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Relapse is least common in patients with indolent B cell (iB) malignancies (ie, iB non-Hodgkin lymphoma [NHL]) who undergo nonmyeloablative allogeneic transplantation (NMAT) in complete remission (CR). However, for the many patients unable to achieve this state, outcomes are poorly described and methods to improve results are unknown. We sought to describe the long-term follow-up and predictive factors for these poor-risk patients unable to achieve CR before NMAT. We identified and evaluated patients with iB-NHL including chronic lymphocytic leukemia treated with fludarabine/total body irradiation-based NMAT that had evidence of persistent disease before NMAT. From December 1998 to April 2009, 89 patients were identified, most commonly with small/chronic lymphocytic lymphoma (n = 62) and follicular lymphoma (n = 24). Pretransplant anti-CD20 radioimmunotherapy (RIT) using standard yttrium-90-ibritumomab tiuxetan was administered to 18 patients (20%) who more frequently had chemoresistant disease (81% versus 39%, P = .003), disease bulk > 5 cm (61% versus 15%, P < .001), thrombocytopenia < 25k/μL (33% versus 7%, P = .002), and Hematopoietic Cell Transplant Comorbidity Index scores ≥ 3 (72% versus 37%, P = .006). After adjusting for these imbalances, RIT-treated patients had improved rates of progression-free survival (PFS) (hazard ratio [HR] = .4; 95% confidence interval [CI], .2 to .9, P = .02) and overall survival (OS) (HR = .3; 95% CI, .1 to .8, P = .008) compared with the non-RIT group. The 3-year adjusted estimates of PFS and OS for the RIT and non-RIT groups were 71% and 87% versus 44% and 59%, respectively. The use of RIT was the only factor independently associated with improved PFS and OS. Rates of nonrelapse mortality and graft-versus-host disease (GVHD) were similar between the 2 groups, although over 70% of patients developed clinically significant acute or chronic GVHD. In conclusion, despite relatively high rates of GVHD, patients with persistent iB-NHL can derive durable benefit from NMAT., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

In the S0313 trial, we evaluated the impact of adding ibritumomab tiuxetan consolidation to 3 cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy plus involved field radiotherapy (IFRT) in patients with limited-stage aggressive B-cell non-Hodgkin lymphoma (LD-NHL). Patients with at least 1 stage-modified adverse risk factor (nonbulky stage II, age >60 years, elevated lactate dehydrogenase, or World Health Organization performance status of 2) were treated with CHOP on days 1, 22, and 43, followed 3 weeks later by 40 to 50 Gy of IFRT. An ibritumomab tiuxetan regimen was initiated 3 to 6 weeks following IFRT. Forty-six patients were registered and eligible, with median follow-up of 7.3 years. The progression-free survival estimate is 89% at 2 years, 82% at 5 years, and 75% at 7 years. The overall survival estimate is 91% at 2 years, 87% at 5 years, and 82% at 7 years. Grade 4 adverse events occurring more than once included neutropenia (8), leukopenia (5), and lymphopenia (2). Febrile neutropenia was observed in 4 patients. No cases of treatment-related myeloid neoplasms were noted. In conclusion, patients with high-risk LD-NHL treated with 3 cycles of CHOP plus IFRT followed by ibritumomab tiuxetan consolidation had outcomes that compare favorably to our historical experience. The clinical trial was registered at www.clinicaltrials.gov as #NCT00070018., (© 2015 by The American Society of Hematology.)

This study was conducted to evaluate the efficacy and safety of rituximab and Bortezomib in relapsed or refractory indolent B cell non-Hodgkin's lymphoma (NHL). Treatments consisted of rituximab 375 mg/m(2), i.v. on days 1, 8, 15, and 22 of cycle 1 and on day one of cycles 2-5, bortezomib 1.6 mg/m(2), given by intravenous injection (3-s to 5-s bolus) on days 1, 8, 15, and 22 of a maximum of five cycles. The primary end points were the overall survival (OS) and progression-free survival (PFS). Secondary endpoints included response rate (ORR; CR) and toxicities. From January 2008 to December 2010, 60 successive patients at Tianjin cancer hospital lymphoma department were enrolled in this study. All patients were recurrent or refractory indolent B cell NHL, including follicular lymphoma grades 1-2 (n = 35), small lymphocytic lymphoma/chronic lymphocytic leukemia (LL/CLL; n = 16) and marginal zone lymphoma (n = 9). The median follow-up time was 30 months (range 12-48). The overall response rate was 70.0 %, with a CR/CRu rate of 31.7 %. The 2-year OS and PFS of all patients were 75.0 and 41.0 %, respectively. Grade 3-4 neutropenia and thrombocytopenia occurred in 10 and 3.3 % of patients, respectively. Higher IPI and refractory disease were independently associated with worse survival and PFS. RB chemotherapy in patients with refractory or relapsed indolent B cell NHL was effective with low toxicity.

Rituximab® provides high response rates and effective disease palliation in patients with splenic marginal zone lymphoma (SMZL). We conducted a phase II trial in patients with SMZL who were either untreated or were splenectomized but had shown disease progression within 1 year after splenectomy. Treatment consisted of six courses of Rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone (R-COMP). Fifty-one patients were eligible for the analysis. The overall response rate was 84%. The 6-year progression-free survival and overall survival were 54% and 72%, respectively. Toxicity was substantial (grade≥3 neutropenia: 26%; grade≥3 infections: 8%). Of the 15 deaths, two occurred on treatment (one sepsis and one pneumonia). Six deaths were due to lymphoma progression, four to secondary neoplasia, one to sepsis, one to pneumonia and one to splenectomy complications. R-COMP should be restricted to patients with bulky disease associated with symptoms or to patients with possible histological transformation.

Primary mediastinal B-cell lymphoma (PMBL) is a subtype of diffuse large B-cell lymphoma (DLBCL) that arises in the mediastinum from B-cells of thymic origin. Optimal management of patients with PMBL remains controversial. The present study evaluates outcomes of 27 PMBL patients treated with R-CHOP with or without radiation therapy (RT). It investigates the role of both interim and posttreatment fluorodeoxyglucose-positron emission tomography (FDG-PET) as prognostic markers of outcome. Additionally, it assesses postprogression therapies in the six patients who had progressive disease. At a median follow-up of 41.5 months (range: 6.1-147.2 months), OS was 95.5% (95% CI = 71.9-99.4) and progression-free survival (PFS) was 70.4% (95% CI = 49.4-83.9) for the entire cohort. The negative predictive values of interim and posttreatment FDG-PET scans were both 100%. Patients who failed initial therapy and were treated with salvage regimens and autologous stem cell transplantation (ASCT) all achieved and maintained CR. PMBL patients can achieve excellent outcomes with minimal toxicities when treated with R-CHOP with or without RT. Negative interim and negative posttreatment FDG-PET results identified PMBL patients who achieve long-term remission. However, the significance of both positive interim and positive posttreatment FDG-PET results needs to be better defined. Those who failed initial therapy were successfully treated with salvage regimens and ASCT., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

There are limited data regarding the role of (18)F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET-CT) scanning in primary mediastinal B-cell lymphoma (PMBL). We analyzed 28 patients with PMBL treated with chemotherapy, of whom 25 (89%) also received rituximab and 17 (61%) radiotherapy. PET-CT scans were interpreted using visual analysis and a 5-point scale. After a median follow-up of 2.6 years, four patients relapsed and two died. The 2-year progression-free survival and overall survival were 86% and 94%. PET-CT has excellent negative predictive value (interim, 86-87%; end of treatment, 95%) but limited positive predictive value due to the high frequency of positive scans. Several patients with persistent metabolically active masses underwent biopsies, which showed necrosis but no lymphoma. Thus a negative PET-CT is an excellent predictor of subsequent outcome. However, residual metabolically active masses after treatment should be biopsied to confirm viable lymphoma prior to salvage therapy.

