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The article discusses the study of patients with B-cell lymphoma for administration of lenalidomide in combination with rituximab (R2) and chemotherapy regimen (CHOP). First two cycles were evaluated for evaluation of lenalidomide. Patients from 18-70 years of age were included in the study and the dose of lenalidomide was given in combination with rituximab, doxorubicin, cyclophosphamide and vincristine. It was conclued that the efficacy of immunochemotherapy is increased by R2-CHOP.

The article focuses on the clinical practice guidelines in diagnosing, treating and reexamining diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) as defined by the European Society for Medical Oncology (ESMO). It mentions the requirements for staging and risk assessing of the said disease which include screening test for HIV and hepatitis B and C. Moreover, history and physical examination of patients are needed every three months within a year and every six months for two more years.

The article presents clinical recommendations for diagnosis, treatment and follow-up of diffuse large B-cell non-Hodgkin's lymphoma from the European Society for Medical Oncology (ESMO). The disease constitutes 30 to 58 percent of non-Hodgkin's lymphoma series. Diagnosis is based on a surgical specimen/excisional lymph node or extranodal tissue biopsy providing sufficient material for formalin-fixed samples.

The article presents the clinical recommendations of the European Society for Medical Oncology (ESMO) for the diagnosis, treatment and follow-up of diffuse large B-cell non-Hodgkin's lymphoma (DLBCL). Data on the crude incidence of DLBCL in the European Union is given. Diagnostic procedures include core biopsies and immunohistochemistry. Components of staging and risk assessment are outlined. Also noted are treatment options for stage I disease, stage II and III disease and stage IV disease.

Background Patients with diffuse large B-cell lymphoma treated with first-line anthracycline-based immunochemotherapy and remaining in remission at 2 years have excellent outcomes. This study assessed overall survival (OS) stratified by progression-free survival (PFS) at 24 months (PFS24) using individual patient data from patients with DLBCL enrolled in multi-center, international randomized clinical trials as part of the Surrogate Endpoint for Aggressive Lymphoma (SEAL) Collaboration. Patients and methods PFS24 was defined as being alive and PFS24 after study entry. OS from PFS24 was defined as time from identified PFS24 status until death due to any cause. OS was compared with each patient’s age-, sex-, and country-matched general population using expected survival and standardized mortality ratios (SMRs). Results A total of 5853 patients enrolled in trials in the SEAL database received rituximab as part of induction therapy and were included in this analysis. The median age was 62 years (range 18–92), and 56% were greater than 60 years of age. At a median follow-up of 4.4 years, 1337 patients (23%) had disease progression, 1489 (25%) had died, and 5101 had sufficient follow-up to evaluate PFS24. A total of 1423 assessable patients failed to achieve PFS24 with a median OS of 7.2 months (95% CI 6.8–8.1) after progression; 5-year OS after progression was 19% and SMR was 32.1 (95% CI 30.0–34.4). A total of 3678 patients achieved PFS24; SMR after achieving PFS24 was 1.22 (95% CI 1.09–1.37). The observed OS versus expected OS at 3, 5, and 7 years after achieving PFS24 was 93.1% versus 94.4%, 87.6% versus 89.5%, and 80.0% versus 83.7%, respectively. Conclusion Patients treated with rituximab containing anthracycline-based immunochemotherapy on clinical trials who are alive without progression at 24 months from the onset of initial therapy have excellent outcomes with survival that is marginally lower but clinically indistinguishable from the age-, sex-, and country-matched background population for 7 years after achieving PFS24. [ABSTRACT FROM AUTHOR]

Dose-dense induction and up-front consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating patients with high-risk diffuse large B-cell lymphoma. GELA designed a randomized phase 2 trial evaluating the efficacy of either rituximab,doxorubicin,cyclophosphamide,vindesine, bleomycin, prednisone (R-ACVBP) or rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP14) induction and a positron emission tomography (PET)-driven ASCT or standard immunochemotherapy (SIC) consolidation in age-adjusted international prognosis index 2 (aaIPI2)-aaIPI3 patients. PET was performed at baseline, after 2 (PET2) and 4 (PET4) induction cycles, and centrally assessed using international harmonization project (IHP) criteria. PET2-/ PET4- patients were assigned SIC, PET2-/PET4+ patients were assigned ASCT and PET4- patients were treated with the investigator's choice. The primary end-point wasthe 2007 international working group complete response (CR) rate after induction. Change in maximum standard uptake value (DSUVmax) after PET assessment was explored. Two hundred eleven patients were randomly assigned to R-ACVBP (n 5 109) or R-CHOP14 (n 5 102). PET42/CR rates were 53%/47% with R-ACVBP and 41%/39% with R-CHOP14 (CR 95% confidence interval [CI], 38%-67% and 28%-54%, respectively; P 5 .076). Consolidation in the R-ACVBP and R-CHOP14 groups was SIC in 26% and 23% of patients and ASCT in 28% and 18% of patients, respectively. PET4 positivity was higher with R-CHOP14 vs R-ACVBP (54% vs 41%; P 5 .08), leading to more salvage therapy (37% vs 26%; P 5 .07) and lower event-free survival (EFS; 4-year EFS,31%vs 43%;P< .01), but progression-free survival (PFS) and overall survival (OS) were similar in both groups. PET2-/PET4- and PET2+/PET4- patients had similar outcomes. Using DSUVmax, 79% of the patients were PET2-/PET4-. DSUVmaxPET0-4 >70% was associated with better outcome (4-year PFS, 84% vs 35%; 4-year OS, 91% vs 57%; P < .0001), whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established, as IHP criteria did not properly reflect disease control. DSUVmax may help better select patients needing an alternative to SIC, including ASCT. [ABSTRACT FROM AUTHOR]

