Groupe d'Etude Des Lymphomes De l'Adulte Research Articles

Activity and Event-Free Survival in Intermediate Grade Non-Hodgkin's Lymphoma Treated with Chemoimmunotherapy Utilizing Single Dose Intravenous Methylprednisolone in Lieu of Oral Prednisone

Schein et al first noted that patients with intermediate grade lymphoma treated with combination chemotherapy leading to complete response lasting 24 months were likely to remain relapse-free (Schein, Chabner, Canellos, Young, Berard, DeVita,1975). Subsequent changes in that original C-MOPP regimen have included the use of anthracyclines and rituximab. The University of Iowa/Mayo Clinic Molecular Epidemiology Resource and the Groupe d'Etude des Lymphomes de l'Adulte (GELA) program found that patients with diffuse large B-cell lymphoma achieving event-free status at 24 months with chemoimmunotherapy have subsequent overall survival equivalent to that of the general population (Maurer, 2014). While Rituximab, Cyclophosphamide, Hydroxydaunorubicin [doxorubicin], Oncovin [vincristine] and Prednisone (RCHOP) has served as the reference therapy for intermediate grade non-Hodgkin's lymphoma for two decades (Coiffier, 2002; Pfreundschuh, 2006), oral prednisone given daily for 5 days is problematic for individuals with underlying medical conditions such as diabetes, sleep or psychiatric disorders, or gastrointestinal symptoms. In this retrospective study between January, 2007 and March, 2023, 33 patients with intermediate grade Non-Hodgkin's Lymphoma, (26 with Diffuse Large B-cell subtype, 6 with follicular grade III, 1 with T-cell Immunoblastic) received Methylprednisolone 125 mg intravenously on day 1 instead of oral prednisone for 5 days as part of anthracycline-based treatment that consisted of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 2 mg (total dose) all given intravenously on day 1 with peg-filgastrim 6 mg subcutaneously on day 2 every 21 days. Three patients received mitoxantrone 12 mg/m2 intravenously on day 1 instead of doxorubicin. Patient characteristics: 23 males/10 females, median age-55 (range: 24-85), stages: IV (17 patients), III (4 patients), II (12 patients), B symptoms (16), subtypes: non-germinal center (13), germinal center (12), diffuse B-cell NOS (1), follicular grade III (6), T-cell Immunoblastic (1). Median cycles received (range): 6 (5-8). No patients required dose reduction or omission of methylprednisolone. Complete responses (determined by PET/CT) occurred in 26 (81%). 1 additional patient was PET negative but was lost to follow-up and is not counted as CR here. Three patients having PR after chemoimmunotherapy were converted to CR after involved site radiation. Two other patients achieved only short-lived PR. One patient is too early to evaluate. The median event-free survival has not been reached at 24.8+ months. Median overall survival exceeds 32.6+ months. Chemoimmunotherapy with the substitution of intravenous methylprednisolone on day 1 in place of 5 days of oral prednisone displays activity in intermediate-grade non-Hodgkin lymphoma and event-free survival beyond 24 months.

Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients

AbstractThe survival of patients with aggressive non-Hodgkin lymphoma (NHL) is increasing, but the incidence of secondary cancer and late toxicity is poorly defined for those treated with cyclophosphamide-hydroxydaunomycin/doxorubicin-Oncovin-prednisone (CHOP)–like chemotherapy. From February 1984 to January 1998, 2837 patients with aggressive NHL received the control-arm chemotherapy adriamycin-cyclophosphamide-vindesine-bleomycin-prednisone (ACVBP) in 3 consecutive Groupe d’Etude des Lymphomes de l’Adulte (GELA) studies. With a median follow-up time of 74 months, the 5-year overall and event-free survival rates were 60% and 52%. Two hundred two occurrences of nonneoplastic late toxicity were reported, resulting in a 5.35% cumulative probability of incidence at 7 years. Eighty-one second tumors developed, for which the 7-year cumulative incidence rate was 2.75%; 64 were solid tumors, and 17 were hematologic malignancies. In multivariate analysis, age was the only risk factor for the second development of cancer. Epidemiologic analysis allowed a comparison of this NHL group with the general population. Considering all tumors, no excess of second cancer was observed. In the male population, however, there was an excess of lung cancer (standardized incidence ratio [SIR], 2.45; P < .001) and myelodysplastic syndrome/acute myelocytic leukemia (MDS/AML) (SIR, 5.65; P = .006), and in the female population there was an excess of MDS/AML (SIR, 19.9; P < .001). With a long follow-up, the ACVBP regimen was highly effective for the treatment of aggressive NHL. Increases occurred in secondary MDS/AML and in lung cancer among men.

Case Match Control Analysis of Propel Reveals Survival Advantage for Patients with Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) Treated with Pralatrexate