Given the importance of understanding the genetic variations involved in the pathogenesis of non-Hodgkin's lymphoma (NHL), this pilot study was designed to investigate the impact of CD38 (184C/G; rs6449182) and IL-6 (-174 G/C; rs1800795) gene polymorphism on susceptibility of Egyptians to diffuse large B cell lymphoma (DLBCL); major types of NHL. To the best of our knowledge, this study is the first one that examines CD38 polymorphism in the NHL. Genotyping polymorphism is performed using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) for CD38 and Mutagenically separated PCR (MS-PCR) for IL-6 in 100 Egyptian NHL patients with DLBCL subtype and 119 normal controls. The serum level of IL-6 was measured using Enzyme-linked immunosorbent assay (ELISA). CD38 (184C/G) genotype is significantly increased in NHL patients (p < 0.01), while the GG genotype is significantly increased in controls (p < 0.05). Only two genotypes were found (GG and GC) in IL-6 (-174), no CC in our NHL patients and only one case in the controls. Insignificant change in IL-6 (-174 G/C) genotypes was recorded. Significantly increased serum IL-6 (p < 0.05) was positively correlated (r = 0.17; p < 0.05) with the disease. Taken together, our data stressed the importance of CD38 gene polymorphism in developing DLBCL. Our pilot study indicates that CD38 (184) CG genotype might play a role in DLBCL susceptibility in Egyptians. Additional prospective studies on larger population are needed to confirm our findings.

We have studied the feasibility and efficacy of intensified R-MegaCHOP-ESHAP-BEAM therapy in high-risk aggressive B-cell lymphomas. Altogether 105 patients (19-64 years) with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBL) or follicular lymphoma grade 3 (FL3) with an age-adjusted International Prognostic Index of 2-3 were recruited. Treatment consisted of three cycles of high-dose R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), followed by three cycles of R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, cisplatin) and high-dose consolidation with BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem cell transplant. The 5-year progression-free survival (PFS) was 72% (DLBCL 60%, PMBL 89%) and overall survival (OS) was 74% (DLBCL 61%, PMBL 89%) after a median follow-up of 85 months. However, an independent prognostic factor was age only, with patients ≤ 45 years having 5-year PFS 90% and patients > 45 years having PFS 54%. PMBL had better prognosis than DLBCL/FL3 in patients > 45 years (PFS, 88% vs. 48%), but not in younger patients (PFS, 91% vs. 94%).

Microarray technology allows simultaneous measurements of expression levels for thousands of genes. An important aspect of microarray studies includes the prediction of patient survival based on their gene expression profile. This naturally calls for the use of a dimension reduction procedure together with the survival prediction model. In this study, a new method based on wavelet transform for survival-relevant gene selection is presented. Cox proportional hazard model is typically used to build prediction model for patients' survival using the selected genes. The prediction model will be evaluated with the R2, concordance index, likelihood ratio statistic and Akaike information criteria. The results proved that good performance of survival prediction is achieved based on the selected genes. The results suggested the possibility of developing more advanced tools based on wavelets for gene selection from microarray data sets in the context of survival analysis.

Purpose: Rituximab is a monoclonal antibody targetting the CD20 antigen with the ability to increase overall remission (OR) in B-cell non-Hodgkin's lymphoma (B-NHL). A systematic review and meta-analysis were conducted to determine the risk of the most clinically relevant severe and fatal adverse events (AEs) associated with the use of rituximab in the treatment of B-NHL., Patients and Methods: We included phase III clinical trials that used chemotherapy in combination with rituximab or chemotherapy alone as for B-NHL. Statistical analyses were conducted to calculate summary risk ratio (RR) of the relevant severe and fatal AEs related with rituximab., Results: Eight randomised controlled clinical trials were included in this meta-analysis. Summary RR obtained showed no statistically significant rituximab-associated increased risk in 13 severe adverse events (SAEs) (infection, fever, anaemia, thrombocytopaenia, granulocytopenia, liver toxicity, cardiac toxicity, neurologic toxicity, lung toxicity, mucositis, nausea/vomiting, diarrhoea, alopecia) except leukocytopenia (36.4% versus 31%; RR = 1.13; 95%CI, 1.01-1.27; P = 0.03). The incidences of fatal AEs showed noteworthy difference between rituximab group and control group (RR = 1.45; 95% CI, 1.04-2.02; P = 0.03)., Conclusion: This meta-analysis indicates that there was no proof of statistically higher incidence of most SAEs in rituximab containing group compared with chemotherapy alone. However, fatal infections were more frequently observed in patients who received rituximab. Considering the low-incidence infection-induced death during the treatment period, the effects of rituximab on infections need further investigation.

Human aggressive B-cell non-Hodgkin lymphomas (NHL) encompass the continuum between Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL), and display considerable clinical and biologic heterogeneity, most notably related to therapy response. We previously showed that lymphomas arising in the Eμ-Myc transgenic mouse are heterogeneous, mirroring genomic differences between Burkitt lymphoma and DLBCL. Given clinical heterogeneity in NHL and the need to develop strategies to match therapeutics with discrete forms of disease, we investigated the extent to which genomic variation in the Eμ-Myc model predicts response to therapy. We used genomic analyses to classify Eμ-Myc lymphomas, link Eμ-Myc lymphomas with NHL subtypes, and identify lymphomas with predicted resistance to conventional and NF-κB-targeted therapies. Experimental evaluation of these predictions links genomic profiles with distinct outcomes to conventional and targeted therapies in the Eμ-Myc model, and establishes a framework to test novel targeted therapies or combination therapies in specific genomically defined lymphoma subgroups. In turn, this will rationally inform the design of new treatment options for aggressive human NHL., (©2014 American Association for Cancer Research.)

Diagnosis and treatment patients with lymphoma is still obe of the main problems in theoretical and clinical oncology. Observing increasing tendency of lymphoma incidence in Ukraine it should be noted that the disease is prevalent in young and working-age population. Therefore it is important to improve effectiveness of treatment in primary diagnosed non-Hodgkin lymphoma.

The serum immunoglobulin free light chain (FLC) assay quantitates free kappa (κ) and lambda (λ) light chains. FLC elevations in patients with diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL) are associated with an inferior survival. These increases in FLC can be monoclonal (as in myeloma) or polyclonal. The goal was to estimate the frequency of these elevations within distinct types of B-cell and T-cell non-Hodgkin lymphoma (NHL) and whether the FLC measurements are associated with event-free survival (EFS). We studied serum for FLC abnormalities using normal laboratory reference ranges to define an elevated κ or λ FLC. Elevations were further classified as polyclonal or monoclonal. Four hundred ninety-two patients were studied: 453 B-cell and 34 T-cell NHL patients. Twenty-nine % (142/453) of patients had an elevated FLC of which 10% were monoclonal elevations. Within B-cell NHL, FLC abnormalities were most common in lymphoplasmacytic (79%), mantle cell (68%), and lymphomas of mucosa associated lymphoid tissue (31%); they were least common in follicular (15%). The hazard ratio (HR) for EFS in all patients was 1.41 (95% CI; 1.11-1.81); in all B-cell NHL the HR was 1.44 (95% CI 1.11-1.96); in all T-cell NHL the HR was 1.17 (95% CI 0.55-2.49). FLC abnormalities predicted an inferior OS (HR = 2.75, 95% CI: 1.93-3.90, P < 0.0001). The serum FLC assay is useful for prognosis in both B-cell and T-cell types of NHL. In B-cell NHL further discrimination between a monoclonal and polyclonal elevation may be helpful and should be analyzed in prospective clinical trials., (© 2014 Wiley Periodicals, Inc.)

Epstein-Barr virus (EBV) is associated with aggressive B cell lymphomas (BCLs). Latent membrane protein 1 (LMP1) of EBV is an oncogenic protein required for EBV B cell transformation. However, LMP1 is a weak oncogene in mice. Mice expressing Myc inserted 5' of the Eμ enhancer (iMyc(Eμ)), mimicking the t(8;14) translocation of endemic Burkitt lymphoma, develop delayed onset BCLs. To investigate potential cooperation between LMP1 and oncogenic MYC, we produced mice expressing the LMP1 signaling domain via a hybrid CD40-LMP1 transgene (mCD40-LMP1), and the dysregulated MYC protein of aggressive EBV+ BCLs. mCD40-LMP1/iMyc(Eμ) mice trended toward earlier BCL onset. BCLs from mCD40-LMP1/iMyc(Eμ) mice expressed LMP1 and were transplantable into immunocompetent recipients. iMyc(Eμ) and mCD40-LMP1/iMyc(Eμ) mice developed BCLs with similar immunophenotypes. LMP1 signaling was intact in BCLs as shown by inducible interleukin-6. Additionally, LMP1 signaling to tumor cells induced the two isoforms of Pim1, a constitutively active prosurvival kinase implicated in lymphomagenesis.

Bispecific antibodies are promising agents for immunotherapy. Here, we describe a quadroma-based trifunctional bispecific antibody binding the chemokine receptor CXCR5 and the T-cell antigen CD3 that efficiently prevents tumor growth in a mouse B-cell lymphoma model. CXCR5 regulates the tissue homeostasis of mature B cells and is highly expressed on B-cell non-Hodgkin and lymphocyte-predominant Hodgkin lymphoma, as well as on a subset of CD4(+) T cells known as follicular T-helper cells. In vitro, the bispecific CXCR5::CD3 antibody efficiently recruited effector T cells to CXCR5 expressing B cells and induced a co-stimulation-independent activation of CD8(+) and CD4(+) T cells as demonstrated by the de novo expression of CD25 and CD69, and secretion of the cytokines IFN-γ, TNF-α, IL-6 and IL-10 by peripheral blood mononuclear cells. Notably, at low antibody concentrations, CXCR5::CD3 displayed a significantly higher cytotoxic activity against autologous B cells than its parental antibodies or rituximab. In vivo imaging revealed that CXCR5::CD3 and its parental CXCR5 antibody efficiently prevent tumor growth in a xenograft model of B-cell lymphoma in mice and prolong their survival. Taken together, our results identify CXCR5 as a promising target for antibody-based therapies in the treatment of B-cell malignancies., (© 2014 UICC.)

Despite the efficacy of current immune-chemotherapy for treatment of B-cell non-Hodgkin lymphoma, a substantial proportion of patients relapse, highlighting the need for new therapeutic modalities. The use of live microorganisms to develop anti-tumoural therapies has evolved since Coley's toxin and is now receiving renewed attention. Salmonella Typhimurium has been shown to be highly effective as an anti-tumour agent in many solid cancer models, but it has not been used in haemato-oncology. Here, we report that intra-tumoural administration of LVR01 (attenuated S. Typhimurium strain with safety profile) elicits local and systemic anti-tumour immunity, resulting in extended survival in a lymphoma model. LVR01 induces intra-tumoural recruitment of neutrophils and activated CD8(+) T cells, as well as increasing the natural killer cell activation status. Furthermore, a systemic specific anti-tumour response with a clear T helper type 1 profile was observed. This approach is an alternative therapeutic strategy for lymphoma patients that could be easily moved into clinical trials., (© 2014 John Wiley & Sons Ltd.)

This retrospective study analyzes the results of radioimmunotherapy (RIT) with (90)Y-ibritumomab tiuxetan in 94 Japanese patients with relapsed or refractory low-grade B cell non-Hodgkin lymphoma at a single institution. All patients had previously been administered with 1-8 (median 1) regimens of rituximab alone or combined with other chemotherapeutic regimens at a mean age of 64 years. The overall response rate was 90 % and the complete response (CR) rate was 69 %. The median overall survival was not reached and progression-free survival (PFS) was 26 months, respectively, for the early phase 50 patients during a median follow-up period of 46.5 months. In this cohort, the PFS rates for the 50 early phase patients who had undergone ≤2 and ≥3 previous regimens, and for those who achieved CR compared with those who did not (partial response, PR; stable disease, SD; progressive disease, PD) were 38 and 11 months, respectively. Multivariate analysis showed that these two factors were statistically significant (p = 0.0011 and p <0.0001, respectively). The overall incidence of grade ≥3 non-hematological toxicity was 9 %. Two patients died of treatment-related deteriorating hepatitis C. A second malignancy developed in two patients at 10.5 and 3.5 months after treatment. We recommend administering (90)Y-ibritumomab tiuxetan as early in the disease course as possible, and at the latest as a third-line therapy to maximize the benefits of RIT, which should improve the quality of life for patients.

We retrospectively compared outcomes of patients with relapsed/refractory non-Hodgkin lymphoma (NHL) who underwent stem cell transplantation (SCT) with stable disease or better following a novel combination of lenalidomide and rituximab (LR) treatment and did not undergo SCT in a phase I/II clinical trial. We retrospectively compared outcomes of patients who underwent SCT with that of patients who had stable disease or better following LR treatment and did not undergo SCT. Twenty-two patients enrolled in LR clinical trial and undergone SCT were identified, 13 with mantle cell lymphoma (MCL) and nine with large B-cell lymphoma (LBCL). All patients who underwent SCT achieved complete response. In the MCL subset, there were no significant differences between SCT and non-SCT groups except that non-SCT patients were older and had a higher mantle-cell international prognostic index score. There was no difference between SCT-group and non-SCT-group in response duration (P=0.3), progression-free survival (PFS) (P=0.304) and overall survival (OS) (P=0.87). In LBCL subgroup, there were no significant differences between two groups except that non-SCT group had a higher international prognostic index score. Patients with LBCL who underwent SCT had significantly longer response duration (P=0.001), PFS (P=0.000), and OS (P=0.003) than the non-SCT group. The novel therapeutic combination offers a bridge to SCT in patients with relapsed/refractory aggressive B-cell NHL.

Mediastinal B-cell lymphomas present in the mediastinum and are most frequent in young patients. Nodular sclerosis Hodgkin lymphoma (NSHL) and primary mediastinal B-cell lymphoma (PMBL) are the common types, whereas mediastinal gray-zone lymphoma (MGZL) is extremely rare and has pathological features intermediate between NSHL and PMBL. The indeterminate pathobiology of MGZL has led to uncertainty regarding therapeutic strategy, and its clinical characteristics and treatment have not been characterized. We conducted a prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim in untreated MGZL. We analyzed biomarkers of outcome and compared their clinical and biological characteristics to PMBL. Twenty-four MGZL patients had a median age of 33 years (range, 14 to 59 years), and 46% had mediastinal masses ≥10 cm. At 59 months median follow-up, the event-free survival and overall survival were 62% and 74%, respectively. The serum absolute lymphocyte count, the presence of tumor-infiltrating dendritic cells, CD15 expression on the malignant cells, and tumor morphology were biomarkers of outcome in MGZL. Compared with PMBL, MGZL patients were more likely to be male, express CD15, have lower expression of CD20, and have a worse outcome. DA-EPOCH-R alone is effective in MGZL. The trial was registered at ClinicalTrials.gov (NCT00001337).

