Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols
TL;DR: It is suggestive that a dense infiltrate of FoxP3-positive T cells, dense and interfollicular infiltrate of CD68-positive macrophages and complete follicular dendritic meshworks were associated with a favorable time to progression in CVP-treated patients, while being poor prognostic sign in fludarabine- treated patients.
Abstract: Background The clinical behavior of follicular lymphoma is largely determined by properties of the non-malignant tumor microenvironment. The precise nature of the cell populations is still unclear and published data on their prognostic significance are highly conflicting. This may be partly due to heterogeneous composition and tr eatments. Design and Methods Pre-treatment biopsy samples of patients with follicular lymphoma treated in an EORTC/BNLI trial comparing fludarabine to cyclophosphamide, vincristine and prednisone (CVP) chemotherapy could be retrieved for 61 patients in five Eur opean countries. Immunohistochemical investigations were performed to evaluate tumor cell characteristics, T-cell subsets, follicular dendritic cells and macrophages and associations with clinical outcome were studied. Results Some markers showed a homogeneous prognostic impact, while others had a different and sometimes opposite effect in the treatment arms. CD69 expression on tumor cells was a poor prognostic sign and an interfollicular infiltrate of FoxP3-positive T cells was a good prognostic sign irrespective of the treatment arm. It is suggestive that a dense infiltrate of FoxP3-positive T cells, a dense and interfollicular infiltrate of CD68-positive macr ophages and complete follicular dendritic meshworks were associated with a favorable time to progression in CVP-treated patients, while being a poor prognostic sign in fludarabine-treated patients. Conclusions Our results suggest that characteristic properties of the microenvironment in follicular lymphoma determines the responses to essentially different chemotherapeutic approaches. These data may provide an explanation for the highly conflicting r esults on immunohistochemical markers and the prognostic role of the microenvironment in follicular lymphoma reported thus far and lay the basis for the development of predictive assays to tailor treatment in patients with follicular lymphoma.
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TL;DR: There are arguments in favour of considering early aggressive rituximab and chemotherapy regimens in patients with FL requiring treatment, and it is hoped that new prognostic tools will help to more accurately identify which patients are most likely to benefit.
Abstract: Follicular lymphoma (FL), the most common subtype of indolent lymphoma, is usually diagnosed at an advanced stage (III-IV), although patients are often asymptomatic. Traditionally, a palliative approach to management has been taken, cycling through watchful waiting, radiotherapy, oral alkylating agents and, eventually, combination chemotherapy, as deemed necessary. However, accumulating evidence suggests that in patients requiring treatment, early initiation of an anthracycline-based regimen may achieve better response rates and progression-free survival compared with reserving such options until late in the course of disease. Delivery of myelosuppressive chemotherapy has been facilitated by the availability of granulocyte colony-stimulating factors. Incorporation of the anti-CD20 monoclonal antibody rituximab into upfront chemotherapy regimens further improves outcomes. With a trend towards early use of rituximab chemotherapy combinations, median survival appears to have increased in patients with FL. A number of issues remain to be addressed by ongoing research. These include identification of the most effective rituximab chemotherapy regimen, the impact of treatment on responsiveness to future treatment, the need for rituximab maintenance therapy and the place of newer treatments. Clearly, there are arguments in favour of considering early aggressive rituximab and chemotherapy regimens in patients with FL requiring treatment, and it is hoped that new prognostic tools will help us to more accurately identify which patients are most likely to benefit.
1 citations
Cites background from "Impact of the tumor microenvironmen..."
...[1,6] The Groupe D’Étude des Lymphomes Folliculaires found that watching and waiting, prednimustine (200mg/m2 for 5 days/month for 18 months) and interferon-a (5 MU daily for 3 months then three times weekly for 15 months) achieved similar survival outcomes in patients with low-burden FL.[7] However, neither of the ª 2009 Adis Data Information BV....
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...For instance, the prognostic significance of T cell-based markers appears to differ between patients treated with fludarabine, which specifically targets T cells, and those treated with CVP.[43] Molecular characteristics of the malignant cell itself may correlate with the host immune microenvironment....
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...Where treatment is indicated, patients with high FLIPI scores are treated with R-CHOP if fit; all other patients receive R-CVP....
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...Drugs 2009; 69 (13) two active treatments given can be regarded as aggressive or as standard therapy for FL....
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...Its broad-range antilymphoma activity encompasses DLBCL and FL. Asmonotherapy...
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TL;DR: A single-institution retrospective study in which patients with newly diagnosed diffuse large B-cell lymphoma were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone–like regimens with or without rituximab shows that CD43 might be a biologic prognostic marker for patients with otherwise favorable clinical factors treated with modern immunochemotherapy regimens.
