International Extranodal Lymphoma Study Group Research Articles

Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: A pharmacokinetic–pharmacodynamic analysis from the IELSG no. 20 trial

Background:This analysis was initiated to define the predictive value of the area under the curve of high-dose methotrexate (AUCHD-MTX) in patients with primary central nervous system lymphoma (PCNSL).Patients and methods:We included 55 patients with PCNSL and available pharmacokinetic (PK) data from the International Extranodal Lymphoma Study Group (IELSG) no. 20 trial, randomised to HD-MTX (n=30) or HD-MTX and high-dose cytarabine (HD-AraC) (n=25). Individual AUCHD-MTX from population PK analysis was tested on drug toxicity and clinical outcome using multivariate logistic regression analysis and Cox hazards modelling.Results:AUCHD-MTX, the IELSG score and treatment group were significant predictors for treatment response (complete or partial) in the adjusted model. The AUCHD-MTX did not predict toxicity, with the exception of liver toxicity and neutropaenia. A high AUCHD-MTX was associated with better event-free survival (EFS) (P=0.01) and overall survival (OAS) (P=0.02). Both the AUCHD-MTX and the IELSG score were significant predictors of EFS and OAS in the adjusted model, with a hazard ratio of 0.82 and 0.73, respectively, per 100 μmol l−1 h−1 increase in AUCHD-MTX.Conclusions:Individualised dosing of HD-MTX might have the potential to improve clinical outcome in patients with PCNSL, even when administered concurrently with HD-AraC. In the future, this could be carried out by using first-cycle PK modelling with determination of potential dose adaptations for later cycles using Bayesian analysis.

Primary follicular and marginal-zone lymphoma of the breast: clinical features, prognostic factors and outcome: a study by the International Extranodal Lymphoma Study Group

BackgroundPrimary breast lymphoma (PBL) of low-grade histology is a rare disease. This multicentric retrospective study was carried out to determine clinical features, prognosis and relapse. Patients and methodsPatients with histologically proven, previously untreated follicular or marginal-zone PBL (MZL PBL) diagnosed from 1980 to 2003 were included in the study. Major end points were progression-free survival (PFS), overall survival (OS) and potential prognostic factors. ResultsWe collected data on 60 cases of PBL [36 follicular and 24 marginal-zone lymphoma (MZL)]. Stage was IE or IIE in 57 patients and IVE in three patients due to bilateral breast involvement. Surgery, chemotherapy and radiotherapy (RT), alone or in combination, were used as first-line treatments in 67%, 42% and 52% of patients, respectively. Overall response rate was 98%, with a 93% complete response rate. Five-year PFS were 56% for MZL and 49% for follicular PBL (P=0.62). Relapses were mostly in distant sites (18 of 23 cases); no patients relapsed within RT fields. ConclusionsOur data showed an indolent behaviour of MZL PBL, comparable to other primary extranodal MZL. Conversely, patients with follicular PBL had inferior PFS and OS when compared with limited-stage nodal follicular non-Hodgkin's lymphomas, suggesting an adverse prognostic role of primary breast localisation in this histological subgroup.

Interim Analysis of the IELSG-19 Randomised Study of Chlorambucil Alone Versus Chlorambucil Plus Rituximab Versus Rituximab Alone in Extranodal Marginal Zone Lymphomas of Mucosa-Associated Lymphoid Tissue (MALT lymphoma).

