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Background The nature of a solid retroperitoneal mass can either be autoimmune or neoplastic and should be investigated by imaging and histology. The spectrum of differential diagnoses includes primarily retroperitoneal fibrosis and retroperitoneal tumors. Because treatments of retroperitoneal fibrosis and retroperitoneal tumors vary substantially, accurate and early diagnosis is highly relevant. Case presentation We present a case of a fifty-four-year old woman that was admitted to our hospital with stroke like symptoms. Suspecting a vasculitis, magnet resonance imaging of the head and abdomen were done, which revealed a circular enhancement of a cranial vessel as well as retroperitoneal and peri-aortic masses. Concerning this specific radiographic patterns, an autoimmune process like retroperitoneal fibrosis was hypothesized. Steroid treatment did not lead to significant remission though. On re-evaluation of the mass because of refractory disease, fine needle aspiration did not show malignant cells while surgery and histologic assessment revealed neoplastic lymphoproliferation. The final diagnosis was a non- Hodgkin B- Cell Lymphoma. Chemo- and Immunotherapy was initiated. A control abdominal computer tomography was performed which revealed a significant remission of the retroperitoneal mass. Conclusion Initially, the retroperitoneal mass was highly suspicious for RF. The results of imaging can be useful, however, histology should always be taken into consideration when there is an uncertain clinical presentation. Without histology we would have missed a non-Hodgkin B-Cell Lymphoma in this case. Minimal invasive techniques like fine needle aspiration may be practical but can demonstrate false negative results.

This translational study aimed at gaining insight into the effects of lenalidomide in acute myeloid leukemia (AML). Forty-one AML patients aged 66 or older of the Swiss cohort of the HOVON-103 AML/SAKK30/10 study were included. After randomization, they received standard induction chemotherapy with or without lenalidomide. Bone marrow biopsies at diagnosis and before the 2nd induction cycle were obtained to assess the therapeutic impact on leukemic blasts and microenvironment. Increased bone marrow angiogenesis, as assessed by microvessel density (MVD), was found at AML diagnosis and differed significantly between the WHO categories. Morphological analysis revealed a higher initial MVD in AML with myelodysplasia-related changes (AML-MRC) and a more substantial decrease of microvascularization after lenalidomide exposure. A slight increase of T-bet-positive TH1-equivalents was identifiable under lenalidomide. In the subgroup of patients with AML-MRC, the progression-free survival differed between the two treatment regimens, showing a potential but not significant benefit of lenalidomide. We found no correlation between the cereblon genotype (the target of lenalidomide) and treatment response or prognosis. In conclusion, addition of lenalidomide may be beneficial to elderly patients suffering from AML-MRC, where it leads to a reduction of microvascularization and, probably, to an intensified specific T cell-driven anti-leukemic response. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04467-2.

The incidence of diffuse large B-cell lymphoma (DLBCL) increases with age being patient age at diagnosis an adverse prognostic factor. However, elderly patients are often underrepresented in common studies. To investigate the effect between age and biological characteristics in DLBCL, we analyzed data of 1534 patients encompassing all adult age groups, enriched for the age ≥75 years. Follicular lymphoma (FL) grade 3B with histopathological characteristics of DLBCLs were included. Gender, centroblastic cytology, FL grade 3B morphology, CD10 expression, and ABC/non-GCB-subtype were significantly associated with age after correction for multiple testing and after adjusting for cohorts. Analysis of a subgroup points towards an association of MYC expression with age. Our data indicate that biological features of DLBCL and FL grade 3B are associated with increasing age among adult patients. The prevalence of the ABC/non-GCB-subtype in elderly patients suggests that therapies targeting this molecular subtype should be specifically explored in this subgroup.

Follicular lymphoma (FL) constitutes a significant proportion of lymphomas and shows frequent relapses. Beyond conventional chemotherapy, new therapeutic approaches have emerged, focussing on the interplay between lymphoma cells and the microenvironment. Here we report the immunophenotypic investigation of the microenvironment of a clinically well-characterized prospective cohort (study SAKK35/10, NCT01307605) of 154 treatment-naive FL patients in need of therapy, who have been treated with rituximab only or a combination of rituximab and the immunomodulatory drug lenalidomide/Revlimid® A high ratio of CD4- to CD8-positive T cells (P = 0·009) and increased amounts of PD1+ tumour-infiltrating T cells (P = 0·007) were associated with inferior progression-free survival in the whole cohort. Interestingly, the prognostic impact of PD1+ T cells and the CD4/CD8 ratio lost its significance in the subgroup treated with R2 . In the latter group, high amounts of GATA3+ T helper (Th2) equivalents were associated with better progression-free survival (P < 0·001). We identified tumour microenvironmental features that allow prognostic stratification with respect to immuno- and combined immuno- and immunomodulatory therapy. Our analysis indicates that lenalidomide may compensate the adverse prognostic implication of higher amounts of CD4+ and, particularly, PD1+ T cells and that it has favourable effects mainly in cases with higher amounts of Th2 equivalents. [Correction added on 11 February 2020, after online publication: The NCT-trial number was previously incorrect and has been updated in this version].

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first���line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse., publishedVersion

Over the last few years, there have been many changes in the management of patients with follicular lymphoma, resulting in improvements in progression-free survival and quality of life. In addition to established regimens such as radiotherapy and immunochemotherapy, new treatment options are on the horizon. Furthermore, even the use of established chemotherapy agents has evolved, with new combinations moving to the forefront of the current treatment strategy. Nevertheless, there remains an unmet need for patients who have early relapses, those who are not responsive to anti-CD20 treatment regimens and for those in whom minimal residual disease persists even after immunochemotherapy. This review provides a summary of current developments in the diagnosis, treatment and management of follicular lymphoma, focusing on the clinical issues from a Swiss perspective.

Wir berichten uber einen 53-jahrigen Patienten, der wegen Schmerzen beim Sitzen zum Hausarzt ging. Eine gastroenterologische sowie eine urologische Abklarung blieben unergiebig. Ein Rontgenbild des Beckens zeigte ein abgewinkeltes Os sacrum. Im MRT kam schliesslich eine rund 9 cm grosse Raumforderung zur Darstellung, die nach bioptischer Abklarung einem Plasmozytom entsprach. We report on the history of a 53-year-old patient who went to his primary care physician due to pain while sitting. Clinical, gastroenterological and urological examination did not lead diagnostic. A radiography of the pelvis revealed a kinky sacrum and the MRT showed a tumor mass of about 9 cm in diameter. A plasmacytoma was histologically diagnosed in the biopsy.

