3 (6%) 0 (0%) 0.87 Grade 3-4 neutropenia: 17 (21%) 8 (27%) 8 (17%) 1 (25%) 0.59 Disclosures No relevant conflicts of interest to declare.

scholarly journals Lenalidomide/rituximab induces high molecular response in untreated follicular lymphoma: LYSA ancillary RELEVANCE study

2020 ◽  
Vol 4 (14) ◽  
pp. 3217-3223 ◽  
Author(s):  
Marie-Helene Delfau-Larue ◽  
Marie-Laure Boulland ◽  
Asma Beldi-Ferchiou ◽  
Pierre Feugier ◽  
Hervé Maisonneuve ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Clinical Results ◽  
Induction Treatment ◽  
Molecular Response ◽  
First Line ◽  
Free Survival ◽  
Study Association ◽  
Digital Polymerase Chain Reaction

Abstract Complete molecular response (CMR) after first-line immunochemotherapy reflects treatment efficacy and may predict prognosis in patients with follicular lymphoma (FL). RELEVANCE is the first phase 3 trial comparing the chemotherapy-free regimen lenalidomide/rituximab (R2) vs rituximab/chemotherapy (R-Chemo) in previously untreated FL patients (ClinicalTrials.gov identifier: NCT01650701). The objective of the minimal residual disease (MRD) analysis was to determine the ability of a chemotherapy-free regimen to induce CMR. Of 440 French patients participating in the Lymphoma Study Association (LYSA) RELEVANCE MRD study, all 222 patients with a BIOMED-2–detectable BCL2-JH translocation at diagnosis were analyzed. MRD was quantified by droplet digital polymerase chain reaction with a sensitivity ≤10−4. At week 24 (end of induction treatment), 98% and 78% of patients achieved CMR in peripheral blood (PB) and bone marrow (BM), respectively. Achievement of CMR (in PB and/or BM) had a significant impact on progression-free survival (PFS), with 3-year PFS of 84% and 55% for patients with CMR and detectable MRD, respectively (P = .015). CMR at week 24 was reached more frequently in the R2 arm (105/117; 90%) than in the R-Chemo arm (70/90; 77%) (P = .022). The poor prognostic value in terms of PFS for the persistence of molecular disease was observed irrespective of treatment arm (interaction test, P = .31). In agreement with the clinical results of the RELEVANCE trial, our results show that R2 immunomodulatory treatment in first-line FL can achieve high rates of CMR.

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