Abstract: In this issue of Clinical Lymphoma & Myeloma, two articles appear regarding prognostic biomarkers in lymphoma. Mitrovic and colleagues detail a single-institution retrospective study in which patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)–like regimens with or without rituximab.1 CD43, a sialoglycoprotein with multiple functions that include cell migration, apoptosis, and cell survival, is expressed on T cells, myeloid cells, and certain B-cell subsets.2-5 It is aberrantly expressed in some B-cell lymphomas, and it is used as part of a panel of markers for the diagnosis of small B-cell lymphomas, T-cell lymphomas, and myeloid sarcoma.6-8 The authors confirmed CD43 expression in a subset of DLBCL and showed that CD43+ DLBCL had inferior complete response rates, 2-year event-free survival, and overall survival (OS) compared with CD43– cases. Strikingly, the effect appeared to be primarily seen in the subset of patients that received rituximab and in patients with low International Prognostic Index (IPI). Thus, CD43 might be a biologic prognostic marker for patients with otherwise favorable clinical factors treated with modern immunochemotherapy regimens. The second article reviews the proceedings of the European School of Haematology (ESH)–European Haematology Association (EHA) workshop on biomarkers and prognosis in malignant lymphoma. This article summarizes the current thinking of a collection of leaders in clinical and translational lymphoma research.9 To illustrate some of the advances while adhering to space and scope restraints, this discussion will focus on 3 entities that have been the subject of the intense activity (follicular lymphoma [FL], mantle cell lymphoma [MCL], and DLBCL), followed by commentary about potential application. In FL, a major theme is the balance between molecular genetic and microenvironmental models.9 The former model involves acquired genetic alterations that take place after the primary IGH-BCL2 translocation (present at low levels in normal individuals) and are involved in oncogenesis and progression of FL.10,11 Recent highresolution single-nucleotide polymorphism (SNP) array studies add to known areas of alteration that include deletion of chromosome 6q (del[6q]), del(1p32-26), +7, +12, and +X, among others.10 In particular, uniparental disomy (UPD; copy-neutral loss of heterozygosity [LOH]) detected by SNP array analysis has been shown to be common at chromosome 1p and chromosome 6p.11 Furthermore, A20 (involved in regulating the nuclear factor– B pathway) and PERP (involved in p53-mediated apoptosis) at chromosome 6q23.3-24.1 have been identified as candidate genes in this homozygously deleted region. These findings have been extended with clinical correlates suggesting that UPD at 1p36 is associated with poor OS and UPD at 16p is associated with transformation and shorter progression-free survival.12 The microenvironmental model, spurred by expression profiling studies and subsequent in situ studies of inflammatory cell infiltrates, posits that non-neoplastic immune response signatures reflect inflammatory cell constituents (such as macrophages and regulatory T-cells) in the tumor microenvironment that interact with the tumor cells and affect the clinical behavior and outcome of FL.13-16 Indeed, FL-associated macrophages have been shown to be a poor prognostic factor in at least 3 separate studies.15,17,18 Controversy and conflicting data, however, do exist for certain markers and might be due to technique and/or treatment regimens.19,20 In a different strategy that would be applicable across other lymphoma types, constitutional SNPs of candidate genes have been examined in FL. In particular, SNPs in IL8, IL2, IL12B, IL1RN, DNA repair genes, and 1 carbon metabolism gene have been associated with short survival.21,22 Such observations await confirmation and detailed biologic studies to explain the mechanisms involved. This will identify useful biomarkers in the host germline that influence lymphoma behavior and could further our understanding of lymphoma biology. For MCL, agreement exists that proliferation of tumor cells is a major determinant of prognosis.23 This is driven home by the observation that overexpression of cyclin D1 and cell-cycle dysregulation is present in almost all cases. In cyclin D1–negative MCL cases, there appears to be alteration in other cyclin D genes.24 As outlined in the ESH-EHA article in this issue,9 proliferation index as assessed by Ki-67 is a practical assay evaluated in patients in the setting of multicenter clinical trials. Indeed, a Mantle Cell Lymphoma IPI that includes a weighting for proliferation has been proposed.25 Diffuse large B-cell lymphoma has arguably seen the most activity in developing prognostic markers that improve upon the IPI. Studies have been greatly aided by information gleaned from genome-wide expression studies. These studies have identified germinal center B-cell–like (GCB) and activated B-cell–like (ABC) subtypes of DLBCL as well as mediastinal large B-cell lymphoma as distinct sets of cases. The GCB and ABC types of DLBCL have different prognoses, with the latter having shorter survival times compared with the former, independent of the IPI.26 Functional gene signatures related to germinal center, lymph node, proliferation, and class II major histocompatibility complex could also be indentified and used to determine a prognostic model that has predicted outcome in patients with DLBCL.27 Importantly, in the ESH-EHA workshop, Clinical Lymphoma & Myeloma Vol. 9, No. 2, 121-123, 2009 DOI: 10.3816/CLM.2009.n.031
1 citations
TL;DR: An ongoing study focuses on the rehabilitation and quality of long-term survival in all 6658 Hodgkin lymphoma patients treated in EORTC trials since the earliest beginning.
Abstract: Since 1964, the EORTC Lymphoma Group has conducted nine consecutive randomized phase III trials on early-stage Hodgkin lymphoma aimed at increasing efficacy while decreasing short- and long-term toxicities. Event-free and overall survival significantly improved from about 50% and 70%, respectively, in the early years to over 80% and 90%, respectively, more recently. Identification of prognostic subgroups appeared to be a successful method to tailor treatment strategies. Radiotherapy fields have become more restricted whereas chemotherapy has become standard. Early PET-CT has been introduced to investigate the possibility of treatment adaptation. Longitudinal quality-of-life assessment has become an integral part of our studies. An ongoing study focuses on the rehabilitation and quality of long-term survival in all 6658 Hodgkin lymphoma patients treated in EORTC trials since the earliest beginning. In advanced stages overall outcome has improved as well with 10-year survival rates of over 75%.
1 citations
01 Jan 2007
TL;DR: It is important to have awareness about trends, risk factors and methods used for committing suicide in order to make remedial measures against this preventable cause of death.
Abstract: Background: Suicidal behavior is a major public health problem. Aims: To know the socio-demographic factors affecting suicidal attempts and the modes of suicidal death. Design: The retrospective observational study. Setting: Forensic Medicine and Toxicology Department of a tertiary care hospital. Subjects and Methods: All autopsies performed between January 2001 to December 2005 were analysed for total number of autopsies performed, allegedly suicide autopsies, mode of suicidal deaths, variation in suicidal deaths in relation to age, sex, place of residence and religion. Statistical Analysis Used: Chi-square test was used to analyse the variability of suicidal deaths with age, sex, place of residence and religion. P-value <0.05 was considered statistically significant. Results: Out of total 3485 autopsies 16.24% (566) were allegedly suicidal autopsies. 335 (59.18%) and 231 (40.82%) victims were males and females respectively (p=0.080). 223 (39.39%) and 343 (60.61%) victims were from urban and rural area respectively (p=0.030). Majority of the victims [373 (65.90%)] were between 20-40years of the age. 463 (81.80%), 64 (11.30%), 37 (3.54%) and 2(0.35%) victims were from Hindus, Muslims, Sikhs and Christian religion (p< 0.0001). Poisoning was found to be the most common mode of suicide [243 (42.93%)], followed by burns [168 (29.69%)], hanging [52 (9.18%)], railway trauma cases [23 (4.06%)] and gunshot [23 (4.06%)]. Conclusion: It is important to have awareness about trends, risk factors and methods used for committing suicide in order to make remedial measures against this preventable cause of death.
1 citations
TL;DR: Key issues in the management of follicular lymphoma are illustrated, by difficulty in accurately predicting individual outcomes and judging whether, when and how best to intervene.
Abstract: Follicular lymphoma is by far the most common indolent non-Hodgkin lymphoma worldwide. Management is complicated by difficulty in accurately predicting individual outcomes and judging whether, when and how best to intervene. This article illustrates key issues in the management of this fascinating and enigmatic disease.
1 citations
References
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TL;DR: The Follicular Lymphoma International Prognostic Index was designed from the data recorded over 8 years of nearly 5000 patients registered worldwide to help provide an optimal treatment option for patients with follicular lymphoma.
1,459 citations
National Institutes of Health1, University of Würzburg2, University of British Columbia3, University of Nebraska Medical Center4, University of Rochester5, Oregon Health & Science University6, University of Arizona7, Fred Hutchinson Cancer Research Center8, University of Oslo9, St Bartholomew's Hospital10, University of Barcelona11
TL;DR: The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.