Purpose To explore the prognostic impact and interdependence of the cell-of-origin (COO) classification, dual expression (DE) of MYC and BCL2 proteins, and MYC, BCL2, and BCL6 translocations in two prospectively randomized clinical trials of patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Overall, 452 formalin-fixed paraffin-embedded samples from two prospective, randomized DLBCL trials (RICOVER-60, prospective, randomized study for patients > 60 years, all IPI groups; and R-MegaCHOEP, prospective, randomized study for patients ≤ 60 years with age-adjusted IPI 2,3) of the German High-Grade Non-Hodgkin Lymphoma Study Group were analyzed with the Lymph2Cx assay for COO classification, with immunohistochemistry for MYC and BCL2, and with fluorescent in situ hybridization for MYC, BCL2, and BCL6 rearrangements. Results COO classification was successful in 414 of 452 samples. No significant differences with respect to COO (activated B-cell [ABC]–like DLBCL v germinal center B-cell [GCB]–like DLBCL) were observed in event-free survival, progression-free survival, and overall survival in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the RICOVER-60 trial. Also, no differences with respect to COO were observed in multivariable analyses adjusted for International Prognostic Index factors in event-free survival (hazard ratio [HR] of ABC-like disease v GCB-like disease, 1.0; 95% CI, 0.6 to 1.6; P = .93), progression-free survival (HR, 1.1; 95% CI, 0.6 to 1.8; P = .82), and overall survival (HR, 1.0; 95% CI, 0.6 to 1.8; P = .96). Similar results were observed in the R-MegaCHOEP trial. In patients treated with R-CHOP, DE status was associated with significantly inferior survival compared with nonDE within the GCB, but not within the ABC subgroup. DE status was associated with significantly inferior outcome compared with patients with ABC-like DLBCL without DE (5-year PFS rate, 39% [95% CI,19% to 59%] v 68% [95% CI, 52% to 85%]; P = .03) and compared with patients with GCB-like DLBCL without DE. When data from patients with nonDE were analyzed separately, the outcome of patients in the ABC subgroup was inferior to that of patients in the GCB subgroup (5-year PFS rate, 68% [95% CI, 52% to 85%] v 85% [95% CI, 74% to 96%]; P = .04). Conclusion COO profiling in two prospective randomized DLBCL trials failed to identify prognostic subgroups, whereas dual expression of MYC and BCL2 was predictive of poor survival. Evaluation of prognostic or predictive biomarkers in the management of DLBCL, such as the COO, within prospective clinical trials will be important in the future.

Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) is a rare subtype of Hodgkin's lymphoma. The histological patterns of NLPHL variants are characterized by different localizations of the tumor cells, intranodular and perinodular and by the varying composition of the microenvironment. T-cell/histiocyte-rich B-cell lymphoma may be the result of an aggressive transformation of NLPHL. Classical lymphocyte-rich Hodgkin's lymphoma can usually be clearly distinguished from NLPHL by the immunophenotype of the tumor cells. Further differential diagnoses include follicular lymphoma and the follicular variant of peripheral T-cell lymphoma. Angioimmunoblastic T-cell lymphoma with CD20-positive blasts represents a differential diagnosis to the diffuse variants of NLPHL.

Aberrant expression of the annapoptotic protein BCL (B-cell lymphoma)-2 in ncoplastic germinal centers is one of the diagnostic hallmarks of follicular lymphoma. If BCL-2 cannot be detected by immunohistochemistry, the distinction between florid follicular hyperplasia and follicular lymphoma might become a diagnostic challenge. Most of those cases also lack the typical t(14;18), and the underlying pathophysiologic conditions of follicular lymphoma that lack BCL-2 protein expression arc largely unknown. Here, we collected 18 BCL-2 negative follicular lymphoma cases from 5 different institutions. After restaining, 9 cases proved to be truly BCL-2 negative (6 follicular lymphoma grade 2, 2 follicular lymphoma grade 3a, and 1 follicular lymphoma grade 3b). In 4 additional cases, BCL-2 was very faint (all grade 2). Of the 9 BCL-2 negative follicular lymphoma cases, 2 were negative for CD 10 (22%); all showed expression of BCL-6. Apoptotic level as determined by caspase 3 was the lowest in the BCL-2 positive follicular lymphoma group (15 +/- 8 m(2)), the highest in the normal/reactive group (n = 7, 60 +/- 12 mm(2)) and very similar in the BCL-2 low follicular lymphoma and BCL-2 negative follicular lymphoma groups (25 +/- 13 and 33 +/- 19 mm(2), respectively), assuming an intermediate position between reactive follicles and BCL-2 positive neoplastic follicles (P < .001 [Kruskal-Wallis]). Also noted was a difference in proliferation fractions between the BCL-2 positive follicular lymphoma (27% +/- 15%), the BCL-2 low follicular lymphoma (30% +/- 20%) and the BCL-2 negative follicular lymphoma groups (30% +/- 22%). Regarding the network of follicular dendritic cells, 8 (89%) of 9 cases from the BCL-2 negative subgroup showed disrupted, weakly developed networks, whereas all of the follicular lymphoma BCL-2 low-expression cases showed a well-defined and strongly developed follicular dendritic cell network. Among BCL-2 negative follicular lymphoma, BCL-2 and BCL-6 breaks were found in 1 case each, whereas in the follicular lymphoma BCL-2 low group, only 1 case with a BCL-6 break was recorded. No statistically significant result was achieved upon assessment of BCL-2 alpha or BCL-2 beta RNA or the ratio of alpha/beta isolated by real-time polymerase chain reaction. Taken together, BCL-2 negative follicular lymphoma did not show a BCL-2 break on the genetic level and showed both increased apoptotic and proliferation rates compared with BCL-2-positive follicular lymphoma. In our series, BCL-6 breaks were infrequent in BCL-2 negative follicular lymphoma. (C) 2012 Elsevier Inc. All rights reserved.

The survival of diffuse large B-cell lymphoma patients varies considerably, reflecting the molecular diversity of tumors. In view of the controversy whether cytologic features, immunohistochemical markers or gene expression signatures may capture this molecular diversity, we investigated which features provide prognostic information in a prospective trial in the R-CHOP treatment era. Within the cohort of DLBCLs patients treated in the RICOVER-60 trial of the German High-Grade Lymphoma Study Group (DSHNHL), we tested the prognostic impact of IB morphology in 949 patients. The expression of immunohistochemical markers CD5, CD10, BCL2, BCL6, human leukocyte antigen (HLA)–DR, interferon regulatory factor-4/multiple myeloma-1 (IRF4/MUM1), and Ki-67 was assessed in 506 patients. Expression of the immunohistochemical markers tested was of modest, if any, prognostic relevance. Moreover, the Hans algorithm using the expression patterns of CD10, BCL6, and interferon regulatory factor-4/multiple myeloma-1 failed to show prognostic significance in the entire cohort as well as in patient subgroups. IB morphology, however, emerged as a robust, significantly adverse prognostic factor in multivariate analysis, and its diagnosis showed a good reproducibility among expert hematopathologists. We conclude, therefore, that IB morphology in DLBCL is likely to capture some of the adverse molecular alterations that are currently not detectable in a routine diagnostic setting, and that its recognition has significant prognostic power.

Mantle cell lymphoma (MCL) has a poor prognosis with often short and incomplete remissions. We aimed to test the efficacy and tolerability of gemcitabine in treating MCL. Gemcitabine was given in doses of 1000 mg/m(2) as a 30 min infusion on days 1 and 8 of each 3 week cycle for a maximum of nine cycles. Eighteen patients with a median age of 70 years were recruited. MCL was newly diagnosed in half of patients and relapsed in the remainder. Fifteen patients had Ann Arbor stage IV. The best-recorded responses were 1 CR (complete remission), 4 PRs (partial responses), 8 SDs (stable diseases) and 4 PDs (diseases progression). The response rate (RR) (CR + PR) was 5 (28%; 95% confidence interval: 7.1, 48.5). The patient achieving a CR had stage IV disease. Most haematological adverse events occurred during the first chemotherapy cycle. Three patients developed non-haematological serious adverse events: dyspnea, glomerular microangiopathy with haemolytic uremic syndrome (HUS) and hyperglycaemia. The median time-to-progression and treatment response duration (TRD) was 8.0 (95% confidence interval: 5.5, 9.3) and 10.6 (95% confidence interval: 5.5, 10.9) months, respectively. We conclude that Gemcitabine is well tolerated, moderately active and can induce disease stabilization in patients with MCL.