Background: Our aim was to evaluate whether the cell of origin (COO) as defined by the Hans algorithm and MYC/BCL2 coexpression, which are the two main biological risk factors in elderly patients treated with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone (R-CHOP), maintain their prognostic value in a large prospective clinical trial. Patients and methods: We evaluated 285 paraffin-embedded samples from patients (60-80 years of age) enrolled in the Lymphoma Study Association trial LNH03-6B who were treated with R-CHOP. We correlated the COO defined by the transcriptome according to the Wright algorithm with that defined by the Hans algorithm in a subset of 62 tumors with available frozen tissue samples. Results: The non-germinal center B-cell-like phenotype according to the Hans algorithm and BCL2 expression (but not MYC and BCL2 coexpression) predicted worse progression-free survival [hazard ratio (HR)=1.78, P = 0.003 and HR = 1.79, P = 0.003, respectively] and overall survival (HR = 1.85, P = 0.005 and HR = 1.67, P = 0.02, respectively) independently of the International Prognostic Index. The correlation between the Hans algorithm and the Wright algorithm was 91%, with an almost perfect concordance according to a kappa test (0.81). Conclusions: Our results suggest that immunohistochemically defined COO remains a useful tool for predicting prognosis in diffuse large B-cell lymphoma when performed under optimized standardized conditions and that BCL2 expression may help to identify elderly patients at risk for relapse and who could potentially respond to anti-BCL2 targeted agents. In this prospective phase III trial, the coexpression of MYC and BCL2 does not appear to predict worse survival. Clinical trial Number: NCT00144755 [ABSTRACT FROM AUTHOR]

Background: Most peripheral T-cell lymphoma (PTCL) patients have a poor outcome and the identification of prognostic factors at diagnosis is needed. Patients and methods: The prognostic impact of total metabolic tumor volume (TMTV0), measured on baseline [18F] 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography, was evaluated in a retrospective study including 108 PTCL patients (27 PTCL not otherwise specified, 43 angioimmunoblastic T-cell lymphomas and 38 anaplastic large-cell lymphomas). All received anthracycline-based chemotherapy. TMTV0 was computed with the 41% maximum standardized uptake value threshold method and an optimal cut-off point for binary outcomes was determined and compared with others prognostic factors. Results: With a median follow-up of 23 months, 2-year progression-free survival (PFS) was 49% and 2-year overall survival (OS) was 67%. High TMTV0 was significantly associated with a worse prognosis. At 2 years, PFS was 26% in patients with a high TMTV0 (>230 cm³, n = 53) versus 71% for those with a low TMTV0, [P < 0.0001, hazard ratio (HR) = 4], whereas OS was 50% versus 80%, respectively, (P = 0.0005, HR = 3.1). Inmultivariate analysis, TMTV0 was the only significant independent parameter for both PFS and OS. TMTV0, combined with PIT, discriminated even better than TMTV0 alone, patients with an adverse outcome (TMTV0 >230 cm³ and PIT >1, n = 33,) from those with good prognosis (TMTV0 ≤230 cm³ and PIT ≤1, n = 40): 19% versus 73% 2-year PFS (P < 0.0001) and 43% versus 81% 2-year OS, respectively (P = 0.0002). Thirty-one patients (other TMTV0-PIT combinations) had an intermediate outcome, 50% 2-year PFS and 68% 2-year OS. Conclusion: TMTV0 appears as an independent predictor of PTCL outcome. Combined with PIT, it could identify different risk categories at diagnosis and warrants further validation as a prognostic marker. [ABSTRACT FROM AUTHOR]

BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24) that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U) showing a t(9;22)(p24;q11), which generates a BCR-JAK2 fusion gene by fusing the BCR at intron 13 to JAK2 at intron 17 on the derivative chromosome 22. Most reported JAK2 fusions cases reveal an aggressive clinical course and long-term remissions have only been achieved after allogeneic stem cell transplantation (ASCT). To the best of our knowledge, this is the thirteenth case reported worldwide to describe a BCR-JAK2 fusion transcript in MPN-U. The present report revealed a sustained complete clinical, hematologic, and cytogenetic remission 35 months after diagnosis and ~24 months after ASCT. Regarding BCR-ABL1  negative MPN patients this case report provides strong support for a role of JAK2 activation in the oncogenesis and suggests a possible diagnostic and therapeutic target that should be investigated. [ABSTRACT FROM AUTHOR]

