We examined the prognostic influence of gender in chronic lymphocytic leukemia. Data from four randomized trials (involving 1821 patients) and three registration studies of stage-A disease (involving ...1299 patients) were analyzed. Overall survival at 10 years was better for women than men in all trials (27% versus 15%; P=0.0001) and in the registration series (55% versus 43%; P<0.0001). More women than men in the trials were Binet stage A-progressive (26% versus 15%), but gender was an independent predictor of survival in multivariate analysis of clinical variables (P<0.0001). Women responded better to treatment (overall response 83%) than men (71%; P<0.0001), within each stage and age group, although fewer women than men received the full treatment dose (79% versus 85%; P=0.01). Women were more likely than men to experience toxicity (85% versus 78%, P=0.01), particularly gastro-intestinal toxicity (57% versus 42%, P<0.0001). Laboratory markers in the LRF CLL4 trial showed a significantly lower incidence in women than men of unmutated IGHV genes, raised beta-2 microglobulin, CD38 and Zap-70 positivity and TP53 deletions/mutations and/or 11q deletions. We also highlight the higher male:female ratios in randomized trials versus studies of early chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. Chronic lymphocytic leukemia in women runs a more benign clinical course than in men. Gender was also an independent predictor of response, suggesting that pharmacokinetic differences between the sexes and a possible effect of estrogens may contribute to the better outcome. Understanding the reasons for the different outcome by gender may improve patients' management. (LRF CLL4 controlled-trials.com identifier: ISRCTN58585610).
NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in chronic lymphocytic leukemia but to date they have not been validated in a prospective, controlled clinical ...trial. We have assessed the impact of these mutations in a cohort of 494 patients treated within the randomized phase 3 United Kingdom Leukaemia Research Fund Chronic Lymphocytic Leukemia 4 (UK LRF CCL4) trial that compared chlorambucil and fludarabine with and without cyclophosphamide in previously untreated patients. We investigated the relationship of mutations in NOTCH1 (exon 34) and SF3B1 (exon 14-16) to treatment response, survival and a panel of established biologic variables. NOTCH1 and SF3B1 mutations were found in 10% and17% of patients, respectively. NOTCH1 mutations correlated with unmutated IGHV genes, trisomy 12, high CD38/ ZAP-70 expression and were associated with reduced overall (median 54.8 vs 74.6 months, P = .02) and progression-free (median 22.0 vs 26.4 months, P = .02) survival. SF3B1 mutations were significantly associated with high CD38 expression and with shorter overall survival (median 54.3 vs 79.0 months, P < .001). Furthermore, multivariate analysis, including baseline clinical variables, treatment, and adverse prognostic factors demonstrated that although TP53 alterations remained the most informative marker of dismal survival in this cohort, NOTCH1 (HR 1.58, P = .03) and SF3B1 (HR 1.52, P = .01) mutations have added independent prognostic value.
•This is the first study to validate the importance of NOTCH1 and SF3B1 gene mutations in the context of a randomized, prospective clinical trial.•Mutations in both genes are independent prognostic biomarkers, and therefore have clinical utility in the accurate risk-adapted stratification of CLL patients.
Autoimmune hemolytic anemia (AHA) is a common complication in chronic lymphocytic leukemia (CLL). The UK LRF CLL4 trial is the largest prospective trial in CLL to examine the prognostic impact of ...both a positive direct antiglobulin test (DAT) and AHA. Seven-hundred seventy-seven patients were randomized to receive chlorambucil or fludarabine, alone or with cyclophosphamide (FC). The incidence pretreatment of a positive DAT was 14%. Ten percent developed AHA. The DAT correctly predicted the development, or not, of AHA after therapy in 83% of cases, however only 28% of DAT-positive patients developed AHA. Of 299 patients tested both before and after treatment, those treated with single-agent fludarabine were most likely to remain DAT positive and to change from negative to positive. Patients treated with chlorambucil or fludarabine were more than twice as likely to develop AHA as those receiving FC. In a multivariate analysis, stage C disease and high β2 microglobulin were independent predictors of a positive DAT result. AHA, or a positive DAT, with or without AHA, independently predicted for reduced overall survival (OS). Four deaths, all on fludarabine monotherapy, were attributed to AHA. In conclusion, DAT status at the time of initiation of therapy provides a new prognostic indicator, although FC may protect against AHA. This trial was registered at http://isrctn.org as no. 58585610.
Many prognostic markers have been identified in chronic lymphocytic leukemia, but there have been few opportunities to assess their relative importance in a large randomized trial. The aim of this ...study was to determine which of the available markers independently predicted outcome in patients requiring treatment and to use these to define new risk groups.
A broad panel of clinical and laboratory markers, measured at randomization in patients entering the LRF CLL4 trial, was assessed with respect to treatment response, progression-free and overall survival, at a median follow-up of 68 months.
Using the factors identified as independent predictors for progression-free survival, patients were subdivided into three risk groups: 6% had poor risk with known TP53 loss of greater than 10%; 72% had an intermediate risk without TP53 loss (≤ 10%) and with at least one of: unmutated IGHV genes and/or IGHV3-21 usage, 11q deletion, β-2 microglobulin greater than 4 mg/L; 22% had a good risk (with none of the above and mutated IGHV genes). The 5-year progression-free survival rates for these three groups were 0%, 12% and 34%, respectively, and the corresponding 5-year overall survival rates were 9%, 53% and 79% (both P<0.00005 independent of treatment allocation). In the intermediate risk group 250 patients, with data for all three risk factors, were further subdivided into intermediate-low (one risk factor) or intermediate-high (2 or 3 risk factors). The 5-year progression-free survival rates were 18% and 7% (P=0.0001) and the 5-year overall survival rates were 68% and 40% (P<0.00005), respectively.
This study demonstrates the role of biomarkers in prognosis and shows that, in patients requiring treatment, disease stage may no longer be an independent predictor of outcome. If validated independently, the risk groups defined here may inform the design of future trials in chronic lymphocytic leukemia.
Summary
Splenic marginal zone lymphoma (SMZL) is a rare B‐cell malignancy, with no standard treatment other than splenectomy. Rituximab has shown encouraging results. We therefore retrospectively ...assessed 43 patients from two centres, who received rituximab, either alone or with chemotherapy. All patients responded, 34/43 (79%) achieving a complete response (CR), compared with 3/10 (30%) after chemotherapy without rituximab (P = 0·005). Of these 10 patients, 9 (90%) subsequently achieved a CR after rituximab (P = 0·02). Rituximab monotherapy appeared equally as effective as rituximab combination therapy (90% vs. 79% CR, P = 0·7) with significantly less toxicity (12·5% vs. 83%, P = 0·002). Splenectomized patients were more likely to obtain a CR with rituximab (16/16, 100%) than unsplenectomized patients (18/27, 67%, P = 0·008). Disease‐free survival (DFS) at 3 years was better after rituximab than after splenectomy alone 79% (95% confidence interval 60–89) vs. 29% (8–54), Hazard ratio (HR) 0·28 (0·12–0·68), P = 0·003 and better than after chemotherapy without rituximab 25% (4–55), HR 0·21 (0·08–0·51), P = 0·0004. Survival at 3 years after rituximab was 98%. In summary, the CR and DFS rates after rituximab, given alone or with chemotherapy, were significantly better than after chemotherapy without rituximab in the same patients, with manageable toxicity. Rituximab, with or without splenectomy, should be considered for the treatment of SMZL.