Plasma cell myelomas (PMs) have a poor prognosis. Cancer-testis (CT) antigens are immunogenic proteins, representing potential targets for tumor vaccination strategies. The expression of the CT antigens GAGE, MAGE-A4, MAGE-C1/CT-7, and NY-ESO-1 was investigated on paraffin-embedded bone marrow biopsies from 219 PM and 8 monoclonal gammopathy of undetermined significance (MGUS) patients. The frequency and prognostic impact of these CT antigens were compared with known morphological prognostic markers (i.e. Mib1 labeling index) and the presence of the translocations t(4;14)(p16.3; q32) and t(11;14)(q13;q32). We show that MAGE-C1/CT-7 is the most prevalent CT antigen, expressed in 57% of PMs in a high percentage of tumor cells. While MAGE-C1/CT-7 was absent in non-malignant plasma cells, plasma cells of patients with MGUS did express MAGE-C1/CT-7, but no other CT antigens. MAGE-C1/CT-7 was more frequently expressed in PMs with an elevated proliferation rate (Mib1 >10%) compared to PMs with a low proliferation rate (Mib1

Purpose To evaluate the effect of single-agent rituximab given at the standard or a prolonged schedule in patients with newly diagnosed, or refractory or relapsed mantle cell lymphoma (MCL). Patients and Methods After induction treatment with the standard schedule (375 mg/m2 weekly × 4), patients who were responding or who had stable disease at week 12 from the start of treatment were randomly assigned to no further treatment (arm A) or prolonged rituximab administration (375 mg/m2) every 8 weeks for four times (arm B). Results The trial enrolled 104 patients. After induction, clinical response was 27% with 2% complete responses. Among patients with detectable t(11;14)-positive cells in blood and bone marrow at baseline, four of 20, and one of 14, respectively, became polymerase chain-reaction–negative after induction. Anemia was the only adverse predictor of response in the multivariate analysis. After a median follow-up of 29 months, response rate and duration of response were not significantly different between the two schedules in 61 randomly assigned patients. Median event-free survival (EFS) was 6 months in arm A versus 12 months in arm B; the difference was not significant (P = .1). Prolonged treatment seemed to improve EFS in the subgroup of pretreated patients (5 months in arm A v 11 months in arm B; P = .04). Thirteen percent of patients in arm A and 9% in arm B presented with grade 3 to 4 hematologic toxicity. Conclusion Single-agent rituximab is active in MCL, but the addition of four single doses at 8-week intervals does not seem to significantly improve response rate, duration of response, or EFS after treatment with the standard schedule.

Cytogenetic and molecular analyses are essential disease-monitoring parameters in chronic myelogenous leukemia (CML) treated with imatinib. However, a bone marrow morphologic response has not been defined. We reviewed bone marrow histology and cytology of 39 imatinib-treated patients with CML over 49 weeks and introduced a morphologic response score. A significant positive correlation with a complete cytogenetic response was shown for absence of dry tap (P = .04) and abnormal megakaryocytes (P0.001), normalization of cellularity (P = .001) and reduction of fibrosis (P = .01), myelopoiesis:erythropoiesis index (P = .001), blast (P = .001) and basophil count (P0.001). The morphologic score integrating these parameters showed an early and late correlation with cytogenetic response. In conclusion, morphologic criteria for complete cytogenetic response in patients with CML treated with imatinib can be defined. Persistent high-level morphologic abnormalities herald early on a high likelihood to fail treatment and call for more intense or alternative therapy.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity. We performed a matched-pair analysis to evaluate the prognostic impact of several histopathological features in this distinct Hodgkin lymphoma subtype. Lymph node samples of NLPHL patients were tested for CD15, IgD, phosphorylated STAT6, ICOS and Epstein-Barr virus status of the malignant lymphocyte-predominant cells as well as epithelioid cell clusters and activated T cells in the microenvironment. None of these features was associated with a particular clinical outcome. However, patients presenting with epithelioid cell clusters showed a non-significant trend towards a lower relapse rate, justifying further evaluation of this marker.

Rituximab 375 mg/m(2) weekly x 4 has been reported to induce a 60% response rate in patients with relapsed follicular lymphomas (FL). Our aim was to examine the effect of this rituximab schedule on circulating FL cells in an ongoing multicenter study. One hundred fifty-four patients with FL were examined by nested polymerase chain reaction (PCR) at baseline for the presence of t(14;18) translocation-carrying lymphoma cells in bone marrow and/or blood. Sixty-four patients (42%) had PCR-detectable t(14;18)(+) FL cells. Pretreatment characteristics of these 64 patients were as follows: one had stage I, nine had stage II, 14 had stage III, and 40 had stage IV disease. Thirty-five patients had bulky disease (or = 5 cm) and 25 patients had an elevated serum lactate dehydrogenase (LDH) level. Bone marrow was morphologically assessed in 64 patients, and 39 of these patients had an infiltration with FL cells. Blood samples from 51 patients were available for PCR analysis between weeks 8-12 after induction therapy, and 28 of these patients (55%) were PCR negative. Paired blood and bone marrow samples were available for PCR analysis from 39 patients between weeks 8-12 after induction therapy with rituximab. Thirteen of these patients (33%) did not have PCR-detectable cells in blood and bone marrow, while 26 patients (67%) still had circulating t(14;18)(+) cells in either bone marrow (eight patients), blood (one patient), or both (17 patients). PCR negativity in blood and bone marrow in 13 patients was statistically significantly associated with partial or complete response after induction therapy with rituximab (P = 0.006). However, clearance of PCR-detectable t(14;18)(+) cells in bone marrow and/or blood could not be associated with any low tumor burden pretreatment characteristics such as stages I/II, absence of morphological bone marrow infiltration or tumor bulk ofor = 5 cm, and normal serum LDH.

Background: Infiltration of non-haematopoietic organs by small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL) is not unusual in late-stage disease and thus quite frequently encountered in post-mortem examinations. However, primary manifestation of SLL/CLL in the prostate is rarely diagnosed. Patients and Methods: We report two cases of primary prostatic SLL/CLL, in one case in combination with prostate carcinoma, and discuss diagnostic pitfalls, pathophysiological mechanisms and therapeutic management, together with an overview of the literature. Conclusions: Lymphocytic infiltration of the prostate associated with obstructive symptoms is rare but can already occur in very early disease. Microscopically, SLL/CLL infiltration can be distinguished from chronic prostatitis by its pattern of infiltration and by immunohistochemistry. As the incidence of both SLL/CLL and prostatic carcinoma increases with age, composite tumours might occur more often in the future.

We report on a patient with recurrent T-cell-rich B-cell lymphoma (TCRBCL), initially misdiagnosed as a lymphocyte-rich Hodgkin's disease. This case exemplifies the diagnostic problems of TCRBCL and the need for immunophenotypic analysis to differentiate TCRBCL from Hodgkin's disease, nodular paragranuloma and peripheral T-cell lymphoma. A rather unusual aspect is the long disease-free interval between the excision of the node in and the late relapse in 1996. The significance of the abundant T-cell infiltration in this B-cell neoplasm will be discussed and the concepts concerning antitumor response will be reviewed. Based on epidemiological data and the clinical behaviour TCRBCL does not seem to represent a distinctive pathological entity.

