scholarly journals Deep Phenotypic Analysis Reveals a Monocyte Subpopulation Predictive of Relapse/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2863-2863
Author(s):  
Edward Truelove ◽  
Frances Seymour ◽  
Janet Matthews ◽  
John G. Gribben
Keyword(s):  
Peripheral Blood ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Peripheral Blood Monocyte ◽  
Blood Monocyte ◽  
Phenotypic Analysis ◽  
Poor Risk ◽  
Large B Cell Lymphoma ◽  
Risk Patients ◽  
Good Risk

Abstract Background: Diffuse large B cell lymphoma (DLBCL) is the most frequent lymphoma subtype with up to two thirds of patients achieving cure following standard immuno-chemotherapy. However, approximately 10-15% will be primary refractory and a further 20-30% relapse. There is an urgent need for improved biomarkers to identify these poor risk patients at diagnosis who are destined to fail standard therapy so that novel approaches can be considered. The diagnostic peripheral blood monocyte count is known to be predictive of outcome in DLBCL, with higher counts identifying patients with worse outcome but mechanistic understanding is currently lacking. The aim of this study was to investigate the peripheral blood monocyte population driving this phenomenon and we present here a deep phenotypic analysis of the monocyte compartment at diagnosis in patients with extremes of outcome following immuno-chemotherapy. Methods: We identified 112 immuno-chemotherapy treated DLBCL patients with viably cryopreserved peripheral blood mononuclear cells (PBMCs) in our tissue bank. The diagnostic absolute monocyte (AMC) and lymphocyte counts (ALC) were examined as prognostic variables. For phenotypic analysis a subset of 20 patients, 10 with relapse/refractory disease within 12 months of therapy (Poor risk) and 10 with continued complete remission >24 months post therapy (Good risk), were selected. PBMCs from these patients were stained with a panel of 29 metal-tagged antibodies designed to identify immune populations and characterize the monocyte compartment and analyzed using cytometry by time-of-flight (CyTOF2TM). Samples were acquired in batches run with the same healthy donor control PBMCs to ensure consistency of staining. Normalized data were subjected to traditional Boolean gating in Cytobank (www.mrc.cytobank.org) to identify CD45+ live single cells and further analyzed using FlowSOM and CITRUS. Results: In the full 112 patient cohort, a higher diagnostic AMC (≥0.6 x 109/L) predicted worse outcome (5-year OS, 59% vs 74%, p=0.047*). The lymphocyte to monocyte ratio (LMR) was more discriminatory, with a low LMR (<2.6) predicting worse outcome (5-year OS, 49% vs 81%, p=0.0009*). CyTOF analysis of the CD45+ events from all 20 DLBCL patients were clustered in an unsupervised manner with FlowSOM and visualized according to the tSNE algorithm. This identified all expected immune populations with further subdivision into multiple clusters / sub-populations based on protein marker expression. Repeating the FlowSOM analysis by outcome revealed clusters with clear differences between the 2 groups, including striking changes to the monocyte compartment (Figure 1). CITRUS, an algorithm for automated biomarker discovery, was used to further assess the differences in the monocyte compartments between poor risk and good risk DLBCL patients. This identified a monocyte subset, representing approximately 10% of non-lymphoid CD45+ PBMCs, with increased abundance in poor risk patients with relapsed/refractory disease (p=0.0028*, Figure 2). This subset expressed markers including HLA-DR, CD11b, CD13, CD14, CD33, SIRPα (CD172a), CCR2 (CD192, monocyte chemo-attractant protein receptor), CD206 and PD-L1 (CD274). Conclusions: We confirmed the previous finding that the diagnostic AMC is predictive of outcome in our cohort of DLBCL patients and have identified differences in the peripheral blood monocyte compartment between patients with good and poor risk disease. Unsupervised analysis using FlowSOM identified monocyte clusters with greater abundance in poor risk patients. A second high-dimensional single cell data analysis algorithm, CITRUS validated this finding by revealing a stratifying monocyte sub-population that was enriched in poor risk patients. This phenotype of peripheral blood monocytes may account for the adverse nature of a higher AMC at diagnosis. We are now functionally characterizing these monocytes and evaluating their relationship to differences between the lymphoid populations of good and poor risk patients. Disclosures Seymour: Celgene: Research Funding. Gribben:Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria; Abbvie: Honoraria; Kite: Honoraria; Acerta Pharma: Honoraria, Research Funding; Wellcome Trust: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; NIH: Research Funding; Unum: Equity Ownership; Roche: Honoraria; Novartis: Honoraria; Cancer Research UK: Research Funding; Medical Research Council: Research Funding; TG Therapeutics: Honoraria.

