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The current landscape of multiple myeloma treatment

Cavo, Michele; Attal, Michel; Gertz, Morie A; Giralt, Sergio; Ludwig, Heinz; Morgan, Gareth J; Anderson, Kenneth C
PMID: 18954677
ISSN: 0145-2126
CID: 3650272

Combinations of ZAP-70, CD38 and IGHV mutational status as predictors of time to first treatment in CLL

Morilla, Alison; Gonzalez de Castro, David; Del Giudice, Ilaria; Osuji, Nnenna; Else, Monica; Morilla, Ricardo; Brito Babapulle, Vasantha; Rudenko, Hannah; Matutes, Estella; Dearden, Claire; Catovsky, Daniel; Morgan, Gareth J
ZAP-70, CD38 and IGHV mutations have all been reported to have prognostic impact in chronic lymphocytic leukemia (CLL), both individually and in paired combinations. We aimed to determine whether the combination of all three factors provided more refined prognostic information concerning the treatment-free interval (TFI) from diagnosis. ZAP-70, CD38 and IGHV mutations were evaluated in 142 patients. Combining all three factors, the ZAP-70-/CD38-/Mutated group showed the longest median TFI (62 months, n = 37), ZAP-70+/CD38+/Unmutated cases the shortest (11 months, n = 37) and cases discordant for > or = 1 factor, an intermediate TFI (27 months, n = 68) (p = 0.006). Analysis of discordant cases revealed values that were otherwise masked when measuring single prognostic factors. The presence or absence of cytogenetic abnormalities did not explain the variability among discordant cases. Simultaneous analysis of ZAP-70, CD38 and IGHV mutations in CLL provides more discriminatory prediction of TFI than any factor alone.
PMID: 19021053
ISSN: 1029-2403
CID: 3647502

Deletions of CDKN2C in multiple myeloma: biological and clinical implications

Leone, Paola E; Walker, Brian A; Jenner, Matthew W; Chiecchio, Laura; Dagrada, Gianpaolo; Protheroe, Rebecca K M; Johnson, David C; Dickens, Nicholas J; Brito, Jose Luis; Else, Monica; Gonzalez, David; Ross, Fiona M; Chen-Kiang, Selina; Davies, Faith E; Morgan, Gareth J
PURPOSE/OBJECTIVE:Deletions of chromosome 1 have been described in 7% to 40% of cases of myeloma with inconsistent clinical consequences. CDKN2C at 1p32.3 has been identified in myeloma cell lines as the potential target of the deletion. We tested the clinical impact of 1p deletion and used high-resolution techniques to define the role of CDKN2C in primary patient material. EXPERIMENTAL DESIGN/METHODS:We analyzed 515 cases of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma using fluorescence in situ hybridization (FISH) for deletions of CDKN2C. In 78 myeloma cases, we carried out Affymetrix single nucleotide polymorphism mapping and U133 Plus 2.0 expression arrays. In addition, we did mutation, methylation, and Western blotting analysis. RESULTS:By FISH we identified deletion of 1p32.3 (CDKN2C) in 3 of 66 MGUS (4.5%), 4 of 39 SMM (10.3%), and 55 of 369 multiple myeloma cases (15%). We examined the impact of copy number change at CDKN2C on overall survival (OS), and found that the cases with either hemizygous or homozygous deletion of CDKN2C had a worse OS compared with cases that were intact at this region (22 months versus 38 months; P = 0.003). Using gene mapping we identified three homozygous deletions at 1p32.3, containing CDKN2C, all of which lacked expression of CDKN2C. Cases with homozygous deletions of CDKN2C were the most proliferative myelomas, defined by an expression-based proliferation index, consistent with its biological function as a cyclin-dependent kinase inhibitor. CONCLUSIONS:Our results suggest that deletions of CDKN2C are important in the progression and clinical outcome of myeloma.
PMCID:2581792
PMID: 18829482
ISSN: 1078-0432
CID: 3647492

Characterising the TP53-deleted subgroup of chronic lymphocytic leukemia: an analysis of additional cytogenetic abnormalities detected by interphase fluorescence in situ hybridisation and array-based comparative genomic hybridisation

Rudenko, Hannah C; Else, Monica; Dearden, Claire; Brito-Babapulle, Vasantha; Jones, Chris; Dexter, Tim; Fenwick, Kerry; Mackay, Alan; Ashworth, Alan; Matutes, Estella; Gonzalez, David; Catovsky, Daniel; Morgan, Gareth J
Deletion of the TP53 gene on chromosome 17p13.1 is the prognostic factor associated with the shortest survival in CLL. We used array-based comparative genomic hybridisation (arrayCGH) to identify additional DNA copy number changes in peripheral blood samples from 74 LRF CLL4 trial patients, 37 with >or=5% and 37 without TP53-deleted cells. ArrayCGH reliably detected deletions on 17p, including the TP53 locus, in cases with >or=50%TP53-deleted cells detected by fluorescence in situ hybridisation, plus seven additional cases with deleted regions on 17p excluding TP53. Losses on chromosomal regions 18p and/or 20p were found exclusively in cases with >or=5%TP53-deleted cells (p<0.001), 38% having one or both losses. The incidence of additional cytogenetic abnormalities, reflecting an increased chromosomal instability, was higher in >or=5%TP53-deleted cases (p=0.02). In particular, amplification of 2p and deletion of 6q were both more frequent. Cases with >20%TP53-deleted cells had the worst prognosis in the LRF CLL4 trial.
PMID: 18949611
ISSN: 1029-2403
CID: 3650262

Genomic variation in myeloma: design, content, and initial application of the Bank On A Cure SNP Panel to detect associations with progression-free survival

Van Ness, Brian; Ramos, Christine; Haznadar, Majda; Hoering, Antje; Haessler, Jeff; Crowley, John; Jacobus, Susanna; Oken, Martin; Rajkumar, Vincent; Greipp, Philip; Barlogie, Bart; Durie, Brian; Katz, Michael; Atluri, Gowtham; Fang, Gang; Gupta, Rohit; Steinbach, Michael; Kumar, Vipin; Mushlin, Richard; Johnson, David; Morgan, Gareth
BACKGROUND:We have engaged in an international program designated the Bank On A Cure, which has established DNA banks from multiple cooperative and institutional clinical trials, and a platform for examining the association of genetic variations with disease risk and outcomes in multiple myeloma. We describe the development and content of a novel custom SNP panel that contains 3404 SNPs in 983 genes, representing cellular functions and pathways that may influence disease severity at diagnosis, toxicity, progression or other treatment outcomes. A systematic search of national databases was used to identify non-synonymous coding SNPs and SNPs within transcriptional regulatory regions. To explore SNP associations with PFS we compared SNP profiles of short term (less than 1 year, n = 70) versus long term progression-free survivors (greater than 3 years, n = 73) in two phase III clinical trials. RESULTS:Quality controls were established, demonstrating an accurate and robust screening panel for genetic variations, and some initial racial comparisons of allelic variation were done. A variety of analytical approaches, including machine learning tools for data mining and recursive partitioning analyses, demonstrated predictive value of the SNP panel in survival. While the entire SNP panel showed genotype predictive association with PFS, some SNP subsets were identified within drug response, cellular signaling and cell cycle genes. CONCLUSION/CONCLUSIONS:A targeted gene approach was undertaken to develop an SNP panel that can test for associations with clinical outcomes in myeloma. The initial analysis provided some predictive power, demonstrating that genetic variations in the myeloma patient population may influence PFS.
PMID: 18778477
ISSN: 1741-7015
CID: 3695892

The feasibility of using topotecan, vinorelbine, thiotepa and gemcitabine (TVTG) in adult patients with relapsed/refractory acute lymphoblastic leukaemia/lymphoma [Letter]

Hiwarkar, P; Arkenau, H-T; Treleaven, J; Morgan, G; Potter, M; Ethell, M
PMID: 18305560
ISSN: 1476-5551
CID: 3706672

The role of maintenance chemotherapy after autotransplantation for acute lymphoblastic leukemia in first remission: single-center experience of 100 patients

Sirohi, B; Powles, R; Treleaven, J; Kulkarni, S; Saso, R; Potter, M; Ethell, M; Morgan, G; Singhal, S; Mehta, J
A total of 100 adults with ALL in first CR received melphalan (110 mg/m(2)) with TBI followed by autologous marrow (n=35) or single-agent melphalan (200 mg/m(2)) followed by autologous blood stem cells (n=65). After adequate hematologic recovery, maintenance chemotherapy with 6-mercaptopurine, methotrexate and vincristine-prednisone was administered for 2 years. Six patients, all TBI recipients (P=0.001), died of toxicity. In total 70 patients received 6-mercaptopurine, 53 received methotrexate and 40 received vincristine-prednisone. The cumulative incidence of relapse at 7 years was 45%. The 7-year probabilities of disease-free survival (DFS) and overall survival were 45 and 48%. Age 30 years, >4 weeks to attain remission, and karyotypes t(4;11) and t(9;22) were associated with adverse outcome. Patients with 0 (standard risk), 1 (intermediate risk), and 2-3 (high risk) adverse features had 7-year cumulative incidences of relapse of 19, 53 and 82% (P<0.0001), and 7-year DFS probabilities of 73, 36 and 7% (P<0.0001). The 7-year probabilities of DFS for patients receiving 0, 1, 2 and 3 maintenance chemotherapy agents were 15, 29, 58 and 61% (P<0.0001). Maintenance chemotherapy intensity was an independent determinant of outcome in Cox analysis. Maintenance chemotherapy after autotransplantation reduces relapse and improves outcome in adult patients with ALL.
PMID: 18408773
ISSN: 0268-3369
CID: 3706682

Lenalidomide: a new therapy for multiple myeloma

Palumbo, Antonio; Miguel, Jesús San; Sonneveld, Pieter; Moreau, Philippe; Drach, Johannes; Morgan, Gareth; Einsele, Hermann
The last decade has seen rapid evolution in the management of multiple myeloma. Cytogenetic, molecular, and proteomic techniques have led to a better understanding of the pathophysiology and prognostic markers of this heterogeneous malignancy. New immunomodulatory drugs, such as lenalidomide, which interrupt myeloma growth and survival pathways have entered into clinical usage. Combined with dexamethasone, oral lenalidomide has proved to be highly effective in patients whose disease has become resistant to conventional therapy. Currently, several clinical trials are ongoing in order to define the optimal use of this new agent and its combinations across the spectrum of patients with myeloma. Whether the ultimate outcome of future research will be a single-treatment solution for all patients, or whether treatments will become better-tailored to the individual (based on prognostic markers and pre-existing co-morbidities) has yet to be determined.
PMID: 18230411
ISSN: 0305-7372
CID: 3695882

Streptolysin-O reversible permeabilisation is an effective method to transfect siRNAs into myeloma cells

Brito, Jose L R; Davies, Faith E; Gonzalez, David; Morgan, Gareth J
RNA interference (RNAi) has been shown to be a valuable tool to specifically target gene expression in a number of organisms becoming an indispensable weapon in the arsenal in functional genomics. In this study, we demonstrate that streptolysin-O (SLO) reversible permeabilisation is an efficient method to deliver small interfering RNAs (siRNAs) to hard-to-transfect human myeloma cell lines. We used published, pre-validated siRNAs for ERK2 and non-silencing siRNA control. We transfected siRNAs into human myeloma cell lines using SLO reversible permeabilisation method. Flow cytometry and western blot analysis were performed to assess the effect of SLO on transfection efficiency and ERK2 knockdown. These experiments demonstrate that SLO reversible permeabilisation method is an efficient and easy-to-use method to deliver siRNAs into human myeloma cell lines. Optimised SLO permeabilisation method showed to transfect >80% of JIM-3, H929, RPMI8226 and U266 cells, with minimal effect on cell viability (<10%) and cell cycle. Equally important, SLO permeabilisation induced a substantial knockdown of ERK2 at the protein level. These studies demonstrate that reversible SLO permeabilisation can successfully be applied to hard-to-transfect human myeloma cell lines to effectively silence genes.
PMID: 18299137
ISSN: 0022-1759
CID: 3647432

Untangling the unfolded protein response

Davenport, Emma L; Morgan, Gareth J; Davies, Faith E
Resistance to current cancer therapies has forced scientists to investigate new avenues of therapy distinct from those aimed at single targets, to strategies based on targeting families of proteins, on which cancers rely for their ability to survive stress. Two such protein families are the heat shock proteins (HSP), especially the HSP90 family, and proteins involved in mediating the unfolded protein response (UPR). HSP90 stabilises key survival factors in cancer cells including AKT, ERB2 and HIF1alpha, which alone makes HSP90 inhibitors extremely interesting as potential therapies. In addition targeting HSP90 can destabilise the UPR inducing cell death. A broad range of cancer-types rely on the UPR to correctly fold key signalling proteins properly, as well as to allow the cell to cope with the hypoxic environment associated with tumour development. These associations suggest that a range of tumours may be targeted using HSP90 inhibitors and that the development of specific inhibitors of the UPR may be of interest. In this article, based on work in multiple myeloma, we highlight the importance of targeting multiple signalling pathways simultaneously, using the UPR and heat shock proteins as examples, as a means of effectively killing cancer cells.
PMID: 18414035
ISSN: 1551-4005
CID: 3647442