Faculty Bibliography

A population-based case-control study of lymphomas in England collected height and weight details from 699 non-Hodgkin's lymphoma (NHL) cases and 914 controls. Obesity, defined as a body mass index (BMI) over 30 kg m(-2) at five years before diagnosis,, was associated with an increased risk of NHL (OR = 1.5, 95% CI 1.1-2.1). The excess was most pronounced for diffuse large B-cell lymphoma (OR = 1.9, 95% CI 1.3-2.8). Genetic variants in the leptin (LEP 19G > A, LEP -2548G > A) and leptin receptor genes (LEPR 223Q > R), previously shown to modulate NHL risk, as well as a polymorphism in the energy regulatory gene adiponectin (APM1 276G>T), were investigated. Findings varied with leptin genotype, the risks being decreased with LEP 19AA (OR = 0.7, 95% CI 0.5-1.0) and increased with LEP -2548GA (OR = 1.3, 95% CI 1.0-1.7) and -2548AA (OR = 1.4, 95% CI 1.0-1.9), particularly for follicular lymphoma. These genetic findings, which were independent of BMI, were stronger for men than women.

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.

In this article, we will discuss how treatment strategies for myeloma have evolved and outline the challenges now faced following the introduction of a number of novel active agents. In particular, we will focus on how achieving a maximum response and maintaining such responses is becoming a key therapeutic strategy and how novel agents can be used to achieve this in the context of current strategies such as autologous transplantation.

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.

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.

A simple high throughput micro-fluorescence in situ hybridisation technique (FISH) was used to detect chromosome 13 deletions (delta13), immunoglobulin heavy chain (IgH) rearrangements, t(11;14)(q13;q32), t(4;14)(p16;q32), t(14;16)(q23;q32), p53 loss, and numerical changes of chromosomes 3, 6, 7, 9, 10, 11 and 17 in 228 cases of multiple myeloma (MM), including 33 asymptomatic/smouldering MM (SMM). The patients were not part of a clinical trial and were from 30 different hospitals. In all, 98.4% of cases were abnormal, with 43% having IgH rearrangements and 42% Delta13. The low incidence of IgH rearrangements was due to a decrease in this finding with age (P = 0.001) and the relatively high proportion of elderly patients in our study population (41% >70 years old). The incidence of specific IgH translocations was t(4;14) 11%, t(11;14) 16% and t(14;16) 3%. Univariate statistical testing showed delta13 (P = 0.002), and t(14;16) (P = 0.005) to be associated with shorter survival. This effect was exaggerated for patient's aged 70 years or under but no effect on survival was seen for those over 70 years. In younger patients t(4;14) (P = 0.044) and p53 deletion (P < 0.001) were also significant poor prognostic indicators. Multivariate analysis showed delta13 and t(14;16) to be independent prognostic variables when considered with age and clinical parameters.

PURPOSE/OBJECTIVE:Early mortality in multiple myeloma (MM) is usually attributed to combined effects of active disease and comorbid factors. We have studied early deaths in a series of large multicenter trials to assess direct causes of death, their predictability, and whether current management strategies have reduced their frequency. PATIENTS AND METHODS/METHODS:A total of 3,107 newly diagnosed patients entered onto United Kingdom Medical Research Council MM trials from 1980 to 2002 were studied. Trial files, final clinical summaries, and postmortem reports were analyzed. RESULTS:Death within 60 days of trial entry occurred in 299 patients (10%). Logistic regression modeling identified beta 2-microglobulin, performance status, and age as the most important predictors of early death, but only with 61% sensitivity and 73% specificity. Forty-five percent of deaths were attributable to infection, which was often associated with bone pain (particularly thoracic pain) and delay in presenting to medical care. Neutropenia was present at diagnosis in only 11 of the 135 deaths from infection. Renal failure was present in 28% of early deaths and was linked to light-chain MM, hypercalcemia, dehydration, and nonsteroidal anti-inflammatory drugs. There was no time related reduction in the percentage or nature of early deaths in 1,550 patients older than 65 years receiving similar therapy between 1982 and 2002. CONCLUSION/CONCLUSIONS:A tenth of patients die within 60 days of diagnosis of MM. Infection and renal failure are the main direct causes of early mortality, which cannot be accurately predicted by presenting prognostic features. All patients should be considered at high risk of death during induction therapy.

We have assessed autologous stem cell transplantation after treatment with fludarabine in previously untreated patients with chronic lymphocytic leukemia (CLL). This study is the first to enroll previously untreated patients and follow them prospectively. The initial response rate to fludarabine was 82% (94 of 115 patients). Stem cell mobilization was attempted in 88 patients and was successful in 59 (67%). Overall 65 of 115 patients (56%) entered into the study proceeded to autologous transplantation. The early transplant-related mortality rate was 1.5% (1 of 65 patients). The number of patients in complete remission after transplantation increased from 37% (24 of 65) to 74% (48 of 65), and 26 of 41 patients (63%) who were not in complete remission at the time of their transplantation achieved a complete remission after transplantation. The 5-year overall and disease-free survival rates from transplantation were 77.5% (CI, 57.2%-97.8%) and 51.5% (CI, 33.2%-69.8%), respectively. None of the variables examined at study entry were found to be predictors of either overall or disease-free survival. Sixteen of 20 evaluable patients achieved a molecular remission on a polymerase chain reaction (PCR) for immunoglobulin heavy-chain gene rearrangements in the first 6 months following transplantation. Detectable molecular disease by PCR was highly predictive of disease recurrence. It is of concern that 5 of 65 (8%) patients developed posttransplant acute myeloid leukemia/myelodysplastic syndrome.

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.