The Absolute Monocyte and Lymphocyte Counts at Diagnosis Predict Survival and Identify High-Risk Patients In Diffuse Large-B-Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3088-3088
Author(s):  
Ryan A. Wilcox ◽  
Kay Ristow ◽  
Thomas M. Habermann ◽  
David James Inwards ◽  
Ivana Micallef ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Confidence Interval ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Hazard Ratio ◽  
Poor Risk ◽  
Large B Cell Lymphoma ◽  
Risk Patients ◽  
Good Risk

Abstract Abstract 3088 Background: Despite the use of modern immunochemotherapy (R-CHOP) regimens, almost 50% of patients with diffuse large-B-cell lymphoma (DLBCL) will relapse. Current prognostic models, most notably the International Prognostic Index, are comprised of patient and tumor characteristics and are unable to identify patients with less than a 50% chance of long-term survival. However, recent observations demonstrate that factors related to host adaptive immunity and the tumor microenvironment are powerful prognostic variables in non-Hodgkin lymphoma Methods: We retrospectively examined the absolute neutrophil count (ANC), monocyte count (AMC) and lymphocyte count (ALC), obtained from an automated complete blood count with differential, as prognostic variables in a cohort of 255 consecutive DLBCL patients that were uniformly treated with R-CHOP between 2000 and 2007 at a single institution. The primary study objective was to assess if ANC, AMC, and ALC at diagnosis were predictors of overall survival (OS) in DLBCL. Results: At diagnosis, the median ANC was 4720/uL (range 1190–17690), the median AMC was 610/uL (range 30–4040), and the median ALC was 1220/uL (range 140–5410). The median follow-up for these patients was 48 months. In the univariate analysis, each of these variables predicted OS as continuous variables. As dichotomized variables, an elevated ANC (≥5500/μL; hazard ratio 1.75, 95% confidence interval 1.14–2.60, p=0.01) and AMC (≥610/μL; hazard ratio 3.36, 95% confidence interval 2.10–5.59, p<0.0001) were each associated with inferior OS. In contrast, the presence of lymphopenia, defined as an ALC ≤1000/uL, was associated with inferior OS (hazard ratio 2.21, 95% confidence interval 1.43–3.39, p=0.0004). When components of the IPI were included on multivariate analysis only the AMC and ALC were independently significant prognostic factors for OS, with hazard ratios of 3.37 (95% confidence interval 2.05–5.74, p<0.0001) and 2.19 (95% confidence interval 1.38–3.44, p=0.0009), respectively. The dichotomized AMC and ALC generated the AMC/ALC prognostic index (PI) and stratified patients into 3 risk groups: very good (AMC <610/uL and ALC >1000/uL), good (AMC ≥610/uL or ALC ≤1000/uL), and poor-risk (AMC ≥610/uL and ALC ≤1000/uL) populations. For both the very good (n=79) and good-risk (n=134) groups median OS has not been reached with estimated 5-year overall survival of 88% and 69%, respectively. Median OS for poor-risk (n=42) patients was 1.7 years (95% confidence interval 1.1–2.7 years) with an estimated 5-year overall survival of 28% (p<0.0001). By comparison, the R-IPI was unable to identify a group of patients with a median survival less than 8 years. The estimated 5-year OS was 93%, 71% and 53% for very good, good and poor-risk patients, respectively. We sought to determine whether the AMC/ALC PI may provide additional prognostic information when combined with the R-IPI. To test this possibility, the 171 very good/good risk and 84 poor risk patients identified by the R-IPI were subsequently risk stratified using the AMC/ALC PI. Among R-IPI very good/good risk patients a subset of poor risk patients (n=21) with a median OS of 2.2 years (95% confidence interval 1.1–6.6 years) and 35% 5-year OS could be identified with the AMC/ALC PI. In contrast, 5-year OS ranged from 75%-88% among very good and good risk patients. Similarly, stratification of R-IPI poor risk patients by the AMC/ALC PI identified subsets of very good (n=19) and good risk (n=44) patients with median OS that had not been reached and 86% and 55% 5-year OS, respectively. High risk (n=21) patients had a median OS of 1.4 years (95% confidence interval 0.9–2.2 years) and an estimated 5-year OS of less than 25%. Conclusions: Measurement of AMC and ALC at diagnosis is widely applicable, cost effective, predicts OS, and identifies high-risk patients with DLBCL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Open-Labeled, Multicenter Phase II Study of Bortezomib for Maintenance Therapy in Patients with High Risk Diffuse Large B Cell Lymphoma (DLBCL): Borma Trial from Consortium for Improving Survival of Lymphoma (CISL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2884-2884
Author(s):  
Jae-Cheol Jo ◽  
Ho Sup Lee ◽  
Cheolwon Suh ◽  
Hye Jin Kang ◽  
Won Seog Kim ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
B Cell ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Risk Patients ◽  
Large B Cell Lymphoma ◽  
Risk Patients

Background: High-intermediate or high risk in international prognostic index (IPI) has a long-term chance of cure in the range about 50% in patients with diffuse large B cell lymphoma (DLBCL) treated by R-CHOP. These high risk patients should be considered for additional new treatment to standard R-CHOP or investigational approaches in the context of clinical trials that are designed to ensure that potentially curative therapy. Bortezomib inhibits NF-κB activation through proteasome inhibition, providing rationale for its use in cells that constitutively express NF-κB. Non-germinal center B cell (GCB) DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic NF-κB pathway, which can inhibit chemotherapy. There is no study of bortezomib as maintenance therapy after treated with R-CHOP in high risk patients with DLBCL. So we applied additional bortezomib as maintenance therapy in order to assess improving efficacy and survival rates in high risk patients with non-GCB DLBCL who had been confirmed complete response (CR) after treated with R-CHOP. Methods: Patients with newly diagnosed stage II(bulky)-IV DLBCL with high or high intermediate IPI score of 3 to 5, and patients achieving a CR at the end of 6 or 8 cycles of R-CHOP21 were eligible for enrollment. Non-GCB DLBCL according to Hans criteria confirmed by central review was need before enrollment. Bortezomib maintenance treatment was consisted of bortezomib 1.3mg/m2 subcutaneously administration day 1 and day 15 per 28-day cycle with a total of 12 cycles. The primary endpoint was 3-year progression-free survival (PFS). Secondary endpoints were 3-year overall survival (OS), and toxicites. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. Results: Fifty-nine patients were enrolled between May 2014 and Oct 2018. The type of Non-GCB DLBCL in all patients was confirmed by the central pathology review. The median age was 65 years (range: 27-86 years), and 60% were > 61 years. The baseline clinical features were as follows: female sex, 45.8%; ECOG >1, 10.2%; stage II bulky (>10cm), 6.8%; stage III/IV, 93.2%. At the time of analysis, 29 patients completed 12-cycles of bortezomib maintenance, and 3 patients is ongoing. Seven patients did not finished maintenance therapy due to toxicities (fatigue, atrial flutter, neuropathy, pleural effusion, thrombocytopenia), and withdrawal of informed consent (n=4). Sixteen patients experienced disease progression during bortezomib maintenance treatment. With a median follow-up of 25.1 months, 3-year PFS rate was 56.9% and 3-year OS rate was 86.4% (Figure 1). Toxicity was assessed in 489 cycles of bortezomib maintenance in all 59 patients. There was no treatment-related death and febrile neutropenia. Conclusion: Bortezomib maintenance showed 3-year PFS rate of 56.9% with acceptable toxicities in patients with high risk DLBCL achieving a CR at the end of 6 or 8 cycles of R-CHOP21. Figure 1 Disclosures Kim: Celltrion: Research Funding; Novartis: Research Funding; J + J: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

Charlson Comorbidity Index Is An Independent Prognostic Factor Among Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3923-3923
Author(s):  
Jin Takeuchi ◽  
Atsuko Hojo
Keyword(s):  
Elderly Patients ◽  
Charlson Comorbidity Index ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Poor Risk ◽  
Risk Patients ◽  
Comorbidity Index ◽  
Good Risk

Abstract 3923 Poster Board III-859 Introduction Wide use of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has improved the clinical outcome for elderly patients with DLBCL; however, a higher prevalence of coexisting disorders remains a problem. Correlation between their comorbidities and prognosis has not yet been well investigated. Patients and methods We retrospectively analyzed all patients over 65 years old who had been newly diagnosed with DLBCL at our institution from 2001 to 2008. To assess their comorbid medical status, we calculated the Charlson Comorbidity Index (CCI) for patient excluding primary disease. Prognostic factors were identified by Cox proportional hazards regression model. We classified patients into a low CCI group (CCI 0-1) and a high CCI group (CCI 2 or higher). Kaplan-Meyer curves for each group were evaluated by logrank test. Results A total of 80 patients were enrolled in this analysis. The median age was 73 (range 66-90) and the median observation period was 28 months (range 4-90 months). 62 patients (77.5%) were treated with R-CHOP, 15 (18.6%) underwent some other regimen, and 3 (3.8%) were given best supportive care only. According to revised International Prognostic Index (r-IPI), 43 patients were in the good risk group and the others were in the poor risk group. The estimated 3 year over all survival (OS) rate for these groups were 90% and 45% (p<0.0001). As for CCI, 14 patients (17.5%) were assigned to the high CCI group. Multivariate analysis revealed high CCI was associated with worse OS, while independent of r-IPI [Hazard Ratio (HR) 3.20, 95% Confidence interval (CI) 1.28-7.41, p=0.0145]. Among r-IPI poor risk patients, the high CCI group was inferior to the low CCI group for the 3 year OS rate (14% vs 56% p=0.0358), whereas this was not significant among r-IPI good risk patients (69% vs 94% p=0.0617). Conclusions Among elderly patients with DLBCL, high CCI is independently associated with poor survival. Patients having both poor r-IPI and high CCI may need discrete strategies. Disclosures: No relevant conflicts of interest to declare.

Rituximab and CODOX-M / IVAC Without Stem Cell Transplantation For Poor Risk Diffuse Large B Cell Lymphoma (IPI3-5) and Burkitts Lymphoma Is Feasible and Gives a High Response Rate: Preliminary Results Of a Phase 2 UK National Cancer Research Institute Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4348-4348 ◽  
Author(s):  
Andrew McMillan ◽  
Kirit M Ardeshna ◽  
Jo Gambell ◽  
Andrew Jack ◽  
Amy Kirkwood ◽  
...  
Keyword(s):  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Poor Risk ◽  
Large B Cell Lymphoma ◽  
Pet Scanning ◽  
Burkitts Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Introduction R-CHOP is the standard of care for patients with diffuse large B cell lymphoma (DLBCL) however poor risk patients (IPI 3-5) still have an inadequate outcome. Neither first remission high dose chemotherapy and peripheral blood stem cell transplantation (HDC+PBSCT) nor selection of cases for intensification by interim PET scanning have demonstrated a proven benefit. In the case of Burkitts lymphoma (BL) there is a paucity of data on the addition of Rituximab to the CODOX-M and IVAC regimen. Patients and Methods 113 patients with DLBCL and 37 with BL were recruited from 53 UK sites between May 2008 and April 2013. Median age was 49 years (18-65). For DLBCL patients IPI scores were 3 – 72 ( 64%), 4 -40 (35%) and 5 – 1 (1%). All patients received the modified CODOX-M and IVAC regimen including all CNS directed therapy( Mead et al Ann Oncol. 2002 Aug;13(8):1264-74) and 8 doses of rituximab. The primary end point of the study was Progression Free survival (PFS) and secondary endpoints included toxicity and CR rate. Results The main toxicities reported were neutropenia ( 89% grade 3 or 4), thrombocytopenia (84.2% grade 3 or 4), infection 61.6% grade 3 or 4 and mucositis (30.1% grade 3 or 4). 4 patients were excluded from toxicity assessment as they did not start therapy after registration. There were 8 treatment related deaths observed (infection with neutropenia (5), GI haemorrhage (1), acute cerebral haemorrhage (1) and bowel perforation (1) ). 78 patients with DLBCL and 31 with BL have completed all therapy ( 78.5 % of patients with available data) with an overall response rate of 92 % for DLBCl and 94% for BL. In patients who completed all therapy CR was achieved in 34 (44%), CR (u) in 8 (10%) and PR in 30 (38%) for DLBCL patients and CR was achieved in 21 (68%), CR (u) in 6 (19%) and PR in 2 (6%) in BL patients. 3 patients ( 2 DLBCL and 1 BL) who progressed during therapy have been included in the response analysis. End of treatment PET scanning was not obligatory. 80 patients with DLBCL and 30 patients with BL remain alive and without progression at a median follow up of 18.6 and 19.3 months respectively. Conclusion The R-CODOX-M -R-IVAC regimen can be delivered to patients with poor risk DLBCL in a multicentre setting. High rates of haematological toxicity and consequent infection are inevitable with treatment of this intensity but appear acceptable when compared with other treatments such as HDC+PBSCT. Response rates are encouraging in view of the very poor risk IPI profile of the patients included in this study. Burkitts lymphoma patients also achieved an excellent response rate with no apparent additional toxicity attributable to the addition of rituximab to the regimen. We currently plan the first analysis for the primary endpoint of PFS in 2015. The Trial was supported by Leukaemia and Lymphoma Research (LLR). Disclosures: McMillan: Roche: Consultancy, Honoraria; Amgen: Research Funding. Off Label Use: Rituximab usage in Burkitts Lymphoma. Ardeshna:Roche: Honoraria, Research Funding. Jack:Roche/Genentech: Research Funding. Patmore:Roche: Consultancy, Honoraria. Pettengell:Roche: Honoraria; Amgen: Honoraria. Linch:Roche: Honoraria, Research Funding.

scholarly journals Sequencing-Based Detection of Circulating Tumor DNA in the Autologous Stem Cell Grafts of Patients with Diffuse Large B-Cell Lymphoma Undergoing Hematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3156-3156 ◽  
Author(s):  
Alex F. Herrera ◽  
Reid W. Merryman ◽  
Katherine A. Kong ◽  
Heather Sun ◽  
Jennifer R. Brown ◽  
...  
Keyword(s):  
Stem Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Circulating Tumor Dna ◽  
Large B Cell Lymphoma ◽  
Consensus Primers ◽  
Tumor Dna ◽  
Large B Cell