Mantle cell lymphoma (MCL) is a relatively rare lymphoma entity accounting for an estimated 3%-6% of all non-Hodgkin's lymphoma cases. Characterised by both the incurability of indolent lymphomas and the rapid growth of aggressive lymphomas, MCL has a median overall survival of only 4-5 years. Although the disease often shows an encouraging response to first-line treatment, its clinical course is usually marked by recurrent relapses, resulting in a dismal long-term outcome. The choice of therapy for managing the disease is a complex problem that still requires evidence-based guidance. Owing to the rarity of MCL, the bulk of data comes from phase II trials in small numbers of patients. Nevertheless, therapeutic strategies for MCL have evolved in an effort to adapt treatment according to the individual patient's risk profile, and the overall survival has nearly doubled in the last 30 years. The use of effective immunochemotherapy regimens in first-line therapy, advances in stem cell transplantation, and the development of more active salvage therapy regimens have improved the outcome. This review will summarise the key factors that drive clinical practice with respect to the management of MCL.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for approximately 5% of all Hodgkin lymphoma cases. The aim of this study was to evaluate the prognostic implication of histopathologic NLPHL variants. Biopsies of 423 NLPHL patients treated within 9 prospective clinical trials performed by the German Hodgkin Study Group were classified as tumor cell-rich cases (n = 10), typical NLPHL (n = 308), or histopathologic variants (n = 105). Histopathologic variants were characterized by the presence of lymphoma cells outside the B-cell nodules or B-cell depletion of the microenvironment. Compared with typical NLPHL, histopathologic variants were associated with advanced disease (29.5% vs 14.6%, P = .0012) and a higher relapse rate (18.1% vs 6.5% at 5 years, P = .0009). Variant histology represented an independent prognostic factor (odds ratio = 2.955) in a multivariate model of progression/relapse. A prognostic score, including the risk factors variant histopathologic growth pattern, low serum albumin, and male gender, was derived from this model and allowed the definition of 3 distinct risk groups. NLPHL patients presenting with histopathologic variants have a poorer outcome compared with those showing typical histology. The newly developed prognostic score combining histologic and clinical features allows allocating NLPHL patients to defined risk groups.

MYC rearrangements occur in 5% to 10% of diffuse large B-cell lymphomas (DLBCL) and confer an increased risk to cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) and rituximab (R)-CHOP treated patients. We investigated the prognostic relevance of MYC-, BCL2- and BCL6-rearrangements and protein expression in a prospective randomized trial. Paraffin-embedded tumor samples from 442 de novo DLBCL treated within the RICOVER study of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry and fluorescence in situ hybridization (FISH) to detect protein expression and breaks of MYC, BCL2, and BCL6. Rearrangements of MYC, BCL2, and BCL6 were detected in 8.8%, 13.5%, and 28.7%, respectively. Protein overexpression of MYC (>40%) was encountered in 31.8% of tumors; 79.6% and 82.8% of tumors expressed BCL2 and BCL6, respectively. MYC translocations, MYChigh, BCL2high, and BCL6low protein expressions were associated with inferior survival. In multivariate Cox regression modeling, protein expression patterns of MYC, BCL2 and BCL6, and MYC rearrangements were predictive of outcome and provided prognostic information independent of the International Prognostic Index (IPI) for overall survival and event-free survival. A combined immunohistochemical or FISH/immunohistochemical score predicts outcome in DLBCL patients independent of the IPI and identifies a subset of 15% of patients with dismal prognosis in the high-risk IPI group following treatment with R-CHOP. Registered at http://www.cancer.gov/clinicaltrials: RICOVER trial of the DSHNHL is NCT 00052936.

The Lymph2Cx Cell-of-origin (COO) assay enables the identification of molecular GCB and ABC subtypes of diffuse large B-cell lymphomas (DLBCL) using RNA from formalin-fixed paraffin-embedded (FFPE) samples. In order to explore the prognostic power of this COO assay within the frame of prospectively randomized clinical trials for the first time, we retrospectively performed COO analyses in patient samples from two clinical trials (RICOVER-60: n=360 and R-MegaCHOEP: n=92) of the German High Grade Lymphoma Study Group (DSHNHL) using the Nanostring nCounter®-platform. Immunohistochemistry was done for MYC, FOXP1, LMO2, GCET1, CD5, CD10, BCL2, BCL6, IRF4/MUM1 protein expression, and fluorescence in-situ hybridization was performed for MYC, BCL2 and BCL6 genes with break-apart probes. COO classification was successfully obtained from 414 samples (326/360 (91%) and 88/92 (96%) FFPE samples from the RICOVER60 and R-MegaCHOEP trials, respectively). In the RICOVER-60 study (patients aged > 60 and In RICOVER-60, the ABC-DLBCL group was associated with inferior clinical outcome compared with the GCB subtype (p=0.041, p=0.022 and p=0.034 for EFS, PFS and OS, respectively). A significant survival difference was also seen in CHOP-treated patients. This effect, however, was completely abrogated in R-CHOP treated patients with no significant difference observed in EFS, PFS and OS. This result was confirmed in multivariable analyses adjusted for IPI factors. We found the same results for all RICOVER-60 patients after adjustment for IPI factors (EFS: HR=1.1, PFS: HR=1.2, OS: HR=1.2 for ABC vs. GCB) and after adjustment for IPI factors, bulky disease, gender and age > 70 years. In keeping with this result, no survival differences were observed between ABC-DLBCL and GCB-DLBCL patients in the R-MegaCHOEP trial for EFS, PFS and OS, and this was also confirmed in multivariable analysis (data not shown). In the RICOVER-60 trial, patients with concomitant over-expression of both BCL2 (50-100%) and MYC (40-100%) (MYC+/BCL2+ DE DLBCL) showed significantly inferior survival in all R-CHOP treated patients and especially in the GCB subgroup compared with non-expressers [MYC-/BCL2- DLBCL; MYC-/BCL2+] (p In summary, COO profiling alone failed to identify prognostic subgroups, whereas MYC/BCL2 double expression was highly predictive of poor survival. These data from prospective randomized trials demonstrate that older patients and young high-risk patients show significant differences in molecular profiles and, furthermore, indicate that complete subtyping using different molecular methods will be necessary to predict survival under current standard therapy. Only comprehensive molecular analysis of individual patient samples will allow identification of optimal therapy including new molecules. Disclosures Scott: NanoString Technologies: Patents & Royalties: named inventor on a patent for molecular subtyping of DLBCL that has been licensed to NanoString Technologies. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding.

Approximately 5-10% of diffuse large B-cell lymphomas (DLBCL) harbor a 8q24/MYC rearrangement (MYC+). We determined the prognostic significance of MYC rearrangement in patients with relapsed/refractory DLBCL prospectively treated by R-ICE or R-DHAP followed by high-dose therapy and autologous stem cell transplantation. Twenty-eight (17%) of the 161 patients analyzed presented a MYC+ rearrangement, targeted as either simple hit (25%) or complex hits (n=75%) including MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6. Results were statistically highly concordant in matched primary and relapsed biopsies (n = 45). Compared to the MYC− DLBCL patients, the MYC+ DLBCL patients presented with a more elevated lactico-deshydrogenase level (P = .0006) and a more advanced age adjusted international prognostic index (P = .0039). The 4-year PFS and OS were significantly lower in the MYC+ DLBCL patients than those in the MYC− DLBCL patients, with rates of 18% vs 42% (P = .0322), and of 29% vs 62% (P = .0113), respectively. Type of treatment, R-DHAP or R-ICE, had no impact on survivals, with 4-year PFS rates of 17% vs 19% and 4-year OS rates of 26% vs 31%. In conclusion, MYC rearrangement is an early event in DLBCL. MYC+ DLBCL patients have a significant inferior prognosis than MYC− DLBCL patients. Their outcome was not influenced by the proposed salvage therapy.

