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

Abstract Introduction Patients 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 methods We 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. Results 1037 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). Conclusions Rituximab 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. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v126.23.2716.2716 ◽

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.

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

Blood ◽

10.1182/blood.v126.23.5100.5100 ◽

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.

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A Phase IIIb Study of Rituximab Maintenance Therapy in Patients with Follicular Non-Hodgkin’s Lymphoma Who Have Responded to Induction Therapy - MAXIMA-Protocol.

Blood ◽

10.1182/blood.v108.11.4706.4706 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4706-4706 ◽

Cited By ~ 1

Author(s):

Manfred Hensel ◽

Mathias Witzens-Harig ◽

Peter Dreger ◽

Anthony D. Ho ◽

Daniel Thurley ◽

...

Keyword(s):

Overall Survival ◽

Complete Remission ◽

Maintenance Therapy ◽

Follicular Lymphoma ◽

Induction Therapy ◽

Randomized Trials ◽

Phase Iii ◽

First Line ◽

Free Survival ◽

Rituximab Maintenance

Abstract Five randomized trials (four Phase III and one phase II) have confirmed that rituximab maintenance therapy provides clinical meaningful improvements in terms of Progression Free Survival, Event Free Survival and response duration for patients. Two studies have also found an overall survival advantage for rituximab maintenance therapy (Hoechster et al. 2005, van Oers et al. 2005) and a third study could demonstrate a strong trend towards overall survival advantage (Dreyling et al. 2006). A Cochrane meta-analysis of several randomised Phase III trials (Schulz et al. 2005) demonstrated that rituximab plus-chemotherapy for first-line treatment of Follicular Lymphoma is superior to chemotherapy alone and significantly prolongs overall survival. To further broaden the available basis for maintenance treatment in the first-line and relapsed setting, the MAXIMA (MAintenance rituXImab in Follicular LymphoMA) trial has been started in August 2006 and will last 5 years. Patients with first line or relapsed/refractory advanced Follicular Lymphoma are included in this trial. In total 500 patients are planned for this international trial running in 23 countries. Patients who achieve a Complete Remission, Complete Remission unconfirmed or Partial Remission after rituximab containing induction therapy (rituximab with or without chemotherapy) are eligible to enter the study to receive rituximab maintenance therapy administered at the standard dose of 375 mg/m2 every 2 months for 2 years. This regimen is also investigated in the ongoing PRIMA study, and also in an ongoing SAKK study which investigates the benefit of rituximab maintenance therapy for up to five years. The previous five randomized trials did not detect significant safety issues for rituximab maintenance therapy. The main objective of the MAXIMA trial is to confirm this safety data in a wider patient population. Secondary objectives of the study include standard time dependent parameters (PFS, EF, OS). In addition, the effect of rituximab maintenance therapy on improving response quality (PR =>CR) after induction therapy will be evaluated.

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Intensive Induction, Autologous Stem Cell Transplantation and Rituximab Maintenance Has Changed Event Free Survival and Overall Survival in Mantle Cell Lymphoma Patients. Using Gemcitabine and Oxaliplatin in First Line Therapy

Blood ◽

10.1182/blood.v120.21.2034.2034 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2034-2034 ◽

Cited By ~ 1

Author(s):

Vladimir I. Vorobyev ◽

Yuri Yu. Lorie ◽

Evgenii' E. Zvonkov ◽

Eduard G. Gemdjian ◽

Aminat U. Magomedova ◽

...

Keyword(s):