This study shows on a large sample that in patients with follicular lymphoma who received total body irradiation-based autologous stem-cell transplantation after 1995 increased non-relapse mortality and treatment-related myelodysplastic syndromes/acute myelogenous leukaemia risks did not emerge compared with carmustin, etoposide, cytarabine and melphalan (BEAM) while disease control was at least equivalent.Background The aim of this study was to investigate the impact of the high-dose regimen on the outcome of patients with follicular lymphoma (FL) having had autologous stem-cell transplantation (ASCT) in a recent time period. Patients Between 1995 and 2007, 2233 patients with FL had their first ASCT with either a total body irradiation (TBI)-containing regimen or carmustin, etoposide, cytarabine and melphalan (BEAM), of which 47% were autografted in first remission. Results After a median observation time of 73 months (interquartile range 30–107), 5- and 10-year non-relapse mortality (NRM) was similar (6% and 10% in both groups). No significant NRM differences became evident after multivariate adjustment for confounders. Secondary malignancies were observed in 9.7% and 7.9% of the patients after TBI and BEAM (P = 0.19), which were treatment-related myelodysplastic syndromes/acute myelogenous leukaemia (t-MDS/AML) in 3.4% and 2.8% (P = 0.57). The median time to t-MDS/AML was around 50 months in both groups. Because of a lower relapse incidence, TBI was associated with better event-free survival reaching statistical significance in the patients transplanted in first remission but not in those transplanted beyond first remission. Conclusions In patients with FL who received TBI-based ASCT after 1995 increased NRM and t-MDS/AML risks did not emerge compared with BEAM while disease control was at least equivalent. [ABSTRACT FROM PUBLISHER]

Background Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin lymphoma with poor overall prognosis, requiring the development of new therapies. Lenalidomide is an immunomodulatory agent demonstrating antitumor and antiproliferative effects in MCL. We report results from a long-term subset analysis of 57 patients with relapsed/refractory MCL from the NHL-003 phase II multicenter study of single-agent lenalidomide in patients with aggressive lymphoma Design Lenalidomide was administered orally 25 mg daily on days 1–21 every 28 days until progressive disease (PD) or intolerability. The primary end point was overall response rate (ORR). Results Fifty-seven patients with relapsed/refractory, advanced-stage MCL had a median of three prior therapies. The ORR was 35% [complete response (CR)/CR unconfirmed (CRu) 12%], with a median duration of response (DOR) of 16.3 months (not yet reached in patients with CR/CRu) by blinded independent central review. The median time to first response was 1.9 months. Median progression-free survival was 8.8 months, and overall survival had not yet been reached. The most common grade 3/4 adverse events (AEs) were neutropenia (46%), thrombocytopenia (30%), and anemia (13%). Conclusions These results show the activity of lenalidomide in heavily pretreated, relapsed/refractory MCL. Responders had a durable response with manageable side-effects. Clinical trial number posted on www.clinicaltrials.gov NCT00413036. [ABSTRACT FROM AUTHOR]

Background The superiority of a chemotherapy with doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) in comparison with cyclophosphamide, doxorubicin, vincristin and prednisone plus radiotherapy for young patients with localized diffuse large B-cell lymphoma (DLBCL) was previously demonstrated. We report the results of a trial which evaluates the role of rituximab combined with ACVBP (R-ACVBP) in these patients. Patients and methods Untreated patients younger than 66 years with stage I or II DLBCL and no adverse prognostic factors of the age-adjusted International Prognostic Index were randomly assigned to receive three cycles of ACVBP plus sequential consolidation with or without the addition of four infusions of rituximab. Results A total of 223 patients were randomly allocated to the study, 110 in the R-ACVBP group and 113 in the ACVBP group. After a median follow-up of 43 months, our 3-year estimate of event-free survival was 93% in the R-ACVBP group and 82% in the ACVBP group (P = 0.0487). Three-year estimate of progression-free survival was increased in the R-ACVBP group (95% versus 83%, P = 0.0205). Overall survival did not differ between the two groups with a 3-year estimates of 98% and 97%, respectively (P = 0.686). Conclusion In young patients with low-risk localized DLBCL, rituximab combined with three cycles of ACVBP plus consolidation is significantly superior to ACVBP plus consolidation alone. [ABSTRACT FROM PUBLISHER]

Background Diffuse large B-cell lymphomas (DLBCLs) arising in specific extranodal sites have peculiar clinicopathologic features. Patients and methods We analyzed a cohort of 187 primary Waldeyer's ring (WR) DLBCLs retrieved from GELA protocols using anthracyclin-based polychemotherapy. Results Most patients (92%) had stage I–II disease. A germinal center B-cell-like (GCB) immunophenotype was observed in 61%, and BCL2 expression in 55%, of WR DLBCLs. BCL2, BCL6, IRF4 and MYC breakpoints were observed in, respectively, 3 of 42 (7%), 9 of 36 (25%), 2 of 26 (8%) and 4 of 40 (10%) contributive cases. A variable follicular pattern was evidenced in 30 of 68 (44%) large biopsy specimens. The 5-year progression-free survival (PFS) and the overall survival (OS) of 153 WR DLBCL patients with survival information were 69.5% and 77.8%, respectively. The GCB immunophenotype correlated with a better OS (P = 0.0015), while BCL2 expression predicted a worse OS (P = 0.037), an effect overcome by the GCB/non-GCB classification. Compared with matched nodal DLBCLs, WR DLBCLs with no age-adjusted international prognostic index factor disclosed a better 5-year PFS rate (77.5% versus 70.7%; P = 0.03). Conclusions WR DLBCLs display distinct clinicopathologic features compared with conventional DLBCLs, with usual localized-stage disease, common follicular features and a high frequency of GCB immunophenotype contrasting with a low rate of BCL2 rearrangements. In addition, they seem to be associated with a better outcome than their nodal counterpart. [ABSTRACT FROM PUBLISHER]

Background The purpose of this study was to report long-term results of rituximab induction monotherapy in patients with low-tumor-burden follicular lymphoma (LTBFL). Patients and methods Of 49 first-line LTBFL patients who received weekly doses of rituximab (375 mg/m2), 46 have been followed with a long-term analysis of clinical and molecular responses. Results Best clinical response (at any staging within a year following treatment) was 80%, 24 (52%) patients had complete or unconfirmed complete response, 13 (28%) had partial response and 9 (20%) had stable or progressive disease. Of 31 patients having a positive bcl2-JH rearrangement, 15 (48%) became negative following treatment. Conclusion A significant proportion of patients remain progression-free 7 years after a single 4-dose rituximab treatment in first-line LTBFL. The 7-year overall survivalOS is very high in this selected population of patients. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented in response to an article about Follicular lymphoma (FL) that was published in the previous issue.

Background: Limited experience is available on the feasibility and efficacy of autologous stem-cell transplantation (ASCT) in patients with mantle cell lymphoma (MCL) beyond 65 years.Design and methods: We analysed 712 patients with MCL treated with ASCT from 2000 to 2007 and reported to the European Group for Blood and Marrow Transplantation registry. Patients >65 years were compared with patients <65 years for the end points non-relapse mortality (NRM), relapse incidence, progression-free survival (PFS), and overall survival (OS).Results: Seventy-nine patients were ≥65 years old. Median time from diagnosis to ASCT was longer in the elderly patients (11 versus 9 months, P = 0.005); they had more commonly received at least two treatment lines (62.0% versus 47.9%, P = 0.02) and were less commonly in first complete remission at ASCT (35.4% versus 51.2%, P = 0.002). Median follow-up after ASCT was 19 and 25 months, respectively. NRM was comparable at 3 months (3.8% versus 2.5%) and at 5 years (5.6% versus 5.0%). There were no differences in relapse rate (66% versus 55% at 5 years), PFS (29% versus 40%) and OS (61% versus 67%) between both populations of patients.Conclusion: ASCT beyond 65 years of age is feasible in selected patients with MCL and results in similar disease control and survival as in younger patients. [ABSTRACT FROM AUTHOR]

Background: Lenalidomide is an immunomodulatory agent with antitumor activity in B-cell malignancies. This phase II trial aimed to demonstrate the safety and efficacy of lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular grade 3 lymphoma (FL-III), or transformed lymphoma (TL).Methods: Patients received oral lenalidomide 25 mg on days 1–21 every 28 days as tolerated or until progression. The primary end point was overall response rate (ORR).Results: Two hundred and seventeen patients enrolled and received lenalidomide. The ORR was 35% (77/217), with 13% (29/217) complete remission (CR), 22% (48/217) partial remission, and 21% (45/217) with stable disease. The ORR for DLBCL was 28% (30/108), 42% (24/57) for MCL, 42% (8/19) for FL-III, and 45% (15/33) for TL. Median progression-free survival for all 217 patients was 3.7 months [95% confidence interval (CI) 2.7–5.1]. For 77 responders, the median response duration lasted 10.6 months (95% CI 7.0–NR). Median response duration was not reached in 29 patients who achieved a CR and in responding patients with FL-III or MCL. The most common adverse event was myelosuppression with grade 4 neutropenia and thrombocytopenia in 17% and 6%, respectively.Conclusion: Lenalidomide is well tolerated and produces durable responses in patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma. [ABSTRACT FROM AUTHOR]

Gene expression profiling has identified two major molecular subtypes of diffuse large B-cell lymphoma (DLBCL) that are histologically indistinguishable but differ in cure rates. Here, we investigated whether the isotype of the B-cell receptor (BCR) expressed by the tumoral cells correlated with the molecular subtype and survival. Gene expression analysis clustered the 53 patients included in this study into three subgroups, 17 germinal center B-cell-like (GCB) cases, 26 activated B-cell-like (ABC) cases and 10 intermediate cases. The molecular subtype was correlated with the isotype, as 15/17 GCB cases expressed a secondary isotype (immunoglobulin (Ig)G or IgA), whereas 24/26 ABC cases expressed a primary isotype (IgM or IgD) (P<0.0001). There was a trend toward a worse outcome for patients with an ABC DLBCL and a shorter overall survival for patients with IgM+ tumor (P=0.21 and 0.014, respectively). Finally, fluorescence in situ hybridization (FISH) analysis revealed a striking asymmetric pattern, as the IGHM gene is conserved only on the productive IGH allele in most IgM+ tumors. Taken together, these data indicate that the isotype of the BCR is a reliable indicator for the GCB and ABC subtypes in DLBCL, and suggest that the conservation of an IgM is required for ABC DLBCL lymphomagenesis to occur. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) B cells contract tight connections with their microenvironment, which governs the pathogenesis and progression of the disease. Indeed, specific immune response gene signatures, obtained from whole biopsy samples, have been associated with patient survival. In this study, we performed gene expression profiling of purified B cell and non-B cell compartments obtained from FL and reactive lymph nodes. We identified 677 non-redundant genes defining the FL interface and involving 26 FL-specific functional networks. This approach highlighted an interleukin-4 (IL-4)-centered pathway associated with an activation of signal transducer and activator of transcription 6 (STAT6), which favors overexpression of IL-4-target genes. In addition, FL microenvironment was characterized by a strong enrichment in follicular helper T cells (T(FH)), as demonstrated through transcriptomic and flow cytometry analyses. The majority of phospho-STAT6(pos) B cells were located at the vicinity of cells expressing the programmed death 1 (PD-1) T(FH) marker. Moreover, purified FL-derived T(FH), expressed IL4 at very high levels compared with purified tonsil-derived T(FH) or non-T(FH) microenvironment. Altogether, our study demonstrated that tumor-infiltrating T(FH) specifically express functional IL-4 in FL, creating an IL-4-dependent T(FH)-B cell axis. This cross talk could sustain FL pathogenesis and represent a new potential therapeutic target. [ABSTRACT FROM AUTHOR]

Background: This prospective multicentric phase II study aimed to confirm the results of the C5R protocol of high-dose methotrexate (MTX)-based chemotherapy (CT) for immunocompetent primary central nervous system lymphoma. [ABSTRACT FROM PUBLISHER]

Background: This study compared the induction regimens doxorubicin, cyclophosphamide and etoposide (ACE) with doxorubicin, cyclophosphamide, vincristine, bleomycin and prednisone (ACVBP) before high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) for patients with poor-risk diffuse large B-cell lymphoma (DLBCL). A second randomisation compared rituximab with observation post-ASCT. [ABSTRACT FROM PUBLISHER]

CD4+CD56+ haematodermic neoplasms (HDN) constitute a rare disease characterized by aggressive clinical behaviour and a poor prognosis. Tumour cells from HDN are leukaemic counterparts of plasmacytoid dendritic cells (pDCs). Despite increased knowledge of the ontogenetic origin of these tumours, the genetic causes and oncogenic signalling events involved in malignant transformation are still unknown. To delineate novel candidate regions and disease-related genes, we studied nine typical CD4+CD56+ HDN cases using genome-wide high-resolution array comparative genomic hybridization (CGH). Genomic imbalances, which were predominantly losses, were frequently detected. Gross genomic losses or gains involving an entire chromosome were observed in eight cases. The most frequent imbalances were deletions of chromosome 9, chromosome 13 and partial losses affecting 17p or 12p. Combinations of deletions of tumour suppressor genes (TSG), namely RB1, CDKN1B (p27), CDKN2A, (p16ink4a, p14arf) or TP53 (p53), were observed in all cases. These results indicate that deletion events altering G1/S regulation are crucial for HDN oncogenesis. Furthermore, in addition to frequent sporadic gene losses, in one case we observed a 8q24 interstitial deletion that brought MYC closer to miR-30b/miR-30d, which may be related to their deregulation. Taken together, these results indicate that in addition to frequent G1/S checkpoint alterations, various genetic events could contribute to the chemoresistance of the tumour.Leukemia (2009) 23, 698–707; doi:10.1038/leu.2008.359; published online 22 January 2009 [ABSTRACT FROM AUTHOR]

Gene expression profiles have been associated with clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated with anthracycline-containing chemotherapy. Using Affymetrix HU133A microarrays, we analyzed the lymphoma transcriptional profile of 30 patients treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and 23 patients treated with rituximab (R)-CHOP in the Groupe d'Etude des Lymphomes de l'Adulte clinical centers. We used this data set to select transcripts showing an association with progression-free survival in all patients or showing a differential effect in the two treatment groups. We performed real-time quantitative reverse transcription-PCR in the 23 R-CHOP samples of the screening set and an additional 44 R-CHOP samples set to evaluate the prognostic significance of these transcripts. In these 67 patients, the level of expression of 16 genes and the cell-of-origin classification were significantly associated with overall survival, independently of the International Prognostic Index. A multivariate model comprising four genes of the cell-of-origin signature (LMO2, MME, LPP and FOXP1) and two genes related to immune response, identified for their differential effects in R-CHOP patients (APOBEC3G and RAB33A), demonstrated a high predictive efficiency in this set of patients, suggesting that both features affect outcome in DLBCL patients receiving immunochemotherapy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related to the molecular characterization of three t(3;8)(q27;q24) translocations from diffuse large B-cell lymphomas in the November 8, 2007 issue.

To evaluate the outcome of a large series of patients who received high-dose treatment (HDT) for follicular lymphoma (FL), 693 patients undergoing HDT (total-body irradiation (TBI)-containing regimen: 58%; autologous bone marrow (BM)/peripheral blood progenitor cells (PBPCs): 378/285 patients) were included in the study. A total of 375 patients (54%) developed recurrent lymphoma, 10-year progression-free survival (PFS) being 31%. On multivariate analysis, younger age (P=0.003) and HDT in first complete remission (CR1) (P<0.001) correlated with longer PFS. With a median follow-up of 10.3 years, 330 patients died. Ten-year overall survival (OS) from HDT was 52%. Shorter OS was associated on multivariate analysis with older age (P<0.001), chemoresistant disease (P<0.001), BM+PBPC as source of stem cells (P=0.007) and TBI-containing regimens (P=0.004). Thirty-nine patients developed secondary myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), in 34 cases having received TBI as the conditioning regimen. The 5-year non-relapse mortality (NRM) was 9%. On multivariate analysis, older age (P<0.001), refractory disease (P<0.001) and TBI (P=0.04) were associated with a higher NRM. This long follow-up study shows a plateau in the PFS curve, suggesting that a selected group of patients might be cured with HDT. On the downside, TBI-containing regimens are associated with a negative impact on survival.Leukemia (2007) 21, 2324–2331; doi:10.1038/sj.leu.2404850; published online 19 July 2007 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which offers a study on nodular lymphocyte-predominant Hodgkin's lymphoma and classical Hodgkin's lymphoma through conventional cytogenetics.

Four chromosomal defects associated with outcome are commonly evaluated by fluorescent in situ hybridization (FISH) in chronic lymphocytic leukemia (CLL), namely deletions of the 13q13-q14, 11q22 and 17p13 regions and trisomy 12. In this study, we compared a quantitative PCR method – quantitative multiplex PCR of short fluorescent fragment (QMPSF) – with FISH for the detection of these acquired aneuploidies in a series of 110 patients with Binet stage A CLL. Genes located in the deleted or gained regions were selected as target genes and amplified using a method based on the simultaneous amplification of short fluorescent genomic fragments under quantitative conditions. A chromosomal imbalance involving one or several of the four loci was detected by either method in 72 patients (65%). A chromosome 13 deletion was present in 61 patients (54%), a 11q22 deletion in nine (8%), a trisomy 12 in nine and a 17p deletion in one. FISH and QMPSF results were identical for 103 out of 110 patients and discrepancies could be explained in most cases. This study demonstrates that a quantitative multiplex PCR represents a cost-effective method that could replace FISH in CLL patients. However, although QMPSF is perfectly adapted to the detection of primary defects, care should be taken when searching for clonal evolutions present in a small proportion of tumor cells.Leukemia (2007) 21, 1460–1463; doi:10.1038/sj.leu.2404727; published online 10 May 2007 [ABSTRACT FROM AUTHOR]

Chromosomal translocations joining the immunoglobulin (IG) and MYC genes have been extensively reported in Burkitt's and non-Burkitt's lymphomas but data concerning MYC rearrangements with non-IG partners are scarce. In this study, 8q24 breakpoints from 17 B-cell lymphomas involving non-IG loci were mapped by fluorescence in situ hybridization (FISH). In seven cases the breakpoint was inside a small region encompassing MYC: in one t(7;8)(p12;q24) and two t(3;8)(q27;q24), it was telomeric to MYC whereas in four cases, one t(2;8)(p15;q24) and three t(8;9)(q24;p13) it was located in a 85 kb region encompassing MYC. In these seven cases, partner regions identified by FISH contained genes known to be involved in lymphomagenesis, namely BCL6, BCL11A, PAX5 and IKAROS. Breakpoints were cloned in two t(8;9)(q24;p13), 2.5 and 7 kb downstream from MYC and several hundred kb 5' to PAX5 on chromosome 9, joining MYC to ZCCHC7 and to ZBTB5 exon 2, two genes encoding zinc-finger proteins. In these seven cases, MYC expression measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) was significantly higher when compared to that of patients without 8q24 rearrangement (P=0.006). These results suggest that these rearrangements are the consequence of a non-random process targeting MYC together with non-IG genes involved in lymphocyte differentiation and lymphoma progression. [ABSTRACT FROM AUTHOR]

The article presents critical features of de novo t(14;18) and t(3;14) DLBCL, which proves the presence of orchestrated multiple molecular mechanisms in tumor cells for survival at distinct sites. The process diffuses large B-cell lymphoma producing germinal center-B cell and non-germinal center-B cell under glycosylation. The article also focuses on glycosylation, to study the association of tumor origins with chromosomal abnormalites by classifying the disease heterogeneity.

The t(3;14)(q27;q32) is the most common translocation involving BCL6 in B-cell lymphoma. Although this translocation was predominantly associated with diffuse large B-cell lymphoma (DLBCL), recent studies have shown that it can also be found in follicular lymphomas (FL), often associated with a large cell component. To further investigate the relationship that might exist between this translocation and the phenotype of the tumors, we studied 34 lymphomas with a t(3;14)(q27;q32). Twenty cases were DLBCL, 14 FL and most cases, regardless of histology, were negative for the expression of CD10 (26/32, 81%). We identified the IGH switch region involved in the translocation for 32 cases. Our data indicate that in DLBCL most breakpoints involve the switch μ (17/19; 89%), whereas in FL most involve a switch γ (9/13; 70%) (P=0.0016, Fisher's exact test). This correlation between the histology and the structure of the translocated allele suggests that the lymphomas with Sμ and Sγ translocations may originate from different cells, or that the substituted regulatory regions that come to deregulate BCL6 may affect the presentation of the disease. [ABSTRACT FROM AUTHOR]

Genetic modifications of the BCL6 gene in lymphoma include translocations, deletions, and somatic mutations (SM) of the 5′ noncoding region. Three single-nucleotide polymorphisms (SNPs) of the major mutation cluster region (MMC) have been reported, including two substitutions (397G/C, 502G/A) and one deletion (520ΔT). Clinical and biological relevance of these SNPs are unknown. Based on a case–control study, BCL6 SNPs frequencies were assessed in 97 t(14;18) follicular lymphomas (FL) and in 54 lymphomas with 3q27 rearrangement. Allele frequencies were similar in the FL and controls groups. The 397 G/C genotype was correlated to a higher-grade transformation risk (P=0.02). SM were observed in 39.1% of FL and were characterized by a clustering distribution (hot spots spanning position 420–435, 106–127, and 590–600). No correlation between genotypes or acquired mutational status and BCL6 expression was demonstrated. However, gel mobility-shift assays, using SNPs containing probes show results representative for protein/DNA complexes. This study demonstrates that the first BCL6 intron is a highly variable region as a consequence of both SNP and SM, which may contribute to biology and outcome of FL.Leukemia (2005) 19, 1824–1830. doi:10.1038/sj.leu.2403915; published online 11 August 2005 [ABSTRACT FROM AUTHOR]

Identifies a subtype of indolent lymphoma which is closely related to typical follicular lymphoma, but is characterized by distinctive pathological features. Use of immunophenotype and mutational analysis of the first BCL-6 intron, a marker of germinal center transit; Cytogenetic analysis and histology; PCR amplification of t(14;18) translocation.

Compares the level of BCL-6 mRNA expression by a real-time quantitative reverse transcription-polymerase chain reaction using TaqMan technology in node biopsies of follicle center lymphomas (FCL) and diffuse large B cell lymphomas (DLBCL). Cytogenetic and Southern blot analysis in DLCBL and FCL; RNA extraction and cDNA synthesis.

The t(14;18)(q32;q21) translocation is closely associated with follicular lymphoma (FL), and is routinely assessed with molecular methods exploring BCL2 breakpoints for both diagnosis and minimal residual disease (MRD) monitoring. We and others have previously reported new recurrent breakpoints (3'BCL2 and 5'mcr) which could be easily analyzed. In this study, we characterized the BCL2 breakpoints in 113 untreated patients with t(14;18)-positive FL and correlated their location with the location of JH break and with the clinical features. Breakpoints were respectively located at the major breakpoint region (MBR) in 73 cases (65%), at the minor cluster region (mcr) in 10 cases (9%), at 3'BCL2 in 14 cases (12%) and at 5'mcr in seven cases (6%). Finally, the breakpoint could not be located in nine patients (8%). 5'mcr cases were associated with bulky and high-stage disease, with frequent extranodal involvement and bone marrow infiltration. Survival studies did not show any correlation between breakpoint location and clinical outcome. The joining JH6 segment was the most frequently involved whatever the breakpoint location. In conclusion, unusual BCL2 breakpoints are found in about 20% of newly diagnosed follicular lymphomas and their study should be considered in the investigation of BCL2-JH rearrangement. It was not possible, in this series, to demonstrate any correlation between breakpoint location and either initial characteristics of the disease or survival of the patients. [ABSTRACT FROM AUTHOR]

The t(14;18)(q32;q21) translocation is the most common translocation in B cell malignancies being found in 80% of follicular lymphomas and about 20% of diffuse large B cell lymphomas. Only rare cases of de novo acute B cell lymphoblastic leukemia with t(14;18) have been described. We describe five cases of this entity which appears to have very homogeneous clinical, phenotypic and genotypic features. None of these patients had prior history of follicular lymphoma. The disease was characterized by acute clinical features with nodal and/or extranodal disease, massive bone marrow infiltration and rapid increase of circulating blast cells of mature B cell phenotype. All patients disclosed complex chromosomal and molecular abnormalities involving at least the BCL-2 and c-MYC genes. Furthermore, three patients had evidence of BCL-6 involvement and one patient had a p53 mutation. Despite intensive chemotherapy, including for two patients allogeneic bone marrow transplantation in first complete remission, all patients died within a few months. Neuro-meningeal relapse occurred in three of the five patients in spite of neuro-meningeal prophylaxis. De novo leukemia/lymphoma with t(14;18) is a rare entity with a very poor prognosis. Whether early bone marrow transplant could modify the natural history of the disease remains to be determined. An intensive neuro-meningeal prophylaxis appears to be mandatory in these patients. [ABSTRACT FROM AUTHOR]