Background Mantle cell lymphoma accounts for 6% of all B-cell lymphomas and is generally incurable. It is characterized by the translocation t(11;14) leading to cyclin D1 over-expression. Cyclin D1 is downstream of the mammalian target of rapamycin threonine kinase and can be effectively blocked by mammalian target of rapamycin inhibitors. We set out to examine the single agent activity of the orally available mammalian target of rapamycin inhibitor everolimus in a prospective, multicenter trial in patients with relapsed or refractory mantle cell lymphoma ([NCT00516412][1]). Design and Methods Eligible patients who had received a maximum of three prior lines of chemotherapy were given everolimus 10 mg for 28 days (one cycle) for a total of six cycles or until disease progression. The primary endpoint was the best objective response. Adverse reactions, progression-free survival and molecular response were secondary endpoints. Results Thirty-six patients (35 evaluable) were enrolled and treatment was generally well tolerated with Common Terminology Criteria grade ≥3 adverse events (>5%) including anemia (11%), thrombocytopenia (11%) and neutropenia (8%). The overall response rate was 20% (95% CI: 8–37%) with two complete remissions and five partial responses; 49% of the patients had stable disease. At a median follow-up of 6 months, the median progression-free survival was 5.5 months (95% CI: 2.8–8.2) overall and 17.0 (6.4–23.3) months for 18 patients who received six or more cycles of treatment. Three patients achieved a lasting complete molecular response, as assessed by polymerase chain reaction analysis of peripheral blood. Conclusions Everolimus as a single agent is well tolerated and has anti-lymphoma activity in relapsed or refractory mantle cell lymphoma. Further studies of everolimus in combination with chemotherapy or as a single agent for maintenance treatment are warranted. ([Clinicaltrials.gov][2] identifier: [NCT00516412][1]) [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00516412&atom=%2Fhaematol%2F97%2F7%2F1085.atom [2]: http://Clinicaltrials.gov

Purpose To evaluate the prognostic value of the cell of origin (COO) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBLC), prospectively treated by rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) versus rituximab, ifosfamide, carboplatin, and etoposide and followed by intensive therapy plus autologous stem-cell transplantation on the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) trial. Patients and Methods Among the 396 patients included on the trial, histologic material was available for a total of 249 patients at diagnosis (n = 189 patients) and/or at relapse (n = 147 patients), which included 87 matched pairs. The patient data were analyzed by immunochemistry for CD10, BCL6, MUM1, FOXP1, and BCL2 expression and by fluorescent in situ hybridization for BCL2, BCL6 and c-MYC breakpoints. The correlation with survival data was performed by using the log-rank test and the Cox model. Results Characteristics of immunophenotype and chromosomal abnormalities were statistically highly concordant in the matched biopsies. In univariate analysis, the presence of c-MYC gene rearrangement was the only parameter to be significantly correlated with a worse progression-free survival (PFS; P = .02) and a worse overall survival (P = .04). When treatment interaction was tested, the germinal center B (GCB) –like DLBCL that was based on the algorithm by Hans was significantly associated with a better PFS in the R-DHAP arm. In multivariate analysis, independent prognostic relevance was found for the GCB/non-GCB the Hans phenotype interaction treatment (P = .04), prior rituximab exposure (P = .0052), secondary age-adjusted International Prognostic Index (P = .039), and FoxP1 expression (P = .047). Confirmation was obtained by gene expression profiling in a subset of 39 patients. Conclusion COO remains a major and independent factor in relapsed/refractory DLBCL, with a better response to R-DHAP in GCB-like DLBCL. This needs confirmation by a prospective study.

Ischemic stroke is a serious disease leading to significant morbidity and mortality. Multifocal and recurrent strokes are usually caused by embolic diseases, i.e. atrial fibrillation, but rare causes like cerebral vasculitis and clotting disorders are also well known. Here we report on two patients suffering from the very rare intravascular large B-cell lymphoma leading to multifocal and recurrent strokes in the brain and spinal cord as the prominent neurological symptom. The difficulties and the need for diagnostic brain biopsy in making an ‘in vivo’ diagnosis in this particular disease are outlined. Furthermore, the prerequisite for an interdisciplinary approach in these patients is strongly emphasized. Delayed diagnosis for several reasons was the most probable cause for cerebral relapse leading to death in one patient a few months after diagnosis. Conversely, early initiation of immunochemotherapy with a classical lymphoma schedule (R-CHOP) led to long-lasting remission of the disease in the other patient. With this report we like to improve alertness to intravascular large B-cell lymphoma as a cause for multifocal and recurrent strokes.

BACKGROUND: Mesenteric alterations are associated with non-Hodgkin's lymphoma (NHL), but the frequency and prognostic value of mesenteric alterations are unknown in patients with NHL. PATIENTS AND METHODS: We retrospectively screened 120 patients that were treated for NHL between January 1996 and December 2001 for the presence of mesenteric alterations, defined on computed tomography (CT) scans as nodular or diffuse infiltration of the abdominal mesentery with increased density of mesenteric fat. RESULTS: 21 patients (17.5%) had radiological findings of mesenteric alterations at the time of the initial NHL diagnosis. Mesenteric alterations were significantly associated with mesenteric lymphadenopathy (p = 0.01). In about 50% of the patients, mesenteric alterations could not be explained by direct mesenteric tumour invasion or overt lymphatic obstruction. Patients with initial findings of mesenteric alterations tended to have a better 4-year survival as compared to patients without such findings (79 vs. 43%, p = 0.11). The International Prognostic Index (IPI) score was the only independent predictor of survival in the multivariate analysis. CONCLUSION: This retrospective screening study found a moderate prevalence of mesenteric alterations in patients with various subtypes of NHL. The diagnostic and prognostic value of mesenteric alterations should be further assessed in prospective studies.

Aims: The quick diagnosis of Burkitt's lymphoma (BL) and its clear-cut differentiation from diffuse large B-cell lymphoma (DLBCL) is of great clinical importance since treatment for these two disease entities differ markedly and should promptly be initiated in BL. However, these two tumours are difficult to distinguish using the current WHO classification, particularly in regard to BL variants, i.e., BL with plasmacytoid differentiation and atypical Burkitt's/Burkitt's-like lymphomas. Methods: We studied 39 cases of highly proliferative blastic B-cell lymphoma (HPBCL) to establish a practical differential-diagnostic algorithm. Characteristics set for BL were a typical morphology, a mature B-cell phenotype of CD10+, Bcl-6+ and Bcl-2- tumour cells, a proliferation rate of >95%, and the presence of C-MYC rearrangements in the absence of t(14;18)(q32;q21). All cases were selectively negative for cyclin D-1, CD5, CD23, LMP-EBV, CD34 and TdT, and there were no cases of endemic or immunodeficiency-associated Burkitt's lymphoma. Results: Altogether the set BL characteristics were found in only 5/39 cases (12.8%), whereas the majority of tumours revealed mosaic features (87.2%). In a second attempt, we followed a pragmatic stepwise approach for a classification algorithm that includes the assessment of C-MYC status to stratify HPBCL into four predefined diagnostic categories (DC), namely DC I (5/39, 12.8%): "classical BL", corresponding to the classical variant of sporadic BL in the WHO classification; DC II (11/39, 28.2%): "atypical BL", corresponding to the atypical Burkitt's/Burkitt's-like variants of sporadic BL in the WHO classification; DC III (9/39, 23.1%): "C-MYC+ DLBCL"; and DC IV (14/39, 35.9%): "C-MYC- HPBCL". Conclusion: This proposal may serve as a robust and objective operational basis for therapeutic decisions for HPBCL within one week and is applicable to be evaluated for its prognostic relevance in prospective clinical trials.

