Aggressive Large B-cell Lymphoma Research Articles

Aggressive Large B-Cell Lymphoma in a Systemic Lupus Erythematosus Patient with Chronic Active Epstein-Barr Virus Infection: A Case Report

A link between Epstein-Barr Virus (EBV) infection, systemic lupus erythematosus (SLE) and non-Hodgkin's lymphoma (NHL) has been recently reported in literature. Here we report a case of diffuse large B-cell lymphoma (DLBCL) with a particularly aggressive clinical course in an SLE patient with EBV infection. A 49-year-old woman with a long history of SLE was admitted to the Department of Experimental and Clinical Medicine and dramatically died a few hours later. The autopsy described no evidence of active lymphoproliferative disorder. Instead, histological examination demonstrated an atypical lymphocitic proliferation in lymph node, kidneys, pericardium and uterus. Immunoistochemically, the lymphomatous cells were positive with CD19, CD20, CD22 and CD79a, which was consistent with a DLBCL. The cells were also reactive to EBV markers, indicating the possible role of previous EBV infection in DLBCL pathogenesis.

Rituximab Plus Bendamustin (R-B) Treatment In Patients with Aggressive Large B-Cell Lymphoma (LBCL): Response and Tolerability - a Single Institution Experience

AbstractAbstract 4900 Introduction:Clinical studies have shown that Rituximab plus Bendamustin (R-B) in indolent lymphoma results in favourable responses, progression free survival (PFS) and lower toxicity as compared to R-CHOP. The aim of this analysis was to characterize response and tolerability of R-B in patients with LBCL, who were not qualifying for R-CHOP due to age, comorbidity and/or prior pretreatment (including anthracyclines). Methods:We retrospectively identified consecutive patients with LBCL receiving at least two cycles of R-B in our department between 2003 and 2010 using our electronic tumor documentation system. Patient characteristics, response to R-B, and toxicity were assessed. Results:We identified 9 caucasian patients (5 females, 4 males) with LBCL; their median age was 71 years (range; 51–82). Two presented with stage I/II, seven with stage III/IV disease at initial diagnosis and before R-B. Six patients had a low or intermediate IPI and three were high risk. Four patients received R-B as first-line therapy, and five were treated for relapsed or refractory disease.Main determinants for the R-B-selection were contraindications for anthracyclines in five patients and advanced age and/or poor performance status in four patients.A median of four R-B-cycles were applied (range; 2–6). Response with achievement of CR and PR was observed in 6/9 (CR: 2, PR: 4), two achieved SD. Only one pt showed PD after four R-B cycles. The response of R-B in first-line vs. relapsed appeared similar.Of note, one female patient with secondary LCBL, after initial Hodgkin's lymphoma and C-MOPP chemotherapy (CTx) and mediastinal irradiation - with excellent response to R-B- failed to successfully mobilize PBSC thereafter. However, she was effectively mobilized with R-Ara-C-thiotepa (peripheral blood CD34+ cells were 5.82 vs. 54/μl, obtaining no vs. 6.72 × 106 CD34+ cells/kg KG via leukapheresis, respectively). Clinical tolerance of R-B in all patients was excellent in a total of 31 R-B-cycles, only two major CTC-events occurred: one infection (CTC grade III) and one thromboembolism (grade IV). Median PFS and overall Survival (OS) were 16 (7- not reached) and 20 (11-21) months. Conclusions:If standard R-CHOP cannot be given due to age, comorbidity or CTx-contraindications (e.g. anthracyclines), R-B may represent an effective treatment in LBCL. Larger cohorts and prospective clinical trials are needed to confirm these promising results. Currently, patients with grade III/IV follicular lymphoma are additionally evaluated for response and tolerability under R-B, also being presented at the meeting. Disclosures:No relevant conflicts of interest to declare.

Aggressive large B-cell lymphoma with plasma cell differentiation: immunohistochemical characterization of plasmablastic lymphoma and diffuse large B-cell lymphoma with partial plasmablastic phenotype

Plasmablastic lymphoma has recently come to be considered a distinct entity among mature B cell neoplasms, although the limits with diffuse large B-cell lymphoma (DLBCL) need to be more accurately defined. Here we show the results of an immunohistochemical study of 35 cases of plasmablastic lymphoma compared with a set of 111 conventional DLBCLs. Our results demonstrate that the use of a limited combination of immunohistochemical markers (PAX5&CD20, PRDM1/BLIMP1 and XBP1s) enables the identification of a plasmablastic immunophenotype highly characteristic of plasmablastic lymphoma cases and associated with an aggressive clinical behavior. Additionally, the study shows that the acquisition of a partial plasmablastic phenotype (PRDM1/BLIMP1 expression) in DLBCL is associated with shorter survival in R-CHOP-treated patients. The use of a restricted combination of immunohistochemical markers (PAX5&CD20, PRDM1/BLIMP1 and XBP1s) enables a more accurate definition of terminal differentiation for large B-cell lymphoma.

Front-line High-Dose Chemotherapy with Rituximab Showed Excellent Long-Term Survival in Adults with Aggressive Large B-Cell Lymphoma: Final Results of a Phase II GOELAMS Study

To evaluate the effect of rituximab in poor-prognosis patients with diffuse large B-cell lymphoma (DLBCL), a multicenter phase II trial combining rituximab with chemotherapy followed by high-dose therapy (HDT) with autologous stem cell transplant was conducted by the Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang (GOELAMS). Patients were aged 18 to 60 years, with newly diagnosed CD20-expressing DLBCL, and at least 2 adverse risk factors as defined by the age-adjusted International Prognostic Index (aa-IPI). The treatment consisted of 2 courses of high-dose CHOP-like regimen on day 1 and 15 and 1 course of methotrexate and cytarabine on day 36. Four doses of rituximab (375 mg/m(2)) were infused on days 1, 15, 22, and 36. For patients who achieved at least a partial remission (PR), HDT followed by autologous stem cell transplant was performed on day 66. From April 2002 to May 2003, 42 patients were eligible. Half were high aa-IPI risk patients. Thirty-eight patients (90%) completed the treatment. Treatment-related mortality was 7% and no toxic death was related to rituximab. Complete response rate after the end of the full treatment was 67%. With a median follow-up of 66 months, event-free survival and overall survival rates were 55% and 74%, respectively. Median survival was not reached. First-line HDT with rituximab offers promising results for young adults with intermediate high or high aa-IPI high-grade lymphoma. Immediate and late toxicities were low. This treatment is being randomly compared prospectively with CHOP-14-rituximab in young adults with DLBCL (GOELAMS 075 trial).

MYC gene amplification in double minute chromosomes in an aggressive large B-cell lymphoma with leukemic presentation: a case report

Double-minute chromosomes (dmin) are small chromatin particles that lack a centromere. They represent extrachromsomal form of gene amplification. Dmin are very rarely encountered in lymphoid neoplasms. We describe a case of a leukemic presentation of large B-cell lymphoma with dmin. Fluoresence in situ hybridization analysis identified these dmin as comprising MYC genes.

New Drugs for the Treatment of Advanced-Stage Diffuse Large Cell Lymphomas

The rapid pace of discovering new signaling pathways that influence the growth and survival of different types of cancer cells has produced a daunting array of potentially new, "drugable" targets for the treatment of cancer. This has been particularly true for the lymphomas. The empiric observation that many kinds of "novel targeted" drugs appear to exhibit relatively selective patterns of activity is testament to the concept that the lymphomas represent an incredibly diverse group of human cancers. Targeting one pathway in a subtype of lymphoma may not be universally effective against all subtypes of lymphoma, even closely related ones. These observations suggest that pharmacologically driven "target identification" plays an important role in the continued development of new therapeutic agents, and underscores the need for more research into the biologic basis for different subtypes of lymphoma. Over the past 10 years, there has been an explosion of new drugs making their way through preclinical laboratories and early clinical studies. These experiences have taught us some frustrating lessons. Sometimes, the strongest biologic rationale is associated with the poorest clinical results. Sometimes, where no rationale exists, golden therapeutic opportunities emerge. In either case, both experiences typically end up teaching us something about the disease we didn't historically appreciate. In this review, we will take a close look at some of the more intriguing targets in aggressive large B-cell lymphomas, all of which now have small molecules that can profoundly affect their activity, activity we hope will lead to new treatment opportunities. We will focus on the biologic rationale for targeting novel pathways regulated by Bcl-6, Bcl-2, BLysS, and APRIL for example. In addition, we will review how new concepts in structural biology and chemical design can help produce new generation compounds with novel activity, as is the case for pralatrexate and targeting the reduced folate carrier-type-1. Clearly, given the breadth and depth of information emerging on these and other relevant biologic pathways, we are limited to discussing only a few illustrative examples, which should in no way detract from the importance of other critical signaling and survival pathways now being exploited in the treatment of lymphoma.

Primary Cardiac Non‐Hodgkin's Lymphoma Diagnosed by Transthoracic Echocardiography

Primary cardiac lymphomas are extremely rare and can be diagnosed by echocardiography. We present the case of a 79-year-old man with an intracardiac mass, shown to be an aggressive large B-cell lymphoma by mediastinal aspiration, who had rapid regression of the tumor following one cycle of chemotherapy.

Dose Adjusted EPOCH Chemotherapy Plus Rituximab Combination (DA-R-EPOCH), an Effective Upfront Therapy for Patients with Poor-Risk Aggressive B-Cell Lymphomas. Results of a Pilot Study in a Single Center.

Poor risk aggressive non-Hodgkin's lymphomas have a short EFS and OS when treated with conventional chemotherapy schedules. High dose therapy followed by stem cell rescue has been attempted with disparate results. Based on Wilson WH et al. schedule (Wilson WH, Grossbard ML, Pitaluga S et al. Blood 2002; 99: 2685–93), a pilot study has been conducted in order to assess the efficacy and toxicity of DA-R-EPOCH in patients with Intermediate-High/High (IH/H) IPI score diffuse large B-cell (DLBCL) and follicular large (grade 3b) B-cell (G3bFL) lymphomas. No restrictions were done regarding the performance status.Methods. From August 2002 to May 2005, 28 untreated patients (pts) were enrolled in the study. Basically the regimen consisted on 6 cycles every 21 days of Rituximab (day 1) followed by a 96 hours infusion of etoposide, vincristine and doxorubicine and bolus cyclophosphamide on day 5 plus prednisone for 5 days. The doxorubicine, etoposide and cyclophosphamide doses were adjusted according to the hematological toxicity as reported by Wilson WH et al (Wilson WH, Gutierrez M, O'Connor P et al. 2002; 29 (Suppl. 2):41–7). Response rate and survivals were calculated in intention to treat. Pts not reaching a PR ≥ 70% after 3 cycles or a CR/CRu after completion of therapy were assigned as failure in the time to treatment failure (TTF) calculation.Results. Patients characteristics: median age 62,5 years (range:26–72); male/female: 11/17; DLBCL 21 (75%) and G3bFL 7 (25%); 19 (68%) had IV clinical stage; 13 (46%) B symptoms; PS (ECOG) > 2 in 12 pts (42%); 21 pts (75%) had extranodal and 10 (36%) bone marrow involvement; 32% had serum albumin < 3 g/dL; Hb < 100 g/L in 13 (46%); 46% had high b2microglobulin levels, and 100% elevated LDH. High age-adjusted IPI score in 15 pts (54%). Dose adjustment: Dose escalation could be done in most patients (18 out of 21 receiving all 6 cycles). There were an inverse correlation between the mean dose of doxurubicin given and age (r=−0.555; P2=0.009) and IPI (r=−0.507; P2=0.019). Response and survival: 17 out of 23 pts evaluated for response (74%) achieved a CR/CRu. There were 2 early deaths. At a median follow up of 14 months (range: 2–35) the estimated 2-year TTF and OS were 58% and 73% respectively. Toxicity: After 143 cycles administered grade 3–4 mucositis was observed in 9 courses (6%), grade 3–4 nueropathy in 1 (<1%) and neutropenic fever in 20 (14%).Conclusion. DA-R-EPOCH is a feasible approach and as effective as other more intensive chemotherapy schedules as upfront therapy in patients with intermediate-high or high risk IPI score aggressive large B-cell lymphomas (DLBCL and G3bFL) with acceptable toxicity. Updated data will be presented at the meeting.

Front-Line High-Dose Chemotherapy (HDT) Combined with Rituximab for Adults with Aggressive Large B-Cell Lymphoma (DLBCL) : Goelams 074 Trial.

Background: The beneficial effect of adding rituximab to CHOP has been shown for elderly patients with DLBCL (Coiffier et al, N.E.J.M 2002). We have shown that HDT with autologous stem cell transplantation is superior to CHOP in young adults with DLCL ( Milpied et al GOELAMS 072 trial, N.E.J.M 2004). The feasibility of adding rituximab to front-line HDT remains to be established.Methods: A prospective pilot trial was proposed to patients with DLBCL, with intermediate-high or high adjusted IPI, up to the age of 60 y.o. This program consisted of 2 courses of high-dose CHOP-like regimen, 15 days apart, with rituximab (375/mg/m2) on day 1 of each course, followed by rituximab on d 22, harvest of G-CSF mobilised peripheral blood stem cells on d 28,29, then rituximab on d 36 followed by a course of high-dose methotrexate with cytarabin. For patients who achieved at least a PR after these 3 courses, a BEAM regimen started on d 66 to 80 followed by the infusion of stem cells.Results: Between 04/2002 and 05/2003, 42 pts gave their informed consent and were included in that trial. Median age was 50 y.o (18–60 y.o), 23 had WHO PS ≥ 2, the LDH level was >N in 41 pts and 38 had stage III or IV disease. The age-adjusted IPI was intermediate-high in 23 and high in 19 pts. The program was completed in 30 pts (71%), 3 pts died of toxicity before the BEAM regimen, 8 pts failed to achieve at least a PR after the first 3 courses and 1 refused the autologous transplant. On an intent-to-treat basis, the response rate at the end of the treatment was CR/Cru=64%, PR=7%, less than PR or progression= 22% and toxic death=7%. No toxic death was directly attributable to the addition of rituximab. With a median FU of 19 m, the KM 2y probability of OS and EFS are 79% and 59% respectively, these figures compare to those achieved without rituximab in the previous trial as shown on the table:Conclusion : The addition of 4 doses of rituximab to this HDT program is feasible with no unexpected toxicity, allows the harvesting of sufficient numbers of stem cells to support an autologous transplant with a BEAM regimen in responding patients. This treatment is now being randomly prospectively compared with CHOP-14-rituximab in youg adults with DLBCL (Goelams 075 trial).Supported in part by Roche which kindly provided rituximab for that trial and by DRC Nantes programme N°:02/2N 2002.GOELAMS 072 (IPI 2 only)GOELAMS 074 (IPI 2–3)2y OS80%79%2y EFS60%59%