We report our experience with 129 cases of double hit lymphoma (DHL), defined as B-cell lymphoma with translocations and/or extra signals involving MYC plus BCL2 and/or BCL6. All cases were reviewed for histopathological classification. Median age was 62 years (range, 18-85), 84% of patients had advanced-stage disease, and 87% had an International Prognostic Index score ≥2. Fourteen patients (11%) had a history of low-grade follicular lymphoma. MYC translocation was present in 81%, and extra signals of MYC in 25% of patients. IGH-BCL2 translocation was present in 84% and extra signals of BCL2 in 12% of patients. Two-year event-free survival (EFS) rates in all patients and patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and R-HyperCVAD/MA (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine plus methotrexate) were 33%, 25%, 67% and 32%, respectively. In patients achieving complete response with initial therapy (n = 71), 2-year EFS rates in patients who did (n = 23) or did not (n = 48) receive frontline stem cell transplantation were 68% and 53%, respectively (P = 0·155). The cumulative incidence of central nervous system involvement was 13% at 3 years. Multivariate analysis identified performance status ≥2 and bone marrow involvement as independent adverse prognostic factors for EFS and OS. Further research is needed to identify predictive and/or targetable biological markers and novel therapeutic approaches for DHL patients., (© 2014 John Wiley & Sons Ltd.)

Lymphoma cells are subject to higher levels of oxidative stress compared with their normal counterparts and may be vulnerable to manipulations of the cellular redox balance. We therefore designed a phase 2 study of imexon (Amplimexon/NSC-714597), a prooxidant molecule, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Imexon was administered at 1000 mg/m(2) IV daily for 5 days in 21-day cycles. Gene expression analysis performed on pretreatment tumor specimens included 13 transcripts used to generate a redox signature score, previously demonstrated to correlate with lymphoma prognosis. Twenty-two patients were enrolled having follicular (n = 9), diffuse large B-cell (DLBCL) (n = 5), mantle cell (n = 3), transformed follicular (n = 2), small lymphocytic (n = 2), and Burkitt (n = 1) lymphoma. The most common grade 3/4 adverse events were anemia (14%) and neutropenia (9%). The overall response rate was 30%, including responses in follicular lymphoma (4 of 9) and DLBCL (2 of 5). Gene expression analyses revealed CD68 and the redox-related genes, GPX1 and SOD2, as well as a higher redox score to correlate with clinical responses. Therefore, pretreatment markers of oxidative stress may identify patients likely to respond to this therapeutic approach. This trial was registered at www.clinicaltrials.gov as #NCT01314014., (© 2014 by The American Society of Hematology.)

Background: Coeliac disease is a common enteropathy characterized by an increased mortality mainly due to its complications. The natural history of complicated coeliac disease is characterised by two different types of course: patients with a new diagnosis of coeliac disease that do not improve despite a strict gluten-free diet (type A cases) and previously diagnosed coeliac patients that initially improved on a gluten-free diet but then relapsed despite a strict diet (type B cases). Our aim was to study the prognosis and survival of A and B cases., Methods: Clinical and laboratory data from coeliac patients who later developed complications (A and B cases) and sex- and age-matched coeliac patients who normally responded to a gluten-free diet (controls) were collected among 11 Italian centres., Results: 87 cases and 136 controls were enrolled. Complications tended to occur rapidly after the diagnosis of coeliac disease and cumulative survival dropped in the first months after diagnosis of complicated coeliac disease. Thirty-seven cases died (30/59 in group A, 7/28 in group B). Type B cases presented an increased survival rate compared to A cases., Conclusions: Complicated coeliac disease is an extremely serious condition with a high mortality and a short survival. Survival depends on the type of natural history.

'Double-Hit' (DH) B cell non-Hodgkin lymphomas are characterized by the presence of a MYC rearrangement and additional rearrangement(s) most commonly involving BCL2 and/or BCL6. Patients with DH lymphomas are unlikely to achieve long-term survival when treated with standard immunochemotherapy alone. DH gene rearrangements can be identified through metaphase karyotyping or more sensitive fluorescence in situ hybridization (FISH), although the latter is not routinely performed. We report 53 cases of B cell lymphoma that underwent diagnostic metaphase karyotying or FISH for MYC rearrangements. DH lymphoma was detected in 17 cases. No baseline factor, including age, serum lactate dehydrogenase, stage, International Prognostic Index or histology predicted for DH status. The median overall survival was significantly shorter for DH compared to non-DH lymphoma patients (8·2 vs. 56·8 months, P < 0·001). DH status retained the most statistically significant association with overall survival on multivariate Cox regression analysis. DH status could not be inferred by baseline disease- or patient-related characteristics and was most predictive of overall survival in this cohort of B cell lymphoma patients. These findings support the practice of routine performance of FISH for DH gene rearrangements on B cell lymphoma specimens in order to effectively identify DH patients who may benefit from risk-adapted therapy., (© 2014 John Wiley & Sons Ltd.)

Background: In primary cutaneous B-cell lymphomas (PCBCL), radiotherapy - or surgery in a minority of cases - is the first-line treatment in follicle center lymphoma (PCFCL) and marginal zone B-cell lymphoma (PCMZL). Conversely, patients with multifocal skin involvement or relapsed/refractory disease deserve a systemic chemotherapy. In diffuse large B-cell lymphoma, leg type (PCLBCL-LT), due its poorer outcome, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like regimens are the most commonly used frontline, although hard to propose in elderly patients. In this regard, the association of rituximab (R) and pegylated liposomal doxorubicin (PLD) can be considered a promising, alternative approach., Aims: Based on the favorable results reported with R and PLD in several recent trials, we decided to test efficacy and safety of this combination., Methods: Twelve patients with PCBCL were treated with R plus PLD, and 7 had relapsed disease. Treatment plan consisted of 2 monthly cycles of R 375 mg/m(2) and PLD 20 mg/m(2) day 1;15, followed (in responders) by two cycles given only at day 1. All patients received prophylactic pyridoxine to prevent palmar-plantar erythrodysesthesia (PPE)., Results: Ten of 12 patients had a response (eight complete; two partial), remarkably 2/3 with PCLBCL-LT. Two patients did not respond (one progressive disease, PD, and one stable disease). Three patients died after a median follow-up of 56 months, two patients due to PD, and 1 due to a second neoplasm. Two out of 10 responders relapsed after 31 and 32 months, respectively. Hematological toxicity was negligible (one case of grade 2 neutropenia), as well as extra-hematological toxicity (two cases of grade 2 PPE)., Conclusions: These preliminary data suggest that R-PLD is effective and well tolerated in all subsets of PCBCL and may be offered frontline in indolent cases unsuitable for radiotherapy or surgery as well as in more aggressive cases with contraindications to CHOP-like regimens., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Intravascular lymphomatosis (IVL) is a rare and clinically devastating form of extranodal B-cell non-Hodgkin's lymphoma. We performed a comprehensive analysis of the literature on IVL's published between 1959 and 2011 and evaluated the natural history as well as identified prognostic and predictive factors in patients. Nonparametric two-tailed Mann-Whitney U-test and Mantel-Cox log rank test were used to evaluate the survival intervals and prognostic factors. Multivariate analysis of variance (MANOVA) and chi-squared statistics were carried out to examine treatment-related predictive factors. Of the 740 patients with IVL, 651 (88%) had a diagnosis of B-cell lymphoma, 45 (6%) with T-cell lymphoma, and 12 patients (2%) with NK cell lymphoma. Central nervous system (CNS) IVL had the highest proportion of postmortem diagnosis, 250 (60%) compared to 21 (8%) of skin, 28 (11%) of bone marrow (BM) and spleen, and 17 (7%) of lung IVL's. Age <70 years (P = 0.0073), non-CNS site of initial diagnosis (P = 0.0014), lactate dehydrogenase (LDH) <700 (P = 0.0112), and rituximab treatment (P < 0.0001) were favorable prognostic factors. Gender, ethnicity, hemoglobin, BM biopsy, and the type of imaging studies used were not significant. Rituximab and doxorubicin treatment worked significantly better in patients with age >71 and LDH >577 compared to nonrituximab, nondoxorubicin regimens (MANOVA 2 degrees of freedom, P = 0.0345), with a median time from treatment to death of 20.0 (95% confidence interval [CI] 14.0-N/A, n = 14) months versus 2.0 (95%CI 0.5-N/A, n = 5) (χ(2) = 4.7, P = 0.0304). Patients with CNS IVL relapsed primarily in the CNS (88%) while same-organ relapse occurred less frequently in skin (23%), BM and spleen (50%) and lung (20%) IVL's. Our results indicate that IVL is primarily a disease of B-lymphoma cells. Timely diagnosis and treatment with rituximab-based chemotherapy improve patient survival. The pattern of recurrence is different between CNS IVL and IVL's in other organs., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

B cell lymphomas are cancers that arise from cells that depend on numerous highly orchestrated interactions with immune and stromal cells in the course of normal development. Despite the recent focus on dissecting the genetic aberrations within cancer cells, it has been increasingly recognized that tumour cells retain a range of dependence on interactions with the non-malignant cells and stromal elements that constitute the tumour microenvironment. A fundamental understanding of these interactions gives insight into the pathogenesis of most B cell lymphomas and, moreover, identifies novel therapeutic opportunities for targeting oncogenic pathways, both now and in the future.

To define the role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement (ECFI) of aggressive B-cell lymphoma, we analyzed 11 consecutive German High-Grade Non-Hodgkin Lymphoma Study Group trials. ECFI occurred in 290/4155 (7.0%) patients (orbita, 31; paranasal sinuses, 93; main nasal cavity, 38; tongue, 27; remaining oral cavity, 99; salivary glands, 54). In a multivariable analysis adjusted for International Prognostic Index rituximab improved event-free and overall survival both in patients with and without ECFI. Three-year event-free (79% vs 79%; P = .842) and overall survival (86% vs 88%; P = .351) rates were similar in 145 patients receiving and 57 not receiving radiotherapy. Without rituximab, the 2-year cumulative rate of central nervous system (CNS) disease was increased in 205 ECFI patients compared with 2586 non-ECFI patients (4.2% vs 2.8%; P = .038), whereas this was not observed with rituximab (1.6% in 83 ECFI vs 3.4% in 1252 non-ECFI patients; P = .682). In 88 ECFI patients who received intrathecal prophylaxis with methotrexate, the 2-year rate of CNS disease was 4.2% compared with 2.3% in 191 patients who did not (P = .981). In conclusion, rituximab eliminates the increased risk for CNS disease in patients with ECFI. This retrospective analysis does not support intrathecal prophylaxis or radiotherapy to ECFI patients in complete remission/unconfirmed complete remission. These findings should be confirmed in a prospective study., (© 2014 by The American Society of Hematology.)

Inactivation of p53, the master regulator of cellular stress and damage signals, often allows cells that should die or senesce to live. Loss of Dicer, an RNase III-like enzyme critical in microRNA biogenesis, causes embryonic lethality and activation of the p53 pathway. Several nonhematopoietic cell types that contain inactivated p53 have been shown to survive Dicer deletion, suggesting that p53 loss may protect cells from the negative consequences of Dicer deletion. However, here, we report that loss of p53 did not provide a survival advantage to B cells, as they underwent rapid apoptosis upon Dicer deletion. Moreover, a deficiency in p53 neither rescued the Dicer deletion-induced delay in Myc-driven B-cell lymphomagenesis, nor allowed a single B-cell lymphoma to develop with biallelic deletion of Dicer. A p53 deficiency did, however, restore the pre-B/B-cell phenotype and CD19 surface expression of the lymphomas that emerged in conditional Dicer knockout Eμ-myc transgenic mice. Moreover, p53 loss in transformed B cells did not confer protection from apoptosis, as Dicer deletion in established p53-null B-cell lymphomas induced apoptosis, and all of the 1,260 B-cell lymphoma clones analyzed that survived Cre-mediated Dicer deletion retained at least one allele of Dicer. Moreover, Dicer deletion in lymphomas in vivo reduced tumor burden and prolonged survival. Therefore, inactivation of p53 is insufficient to allow untransformed B cells and B-cell lymphomas to survive without Dicer, presenting a potential therapeutic opportunity for the treatment of B-cell lymphomas., (©2014 American Association for Cancer Research.)

Purpose: The low immunogenicity of many cancer cells and the immunosuppression by various cancers and anticancer therapies have been an obstacle in the development of efficacious immunotherapies. Our goal was to test whether Toll-like receptor (TLR) agonists and anticancer chemotherapeutic agents synergize in rendering tumor cells more immunogenic., Experimental Design: We treated B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 and the genotoxic anticancer agent 1-β-D-arabinofuranosylcytosine (Ara-C). The effects on the immunogenicity of tumor cells were measured in transfer experiments and in vitro studies., Results: The treatment of B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 enhanced the anticancer effects of the genotoxic agent Ara-C. Mice injected with cotreated tumor cells survived longer than mice challenged with Pam3CSK4 or Ara-C-treated cells. Administration of Pam3CSK4 or Ara-C reduced the tumor load of mice injected with tumor cells. Cotreatment had no effect on the rate of apoptosis or proliferation of Ara-C-treated cells, but upregulated the expression of several immunomodulatory molecules. Consistent with an increased immunogenicity of Pam3CSK4 and Ara-C-treated B-cell lymphoma cells, rejection of cotreated tumor cells required natural killer cells and T cells. We demonstrate that the upregulation of immunomodulatory molecules in response to Pam3CSK4 and Ara-C depended in part on NF-κB., Conclusion: TLR agonists can increase the efficacy of conventional cancer therapies by altering the immunogenicity of B-cell lymphoma cells., (©2014 American Association for Cancer Research.)

Background: Previous Japanese studies of childhood B-cell non-Hodgkin lymphoma (B-NHL) have shown a favorable outcome, though the study size was too small to effectively assess the efficacy and safety of treatment for childhood B-NHL., Procedure: We performed a nation-wide prospective B-NHL03 study to assess the efficacy and safety of short-pulse intensive chemotherapy for children with B-NHL. They were stratified into four treatment groups according to disease stage, tumor resectability and bone marrow/CNS involvement: Group 1 with all resected stage I/II, Group 2 with non-resected stage I/II, Group 3 with stage III & CNS-negative stage IV, and Group 4 with CNS-positive stage IV & Burkitt leukemia. Treatment duration was 2 courses for Group 1, 4 courses for Group 2, and 6 courses for Groups 3 and 4, respectively. CNS irradiation was omitted in all patients., Results: The follow-up time ranged from 0.8 to 88 months, with a median of being 45 months. For 321 patients analyzed in this study, overall survival and event-free survival (EFS) at 4 years was 92.7% and 87.4%, respectively. The 4-year EFS according to treatment group were 94% for Group 1 (n = 17), 98% for Group 2 (n = 103), 84% for Group 3 (n = 111), and 78% for Group 4 (n = 90). There was no significant difference in outcome by histology. Therapy-related death occurred in three patients in remission., Conclusions: Our nationwide large-scale study resulted in a cure rate above 90% with <1% toxic death in childhood B-NHL., (© 2014 Wiley Periodicals, Inc.)

Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B-NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B-NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival (PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B-NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted., (© 2014 Merck Sharp & Dohme Corp. British Journal of Haematology published by John Wiley & Sons Ltd.)

NR4A1 (Nur77) and NR4A3 (Nor-1) function as tumor suppressor genes as demonstrated by the rapid development of acute myeloid leukemia in the NR4A1 and NR4A3 knockout mouse. The aim of our study was to investigate NR4A1 and NR4A3 expression and function in lymphoid malignancies. We found a vastly reduced expression of NR4A1 and NR4A3 in chronic lymphocytic B-cell leukemia (71%), in follicular lymphoma (FL, 70%), and in diffuse large B-cell lymphoma (DLBCL, 74%). In aggressive lymphomas (DLBCL and FL grade 3), low NR4A1 expression was significantly associated with a non-germinal center B-cell subtype and with poor overall survival. To investigate the function of NR4A1 in lymphomas, we overexpressed NR4A1 in several lymphoma cell lines. Overexpression of NR4A1 led to a higher proportion of lymphoma cells undergoing apoptosis. To test the tumor suppressor function of NR4A1 in vivo, the stable lentiviral-transduced SuDHL4 lymphoma cell line harboring an inducible NR4A1 construct was further investigated in xenografts. Induction of NR4A1 abrogated tumor growth in the NSG mice, in contrast to vector controls, which formed massive tumors. Our data suggest that NR4A1 has proapoptotic functions in aggressive lymphoma cells and define NR4A1 as a novel gene with tumor suppressor properties involved in lymphomagenesis.

Chromosomal translocations affecting the MYC oncogene are the biological hallmark of Burkitt lymphomas but also occur in a subset of other mature B-cell lymphomas. If accompanied by a chromosomal break targeting the BCL2 and/or BCL6 oncogene these MYC translocation-positive (MYC(+)) lymphomas are called double-hit lymphomas, otherwise the term single-hit lymphomas is applied. In order to characterize the biological features of these MYC(+) lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation-positive lymphomas (31 single-hit, 46 double-hit and 3 MYC(+)-lymphomas with unknown BCL6 status). Comparison of single-hit and double-hit lymphomas revealed no difference in MYC partner (IG/non-IG), genomic complexity, MYC expression or gene expression profile. Double-hit lymphomas more frequently showed a germinal center B-cell-like gene expression profile and had higher IGH and MYC mutation frequencies. Gene expression profiling revealed 130 differentially expressed genes between BCL6(+)/MYC(+) and BCL2(+)/MYC(+) double-hit lymphomas. BCL2(+)/MYC(+) double-hit lymphomas more frequently showed a germinal center B-like gene expression profile. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In this series of lymphomas, in which immunochemotherapy was administered in only a minority of cases, single-hit and double-hit lymphomas had a similar poor outcome in contrast to the outcome of molecular Burkitt lymphoma and lymphomas without the MYC break. Our data suggest that, after excluding molecular Burkitt lymphoma and pediatric cases, MYC(+) lymphomas are biologically quite homogeneous with single-hit and double-hit lymphomas as well as IG-MYC and non-IG-MYC(+) lymphomas sharing various molecular characteristics.

Background: Interferon-alfa is used in the treatment of primary cutaneous B-cell lymphoma (PCBCL). Therapy with interferon-alfa has thus far been reported solely in case reports and small case series, mostly describing intralesional use., Objective: We sought to evaluate efficacy, response rate, time to response, duration of response, and safety of subcutaneously administered interferon-alfa for the treatment of cutaneous B-cell lymphoma., Methods: We conducted a retrospective chart analysis of patients given the diagnosis of PCBCL and treated with interferon-alfa subcutaneously at a tertiary referral center., Results: Fifteen patients with indolent subtypes of PCBCL were identified. The overall response rate was 66.7%; all responding patients went into complete remission. Response was not significantly associated with the maximum tolerated dose. Within the median follow-up time of 40 months, 90% of the responders experienced a relapse; median duration of response was 15.5 months. Adverse events were predominantly mild and in no case led to cessation of therapy., Limitations: Retrospective nature of the analysis and small number of patients because of scarcity of the disease are limitations., Conclusion: Treatment of indolent PCBCL with subcutaneously injected interferon-alfa demonstrated good response rates and tolerability. Response was not dose dependent. Relapses were observed in nearly all responding patients raising the question of interferon-alfa maintenance therapy in PCBCL., (Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Primary central nervous system lymphoma (PCNSL) is a rare aggressive variant of diffuse large B-cell lymphoma with a poor prognosis and no defined optimal therapeutic strategies. Our aim was to compare the role of intrathecal chemotherapy with current high-dose methotrexate (HDMTX) treatments. Clinicopathologic characteristics, therapy, and outcomes of patients with PCNSL at Moffitt Cancer Center were reviewed in 89 patients identified over an 11-year period. Patients treated initially with HDMTX-based therapy showed improved overall and progression-free survival, with no improvement shown with added radiation or intrathecal therapy. Age and performance status were also important prognostic indicators. Our conclusion is that initial therapy in PCNSL should include an HDMTX backbone. The use of intrathecal chemotherapy or radiation therapy initially likely does not improve outcomes. Future multicenter phase III clinical trials are needed to better establish the superior initial treatment in PCNSL.

Purpose: Diffuse large B-cell lymphomas (DLBCLs) are rare tumors of the head and neck that often have non-specific presentations and significant morbidity and mortality. In this analysis we use a large cohort to compare the demographic and disease-specific parameters affecting survival and incidence of DLBCLs., Methods: The United States National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry was utilized to extract data regarding sinonasal diffuse large B-cell lymphoma between 1973 and 2009. A total of 852 cases of sinonasal DLBCLs were found. Presenting symptoms, demographics, disease specific survival, relative survival and survival by treatment modality were described for this rare tumor., Results: Overall disease specific survival (DSS) at 1-year was 84.7% and at 5 years was 68.0%. DSS was significantly lower for those not treated with radiation therapy, with 1- and 5-year survival rates of 77.3% and 62.5%, versus those treated with radiation therapy, with 1- and 5-year rates of 89.2% and 71.5% (p<0.05). Prognosis was significantly better for patients treated with radiation therapy (HR 0.6, p<0.05) while it was poorer for patients with involvement of multiple sinuses (HR 1.5, 1.8, p<0.05)., Conclusions: DLBCLs of the sinonasal tract are rare tumors of the head and neck. Survival is significantly improved for those treated with radiation therapy while the involvement of multiple sinuses is a negative prognostic indicator., (© 2014.)

To evaluate the validity of a decrease in the radiation dose for patients who were good responders to chemotherapy for localized diffuse large B-cell lymphoma (DLBCL), 91 patients with localized DLBCL who underwent radiotherapy after multi-agent chemotherapy from 1988-2008 were reviewed. Exclusion criteria were as follows: central nervous system or nasal cavity primary site, or Stage II with bulky tumor (≥10 cm). Of these patients, 62 were identified as good responders to chemotherapy. They were divided into two groups receiving either a higher or a lower radiation dose (32-50.4 Gy or 15-30.6 Gy, respectively). There were no statistically significant differences between the lower and higher dose groups in progression-free survival, locoregional progression-free survival or overall survival. Adaptation of decreased radiation dose may be valid for localized DLBCL patients who show a good response to chemotherapy.

Purpose: Describe the epidemiology, clinical profiles and outcomes associated with head and neck (H&N) involvement in children/adolescents with B-cell non-Hodgkin lymphoma (B-NHL)., Methods: Analysis of children/adolescents with H&N B-NHL prospectively enrolled in the SFOP LMB-89 trial (July 1989-June 1996)., Results: One hundred and twelve of 561 patients (20%) had H&N involvement. The mean age of the patients was 8.4 years. Murphy staging differed between the H&N patients and the others (P < 0.0001): 9% versus 5% of the patients presented with stage I disease, 36% versus 11% presented with stage II disease, 12% versus 59% presented with stage III disease, 17% versus 10% with stage IV disease and 27% versus 16% with B-AL. Twenty-nine H&N patients (26%) had CNS involvement at diagnosis versus 8.5% in the group without H&N involvement (P < 0.0001). Patients were treated according to the LMB89 protocol: 3 H&N patients were allocated to group A, 70 to group B and 39 to group C. Ninety-seven percent of H&N patients achieved CR and event-free and overall survival at 4 years was 95.5% (5 deaths in patients with CNS disease). On multivariate analysis, EFS was significantly better in H&N patients than in non-H&N patients (P = 0.021), but not OS (P = 0.11)., Conclusion: The H&N site is the second most common location for B-NHL at diagnosis and is more frequently associated with disseminated disease and CNS involvement than other sites. However, outcomes are no worse for these patients than for the rest of the population., (© 2013 Wiley Periodicals, Inc.)

The optimal therapy for primary mediastinal B-cell lymphoma is a subject of ongoing debate, with no accepted standard of care. We performed a retrospective analysis of 63 patients in the modern era treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), with or without radiation. Median age was 37 years (range 20-82). Eighty percent had limited stage disease and 71% were bulky. By age-adjusted International Prognostic Index (IPI), 15% were low-risk, 52% low-intermediate, 27% high-intermediate and 6% high-risk. Some 77% of responding patients received consolidative radiotherapy. Overall and complete response rates were 79% and 71%. Primary induction failure occurred in 13 (21%) patients. Five-year PFS and OS were 68% and 79%, respectively. Adverse prognostic features included increased IPI, advanced stage, advanced age and multiple extranodal sites. These data demonstrate an unacceptably high rate of primary refractory disease on R-CHOP, particularly among patients with high-risk features. Novel treatment approaches are needed that reduce primary refractory disease and reliance on mediastinal radiation in young people.

Enhanced proliferative signaling and loss of cell cycle regulation are essential for cancer progression. Increased mitogenic signaling through activation of the mTOR pathway, coupled with deregulation of the Cyclin D/retinoblastoma (Rb) pathway is a common feature of lymphoid malignancies, including plasmacytoma (PCT), multiple myeloma (MM), Burkitt's lymphoma (BL), and mantle cell lymphoma (MCL). Here we evaluate the synergy of pharmacologically affecting both of these critical pathways using the mTOR inhibitor sirolimus and the histone deacetylase inhibitor entinostat. A dose-matrix screening approach found this combination to be highly active and synergistic in a panel of genetically diverse human MM cell lines. Synergy and activity was observed in mouse PCT and human BL and MCL cell lines tested in vitro, as well as in freshly isolated primary MM patient samples tested ex vivo. This combination had minimal effects on healthy donor cells and retained activity when tested in a co-culture system simulating the protective interaction of cancer cells with the tumor microenvironment. Combining sirolimus with entinostat enhanced cell cycle arrest and apoptosis. At the molecular level, entinostat increased the expression of cell cycle negative regulators including CDKN1A (p21) and CDKN2A (p16), while the combination decreased critical growth and survival effectors including Cyclin D, BCL-XL, BIRC5, and activated MAPK., (Published by Elsevier B.V.)

The aim of this prospective phase II trial was to determine the safety and efficacy of a nonmyeloablative conditioning program incorporating peritransplant rituximab in patients with CD20+ B cell non-Hodgkin lymphoma (B-NHL) receiving an allogeneic stem cell transplant (allo-SCT). Fifty-one adult B-NHL patients, with a median age of 54 years, were treated with cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. Rituximab 375 mg/m(2) was given on day -8 and in 4 weekly doses beginning day +21. Equine antithymocyte globulin was given to recipients of volunteer unrelated donor grafts. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil and tacrolimus, sirolimus, and methotrexate in 8 and 43 patients, respectively. Thirty-three patients received grafts from unrelated donors, and 18 received grafts from matched related donors. All patients engrafted. Full donor chimerism in bone marrow and peripheral T cells was seen in 92% and 89% of patients, respectively, at 3 months after allo-SCT. The cumulative incidence of grades II to IV acute GVHD at 6 months was 25% (95% confidence interval [CI], 13% to 38%) and grades III to IV was 11% (95% CI, 2% to 20%). The 2-year cumulative incidence of chronic GVHD was 29% (95% CI, 15% to 44%). The 2-year event-free and overall survival for all patients was 72% (95% CI, 59% to 85%) and 78% (95% CI, 66% to 90%), respectively. The 2-year event-free survival for chemosensitive patients was 84% (95% CI, 72% to 96%) compared with 30% (95% CI, 2% to 58%) for chemorefractory patients before allo-SCT (P < .001). This nonmyeloablative regimen, with peritransplant rituximab, is safe and effective in patients with B-NHL., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The use of specific immunoglobulin heavy chain variable region (VH) genes has been associated with increased patient survival in human B-cell lymphomas (hBCL). Given the similarity of human and canine BCL (cBCL) in morphology and clinical treatment, we examined the choice of VH in cBCL and determined whether VH gene selection was a distinct feature associated with survival time in dogs. VH gene selection and mutational status in 52 cBCL, including 29 diffuse large B-cell lymphomas (cDLBCL, the most common subtype of cBCL), were analyzed by comparison with the 80 published canine germline VH gene sequences. We further examined the prognostic impact of the subgroups defined by these features on canine survival. We found that VH1-44 was preferentially expressed in the majority of the 52 cBCLs (60%) as well as in the majority of the cDLBCL subset (59%). VH1-44 gene expression was associated with a statistically better overall survival (p=0.039) in cBCL patients, as well as in the cDLBCL subset of patients (p=0.038). These findings suggest that VH gene selection in cBCL is not random and may therefore have functional implications for cBCL lymphomagenesis, in addition to being a useful prognostic biomarker., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Survival rates determined at diagnosis are often too negative for cancer survivors. Conditional relative survival reflects actual prognosis during follow-up better. Data from all 54,015 patients newly diagnosed in the Netherlands with B-cell non-Hodgkin lymphoma during 1989-2008, aged 15-89 years (Netherlands Cancer Registry), were used. Five-year conditional relative survival was computed for every additional year of survival up to 16 years after diagnosis, according to entity, grade, gender, age, and Ann Arbor stage. The prognosis for survivors of indolent B-cell non-Hodgkin lymphoma improved slightly with each additional year survived up to 91%. For patients with aggressive non-Hodgkin lymphoma conditional relative survival improved strongly during the first year after diagnosis (from 48% to 68%) and gradually thereafter to 93% after 16 years. There were differences between morphological entities. Initial differences in conditional relative survival at diagnosis between groups with different disease stages became smaller with increasing number of years survived. Age remained a prognostic indicator, also after prolonged follow-up. These results help caregivers to plan optimal surveillance and inform patients about their actual prognosis during follow-up. Long-lasting excess mortality among patients with B-cell non-Hodgkin lymphoma indicates the need for additional care long after their diagnosis.

Background: Lenalidomide is an immunomodulatory drug with effects on the immune system that may enhance antibody-dependent cell-mediated cytotoxicity and reverse tumor-induced immune suppression. Furthermore, single-agent lenalidomide has therapeutic activity in relapsed/refractory B-cell lymphomas. These immunologic effects potentially may enhance the action of rituximab., Methods: To test the efficacy of lenalidomide combined with rituximab, the authors conducted a phase 2 trial of lenalidomide, low-dose dexamethasone, and rituximab in patients who had rituximab-resistant, relapsed/refractory, indolent B-cell or mantle cell lymphomas. Patients received two 28-day treatment cycles of lenalidomide 10 mg daily and dexamethasone 8 mg once weekly (part I). During cycle 3, 4 weekly doses of rituximab 375 mg/m2 were administered with lenalidomide-dexamethasone (part II). After the part II response assessment, stable or responding patients continued to receive lenalidomide-dexamethasone., Results: Twenty-seven patients with follicular (n=18), mantle cell (n=5), small lymphocytic (n=3), and marginal zone (n=1) lymphomas started therapy; 3 of 27 patients discontinued therapy because of adverse events and were not evaluable for response. For 24 patients, the overall response rate after part I was 29% (4 patients had a complete response [CR] or CR unconfirmed, and 3 patients had a partial response), and the overall response rate after part II was 58% (8 patients had a CR, and 6 patients had a partial response). For 27 patients, at a median follow-up of 12.2 months, the median progression-free survival was 23.7 months., Conclusions: The combination of lenalidomide, low-dose dexamethasone, and rituximab achieved high response rates with durable responses in patients with rituximab-resistant, indolent B-cell and mantle cell lymphomas. Overall response rate increased from 29% after two 28-day cycles of lenalidomide and low-dose dexamethasone to 58% after the addition of rituximab, suggesting that lenalidomide can overcome resistance to rituximab., (© 2013 American Cancer Society.)

Background: Data regarding childhood and adolescent non Hodgkin lymphomas in Iran are limited. The aim of this study was to assess the epidemiological and histomorphological features and survival of affected patients in our center., Materials and Methods: The clinicopathologic features and outcome of 44 children and adolescents with non Hodgkin lymphoma diagnosed during 2004-2012, were investigated retrospectively. The influence of potential prognostic parameters in overall survival was investigated by log-rank test and Cox regression analysis., Results: The mean age at presentation was 13.8 ± 6.16 years with a male predilection (M: F=3:1). Malignant lymphoma, not otherwise specified, diffuse large cell lymphoma and Burkitt lymphoma were the three most common histological types observed. The tumors were 36.4% intermediate grade, 27.3% high grade and 34.1% belonged to the malignant lymphoma not otherwise specified group. Immunohistochemistry findings were available in 39 cases. Out of these cases 33 (84.6%) had B cell lineage, 4 (10.25%) T cell lineage and 2 (5.12%) of the cases belonged to miscellaneous group. 3 year and 5 year survivals were 48% and 30% respectively and median survival was 36 months (95%CI=21.7-50.3 months). Overall survival in patients with high grade tumors was 19.5 months, in the intermediate group,79 months , and for malignant lymphomas not otherwise specified it was 33.6 months (p value=0.000)., Conclusions: The survival rate for children and adolescents with non Hodgkin lymphomas at our center during 2004-2012 was at a low level.

Interkeukin-2 receptor (IL-2R) is comprised of three different subunits (α, β, and γ chain) and is expressed on B cells and NK cells besides T cells. CD25 is also known as the IL-2Rα chain on cell membranes, while soluble IL-2R (sIL-2R) is generated by the proteolytic cleavage of the IL-2Rα chain. Levels of sIL-2R in sera are monitored as a marker of disease activity in patients with lymphoma. However, elevated serum sIL-2R levels are also found in inflammatory diseases, such as infectious diseases. Levels of sIL-2R in sera are thought to reflect tumor burden in adult T-cell leukemia/lymphoma due to the expression of CD25 on tumor cells. Conversely, sIL-2R is thought to be mainly derived from activated T cells infiltrating tumor tissues in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) because lymphoma cells except for a subtype of DLBCL are mainly negative for CD25. Matrix metalloproteinase-9, a protease capable of cleaving the membrane bound IL-2Rα chain, is mainly produced by tissue-associated macrophages. Increased macrophages in tumor tissues are reported to be associated with poor prognosis, especially in Hodgkin's lymphoma. We found increased macrophages in DLBCL and FL compared with reactive lymphoid hyperplasia as well as a positive correlation between the levels of sIL-2R in sera and the number of macrophages in tumor tissues in FL and extranodal DLBCL.

Post-transplant lymphoproliferative disorders (PTLD) are one of the fatal complications of transplantation, and there is scarcity of data on the relevance of antigen expression by tumor cells in PTLD. In the current study, we aimed to investigate the potential effects of CD20 antigen expression by PTLD lesions developing in heart/lung transplant recipients. A comprehensive search was performed for reports indicating CD20 antigen tests in PTLD lesions developing in heart and/or lung transplant recipients. For data accumulation, we developed a standard questionnaire and data of patients presented in different published reports were entered into it. Finally, data from 26 previously published reports from different centers around the world were included in the analysis. CD20-positive PTLD lesions are significantly more likely to be of the B cell type (P = 0.006). PTLD in patients with a CD20-positive test represented relevantly shorter time from transplantation to PTLD, although it did not reach a significance level (P = 0.08). At the last follow-up, 53% patients were dead. Survival analysis showed no prognosis difference regarding CD20 test. When data were reanalyzed separately for heart and lung transplant recipients, lung recipients developing PTLD with a CD20-positive test were significantly more likely to represent remission episodes (P = 0.03), and also represented a significantly better outcome than CD20-negative PTLD patients (P = 0.04). CD20-positive PTLD lesions in heart/lung recipients are more likely of the B cell type and develop PTLD lesions earlier than their CD20-negative counterparts. Lung recipients developing CD20-positive PTLD lesions represented higher remission rates and better outcome. Further studies with prospective follow-up of patients are needed for confirming our findings.

Objective: To explore thymidine phosphorylase (TP) expression in B-cell lymphomas (BCLs). TP is expressed by tumor and stromal cells in a variety of cancers., Study Design: Paraffin-embedded tissues from follicular lymphomas, diffuse large BCLs (DLBCLs), and benign lymph nodes were studied using immunohistochemical staining with antibodies for TP and CD68. Prognostic markers were used to stain DLBCLs. We correlated TP expression in DLBCL indirectly with prognostic immunomarkers and directly with survival data., Results: TP expression in BCLs was noted in a subset of malignant B cells. TP expression in higher-grade lymphoma was identified in 66% of cases and 11% of lower-grade lymphomas. Macrophages/stromal cells demonstrated an intense cytoplasmic and/or nuclear staining pattern in both lymphoma and benign lymph nodes, confirmed by CD68 coexpression. Increased macrophage/ stromal cells in higher-grade lymphomas are associated with enhanced TP expression in neoplastic B cells (observation only). Sixty-eight percent of TP-positive DLBCLs were of nongerminal center origin, indicating poorer prognosis., Conclusion: TP is more likely expressed by malignant B cells in higher-grade lymphomas, and expression of TP possibly results from changes intrinsic to the tumor cells or interactions between microenvironment and tumor. TP positivity in DLBCL correlates with nongerminal center origin and worse outcome.

The synthesis, characterization and results of evaluation of the biological behavior of HPMA copolymer conjugates bearing anti-cancer drugs doxorubicin and mitomycin C are described. Two HPMA copolymer carrier types were synthesized: the linear copolymer and the biodegradable high-molecular-weight diblock copolymer containing a degradable disulfide bond. The polymer-drug conjugates incubated in buffers modeling the intracellular environment released the drugs more rapidly than those incubated in bloodstream conditions. Significant in vitro and in vivo antitumor synergistic activity of the conjugates in the treatment of EL-4 T-cell demonstrates their high potential for solid tumor treatment., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)