Follicular lymphomas (FL) are closely associated with a t(14;18)(q32;q21) translocation, leading to a bcl2 protein over-production. This translocation probably constitutes a very early step in the development of the disease. Besides the cytogenetic assay, t(14;18) detection can be achieved using either Southern blot or polymerase chain reaction (PCR). Since 1990, several publications have reported discrepancies between the results of cytogenetic and molecular analysis of t(14;18). Using methods able to explore long DNA fragments, several authors reported breakpoints located outside the usual breakpoint regions. However, these techniques cannot be easily used in routine. The aim of this study was to develop a simple PCR assay to amplify rearrangements usually not detected in FL. We selected a group of 83 patients with a t(14;18) on cytogenetic analysis: using usual probes and primers, 54/83 (65.1%) showed a MBR rearrangement, 7/83 (8.4%) were mcr positive and 22/83 (26.5%) remained negative. Among these 22 rearrangements, nine could be detected using this new PCR assay. Four breakpoints were located in a 20 bp area suggesting a recurrent breakpoint cluster close to an Alu repetitive sequence. Finally, remaining negative cases (13/83, 15.6%) suggest that other breakpoints are located between the MBR and mcr regions. [ABSTRACT FROM AUTHOR]

The EMA86 study showed efficacy of intensive sequential chemotherapy with mitoxantrone, 12 mg/m2 day on days 1-3, etoposide, 200 mg/m2/day as a continuous infusion on days 8-10 and cytarabine (araC), 500 mg/m2/day as continuous infusion on days 1-3 and 8-10 (EMA regimen) in previously treated patients with AML. The goal of the EMA91 study was to determine whether administration of GM-CSF between the two sequences of EMA chemotherapy and during the second sequence could increase therapeutic efficacy by potentially increasing leukemic cell recruitment into the S phase of cell cycle before the second sequence. One hundred and ninety-two patients aged less than 65 years with previously treated AML received GM-CSF, 5 microg/kg/day or placebo from day 4 to day 8 of EMA chemotherapy. One hundred and twenty were refractory and 72 were in first relapse after a complete remission (CR) of more than 6 months duration. CR rates after one course of chemotherapy were 65% in the GM-CSF group (refractory: 51%; first relapse: 89%), not significantly different from the 59% CR rate (refractory: 46%; first relapse: 81%) in the placebo group. Median time to recovery of neutrophils was 38 and 37 days and median time to last platelet transfusion 32 and 32 days respectively in the GM-CSF and placebo groups. WHO grade > or = 3 non-hematologic toxicities were mainly sepsis (45% and 51%, respectively) and mucositis (34% and 31%) and did not differ between the two groups. Toxic death rate was 5% and 8%, respectively, in the GM-CSF and placebo groups. Patients achieving CR were scheduled to receive six courses of maintenance with reduced-dose EMA. Time to progression tended to be longer in the GM-CSF group (median 154 vs 115 days, progression-free rate at 18 months 33% vs 19%, P = 0.08), particularly in refractory patients (P = 0.06). However, at the current follow-up, this did not translate into a significantly longer disease-free survival and survival. Cell cycle studies showed increased recruitment of cells in the S phase between day 4 and day 8 in the GM-CSF group compared to placebo (P = 0.006). However, this did not significantly relate to prognosis in this cohort of patients. GM-CSF might marginally increase efficacy of sequential chemotherapy without increasing its toxicity in the absence of any detected relationship between this effect and observed leukemic cell recruitment into the cell cycle. [ABSTRACT FROM AUTHOR]

Splenic lymphoma with villous lymphocytes (SLVL) is a B cell chronic lymphoproliferative disorder. Splenectomy and/or chlorambucil are usually regarded as the most effective treatment in SLVL patients. However, a few patients relapse and the second-line treatment remains questionable. In a retrospective study, we evaluated the efficacy and toxicity of fludarabine (FDR) in 10 SLVL patients. The median duration between diagnosis and treatment was 17 months (range, 1-30). Two patients were previously untreated. The patients received FDR 25 mg/m2/day by venous infusion for 5 days with a median of four cycles of chemotherapy (range, 2-6). All patients were assessable: five patients achieved a good and persistent response after a median follow-up of 14 months (5-31), two achieved a good response but relapsed after a follow-up of 15 and 36 months. One out of the three partial responders have a persistent response. The treatment was well tolerated. FDR appears to be an efficient therapy with a favorable toxicity profile for patients in relapse after splenectomy or resistant to CLB. Furthermore it could constitute an alternative to splenectomy in older patients. A longer follow-up and the study of a larger group of patients are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

A correction to the article "Recurrent Genomic Aberrations Combined with Deletions of Various Tumour Suppressor Genes May Deregulate the G1/S Transition in CD4+CD56 Haematodermic Neoplasms and Contribute to the Aggressiveness of the Disease," that was published in the January 2009 issue is presented.

Provides update on the efficacy of fludarabine as a therapy in patients with splenic lymphoma with villous lymphocytes (SLVL). Characteristics of marginal zone lymphoma; Increase in the number of peripheral blood villous lymphoid cells; Treatment of SLVL.