Abstract Introduction: High dose chemotherapy followed by autologous stem cell transplantation (ASCT) cures a subset of patients with chemosensitive relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL). Several factors associated with post-ASCT outcome have been identified, including pre-ASCT PET status, but better biomarkers are needed in order to optimally select candidates for the procedure. In other lymphoma subtypes with defining chromosomal translocations, PCR detection of pre- and post-ASCT minimal residual disease (MRD) in peripheral blood and of tumor contamination in the stem cell product is associated with inferior outcome. Until recently, MRD detection in DLBCL was limited by the rarity of detectable circulating disease using conventional techniques. The immunosequencing platform (Adaptive Biotechnologies, Corp.) is a next-generation-sequencing (NGS)-based MRD assay that detects small amounts of circulating tumor DNA (CTD) in patients with lymphoid malignancies. The assay detects CTD at diagnosis in most DLBCL patients and CTD levels track with response to induction therapy (Armand, 2013). Persistence of CTD or recurrence of CTD after completion of therapy is highly associated with DLBCL relapse (Kurtz, 2015; Roschewski, 2015). We evaluated whether CTD in autologous stem cell grafts was predictive of outcome in patients with rel/ref DLBCL undergoing ASCT. Methods: We retrospectively studied patients with rel/ref DLBCL, including transformed indolent lymphoma (TIL), who had paired archival tumor and autologous stem cell specimens and underwent ASCT at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2003-2013. Genomic tumor DNA was extracted from archival formalin-fixed paraffin-embedded (FFPE) tissue and analyzed using the NGS-based MRD assay. PCR amplification of IGH-VDJ, IGH-DJ,and IGK regions using universal consensus primers was performed followed by NGS to determine the tumor clonotype(s), defined as having a frequency > 5% in the tumor specimen. DNA from all available autologous peripheral blood or bone marrow stem cell specimens from each patient was amplified using universal consensus primers and sequenced to determine the level of CTD, defined as the number of lymphoma molecules per diploid genome. Results: We identified 98 eligible patients with rel/ref DLBCL/TIL. The median age was 60 (range 22-77) years; 63% were male; 65% had DLBCL, 29% had TIL, and 5% had primary mediastinal DLBCL; the median number of prior lines of therapy was 2 (range 2-5); all had received prior rituximab; 38% had primary refractory disease; 60% were in complete remission at ASCT; 96% received CBV conditioning. Median follow-up was 56 (range 19-123) months. The 4y progression-free survival (PFS) and overall survival (OS) in the entire cohort were 46% and 64%, respectively. Among 83 patients (85%) with sufficient DNA for clonotype determination, a clonotype was identified in 59 (71%). CTD data was complete in 53 patients (52 received peripheral blood stem cells (PBSC) and 1 received bone marrow). Eight patients (15%) had detectable CTD (CTD+) in the stem cell autografts (all PBSC) and 6/8 relapsed after ASCT. One CTD+ patient had early non-relapse mortality less than 1 month after ASCT and was never restaged. Seven of 8 CTD+ patients had TIL histology, 5 of whom relapsed (4 with aggressive lymphoma). The 4y PFS and OS in CTD+ v CTD- patients were 13% v 48% (p=0.01), and 38% v 67% (p=0.013), respectively [Figure 1]. In multivariable models including CTD status and pre-ASCT characteristics, CTD+ was the only factor associated with OS (HR 3.1, p=0.018), but was not significantly associated with PFS. Discussion: In patients with rel/ref DLBCL undergoing ASCT, the presence of CTD in the autologous stem cell graft is associated with inferior survival. CTD detection in the autograft may be more common in patients with TIL. In studies evaluating CTD detection in DLBCL, the plasma compartment has been more sensitive for detecting CTD than mononuclear cells. The use of concentrated cell specimens in this study may have decreased the sensitivity of the assay. Nevertheless, if the present findings are confirmed in a larger population, CTD detection may permit the identification of a subgroup of patients with a particularly poor outcome after ASCT, for whom alternative approaches could be considered. Figure 1. Overall (A) and Progression-Free (B) Survival in CTD+ vs CTD- Patients Figure 1. Overall (A) and Progression-Free (B) Survival in CTD+ vs CTD- Patients Figure 2. Figure 2. Disclosures Herrera: Sequenta, Inc.: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Kong:Adaptive Biotechnologies, Corp.: Employment, Other: Stockholder. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Rodig:Perkin Elmer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding. Faham:Adaptive Biotechnologies Corp.: Employment, Other: Stockholder. Armand:BMS: Research Funding; Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding.

