Julie M. Vose

An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma

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

Gains of MYC locus and outcome in patients with diffuse large B‐cell lymphoma treated with R‐CHOP

Paresh Vyas Eva Hellström-Lindberg James S. Wainscoat Jacqueline Boultwood LLR Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, Oxford, UK, Department of Haematology Oncology, University of Pavia Medical School, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, Medizinische Klinik II, St Johannes Hospital, Duisburg, Germany, Department of Medicine, Division of Haematology, Karolinska Institutet, Stockholm, Sweden, Department of Haematology, Royal Bournemouth Hospital, Bournemouth, and WIMM, John Radcliffe Hospital, Oxford, UK. E-mail: jacqueline.boultwood@ndcls.ox.ac.uk

Diffuse large B-cell lymphoma with concordant bone marrow involvement has peculiar genomic profile and poor clinical outcome

Bone marrow (BM) involvement in diffuse large B‐cell lymphoma (DLBCL) can be morphologically discordant from the primary tumor. Concordant BM infiltration has been shown associated with a poorer outcome in patients treated with CHOP. In order to evaluate tumor‐related factors leading to BM involvement in DLBCL, we performed an integrated analysis of i) genomic profiles obtained with a high‐density genome wide SNP‐based arrays ii) immunomorphological and iii) clinical data from 133 patients uniformly treated with R‐CHOP. BM infiltration was found in 27 of 133 (20%) cases; and it was concordant in 18/27 (67%) cases. Concordant infiltration, but not discordant, influenced negatively OS, PFS and DFS and was associated with higher serum LDH, lower CR and higher PD rates. No association with cell of origin was found between BM+ and BM‐ DLBCL. As compared with BM‐ cases, BM+ DLBCL showed absence of 7q gain. Copyright

Clinical and molecular characterization of diffuse large B-cell lymphomas with 13q14.3 deletion

BACKGROUNDnDeletions at 13q14.3 are common in chronic lymphocytic leukemia and are also present in diffuse large B-cell lymphomas (DLBCL) but never in immunodeficiency-related DLBCL. To characterize DLBCL with 13q14.3 deletions, we combined genome-wide DNA profiling, gene expression and clinical data in a large DLBCL series treated with rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 days (R-CHOP21).nnnPATIENTS AND METHODSnAffymetrix GeneChip Human Mapping 250K NspI and U133 plus 2.0 gene were used. MicroRNA (miRNA) expression was studied were by real-time PCR. Median follow-up of patients was 4.9 years.nnnRESULTSnDeletions at 13q14.3, comprising DLEU2/MIR15A/MIR16, occurred in 22/166 (13%) cases. The deletion was wider, including also RB1, in 19/22 cases. Samples with del(13q14.3) had concomitant specific aberrations. No reduced MIR15A/MIR16 expression was observed, but 172 transcripts were significantly differential expressed. Among the deregulated genes, there were RB1 and FAS, both commonly deleted at genomic level. No differences in outcome were observed in patients treated with R-CHOP21.nnnCONCLUSIONSnCases with 13q14.3 deletions appear as group of DLBCL characterized by common genetic and biologic features. Deletions at 13q14.3 might contribute to DLBCL pathogenesis by two mechanisms: deregulating the cell cycle control mainly due RB1 loss and contributing to immune escape, due to FAS down-regulation.BACKGROUNDnDeletions at 13q14.3 are common in chronic lymphocytic leukemia and are also present in diffuse large B-cell lymphomas (DLBCL) but never in immunodeficiency-related DLBCL. To characterize DLBCL with 13q14.3 deletions, we combined genome-wide DNA profiling, gene expression and clinical data in a large DLBCL series treated with rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 days (R-CHOP21).nnnPATIENTS AND METHODSnAffymetrix GeneChip Human Mapping 250K NspI and U133 plus 2.0 gene were used. MicroRNA (miRNA) expression was studied were by real-time PCR. Median follow-up of patients was 4.9 years.nnnRESULTSnDeletions at 13q14.3, comprising DLEU2/MIR15A/MIR16, occurred in 22/166 (13%) cases. The deletion was wider, including also RB1, in 19/22 cases. Samples with del(13q14.3) had concomitant specific aberrations. No reduced MIR15A/MIR16 expression was observed, but 172 transcripts were significantly differential expressed. Among the deregulated genes, there were RB1 and FAS, both commonly deleted at genomic level. No differences in outcome were observed in patients treated with R-CHOP21.nnnCONCLUSIONSnCases with 13q14.3 deletions appear as group of DLBCL characterized by common genetic and biologic features. Deletions at 13q14.3 might contribute to DLBCL pathogenesis by two mechanisms: deregulating the cell cycle control mainly due RB1 loss and contributing to immune escape, due to FAS down-regulation.

Integrated profiling of diffuse large B-cell lymphoma with 7q gain

To characterize diffuse large B‐cell lymphoma (DLBCL) with chromosome 7 gains, we combined clinical data with genomic, RNA and miRNA profiling. Gains were associated with age >60u2003years, female gender, a trend for higher complete response rate, lower death rate, and better overall survival in patients treated with R‐CHOP. Lesions were inversely associated with bone marrow involvement and number of extra‐nodal sites. Differentially expressed transcripts were enriched of genes belonging to specific pathways and miRNAs targets. MIR96, MIR182, MIR589, MIR25 were shown significantly up‐regulated in 7q+ DLBCL by real‐time PCR.