Overall survival (OS) remains the gold standard proof of a clinical benefit, and differences in OS can only be determined in randomized Phase 3 clinical studies. However, in rare diseases, the conduct of randomized studies is very challenging, takes protracted periods of time to conduct, can be very expensive while not offering the promise of significant commercial return, and could become clinically irrelevant as other new agents and combinations emerge over the extended time frame of the study. Many drugs approved in this setting are often approved on surrogate end-points like progression free survival (PFS) or complete response (CR) rates in single arm Phase 2 studies. A middle-ground approach could involve using case-matched control analyses (CMCA), which are statistically more robust that single arm Phase 2 studies, and can provide meaningful insights into the likelihood of success in the randomized setting. CMCA require access to large well annotated datasets with a representative patient population, and can be used to benchmark a new drug in a defined patient population. Unfortunately, these types of analyses have not been routinely used in oncology, certainly not in patients with PTCL. We established an integrated international database of patients with R/R PTCL in order to better clarify the clinical benefit and survival advantage of pralatrexate in patients with R/R PTCL, using the original raw data from the PROPEL study.Data Source. The control population is derived from a collection of four historical databases of patients with R/R PTCL, including: Memorial Sloan-Kettering Cancer Center (MSKCC), University of Nebraska Medical Center (UNMC), Groupe d'Etude des Lymphomes de l'Adulte (GELA), and Samsung Medical Center (SMC). These databases were all annotated with the criteria used to define the PROPEL study population. The cases are from the PROPEL study, an international, multicenter single arm phase II study or pralatrexate in patient with R/R PTCL. The analysis was conducted by an independent statistician in collaboration with investigators from Columbia University.Method for Matching. The propensity score match was used to match cases and controls. The following characteristics are used in the match process: histology, number of previous treatments received, age at diagnosis (with 20 years interval), and sex. With 1:1 ratio match, the process identified 83 cases and 83 controls. The analysis population includes 68.7% female from cases and 66.3% from controls. For cases and controls, the age distributions are similar: mean age is 57.2 with the range (21 - 83) for cases and 56.7 with range (24 - 89). About 60% of patients received less than three previous treatments in both cases and controls ( 58% vs 59%). More than half of the patients in both cases and controls had histology PTCL-unspecified. Other histology above 10% are AILT and ALCL, primary systemic type.Results. In total, 83 patients out of 109 treated on the PROPEL study were successfully matched with the control population. The cases were matched 1 : 1. Overall survival was plotted for each of the two study populations. The survival curves for the control population were found to be nearly identical to that reported for this population from other datasets, including the ones reported from the International T-Cell Lymphoma Project, the British Columbia experience and the T-Cell Project. The overall survival was 4.04 months (95% CI 2.83, 5.78), which is consistent with historical controls describing the natural history of R/R PTCL in this population. The PROPEL study, which reported an overall response rate of 29% in patients with multiply relapsed PTCL, reported on one of the most diverse and heavily treated populations of R/R PTCL. In PROPEL, the median number of prior therapies was three, with 19% of patient receiving more than 5 lines of prior therapy. The median OS in for the pralatrexate treated cohort in this analysis was 16.6 months (95% CI: 11.99-25.56). There was a highly significant difference in the OS between these two populations, with a hazard ratio of 0.426 (95% CI: 0.296-0/61). The OS curves are shown below. This CMCA demonstrates a highly significant difference in OS in favor of patients treated with pralatrexate. This approach can be used to better understand how new drugs in orphan diseases perform in heterogeneous patient populations. Additional statistical and sensitivity analyses will be reported. [Display omitted] DisclosuresO'Connor:Seattle Genetics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Spectrum: Research Funding; Seattle Genetics: Research Funding; Spectrum: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; TG Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Celgene: Research Funding. Volinn:LLXSolutions,LLC: Employment.

Event-Free Survival at 24 Months Is a Robust End Point for Disease-Related Outcome in Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy

Studies of diffuse large B-cell lymphoma (DLBCL) are typically evaluated by using a time-to-event approach with relapse, re-treatment, and death commonly used as the events. We evaluated the timing and type of events in newly diagnosed DLBCL and compared patient outcome with reference population data. Patients with newly diagnosed DLBCL treated with immunochemotherapy were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER) and the North Central Cancer Treatment Group NCCTG-N0489 clinical trial from 2002 to 2009. Patient outcomes were evaluated at diagnosis and in the subsets of patients achieving event-free status at 12 months (EFS12) and 24 months (EFS24) from diagnosis. Overall survival was compared with age- and sex-matched population data. Results were replicated in an external validation cohort from the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Lymphome Non Hodgkinien 2003 (LNH2003) program and a registry based in Lyon, France. In all, 767 patients with newly diagnosed DLBCL who had a median age of 63 years were enrolled onto the MER and NCCTG studies. At a median follow-up of 60 months (range, 8 to 116 months), 299 patients had an event and 210 patients had died. Patients achieving EFS24 had an overall survival equivalent to that of the age- and sex-matched general population (standardized mortality ratio [SMR], 1.18; P = .25). This result was confirmed in 820 patients from the GELA study and registry in Lyon (SMR, 1.09; P = .71). Simulation studies showed that EFS24 has comparable power to continuous EFS when evaluating clinical trials in DLBCL. Patients with DLBCL who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. EFS24 will be useful in patient counseling and should be considered as an end point for future studies of newly diagnosed DLBCL.

Prognostic Value of Six Germline Single Nucleotide Polymorphisms At the REL, HLA-DRA, GATA3 and PVT1 Loci Identified in a Classical Hodgkin Lymphoma Genome-Wide Association Study: A Meta-Analysis of 601 Patients for Progression-Free Survival From Two Independent Studies