Impact of Rituximab on Peripheral Blood Stem Cell Mobilization and Collection Following ACVBP Regimen in Poor Risk Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Results from a Large Cohort of Patients from Two Prospective GELA Trials.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2314-2314
Author(s):  
Francois Lefrere ◽  
Dominique bastit-Barrau ◽  
Suzanne Mathieu ◽  
Alain Bohbot ◽  
Philippe Bourrin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cell ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Blood Stem Cell ◽  
Poor Risk ◽  
Cd34 Cells ◽  
Risk Patients ◽  
Pbsc Mobilization

Abstract &lt;&gt;The ACVBP regimen is commonly used in young poor-risk patients with DLBCL candidates to first line consolidative high-dose therapy followed by autologous stem cells transplantation in GELA trials. The combination with the monoclonal anti-CD20 antibody rituximab (R-ACVBP) is now routinely used, as induction treatment and to mobilize peripheral blood stem cell (PBSC). The aim of the present study was to assess the impact of rituximab on PBSC mobilization and collection in patients with newly diagnosed DLBCL receiving ACVBP chemotherapy. We reviewed the data from two prospective controlled trials. The first, conducted between 1999 and 2003, involved patients presenting with 2 or 3 adverse prognostic factors on the basis of the age-adjusted IPI (aa-IPI), treated by ACVBP (LNH 98B-3) (ASCO2007:8018). In the second trial (LNH 03-3B), conducted between 2004 and 2007, similar patients received the same initial inductive chemotherapy combined to rituximab (375mg/m2 at D1). 137 and 91 patients in the ACVBP and the R-ACVBP groups are here analyzed, respectively. Clinical and biological characteristics at diagnosis of the two groups of patients were similar (aa-IPI 2 and aa-IPI 3: 75% and 25%, respectively). The conditions for G-CSF administration and stem cell collections were identical. PBSC mobilizations were performed following the third or fourth cycle of (R)-ACVBP. The median delay between day 1 of chemotherapy and the first hemapheresis was identical for both groups. First hemapheresis was performed with a median peripheral white blood cell concentration of 16.2 x 109/l and 16.6 x 109/l for ACVBP and R-ACVBP groups, respectively. The median peak number of peripheral blood CD34+ cells observed the same day of first hemapheresis in ACVBP and R-ACVBP group was 69 x 106/l and 63 x 106/l, respectively (p = 0.5). The median number of CD34+ cells collected were 7.1 x 106 and 6.0 x 106 CD34 cells/kg for ACVBP and R-ACVBP groups (p = 0.12) while the median number of hemapheresis to target a minimal number of 3 x 106 CD34 cells/kg was identical, of one, in both groups. Failure of stem cell collection , defined as less than 3 x 106 CD34 cells/kg harvested, was observed in 8% and 4% of the patients who received ACVBP or R-ACVBP , respectively (p = 0.13). We conclude that rituximab combined to ACVBP regimen does not impair PBSC mobilization and collection.

Serum Soluble Tumor Necrosis Factor Recepter 2 Levels Is Associated with the Outcome of Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP Regimen

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1575-1575
Author(s):  
Nobuhiko Nakamura ◽  
Naoe Goto ◽  
Hisashi Tsurumi ◽  
Masao Takemura ◽  
Nobuhiro Kanemura ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Risk Group ◽  
B Cell Lymphoma ◽  
High Serum ◽  
Chop Regimen ◽  
Poor Risk ◽  
Large B Cell Lymphoma ◽  
Necrosis Factor ◽  
Good Risk

Abstract Abstract 1575 Background: We have previously reported that serum concentration of serum-soluble tumor necrosis factor receptor 2 (sTNF-R2) predicts the clinical outcome of patients with aggressive non-Hodgkin's lymphoma (NHL) treated with CHOP without rituximab (Goto et al. 2005). We extracted the diffuse large B-cell lymphoma (DLBCL) patients from aggressive NHL, used in our previous study, and extended our observation period. We found that serum sTNF-R2 level was a strong independent prognostic factor even for long-term observation in the CHOP era (8-year overall survival (OS); high serum sTNF-R2 group: 17.6%, low sTNF-R2 group: 69.8%, P<0.0001). Based on the result, we analyzed serum sTNF-R2 for patients with DLBCL who had received the CHOP plus rituximab (R-CHOP) regimen. Purpose: We aim to re-assess the prognostic significance of serum sTNF-R2 for DLBCL patients treated with R-CHOP regimen, and to assess sTNF-R2 with subtype of DLBCL, such as germinal center B cell type (GCB type) and non-GCB type which were classified by Hans et al. method (Hans et al. 2004). Methods: Consecutive 154 untreated patients with DLBCL prospectively participated in this study between 2002 and 2008. The patients were treated with R-CHOP. Results: In all patients with DLBCL, the median of serum sTNF-R2 level was 13.72 ng/ml (range 2.66–112.5 ng/ml). Various poor prognostic indicators, such as elderly age, poor performance status, increased LDH, multiple extranodal involvement sites, advanced disease, and existence of B-symptoms, were strongly associated with high serum sTNF-R2 levels. Serum sTNF-R2 levels significantly correlated with the increasing grade of international prognostic index (IPI), revised-IPI (R-IPI) (Sehn et al. 2007), and subtype, respectively (P<0.0001, P<0.0001, P=0.0058). We established the cut-off value for sTNFR2 at 20 ng/ml which was determined by ROC analysis. Patients with high sTNF-R2 (20 ng/ml and over) at onset had significantly lower OS rate (5-year: 29%), than that with low sTNF-R2 (5-year: 83%), respectively (P <0.0001). Multivariate analysis involving R-IPI, subtypes of DLBCL and serum sTNF-R2 revealed that sTNFR-2 significantly correlated with OS and progression free survival (PFS) (OS: P = 0.0001, PFS: P= 0.0085). Additionally, as the OS rate was about 50% even in the poor prognosis group of R-IPI, we tried to divide risk categories of R-IPI into low and high sTNF-R2 groups, resulting actually in five groups: very good risk group, good risk group with high sTNF-R2, good risk group with low sTNF-R2, poor risk group with high TNF-R2, and poor risk group with low sTNF-R2. A strong significant difference was observed. (5-year OS; very good risk group: 100%, good risk group with high sTNF-R2: 20%, good risk group with low sTNF-R2: 85%, poor risk group with high TNF-R2: 28.6%, and poor risk group with low sTNF-R2: 77.8%.) Conclusion: These results suggest that a high serum sTNF-R2 level predicts a poor prognosis in DLBCL and may be a useful biomarker for selecting appropriate treatment. Upfront high dose chemotherapy or alternative therapy of first line chemotherapy instead of R-CHOP might be well indicated for DLBCL patients with high serum sTNF-R2. Disclosures: No relevant conflicts of interest to declare.

Neutrophil toxicity and primary prophylaxis in diffuse large B cell lymphoma treated with R-CHOP

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19548-e19548
Author(s):  
N. Naqi ◽  
J. Khatak
Keyword(s):  
Febrile Neutropenia ◽  
Cell Lymphoma ◽  
Performance Status ◽  
B Cell Lymphoma ◽  
Primary Prophylaxis ◽  
High Risk Factors ◽  
Large B Cell Lymphoma ◽  
Risk Patients ◽  
Post Therapy ◽  
Good Risk

e19548 Background: Three weekly R-CHOP therapy is regarded as standard treatment in advanced stage Diffuse Large B Cell Lymphoma (DLBCL) patients with low to intermediate-risk International prognostic index (IPI). This regimen is associated with intermediate risk (10–20%) of febrile neutropenia. Primary prophylaxis with colony-stimulating factor (CSFs) is therefore not recommended except in the presence of high risk factors as defined in the National Comprehensive Cancer Center Network guidelines for use of myeloid growth factors v.1.2008. It is however well realized that a significant number of good risk patients will still develop significant neutrophil toxicity. Methods: This observational study was conducted at Oncology department Combined Military Hospital, Rawalpindi, on fifty good risk patients of advanced stage DLBCL, treated with R-CHOP regimen without primary CSFs prophylaxis. NCI Common Toxicity Criteria version 3.0 was used for grading toxicity and significant neutrophil toxicity was defined as Grade 4 neutropenia between day 7 and 10 post therapy, febrile neutropenia and Grade 2 or more neutrophil toxicity persisting on day 1 of next cycle. Good risk patients were recruited by the following exclusion criteria: WHO Performance status scale 4, concurrent immunosuppressive drug therapy, abnormal hepatic or renal functions and inadequate hematological values. Results: 10(20%) patients, developed significant neutrophil toxicity. In this group 7(70%) had grade 4 neutropenia and 3(30%) patients developed febrile neutropenia. 8(80%) of these patients developing significant toxicity had WHO Performance scale ≥ 2. 2(20%) patients developing Grade 4 toxicity between days 7 and 10 post therapy had good performance status (0 or 1) and toxicity resolved by next cycle without getting complicated to febrile neutropenia. Conclusions: Performance status in terms of scale has not been defined in the high risk factors for developing febrile neutropenia in the NCCN guidelines on myeloid growth factors use. We observed that DLBCL patients with WHO performance status scale ≥ 2 treated with R-CHOP therapy at 3 weekly intervals are at greatest risk for developing significant neutrophil toxicity and febrile neutropenia. No significant financial relationships to disclose.

Serum Albumin and Peripheral Blood Lymphocyte/Monocyte Ratio at Diagnosis May Provide Additional Prognostic Information in R-IPI Good Risk Diffuse Large-B-Cell Lymphoma Patients Treated with R-CHOP

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2658-2658 ◽  
Author(s):  
Branimir Spassov ◽  
Donka Vassileva ◽  
Georgi Michaylov ◽  
Gueorgui Balatzenko ◽  
Margarita Guenova
Keyword(s):  
Risk Group ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Risk Groups ◽  
Prognostic Information ◽  
Poor Risk ◽  
Risk Patients ◽  
Good Risk

Abstract Background and Aim: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Currently, the standard of care in DLBCL patients (pts) is rituximab-CHOP immunochemotherapy (R-CHOP) and the prognostic stratification is performed by the Revised International Prognostic Index (R-IPI), identifying 3 distinct prognostic groups with a very good, good and poor outcome. A lot of new prognostic markers have been introduced into the clinical practice to perform better pts' stratification. Particular prognostic relevance has been attributed to serum albumin (SA), β2-microglobulin (B2M), peripheral blood lymphocyte/ monocyte ratio (LMR), neutrophil/lymphocyte ratio (NLR) etc. However the data of these prognostic factors across the different R-IPI prognostic groups are limited. Therefore, we decided to access whether SA, B2M, LMR and NLR were predictors of overallsurvival (OS) across the different R-IPI groups of R-CHOP treated DLBCL pts. Patients and Methods: We retrospectively reviewed the clinical outcome of 281 R-CHOP treated DLBCL pts with median age 58 years and 51.8 % male. According to the R-IPI score, the pts in very good, good and poor risk were 24.2%, 54.8% and 21%, respectively. Laboratory levels of albumin, absolute lymphocyte, monocyte and neutrophil count were recorded, and LMR and NLR - calculated. Serum B2M levels were measured by radioimmunoassay. A receiver operating characteristic (ROC) curve analysis was used to illustrate in our data set the best cut off values of SA, B2M, LMR and NLR to predict OS by Kaplan-Meier method. Univariate analysis to evaluate differences between variables was performed by the log rank. A multivariate analysis was performed by Cox proportional-hazards models. Results: The estimated 5-year OS was 87.1%, 74% and 31% for R-IPI very good, good and poor-risk patients, respectively. The median values of SA, B2M, LMR and NLR were 40.7 g/L, 2.9 mg/L, 2.95 and 2.86, respectively. Our data showed that on univariate analysis inferior OS was associated with decreased SA (≤39.4 g/L; 95% confidence interval (CI) 0.70-0.82, p=<0.001), elevated B2M (>2.6 mg/L; 95% CI 0.68-0.80, p=<0.001), reduced LMR (≤2.16; 95% CI 0.71-0.81, p=<0.001) and increased NLR (>2.61; 95% CI 0.66-0.77, p=<0.001), presented as dichotomized variables. On multivariate analysis the independent prognostic significance was confirmed only for SA and LMR, with hazard ratios of 0.23 (95% CI 0.11-0.49, p<0.001) and 0.41 (95% CI 0.21-0.81, p=0.011), respectively. Based on the dichotomized SA and LMR values a SA/LMR prognostic index (PI) was created stratifying patients into 3 risk groups: very good (SA >39.4 g/L and LMR >2.16; n=75), good (SA ≤39.4 g/L or LMR ≤2.16; n=52) and poor-risk (SA ≤39.4 g/L and LMR ≤2.16; n=41) populations. The estimated 5-year OS was 88.7% for very good, 51.7% for good, and 8.8% for poor SA/LMR PI group (p<0.001). Median OS for poor-risk patients was 1.1 years (95% CI 1.03-1.72 years) and not reached for both the very good and good-risk groups. We sought to determine whether the SA/LMR PI may provide additional prognostic information within the R-IPI risk groups. Due to low number of deaths - 4.4% (3/68), no statistics could be calculated in very good R-IPI risk group. Within the R-IPI good risk patients SA/LMR PI allowed us to discriminate 3 subgroups, characterized by significant differences in 3-year and median OS (Figure 1): a SA/LMR PI poor risk subgroup (n=18) with 10.4% 3-years OS and 1.13 years (95% CI 0.82-1.44 years) median OS; a SA/LMR PI good risk subgroup (n=32) with 59.5% 3-years OS and median not reached; and a SA/LMR PI very good risk subgroup (n=50) with not reached median OS and 91.3% 3-years OS comparable to the OS in R-IPI very good patients (p=0.229). Only SA retained its independent prognostic significance in R-IPI poor risk group. Conclusion: SA and LMR are independent prognostic markers to predict survival in DLBCL pts. Adding these variables to prognostic models such as the R-IPI score might improve their predictive ability, providing particularly relevant information within the R-IPI good risk group. A subgroup of R-IPI good risk pts with a very good SA/LMR PI was identified, comparable to the R-IPI very good risk category in terms of OS. Figure 1. Overall survival of R-CHOP treated R-IPI good risk DLBCL patients according to SA and LMR at diagnosis Figure 1. Overall survival of R-CHOP treated R-IPI good risk DLBCL patients according to SA and LMR at diagnosis Disclosures No relevant conflicts of interest to declare.

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