Development and Validation of a Robust QSAR Model for Benzothiazole Hydrazone Derivatives as Bcl-XL Inhibitors

Background: B-cell Lymphoma Extra Large (Bcl-XL) belongs to B-cell Lymphoma two (Bcl-2) family. Due to its over-expression and anti-apoptotic role in many cancers, it has been proven to be a more biologically relevant therapeutic target in anti-cancer therapy. In this study, a Quantitative Structure Activity Relationship (QSAR) modeling was performed to establish the link between structural properties and inhibitory potency of benzothiazole hydrazone derivatives against Bcl-XL. Methods: The 53 benzothiazole hydrazone derivatives have been used for model development using genetic algorithm and multiple linear regression methods. The data set is divided into training and test set using Kennard-Stone based algorithm. The best QSAR model has been selected with statistically significant r2 = 0.931, F-test =55.488 RMSE = 0.441 and Q2 0.900. Results: The model has been tested successfully for external validation (r2 pred = 0.752), as well as different criteria for acceptable model predictability. Furthermore, analysis of the applicability domain has been carried out to evaluate the prediction reliability of external set molecules. The developed QSAR model has revealed that nThiazoles, nROH, EEig13d, WA, BEHv6, HATS6m, RDF035u and IC4 descriptors are important physico-chemical properties for determining the inhibitory activity of these molecules. Conclusion: The developed QSAR model is stable for this chemical series, indicating that test set molecules represent the training dataset. The model is statistically reliable with good predictability. The obtained descriptors reflect important structural features required for activity against Bcl-XL. These properties are designated by topology, shape, size, geometry, substitution information of the molecules (nThiazoles and nROH) and electronic properties. In a nutshell, these characteristics can be successfully utilized for designing and screening of novel inhibitors.

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PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell–inflamed phenotype

Blood ◽

10.1182/blood-2018-10-879015 ◽

2019 ◽

Vol 133 (21) ◽

pp. 2279-2290 ◽

Cited By ~ 28

Author(s):

James Godfrey ◽

Sravya Tumuluru ◽

Riyue Bao ◽

Michael Leukam ◽

Girish Venkataraman ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Immune Escape ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Data Set ◽

Large B Cell Lymphoma ◽

Programmed Death ◽

Large B Cell ◽

Gene Alterations

Abstract Programmed death-ligand 1 (PD-L1) expression on malignant cells is a dominant immune escape mechanism across a variety of human cancers. A unique genetic mechanism underlying PD-L1 upregulation has been uncovered in classical Hodgkin lymphoma (cHL), in which copy gains of the chromosomal region (9p24.1) containing the programmed death-1 (PD-1) ligands PD-L1 and PD-L2 are recurrently observed. While chromosome 9p24.1 copy-number alterations are ubiquitous in cHL, they also occur in diffuse large B-cell lymphoma (DLBCL), albeit with a lower incidence. Here, fluorescence in situ hybridization was used to identify DLBCLs harboring PD-L1 gene alterations, thereby enabling a characterization of the immunogenomic landscape of these lymphomas. Among 105 DLBCL cases analyzed, PD-L1 alterations were identified in 27%. PD-L1 alterations were highly enriched among non–germinal center DLBCLs and exhibited robust PD-L1 protein expression. These lymphomas were heavily infiltrated by clonally restricted T cells and frequently downregulated human leukocyte antigen expression. RNA sequencing of PD-L1–altered DLBCLs revealed upregulation of genes involved in negative T-cell regulation and NF-κB pathway activation, while whole-exome sequencing identified frequent mutations in genes involved in antigen presentation and T-cell costimulation. Many of these findings were validated in a large external data set. Interestingly, DLBCL patients with PD-L1 alterations had inferior progression-free survival following front-line chemoimmunotherapy; however, in the relapsed/refractory setting, PD-L1 alterations were associated with response to anti-PD-1 therapy. Collectively, our results indicate that PD-L1 alterations identify a unique biological subset of DLBCL in which an endogenous antilymphoma immune response has been activated, and that is associated with responsiveness to PD-1 blockade therapy.