Overall Survival ◽

Progression Free Survival ◽

Hematological Toxicity ◽

High Dose ◽

Event Free Survival ◽

First Line ◽

Free Survival ◽

Rituximab Maintenance ◽

First Line Therapy ◽

Mantle Cell

Abstract Abstract 2034 Background: Mantle cell lymphoma (MCL) is aggressive B-cell neoplasm diagnosed predominantly among elderly men. (R)CHOP-like schemes are effective in remission induction, but the progression-free survival is disappointingly short (median 16–20 months) with median overall survival of 3–4 years. Upfront use of high-dose cytarabine (12 g/m2), autoSCT and rituximab at all stages of therapy is the most effective treatment but possible only with patients younger 65 years. Decrease in AraC doses to 4 g/m2 per cycle significantly reduce progression free survival. Prominent efficacy of gemcitabine-oxaliplatin combinations and irinotecan in relapsed and refractory MCL patients allowed including these drugs in first-line treatment in cases when the scheme R-HD-Met-AraC (Romanguera J. 2005) is impossible. Aim: Toxicity and efficacy assessment of schemes R-DA-EPOCH/R-GIDIOX and R-DA-EPOCH/ R-HD-Met-AraC in primary MCL patients eligible for autoSCT. Patients and Methods: Since May 2008 35 untreated MCL patients (median 55 years (29–63), males/females 68,5%/31,5%, MIPIb: 34% low, 26% intermediate, 40% high risk) were enrolled. After first R-EPOCH course (Wilson W. 2003) patients were stratified according to toxicity they had received either R-DA-EPOCH/R-HD-Met-AraC or R-DA-EPOCH/R-GIDIOX. In the absence of hematological toxicity grade 4 for more than 3 days, severe infection complications and signs of renal failure patients underwent treatment under the scheme R-HD-Met-AraC (rituximab 375 mg/m2 day 0, methotrexate 1000 mg/m2 24 hours CI day 1, cytarabine 3000 mg/m2 q 12 hrs days 2–3). If there was one of these complications patients underwent treatment under the scheme R-GIDIOX (rituximab 375 mg/m2 day 0, gemcitabine 800 mg/m2 days 1 and 4, oxaliplatin 120 mg/m2 day 2, irinotecan 100 mg/m2 day 3, dexamethasone 10 mg/m2 IV days 1–5, ifosfamide 1000 mg/m2 days 1–5). Further these courses are rotated: either R-DA-EPOCH/R-HD-Met-AraC or R-DA-EPOCH/R-GIDIOX. Depending on the terms of response, patients received 6–8 courses (3–4 cycles) of chemotherapy and autoSCT (BEAM-R) with in vivo purging by rituximab before harvest and reinfusion. Patients with residual tumor after autoSCT were consolidated with local radiotherapy. Rituximab maintenance was performed every three months for 3 years. The protocol was approved by the local ethics committee. Patients were analyzed in an intent-to-treat basis. Overall survival (OS) and event-free survival (EFS) rates were estimated (± standard error) by using the Kaplan-Meier method. Efficacy of the therapy was assessed by Cheson's response criteria (2008). Toxicity assessment was performed 93 R-DA-EPOCH, 60 R-HD-Met-AraC and 46 R-GIDIOX courses. Results: A median follow-up is 23 months (range 3–54). Toward August 2012 26 patients underwent autoSCT: 14 from R-HD-Met-AraC arm and 12 from R-GIDIOX arm. 1 induction death after first HD-Met-AraC course (acute renal failure and septic shock). Maintenance therapy with rituximab was completed in three patients. All patients achieved CR in R-HD-Met-AraC arm. In R-GIDIOX arm OR was 100%: 11 CR and 1 PR (without progression for 26 months after autoSCT). Main non-hematological toxicity of R-GIDIOX was hepatic, with elevated aminotransferases grades 1–2 and 3–4 in 59,5% and 7,1% of courses respectively, without clinical signs. The sources of stem cells were PB in 23 patients and BM in 3 cases of harvest failure after R-GIDIOX. Hematological toxicity of R-GIDIOX course: leukopenia grade 4 was in 71,4% (medium duration was 5,4 days, range 1–13), thrombocytopenia grade 4 was in 42,9%. The estimated 4-years OS rates for the R-GIDIOX group and the R-HD-Met-AraC group were 100% and 68% ± 17%. The estimated 4-years EFS rates for the R-GIDIOX group and the R-HD-Met-AraC group were 90% ± 10% and 69% ± 14%. Conclusions: Our main goal was to incorporate intensive induction, autoSCT and rituximab maintenance in first line therapy MCL patients. However, HD-Met-AraC scheme is highly toxic and its use is possible only in 2/3 of patients younger 65 years. R-GIDIOX scheme is less toxic than R-HD-Met-AraC and equally effective in response induction and mobilizing, so it could be recommended for those in whom high-dose AraC and methotrexate can potentially cause severe adverse consequences. Such an integrated approach might lead to a shift of paradigm of MCL from an incurable to a curable lymphoma. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v122.21.4387.4387 ◽

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.