AbstractAbstract 3637 Background:A recent large genome-wide association study confirmed the important role of the major histocompatibility complex in classical Hodgkin Lymphoma (cHL) susceptibility (rs6903608), but also identified significant associations with genetic variants outside of the HLA region at chromosomal regions 2p16.1 (REL, rs1432295), 8q24.21 (PVT1, rs2608053, rs2019960), and 10p14 (GATA3, rs501764, rs485411). These single nucleotide polymorphisms (SNPs) are localized in or near important genes involved in lymphoma pathogenesis: REL, which encodes for c-rel, is a member of NFkB pathway; PVT1, which is downstream of the MYC locus, encodes for non-coding microRNAs, some of which have oncogenic properties; and GATA3, which is a critical transcriptional factor for priming lymphoid T-cells for Th2 phenotype, is aberrantly expressed in HL. We investigated whether these six SNPs described in cHL etiology also influence the outcome of newly diagnosed cHL patients in two independent cohorts. Patients and Methods:The first cohort consisted of 342 cHL patients from the Groupe d’Etude des Lymphomes de l’Adulte (GELA) who were prospectively enrolled between 1998 and 2002. The second cohort consisted of 259 patients prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER). DNA for genotyping was extracted from a blood samples collected at diagnosis, and genotyping was conducted using Taqman technology (ABI Prism 7000, Applied Biosystems) for HLA-DRA, PVT1, GATA3 and PCR-based restriction fragment length polymorphism for REL in GELA cohort and Illumina iSelect for the 6 SNPs in MER cohort. Both cohorts were followed for disease progression, re-treatment and death. In the GELA series, the median age was 32 years (range, 15–93), 57% were male, and 72% had an Ann Arbor stage I–II. Histology was nodular sclerosis in 84%, and 29% of available cases (n=40/140) were EBV positive. In the MER series, the median age was 38 years (range, 18–89), 53% were male, and 53% had an Ann Arbor stage I-II. Nodular sclerosis was the most common subtype (62%) and 23 of 115 available cases were EBV positive (20%). The International Prognostic Score (IPS) was 0–1 in 46% and 52% of GELA and MER patients, respectively. ABVD regimen was used for 60% and 88% of the GELA and MER patients, respectively. The 5-year progression free survival (PFS) was 83% and 75% in GELA and MER cohorts, respectively. We estimated the prognostic value of each individual SNP for PFS for allelic and genotypic (dominant and recessive) modes of transmission in each series. In order to increase power, we then performed a meta-analysis of the two studies. Results:Consistent with prior reports, the minor allele frequencies for REL (rs1432295), HLA-DRA (rs6903608), PVT1 (rs2608053), PVT1 (rs2019960), GATA3 (rs501764) and GATA3 (rs485411) were 0.44, 0.50, 0.43, 0.29, 0.22, 0.28 in the GELA and 0.46, 0.41, 0.46, 0.27, 0.25, 0.31 in the MER series, respectively. In GELA, GATA3 (rs501767) was associated with PFS in the ordinal model (HR=1.66, 95%CI 1.11–2.49, P=.01), while there were suggestive associations for PVT1 (rs2608053) (HR=1.76, 95%CI 0.95–3.26, P=.07) and REL (rs1432295) (HR=0.63, 95%CI 0.37–1.06, P=.08) in the dominant model. In the MER, PVT1 (rs2608053) was associated with PFS in the ordinal model (HR=1.42, 95%CI 0.99–2.03, P=.06), while there was a suggestive association with HLA-DRA (rs6903608) in the dominant model (HR=0.64, 95%CI 0.39–1.05, P=.08) for whole cohort but also for EBV negative cHL (HR=0.41, 95%CI 0.17–0.99, P=.05). In a meta-analysis of the two studies, PVT1 (rs2608053) was significantly associated with PFS in the ordinal (HR=1.34, 95%CI 1.04–1.73, P=.02) and the dominant (HR=1.88, 95%CI 1.20–2.95, P=.006) models. Further adjustment for IPS had minimal impact on these associations (ordinal HR=1.30, 95%CI 1.00–1.70; dominant HR=1.78, 95%CI 1.13–2.83). Patients with PVT1(rs2608053) GG, GA, AA genotypes had a 5-year PFS rate of 83%, 74% and 73% in GELA and 86%, 70%, and 73% in the MER, respectively. Conclusions:The non-HLA cHL susceptibility locus PVT1 (rs2608053) was associated with PFS in two independent cohorts of cHL cases, and after adjustment for the IPS. While associations with GATA3 and REL were only observed in one of the studies, their evaluation in other studies is warranted. Functional studies of PVT1 in cHL pathogenesis should be pursued. Disclosures:No relevant conflicts of interest to declare.

Expression of MYC, IgM, As Well As Non-Germinal Centre B-Cell Like Immunophenotype and Positive Immunofish Index Predict a Worse Progression Free Survival and Overall Survival in a Series of 670 De Novo Diffuse Large B-Cell Lymphomas Included in Clinical Trials: A GELA Study of the 2003 Program