Abstract 3939Poster Board III-875The available clinical information on MALT lymphoma is mostly based on retrospective series. In 2003 the International Extranodal Lymphoma Study Group launched the IELSG-19 study to compare Chlorambucil alone versus the combination of Chlorambucil and Rituximab. Because of the excellent initial recruitment, a third arm with Rituximab alone was later introduced. The study is still ongoing and at the end of July 2009, 403 patients (pts) of the 450 planned have entered. The Italian Lymphoma Intergroup and the French GELA group were the main contributors to this study together with Cancer Research UK, the Catalan Hematology Group and the Oncology Institute of Southern Switzerland.All the MALT lymphoma pts with localized disease at any extranodal site who do not respond or are not suitable to local therapy, the H.pylori-negative gastric lymphomas or those who failed antibiotic therapy are eligible, as well as those with disseminated or multifocal MALT lymphoma. Histology review of all cases is underway.A planned interim analysis was performed in April 2009 on the first 320 pts, 169 men (53%) and 151 women (47%); 292 pts (91%) had no previous treatment. The treatment was completed in in 86% of the 320 analysed pts, in 64% without dose changes or time delay. The primary MALT lymphoma site was the stomach in 138 pts (43%);182 pts (57%) had a non-gastric presentation. The most common non-gastric sites were the lungs (N=42, 13%), the ocular adnexa (N=32; 10%), the intestine (N=29; 9%), the salivary glands (N=26; 8%), and the skin (N=21; 7%). In 95 pts (30%) the lymphoma involved more than 1 extranodal site. Lymph node involvement was present in 118 pts (37%); 181 pts (58%) had localized disease (Ann Arbor stage I-II) while 129 (42%) had advanced stage. The ECOG performance status was 0 in 230 pts (74%). According to the international prognostic index (IPI) 190 pts (59%) had a low risk, 68 (21%) a low-intermediate risk, 54 (17%) an intermediate-high risk, and only 8 (2.5%) a high risk score. B-symptoms were present in 33 pts (11%) and LDH levels were higher than normal in 31 (10%).The median age is 61 year (range, 26-81). At a median follow-up of 40 months, overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) are 96%, 88%, and 62%, respectively.Among the main clinical characteristics, the presence of B-symptoms, elevated LDH, more than one extranodal site, advanced stage, poorer performance and unfavourable IPI scores were significantly (p<0.05) associated with shorter OS, PFS and EFS. The presence of lymph nodal involvement was significantly associated with shorter PFS and EFS but did not affect the OS. Patient younger than 60 years had longer OS and PFS but age had no effect on the EFS. Differently from previous series, there were no differences in outcome between pts with gastric and non-gastric localization; this finding is likely due to the fact that H. pylori-positive gastric MALT lymphoma pts still responding to antibiotics were excluded from the study.This is by far the largest prospective study ever conducted in MALT lymphomas; further analyses are in progress. Disclosures:Zucca:Mundipharma: Research Support; Johnson & Johnson: Research Support; Roche: Research Support.

Uncertainty and discordance in the staging and prognosis of diffuse large B‐cell lymphoma with isolated bilateral testicular involvement

American Journal of HematologyVolume 84, Issue 11 p. 762-763 LetterFree Access Uncertainty and discordance in the staging and prognosis of diffuse large B-cell lymphoma with isolated bilateral testicular involvement† Ronald S. Go, Corresponding Author Ronald S. Go [email protected] Center for Cancer and Blood Disorders, Gundersen Lutheran Health System, La Crosse, WisconsinCenter for Cancer and Blood Disorders, Gundersen Lutheran Health System, Mail Stop: EB2-001, 1900 South Avenue, La Crosse 54601, WI 54601Search for more papers by this authorJacob D. Gundrum, Jacob D. Gundrum Department of Medical Research, Gundersen Lutheran Medical Foundation, La Crosse, WisconsinSearch for more papers by this author Ronald S. Go, Corresponding Author Ronald S. Go [email protected] Center for Cancer and Blood Disorders, Gundersen Lutheran Health System, La Crosse, WisconsinCenter for Cancer and Blood Disorders, Gundersen Lutheran Health System, Mail Stop: EB2-001, 1900 South Avenue, La Crosse 54601, WI 54601Search for more papers by this authorJacob D. Gundrum, Jacob D. Gundrum Department of Medical Research, Gundersen Lutheran Medical Foundation, La Crosse, WisconsinSearch for more papers by this author First published: 10 August 2009 https://doi.org/10.1002/ajh.21522Citations: 4 † Conflict of interest: Nothing to report. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References 1 Carbone PP,Kaplan HS,Musshoff K, et al. Report of the committee on Hodgkin's disease staging classification. Cancer Res 1971; 31: 1860– 1861. 2 Gospodarowicz M. Individuality versus conformity. Is perfection necessary in staging and prognostic classifications of specific primary extranodal lymphomas? Ann Oncol 1999; 10: 1405– 1407. 3 Armitage JO. Staging non-Hodgkin lymphoma. CA Cancer J Clin 2005; 55: 368– 376. 4 Zucca E,Conconi A,Mughal TI, et al. Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the international extranodal lymphoma study group. J Clin Oncol 2003; 21: 20– 27. 5 Bentley RC,Devlin B,Kaufman RE, et al. Genotypic divergence precedes clinical dissemination in a case of synchronous bilateral B-cell malignant lymphoma of the testes. Hum Pathol 1993; 24: 675– 678. 6 Salvatore JR,Ross RS. Primary bilateral adrenal lymphoma. Leuk Lymphoma 1999; 34: 111– 117. 7 Ryan G,Martinelli G,Kuper-Hommel M, et al. Primary diffuse large B-cell lymphoma of the breast: Prognostic factors and outcomes of a study by the international extranodal lymphoma study group. Ann Oncol 2008; 19: 233– 241. 8 Hoffman PM,McKelvie P,Hall AJ, et al. Intraocular lymphoma: A series of 14 patients with clinicopathological features and treatment outcomes. Eye 2003; 17: 513– 521. 9 Kojima M,Shimizu K,Nishikawa M, et al. Primary salivary gland lymphoma among Japanese: A clinicopathological study of 30 cases. Leuk Lymphoma 2007; 48: 1793– 1798. 10 Decaudin D,de Cremoux P,Vincent-Salomon A, et al. Ocular adnexal lymphoma: A review of clinicopathologic features and treatment options. Blood 2006; 108: 1451– 1460. 11 Cordier JF,Chailleux E,Lauque D, et al. Primary pulmonary lymphomas. A clinical study of 70 cases in nonimmunocompromised patients. Chest 1993; 103: 201– 208. 12 Cortelazzo S,Mian M,Rossi A, et al. Primary extranodal diffuse large B-cell lymphomas (DLBCL) arising in distinct sites of head and neck have different clinical characteristics and outcome. Haematologica 2007; 92 (s1). Abstract 0863. 13 Rohatiner A,d'Amore F,Coiffier B, et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol 1994; 5: 397– 400. 14Surveillance, Epidemiology, and End Results. Available at: http://seer.cancer.gov/Accessed on July 2, 2009. Citing Literature Volume84, Issue11November 2009Pages 762-763 ReferencesRelatedInformation

