Multicentre validation of a prognostic index for overall survival in chronic lymphocytic leukaemia

2010 ◽  
Vol 29 (2) ◽  
pp. 91-99 ◽  
Author(s):  
Pietro Bulian ◽  
Michela Tarnani ◽  
Davide Rossi ◽  
Francesco Forconi ◽  
Giovanni Del Poeta ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Prognostic Index

Chronic Lymphocytic Leukaemia Has a More Aggressive Phenotype in Asians Compared to Caucasians.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4965-4965
Author(s):  
Belinda Austen ◽  
Chaminda Gunawardana ◽  
Guy Pratt ◽  
Farooq Wandroo ◽  
Abe Jacobs ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Age Of Onset ◽  
Western World ◽  
Control Group ◽  
Aggressive Phenotype ◽  
Racial Origin ◽  
Asian Patients ◽  
Younger Age

Abstract Chronic lymphocytic leukaemia (CLL) is the commonest leukaemia in the western world with an incidence of 3 per 100,000. The precise aetiology remains obscure but there is clear evidence for a genetic predisposition. CLL has a seven-fold increased incidence amongst relatives of index cases compared to controls and the disease is also more common in males. These genetic subgroups can also determine phenotype as familial CLL has a younger age of onset and increased association with second malignancies compared to sporadic cases. Similarly, CLL is more aggressive and more frequently requires treatment in males in comparison to female patients. The incidence of CLL also varies according to racial origin and has been found to be up to 20-fold less common in Japanese and Asian populations compared to Caucasian populations. However, it is not known whether or not there is also phenotypic variation in CLL patients according to racial origin. We studied 29 Asian patients with a diagnosis of CLL and compared disease characteristics with a control group of 277 Caucasians. We found that CLL in Asians was diagnosed at a younger age (median age 62yr in Asians vs 70yr Caucasians, p=0.001) and was also more common in males (M:F Asians 3.1:1; Caucasians 1.3:1, p=0.023). No association was seen between racial origin and either IGVH status or CD38 status. Interestingly, we also found that the Asian population had a more aggressive clinical phenotype as indicated by a shorter time to the requirement of first treatment (TTFT) (p=0.019). This observation was independent of both age and gender. Although no difference was seen in overall survival between the two groups, ‘non-leukaemia related’ deaths were more common in the older Caucasian population. 27.5% of Caucasian deaths occurred in patients who had never required treatment for CLL whereas no deaths occurred among untreated Asian patients, for whom the primary cause of death was progressive leukaemia. The failure to observe a difference in overall survival was therefore partly accounted for by an increase in non-leukaemia related deaths in Caucasians. In conclusion, we have shown that there are phenotypic differences in CLL patients according to the racial origin. CLL in Asian patients occurs at a younger age and is associated with a more aggressive phenotype. The mechanisms underlying these observations are unknown but warrant further investigation.

Levels of Phosphorylated P70 S6 Kinase and Phosphorylated ERK1&2 Predict Overall Survival and Time to First Treatment In Chronic Lymphocytic Leukaemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1363-1363
Author(s):  
James R Bailey ◽  
Gina L Eagle ◽  
Pointon Jo ◽  
Ria Brathwaite ◽  
Abbott Jody ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Overall Survival ◽  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Median Time ◽  
Lymphocytic Leukaemia ◽  
S6 Kinase ◽  
P70 S6 Kinase ◽  
Time To First Treatment ◽  
Extracellular Regulated Kinase

Abstract Abstract 1363 Chronic lymphocytic leukaemia (CLL) is a clinically heterogeneous disease characterised by an accumulation of malignant B lymphocytes. Central to the survival of CLL-cells is the B-cell Receptor (BCR), a structurally complex moiety which contains an immunoglobulin molecule with antigenic specificity. Stimulation of the BCR by antigen binding may lead to the activation of multiple intracellular kinase cascades with a variety of intracellular functions. Kinases known to be activated include phosphorylated Extracellular Regulated Kinase (pERK) and P70 S6 Kinase (P70S6K). Increased levels of phosphorylated Extracellular Regulated Kinase (pERK) are found in CLL cells induced to proliferate and inhibition of the ERK pathway promotes chemotherapy induced apoptosis in B-cell lines. P70S6K regulates cell cycle behaviour in B cells and it has been shown that inhibition of P70S6K activation by phosphorylation with rapamycin leads to cell cycle arrest in CLL cells. We investigated the relationships between pERK isoforms 1&2 (pERK1&2) and phosphorylated-P70S6K concentrations (both baseline and after BCR-crosslinking) and overall survival (OS) as well as time to first treatment (TTFT) in a cohort of patients with CLL. Lymphocytes were isolated from patients with CLL attending Haematology Clinic at the Hull and East Yorkshire NHS Trust. Collections were made after taking informed consent according to the Declaration of Helsinki with Local Ethics Committee approval (05/Q1104/33). pERK1&2 concentrations and phospho-P70S6K were measured quantitatively using ELISA according to the manufacturer's protocol (#SUV1018 &#DYC896, RnD Systems) in 99 such cases. Kinase concentrations were assayed at baseline in unstimulated cells and also after stimulation by antibody mediated BCR-crosslinking using a goat anti-human IgM antibody (#109-006-129, Jackson ImmunoResearch). The mutational status of the variable region of the immunoglobulin gene (IgVH status) was determined in all cases. The pERK1&2 and phospho-P70S6K concentrations measured were correlated with clinical stage, IgVH, ZAP70 and CD38 status. The individual kinase concentration measurements were then ranked and those in the upper quartile were regarded as being elevated. Statistical analysis was performed to assess the relationships between elevated pERK1&2 and phospho-P70S6K concentrations and OS/TTFT in both unstimulated CLL cells as well as after BCR-crosslinking. An elevated baseline concentration of intracellular pERK1&2 was found to define a subset of IgVH mutated patients with a reduced mean overall survival (157 vs. 259 months, p=0.011) and, also, to identify patients with a shorter median time to first treatment (8 vs. 31 months, p=0.050). An elevated baseline concentration of P70S6K defined subsets of both IgVH mutated (168 vs. 254 months, p=0.046) and CD38 positive (57 vs. 234 months, p=0.000) patients with a reduced overall survival. An elevated concentration of pERK after BCR-crosslinking was shown to define a subset of ZAP70 negative patients with reduced overall survival (99 vs. 233 months, p=0.020), as well as identifying patients with a shorter median time to first treatment (8 vs. 37 months, p=0.011). Our results demonstrate that increased baseline intracellular pERK1&2 and phospho-P70S6K concentrations can be used in conjunction with established prognostic markers to identify patients with a reduced OS and, in the case of pERK1&2, TTFT. An unmutated IgVH status was associated with higher absolute pERK1&2 and phospho-P70S6K baseline concentrations. This suggests that increased intracellular signalling activity may contribute to the adverse prognosis seen in unmutated IgVH patients. The findings support the investigation of kinase inhibitors as novel agents in the management of bad risk CLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Low BACH2 Expression Predicts Adverse Outcome in Chronic Lymphocytic Leukaemia

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 23
Author(s):  
Carmela Ciardullo ◽  
Katarzyna Szoltysek ◽  
Peixun Zhou ◽  
Monika Pietrowska ◽  
Lukasz Marczak ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Protein Interaction ◽  
Lymphocytic Leukaemia ◽  
Prognostic Index ◽  
Direct Interaction ◽  
Protein Interaction Networks ◽  
Interaction Networks ◽  
Nucleic Acid Metabolism ◽  
Basic Leucine Zipper

Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with a highly variable clinical outcome. There are well-established CLL prognostic biomarkers that have transformed treatment and improved the understanding of CLL biology. Here, we have studied the clinical significance of two crucial B cell regulators, BACH2 (BTB and CNC homology 1, basic leucine zipper transcription factor 2) and BCL6 (B-cell CLL/lymphoma 6), in a cohort of 102 CLL patients and determined the protein interaction networks that they participate in using MEC-1 CLL cells. We observed that CLL patients expressing low levels of BCL6 and BACH2 RNA had significantly shorter overall survival (OS) than high BCL6- and BACH2-expressing cases. Notably, their low expression specifically decreased the OS of immunoglobulin heavy chain variable region-mutated (IGHV-M) CLL patients, as well as those with 11q and 13q deletions. Similar to the RNA data, a low BACH2 protein expression was associated with a significantly shorter OS than a high expression. There was no direct interaction observed between BACH2 and BCL6 in MEC-1 CLL cells, but they shared protein networks that included fifty different proteins. Interestingly, a prognostic index (PI) model that we generated, using integrative risk score values of BACH2 RNA expression, age, and 17p deletion status, predicted patient outcomes in our cohort. Taken together, these data have shown for the first time a possible prognostic role for BACH2 in CLL and have revealed protein interaction networks shared by BCL6 and BACH2, indicating a significant role for BACH2 and BCL6 in key cellular processes, including ubiquitination mediated B-cell receptor functions, nucleic acid metabolism, protein degradation, and homeostasis in CLL biology.

scholarly journals The Role of HOXA4 in Chronic Lymphocytic Leukaemia Progression and Response to Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3924-3924
Author(s):  
Timothy M Barrow ◽  
Laura Woodhouse ◽  
Gesa Junge ◽  
Susan J Tudhope ◽  
Charlotte Behardien ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Overall Survival ◽  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Drug Sensitivity ◽  
Lymphocytic Leukaemia ◽  
Response To Therapy ◽  
Bone Marrow Niche ◽  
Ongoing Work

Abstract Chronic lymphocytic leukaemia (CLL) is the most common form of adult leukaemia worldwide. Patients display a highly variable clinical course, with some requiring immediate therapeutic intervention while others can remain untreated for years. We have previously reported that DNA methylation of the homeobox A4 (HOXA4) promoter can serve as part of a three gene prognostic signature with CD38 and BTG4 to predict time to first treatment (TTT) in Stage A patients. HOXA4 encodes a transcription factor that is expressed in haematopoietic progenitor cells and is involved in embryonic development and B-cell differentiation, and its aberrant epigenetic regulation has been identified in multiple forms of leukaemia. In this study we have sought to elucidate the role of HOXA4in the progression of CLL and determine the functional consequences of its expression. We analysed DNA methylation of the HOXA4 promoter by pyrosequencing in a heterogeneous cohort of 163 CLL patients (median age: 70; median follow-up: 10 years), of whom 60% were Binet Stage A, 16% Stage B and 24% Stage C. Data was collected regarding treatment history, TTT and overall survival, as well as cytogenetic abnormalities and IGVH mutation status. HOXA4 methylation increased with disease progression and was significantly higher in Stage C patients (median 74%) than those with Stage A (62%; p = 0.03) and Stage B disease (65%; p < 0.05). HOXA4 methylation was positively correlated with IGVH sequence homology (r = 0.34, p < 0.0001) and negatively associated with TTT among patients who have started chemotherapy (p = 0.04) and with overall survival (p = 0.04). No associations were observed between HOXA4 methylation and 11q, 13q or 17p deletions, or TP53 and ATMmutations. To investigate the role of HOXA4 in the evolution of the disease, we analysed samples taken at multiple timepoints from 42 patients, of whom 29 were undergoing treatment and 13 remained untreated. HOXA4methylation significantly increased in patients undergoing treatment (p = 0.01), but did not differ in untreated patients (p = 0.19). We hypothesised that silencing of HOXA4 may be selected for during treatment due to its expression conferring increased sensitivity to chemotherapy. Using a lentiviral system, we observed that re-expression of HOXA4increased drug sensitivity in a malignant differentiated B-cell line (Raji). Significantly higher apoptosis was identified after treatment with 3 μM and 10 μM fludarabine (both p < 0.001) and 1 μM and 10 μM ibrutinib (p < 0.01 and p < 0.001), but not 1 μM and 10 μM idelalisib. To confirm the translational relevance our observations, we overexpressed HOXA4 in primary CLL cells derived from four patients and confirmed increased apoptosis in response to 3 μM and 10 μM fludarabine treatment in comparison to control cells (p = 0.02 and p < 0.01). Further work is underway in primary CLL cells to elucidate the pathways under the control of HOXA4 that may confer this drug sensitivity. Our ongoing work may indicate that HOXA4 is also implicated in the progression of CLL through directing malignant cells to the protective bone marrow niche, thereby further reducing sensitivity to antimetabolites. In cell lines HOXA4 up-regulates the expression of RGS2 and RGS16, which are negative regulators of the CXCR4-CXCL12 signalling axis, and we have identified selection for biallelic HOXA4methylation in primary acute lymphoblastic leukaemia cells following engraftment in mice (median in primary cells: 80%; engrafted cells: 92%; p < 0.0001). To determine the origins of HOXA4 dysregulation during the course of the disease, we analysed prospective blood samples from the European Prospective Investigation into Cancer and Nutrition (EPIC) from 20 individuals diagnosed with CLL up to 17 years after blood draw (median: 7 years) and 20 age-matched controls who remained free of cancer. We observed that HOXA4methylation was significantly higher among future CLL patients (median: 49% vs 42%; p = 0.01) and was inversely correlated with time to diagnosis, but did not reach statistical significance (r = -0.39, p = 0.09). Together, our findings suggest that silencing of the HOXA4 gene is an early event in CLL which is selected for during the course of disease through reduced sensitivity to chemotherapeutic agents. Our ongoing work will identify downstream targets that may be implicated in conferring sensitivity, and which may serve as biomarkers to predict prognosis and inform treatment strategies. Disclosures Junge: AstraZeneca: Other: Salary, Research Funding.

A Common Genetic Variant in the 3′UTR of IRF4/MUM1 Associates with Risk of Disease and Poor Prognosis in Chronic Lymphocytic Leukaemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1060-1060
Author(s):  
James M Allan ◽  
Nicola Sunter ◽  
Andrew Hall ◽  
Tryfonia Mainou-Fowler ◽  
Graham Jackson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukaemia ◽  
Poor Prognosis ◽  
Genetic Variant ◽  
Lymphocytic Leukaemia ◽  
Rank Test ◽  
Log Rank Test ◽  
Significant Difference ◽  
Risk Of Disease

Abstract High frequency low penetrance risk alleles for chronic lymphocytic leukaemia (CLL) have been identified at 6p25.3 (rs872071, IRF4/MUM1), 11q24.1 (rs735665, GRAMD1B), 15q23 (rs7176508), 2q37.1 (rs13397985, SP140), 2q13 (rs17483466, ACOXL) and 19q13.32 (rs11083846, PRKD2). Given a role in determining risk of disease it is plausible that these allelic variants also play a role in disease progression and overall survival. In order to test this hypothesis, polymorphic status was determined in a case series of 403 patients diagnosed with CLL recruited via 5 clinical centres in the United Kingdom. Mean follow-up time was 4447 days and 169 patients were deceased at the time of last follow-up. Kaplan-Meier survival analysis and the log-rank test were used to investigate the prognostic significance of constitutional genetic markers. Polymorphic variation at rs735665, rs7176508, rs13397985, rs17483466 and rs11083846 was not significantly association with time from diagnosis to first treatment (p&gt;0.05, log-rank test). However, a genetic variant in the 3′UTR of the interferon regulatory factor 4 (IRF4)/multiple myeloma oncogene 1 (MUM1) gene was significantly associated with poor prognosis. Specifically, carriers of the disease-associated variant at rs872071 had a significantly shorter mean time from diagnosis to first treatment (3983 days), compared to non-carriers (7340 days)(p=0.001), although there was no significant difference in overall survival (p=0.29). The association with time to first treatment remained significant in multivariate Cox regression analysis that included age, gender, immunoglobulin heavy chain variable region mutational status and stage of disease at diagnosis in the model (p=0.021). IRF4 is expressed in germinal centre (GC) and post-GC B-cells, and is important for B-cell maturation and homeostasis. Taken together with the aetiological evidence, these data suggest that common allelic variation in IRF4 not only affects risk of CLL, but also predicts poor prognosis.

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