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Low CCL19 Expression is Associated With Adverse Clinical Outcomes For Follicular Lymphoma Patients Treated With Chemoimmunotherapy

10.21203/rs.3.rs-793392/v1 ◽

2021 ◽

Author(s):

Yu Zhou ◽

Shasha Wang ◽

Yunxia Tao ◽

Haizhu Chen ◽

Yan Qin ◽

...

Keyword(s):

Follicular Lymphoma ◽

Plasma Cells ◽

Cox Regression ◽

Progression Free Survival ◽

Gene Set Enrichment Analysis ◽

Sequencing Data ◽

First Line ◽

Hub Genes ◽

Cox Regression Analysis ◽

Subset Analysis

Abstract Background: This study aimed to recognize the hub genes associated with prognosis in follicular lymphoma (FL) treated with first-line rituximab combined with chemotherapy.Method: RNA sequencing data of dataset GSE65135 (n=24) were included in differentially expressed genes (DEGs) analysis. Weighted gene co-expression network analysis (WGCNA) was applied for exploring the coexpression network and identifying hub genes. Validation of hub genes expression and prognosis were applied in dataset GSE119214 (n=137) and independent patient cohort from Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (n=32), respectively, by analyzing RNAseq expression data and serum protein concentration quantified by ELISA. The Gene Set Enrichment Analysis (GSEA), gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments analysis were performed. CIBERSORT was applied for tumor-infiltrating immune cells (TIICs) subset analysis. Results: A total of 3260 DEGs were obtained, with 1861 genes upregulated and 1399 genes downregulated. Using WGCNA, eight hub genes, PLA2G2D, MMP9, PTGDS, CCL19, NFIB, YAP1, RGL1, and TIMP3 were identified. Kaplan-Meier analysis and multivariate COX regression analysis indicated that CCL19 independently associated with overall survival (OS) for FL patients treated with rituximab and chemotherapy (HR = 0.47, 95%CI [0.25-0.86], p = 0.014). Higher serum CCL19 concentration was associated with longer progression-free survival (PFS, p=0.014) and OS (p=0.039). TIICs subset analysis showed that CCL19 expression had a positive correlation with monocytes and macrophages M1, and a negative correlation with naïve B cells and plasma cells. Conclusion: CCL19 expression was associated with survival outcomes and might be a potential prognostic biomarker for FL treated with first-line chemoimmunotherapy.

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Low CCL19 expression is associated with adverse clinical outcomes for follicular lymphoma patients treated with chemoimmunotherapy

Journal of Translational Medicine ◽

10.1186/s12967-021-03078-9 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Yu Zhou ◽

Shasha Wang ◽

Yunxia Tao ◽

Haizhu Chen ◽

Yan Qin ◽

...

Keyword(s):

Follicular Lymphoma ◽

Plasma Cells ◽

Cox Regression ◽

Progression Free Survival ◽

Gene Set Enrichment Analysis ◽

Sequencing Data ◽

First Line ◽

Hub Genes ◽

Cox Regression Analysis ◽

Subset Analysis

Abstract Background This study aimed to recognize the hub genes associated with prognosis in follicular lymphoma (FL) treated with first-line rituximab combined with chemotherapy. Method RNA sequencing data of dataset GSE65135 (n = 24) were included in differentially expressed genes (DEGs) analysis. Weighted gene co-expression network analysis (WGCNA) was applied for exploring the coexpression network and identifying hub genes. Validation of hub genes expression and prognosis were applied in dataset GSE119214 (n = 137) and independent patient cohort from Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (n = 32), respectively, by analyzing RNAseq expression data and serum protein concentration quantified by ELISA. The Gene Set Enrichment Analysis (GSEA), gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments analysis were performed. CIBERSORT was applied for tumor-infiltrating immune cells (TIICs) subset analysis. Results A total of 3260 DEGs were obtained, with 1861 genes upregulated and 1399 genes downregulated. Using WGCNA, eight hub genes, PLA2G2D, MMP9, PTGDS, CCL19, NFIB, YAP1, RGL1, and TIMP3 were identified. Kaplan–Meier analysis and multivariate COX regression analysis indicated that CCL19 independently associated with overall survival (OS) for FL patients treated with rituximab and chemotherapy (HR = 0.47, 95% CI [0.25–0.86], p = 0.014). Higher serum CCL19 concentration was associated with longer progression-free survival (PFS, p = 0.014) and OS (p = 0.039). TIICs subset analysis showed that CCL19 expression had a positive correlation with monocytes and macrophages M1, and a negative correlation with naïve B cells and plasma cells. Conclusion CCL19 expression was associated with survival outcomes and might be a potential prognostic biomarker for FL treated with first-line chemoimmunotherapy.

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Rituximab maintenance after R-CHOP in the first-line treatment of follicular lymphoma: A GOTEL phase II trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e19502 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e19502-e19502

Author(s):

A. Rueda ◽

M. Provencio ◽

M. Abrio ◽

J. Gómez-Codina ◽

M. Llanos ◽

...

Keyword(s):

Overall Survival ◽

Follicular Lymphoma ◽

Induction Therapy ◽

Maintenance Phase ◽

Severe Toxicity ◽

Advanced Stage ◽

Line Treatment ◽

First Line ◽

Rituximab Maintenance ◽

First Line Treatment

e19502 Background: Rituximab maintenance have demonstrated improvements in progression-free and overall survival in relapsed patients with follicular lymphoma (FL). Ongoing trials are evaluating the benefit of rituximab maintenance following treatment of therapy-naive patients (pts) treated with rituximab-containing chemoinmunotherapy induction regimens. Methods: The current study evaluated the activity and toxicity of rituximab maintenance after chemoinmunotherapy in the first line treatment of advanced-stage FL. Pts with advanced stage FL were eligible. The induction treatment consisted in 8 courses of chemoinmunotherapy with R-CHOP (rituximab 375 mg/m2; cyclophosphamide 750 mg/m2; doxorubicin 50 mg/m2 and vincristine 2 mg). Pts entering a complete (CR) or partial remission (PR) received maintenance with 6 doses of rituximab (375 mg/m2/d) to be given every two months after the end of induction therapy. Results: From December 2004 to November 2006, 52 pts were included. Median age was 52 years (range, 36–85) and 26 pts were women. At baseline 32 (62%) pts had stage IV and 20 (38%) stage III. According to the Follicular Lymphoma International Prognostic Index (FLIPI), 8 pts (15%) had low risk disease, 24 pts (46%) intermediate risk, and 20 pts (39%) high risk disease. Six (12%) pts did not receive maintenance (3 pts progressed during induction, 2 pts refused maintenance and 1 pt had severe toxicity to induction). Of the 46 pts included in the maintenance phase, 32 (69%) were in CR/CRu and 14 pts (31%) in PR after induction therapy. Rituximab was well tolerated in the maintenance phase. Only 5 pts didn´t receive the 6 scheduled courses (toxicity: 1; progressive disease: 2; cardiovascular events: 2). Grade 3–4 toxicity occurred as follow: neutropenia in 4 pts (9%), and fever in 1 pt (2%). No severe infections were seen. After maintenance, 40 (87%) pts were in CR/CRu, 4 pts (9%) in PR and 2 (4%) progressed. With a median follow-up of 27 months, progression-free and overall survival at 30 months were 82% and 92%, respectively. Conclusions: Rituximab maintenance after first-line R-CHOP is safe and increase the complete remission rate obtained in the induction phase. No significant financial relationships to disclose.

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Combined Immuno-Chemotherapy Followed by Rituximab Maintenance Is an Effective Salvage Treatment after Prior Rituximab Containing Therapy: Results of a GLSG-Subgroup Analysis in Patients with Relapsed Indolent Lymphoma.

