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.

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

Consolidation with Alemtuzumab in First Remission Induces Pronounced MRD Reduction and Clinical Remissions - Update on a Randomized Phase III Trial of the German CLL Study Group (GCLLSG).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2506-2506 ◽  
Author(s):  
Matthias Ritgen ◽  
C. Schweighofer ◽  
Günther Fingerle-Rowson ◽  
Barbara Eichhorst ◽  
Raimunde Busch ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Late Stage ◽  
Clinical Remission ◽  
Lymphocytic Leukaemia ◽  
Phase Iii ◽  
Remission Induction ◽  
Control Group ◽  
Consolidation Therapy ◽  
Phase Iii Trial

Abstract The monoclonal antibody alemtuzumab is known to be effective in combination or alone in patients with late stage chronic lymphocytic leukaemia. Flow cytometric studies on minimal residual disease (MRD) showed the high potency beyond clinical response criteria even in late stage chronic lymphocytic leukaemia (CLL). The aim of the phase III trial of the GCLLSG was to investigate the role of alemtuzumab as consolidation therapy in CLL patients in first clinical remission after fludarabin (F) or F plus cyclophosphamide (FC). Patients in partial or complete clinical remission were randomized to either arm A (alemtuzumab 3 x 30 mg i.v. for up to 12 wks) or no further treatment (arm B). From 21 eligible patients 11 (1CR, 1 nPR, 9PR) were randomized to arm A. All patients received standard infection prophylaxis with famciclovir and trimethoprim/sulfamethoxazole. Before, at 6 and 12 weeks after start of consolidation therapy and regulary during follow up blood and bone marrow samples were send for molecular MRD assessment by allele specific real time PCR. The PCR allowed MRD assessment with a sensitivity of at least 10E-4 in 11 eligible cases. Results: MRD analysis showed clear reduction of CLL content by first line treatment to a median MRD level of 2.2E-3. Short after alemtuzumab treatment all treated patients showed pronounced MRD reduction to a median MRD level of 5.0E-5. During molecular follow-up median MRD level remained below 1E-4 for one year with a tendency to increase afterwards. After a median follow-up of 31.3 months from start of initial treatment occurred one relapse in the treatment arm compared to 7 of 10 in arm B. The median progression free survival (PFS) calculated from start of consolidation therapy was significantly shorter in the control group versus the treatment group (pfs 25.2; p= 0.04). Nevertheless due to severe acute infections (CTC III and IV) this study had to be stopped prematurely. Conlusion: The addition of alemtuzumab as a consolidation regimen after remission induction by F or FC is highly effective and leads to sustained MRD reduction below 10E-4. This translates into significant improved clinical outcome even in this small patient cohort compared to the control group. Encouraged by the molecular responses the GCLLSG initiated a new phase I/II trial as a dose finding study in CLL patients after F based induction of clinical remission.

Vanilloid Receptor (TRPV1) Expression on the Neoplastic B-Cell Lymphocytes in Patients with Chronic Lymphocytic Leukaemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4955-4955
Author(s):  
Jaroslaw Piszcz ◽  
Slawomir Ziarko ◽  
Janusz Kloczko ◽  
Piotr Radziwon ◽  
Eliza Blusiewicz ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Peripheral Blood ◽  
Concentration Ratio ◽  
Lymphocytic Leukaemia ◽  
Vanilloid Receptor ◽  
Control Group ◽  
Study Group ◽  
Newly Diagnosed ◽  
Vanilloid Receptors

Abstract Background: Endocannabinoids take part in physiology of neural and immune system. Last data showed that these compounds and their receptors play an important role in proliferation and apoptosis of different neoplastic cells. Cannabinoids were shown to increase the apoptosis in human neoplastic cells through a number of mechanisms including vanilloid receptors (Sanchez et al. 1998, Maccarone et al. 2000). The vanilloid receptor family of cation channels includes the capsaicin-sensitive, proton- and heat-activated vanilloid receptor type I (TRPV1). Furthermore Saunders et al. (2006) showed that TRPV1 are expressed on normal lymphocytes in human peripheral blood. Aims: The aim of our study was the assessment of receptor TRPV1 mRNA expression in the lymphocytes B derived from patients with newly diagnosed chronic lymphocytic leukaemia. Material and methods: The study group contains newly diagnosed, untreated adult patients with B-cell chronic lymphocytic leukaemia; 11 males and 10 females, aged from 46 to 74. The patients were in A-C stage according to Binet. We used 13 samples from healthy donors as a control group. The isolation of mononuclear cells from peripheral blood was carried out with the use of density centrifugation method. The resolution of mononuclear cell population to lymphocytes B subpopulation was done with negative isolation method utilizing magnetic microballs (Dynal). Total RNA was isolated from B-lymphatic cells of which 10ng was used in each reaction. Quantitative RT-PCR was carried out with the use of Light Cycler (Roche) and respective commercial kits. The nucleotides sequence of the studied receptor and parameters of the amplification process were based on method previously described by Qiao et al (2003). We used house keeping gene hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase) (G6PDH) as a reference gene. Amplification product was sequenced by ABI PRISM (Applied Biosystem). All results are presented as a mean concentration ratio of TRPV1 to G6PDH mRNA ± standard error. Statistical analysis was performed using Shapiro-Wilk, non parametric U Mann-Whitney Tests. Results: We found that concentration ratio of studied transcript was significantly lower in the study group in comparison to the control group (0,048± 0,012 vs. 106,836± 40,215 respectively. We found no differences between the subgroups irrespectively of gender, age, stage of the disease and some prognostic factors (LDH, lymphocyte doubling time, β2-microglobulin). Conclusions: The results confirm the existence of vanilloid receptors on the lymphocytes B of healthy individuals and for the first time show presence of this type of receptors in CLL group. The lower level of TRPV1 transcripts in the group of patient may suggests their potential role in the process of leukemic transformation. Thus the effect of endocannabinoids through this receptor may be altered in CLL. However, further studies are required to elucidate the nature of relationship between this type of receptor and neoplastic development of CLL.

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 Chronic lymphocytic leukaemia trends and features at a tertiary hospital in South Africa (2011–2016)

2021 ◽  
Vol 5 ◽  
Author(s):  
Fungai Musaigwa ◽  
Ravnit Grewal ◽  
Akin Abayomi ◽  
Carmen C. Swanepoel
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Developed Countries ◽  
Tertiary Hospital ◽  
Men And Women ◽  
Laboratory Service ◽  
Younger Age ◽  
Trisomy 12 ◽  
Chromosome 13Q14 ◽  
Age Range

Background: Chronic lymphocytic leukaemia (CLL) is a common lymphoproliferative disorder in developed countries. However, this condition is rare in Africa and there is a paucity of information on CLL, specifically on the continent.Aim: This study described, retrospectively, the frequency, demographics and laboratory features of CLL cases diagnosed from 2011 to 2016.Setting: Department of Pathology, National Health Laboratory Service, Tygerberg Academic Hospital, Cape Town.Methods: A retrospective analysis was performed for all CLL diagnoses made between 01 January 2011 and 31 December 2016.Results: Eighty CLL cases were diagnosed between 2011 and 2016. Men and women presented with the disease equally (48.8% vs. 51.2%, p 0.05). The mean age at diagnosis was 66.79 years (range of 37–95 years) and the modal age range (36.3%) was 60–69 years. Men presented with the disease at a significantly younger age than women (mean = 64 years vs. mean = 69.5 years, p 0.05). There were three (3.75%) human immunodeficiency virus (HIV)-positive patients (age range 43–50 years). Chromosome 13q14 deletion was found in 6 out of 19 patients (31.6%). Trisomy 12 and deletion 11q22 were found in 5 out of 21 (24%) and 7 out of 21 (33.3%) patients, respectively. Deletions 13q34 and 17p were negative for 6 and 20 patients, respectively.Conclusion: Chronic lymphocytic leukaemia at our facility presented equally in men and women. Men presented with the disease at a younger age than women. Additionally, our findings suggested that HIV is uncommon amongst CLL patients tested for HIV.

Non–Acquired Immunodeficiency Syndrome-Defining Malignancies in Patients Infected With Human Immunodeficiency Virus

2003 ◽  
Vol 127 (5) ◽  
pp. 589-592
Author(s):  
Byron P. Demopoulos ◽  
Eleftherios Vamvakas ◽  
Jacqueline E. Ehrlich ◽  
Rita Demopoulos
Keyword(s):  
Human Immunodeficiency Virus ◽  
Acquired Immunodeficiency Syndrome ◽  
Age Of Onset ◽  
Age At Diagnosis ◽  
Hiv Positive ◽  
Control Group ◽  
Younger Age ◽  
Immunodeficiency Virus ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome

Abstract Context.—Non–acquired immunodeficiency syndrome (AIDS)-defining malignancies that occur in patients infected with human immunodeficiency virus (HIV) and the demographics and pathologic features associated with these malignancies have not been completely defined. Objective.—This study describes the age of onset of malignant disease in patients seropositive for HIV and in control patients presumed to be negative for HIV, but with the same primary site. We compare the demographics and histopathology for both groups. Design.—From 1993 to 1997, 57 cases involving HIV-positive patients with malignancies from 16 primary sites were recorded in the Cancer Registry files at Bellevue Hospital; 519 cases involving patients negative for HIV were recorded during this same period. We compared the age at diagnosis, sex, race, tumor histology, stage, and grade between these 2 groups. Results.—The average age of HIV-positive patients was 47.6 years, compared with 60.3 years in the control group (P < .001). When the 16 cancer sites were compared individually, HIV-positive patients were significantly younger at onset of lung (HIV-positive patients/control group) (19/245), skin (11/77), penile (3/5), laryngeal (3/18), tongue (5/16), and colorectal (2/38) carcinomas. Patients infected with HIV had a more frequent history of smoking (41/328; P = .04) and illicit drug use (30/49; P < .001). The HIV-positive patients also were found to have a lower clinical stage of disease, compared with controls, largely due to the higher prevalence of stage 0 tumors (13/46; P = .01). Conclusions.—The finding of younger age at diagnosis in HIV-positive compared to presumed HIV-negative patients may be related in part to earlier detection, as well as preexisting immunosuppression. The specific sites for which a significant difference in age between the HIV-positive and control cases was observed may be related to the mechanisms of immunosurveillance in parts of the body that have ready access to the outside environment. Knowledge of younger age of onset for these malignancies should prompt closer physical examination of these sites by clinicians.

Quantitative RT-PCR Assessment of Cannabinoid Receptor CB2 and Fatty Acid Amine Hydrolase in Neoplastic Cells of Patients with B-Cell Chronic Lymphocytic Leukaemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4995-4995
Author(s):  
Jaroslaw A. Piszcz ◽  
Janusz S. Kloczko ◽  
Slawomir Ziarko ◽  
Piotr Radziwon ◽  
Katarzyna Z. Mazgajska-Barczyk
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Control Group ◽  
Study Group ◽  
Cb2 Receptor ◽  
Rt Pcr ◽  
Fatty Acid Amine

Abstract Background: Chronic lymphocytic leukaemia (CLL) is one of the diseases in which processes of proliferation and apoptosis are seriously altered. Endocannabinoid system can modulate these processes. Cannabinoid receptor CB2 mainly expressed on lymphocytes and fatty acid amine hydrolase (FAAH) constitute a part of endocannabinoid system responsible respectively for interaction and degradation of cannabinoids. Both the receptor and enzyme are membrane proteins that can influence the lymphocyte fate. It has recently been suggested that this system may be a new potential target of anticancer therapy. Aims: The aim of our study was the assessment of receptor CB2 and FAAH mRNA expression in the lymphocytes B derived from patients with newly diagnosed chronic lymphocytic leukaemia. Material and methods: We assessed 15 peripheral blood samples from the CLL patients and 5 samples from healthy donors as a control group. The expression of CB2 receptor and FAAH proteins were measured indirectly by determination of their specific mRNA. The isolation of mononuclear cells from peripheral blood was carried out with the use of density centrifugation method. The resolution of mononuclear cell population to lymphocytes B subpopulation was done with negative isolation method utilising magnetic microballs. Total RNA was isolated from B-lymphatic cells of which 10ng was used in each reaction. RT-PCR was carried out with the use of Light Cycler (Roche) and respective commercial kits. The nucleotides sequence and parameters of the amplification process were based on method previously described by Matias et al (2002). Results: We found significantly higher mRNA levels of CB2 receptor in the study group in comparison to the control group. The levels of FAAH mRNA were also higher in the study group in comparison to the controls. Furthermore the number of mRNA copies was higher in case of CB2 receptor than FAAH in the CLL patients. Those numbers were comparable in the healthy controls. The results are presented as a mean number of copies in figure below. Conclusions: The results of our study show that during the leukaemic transformation there might be an alteration in the expression of some constituents of the endocannabinoid system. Those findings suggest the potential role of the endocannabinoid system in the neoplastic processes. Thus the assessment of the CB2 and FAAH mRNA might help to understand the biological reactions underlying the complex etiology of neoplastic disorders. Furthermore the explanation of all aspects of the role of endocannabinoid system in lymphoid malignancies should help to make it a new target of antileukaemic treatment. figure1 figure1.

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