Abstract: background Patients with follicular lymphoma may survive for periods of less than 1 year to more than 20 years after diagnosis. We used gene-expression profiles of tumor-biopsy specimens obtained at diagnosis to develop a molecular predictor of the length of survival. methods Gene-expression profiling was performed on 191 biopsy specimens obtained from patients with untreated follicular lymphoma. Supervised methods were used to discover expression patterns associated with the length of survival in a training set of 95 specimens. A molecular predictor of survival was constructed from these genes and validated in an independent test set of 96 specimens. results Individual genes that predicted the length of survival were grouped into gene-expression signatures on the basis of their expression in the training set, and two such signatures were used to construct a survival predictor. The two signatures allowed patients with specimens in the test set to be divided into four quartiles with widely disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independently of clinical prognostic variables. Flow cytometry showed that these signatures reflected gene expression by nonmalignant tumor-infiltrating immune cells. conclusions The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.
1,336 citations
"Impact of the tumor microenvironmen..." refers background in this paper
...From a biological point of view, the clinical behavior of FL is determined principally by the tumor microenvironment rather than by inherent properties of the tumor cells themselves.(5-7) Specific T-cell and accessory cell populations, including macrophages and follicular dendritic cells, have been reported to have an influence on overall and/or progression-free survival, either as a poor or a good prognostic parameter....
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...haematologica | 2009; 94(1) | 75 | tance of the microenvironment in the clinical behavior of FL.(5-7) The precise nature of the relevant cell populations is still unclear, and published data on the prognostic significance of cell populations, including T-cell subsets, macrophages and follicular dendritic cells, are conflicting....
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Journal Article•
TL;DR: The population of CD4+CD25+ immunoregulatory cells is characterized and it is demonstrated that they can suppress not only the induction of disease post-thymectomy, but can also efficiently suppress disease induced by cloned autoantigen-specific effector cells.
Abstract: Thymectomy of susceptible strains of mice on day 3 of life results in a spectrum of organ-specific autoimmunity that can be prevented by reconstitution of the thymectomized animals early in life with normal adult lymphocytes. The effectors and suppressors of autoimmunity in this model have been convincingly shown to be CD4+ T cells. It has been demonstrated recently that the regulatory CD4+ T cells that prevent disease coexpress CD25. We have further characterized the population of CD4+CD25+ immunoregulatory cells and demonstrated that they can suppress not only the induction of disease post-thymectomy, but can also efficiently suppress disease induced by cloned autoantigen-specific effector cells. Furthermore, the CD4+CD25+ T cells appear to be members of a unique lineage of regulatory T cells, as the induction of CD25 expression on a monospecific population of T cells derived from TCR transgenic SCID mice did not result in suppression of post-thymectomy autoimmunity. In addition, the TCR transgenic SCID mice were highly susceptible to autoimmune disease induced by the cloned line of autoantigen-specific effectors, while normal mice were relatively resistant. The capacity of the cloned line to transfer disease to nu/nu recipients could be inhibited by normal spleen cell populations containing CD4+CD25+ cells and by purified CD4+CD25+ cells. Although the target Ag(s) and mechanism of action of the CD4+CD25+ T cells remain to be determined, it is likely that they also play an important role in modulating other autoimmune diseases that are mediated by activation of "ignorant" self-reactive T cells present in the normal peripheral lymphocyte pool.
927 citations
"Impact of the tumor microenvironmen..." refers background in this paper
...It has been shown that fludarabine has a rather specific effect on FoxP3-positive regulatory T cells in patients with B-cell chronic lymphocytic leukemia, in that both the frequency and the inhibitory functions of these cells are reduced after treatment.(23-25) Very likely, interference with the tumor microenvironment may result in different responses depending on the specific role of the microenvironment in a specific class of FL....
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TL;DR: This is the first report demonstrating that CY, in addition to decreasing cell number, inhibits the suppressive capability of T(REGs), and the relevance of the loss of suppressor functionality and the changes in gene expression are discussed.
889 citations
"Impact of the tumor microenvironmen..." refers background in this paper
...Similar effects of cyclophosphamide have been shown on regulatory T cells too.(26)...
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TL;DR: The Follicular Lymphoma International Prognostic Index was designed from the data recorded over 8 years of nearly 5000 patients registered worldwide to help provide an optimal treatment option for patients with follicular lymphoma.
Abstract: Although numerous treatment approaches are proposed for patients with follicular lymphoma, criteria to help in choosing a treatment for a given patient and for comparing trial results are lacking. Several retrospective studies have analyzed prognostic factors, but their conclusions rely on limited numbers of patients treated during long periods, and their results are discordant. The Follicular Lymphoma International Prognostic Index was designed from the data recorded over 8 years of nearly 5000 patients registered worldwide. Five factors are used (age, Ann Arbor stage, number of nodal sites, serum lactate dehydrogenase level, and hemoglobin level) to build a three-category index. This index, together with new biologic markers such as gene profiling and proteomics, could help provide an optimal treatment option for patients with follicular lymphoma.
863 citations