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Establishment of a Nomogram for Patients with Primary Mediastinal Large B-Cell Lymphoma Based on the SEER Database and Validation of Real-World Data

Blood ◽

10.1182/blood-2021-152934 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1341-1341

Author(s):

Hua Wang ◽

Guanjun Chen ◽

Bibo Fu

Keyword(s):

Prognostic Factors ◽

B Cell ◽

Cell Lymphoma ◽

External Validation ◽

B Cell Lymphoma ◽

Seer Database ◽

Real World Data ◽

Decision Curve Analysis ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background Primary mediastinal large B-cell lymphoma (PMBCL) is a rare disease with the majority of patients being rapidly progressive anterior mediastinal large tumors. Due to the rarity of PMBCL, information on the incidence, clinical features, prognostic factors and models of PMBCL is limited. The present study is one of the largest studies on the incidence and prognostic factors of PMBCL and is the first to establish a nomogram model of PMBCL and validate it with real-world data. We also compared the newly established Nomogram with the existing IPI prognostic model. We believe that our findings can help clinicians to quickly and accurately assess the predicted survival of patients and help them to perform individualized risk stratification of patients. Methods Based on data from the Surveillance, Epidemiology and End Results (SEER) database, 797 patients diagnosed with PMBCL were enrolled in this study. The 797 patients were randomly divided into training and internal validation groups in a 7:3 ratio, and 116 patients diagnosed with PMBCL were included in the external validation group based on data from the Sun Yat-sen University Cancer Center and the First Affiliated Hospital of Guangzhou Medical University. Independent prognostic factors were screened by Cox regression analysis. R-coding was used to construct nomograms predicting overall survival (OS). Discriminations and corrections of the new model were assessed using the consistency index (C-index), subject operating characteristic curves (ROC) and calibration curves, and compared with the conventional international prognostic index (IPI) using decision curve analysis (DCA) to assess its accuracy and benefit. Results From 2001 to 2016, the incidence of primary mediastinal large B-cell lymphoma showed a relatively stable increasing trend with an APC of 11.8% (95% confidence interval 8.8-14.0, P<0.05), and this trend was more pronounced in the female population. Multivariate models showed that age and Ann arbor staging were significantly associated with OS, while the variable of extra-nodal invasion was included in the modeling based on clinical experience. In the training cohort, the C-index of the nomogram for OS was 0.712. the C-index for the internal and external validation cohorts was 0.667 and 0.690, respectively. The calibration curve also showed high predictive accuracy. The C-index and ROC curves of nomogram showed better results compared to IPI scores, and also yielded better net gains in decision curve analysis. Conclusion In summary, we successfully established a validated nomogram for predicting OS in patients with PMBCL, which can help clinicians to select appropriate individualized treatment for their patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Genetic Map of Relapsed and Refractory Diffuse Large B-cell Lymphoma: A Systemic Review and Association Analysis

10.21203/rs.3.rs-93266/v1 ◽

2020 ◽

Author(s):

Fan Gao ◽

Lei Tian ◽

Jing Wang ◽

Fei Dong ◽

Kai Hu ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Strong Association ◽

Gene Mutations ◽

B Cell Lymphoma ◽

Data Set ◽

Common Gene ◽

Large B Cell Lymphoma ◽

The Common ◽

Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin lymphoma (NHL). In recent years, a deeper understanding of the genetic subtypes of diffuse large B lymphoma has been reached, and these advances have also been applied to research on relapsed and refractory diffuse large B-cell lymphoma (RRDLBCL). We screened 1495 documents, compiled the whole-exome sequencing data of several studies, formed a data set including 92 observations, and performed association analysis on the high-frequency mutations among them. The most common mutations in the data set include TTN (34/92, 37.0%), KMT2D (29/92, 31.5%), TP53 (25/92, 27.2%), IGLL5 (25/92, 27.2%), CREBBP (21 /92, 22.8%), BCL2 (21/92, 22.8%), MYD88 (20/92, 21.7%), and SOCS1 (19/92, 20.7%). Among these, CREBBP, KMT2D, and BCL2 have a strong association with each other, and SOCS1 has a strong association with genes such as ACTB, CIITA, and GNA13. There is also a strong association between SOCS1 and STAT6. Though TP53 and MYD88 lack significant associations with most genes, the association between MYD88 and PIM1 is significant. Through SOM clustering and expression-level analysis of common gene mutations, we believe that RRDLBCL can be divided into four main types: (1) JAK-STAT-related type, including STAT6, SOCS1, ITPKB, CIITA, and B2M. The expression lineage is similar to PMBL and cHL. (2) EZB type: BCL2 and EZHZ are the main types of mutations. Epigenetic mutations such as KMT2D and CREBBP are more common in this type, and are often accompanied by BCL2 mutations. (3) MCD type, including MYD88, CD79B and PIM1. These genes are involved in the BCR signaling pathway and related pathways, and are connected by the common NF-κB pathway. (4) Undefined type (Sparse Mutation type). These patients are mainly individuals with sparse mutations, including some patients with TP53 mutations (30.3%, 10/33), but who generally lack characteristic mutations. Among the common gene mutations, the expression changes in BCL2, PIM1, STAT6, ITPKB, and GNA13 have more significant prognostic significance. We also reviewed the literature from recent years concerning the previously mentioned common gene mutations.

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Baseline PET/CT imaging parameters for prediction of treatment outcome in Hodgkin and diffuse large B cell lymphoma: a systematic review

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-021-05233-2 ◽

2021 ◽

Author(s):

R. Frood ◽

C. Burton ◽

C. Tsoumpas ◽

A. F. Frangi ◽

F. Gleeson ◽

...

Keyword(s):

B Cell ◽

Clinical Utility ◽

Cell Lymphoma ◽

External Validation ◽

Predictive Ability ◽

B Cell Lymphoma ◽

Risk Of Bias ◽

Large B Cell Lymphoma ◽

Pet Ct ◽

Large B Cell

Abstract Purpose To systematically review the literature evaluating clinical utility of imaging metrics derived from baseline fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for prediction of progression-free (PFS) and overall survival (OS) in patients with classical Hodgkin lymphoma (HL) and diffuse large B cell lymphoma (DLBCL). Methods A search of MEDLINE/PubMed, Web of Science, Cochrane, Scopus and clinicaltrials.gov databases was undertaken for articles evaluating PET/CT imaging metrics as outcome predictors in HL and DLBCL. PRISMA guidelines were followed. Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool. Results Forty-one articles were included (31 DLBCL, 10 HL). Significant predictive ability was reported in 5/20 DLBCL studies assessing SUVmax (PFS: HR 0.13–7.35, OS: HR 0.83–11.23), 17/19 assessing metabolic tumour volume (MTV) (PFS: HR 2.09–11.20, OS: HR 2.40–10.32) and 10/13 assessing total lesion glycolysis (TLG) (PFS: HR 1.078–11.21, OS: HR 2.40–4.82). Significant predictive ability was reported in 1/4 HL studies assessing SUVmax (HR not reported), 6/8 assessing MTV (PFS: HR 1.2–10.71, OS: HR 1.00–13.20) and 2/3 assessing TLG (HR not reported). There are 7/41 studies assessing the use of radiomics (4 DLBCL, 2 HL); 5/41 studies had internal validation and 2/41 included external validation. All studies had overall moderate or high risk of bias. Conclusion Most studies are retrospective, underpowered, heterogenous in their methodology and lack external validation of described models. Further work in protocol harmonisation, automated segmentation techniques and optimum performance cut-off is required to develop robust methodologies amenable for clinical utility.

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B Cell Lymphoma, Unclassifiable: Survival Advantage for Aggressive Therapy

Blood ◽

10.1182/blood.v118.21.2689.2689 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2689-2689

Author(s):

Erin Cobain ◽

Tahamtan Ahmadi ◽

Marc Hoffmann ◽

Alison W. Loren ◽

Noelle V. Frey ◽

...

Keyword(s):

Disease Control ◽

B Cell ◽

Burkitt Lymphoma ◽

Conflicts Of Interest ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Data Set ◽

Hiv Test

Abstract Abstract 2689 Background: Burkitt lymphoma (BL) and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BLL) are mature B-cell non-Hodgkin lymphomas with an aggressive clinical course. Whereas the advent of short, intensive, multi-agent chemoimmunotherapy regimens has significantly improved the outcomes for BL patients (pts), questions remain regarding the optimal therapy for BLL. Patients and Methods: We analyzed 25 patients (pts), aged 20 to 73 (median: 51 years), treated at the University of Pennsylvania for either BL or BLL from 2005 to 2010. All pts had c- myc+ lymphoma, with a Ki-67>98% and a negative HIV test. In order to be classified as BLL, expression of bcl-6 was required. Bcl-2 expression was noticed in 7/14 (50%) of BLL cases. All patients had Stage III/IV disease. All but two pts had high-risk disease by IPI. All 10 pts with BL were treated with the R-HyperCVAD regimen. Of the 14 pts with BLL, 7 where treated with R-HyperCVAD and 7 with R-CHOP (+ intrathecal prophylaxis in five out of seven pts). No differences in IPI, PS or co-morbidities were noted between the three groups. Notably, patients treated with R-CHOP were slightly younger with median of 52 years vs. median age of 62 years for those with BLL, treated with R-HyperCVAD. Results: Overall response rate (ORR) to R-HyperCVAD in BL was 70%, with two treatment-related deaths. At median follow up of 24 months, progression-free survival (PFS) was 72% (95% CI: 36–90%). ORR in BLL treated with R-HyperCVAD was 86% with one treatment-related death vs.57% when treated with R-CHOP, with two treatment-related deaths. At median follow up of 9 months for both groups, PFS for BLL treated with R-HyperCVAD was 54% (95% CI: 14–83%), whereas only one pt treated with R-CHOP was free of disease after 9 months with a median PFS of 8 months and median overall survival (OS) of 9 months. Within our data set, only one of the six pts with primary refractory disease and one of four relapses responded to salvage therapy. None of the BL/BLL pts treated with R-HyperCVAD, who achieved a CR, relapsed. Four of the seven relapses after R-CHOP presented with CNS involvement. Conclusion: Our data suggest that R-HyperCVAD allows for long-term disease control in both BL and BLL, with a somewhat lower PFS in BLL. In contrast, R-CHOP appears to be inferior with no long-term disease control in BLL. Disclosures: No relevant conflicts of interest to declare.

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Diffuse Large B-Cell Lymphoma Cell of Origin Determination from Formalin-Fixed Paraffin-Embedded Tissues

Blood ◽

10.1182/blood.v126.23.5052.5052 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5052-5052 ◽

Cited By ~ 1

Author(s):

Zijun Yidan Xu-Monette ◽

Debrah Thompson ◽

Bonnie LaFleur ◽

Patrick Roche ◽

Monica Reinholz ◽

...

Keyword(s):

B Cell ◽

Molecular Diagnostics ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Ffpe Tissue ◽