No advantage for chlorambucil maintenance therapy in gastric MALT lymphoma

Introduction: In the 1980s, Isaacson and colleagues [1,2] described a malignant lymphoma that occurred in association with mucosa-associated lymphoid tissue (MALT). These small-cell lymphomas were shown to have an indolent course and sometimes were cured with surgery or involved-fi eld radiotherapy. These lesions were previously sometimes called “pseudo lymphomas.” It became apparent that they could occur at any site of epithelial tissue—not just at mucosal sites. The most common MALT lymphomas occur in the stomach. In the 1990s, Wotherspoon and colleagues [3] documented the association of gastric MALT lymphomas and Helicobacter pylori infection, and it was shown that the lymphoma could regress when the H. pylori was eradicated [4]. Although H. pylori eradication has become the standard therapy for patients with localized gastric MALT lymphomas with documented infection by the microorganism, other therapies are also effective. Patients can respond to single-agent or combination chemotherapy regimens, rituximab alone or in combination, and involved-fi eld radiotherapy. In fact, the highest proportion of durable remissions seems to be associated with radiotherapy [5]. In this study, investigators from the International Extranodal Lymphoma Study Group, the United Kingdom Lymphoma Group, and the Group d’Etude des Lymphomes de l’Adulte tested the value of adjuvant chlorambucil after H. pylori eradication therapy in patients with nonprogressive gastric MALT lymphomas.

Infectious agents and lymphoma development: molecular and clinical aspects

This review is focused on the role of infectious agents in the development of some lymphoma entities. Associations involving bacterial infections mostly regard marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT)-type. Some paradigmatic examples of these associations include the Helicobacter pylori-related gastric MALT lymphoma and the more recently reported links between Chlamydophila psittaci and ocular adnexal MALT lymphomas and Borrelia burgdorferi and cutaneous MALT lymphomas. The well-documented association between Epstein-Barr virus infection and related lymphoproliferative disorders are analysed as an example of lymphotropic virus with tumourigenic activity. Molecular, biological and clinical features as well as therapeutic implications of these associations are analysed and future perspectives in this field are discussed.

Primary central nervous system lymphoma

Primary central nervous system (CNS) lymphoma is being increasingly recognized in immunosuppressed as well as immunocompetent individuals. It has a poor prognosis and the majority of these have diffuse large B-cell type of morphology. To categorize cases of primary CNS lymphoma according to the International Extranodal Lymphoma Study Group (IELSG) score and to correlate the score with reactive CD3 collar around blood vessels and necrosis. We reviewed the clinico-pathological, morphological and immuno-histochemical features of 30 cases of primary CNS lymphoma reported at our institute in the last nine years and categorized them according to the score given by IELSG. All our cases were HIV-negative and had diffuse large cell histology. Twenty-seven of the 30 cases were associated with poor prognostic factors of intermediate to high risk according to the IELSG score. Reactive CD3 collar around the blood vessels was seen in seven cases which had low to intermediate IELSG score. However, no significant statistical difference of perivascular reactive CD3 collar and necrosis was seen with IELSG score. Approximately 90% (27 cases) were associated with poor prognostic factors in the present study according to the IELSG score. Perivascular reactive CD3 collar was seen in cases with low to intermediate IELSG score. A larger study is required to further validate that the presence of reactive perivascular CD3 collar is associated with good prognosis. This histological marker could be supplemented with IELSG score to stratify the patients of primary CNS lymphoma according to their aggressiveness.