Background Endoscopic dacryocystorhinostomy (DCR) is the standard treatment of nasolacrimal duct obstruction. Only in rare cases, blockage may be caused by malignant tumors and even more exceptionally by lymphatic neoplasms so that biopsies are not routinely taken for diagnostic purposes. Methods A computerized retrieval system was used for this retrospective study to identify all patients with histologically documented lymphoproliferative infiltration in the lacrimal drainage system from 2001 to 2009. Results In four of 191 patients (2.1%), infiltration of the nasolacrimal sac mucosa with a small lymphocytic lymphoma (SLL)/chronic lymphatic leukemia (CLL) was found. Patients who develop symptoms like epiphora within the course of known CLL are highly suspicious for lymphoproliferative infiltration of the lacrimal drainage associated lymphoid tissue. Conclusion A proactive approach with ophthalmologic consultation and DCR should be followed in these patients to avoid dacryocystitis.

Introduction: Sequential high dose (SHiDo) chemotherapy with stem cell support has been shown to prolong the event-free survival in patients with diffuse large B-cell lymphoma. Methods: To confirm this result in a multicenter trial, we randomized patients with aggressive NHL, to receive either eight cycles of CHOP or SHiDo. The primary endpoint was overall survival. Results: 129 evaluable patients were randomized to receive either CHOP or SHiDo: median age, 48 years; 62% male; stage III+IV: 73%; age adjusted International Prognostic Index 1/2/3: 21%/52%/27%. Toxicity grades 3+4 were more pronounced in the SHiDo-arm with 13% versus 3% of patients with fever; 34% versus 13% with infections; 13% versus 2% with esophagitis/dysphagia/gastric ulcer. The remission rates were similar in SHiDo and CHOP arms with 34%/37% complete remissions and 31%/31% partial remissions, respectively. After a median observation time of 48 months, there was no difference in overall survival at 3 years, with 46% for SHiDo and 53% for CHOP ( P= 0.48). Conclusion: In this multicenter trial, early intensification with SHiDo did not confer any survival benefit in previously untreated patients with aggressive NHL and was associated with a higher incidence of grades 3/4 toxicity.

A primary extramedullary myeloid cell tumor (pEMT) of an inguinal lymph node was completely excised without subsequent anti-tumor therapy in a 6-year-old child. Clinical observation and monitoring of blood and bone marrow (BM) did not reveal any pathologic results before 32 months, when a precursor B lymphoblastic leukemia was diagnosed. Identical T-cell receptor gamma rearrangement in nodal pEMT and in precursor B lymphoblastic leukemia in BM indicates a clonal relationship of these two tumors. Pediatr Blood Cancer 2007;49:1039–1046. © 2006 Wiley-Liss, Inc.

The diagnostic impact of bone marrow cytology in combination with flow cytometry analysis of aspirate smears and bone marrow histology together with immunohistochemical examination of trephine biopsies was compared in 141 routine cases. Diagnoses achieved by the two methods were concordant in 80.5% of cases. In discordant cases, clinical follow-up data of at least one year confirmed the correctness of cytological and histological diagnoses. For infiltration by malignant disease, both methods were concordant in 86.5% of samples and correlated well for the degree of infiltration (r = 0.64, p

The potential benefits of extended rituximab treatment have been investigated in a randomized trial comparing the standard schedule with prolonged treatment in 202 patients with newly diagnosed or refractory/relapsed follicular lymphoma (FL). All patients received standard treatment (rituximab 375 mg/m(2) weekly x 4). In 185 evaluable patients, the overall response rate was 67% in chemotherapy-naive patients and 46% in pretreated cases (P

Background FcγRIIB promotes rituximab internalisation on various B-cell targets, including in follicular lymphoma, which may lead to reduced efficacy. We analysed diagnostic tumour samples from the SAKK 35/98 trial, which has follow-up data of nearly 10 years to determine the relation of FcγRIIB expression with responses and clinical outcomes after rituximab monotherapy in follicular lymphoma. Methods Available archived tissue samples were stained with an anti-human FcγRIIB antibody. Positive samples were graded into negative/low intensity staining (n=116) or medium/high staining (n=13) by a histopathologist masked to clinical outcomes. Failure-free survival (FFS) was defined as time from first rituximab infusion until failure to achieve complete/partial response at week 12, progression, relapse, a second cancer, or death from any cause. Objective response rate (ORR) was associated with intensity staining levels with Fisher's exact test. All time-to-event endpoints were evaluated with the Kaplan-Meier method; groups were compared with the log-rank test. Hazard ratio (HR) was assessed with Cox proportional hazards models. Findings Patients expressing medium/high levels of FcγRIIB were less likely to respond to rituximab than were those with negative/low levels (ORR 23·1% [95% CI 7·5–50·9] vs 58·6% [49·5–67·2], p=0·02). FFS was higher in the negative/low staining group than in the medium/high staining group (median 8·3 months [95% CI 2·8–13·4, IQR 2·76–28·5] vs 2·8 [not calculable, 2·76–2·76], p=0·002; HR 0·43 [95% CI 0·23–0·78]). There was a non-significant trend towards better overall survival in the low/negative group compared with the medium/high group (median 140·0 months vs 50·0, p=0·13; HR 0·56 [95% CI 0·26–1·20]). Interpretation Elevated FcγRIIB expression level is associated with poor response to rituximab in patients with follicular lymphoma. This group may show better results with non-internalising type II antibodies, a hypothesis for validation in future prospective clinical trials. Funding Cancer Research UK.

Abstract 2747 Background: Single-agent immunotherapy with rituximab is a viable treatment option for low risk FL, with limited toxicity and a long duration of response in some patient subsets. We have previously shown that high expression of FcγRIIB promotes rituximab internalisation on various B cell targets, including FL (Blood 2011 118:2530–2540), something not seen with type II anti-CD20 antibodies. The SAKK 35/98 trial examined rituximab monotherapy in FL and now has long-term follow-up data of almost 10 years (JCO 2010 28:4480–4484). We analysed diagnostic tumour samples from this trial to determine the relationship of FcγRIIB expression to responses and clinical outcomes after rituximab treatment in FL. Methods: 202 patients (pts) with newly diagnosed or relapsed FL received induction treatment with rituximab 375 mg/m2 weekly for 4 weeks. Pts with stable or responding disease at week 12 were randomized into 2 groups: no further treatment or prolonged treatment with single infusions of rituximab 375 mg/m2 at weeks 12, 20, 28 and 36. Archived tissue samples from 135 evaluable pts were stained using an anti-human FcγRIIB antibody (clone EP888Y, Abcam) at a dilution of 1:3000 on a Dako autostainer. The samples were pretreated with the Dako EnVisionFLEX target retrieval solution high pH and detection using the Dako AS-Link 48 with Dako EnVision flex plus detection kit. Positive samples were graded into negative/low intensity staining (n=120) versus medium/high (n=13) by an expert lymphoma histopathologist blinded to the clinical outcomes. Data from 2 slides and response at week 12 data for 4 pts were unavailable (1 of whom also has missing slide data), resulting in 130 pts available for analysis. Failure-free survival (FFS) was defined as time from registration until failure to achieve complete/partial response at week 12, progression, relapse, a second cancer or death from any cause. Objective response rate (ORR) was associated with intensity staining levels using Fisher's exact test. All time-to-event endpoints were evaluated using the Kaplan-Meier method; groups were compared using the log-rank test. The hazard ratio (HR) was assessed using Cox proportional hazards models. Results: Registered and randomised pts had very similar baseline characteristics; previously untreated pts had slightly more favourable characteristics but were balanced between the 2 treatment arms. Pts expressing medium/high levels of FcγRIIB were less likely to respond to rituximab by week 12 (ORR 58.1% vs 23.1%, Fisher's exact test, p=0. 02), a finding independent of prior therapy. For FFS, there was a statistically significant difference (p=0.001; HR=0.42; 95% confidence interval (C.I.): 0.23–0.77) between the negative/low staining group (median: 21.4 months; 95% C.I.: 7.0–34.2) and the medium/high staining group (median: 7.0 months; 95% C.I.: Not calculable). The interaction between staining levels and randomised treatment groups for FFS was not statistically significant. There was a non-significant trend towards better overall survival in the low/negative group (median: 140.0 vs 50.0 months; p=0.15; HR=0.57; 95% C.I.: 0.27–1.23); however the event rate was lower (36.8% vs 61.5%). Conclusion: Elevated FcγRIIB expression level is associated with poor response to rituximab in pts with FL. This group may show better results with non-internalising type II antibodies, a hypothesis for validation in future prospective clinical trials. Disclosures: Ghielmini: Roche: Honoraria, Speakers Bureau. Johnson:Roche: Honoraria.

Abstract 594FN2 Background . Approximately 5% to 10% of DLBCLs harbor a MYC/8q24 oncogene rearrangement. We determined the prognostic significance of MYC+ DLBCL in a selected population of patients with relapsed/refractory DLBCL included in the CORAL and prospectively treated by RICE or RDHAP followed by BEAM and ASCT1. METHODS. Among the 396 patients included, 150 patients were analysed with break-apart FISH probes for MYC/8q24, BCL2/18q21, and BCL6/3q27. Correlations with clinical characteristics at diagnosis and at relapse, immunohistochemistry (IHC) for CD10, BCL6, MUM1, FOXP1, and BCL2 expression, cell of origin determined according to different IHC algorithms2-5 and by transcriptomic analysis, response to treatment and survivals were analysed considering presence or absence of MYC rearrangement. RESULTS. Twenty-four (16%) cases exhibited a MYC rearrangement, associated in 87.5% (n=21) of the cases with a BCL2/18q21 rearrangement (n=16), with a BCL6/3q27 rearrangement (n=4), and with both BCL2/18q21 and BCL6/3q27 rearrangements (n=4). Among the matched cases analysed (n=57), biological characteristics including tumor immunophenotype and breakpoints occurrence, were identical between primary and secondary biopsies. Presence of MYC+ rearrangement was significantly associated with CD10 expression (p= 0.0067) and a GC phenotype, based either on Hans algorithm (p Disclosures: No relevant conflicts of interest to declare.

Abstract 993 Purpose: Cell of origin (COO) has a major prognostic impact in DLBCL. However this impact has never been analysed in the context of relapsed/refractory DLBCL. The purpose of this study was to evaluate the prognostic value of COO immunohistochemical markers and BCL2, BCL6 and c-MYC translocations in a well-defined cohort of patients included in the CORAL trial1. Methods: Enrolled patients had CD20+ DLBCL in first relapse or refractory after upfront therapy. Treatment was randomized to either R-ICE (rituximab, ifosfamide, etoposide, carboplatin) or R-DHAP (rituximab, dexamethasone, aracytine, cisplatin). Responding patients had high-dose chemotherapy and ASCT. Paraffin-embedded tumor samples of 249 patients were analysed by immunochemistry for CD10/MME, BCL6, MUM1/IRF4, FOXP1, BCL2 expression and for BCL2, BCL6 and c-MYC breakpoints by FISH, and were categorized according to different COO algorythms2-5. Primary biopsy at diagnosis and relapse biopsy were available for 189 and 147 patients respectively, including 87 matched pairs. Results: With a median follow-up at 27 months, there was no significant difference between R-ICE and R-DHAP for 2-year progression-free survival (PFS) (56.7%+/−5% vs 60%+/−5%, p=0.24) or overall survival (OS) (46%+/−5% vs 60%+/−5%, p=0.24). We confirmed that early relapse, prior rituximab exposure and secondary aaIPI had adverse prognostic value. In univariate analysis, absence of bcl6 expression, non-GC phenotype2, ABC phenotype4, at diagnosis were associated with an unfavourable PFS (p=0.038, p=0.0044, p=0.044, respectively), whereas only non-GC phenotype2 was associated to a worse OS (p=0.027). At relapse, expression of Foxp1 and bcl2, c-MYC breakpoint, ABC phenotype4, immunoFISH index5 was associated with an unfavourable PFS (p=0.02, p=0.027, p=0.03, p=0.032, p=0.02, respectively), and c-MYC breakpoint was associated with a worse OS (p=0.01). Tumor immunophenotype and FISH analysis at diagnosis and at relapse were statistically concordant in matched pairs (Wilcoxon's test between 0.42 and 1). In the whole group, only c-MYC breakpoint present in 13% of the patients was correlated with worse PFS (p= 0.02) and OS (p =0.04). Statistical interaction were found between GC/non-GC classification2 and the treatment R-ICE vs R-DHAP. Patients with GC B-cell like DLBCL subtype treated with R-DHAP have a better 2-year PFS (64% +/−7%) than those with GC B-cell like DLBCL treated with R-ICE (42% +/−7%), and the patients with ABC B-cell like DLBCL treated either with R-DHAP (35%+/−7%) or R-ICE (45%+/−7%) (p= 0.04). In multivariate analysis, only GC/non-GC phenotype2 interaction with the treatment, FOXP1 expression, prior rituximab exposure, secondary aaIIPI, time to relapse were statistically significant. Preliminary results of gene expression profiling seem to confirm these data and are currently under validation. Conclusion: COO remains a major factor in relapsed patients with a better response to R-DHAP salvage chemotherapy in GC-B DLBCL, underlying the importance of molecular DLBCL subtyping. Treatment of ABC subtype is still unsatisfactory. Disclosures: Schmitz: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gisselbrecht:Roche: Research Funding.

Therapy of low-grade non-Hodgkin's lymphoma (NHL) with anti-CD20 specific antibodies (Rituximab) has recently been approved for the treatment of follicular and relapsed or refractory NHL in various countries. Rituximab has shown efficacy without concomitant chemotherapy [1-4], suggesting a new therapeutic principle that probably includes apoptosis induction [5, 6]. To our knowledge, little experience and no published information exists on the use of Rituximab in multiple myeloma. We report the case of a patient in whom Rituximab was used as fourth line therapy of multiple myeloma. Rapid acceleration of tumor progression during anti-CD20 therapy was seen, suggesting that Rituximab promoted tumor growth. In April 1997, a 54-year-old white male with sequelae of a poliomyelitic infection in childhood presented with progressive back pain on thoracic level 8/9. Complete work-up revealed an osteolytic fracture of the eighth thoracic vertebrae, osteolytic lesions of ribs, the left humerus and skull. Vertebral biopsy showed infiltration by malignant plasma cells that were mostly CD20-positive (see Figure 1), bone marrow infiltration was < 5%. Immunofixation revealed a monoclonal IgG lambda

Mantle cell lymphoma (MCL) has a very poor prognosis. Remissions are often incomplete and short with a median survival of less than 3 years and a 5 year survival of < 30%. Young patients are usually treated with intensive chemotherapy regimens or a stem cell transplant. In elderly, unfit patients aggressive treatments are not a realistic approach. This trial set out to assess Gemcitabine in the treatment of patients with newly diagnosed, relapsed or chemotherapy resistant MCL not fit enough for intensive chemotherapy regimens. The primary endpoint was the objective response. Eligibility criteria were a WHO performance status < 2, age ≥ 18 years, a histologically confirmed diagnosis of MCL along with at least one measurable lesion of diameter ≥ 11 mm, ≤ 2 previous lines of chemotherapy. Gemcitabine was given in doses of 1000mg/m2 as a 30 minute infusion on days 1 and 8 of each 3 week cycle for a total of 9 cycles. To prevent flu-like symptoms, one dose of steroids per Gemcitabine infusion was administered. Response duration was read as the time from trial registration to a relapse for patients reaching a remission on the trial therapy. Progression-free survival was defined as the time from trial registration to death or disease progression, treatment failure as early termination of the trial treatment. Patient enrollment began in Aug 2004. Stage I analysis concluded the trial treatment was not promising for further investigation, due to only 1 (10%) patient reaching a remission, and patient accrual stopped after the inclusion of 18 patients in March 2006. Median age at enrollment was 70 years. 66% of the patients were male. MCL was newly diagnosed in 50% of the patients and relapsed in the remainder. Ann Arbor stage IV rating was present in 15 patients, stage II in 1 patient and stage I in 2 patients. Bone marrow involvement was reported in 10 patients. Gastrointestinal tract involvement was reported in 4 patients. Involvement of > 1 extranodal organ was seen in 3 patients. One CR, 4 PRs, 8 SDs and 4 PDs were recorded as a best response. The patient achieving a CR was one of the patients presenting with a stage IV disease. Most myelotoxicities occurred during the first chemotherapy cycle. Neutropenia CTC grade 1 in 24 (19.8%), grade 2 in 35 (28.9%) and grade 3/4 was seen in 24 (19.8%) of the cycles. Thrombocytopenia CTC grade 1 was recorded in 55 (45.5%) cycles and grade 2/3 in 9 (7.7%) cycles. Three patients developed non-hematological serious adverse events, defined as an inpatient or prolonged hospitalisation or a life threatening illness related to the trial medication; dyspnea, glomerular microangiopathy with hemolytic uremic syndrome, and hyperglycemia. The median time-to-progression and response duration was 8.0 (95% confidence interval: 5.5 – 9.3) and 10.6 (95% confidence interval: 5.5 – 10.9) months respectively. The median time-to-treatment failure was not reached. We conclude that Gemcitabine is well tolerated and that it can stabilise MCL in elderly patients. However, Gemcitabine as a monotherapy has only limited activity in MCL patients in terms of treatment response. Further trials should therefore assess gemcitabine in frail patients with MCL.

We analyzed the clinical and biological prognostic factors for efficacy and described the toxicity of treatment by study arm for 306 patients participating in two identical and parallel trials, one in follicular (FL) and one in mantle cell lymphoma (MCL). Chemotherapy naïve or pre-treated patients were treated with 4 weekly doses of rituximab (induction). Those responding or with stable disease were randomized to either no further treatment (arm A) or 4 more doses of rituximab given at 2-month intervals (arm B). Characteristics of the patients (4 variables), previous treatment (6 variables), disease (9 variables), histology (26 variables), blood cell counts (6 variables), lymphocytes subsets (5 variables), blood chemistry values (8 variables) and Fc receptor phenotype (3 variables) were collected at trial entry and during follow-up.We constructed multivariate models to identify prognostic factors for response and for event-free survival (EFS). In 273 eligible and evaluable cases the response rate was 44%. In these patients, the favorable prognostic factors for response were a disease diameter < 5 cm (odds ratio =2.5, p=0.0006), a follicular histology (OR=2.4, p=0.0029), a normal hemoglobin (OR= 2.4, p=0.0033) and a low blood lymphocyte count (OR=2.0, p=0.02), all determined at treatment start. At a median follow up of 54 months, the EFS for all 212 randomized cases was 9.1 months in arm A and 15.4 months in arm B (p=0.005). Factors prognostic for EFS in a multivariate model based on 162 patients were: having responded to rituximab induction (hazard ratio=0.44, p

Abstract 2803 Introduction: Mantle cell lymphoma (MCL) accounts for 6% of all B-cell lymphomas and remains incurable for most patients. Those who relapse after first line therapy or hematopoietic stem cell transplantation have a dismal prognosis with short response duration after salvage therapy. On a molecular level, MCL is characterised by the translocation t[11;14] leading to Cyclin D1 overexpression. Cyclin D1 is downstream of the mammalian target of rapamycin (mTOR) kinase and can be effectively blocked by mTOR inhibitors such as temsirolimus. We set out to define the single agent activity of the orally available mTOR inhibitor everolimus (RAD001) in a prospective, multi-centre trial in patients with relapsed or refractory MCL (NCT00516412). The study was performed in collaboration with the EU-MCL network. Methods: Eligible patients with histologically/cytologically confirmed relapsed (not more than 3 prior lines of systemic treatment) or refractory MCL received everolimus 10 mg orally daily on day 1 – 28 of each cycle (4 weeks) for 6 cycles or until disease progression. The primary endpoint was the best objective response with adverse reactions, time to progression (TTP), time to treatment failure, response duration and molecular response as secondary endpoints. A response rate of ≤ 10% was considered uninteresting and, conversely, promising if ≥ 30%. The required sample size was 35 pts using the Simon's optimal two-stage design with 90% power and 5% significance. Results: A total of 36 patients with 35 evaluable patients from 19 centers were enrolled between August 2007 and January 2010. The median age was 69.4 years (range 40.1 to 84.9 years), with 22 males and 13 females. Thirty patients presented with relapsed and 5 with refractory MCL with a median of two prior therapies. Treatment was generally well tolerated with anemia (11%), thrombocytopenia (11%), neutropenia (8%), diarrhea (3%) and fatigue (3%) being the most frequent complications of CTC grade III or higher. Eighteen patients received 6 or more cycles of everolimus treatment. The objective response rate was 20% (95% CI: 8–37%) with 2 CR, 5 PR, 17 SD, and 11 PD. At a median follow-up of 6 months, TTP was 5.45 months (95% CI: 2.8–8.2 months) for the entire population and 10.6 months for the 18 patients receiving 6 or more cycles of treatment. Conclusion: This study demonstrates that single agent everolimus 10 mg once daily orally is well tolerated. The null hypothesis of inactivity could be rejected indicating a moderate anti-lymphoma activity in relapsed/refractory MCL. Further studies of either everolimus in combination with chemotherapy or as single agent for maintenance treatment are warranted in MCL. Disclosures: Off Label Use: everolimus for the treatment of mantle cell lymphoma.

Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). Although RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the preexisting CLL, the mechanisms leading to RS have not been clarified. To better understand the pathogenesis of RS, we analyzed a series of cases including 59 RS, 28 CLL phase of RS, 315 CLL, and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell-cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL phase, being present in approximately one half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. Although RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL phase preceding RS had not a generalized increase in genomic complexity compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions.