Incidence Of Chronic Lymphocytic Leukemia Research Articles

Thyroid nodule: first manifestation of chronic lymphocytic leukaemia

The presence of chronic lymphocytic leukaemia (CLL) cells in the thyroid gland is most likely due to a secondary involvement by a systemic disease. The reported incidence of CLL involving the thyroid is extremely low, representing about 3-4% of all thyroid lymphoproliferative neoplasm. We report a rare case of CLL presenting initially in the thyroid gland. Systemic disease was detected as a result of thyroid investigation. An 85 years old woman, with multinodular goiter without adenophaties, was referred to our department, carrying a fine needle aspiration biopsy (FNAB) report of a private institution referring "lymphoid monomorphic proliferation" and suggesting a "Core-needle biopsy" for further investigation. She was euthyroid (TSH-0.5 uU/mL (0.4-4.0), thyroid antibodies negative, including TRab). The patient denied systemic symptoms and at physical examination there were no adenophaties or organomegalies. FNAB analysis was repeated. Although the patient denied constitutional symptoms and there were no relevant findings in physical examination, technetium 99m thyroid gamagraphy (GG) and blood count were additionally asked. FNAB analysis concluded lymphocytic tiroiditis, but thyroid GG revelled global hypocaptation and blood count showed 173.4 x 109 leukocyte/L with 94% lymphocyte. An ecoguided FNAB with flow cytometry identified thyroid infiltration by monotonous population of blasts with phenotype consistent with CLL/malignancy of mature B-cells. CLL/malignancy of mature B-cells was also detected in peripheral blood analysis, suggesting systemic disease with secondary thyroid involvement. The patient started chemotherapy with rituximab and chlorambucil with good response. Pos-treatment GG revelled "Increased levels of uptake in the middle third of the right lower lobe, with low uptake of the remaining parenchyma". In conclusion, good communication with the pathologist can improve diagnostic accuracy and dictate appropriate therapy. The use of techniques such as flow cytometry, immunoglobulin gene rearrangements, and immunohistochemistry has improved diagnostic accuracy and obviated more invasive procedures, such as core needle or open surgery biopsy. Apart from chemotherapy, immunochemotherapy with anti-CD20 and anti-CD52 monoclonal antibodies can be used in the treatment of CLL.

Incidence of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis in Calgary, Alberta, Canada

This study provides an update on the incidence of chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) in a major Canadian city using the 2008 World Health Organization (WHO) diagnostic criteria. Incidence calculations were performed using data from a centralized flow cytometry laboratory servicing southern Alberta, Canada. The age-standardized incidence of 4.01 cases of CLL per 100,000 person-years is nearly half the rate previously reported in Canada. Compared to previous criteria based on absolute lymphocyte count rather than absolute B-cell count, utilizing the 2008 WHO criteria resulted in a 47.6% decline in CLL incidence (8.42 cases per 100,000 using 1996 criteria). As a consequence, MBL rates are 64% higher. In contrast to 1996 criteria showing a peak CLL incidence between ages 70-74, age-specific incidence rates show a continuous increase with advancing age using the 2008 guidelines. We also report a higher male to female ratio of CLL than previous Canadian reports (1.80:1). CLL incidence in southern Alberta is lower than rates recently reported in the United States using the same criteria. This difference may be due in part to the low median age and the lower proportion of persons of Caucasian European ancestry present in our study population.

Chronic lymphocytic leukemia and occupational risk

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults. The incidence of CLL is about 3-4/100 000 inhabitants in European countries (25% of all leukemia). About 163 new patients with CLL are diagnosed in Bulgaria every year. The exact causes of the disease are unknown, such as family history is extremely rare. The aim of this work was to investigate occupational risk in patients with CLL. Material and Methods: Available literature for a period of five years was analyzed. The influence of risk factors in the work environment and the incidence of CLL were examined. For the same period was made characteristic of patients with CLL according to demographics and occupation which were registered in the Department of Hematology at the University Hospital - Stara Zagora. Results: Epidemiological studies were focused on the chemical and physical factors of the working environment. It was found an increased risk for CLL in exposed to benzene, chlorinated aromatic hydrocarbons, mineral oils, pesticides. Of all physical factors of the working environment, ionizing radiation and electro-magnetic fields were mostly studied. Data from our study showed that only 22 (42.3%) of registered patients with CLL (52) have noted occupation in their medical records. Work with pesticides were noted 40.9% of patients with CLL, while 18.2% - of exposure to toxic substances. Conclusion: The lack of data on occupational risk assessment for CLL in the country, showed the need for similar studies at regional and national level. The introduction of the electronic health record containing information about the occupation of patients and related conditions of employment is essential for occupational risk assessment and diseases.

The mystery of chronic lymphocytic leukemia (CLL): Why is it absent in Asians and what does this tell us about etiology, pathogenesis and biology?

Chronic lymphocytic leukemia/small lymphocytic lymphoma is common in persons of predominately European descent but rare in Asians. Why is unknown but is likely genetically-determined. Environmental factors may also operate but are likely to be less important. When CLL occurs in Asians it has different features than CLL in persons of predominately European descent. The reason(s) for this is also not understood. We reviewed data on CLL in Asians (mostly Han Chinese but also other ethnic groups) and compared these data with those from persons of predominately European descent with CLL. CLL incidence was about 5–10-fold less in Asians. Asians with CLL are younger, have atypical morphologic and immunologic features, an increased proportion of IGHV mutations and rearrangements and briefer freedom-from-progression than persons of predominately European descent with CLL. These observations provide clues to the etiology and biology of CLL. But the mystery continues; more research is needed.

Short Response Duration to Initial Treatment of Autoimmune Cytopenias in Chronic Lymphocytic Leukemia

Introduction: The incidence of chronic lymphocytic leukemia (CLL) is believed to be low in India. Furthermore, there is no information on the incidence and outcome of autoimmune cytopenias. The incidence of autoimmune cytopenias is 5-10% at any point of the course of CLL. This diagnosis can have an important impact on therapeutic decisions. The prognostic significance of these autoimmune cytopenias in CLL continues to be a topic of debate.Methods: This was a retrospective study done at a tertiary level referral center in North India. Patient records of all CLL patients visiting the hematology clinic for the period 1994-2014 (20 years) were analyzed. Diagnosis of autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (ITP) and pure red cell aplasia (PRCA) was made according to standard criteria. The initial treatment options were categorized as prednisone, chlorambucil and observation. Responses were categorized as overall response rate (ORR) including CR+PR+SD and progressive disease (PD). Time to progression (TTP) was also calculated for each of the treatments and autoimmune cytopenias.Result: Out of a total of 412 CLL patients registered and following up at our clinic, a total of 62 patients (15.0%) developed autoimmune cytopenias. AIHA was seen in 21 patients (5.09%), ITP in 19 patients (4.6%) and PRCA in 22 (5.3%) patients. Autoimmune cytopenia at diagnosis was present in 44 and at follow-up in 18 patients. The median age of the patients was 63 years (SD±10.4). The median hemoglobin of patients with AIHA and PRCA was 70g/l (SD±28) and 60g/L (SD±16) respectively and median platelet count of patients with ITP was 81x109/L (SD±78.3). The best response to steroids was seen in patients with AIHA (ORR=71.4%) and ITP (ORR=80%), while only 40% PRCA patients show response to steroids. The response to chlorambucil was best for ITP (71.4%) followed by PRCA (33.3%) and AIHA (28.5%). The median time to progression of ITP, AIHA and PRCA patients on the above treatment options was 12, 6 and 0 months respectively (p<0.05).Table 1Number of patients as per the autoimmune cytopenia and treatment givenAIHAITPPRCATreatmentTotalORRPDTotalORRPDTotalORRPDPrednisone1410410821046Chlorambucil7257521248None000200000Conclusions: Recent studies have shown contrasting results of autoimmune cytopenias in CLL with most studies showing no impact on overall survival and a few studies showing negative impact. While most studies have concentrated on the survival impact, there is paucity of data on the initial treatment options for these cytopenias and their follow-up. Our study shows that steroids which are the first line in autoimmune conditions are effective only in 70-80% of AIHA and ITP patients, while oral chemotherapy with chlorambucil is effective only in 70% ITP patients and a third of AIHA and PRCA patients. Most other patients have progressive disease. Even those who show initial responses to treatment ultimately progress with time to progression shortest for PRCA patients followed by AIHA and ITP. In conclusion initial treatment of autoimmune cytopenias may atmost delay starting standard therapy for CLL by a few months. DisclosuresNo relevant conflicts of interest to declare.

Treatment Outcome and Prognostic Factors of Korean Patients with Chronic Lymphocytic Leukemia: Multicenter Retrospective Study

Backgrounds: The incidence of chronic lymphocytic leukemia (CLL) in Asian population is very low, while CLL is the most common type of leukemia in Western countries. Asian CLL has been reported to have different immunophenotypes and clinical outcomes compared to those of western CLL. But, data on CLL in Asian countries is very limited because of the disease rarity. Thus, we evaluated the clinical characteristics and treatment outcome of Korean CLL patients and also analyzed prognostic significance of clinical parameters.Methods: We retrospectively analyzed 73 newly diagnosed CLL patients who had received chemotherapy at the 5 centers in Korea between 2000 and 2012. The CLL diagnosis and response evaluation were based on the International Workshop on CLL criteria updated in 2008. Small lymphocytic lymphoma was excluded in this study.Results: The median age of all patients was 60 years (range, 25-93 years). Compared to Western data, the positivity of atypical immunophenotypic markers such as CD 22 and FMC7 were frequently observed (45.5% and 69.2% of evaluable patients, respectively). As the first line chemotherapy, the various regimens were used as followings: chlorambucil (n=45), fludarabine (n=13), fludarabine, cyclophosphamide, and rituximab (FCR) (n=4), cyclophosphamide, vincristine, and prednisolone (CVP) (n=4), fludarabine and cyclophosphamide (FC) (n=3), and the other regimens (n=4). Patients were at Binet A (49.3%), B (11.6%) with active disease or stage C (39.1%) at the time of chemotherapy. The overall response rate after the first line chemotherapy was 69.9% with the complete remission (CR) rate of 15.1%. The FCR regimen achieved the highest CR rate (50%). Fifty patients were treated with the second line chemotherapy. Two patients received allogeneic hematopoietic stem cell transplantation at the refractory state and they are still alive without relapse. Of all included patients, the probability of overall survival (OS) and progression free survival (PFS) at 5-years was 84.9% and 28.7%, respectively. The 5-year relapse free survival (RFS) rate of the 17 patients attaining CR was 42.4%. Univariate and multivariate analyses showed that the higher WBC count (>100x103/¥ìL), the lower platelet count (<80x103/¥ìL), and the constitutional symptoms had a significantly adverse impact on OS (hazard ratio [HR], 6.584, p=0.002; HR, 15.692, p<0.001; HR, 4.769, p=0.010, respectively) (Table 1). The platelet count between 80x103/¥ìL and 110x103/¥ìL, however, had no prognostic significance. Compared to the kappa type of immunoglobulin light chain, the presence of lambda type on leukemic cells was a significant negative prognostic factor for PFS (HR, 2.775, p=0.037), although there was no significant difference on OS. The CR achievement after the second line chemotherapy or more was significantly related to shorter RFS (HR, 7.343, p=0.021) compared to that of the CR achievement after the first line chemotherapy.Conclusion: Thrombocytopenia (<80x103/¥ìL) is the most significant prognostic factor predicting worse survival in Korean CLL patients. In addition, hyperleukocytosis (>100x103/¥ìL), constitutional symptoms, and the lambda type of light chain restriction need to be reflected into the risk stratification system for CLL.Keywords: chronic lymphocytic leukemia, outcome, prognostic factorAbstract 5669. Table 1multivariate analysisOSPFSRFSHR (95% CI)p-valueHR (95% CI)p-valueHR (95% CI)p-valueWBC count (n=68), >100 x103/¥ìL, <100 x103/¥ìL6.584 (1.950-22.231) 10.002----Platelet count (n=68), <80 x103/¥ìL 80 - <110 x103/¥ìL > 110 x103/¥ìL15.692 (3.974-61.963) 1.561 (0.383-6.364) 1<0.0010.535----Constitutional symptoms (+) (n=71)4.769 (1.452-15.660)0.010----Surface immunoglobulin (n=41)kappa (+)--1-lambda (+)2.775 (1.063-7.246)0.037both negative2.781 (0.882-8.767)0.081Chemotherapy response (n=72)--CR11CR2 / CR37.343 (1.357-39.736)0.021CR after Allo-HCT00.993WBC, white blood cell; CR1, complete remission after 1st line chemotherapy; CR2, complete remission after 2nd line chemotherapy; CR3, complete remission after 3rd line chemotherapy; Allo-HCT, allogeneic hematopoietic stem cell transplantation DisclosuresNo relevant conflicts of interest to declare.

Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia

AbstractAlterations of cellular metabolism represent a hallmark of cancer. Numerous metabolic changes are required for malignant transformation, and they render malignant cells more prone to disturbances in the metabolic framework. Despite the high incidence of chronic lymphocytic leukemia (CLL), metabolism of CLL cells remains a relatively unexplored area. The examined untreated CLL patients displayed a metabolic condition known as oxidative stress, which was linked to alterations in their lymphoid compartment. Our studies identified mitochondrial metabolism as the key source for abundant reactive oxygen species (ROS). Unlike in other malignant cells, we found increased oxidative phosphorylation in CLL cells but not increased aerobic glycolysis. Furthermore, CLL cells adapted to intrinsic oxidative stress by upregulating the stress-responsive heme-oxygenase-1 (HO-1). Our data implicate that HO-1 was, beyond its function as an antioxidant, involved in promoting mitochondrial biogenesis. Thus ROS, adaptation to ROS, and mitochondrial biogenesis appear to form a self-amplifying feedback loop in CLL cells. Taking advantage of the altered metabolic profile, we were able to selectively target CLL cells by PK11195. This benzodiazepine derivate blocks the mitochondrial F1F0-ATPase, leads to a surplus production of mitochondrial superoxide, and thereby induces cell death in CLL cells. Taken together, our findings depict how bioenergetics and redox characteristics could be therapeutically exploited in CLL.

Incidence of chronic lymphocytic leukemia and high‐count monoclonal B‐cell lymphocytosis using the 2008 guidelines

The 1996 National Cancer Institute Working Group (NCI-WG 96) guidelines classified disease in individuals who had a B-cell clone with chronic lymphocytic leukemia (CLL) immunophenotype as CLL if their absolute lymphocyte count was ≥5 × 10(9)/L. The 2008 International Workshop on CLL guidelines (IWCLL 2008) classified disease as CLL if the absolute B-cell count was ≥5 × 10(9)/L or as monoclonal B-cell lymphocytosis (MBL) if the absolute B-cell count was <5 × 10(9)/L. The objective of the current study of Olmsted County, Minnesota, was to assess the effects of these changes on incidence rates and presentation from 2000 to 2010. Using diagnostic indices available through the Rochester Epidemiology Project and the Mayo CLL database, the authors identified all patients with newly diagnosed CLL and high-count MBL from 2000 to 2010. Age-specific and sex-specific incidence rates were determined. According to NCI-WG 96 criteria, there were 115 patients with CLL and 8 patients with MBL during the period studied. Using the IWCLL 2008 classification, there were 79 patients with CLL and 40 patients with MBL. Rai stage distribution (low risk, intermediate risk, and high risk) using NCI-WG 96 criteria was 60.9%, 33.9%, and 5.2%, respectively, compared with 43%, 49.4%, and 7.6%, respectively, using IWCLL 2008 criteria. The age-adjusted and sex-adjusted incidence rates (per 100,000) for CLL and MBL were 10.0 and 0.66, respectively, using NCI-WG 96 criteria versus 6.8 and 3.5, respectively, using IWCLL 2008 criteria. The median time to treatment according to NCI-WG 96 criteria was 9.2 years versus 6.5 years with IWCLL 2008 criteria. Use of the IWCLL 2008 guidelines reduced the incidence of CLL, altered the distribution of initial Rai stage at diagnosis, and shortened the median time to treatment.

Lymphoid neoplasm incidence by WHO subtype in Australia 1982–2006

There are limited data characterizing the subtype-specific incidence of lymphoid neoplasms in the World Health Organization (WHO) Classification era. Data were obtained on all incident lymphoid neoplasms registered in Australia during 1982-2006. Subtypes were grouped using the InterLymph nested hierarchical classification, based on the 2008 WHO Classification. Temporal trends were examined using Joinpoint regression; average annual percentage change in incidence was computed. Multiple Poisson regression was used to compare incidence by sex and age. The incidence of all non-Hodgkin lymphoma (NHL) increased by 2.5%/year during 1982-1996 and was stable thereafter. During 1997-2006, several mature B- and natural killer (NK)-/T-cell NHL subtypes increased in incidence, including diffuse large B-cell (1.3%/year), follicular (2.5%/year), Burkitt (6.8%/year), marginal zone (13.2%/year), mantle cell (4.2%/year), peripheral T-cell lymphoma (4.7%/year) and plasmacytoma (7.1%/year). While chronic lymphocytic leukemia incidence was stable, small lymphocytic lymphoma incidence declined (8.1%/year). Hodgkin lymphoma (HL) incidence increased during 1997-2006 (2.2%/year), both classical (4.3%/year) and nodular lymphocyte predominant (12.1%/year) HL. Diagnostic artifact, evidenced by a sustained decline in the incidence of NHL not otherwise specified (NOS; 5.8%/year) and lymphoid neoplasms NOS (5.6%/year), limits the interpretation of temporal trends for some subtypes. A marked male predominance was observed for almost all subtypes. Incidence of mature B- and NK-/T-cell NHL subtypes increased sharply with age, except for Burkitt lymphoma/leukemia. For HL subtypes, a bimodal age distribution was only evident for nodular sclerosis HL. Variation in incidence patterns over time and by sex and age supports etiological differences between lymphoid neoplasm subtypes.

Application of lenalidomide in chronic lymphocytic leukemia

In recent years, the incidence of chronic lymphocytic leukemia (CLL) is increasing. Microenvironment and immune system play a key role in the pathogenesis of CLL. The immune system is aggravated by the use of chemotherapeutic agents, such as fludarabine and cyclophosphamide with rituximab(FCR) which are the current standards in frontline therapy. This leads to an increase of infection incidence in patients, resulting in a poor prognosis. The present situation was changed by lenalidomide. Recent studies indicated that lenalidomide monotherapy in treatment of refractory or relapsed CLL patients, the overall response rate(ORR) reached about 32%-47%, CR roughly was 7%-13%; when lenalidomide and rituximab were combined for treatment of refractory or relapsed CLL patients, the ORR reached about 53%-66%, CR about 12%-13%. Moreover, when lenalidomide and ofatumumab were combined, the efficacy is improved significantly and the adverse reactions are greatly reduced. The adverse reactions are neutrophilic granulocytopenia, thrombocytopenia, anemia, tumor lysis syndrome(TLS), tumor flare reaction(TFR) and venous thromboembolism(VTE). This review focuses on the related studies and the latest progress about lenalidomide in CLL.

Leukemia, lymphoma and multiple myeloma mortality (1950–1999) and incidence (1969–1999) in the Eldorado uranium workers cohort

Uranium workers are chronically exposed to low levels of radon decay products (RDP) and gamma (γ) radiation. Risks of leukemia from acute and high doses of γ-radiation are well-characterized, but risks from lower doses and dose-rates and from RDP exposures are controversial. Few studies have evaluated risks of other hematologic cancers in uranium workers. The purpose of this study was to analyze radiation-related risks of hematologic cancers in the cohort of Eldorado uranium miners and processors first employed in 1932–1980 in relation to cumulative RDP exposures and γ-ray doses. The average cumulative RDP exposure was 100.2 working level months and the average cumulative whole-body γ-radiation dose was 52.2 millisievert. We identified 101 deaths and 160 cases of hematologic cancers in the cohort. Overall, male workers had lower mortality and cancer incidence rates for all outcomes compared with the general Canadian male population, a likely healthy worker effect. No statistically significant association between RDP exposure or γ-ray doses, or a combination of both, and mortality or incidence of any hematologic cancer was found. We observed consistent but non-statistically significant increases in risks of chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma (HL) incidence and non-Hodgkin lymphoma (NHL) mortality with increasing γ-ray doses. These findings are consistent with recent studies of increased risks of CLL and NHL incidence after γ-radiation exposure. Further research is necessary to understand risks of other hematologic cancers from low-dose exposures to γ-radiation.

UGT1A1*28 Polymorphism in Chronic Lymphocytic Leukemia: The First Investigation of the Polymorphism in Disease Susceptibility and Its Specific Cytogenetic Abnormalities

Chronic lymphocytic leukemia (CLL) has been recently attributed to a combination of genetic predisposition and exposure to environmental factors. UDP-glucuronosyltransferase (UGT)1A1*28 is an inborn polymorphism that results in significant downregulation of uridine diphosphate glucuronyltransferase 1-1 (UGT1A1) activity, one of the most critical metabolizing enzymes involved in the detoxification of toxic substances, some of which contribute to CLL pathogenesis. Here, for the first time, we investigated the putative impact of UGT1A1*28 on CLL incidence and on the formation of the most common chromosomal abnormalities of CLL. UGT1A1*28 was investigated in 109 CLL patients and 108 healthy controls, and was associated with karyotypic and fluorescence in situ hybridization (FISH) results. A significant high frequency of the mutant genotype was observed in patients carrying abnormal FISH patterns, especially del(11q) and +12, which are CLL-specific abnormalities. We also observed a significant association between UGT1A1*28 and the intermediate to unfavorable cytogenetic CLL risk groups. No difference, though, was observed in genotypes between patients and controls. Therefore, we could suggest that UGT-deficient individuals may be at a greater risk for developing CLL-specific abnormalities. Our study might serve as a starting point to consider UGT1A1*28 polymorphism as one of the possible predisposing factors of CLL pathogenesis.

Characteristics Of Chronic Lymphocytic Leukemia (CLL) In Senegal. Clinical Features, Cytology, Immunophenotype, Cytogenetic Abnormalities and Altered Expression Of Micro-RNA

The incidence of CLL in Africa is not known for several reasons, among them the difficulty to access the diagnosis since there is only clinical features and cytology which are available in several countries in francophone Africa, especially in Senegal. The WHO criteria which have been published since 2001 from the first revised WHO classification of tumours of haematopoitic and lymphoid tissues cannot be applied since there is no facility for immunophenotyping and cytogenetic. Moreover, no research in place can be set up without any precise diagnosis.In this study, we have developed the flow cytometry technique in the laboratory of Immunology in CHU Le Dantec in Dakar to obtain the immunophenotype looking at the expression of Kappa/lambda light chains, CD19, CD22, CD20, FMC7, CD5, CD10, CD23, CD38. Peripheral blood smears were fixed according to the technique for FISH to detect the following cytogenetic abnormalities: trisomy12, deletion 13q14, deletion 11q22-23, deletion 17p. RNA to test by qRT-PCR the expression of microRNA mir15a, mir16-1, mir181a, mir181b, and mir 34a and 34b was obtained from peripheral blood lymphocytes.Twelve cases of CCL aged ranging from 50 to 80 year old were characterized at clinical level according to the Binet's system: 1 stage A, 5 stage B, 6 stages C. In most of cases (9 cases) hyperlymphocytosis of small lymphocytes with clumped chromatin and scanty cytoplasm was very high (122.000 to 336 000/mm3). The “Matutes” score obtained by immunophenotyping was 5 or 4 for 11 patients in favor of typical CLL. The expression of CD38 which is a marker of unfavorable prognosis is positive in 9 patients. Nine patients had cytogenetic abnormalities: 3 trisomy 12, 6 del 13q14, 2 del 11q22-23, 1 del17p. Four patients had two simultaneous cytogenetic abnormalities (tri 12, tri 13 ; del13q14, del11q22-23 ; del13q24, del17p ; del13q24, tri12).The analysis of mi-RNA showed high expression of mir15a and mir 16-1 and low value of mir181a and mir 181b which were described in aggressive CLL ; however the expression of mir 34a and mir34b was also high.This study shows the aggressiveness of CLL in Senegal, probably due to the delay of the diagnosis. We have also demonstrated the possibility to set up immunophenotype and the possibility of a precise diagnosis of lymphoproliferative disorder in place, in western Africa and the series will be extended. Moreover we have also demonstrated the possibility to construct translational research project from samples characterized in the University Hospital in Dakar gathering the cases from different sanitary structures in the country.Such experiment would be a model for epidemiologic, clinico-biologic and translational research studies in order to set up in the country the capacity building for diagnosis and research. Disclosures:No relevant conflicts of interest to declare.

HLA Is a Determinant Of The Ethnic Predisposition Of Chronic Lymphocytic Leukemia

IntroductionChronic Lymphocytic Leukemia (CLL) displays remarkable ethnic predisposition for Caucasians with a lower incidence of disease in African Americans and relative sparing of Asian Populations. In addition, CLL displays one of the highest familial predispositions of all hematologic malignancies, yet the genetic basis for these differences is not fully defined. Large scale genome wide association studies (GWAS) of CLL have identified the Human Leukocyte Antigen (HLA) locus and other loci associated with the development of CLL but the contribution of individual HLA alleles has not been extensively examined. The National Marrow Donor Program (NMDP) registry contains a large number of disease cases and donor controls across multiple populations as well as high quality classical HLA typing, making it a powerful source of data for inferring HLA associations for hematologic diseases. Using the NMDP dataset, we report the largest study of the HLA associations for chronic lymphocytic leukemia (CLL) to date. MethodsCases consisted of 2,689 US Caucasian and 298 African-American patients with CLL who underwent HLA typing performed for allogeneic donor search reported to the National Marrow Donor Program (NMDP). 50,000 controls were randomly selected for each population from US individuals who voluntarily enrolled in the NMDP unrelated donor registry. To address ambiguous haplotype phasing inherent to HLA typing, we used population haplotype frequencies to calculate probabilities for genotypes for each possible pair of HLA haplotypes. We then incorporated this typing ambiguity into a statistical model using multiple imputation, allowing us to report high-resolution allele, haplotype, and genotype associations. Patients and controls were compared using multivariate logistic regression using a generalized linear model for the covariates of age, birthdate, gender, and geographical location. To control for multiple testing, we adjusted p-values using False Discovery Rate with a cutoff of 0.05. ResultsWe identified several HLA alleles that are associated with an increased susceptibility to the development of CLL as well as several alleles that are protective in the Caucasian as well as the African American (AA) US population. In Caucasians, A*02:01 (OR = 1.203, p = 0.00053), B*15:01 (OR = 1.264, p = 0.0105), B*38:01 (OR = 1.396, p = 0.0198), DRB1*04:02 (OR = 1.675, p = 0.0006) and DRB1*07:01 (OR = 1.223, p = 0.0006) were predisposing and A*01:01 (OR = 0.849, p = 0.01077), B*08:01 (OR = 0.853, p = 0.0437), B*27:05 (OR = 0.743, p = 0.0356) were protective. For African Americans, we find a different collection of high resolution HLA alleles: B*37:01, B*15:17 and DRB1*09:01 were predisposing to the development of CLL (OR 3.017, 3.089 and 2.144, respectively) with highly statistically significant p-values (0.0344, 0.0344, 0.00057, respectively). At the allele family level, B*44 was found to be protective in both Caucasian (OR = 0.843, p = 0.0115) and AA populations (OR = 0.485, p = 0.0309). The allele family C*07 (OR 0.848, p = 0.0046) was protective in Caucasians while C*04 was protective in AA populations (OR = 0.645, p = 0.0422). Association results also revealed additive effects of individual predisposing alleles within the same haplotype, such as the A*02:01∼C*06:02∼B*13:02∼DRB1*07:01 haplotype, which had a higher odds ratio (OR = 2.2, p = 0.000086) than either A*02:01 or DRB1*07:01. We performed a population risk analysis by applying the currently identified allelic disease associations for Caucasians to the known allele frequency seen in other populations, and determined that HLA allele frequency differences contribute to the lower risk of CLL development for both the AA and Asian populations. ConclusionsWe have identified several HLA associations that confer increased risk of development of CLL in both U.S. Caucasians and African Americans as well as several protective alleles. These results confirm the previously identified association with HLA*02:01 (OR 1.32, Di Bernardo, et al) with highly similar odds ratio. In addition, we identify many HLA allele associations that have not been previously observed due to low statistical power. Differences in HLA predispositions and HLA allele frequency between Caucasian, AA and Asian populations contribute to the difference in incidence of CLL in these populations and may confer inherent biologic differences due to their impact on immune surveillance. Disclosures:Hill:Celgene: Honoraria, Research Funding.

Incidence Of Atypical Chronic Lymphocytic Leukemia In 1819 Patients With B Chronic Lymphoproliferative Disorder

Flow cytometry is the diagnostic tool of choice to study abnormal lymphoid population detected in peripheral blood by morphological analysis. The main diagnosed chronic lymphoproliferative disorder (CLPD) is chronic lymphocytic leukemia (CLL). In a significant number of cases, a B-CLPD non-CLL can be diagnosed. Further molecular and histological examinations are then compulsory to characterize such hematologic malignancies. The objective of this study was to determine the incidence of atypical CLL among all B-CLPD diagnosed by flow cytometry.We retrospectively studied the B-CLPD consecutively diagnosed at the hospital of Caen (Normandy, France) between 2000 and 2013. The diagnosis of B-CLPD was based on the detection by flow cytometry of circulating lymphoid abnormal B cells. Multiparametric flow cytometry included markers CD19, CD20, CD22, CD79b, CD5, CD10, CD23, CD43, FMC7, CD38 and light chains (kappa and lambda) of surface immunoglobulin. The diagnosis of CLL was based on the criteria defined by Hallek et al (Blood 2008). The non-CLL B-CLPD were then explored by molecular analyses driven by the phenotype of B-cells (overexpression of cyclin D1 in case of CD5+/CD10-/CD23- B-CLPD and BCL2-JH rearrangement in case of CD10+ B-CLPD). In addition, histological evidence was necessary to classify the B-CLPD non-CLL.1819 B-CLPD were detected by flow cytometry. The distribution of B-CLPD was as follows: 1156 cases (64%) of CLL or immunophenotypic equivalent (leukemic phase of small lymphocytic lymphoma (SLL) and monoclonal B-cell lymphocytosis (MBL)), 297 cases (16%) of marginal zone lymphoma (MZL), 84 cases (5%) of mantle cell lymphoma (MCL), 39 cases (2%) of follicular lymphoma (FL), 26 cases (1%) of hairy cell leukemia (HCL), 13 cases (<1%) of diffuse large B-cell lymphoma (DLBCL), 9 cases (<1%) of Waldenstrom's macroglobulinemia (WM) and 3 cases (<1%) of B-cells prolymphocytic leukemia (B-PLL). 65 cases (4%) remained unclassified due to lack of histological and molecular data. 127 cases (7%) did not meet the diagnostic criteria of CLL established by Hallek et al but were classified as atypical CLL because of the detection of a clonal B-cell proliferation expressing CD5+ / CD23+ / CD43+ / CD10- / FMC7+ / CD79b+ with moderate or high intensity and light chain kappa or lambda with moderate or strong intensity (absence of molecular or histological argument of MZL or MCL was required). CD20 marker was highly expressed in 113 cases (89%) of atypical CLL.We particularly studied the 1532 cases (84%) of B-CLPD expressing CD5 (table). CD5+ CD23+ B-CLPD cases accounted for 1293 (84%) with 1153 cases of CLL, 13 cases of MCL and 127 cases of atypical CLL. CD5+ CD23- B-CLPD accounted for 239 cases (16%) with 72 cases of MCL, 158 cases of MZL, 4 cases of FL, 2 cases of WM, 2 cases of CD23- CLL and one case of B-PLL.CD5+ casesCD5+ CD23+ B-CLPDCD5+ CD23- B-CLPDTotalCLL115301153Atypical CLL1272129MCL137285MZL0158158FL044WM022B-PLL011Total12932391532WHO classification of hematologic malignancies do not include atypical CLL as defined by a clonal proliferation of B-cells expressing CD5+, CD23+, cyclin D1- with no histological evidence of MZL or MCL, and which do not meet all the diagnostic criteria of CLL (Hallek et al, Blood 2008). This concept of atypical CLL, first described by Criel et al (BJH 1997), is particularly interesting, because such B-CLPD seems to have a different outcome as compared with CLL (Oscier et al, BJH 1997) and to have a different biological presentation with atypical morphology of CLL cells (Criel et al, BJH 1997), more frequent trisomy 12 (Matutes et al, BJH 1996) and a stronger intensity of CD20 (Ugo et al, Leuk Lymphoma 2006).Diagnosis of B-CLPD relies on a multidisciplinary approach combining morphological, immunophenotypic, molecular and histological analyses. Despite detailed information of these analyses, there are B-CLPD which remain unclassifiable according WHO classification, especially CD5 positive B-CLPD. The concept of atypical CLL seems to take all its meaning to help define such unclassifiable entities. Disclosures:No relevant conflicts of interest to declare.

Validation of Western common recurrent chromosomal aberrations in Korean chronic lymphocytic leukaemia patients with very low incidence

In Asia, the incidence of chronic lymphocytic leukaemia (CLL) is lower than in Western countries. Only a few studies of CLL have been conducted in Korea, and no long-term clinical outcome data are available. We assessed the frequency of common chromosomal aberrations in Korean CLL patients using interphase fluorescence in situ hybridization (FISH) and investigated their relationship to clinical outcomes. Between 2000 and 2011, conventional cytogenetic studies were performed in 58 patients, and FISH results were available in 48 patients. We used six DNA probes for the detection of del(13q14), trisomy 12, del(11q22), del(17p13), IGH rearrangement and del(6q23). Chromosomal aberrations were identified in 15 of 58 patients (26%) with conventional cytogenetic studies and in 25 of 48 patients (52%) with interphase FISH, including six patients with complex karyotypes. In contrast with the results of Western studies, trisomy 12 was the most common aberration, followed by IGH rearrangement, del(13q14), del(11q22) and del(17p13). Deletion of 6q23 was not observed, and isolated del(13q14) was less frequent than in Western studies. Compared with the other types of chromosomal aberrations, patients with del(11q22) and del(17p13) were more likely to be Rai stage 3-4 and Binet stage C, resulting in poor responses to chemotherapy and worse outcomes. In contrast, patient with trisomy 12 and isolated del(13q14) showed better responses and superior survival outcomes. The incidence of CLL is lower in Korea than in Western countries, and the frequency of chromosomal aberrations differs, perhaps reflecting differences in the pathogenic mechanism between ethnicities. Large prospective studies are needed to further assess the prognostic value of these results in Korean CLL patients.

Preservation of lower incidence of chronic lymphocytic leukemia in Chinese residents in British Columbia: a 26-year survey from 1983 to 2008

The incidence of chronic lymphocytic leukemia (CLL) in the Asian population is up to 10 times lower than that in Caucasians. Studies on CLL in Asian residents in North America may help to determine the relative genetic and environmental causes of such a difference. Computerized records of CLL incidence from the combined British Columbia (BC) databases (n = 2736) and the Hong Kong Cancer Registry (HKCR, n = 572) were traced. Ethnic Chinese cases of CLL in BC were identified (n = 35). The world age standardized rates (WASRs) of CLL (per 100 000) were calculated in BC (1.71), HK (0.28) and BC Chinese (0.4), respectively. Using standard incidence ratios (SIRs), the observed BC Chinese case number was comparable to the figure projected from HK rates (SIR 1.3, p = 0.1) but significantly lower than the figure following BC rates (SIR 0.22, p < 0.0001). The difference was maintained over both genders, in all age groups and through the years. Our data over three decades suggest that genetic factors outplay environmental factors to give lower CLL rates in Chinese.

Abstract 2287: Incidence of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis in Olmsted county, 2000-2010: impact of the 2008 International Workshop on CLL Guidelines.

Abstract Background: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is the most common adult leukemia in the United States. Prior studies in Olmsted County, Minnesota, showed a CLL age and sex adjusted incidence rate of 6.6 per 100,000 during 1985-89. Subsequently, the definition of CLL is now based on the 2008 International Workshop on CLL (IWCLL) Guidelines. Individuals having a CLL immunophenotype by flow cytometry are classified as CLL if the absolute B-cell count (ABC) is &amp;gt;5 x 109/L or classified as monoclonal B-cell lymphocytosis (MBL) if ABC is &amp;lt;5 x 109/L. To assess the impact of these changes on the incidence of CLL and clinically discovered MBL, we conducted an incidence study in Olmsted County for the years 2000-2010. Methods Using diagnostic indexes available through the Rochester Epidemiology Project and the Mayo CLL database, we identified all CLL and clinically identified MBL cases from 2000-2010. Incidence rates and demographics were compared between the older National Cancer Institute-Working Groups 1996 guidelines (NCI-WG 96) defined as absolute lymphocyte count (ALC)&amp;gt; 5 x 109/L and the IWCLL 2008 guidelines defined as ABC &amp;gt; 5 x 109/L. Incidence rates were age and sex adjusted using the 2010 US white population. Time to treatment (TTT) survival analyses was from time of diagnosis to date of first treatment or last follow-up and Cox regression analysis was used. Results Using the NCI-WG 96 classification, there were 8 MBL cases and 115 CLLs in whom 61% were Rai stage 0, 34% were Rai stage 1-2, and 5% were Rai stage 3-4. Using the IWCLL 2008 classification, there were 44 MBL cases and 79 CLLs in whom 43% Rai stage 0, 49% were Rai stage 1-2 and 8% Rai stage 3-4. Median ALC at diagnosis was 8.1 x 109/L for CLL and 5.9 x 109/L for MBL. Median ABC count at diagnosis was 7.1 x 109/L for CLL and 2.8 x 109/L for MBL. The age and sex adjusted incidence rate (per 100,000) for CLL for 2000-2010 was 10.0 using NCI-WG 96 and 6.8 using IWCLL 2008. Rates for MBL were 0.66 using NCI-WG 96 and 3.5 using IWCLL 2008. The median TTT for CLL was 9.2 years using NCI-WG 96 and 6.5 years by IWCLL 2008. Discussion This study demonstrates that reclassification of CLL using the IWCLL 2008 guidelines decreases CLL incidence relative to the NCI-WG 96 criteria. For the first time, this population based study also establishes an incidence rate for clinically identified MBL. Approximately 50% of previously labeled Rai 0 CLL are now reclassified as MBL. Re-classification increases the percent of Rai stage 1-2 and decreases the percent of Rai 0 cases at diagnosis. Reclassification also substantially shortens the median TTT for newly diagnosed CLL cases classified by the 2008 criteria relative to the NCI-WG 96 criteria. In summary, the IWCLL 2008 reclassification has significant implications for incidence studies, staging, and prognosis of CLL and MBL. Citation Format: Aaron D. Norman, Timothy G. Call, Curtis A. Hanson, Neil E. Kay, Clive S. Zent, Wei Ding, James R. Cerhan, Sara J. Achenbach, Kari G. Rabe, Celine M. Vachon, Emily J. Hallberg, Tait D. Shanafelt, Susan L. Slager. Incidence of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis in Olmsted county, 2000-2010: impact of the 2008 International Workshop on CLL Guidelines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2287. doi:10.1158/1538-7445.AM2013-2287

Chromosomal abnormalities by conventional cytogenetics and interphase fluorescence in situ hybridization in chronic lymphocytic leukemia in Taiwan, an area with low incidence—clinical implication and comparison between the West and the East

Chronic lymphocytic leukemia (CLL) is much less prevalent in Taiwan than in the West, but we have recently addressed the distinctly increasing incidence of CLL in Taiwan. We sought to find out whether there is any difference in cytogenetic abnormalities (CA) of CLL between the West and the East. We analyze the CA, by conventional cytogenetics (CG) and fluorescence in situ hybridization (FISH), and their clinical significance in 83 Taiwanese CLL patients and compared the data to those of Western countries. Thirty-five patients (42.2 %) possessed CG-CA and 58 (69.9 %) FISH-CA. By either CG or FISH, deletion of 17p or 11q was associated with poorer overall survival (OS) (P<0.001 and P=0.008, respectively), whereas isolated 13q deletion was associated with better OS (P=0.050). Trisomy 3 by CG was found in five patients; all of them were in Binet A stage but had strikingly poor OS (P<0.001). This prognostic impact was independent from the other CA and Binet stages. We conclude that, though the disease incidence is much different, the CA of CLL in Taiwan are similar to those in the West. The combined CG and FISH analysis is able to predict the patients' prognosis. The clinical significance of trisomy 3 warrants further validation.

Occurrence of chronic lymphocytic leukemia in patients with chronic myelogenous leukemia

Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in the western world and constitutes about 33% of all leukemia's. The incidence of CLL increases with age and are more common in older population. Chronic myeloid leukemia (CML) on the contrary occurs in both young adults and elderly and is a chronic myeloproliferative disease that originates from abnormal pluripotent stem cells and results in involvement of multiple hematopoietic lineages, but predominantly myeloid and less commonly lymphoid. