Faculty Bibliography

Bortezomib is a highly selective, reversible inhibitor of the 26S proteasome that is indicated for single-agent use in the treatment of patients with multiple myeloma who have received at least 2 prior therapies and are progressing on their most recent therapy. Clinical investigations have been completed or are under way to evaluate the safety and efficacy of bortezomib alone or in combination with chemotherapy in multiple myeloma, both at relapse and presentation, as well as in other cancer types. The antiproliferative, proapoptotic, antiangiogenic, and antitumor activities of bortezomib result from proteasome inhibition and depend on the altered degradation of a host of regulatory proteins. Exposure to bortezomib has been shown to stabilize p21, p27, and p53, as well as the proapoptotic Bid and Bax proteins, caveolin-1, and inhibitor kappaB-alpha, which prevents activation of nuclear factor kappaB-induced cell survival pathways. Bortezomib also promoted the activation of the proapoptotic c-Jun-NH2 terminal kinase, as well as the endoplasmic reticulum stress response. The anticancer effects of bortezomib as a single agent have been demonstrated in xenograft models of multiple myeloma, adult T-cell leukemia, lung, breast, prostate, pancreatic, head and neck, and colon cancer, and in melanoma. In these preclinical in vivo studies, bortezomib treatment resulted in decreased tumor growth, angiogenesis, and metastasis, as well as increased survival and tumor apoptosis. In several in vitro and/or in vivo cancer models, bortezomib has also been shown to enhance the antitumor properties of several antineoplastic treatments. Importantly, bortezomib was generally well tolerated and did not appear to produce additive toxicities when combined with other therapies in the dosing regimens used in these preclinical in vivo investigations. These findings provide a rationale for further clinical trials using bortezomib alone or in combination regimens with chemotherapy, radiation therapy, immunotherapy, or novel agents in patients with hematologic malignancies or solid tumors.

Induction chemotherapy followed by high-dose melphalan (HDM) is the standard treatment for fitter patients with myeloma. The place of bortezomib and the thalidomide analogues within this treatment paradigm is yet to be established. We sought to identify patients who may benefit from the introduction of novel agents during their initial management. An intention-to-treat analysis was performed on 383 patients with newly diagnosed myeloma eligible for HDM to determine whether the extent of response to induction therapy and HDM correlated with long-term survival. Early response [complete response (CR) and partial response (PR)] to induction therapy was predictive of overall survival (OS) [median OS, 7.47 years for responders (CR and PR) versus 4.89 years for non-responders; P = 0.035]. The attainment of CR at 3 months post-HDM correlated with a prolonged progression-free survival (PFS) (median PFS, 7.4 years in CR group versus 5.3 years in non-CR group; P = 0.023). This data suggests that, at every stage of treatment, the aim should be to achieve CR. Patients with suboptimal responses could be offered alternative therapy. We propose a multiparametric risk-adapted model that includes response to induction chemotherapy and HDM, for identifying patients who may benefit from novel approaches to treatment.

Broad cross-talk exists between the endocrine and immune systems. Estrogen receptor expression in lymphocytes suggests that hormonal modulation may influence lymphoma risk. Analysis of genetic polymorphisms that affect oestrogen production, such as cytochrome P450 17A1 (CYP17A1) -34T>C, may provide insight into oestrogen's role in lymphomagenesis. CYP17A1-34T>C and CYP17A1 IVS2 105A>C polymorphisms were analyzed in a non-Hodgkin lymphoma (NHL) population-based case-control study. The CYP17A1-34CC genotype was positively associated with NHL [odds ratio (OR) = 1.44, 95% confidence interval (CI) 1.02-2.03], particularly diffuse large B-cell lymphoma (OR = 1.76, CI 1.14-2.71). Associations of CYP17A1 polymorphisms with increased risk of NHL suggest a role for oestrogen in lymphomagenesis.

The emerging understanding of the biology of the hemopoietic stem cell is beginning to shed light on the mechanisms by which benzene gives rise to acute myeloid leukaemia. These mechanisms are complex, affecting not only the DNA, but also the complex intercellular interactions present in the bone marrow microenvironment. The toxic effects of benzene are mediated within the bone marrow and we are beginning to understand the contributions of inter-individual variation in xenobiotic metabolisms and DNA repair to the definition of risk following exposure to benzene in the environment. This process is likely to be accelerated by recent advances in high throughput genotyping. Until now, research has focussed directly on mutation and chromosomal translocations, but we are beginning to understand more how environmental exposures can modify chromatin structure giving rise to heritable changes not affecting DNA. These epigenetic studies are likely to give important further insights into the mode of action of benzene as are studies of its effect on the immune system.

PURPOSE/OBJECTIVE:There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification. PATIENTS AND METHODS/METHODS:Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies. RESULTS:Serum beta2-microglobulin (Sbeta2M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sbeta2M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sbeta2M less than 3.5 mg/L plus serum albumin > or = 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sbeta2M > or = 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and > or = 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system. CONCLUSION) The new ISS is simple, based on easy to use variables (Sbeta2M and serum albumin), and recommended for early adoption and widespread use.

The macrophage colony-stimulating factor receptor is encoded by the c-FMS gene, and it has been suggested that altered regulation of c-FMS expression may contribute to leukaemic transformation. c-FMS is expressed in pluripotent haemopoietic precursor cells and is subsequently upregulated during monocytic differentiation, but downregulated during granulopoiesis. We have examined transcription factor occupancy and aspects of chromatin structure of the critical c-FMS regulatory element located within the second intron (FIRE - fms intonic regulatory element) during normal and leukaemic myelopoiesis. Granulocytic differentiation from normal and leukaemic precursors is accompanied by loss of transcription factors at FIRE and downregulated c-FMS expression. The presence of AML1-ETO in leukaemic cells does not prevent this disassembly. In nonleukaemic cells, granulocytic differentiation is accompanied by reversal to a chromatin fine structure characteristic of c-FMS-nonexpressing cells. In addition, we show that low-level expression of the gene in leukaemic blast cells and granulocytes does not associate with increased CpG methylation across the c-FMS locus.

This study described the haplotypic structure across a region of chromosome 6 including the tumour necrosis factor (TNF) gene, and investigated its influence on the aetiology of myeloma. A total of 181 myeloma cases from the Medical Research Council Myeloma VII trial and 233 controls from the Leukaemia Research Fund Case Control Study of Adult Acute Leukaemia were included in the analysis. Genotyping by induced heteroduplex generator analysis was carried out for single nucleotide polymorphisms (SNP) located at positions -1031, -863, -857, -308 and -238 of the 5' promoter region of TNF-alpha gene, and 252 in the LT-alpha gene; and five microsatellites, TNFa, b, c, d and e. Haplotypes were inferred statistically using the phase algorithm. A limited diversity of haplotypes was observed, with the majority of variation described by 12 frequent haplotypes. Detailed characterization of the haplotype did not provide greater determination of disease risk beyond that described by the TNF-alpha-308 SNP. Some evidence was provided for a decreased risk of myeloma associated with the TNF-alpha-308 variant allele A, odds ratio, 0.57; 95% confidence interval, 0.38-0.86. The results of this study did not support our starting hypothesis; that high producer haplotypes at the TNF locus are associated with an increased risk of developing myeloma.

t(12;21) (TEL/AML1) is the most common genetic event in childhood B-cell acute lymphoblastic leukemia (B-ALL) in Western countries. Samples from 42 children with ALL in Kerala were tested by reverse transcription polymerase chain reaction for TEL/AML1, t(1;19) and t(4;11). Only 2 out of 42 (4.8%) cases were positive for the TEL/AML1, and t(1;19) and t(4;11) were not detected. We conclude that the incidence of TEL/AML1 is lower in the Indian population.