Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B-cells 1. Targeted re-sequencing studies have revealed mutations in various genes in the NFkB pathway 2 , 3 that contribute to the activated B-cell Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease with marked genomic instability and variable response to conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. More clinically aggressive cases of DLBCLs have high level of circulating interleukin 10 (IL10) cytokine and evidence of activated intracellular STAT3 (signal transducer and activator of transcription 3) signaling. We investigated the role of IL10 and its surface receptor in supporting the neoplastic phenotype of DLBCLs. We determined that IL10RA gene is amplified in 21% and IL10RB gene in 10% of primary DLBCLs. Gene expression of IL10, IL10RA and IL10RB was markedly elevated in DLBCLs. We hypothesized that DLBCLs depend for their proliferation and survival on IL10-STAT3 signaling and that blocking the IL10 receptor (IL10R) would induce cell death. We used anti-IL10R blocking antibody, which resulted in a dose-dependent cell death in all tested activated B-cell-like subtype of DLBCL cell lines and primary DLBCLs. Response of germinal center B-cell-like subtype of DLBCL cell lines to anti-IL10R antibody varied from sensitive to resistant. Cells underwent cell cycle arrest, followed by induction of apoptosis. Cell death depended on inhibition of STAT3 and, to a lesser extent, STAT1 signaling. Anti-IL10R treatment resulted in interruption of IL10-IL10R autostimulatory loop. We thus propose that IL10R is a novel therapeutic target in DLBCLs.

A treatment strategy for adults with chemosensitive T-LBL that includes planned consolidation with SCT in first response produces favorable long-term outcome.

Summary:Twenty-six patients with low-grade lymphoma (LGL) (n ‫؍‬ 18) or chronic lymphocytic leukemia (CLL) (n ‫؍‬ 8) received allogeneic BMTs between 1985 and 1998. Median age was 42 years, median interval from diagnosis to transplant 22 months and median number of prior treatments three. Twenty (77%) had stage IV disease; 22 (85%) had never achieved CR. Donor source was HLA matched sibling (n ‫؍‬ 19, 73%), matched unrelated (n ‫؍‬ 6, 23%) or syngeneic (n ‫؍‬ 1). Conditioning therapy included total body irradiation in 23 patients and busulphan in three. Twenty-five received GVHD prophylaxis with cyclosporine A; ؉ methotrexate (n ‫؍‬ 19), ؉ methylprednisolone (n ‫؍‬ 2) or ؉ T cell depletion of allograft ؎ methotrexate (n ‫؍‬ 4). Sixteen patients are alive, a median of 2.4 years post BMT. Death occurred due to transplant complications (n ‫؍‬ 7) or underlying disease (n ‫؍‬ 3). Eighteen (12 LGL, six CLL) of 22 evaluable patients (82%) achieved CR post BMT. Cumulative incidence of refractory/recurrent disease was 18% (95% confidence interval (CI) 7-42%). Overall and event-free survivals were 58% (95% CI 35-75%) and 54% (95% CI 32-72%), respectively. Allogeneic BMT for young patients with advanced LGL or CLL is feasible and can result in long-term disease-free survival. Bone Marrow Transplantation (2000) 25, 605-612. Keywords: low-grade lymphoma; chronic lymphocytic leukemia; allogeneic bone marrow transplantation Low-grade lymphoma (LGL) and chronic lymphocytic leukemia (CLL) are indolent hematologic malignancies with median survival times approaching a decade.1-5 Although clinical remission can be achieved with standard 6-9 and newer 10-14 therapies, prolonged freedom from recurrence has not been demonstrated for patients with advanced stage, making death from disease almost inevitable. 8,9,11,[13][14][15][16] for younger patients, particularly those with refractory or recurrent disease, a more aggressive approach to treatment can be justified. 17-20High-dose therapy with allogeneic stem cell support is an attractive option for such patients, where marrow involvement is common and the occurrence of a graftversus-leukemia/lymphoma (GVL) effect 21-26 may contribute to the achievement of long-term disease control. Worldwide experience with allogeneic transplantation in this setting is, however, still limited. We report results from 26 patients with LGL or CLL receiving allogeneic BMT at the Vancouver General Hospital since 1985. Patients and methods PatientsTwenty-six patients with LGL (n ϭ 18) or CLL (n ϭ 8) received allogeneic BMT between September 1985 and January 1998, during which time, a total of 589 allografts and 512 autografts were performed in adults by the Leukemia/BMT Program of British Columbia. Eligibility criteria included: (1) age р50-55 years (related donor) and р45-50 years (unrelated donor); (2) Karnofsky performance score (KPS) у80%; and (3) adequate pre-transplant organ function including left ventricular ejection fraction у40%, forced expiratory volume in 1 s у60% and diffusing capacity for car...

Bortezomib and gemcitabine have each shown activity as single agents in mantle cell lymphoma (MCL), which is incurable. The purpose of this phase II study was to determine the efficacy and safety of the previously unstudied combination of bortezomib and gemcitabine in patients with relapsed or refractory MCL. Patients were eligible if they had relapsed MCL with 1-3 prior therapies. Patients were treated with gemcitabine 1000 mg/m(2) on days 1 and 8 and bortezomib 1.0 mg/m(2) IV on days 1, 4, 8, and 11, on a 21-day schedule. Twenty-six patients were evaluable for toxicity and 25 for response. The overall response rate was 60% and the median progression free survival was 11.4 months. The main adverse effects were hematological, with 40% and 48% of patients experiencing grade 3/4 thrombocytopenia and granulocytopenia, respectively. Bortezomib and gemcitabine is an active combination in relapsed and refractory MCL with clinically meaningful results. It offers a chemotherapy backbone to which other agents, less myelosuppressive, may be added.

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We report a series of 37 cases of lymphoproliferative disorders with 3q27 structural chromosomal abnormalities. Breakpoints at 3q27, the site of the bcl-6 gene, appear in a broad range of B cell lymphoma histologies but are most frequently detected in follicular lymphomas lacking a t(14;18) and diffuse large cell lymphomas. The majority of 3q27 rearrangements result from translocations involving the immunoglobulin heavy or light chain genes, however, involvement of other partner chromosomes is also observed. Molecular rearrangement of bcl-6 is demonstrable in a subset of cases. Bcl-6 is a recently identified gene encoding a zinc-finger protein. It is normally expressed in germinal center B cells where it is believed to have a developmental or differentiation function. Transcriptional deregulation of bcl-6 through translocations, submicroscopic molecular rearrangements or point mutations may be responsible for this gene's putative lymphomagenic potential.