AbstractAbstract 1539 IntroductionDiffuse large B-cell lymphomas (DLBCL) represent a heterogeneous disease with variable clinical outcome. Identifying phenotypic biomarkers of tumor cells on paraffin sections that predict different clinical outcome remain an important goal that may also help to better understand the biology of this lymphoma. Differentiating non-germinal centre B-cell-like (non-GCB) from Germinal Centre B-cell-like (GCB) DLBCL according to Hans algorithm has been considered as an important immunohistochemical biomarker with prognostic value among patients treated with R-CHOP although not reproducibly found by all groups. Gene expression studies have also shown that IgM expression might be used as a surrogate for the GCB and ABC subtypes with a strong preferential expression of IgM in ABC DLBCL subtype. ImmunoFISH index based on the differential expression of MUM-1, FOXP1 by immunohistochemistry and on the BCL6 rearrangement by FISH has been previously reported (C Copie-Bergman, J Clin Oncol. 2009;27:5573-9) as prognostic in an homogeneous series of DLBCL treated with R-CHOP. In addition, oncogenic MYC protein overexpression by immunohistochemistry may represent an easy tool to identify the consequences of MYC deregulation in DLBCL.Our aim was to analyse by immunohistochemistry the prognostic relevance of MYC, IgM, GCB/nonGCB subtype and ImmunoFISH index in a large series of de novo DLBCL treated with Rituximab (R)-chemotherapy (anthracyclin based) included in the 2003 program of the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials. MethodsThe 2003 program included patients with de novo CD20+ DLBCL enrolled in 6 different LNH-03 GELA trials (LNH-03-1B, −B, −3B, 39B, −6B, 7B) stratifying patients according to age and age-adjusted IPI. Tumor samples were analyzed by immunohistochemistry using CD10, BCL6, MUM1, FOXP1 (according to Barrans threshold), MYC, IgM antibodies on tissue microarrays and by FISH using BCL6 split signal DNA probes. Considering evaluable Hans score, 670 patients were included in the study with 237 (35.4%) receiving intensive R-ACVBP regimen and 433 (64.6%) R-CHOP/R-mini-CHOP. Results304 (45.4%) DLBCL were classified as GCB and 366 (54.6%) as non-GCB according to Hans algorithm. 337/567 cases (59.4%) were positive for the ImmunoFISH index (i.e. two out of the three markers positive: MUM1 protein positive, FOXP1 protein Variable or Strong, BCL6 rearrangement). Immunofish index was preferentially positive in the non-GCB subtype (81.3%) compared to the GCB subtype (31.2%), (p<0.001). IgM was recorded as positive in tumor cells in 351/637 (52.4%) DLBCL cases with a preferential expression in non-GCB 195 (53.3%) vs GCB subtype 100(32.9%), p<0.001). MYC was positive in 170/577 (29.5%) cases with a 40% cut-off and in 44/577 (14.2%) cases with a cut-off of 70%. There was no preferential expression of MYC among GCB or non-GCB subtype (p>0.4) for both cut-offs.Progression-free Survival (PFS) was significantly worse among patients with high IPI score (p<0.0001), IgM positive tumor (p<0.0001), MYC positive tumor with a 40% threshold (p<0.001), ImmunoFISH positive index (p<0.002), non-GCB DLBCL subtype (p<0.0001).Overall Survival (OS) was also significantly worse among patients with high IPI score (p<0.0001), IgM positive tumor (p=0.02), MYC positive tumor with a 40% threshold (p<0.01), ImmunoFISH positive index (p=0.02), non-GCB DLBCL subtype (p<0.0001).All significant parameters were included in a multivariate analysis using Cox Model and in addition to IPI, only the GCB/non-GCB subtype according to Hans algorithm predicted significantly a worse PFS among non-GCB subgroup (HR 1.9 [1.3—2.8] p=0.002) as well as a worse OS (HR 2.0 [1.3–3.2], p=0.003). This strong prognostic value of non-GCB subtyping was confirmed considering only patients treated with R- CHOP for PFS (HR 2.1 [1.4–3.3], p=0.001) and for OS (HR 2.3 [1.3–3.8], p=0.002). ConclusionOur study on a large series of patients included in trials confirmed the relevance of immunohistochemistry as a useful tool to identify significant prognostic biomarkers for clinical use. We show here that IgM and MYC might be useful prognostic biomarkers. In addition, we confirmed in this series the prognostic value of the ImmunoFISH index. Above all, we fully validated the strong and independent prognostic value of the Hans algorithm, daily used by the pathologists to subtype DLBCL. Disclosures:No relevant conflicts of interest to declare.

MYC Gene Simple Hit Is a Strong Independent Predictive Factor of Survival in Diffuse Large B-Cell Lymphomas in Contrast to MYC Double-Hit Gene Alterations: A Study by the Groupe d'Etude Des Lymphomes De l'Adulte

AbstractAbstract ▪541▪This icon denotes a clinically relevant abstract IntroductionDiffuse large B-cell lymphomas (DLBCL) represent a heterogeneous group of tumors with variable clinical, morphological, and molecular features. The International Prognostic index (IPI) imperfectly stratifies patients and does not reflect the molecular heterogeneity of the disease. New tools for stratifying DLBCL patients in routine practice are needed.The aim of the study was to analyse the prognostic relevance of CMYC, BCL2 and BCL6 rearrangements and the correlation with CMYC protein expression in a large series of 776 CD20+ de novo DLBCL treated with R-chemotherapy included in the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials. MethodsPatients with de novo CD20+ DLBCL were enrolled in the randomized LNH-03 GELA trials (LNH-03-1B, -2B, -3B, 39B, -6B, 7B-, 5B). Seven hundred seventy six patients treated with anthracyclin based chemotherapy (R-CHOP/R-miniCHOP=483 or R-ACVBP=293) were eligible for the study. Tumor samples were analyzed by Fluorescence in situ hybridization (FISH) using split signal FISH DNA probes for BCL2/18q21, BCL6/8q27 and CMYC/8q24 and were immunostained for the expression of CMYC protein on tissue microarrays. ResultsFive hundred seventy six DLBCL samples were evaluable for MYC rearrangement. Rearrangement of MYC, BCL2, and BCL6 genes were observed in 9.2% (53/576), 15.9 % (82/515), and 23.8% (129/541) of DLBCL, respectively. Fifteen cases showed both BCL2/BCL6 gene rearrangement. MYC rearranged cases (MYC-R+) included 21 MYC simple-hit (MYC-SH) and 32 MYC double or triple hit with concurrent BCL2 and/or BCL6 rearrangement (MYC-DH) DLBCL. There were 33 male and 20 women, with a median age of 62 years [range, 18–93], and 5 were stage I-II and 48 stage III-IV according to Ann Arbor. The common histological feature of the MYC-SH cases was an increased mitotic rate but a starry sky pattern with tingible body macrophages was observed only in 2 cases. MYC protein expression was found positive in 30/45 (66%) evaluable MYC-R+ cases using a cut off of ≥70% of positive tumor cells.In univariate analysis, IPI had a significant impact on OS (P< .0001). BCL2, BCL6 gene alterations did not significantly predict survival (PFS, EFS, OS). MYC-R+ breakpoint was associated with a shorter 5-year OS rate (57.7% vs 73.7%, P= 0.01) which remained significant in the R-CHOP treated group of patients (P=0.04). When separating MYC-SH and MYC-DH DLBCL, MYC-SH maintained a significant impact on survival in the global population as well as in the R-CHOP group of patients. By contrast, MYC-DH had no significant impact on OS in the global population and in the R-CHOP group of patients. In multivariate analysis, the prognostic impact of the IPI, MYC-R+ and MYC-SH breakpoint remained significant. ConclusionThis is the first large extensive study on the prognosis impact of MYC rearrangement in controlled trial of DLBCL patients treated with R-chemotherapy. MYC-SH had an adverse prognostic effect on survival. Interestingly, in contrast to previous published studies, this impact was not maintained in the MYC-DH DLBCL suggesting different biological response to treatment between the two groups. Immunostaining for MYC protein was not efficient to detect MYC rearranged cases. FISH for MYC, BCL2 and BCL6 should be performed systematically to differentiate MYC-SH and MYC-DH in future clinical trials. Disclosures:No relevant conflicts of interest to declare.

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Attenuated immunochemotherapy for diffuse large B-cell lymphoma

In the May, 2011, issue of The Lancet Oncology, Frédéric Peyrade and colleagues reported the efficacy and safety of a decreased dose of CHOP (doxorubicin, cyclophosphamide, vincristine, and prednisone) chemotherapy with a conventional dose of rituximab for patients older than 80 years of age with diffuse large B-cell lymphoma (DLBCL).1 The results of their investigation—done by the Groupe d'Etude des Lymphomes de l'Adulte (GELA)—were uniformly excellent and had a vital effect on the management of very elderly patients with DLBCL.

A therapeutic dilemma between the two "R"s: additional rituximab or radiotherapy for limited, non-bulky diffuse large B-cell lymphoma

TO THE EDITOR: Limited disease, defined as Ann Arbor stage I and non-bulky stage II, accounts for approximately 25% of diffuse large B-cell lymphomas (DLBCLs). Since the Southwest Oncology Group (SWOG) study 8736 demonstrated that 3 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) followed by involved-field radiotherapy (IFRT) was superior to 8 cycles of CHOP [1], a short course of chemotherapy followed by IFRT has been the main treatment for limited, non-bulky DLBCL. This treatment strategy has not changed even after the efficacy of rituximab-CHOP (R-CHOP) was proved in the Groupe d'Etude des Lymphomes de l'Adulte (GELA) study of advanced-stage DLBCL [2]. Hence, the current National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines (Version I. 2011) recommend 2 treatment options for stage I/II, non-bulky DLBCL: 3 cycles of R-CHOP with subsequent IFRT and 6 cycles of R-CHOP with or without IFRT. However, the role of radiotherapy for controlling localized DLBCL has been debatable because radiotherapy-associated toxicity may deteriorate the quality of life as well as survival outcome, and in many patients, the disease may relapse outside the radiation field [1, 3]. There is also the risk of secondary malignancies caused by exposure to the radiation field [1, 3]. This controversial use of radiotherapy for consolidation has been augmented by the result of a GELA trial (LNH 93-4) that compared 4 cycles of CHOP with or without IFRT for patients older than 60 years with limited DLBCL and showed similar outcomes [3]. The need for radiotherapy has been challenged since R-CHOP was used as standard treatment for patients with DLBCL. No study has compared the effect of a short course of R-CHOP plus radiotherapy with extended cycles of R-CHOP alone for limited DLBCL; hence, physicians can choose to perform IFRT or 3 additional cycles of R-CHOP at their discretion. Because the selection of a treatment modality for consolidation after 3 cycles of R-CHOP is debatable, 3 additional cycles of R-CHOP or IFRT are suggested as a therapeutic option in the NCCN guidelines. In the previous issue, Hong et al. reported the results of comparing 3-4 cycles of R-CHOP plus IFRT with 6-8 cycles of R-CHOP alone in limited, non-bulky DLBCL [4]. The 2 groups that were compared showed similar 3-year overall survival (OS). Their OS was comparable to that observed in a previous study (SWOG 0014) that tested the utility of adding 4 doses of rituximab to 3 cycles of CHOP with subsequent IFRT [5]. However, the study by Hong et al. involved a retrospective analysis with a small number of patients. Their results do not provide information helpful in selecting a treatment strategy. Furthermore, extended cycles of R-CHOP might increase the risk of febrile neutropenia, as evidenced by 1 treatment-related mortality that occurred in the group that underwent 6-8 cycles of R-CHOP [4]. Therefore, the selection of additional R-CHOP or IFRT as a consolidation for limited, non-bulky DLBCL will remain a therapeutic dilemma until a prospective study involving a large study population is conducted.

Hematopoietic stem cell transplantation for Hodgkin's disease

Autologous stem cell transplantation (aHSCT) has been considered the gold treatment following salvage chemotherapy for relapsed or refractory Hodgkin's lymphoma. The first randomized trial comparing conventional chemotherapy and aHSCT was published in 1993.(1) Forty patients received BCNU, etoposide, cytarabine, and melphalan (BEAM) as conditioning regimen followed by aHSCT or mini-BEAM in the chemotherapy arm. The results indicated the superiority of transplantation. The European Group for Blood and Marrow Transplantation published a confirmatory randomized study (n = 161 patients), in which dexa-BEAM was chosen for the chemotherapy control arm.(2) With a median follow-up of 3 years, event-free survival (EFS) was 55% versus 34% for the transplant and chemotherapy arms, respectively, reinforcing the recommendation that high-dose chemotherapy with aHSCT rescue should be the treatment of choice for relapsed or refractory disease. Several models have been employed to predict outcomes in patients with relapsed/refractory Hodgkin's lymphoma who undergo high-dose chemotherapy followed by aHSCT. Moskowitz et al. proposed the use of three factors: complete remission < 1 year, presence of B-symptoms and extranodal disease at the time of relapse. Patients with 0-1 risk factors had an EFS of 83%, while patients with 2 and 3 factors had EFS of 27% and 10%, respectively.(3) More recently, functional studies to assess chemosensitivity (FI; PET scan, Ga67 scan) performed before transplant have become excellent prognostic tools.(4,5) Persistence of positive FI before aHSCT identifies a group of patients who will have a worse outcome than those with negative FI after finishing salvage chemotherapy. Chemosensitive disease has better outcomes with autologous transplants, given the higher relapse and toxicity rates among chemorefractory patients. Several approaches have been proposed to overcome this barrier, including tandem transplants. In this approach, patients are submitted to two sequential autologous transplants, usually within one to three months. An investigation by the German Hodgkin Lymphoma Study Group enrolled 43 primary refractory or very unfavorable relapse patients. Patients received salvage chemotherapy with ifosfamide, etoposide and woxorubicin (IVA), underwent stem cell collection and two tandem transplants.(6) Conditioning regimen for the first aHSCT consisted of CBV plus mitoxantrone, while the second transplant was with cytarabine 6 g/m2, melphalan 140 mg/m2 and total body irradiation of 12 Gy, or busulfan 12 mg/kg. Four patients had no response to salvage therapy, seven patients received only one transplant and 32 patients completed the initially planned treatment. Among the 24 patients with unfavorable relapses, 20 achieved complete remission and among the 19 patients with induction failure, ten were in remission. The 2-year survival from the date of progression was 65% for the whole study population, while it was 74% for the 32 patients who completed the treatment. The Groupe d'Etude des Lymphomes de l'Adulte (GELA) treated 245 patients with relapsed disease - 150 of which had primary refractory or very high-risk disease - with a protocol including IVA or MINE for salvage, and single or tandem autologous transplants.(7) Patients with standard risk received the first transplant only, while primary refractory or very high-risk patients proceeded to tandem transplants. The first conditioning regimen included cyclophosphamide, carmustine, etoposide and mitoxantrone, while the second transplant, performed 45 to 90 days after the first, used total body irradiation at 12 Gy, cytarabine and melphalan, or busulfan-based preparative regimen, similar to the German study. With a median follow-up of 51 months, in an intention to treat analysis, 5-year progression-free and overall survival were 46% and 57% for high-risk patients, and 73% and 85% for the standard risk group, respectively. In addition, the 5-year overall survival for patients with chemotherapy-resistant disease was 46% (as opposed to an expected rate of 30% observed in previous studies). These results would suggest that patients who do not respond well to salvage chemotherapy or for early (occurring less than 1 year after achievement of remission), unfavorable relapses, tandem transplants may be superior to standard single aHSCT. There are several unresolved controversies surrounding this issue, however, and this recommendation is not universally accepted. Allogeneic transplants have been explored in younger patients who relapse following aHSCT, but are still considered experimental and should be performed within a clinical trial. There is still controversy as to whether a graft-versus Hodgkin's disease effect exists. However, long-term survival rates of 10-40% have been reported for selected patients. For those without matched related or unrelated donors, several centers are investigating haploidentical (mismatched related) or unrelated cord blood transplantation. Outcomes are better for chemosensitive patients, especially for those that achieve complete remission prior to transplant.(8-10) Non-transplant options include everolimus, and the immunotoxin, brentuximab vedotin drugs that have recently been shown to have activity in relapsing/refractory Hodgkin's lymphoma. In summary, patients with relapsed disease should be referred for transplantation. Hodgkin's lymphoma, however, remains a challenging disease for the minority of patients that are not cured after initial chemotherapy.

Current treatment strategy of diffuse large B-cell lymphomas

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma, accounting for approximately 25-30% of all new patients. Rituximab, a genetically engineered chimeric monoclonal antibody that specifically binds to CD20, is the first monoclonal antibody approved for the treatment of B-cell lymphoma. Rituximab significantly improves treatment outcome in DLBCL. A large-phase III study demonstrated improved overall survival (OS) in patients with DLBCL treated with R-CHOP therapy. The Groupe d'Etude des Lymphomes de l'Adulte (GELA), Eastern Cooperative Oncology Group (ECOG) and German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) studies designed for patients older than 60 years have clearly shown prolonged event-free survival (EFS) and OS among patients who received rituximab and chemotherapy. For patients under 60 years, the MabThera International Trial Group (MInT) study demonstrated improved EFS and OS after the addition of rituximab to CHOP therapy. However, the R-CHOP therapy does not provide a satisfactory treatment outcome in the high-risk group according to the international prognostic index. Therefore, R-CHOP therapy is the new standard therapy in elderly and young, low-risk DLBCL patients. For young, high-risk DLBCL patients, treatment that incorporates rituximab and hematopoietic stem cell transplantation has been administered in clinical studies.

Long-term follow-up of an age-adapted C5R protocol followed by radiotherapy in 99 newly diagnosed primary CNS lymphomas: a prospective multicentric phase II study of the Groupe d’Etude des Lymphomes de l’Adulte (GELA)

BackgroundThis prospective multicentric phase II study aimed to confirm the results of the C5R protocol of high-dose methotrexate (MTX)-based chemotherapy (CT) for immunocompetent primary central nervous system lymphoma. Patients and methodsA total of 99 patients received age-adapted CT (C5R protocol) followed by radiotherapy. Patients younger than 61 years (group 1, n = 45) received the full C5R with MTX, doxorubicin, vincristine, cyclophosphamide, and cytarabine. Patients aged 61–70 years (group 2, n = 36) received reduced doses. Patients older than 70 years (group 3, n = 18) received four courses of MTX, cyclophosphamide, and etoposide. ResultsMedian age was 63 years and 51% of patients had performance status of more than one. Seventeen patients died of toxicity during CT. Complete response was achieved in 56%, 53%, and 28% of patients in groups 1, 2, and 3, respectively. With a median follow-up of 83 months, the 5-year progression-free survival was 31%, 28%, and 11% and the 5-year overall survival 42%, 31%, and 17% for groups 1, 2, and 3, respectively. Leukoencephalopathy occurred in 32% of assessable patients, in both group 1 and groups 2–3. ConclusionThe C5R protocol was feasible in the multicentric setting with favorable long-term survival in patients younger than 60 years. Despite dose adaptation, results in older patients were disappointing.

Efficacy and Safety of Prophylactic Use of Darbepoetin Alfa in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Immunochemotherapy: Results of the Interim Analysis of the LNH03-6B GELA Study.