Cell Of Origin ◽

Data Set ◽

Large B Cell Lymphoma ◽

Equity Ownership ◽

Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) consists of two distinct subtypes, Germinal Center B-cell (GCB) and Activated B-Cell (ABC), each with distinct prognostic and biological profiles. With the advent of new targeted therapeutic approaches for DLBCL treatment, molecular sub-typing of the patient's tumor has been proposed as an important step in therapeutic selection and recommended by 2016 WHO classification guideline. Gene expression-profiling (GEP) based subtyping is considered the gold-standard method for DLBCL molecular sub-typing, but this method was established using fresh frozen / non-fixed tissues on microarray platforms. Since fresh tissue is not routinely collected during patient diagnosis, it severely limits the ability to utilize this assay in routine clinical practice. Multiple immunohistochemical (IHC) approaches have been developed to approximate the GEP methods, but these techniques generally suffer from lower than desired agreement rates with GEP classifications, and require staining of 4 to 8 sections of limited biopsy material. Interpretation of the slides can also be variable, leading to low inter-observer reproducibility. We have developed a 12 gene GEP-based DLBCL cell-of-origin (COO) assay using the HTG EdgeSeq System specifically designed to use a minimal amount of FFPE tissue. To build this system, we profiled a total of 107 samples previously subtyped using the HG-U133 Plus 2.0 Affymetrix microarrray and algorithm (Visco C et al Leukemia 2013); this algorithm was then validated in an additional 58 samples. The methodology we have developed produces 92% concordance with the microarray-based approach. Briefly, 107 DLBCL cases, of which 58 were previously sub-typed as ABC and 49 cases as GCB, were used as the training cohort. After classifier training and cross-validation, a separate cohort of 58 cases were used to verify the performance of the assay/classification system. Approximately 5 mm2 of 5 µm thick FFPE tissue was used to generate the data set for each of the cases. In addition to the DLBCL COO classification, the assay also contains additional genes including potential drug targets, T-cell, B-cell, and macrophage biomarkers, and housekeeping/normalization genes. These markers could be used to further understand the nature of the tumor and potentially help identify the characteristics of atypical tumors and immune infiltrates in the microenvironment. Disclosures Thompson: HTG Molecular Diagnostics, Inc: Equity Ownership. LaFleur:HTG Molecular Diagnostics, Inc: Equity Ownership. Roche:HTG Molecular Diagnostics, Inc: Equity Ownership. Reinholz:HTG Molecular Diagnostics, Inc: Equity Ownership. Wineman:HTG Molecular Diagnostics, Inc: Equity Ownership. Botros:HTG Molecular Inc: Equity Ownership.

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Forkhead Box Protein P1 Expression in Mucosa-Associated Lymphoid Tissue Lymphomas Predicts Poor Prognosis and Transformation to Diffuse Large B-Cell Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2006.05.6150 ◽

2006 ◽

Vol 24 (16) ◽

pp. 2490-2497 ◽

Cited By ~ 98

Author(s):

Xavier Sagaert ◽

Pascale de Paepe ◽

Louis Libbrecht ◽

Vera Vanhentenrijk ◽

Gregor Verhoef ◽

...

Keyword(s):

B Cell ◽

Lymphoid Tissue ◽

Poor Prognosis ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Data Set ◽

Forkhead Box ◽

Large B Cell Lymphoma ◽

Trisomy 3 ◽

Large B Cell

Purpose Gene expression profiling studies have reported upregulated mRNA expression of forkhead box protein P1 (FOXP1) in response to normal B-cell activation and high expression in a poor prognosis subtype of diffuse large B-cell lymphoma (DLBCL). Recently, it was also found that FOXP1 rearrangements and expression of its protein occur in mucosa-associated lymphoid tissue (MALT) lymphomas. In this study, we investigated FOXP1 expression in its relationship to morphology, genetic features, and prognosis in a series of 70 MALT lymphomas. Patients and Methods All samples were morphologically reviewed and stained for FOXP1. Presence of structural and/or numeric aberrations of the FOXP1, BCL10, and MALT1 genes was investigated. For all patients, a complete clinical data set was collected. Results We detected nuclear expression of FOXP1 in 20 of the 70 MALT lymphomas (nine of them featuring structural or numeric aberrations of the FOXP1 locus). FOXP1 positivity was confined to MALT lymphomas with poor clinical outcome (with impact of FOXP1 expression on relapse rate and disease-free survival). It was also found that MALT lymphomas with strong FOXP1 expression are at risk of transforming into an aggressive DLBCL of nongerminal center phenotype if they feature, in addition, a polymorphic histology and the presence of trisomy 3 and 18. Conclusion The data presented show that FOXP1 expression is an independent prognostic factor in MALT lymphomas. The data also support the hypothesis that a subgroup of nongerminal center DLBCLs (those marked by FOXP1 expression and trisomy 3 and 18) might represent a large-cell variant of MALT lymphomas.

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Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3

Blood ◽

10.1182/blood.v99.10.3806 ◽

2002 ◽

Vol 99 (10) ◽

pp. 3806-3812 ◽

Cited By ~ 197

Author(s):

German Ott ◽

Tiemo Katzenberger ◽

Andreas Lohr ◽

Steffi Kindelberger ◽

Thomas Rüdiger ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Cell Lymphoma ◽

Clinical Importance ◽

B Cell Lymphoma ◽

Structural Features ◽

World Health ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

Follicular lymphoma (FL) grades 1 and 2 are regarded as a distinct disease entity, whereas data suggest that FL grade 3 might be an inhomogeneous tumor category. To define the biologic spectrum of FL, 89 follicular lymphomas were studied for their cytologic composition, antigen expression, mitotic and proliferation indices, cytogenetics, and clinical data. In contrast to the homogeneous appearance of FL grades 1 and 2 (29 and 33 cases, respectively), 2 types of FL grade 3 were recognized. Eleven cases of FL 3a displayed structural features similar to those of FL 1 and 2 and were composed of centroblasts and centrocytes, whereas 16 cases of FL 3b, with (n = 4) or without (n = 12) a diffuse large B-cell lymphoma component (DLBL) (FL 3b ± DLBL), consisted exclusively of blasts. In contrast to FL 3a, FL 3b ± DLBL were CD10+ in only 50% of cases and displayed plasmacytoid differentiation in 44% of cases. Although FL3a was t(14;18)+ in 8 of 11 (73%) cases, only 2 of 16 (13%) FL3b ± DLBLs harbored this translocation. In contrast, chromosomal breaks at 3q27 were encountered in 7 of 16 (44%) FL 3b ± DLBL in contrast to only 2 of 11 (18%) FL 3a, and the spectrum of secondary aberrations in FL 3b ± DLBL was similar to that of diffuse large B-cell lymphoma. We conclude, therefore, that FL grade 3 is a heterogeneous disease group and that the distinction proposed in the new World Health Organization classification between FL 3a (with centrocytes) and FL3b (without centrocytes) is of biologic, and possibly clinical, importance.

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Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy

Journal of Clinical Oncology ◽

10.1200/jco.18.01314 ◽

2019 ◽

Vol 37 (3) ◽

pp. 202-212 ◽

Cited By ~ 56

Author(s):

Chulin Sha ◽

Sharon Barrans ◽

Francesco Cucco ◽

Michael A. Bentley ◽

Matthew A. Care ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Germinal Center ◽

Poor Prognosis ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Grade ◽

Data Set ◽

Germinal Center B Cell ◽

Double Hit

Purpose Biologic heterogeneity is a feature of diffuse large B-cell lymphoma (DLBCL), and the existence of a subgroup with poor prognosis and phenotypic proximity to Burkitt lymphoma is well known. Conventional cytogenetics identifies some patients with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphomas) who are increasingly treated with more intensive chemotherapy, but a more biologically coherent and clinically useful definition of this group is required. Patients and Methods We defined a molecular high-grade (MHG) group by applying a gene expression–based classifier to 928 patients with DLBCL from a clinical trial that investigated the addition of bortezomib to standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The prognostic significance of MHG was compared with existing biomarkers. We performed targeted sequencing of 70 genes in 400 patients and explored molecular pathology using gene expression signature databases. Findings were validated in an independent data set. Results The MHG group comprised 83 patients (9%), with 75 in the cell-of-origin germinal center B-cell-like group. MYC rearranged and double-hit groups were strongly over-represented in MHG but comprised only one half of the total. Gene expression analysis revealed a proliferative phenotype with a relationship to centroblasts. Progression-free survival rate at 36 months after R-CHOP in the MHG group was 37% (95% CI, 24% to 55%) compared with 72% (95% CI, 68% to 77%) for others, and an analysis of treatment effects suggested a possible positive effect of bortezomib. Double-hit lymphomas lacking the MHG signature showed no evidence of worse outcome than other germinal center B-cell-like cases. Conclusion MHG defines a biologically coherent high-grade B-cell lymphoma group with distinct molecular features and clinical outcomes that effectively doubles the size of the poor-prognosis, double-hit group. Patients with MHG may benefit from intensified chemotherapy or novel targeted therapies.

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A Study of Outcomes of Diffuse Large B Cell Lymphoma in the Elderly

Blood ◽

10.1182/blood.v118.21.4950.4950 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4950-4950

Author(s):

Marc Hoffmann ◽

Tahamtan Ahmadi ◽

Erin Cobain ◽

Alison Loren ◽

Noelle V Frey ◽

...

Keyword(s):

Elderly Patients ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Standard Chemotherapy ◽

Chop Regimen ◽

Data Set ◽

Large B Cell Lymphoma ◽

Frail Patients ◽

Large B Cell

Abstract Abstract 4950 Introduction: Despite improvements in outcome using chemoimmunotherapy, treating elderly patients with diffuse large B cell lymphoma (DLBCL) remains challenging. Reliable risk stratification beyond age is lacking and consequently elderly patients are often treated with reduced-dose therapeutic regimen with palliative intent. We retrospectively analyzed outcomes of DLBCL patients aged 65 and older treated at the University of Pennsylvania. Patients and method: We identified 41 patients (pts) with diagnosis of DLBCL and age >65 years. Median age was 74 years (range: 65–86). Eight pts (20%) were age 80 or older. There were no differences in IPI, elevated LDH, or bcl-2 expression, whereas bcl-6 expression was more common in patients >80 years with 75% (6/8) vs. 27% (24/33) (p=0.01). Overall, 31 pts were treated with R-CHOP, 2 pts with R-HyperCVAD and one pt with R-CVP. Seven patients with a median age of 77 years were considered too frail for standard chemotherapy and were treated with a “split R-CHOP” regimen consisting of: rituximab 375 mg/m2 day 1, cyclophosphamide 375 mg/m2 day 1 and 15, adriamycin 25 mg/m2 day 1 and 15, vincristine 1 mg day 1 and 15 and Prednisone 50 mg day 1–5 and day 15–19. Results: Overall, the complete remission (CR) rate was 56% with seven treatment related deaths (17%). For patients between 65 to 80 years of age and deemed fit for standard chemotherapy (n=28), CR rate was 57% with four treatment related deaths (14%). Among patients over 80 and deemed fit for standard chemotherapy (n=6), the CR rate was 50% with 2 treatment related deaths (33%). Frail patients treated with the “split R-CHOP regimen” (n=7) had a CR rate of 57% with one (14%) treatment related death. For all patients, the median progression-free survival (PFS) was 1 year with a median overall survival (OS) of 2 years. The median PFS for pts between 65 and 80 years of age treated with standard chemotherapy was 16 months. Median PFS in pts >80 years of age treated with standard chemotherapy was 7 months, whereas median PFS in frail pts treated with “split R-CHOP regimen” was 11.7 months. Conclusions: Our data reveal interesting findings about elderly pts treated for DLBCL. PFS and OS in general are poor as has been reported by others. In our data set, pts>80 years considered fit for standard chemotherapy, had a shorter PFS then fit patients between 65 to 80 years. Intriguingly, PFS among frail elderly patients treated with a “split R-CHOP” regimen appears to be superior to that of elderly deemed more robust who were treated with standard dose RCHOP-21. Though limited by small numbers, our institutional data suggest that frail patients can tolerate a modified R-CHOP regimen although survival remains short. Disclosures: No relevant conflicts of interest to declare.

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