Primary central nervous system lymphoma: A profile of 26 cases from western India

Primary central nervous system (CNS) lymphoma (PCNSL) is a rare malignant non-Hodgkin's lymphoma and it accounts for 1% of all intracranial tumors. Only a few PCNSL studies have been reported from India, and studies on prognostic factors determining outcome, or evaluation of the response to currently accepted treatment, are lacking. This study attempts to further delineate the clinical, radiological and pathological profile of PCNSL in India, to evaluate response to treatment and to assess usefulness of the International Extranodal Lymphoma Study Group (IELSG) score. All patients with pathologically proven PCNSL admitted over three years at a large tertiary care institution were studied. Clinical features, IELSG prognostic score, imaging and pathological features, and response to treatment were evaluated. Results were analyzed using chi 2 test. Of 26 patients found, all except two were immunocompetent. Median age at diagnosis was 59 years. Focal deficits (76.9%) and neuropsychiatric symptoms (57.6%) were the commonest presenting complaints. Except for one case, at least some contrast enhancement was seen in brain lesions of all patients. Pathological studies showed high grade diffuse large B-cell (DLBCL) histology in 96.2% of patients. Of 22 patients who received methotrexate (MTX) based chemotherapy with/without radiotherapy; six died, with a response rate of 72.7%. Median survival was 10 months. Median follow-up duration was 14.5 months. Four patients developed treatment-related cognitive decline. All six patients with IELSG score of 4/5 died, while all 16 patients with a score of 0-3 survived. PCNSL presents most commonly in the sixth decade with focal neurological deficit, behavioral symptoms and cognitive decline. High grade DLBCL is the commonest histological subtype. Steroids should ideally be withheld until biopsy as they may confound the diagnosis. Most immunocompetent patients respond well to high dose MTX-based chemotherapy with/without radiation. High IELSG scores correlate with worse prognosis in patients with PCNSL.

Extranodal lymphoma: a reappraisal

Approximately one-third of non-Hodgkin lymphomas (NHLs) arise primarily from sites other than lymph nodes, spleen or the bone marrow and even from sites which normally contain no native lymphoid tissue [1, 2]. Indeed, extranodal lymphomas can arise in almost every organ [1, 2]. However most of the presentations appears to be clustered in a few sites: skin, stomach, brain, small intestine and—when included in the reports—the Waldeyer’s ring [3, 4]. The extranodal lymphomas represent a challenge in routine lymphoma diagnosis, due to the variety of histological types, molecular abnormalities and clinical pictures that can be present. Correct diagnosis and appropriate treatment of extranodal lymphoma are also complicated by the relative rarity of many of these tumours. Moreover, in comparison with nodal presentation, Band T-cell lymphomas diagnosed at extranodal sites may have quite different outcomes and may frequently require different therapeutic approaches due to specific organ-related problems. The definition of primary extranodal lymphoma is controversial, particularly in the presence of both nodal and extranodal disease. Strict criteria were first proposed in 1961 by Dawson, who defined primary gastric lymphoma as presentation with main disease manifestation in stomach, with or without involvement of regional lymph nodes. Later these criteria were extended to allow for contiguous involvement of other organs (e.g. liver, spleen) and for distant nodal disease providing that the extranodal lesion was the presenting site and, after routine staging procedures, constituted the predominant disease bulk, to which primary treatment must be directed [3]. The inclusion among primary extranodal lymphomas of cases presenting with stage III and IV is also questionable and several authors consider only stage I and II presentation as primary extranodal disease. Since many extranodal lymphomas have the potential to disseminate, this approach may, however, lead to an imperfect representation. On the other hand, extranodal involvement in a disseminated disease may represent a secondary spread. Any chosen definition inevitably introduces a selection bias; in a recent Dutch study the frequency of extranodal NHL fluctuated from 20% to 34% depending on the definition criteria adopted [5]. The incidence of extranodal NHL in Western countries has increased substantially in the last 40 years [4, 6]. This may in part be due to improved diagnostic procedures (particularly in brain and gastrointestinal lymphomas) and changes in classification systems, but much of the change is real and the AIDS epidemic in the 1980s does not completely explain this rise [4]. The aetiology of extranodal lymphomas appears to be multifactorial and includes immune suppression, infections, both viral and bacterial, and exposure to pesticides and other environmental agents. Nevertheless, despite the considerable progress made in the understanding of MALT lymphoma and its relationship to bacterial infections [7], the precise cause of most lymphoid neoplasms remains unknown [1–3]. The proportion of NHL presenting at extranodal sites comprises 25–50% of new lymphoma cases with important geographic variations that may be explained by the variability of the reporting criteria (variable definitions of primary extranodal disease) as well as by different types of data source (referral cancer centres versus tumour registry). True geographic differences are, however, present, for example, the incidence of Epstein–Barr virus and human T-cell lymphotropic virus 1-associated T-cell lymphomas is higher in Asia than in Europe and North America. The histological spectrum of extranodal lymphomas somehow differs from that of nodal lymphomas. Nearly half of the extranodal cases are of diffuse large cell histology. Aggressive subtypes, mainly diffuse large B-cell lymphomas (DLBCLs) are predominant in NHL of central nervous system (CNS), testis, bone and liver while in the gastrointestinal tract a large spectrum of histological disease entities can be seen, comprising DLBCL, MALT lymphoma (including the immunoproliferative small intestinal disease), Burkitt’s lymphoma, enteropathy-associated T-cell lymphoma, mantle cell lymphoma and follicular lymphoma. Although extranodal lymphomas are not rare, the frequency of involvement of any particular site is not high enough for a single institution to answer the major question about their natural history and proper therapy. Attempting to overcome these difficulties, in the late 1990s, the International Extranodal Lymphoma Study Group (IELSG) was created to provide an adequate network to study the extranodal lymphomas. This international collaboration has originated a number of retrospective and prospective trials aimed to clarify the management issues distinct to extranodal presentations (http://www.ielsg.org). Whether or not extranodal lymphomas as a whole have a worse overall survival in comparison with that of nodal cases The author reports no relationships with companies whose products or services are mentioned in this manuscript.

Primary diffuse large B-cell lymphoma of the breast: prognostic factors and outcomes of a study by the International Extranodal Lymphoma Study Group

BackgroundPrimary diffuse large B-cell lymphoma (DLBCL) of breast is rare. We aimed to define clinical features, prognostic factors, patterns of failure, and treatment outcomes. Patients and methodsA retrospective international study of 204 eligible patients presenting to the International Extranodal Lymphoma Study Group-affiliated institutions from 1980 to 2003. ResultsMedian age was 64 years, with 95% of patients presenting with unilateral disease. Median overall survival (OS) was 8.0 years, and median progression-free survival 5.5 years. In multifactor analysis, favourable International Prognostic Index score, anthracycline-containing chemotherapy, and radiotherapy (RT) were significantly associated with longer OS (each P ≤ 0.03). There was no benefit from mastectomy, as opposed to biopsy or lumpectomy only. At a median follow-up time of 5.5 years, 37% of patients had progressed—16% in the same or contralateral breast, 5% in the central nervous system, and 14% in other extranodal sites. ConclusionsThe combination of limited surgery, anthracycline-containing chemotherapy, and involved-field RT produced the best outcome in the pre-rituximab era. A prospective trial on the basis of these results should be pursued to confirm these observations and to determine whether the impact of rituximab on the patterns of relapse and outcome parallels that of DLBCL presenting at other sites.

Long-Term Follow-Up of 132 Immunocompetent Primary Central Nervous System Lymphomas Treated at Leon Berard Cancer Centre: Proposition of a New Prognostic Model.

This study was aimed at analyzing long-term data on survival, relapse, and treatment-related neurotoxicity in all patients with newly diagnosed primary CNS lymphoma (PCNSL) and patients specifically treated with the C5R protocol (Blay et al, Blood 86:2922, 1995). We also identified prognostic factors of survival in order to propose a predictive model.132 patients with PCNSL seen at Leon Berard cancer centre between 1984 and 2006 were analyzed. Median age was 59 years (range: 26–81); 49% of the patients had a performance status (PS) of 2 to 4; 8% had leptomeningeal and ocular involvement. Initial treatment was chemotherapy and radiotherapy in 122 patients and chemotherapy alone in 10. Fifteen patients did not receive high-dose methotrexate as part of initial chemotherapy. The median overall (OS) and progression-free survival (PFS) for the whole series were 21.6 and 13.3 months for a median follow-up of 84.2 months. Twenty-five (19%) patients experienced toxic death, 24 (18%) progressed during treatment and 39 (30%) relapsed. Neurotoxicity was observed in 16% of the patients. Of the 49 patients receiving the intensive C5R protocol, 6 (12%) experienced toxic death, 3 (6%) progressed during treatment, 17 (35%) relapsed and 14% developed leukoencephalopathy. Median OS and PFS for patients treated with the C5R protocol were 73.8 and 44.4 months, respectively. Univariate analysis of the whole series showed that age over 60 years, elevated serum LDH, PS greater than 1 and the International Extranodal Lymphoma Study Group score were prognostic factors for OS and PFS, but not the presence of deep or multiple lesions or a high CSF protein level. The backward regression model integrating age, serum LDH, number and location of lesions, and CSF protein level showed that age, serum LDH and a tumor location within deep regions were predictive of OS and PFS. Four prognostic groups presenting 0, 1, 2 or 3 factors could be significantly distinguished regarding OS and PFS. [Display omitted] This study allowed to identify a new prognostic model using 3 factors. This model has the interest to withdraw the PS which could be a subjective data and CSF protein level for which the accurate cutoff is not well known. This study also showed that, with a long follow-up, patients treated with the C5R protocol have excellent OS and PFS.

IELSG Phase II Studies of Bortezomib in Malt Lymphomas.

The International Extranodal Lymphoma Study Group (IELSG) is coordinating two phase II multicenter studies aimed to assess the antitumor activity and safety of bortezomib treatment in patients (pts) with relapsed or refractory extranodal marginal zone B-cell lymphoma of MALT-type. The IELSG25A study is evaluating bortezomib in pts previously treated with one prior systemic treatment, and the IELSG25B pts previously treated with more than one prior treatment. Bortezomib 1.3 mg/m2 is administered on days 1, 4, 8, and 11 of a 21-day cycle, for up to 6 cycles. Response and progression are determined by International Workshop Criteria. As of July 2007, 18 pts have been enrolled in the studies: 11 (61%) patients were male, median age was 62 years (range, 38–77). At time of enrolment, the Ann Arbor stages distribution was the following: stage I=5 pts (28%), stage II=5 pts (28%), stage IV=8 (44%). In 10 pts primary gastric localization was present, in 5 cases primary skin, in 2 cases primary subcutaneous, in 1 primary lung lymphoma. All patients had ECOG PS=0; in 2 cases (11%) elevated serum LDH was reported. More than 1 site of extranodal localization was present in 4 pts (22%). Median number of prior therapies was 2 (range, 1–3). Median follow-up was 16 months. Nine pts were assessed for response at the end of treatment plan: 3 pts had a CR (33%); 4 a PR (45%) and 2 SD (22%). Five additional pts, with ongoing therapies, have been evaluated after the first two courses of therapy: one pt achieved a CR and 2 pts a PR, in 2 cases a SD was observed. The safety profile of bortezomib is similar to that observed in multiple myeloma and other subtypes of non-Hodgkin lymphoma. The most relevant adverse events grade 3 or higher were peripheral neuropathy and fatigue. One death, non-related to treatment, was observed during the early follow up. These preliminary results suggest that bortezomib is active and safe in relapsed or refractory MALT lymphomas and encourage us to complete the studies accrual.

Primary mediastinal B‐cell lymphoma

Primary mediastinal B-cell lymphoma (PMBCL) is a sub-type of the heterogeneous diffuse large B-cell lymphoma category, and comprises approximately 5% of all non-Hodgkin's lymphomas (NHL). It was first recognized as a distinct clinico-pathologic entity 20 years ago, and recent work has further characterized specific molecular features. Gene expression profiling has suggested a partial overlap with nodular sclerosing Hodgkin lymphoma (HL), with which it shares some clinical features. The optimal management remains a matter of debate. There is uncertainty as to whether weekly alternating chemotherapy regimens may be more effective than CHOP, whether consolidation radiotherapy (RT) to the mediastinum is always required, whether PET scanning can be used to determine this, and whether the use of rituximab as part of initial therapy will change the answers to these questions. The International Extranodal Lymphoma Study Group (IELSG) 26 clinicopathologic study of PMBCL, which has recently opened, represents a first attempt to gather data prospectively on some of these issues.

Definition, Diagnosis, and Management of Intravascular Large B-Cell Lymphoma: Proposals and Perspectives From an International Consensus Meeting

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse LBCL characterized by preferential intravascular growth of malignant lymphocytes, aggressive behavior, and an often fatal course. IVLBCL usually affects elderly patients with poor performance status, elevated lactic dehydrogenase serum levels, anemia, and B symptoms. It displays some differences in clinical presentation among diverse geographical areas, mostly between patients diagnosed in Western countries and Japan. In addition, data from the literature suggest that pathologic diagnostic criteria as well as clinical features of this disease may be broader than described in current classification scheme(s). Under the sponsorship of the International Extranodal Lymphoma Study Group, clinicians and pathologists with interest in IVLBCL, coming from Western and Eastern countries, joined to reach a consensus on defining features as well as to focus on the most urgent unresolved issues in IVLBCL. To this end, a representative group of IVLBCL patients coming from both the aforementioned geographical areas were collectively analyzed. Additional features of IVLBCL were proposed both under clinical and pathologic stand points. At the meeting, it emerged that IVLBCL may have additional histopathologic/cytologic definition criteria with respect to those currently recommended, some clinical features are not randomly distributed worldwide, recent therapeutic approaches, such as anti-CD20-containing regimens, may improve outcome, and kidney, spleen, and liver involvement may show peculiar histopathologic features. Finally, a provisional practical diagnostic approach to hemophagocytosis-associated patients and a proposal for the most useful criteria in the settings of differential diagnosis are included.