Blood ◽

10.1182/blood.v108.11.2769.2769 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2769-2769 ◽

Cited By ~ 5

Author(s):

Martin H. Dreyling ◽

Roswitha Forstpointner ◽

Hans-Peter Boeck ◽

Roland Repp ◽

Hannes Wandt ◽

...

Keyword(s):

Overall Survival ◽

Subgroup Analysis ◽

Progression Free Survival ◽

Observation Time ◽

Long Term Results ◽

Control Group ◽

Indolent Lymphoma ◽

First Line ◽

Effective Treatment Option ◽

Rituximab Maintenance

Abstract Background: Combined immuno-chemotherapy incorporating Rituximab with various chemotherapy regimens has resulted in increased response rates and prolonged progression-free and even overall survival in numerous trials. However, a constant relapse pattern has been observed even after such an optimized first line treatment. Methods: In a subgroup analysis of the GLSG trial for relapsed indolent lymphoma (R-FCM followed by Rituximab maintenance), response and long term results of patients with previous Rituximab containing treatment were compared with the Rituximab naive control group. Induction comprised of 4 courses of chemotherapy with Fludarabine, Cyclophosphamide and Mitoxantrone (FCM) plus Rituximab. Patients responding with a complete (CR) or partial remission (PR) were randomized for observation only versus Rituximab maintenance (4 applications at month 3 and 9). Results: 18 of 268 patients (arm A) with relapsed lymphoma had already previously received a R-containing regimen, the remainder 250 patients (arm B) were Rituximab naive. Overall response (arm A: 83 % vs. group B: 77%) and CR rate (arm A: 39% vs. arm B: 23%) were comparable in both subsets of study patients. Accordingly, progression-free survival after R-FCM was comparable in both subgroups of patients (median PFS in arm A: 15 months, arm B: 27 months) and overall survival as well. Especially, no disadvantage in the Rituximab pretreated patient group was detectable. 9 of the Rituximab pretreated patients responding to R-FCM induction therapy were randomized to maintenance treatment. After a median observation time of 20 months, 3 patients had relapsed and 6 patients remained in remission (3 of them for >20 months) resulting in a similar PFS after rituximab maintenance as in patients who were Rituximab naive. Conclusion: This subgroup analysis strongly suggests that a Rituximab containing salvage therapy induction as well as maintenance is a highly effective treatment option even in patients who received Rituximab in first line therapy.

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Effect of subsequent chemotherapy on overall survival in first-line chemotherapy with targeted agents for patients with metastatic colorectal cancer: Systematic review and meta-analysis of randomized control trials.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.782 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 782-782

Author(s):

Daisuke Sakai ◽

Toshihiro Kudo ◽

Aya Kato ◽

Toshinori Sueda ◽

Hidekazu Takahashi ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Clinical Trials ◽

Metastatic Colorectal Cancer ◽

Randomized Clinical Trials ◽

Progression Free Survival ◽

Cytotoxic Agents ◽

Phase Iii ◽

First Line ◽

Line Chemotherapy

782 Background: One of recent standard first line chemotherapies for metastatic colorectal cancer is doublet of cytotoxic agents, fluorouracil and oxaliplatin or irinotecan, in combination with target agent, bevacizumab, or anti-EGFR antibody as cetuximab or panitumumab for KRAS or RAS wild type (WT). In this decade, nevertheless progression free survival (PFS) of clinical trials was little improved, overall survival (OS) had been increased. Methods: We analyzed data from 14 recently published phase III randomized clinical trials in mCRC to correlate the percentage of patients receiving subsequent chemotherapy with the reported OS. Results: Median PFS and OS were 10.3 and 25.0 months, respectively. In all comer trials, median OS is significantly correlated with the percentage of patients who received subsequent chemotherapy after first line chemotherapy of their disease [regression coefficient (R2) = 0.85 p = 0.0018]. In trials with KRAS WT, a correlation between OS and the rate of subsequent therapy was modest [r2 = 0.605, p = 0.0637]. Median PFS and RR were not correlated with median OS. Conclusions: Our results support the strategy of making salvage chemotherapy available to all patients with advanced CRC to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, PFS might no longer be regarded as the appropriate surrogate end point of OS by which to assess the efficacy of a palliative first-line treatment in CRC.

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