Abstract 1701Poster Board I-727 IntroductionThere are still controversies about the impact of erythropoiesis stimulating agents (ESA) on survival of patients with malignancies. The Groupe d'Etude des Lymphomes de l'Adulte (GELA) has conducted a multicentric prospective randomized phase III study to evaluate efficacy and safety of Darbepoetin alfa (DA) in elderly patients with DLBCL treated by immunochemotherapy. Here, we report the results of the planned interim analysis, held after the inclusion of the first 202 patients, with a median follow-up of 24 months.Patients and methods: Patients between 60 and 80 years old with DLBCL and aaIPI ≥ 1 were eligible. They were firstly randomized between two immunochemotherapy regimens combining Rituximab and CHOP given every 2 (R-CHOP14) or 3 weeks (R-CHOP21) for 8 cycles. They were subsequently randomized between an investigational arm with DA (Arm 1) given in order to maintain hemoglobin level between 13 and 15 g/dL and a conventional arm (Arm 2) with usual management of chemotherapy-induced anemia, including red blood cell transfusions and ESA according to usual practices. The objective was to evaluate the efficacy of DA in association with chemotherapy (R-CHOP) as measured by the EFS at 2 years, events being defined as death from any cause, relapse for complete responders and unconfirmed complete responders, progression during or after treatment and changes of therapy during allocated treatment. Secondary objectives were OS, PFS, DFS, response rate and analysis of toxicity. Results202 patients were included and 201 received study treatment ; 90 patients were randomized in DA group and 111 in conventional treatment group. Median age was 72 years. Patients' characteristics were similar in both arms with a slightly higher proportion of patients with aaIPI 2-3 in conventional arm : 68% compared to 56% (p=NS). Median hemoglobin (Hb) level at randomization was 12.2 g/dL. The median Hb level during treatment in DA arm was 11.9 g/dL and 10.7 g/dL in conventional arm respectively. Overall, 41 patients in conventional group received at least one dose of ESA during treatment. Eighteen percent of patients in DA group had at least one episode of Hb > 15 g/dL during treatment compared to 6% in conventional treatment group. Response rate (CR+CRu) after treatment was similar in both groups (69% in DA arm, 72% in conventional arm). Two-year EFS was 59% in DA arm compared with 49% in conventional arm (p=NS). A similar trend was observed for 2-year PFS (61% vs 51%), 2-year DFS (71% vs 56%) and 2-year OS (74% vs 63%) (p=NS for all). Grade 3-4 hematological toxicity was similar in the two groups. In contrast, proportion of patients receiving at least 1 red cell transfusion was higher in conventional arm (49% versus 36%). A total of 288 AEs were reported as serious (130 in DA group and 158 in symptomatic treatment group), concerning 122 patients (61%). Most SAEs were related to infectious complications. The rate of thromboembolic SAEs (composite criteria with pulmonary embolism, venous thrombosis from any site, coronary disease including myocardial infarction and cerebrovascular event) is slightly higher in DA group (13 SAEs) than in conventional arm (9 SAEs). Finally, the number of patients who died because of treatment toxicity was comparable in DA group (6 patients, 7%) and in conventional treatment group (7 patients, 6%). ConclusionsThe results of interim analysis of the LNH 03-6B provide encouraging results about efficacy and safety of a prophylactic use of DA in this population. It should be confirmed by the final analysis of the LNH03-6B trial which is planned in 2010. DisclosuresNo relevant conflicts of interest to declare.

Do six or eight cycles work better with CHOP-14 and rituximab?

Introduction: Diffuse large B-cell lymphoma (DLBCL) remains the most common form of non-Hodgkin lymphoma and presents with a median age of 65 to 67 years. Furthermore, as a consequence of population demographics, DLBCL is increasingly affl icting an older patient population, with those older than 60 years of age representing the fastest-growing age cohort [ 1 ]. Frequently, patients in this group will have a single chance at curative outcome. The results from the GELA (Groupe d’Etude des Lymphomes de l’Adulte) study have demonstrated improved survival with the addition of rituximab to standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy; however, with long-term follow-up, the benefi t appears greatest for those in the low-risk category [ 2 ]. Strategies to further improve upon these results will be imperative given the increasing incidence in the elderly and relapse rates that still approximate 40%. Concurrent work from the DSHNHL (German High-Grade Non-Hodgkin’s Lymphoma Study Group) in its NHL-B-2 study demonstrated a survival advantage in elderly patients when CHOP chemotherapy was administered in a dose-dense manner every 2 weeks rather than every 3 weeks [ 3 ]. Subsequently, the obvious and clinically relevant question has revolved around the impact of dosedense strategies in the chemoimmunotherapy era.

Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials

AbstractTo evaluate the prognostic significance of clinicobiologic and pathological features in angioimmunoblastic T-cell lymphoma (AITL), 157 AITL patients were retrieved from the GELA LNH87-LNH93 randomized clinical trials. One hundred forty-seven patients received a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)–like regimen with intensified courses in half of them. Histologically, 41 cases were classified as “rich in large cells” and 116 as “classic” (including 19 rich in epithelioid cells, 14 rich in clear cells, and 4 with hyperplastic germinal centers). Sixty-two cases were scored for CD10 and CXCL13 expression according to the abundance of positive lymphoid cells. Median age was 62 years, with 81% advanced stage, 72% B symptoms, 65% anemia, 50% hypergammaglobulinemia, and 66% elevated LDH. Overall 7-year survival was 30%. In multivariate analysis, only male sex (P = .004), mediastinal lymphadenopathy (P = .041), and anemia (P = .042) adversely affected overall survival. Increase in large cells and high level of CD10 and CXCL13 did not affect survival. Intensive regimen did not improve survival. In conclusion, AITL is a morphologically heterogeneous T-cell lymphoma commonly expressing CXCL13 and CD10 and carrying few prognostic factors. It portends a poor prognosis even when treated intensively. However, AITL is not always lethal with 30% of patients alive at 7 years.

Expression of the granzyme B inhibitor PI9 predicts outcome in nasal NK/T-cell lymphoma: results of a Western series of 48 patients treated with first-line polychemotherapy within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials

AbstractNasal NK/T-cell lymphoma is a rare disease entity with a poor outcome. Expression of antiapoptotic proteins has not been extensively investigated in this entity. Forty-eight patients with nasal T/NK-cell lymphoma who received first-line polychemotherapy (n = 44) or chemoradiotherapy (n = 4) were analyzed for expression of active caspase-3 (aC3), granzyme B protease inhibitor 9 (PI9), and Bcl-2 proteins. Lymphomas were CD3+/CD5−/granzyme B+ and EBV-associated. Median age was 46 years. Stage I/II disease was present in 75% of the cases and an International Prognostic Index (IPI) score less than 1 in 65%. With a median follow-up of 6.3 years, 5-year event-free survival (EFS) and overall survival (OS) rates were 39% and 49%, respectively. Apoptotic index was scored as high in 32% of cases and PI9 expression as positive in 68%, whereas 35% disclosed a high number of aC3+ tumor cells. Univariate analysis showed that absence of PI9 and low apoptotic index were associated with poor outcome, but not aC3 expression nor IPI score. By multivariate analysis, both parameters affected independently EFS (P = .02 and .08, respectively) and OS (P = .009 and .04). In view of its constitutive expression by normal NK cells, it is suggested that loss of PI9 expression in tumor cells may reflect some mechanism associated with progression.

Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA)

AbstractThe purpose of this study is to compare our standard chemotherapy regimen (CHVP [cyclophosphamide, doxorubicin, teniposide, and prednisone]) plus interferon with 4 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by high-dose therapy with autologous stem cell transplantation (ASCT) in treatment-naive patients with advanced follicular lymphoma. Four hundred one patients were included from July 1994 to March 2001: 209 received 12 cycles of CHVP plus interferon α for 18 months (CHVP-I arm) and 192 received 4 cycles of CHOP followed by high-dose therapy (HDT) with total body irradiation and ASCT (CHOP-HDT arm). Overall response rates were similar in both groups (79% and 78% after induction chemotherapy, respectively). One hundred thirty-one of the 150 patients eligible for HDT underwent transplantation (87%). Intent-to-treat analysis after a median follow-up of 7.5 years showed that there was no difference between the 2 arms for overall survival (P = .53) or event-free survival (P = .11). Patients with a complete response at the end of the induction therapy had a statistically longer event-free survival and overall survival (P = .02 and < .001, respectively). After long-term follow-up, our study showed that there was no statistically significant benefit in favor of first-line high-dose therapy in patients with follicular lymphoma. High-dose therapy should be reserved for relapsing patients.

Estimating the impact of rituximab on bcl-2-associated resistance to CHOP using competing risks in elderly patients with diffuse large B-cell lymphoma (DLBCL)

7514 Background: In diffuse large B-cell lymphoma, the combination of rituximab and CHOP (R-CHOP) has been proved to reduce bcl-2-associated treatment failure in elderly patients. However, some deaths could be due to age-associated morbidity such as cardio-vascular events. Patients and Methods: We therefore, addressed the question of its long-term impact by a competing risks analysis of 292 patients from the previously updated LNH-98–5 trial by the Groupe d’Etude des Lymphomes de l’Adulte (GELA) (Feugier et al, J Clin Oncol 2005). Using the competing risk formulation of Cox model regression, we investigated the effect of the explanatory variables on different competing events during the disease’s course such as progression, relapse, or death. Results: With a median follow-up of 5 years, R-CHOP was associated with a better survival than CHOP in 193 bcl-2-positive patients (56 ± 9% vs 42 ± 11%, P = 0.01), whereas in 99 bcl-2-negative patients there was no difference (58 ± 14% vs 52 ± 15% vs, P = 0.6). Results of competing risks analysis are given in table. Of particular interest, R-CHOP significantly decreased the risk of progression or relapse in both bcl-2-positive (RR = 2.6, P &lt; 0.001) and bcl-2 negative (RR = 2.2, P = 0.01) and had no impact on the risk of death in complete remission patients (age over 70 remained an adverse factor). After relapse, aa-IPI 2–3 (RR = 2.9, P &lt; 0.0001) and bcl-2 overexpression (RR = 1.5, P = 0.03) had still a significant effect on the risk of death but not front-line R-CHOP and age above 70. Conclusion: These findings highlight the role of rituximab in the sensitization to drug-induced apoptosis without inducing long-term sequel. However, Bcl2 positive patients failed to salvage treatment after relapse. [Table: see text] No significant financial relationships to disclose.

Long-term results and competing risk analysis of the H89 trial in patients with advanced-stage Hodgkin lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte (GELA)

AbstractFrom 1989 to 1996, 533 eligible patients with stage IIIB/IV Hodgkin lymphoma (HL) were randomly assigned to receive 6 cycles of hybrid MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone/Adriamycin [doxorubicin], bleomycin, vinblastine; n = 266) or ABVPP (doxorubicin, bleomycin, vinblastine, procarbazine, prednisone; n = 267). Patients in complete remission (CR) or partial response of at least 75% after 6 cycles received 2 cycles of consolidation chemotherapy (CT) (n = 208) or subtotal nodal irradiation (RT) (n = 210). A better survival probability was observed after ABVPP alone: the 10-year overall survival (OS) estimates were 90% for ABVPP×8, 78% for MOPP/ABV×8, 82% for MOPP/ABV with RT, and 77% for ABVPP×6 with RT (P = .03); and the 10-year disease-free survival (DFS) estimates were 70%, 76%, 79%, and 76%, respectively (P = .09). The 10-year DFS estimates for patients treated with consolidation CT or RT were 73% and 78% (P = .07), and OS estimates were 84% and 79%, respectively (P = .29). These results showed that RT was not superior to consolidation CT after a doxorubicin-induced CR in patients with advanced HL. An analysis of competing risks identified age more than 45 years as a significant risk factor for death, relapse, and second cancers. Prospective evaluation of late adverse events may improve the management of patients with HL.