This book offers multidisciplinary perspectives on the changing relationships between states, indigenous peoples and industries in the Arctic and beyond. It offers insights from Nordic countries, ...Canada, Australia, New Zealand and Russia to present different systems of resource governance and practices of managing industry-indigenous peoples’ relations in the mining industry, renewable resource development and aquaculture. Chapters cover growing international interest on Arctic natural resources, globalization of extractive industries and increasing land use conflicts. It considers issues such as equity, use of knowledge, development of company practices, conflict-solving measures and the role of indigenous institutions. Focus on Indigenous peoples and Governance triangle Multidisciplinary: political science, legal studies, sociology, administrative studies, Indigenous studies Global approach: Nordic countries, Canada, Russia, Australia, New Zealand and Canada Thorough case studies, rich material and analysis The book will be of great interest to legal scholars, political scientists, experts in administrative sciences, authorities at different levels (local, regional and nations), experts in human rights and natural resources governance, experts in corporate social governance.
Summary
This is an historical account of the randomised trials in chronic lymphocytic leukaemia in the UK between the years 1978 to 2004, describing their gestation, the treatments used and the main ...lessons learnt. Those lessons include: (1) how best to use chlorambucil, which was the first effective treatment for CLL; (2) the significant difference in survival between the sexes; and (3) the value of prognostic markers, both morphological and molecular, which continue to be relevant to current practice.
We performed fluorescent in situ hybridization (FISH) for 16q23 abnormalities in 861 patients with newly diagnosed multiple myeloma and identified deletion of 16q del(16q) in 19.5%. In 467 cases in ...which demographic and survival data were available, del(16q) was associated with a worse overall survival (OS). It was an independent prognostic marker and conferred additional adverse survival impact in cases with the known poor-risk cytogenetic factors t(4;14) and del(17p). Gene expression profiling and gene mapping using 500K single-nucleotide polymorphism (SNP) mapping arrays revealed loss of heterozygosity (LOH) involving 3 regions: the whole of 16q, a region centered on 16q12 (the location of CYLD), and a region centered on 16q23 (the location of the WW domain-containing oxidoreductase gene WWOX). CYLD is a negative regulator of the NF-κB pathway, and cases with low expression of CYLD were used to define a “low-CYLD signature.” Cases with 16q LOH or t(14;16) had significantly reduced WWOX expression. WWOX, the site of the translocation breakpoint in t(14;16) cases, is a known tumor suppressor gene involved in apoptosis, and we were able to generate a “low-WWOX signature” defined by WWOX expression. These 2 genes and their corresponding pathways provide an important insight into the potential mechanisms by which 16q LOH confers poor prognosis.
CLLU1, located at chromosome 12q22, encodes a transcript specific to chronic lymphocytic leukemia and has potential prognostic value. We assessed the value of CLLU1 expression in the LRF CLL4 ...randomized trial. Samples from 515 patients with chronic lymphocytic leukemia were collected immediately before the start of treatment. After RNA extraction and cDNA synthesis, CLLU1 expression was assessed by quantitative polymerase chain reaction. In total, 247 and 268 samples were identified as having low and high CLLU1 expression, respectively. The median follow-up was 88 months. High CLLU1 expression was significantly correlated with unmutated IGHV genes, ZAP-70 and CD38 positivity, and absence of 13q deletion (all r>0.2, P<0.0001). At 6 years, patients with high CLLU1 expression had significantly worse progression-free survival (9% versus 17%; P=0.03) and overall survival (42% versus 57%; P=0.0003) than patients with low CLLU1 expression. Among patients with mutated IGHV genes, overall survival at 6 years was 50% in those with high CLLU1 expression and 76% in those with low CLLU1 expression (P=0.005). However, CLLU1 expression was not an independent predictor of overall survival in a multivariate model including TP53 aberrations, beta-2 microglobulin level, age and IGHV mutation status. Nor did it predict response to treatment. CLLU1 expression analysis helps to refine the prognosis of patients with chronic lymphocytic leukemia who have mutated IGHV genes.
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.
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.
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.
Our results suggest that deletions of CDKN2C are important in the progression and clinical outcome of myeloma.
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