Intravascular large B-cell lymphoma: the heterogeneous clinical manifestations of its classical and hemophagocytosis-related forms

In this issue, Ferreri and the International Extranodal Lymphoma Study Group document that the clinical features of patients with intravascular lymphoma (IVL) vary based on the presence or absence of hemophagocytosis (HPC), rather than geographical region, differentiating IVL into classical and HPC-

MATILDE regimen followed by radiotherapy is an active strategy against primary CNS lymphomas

The authors assessed MATILDE chemotherapy followed by response-tailored radiation therapy in 41 patients aged 70 years or younger with primary CNS lymphoma in a Phase II trial. With response rates of 76% after MATILDE and 83% after chemotherapy with or without radiation therapy, this was an active strategy, particularly in low- to intermediate-risk patients (International Extranodal Lymphoma Study Group [IELSG] score). Myelosuppression was the dose-limiting toxicity, with 9.5% of lethal complications. After a median follow-up of 49 months, a plateau in the survival curve (5-year overall survival: 41 +/- 7%) was obtained.

Primary non-Hodgkin’s lymphoma of the breast: First report of the multicentre retrospective study of the International Extranodal Lymphoma Study Group (IELSG-15)

6575 Background: Primary breast lymphoma is a rare poorly-defined condition. This large multi-centre retrospective review investigates its prognosis and patterns of relapse. Methods: Patients presenting with histologically-proven primary non-Hodgkin’s lymphoma of one or both breasts between 1980 and 2003 are included. Data was obtained retrospectively from patient medical records. Central histology review was undertaken where possible. Survival curves were estimated using the Kaplan-Meier method, and prognostic factors analysed by univariate and multivariate analysis. The major study endpoints were progression-free and overall survival. Results: A total of 276 eligible patients were identified. Of these, 202 patients had diffuse large B-cell histology, and form the basis of this analysis. Sixty-seven percent of patients had Stage IE disease, 28% were stage IIE, and 5% were stage IVE(bilateral). B-symptoms were present in 4%. International Prognostic Index (IPI) was 0,1,2 and 3 in 27,37,15 and 3%, respectively. Eighty percent of patients received chemotherapy, 64% radiotherapy, and 50% both, with 87% of patients achieving a complete response at the end of planned first-line therapy. Thirty-seven percent of patients subsequently progressed in one or more sites. The crude rates for recurrence in breast, loco-regional nodes, and central nervous system (CNS) were 15%, 6%, and 5%. Only one breast relapse occurred in an irradiated breast. The median progression-free survival was 5.9 years (95% CI: 3.7, 8.0), with a median follow-up duration of 5.5 years. Median overall survival was 8.4 years (95% CI: 6.5, 10.9). The only statistically significant prognostic factor on multifactor analysis was IPI. Conclusions: The outcome for patients presenting with primary diffuse large B-cell non-Hodgkin’s lymphoma of the breast was significantly worse than that anticipated for Stage I and II nodal lymphomas treated during a similar period. The data suggests that future prospective studies should investigate intensification of treatment, and that the addition of specific prophylactic therapy targeted at the major sites of recurrence may improve prognosis. No significant financial relationships to disclose.

An IELSG International Survey of Primary Effusion Lymphoma (PEL).

PEL is a rare B-cell neoplasm characterized by a preferential involvement of fluid-filled body spaces, consistent infection of the tumor clone by human herpesvirus type-8 (HHV-8) and a close relationship with underlying immunodeficiency status of the host. The International Extranodal Lymphoma Study Group (IELSG) coordinated a retrospective survey involving 15 international institutions to determine the clinico-pathological features and patterns of outcome of PEL. Fourty-three patients (38 males and 5 females) were registered. Median age at diagnosis was 59 years (range 27–102). In 23 (53%) patients an associated human immunodeficiency virus (HIV) infection was reported, in one case the diagnosis of PEL was made after a solid organ transplantation, in two patients other immunodeficiency conditions were present. The tumor HHV-8 infection was demonstrated in 35 out of the 39 tested cases, Epstein-Barr virus infection in 13 of 30 cases. CD4 count was lower than 200/μl in 18 of the 25 cases in whom the data was available. An ECOG perfomance status score ≥ 2 was observed in 29 patients and the presence of B-symptoms in 20 patients. Serum LDH was elevated in 21 of the 39 tested patients. In 4 patients nodal involvement at diagnosis was reported, in 4 cases at least one extranodal site of localization other than serous cavities was present. A low/low-intermediate risk score according to International Prognostic Index was reported in 10 cases, an intermediate-high/high risk score in 29 cases. Twenty-one patients received systemic chemotherapy, in 17 cases an anthracycline-based regimen. Intrapleural cidofovir was administered in 3 patients. Twelve HIV+ patients received highly active anti-retroviral therapy (HAART), four of them as single therapy. Among the 39 patients for whom adequate follow-up data were available, median overall survival was 6.7 months, median cause-specific survival was 13.6 months and median progression-free survival was 8.3 months. Interestingly, cases of tumor complete regression after implementation of the sole HAART, after intrapleural administration of cidofovir or without any treatment were reported. Our data confirm the poor prognosis of PEL but suggest a possible heterogeneity of this entity with respect to its biological and clinical features. A review of the pathological, phenotypical and virological features is forthcoming to validate these preliminary results.

Aberrant methylation in the promoter region of the reduced folate carrier gene is a potential mechanism of resistance to methotrexate in primary central nervous system lymphomas.

We investigated the prevalence and prognostic role of CpG island methylation of the reduced folate carrier (RFC) gene promoter region in primary central nervous system lymphoma (PCNSL) in immunocompetent patients. Genomic DNA from 40 PCNSL was used for methylation-specific polymerase chain reaction and bisulphite genomic sequencing of the RFC promoter region. Human immunodeficiency virus-negative systemic diffuse large B-cell lymphomas (DLBCL) were used as controls (n = 50). The impact on outcome of RFC promoter methylation was assessed in 37 PCNSL patients treated with high-dose methotrexate (HD-MTX)-based chemotherapy +/- radiotherapy. RFC promoter methylation occurred in 12 of 40 (30%) PCNSL and in four of 50 (8%) DLBCL (P = 0.01). Of 37 PCNSL treated with HD-MTX-based chemotherapy, methylation occurred in nine cases (24%, M-PCNSL), while 28 cases (76%, U-PCNSL) were negative. Three M-PCNSL (33%) and 15 U-PCNSL (54%) achieved complete remission (CR) after primary chemotherapy. Logistic regression confirmed the independent association between CR rate and International Extranodal Lymphoma Study Group score (P = 0.03), RFC promoter methylation (P = 0.07) and use of cytarabine (P = 0.08). The 3-year failure-free survival (FFS) and overall survival for M-PCNSL and U-PCNSL was 0% vs. 31 +/- 9% (P = 0.34) and 0% vs. 31 +/- 9% (P = 0.35) respectively. This is the first study to assess the methylation status of the RFC promoter in human tumour samples. RFC methylation is more common in PCNSL compared with systemic DLBCL, and is associated with a lower CR rate to HD-MTX-based chemotherapy. If confirmed in prospective trials on PCNSL treated with HD-MTX alone, these data may suggest the necessity for alternative strategies in M-PCNSL considering the increased risk of MTX resistance by tumour cells.

Pathobiology of Primary Mediastinal B-Cell Lymphoma

Controversy still exists over the response to therapy and prognosis of patients with primary mediastinal B-cell lymphoma (PMBL). Recent data from the International Extranodal Lymphoma Study Group (IELSG) suggest that a MACOP-B (methotrexate, adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin) chemotherapy regimen followed by radiotherapy may be a better induction strategy than other previously used treatments. Although the pathobiology of PMBL has been widely studied, its precise histology, phenotype, and molecular characteristics are still not clear. To date, phenotypic analysis has revealed the following phenotype: positivity for CD45 and CD20, but negativity for CD3, CD10, CD21, Class I/II major histocompatibility antigens, and a variety of other immunohistochemical markers. CD79a is generally detected, despite an absence of surface immunoglobulins (Igs). CD30 staining is observed in most cases, but is weaker and less homogeneous than in classic Hodgkin's lymphoma or anaplastic large cell lymphoma. BCL-2 protein is usually expressed but there are few data describing the expression of MUM1/IRF4, PAX5/BSAP, BCL-6, or the B-cell transcription factors BOB.1, Oct-2, and PU.1. Cytogenetic studies reveal gains in segments of chromosome 9p, including amplification of the REL proto-oncogene and the tyrosine kinase gene JAK2. Other molecular findings include: C-myc mutations or rearrangements, p53 mutations, IgVH gene mutations, and bcl-2 and mal over-expression. bcl-6 mutations and bcl-2 gene rearrangements are generally absent, suggesting that PMBL is of pre-germinal center (GC) origin. However, two recent reports show isotype-switched Ig genes with a high frequency of somatic hypermutations as well as variants in the 5′ noncoding region of the bcl-6 gene. The IELSG collected 137 PMBL cases for extensive pathologic review. Histologically, the lymphomatous growth was predominantly diffuse with sclerosis that induced compartmentalized cell aggregation. It consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. Molecular analysis was performed on 40 cases and showed novel findings. More than half of the cases displayed bcl-6 gene mutations, which usually occurred together with functioning somatic IgVH gene mutations, and BCL-6 and/or MUM1/IRF4 expression. The present study supports the concept that PBML is derived from activated GC or post-germinal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective Ig production despite the expression of Oct-2, BOB.1, and PU.1 transcription factors, and a lack of IgVH gene crippling mutations.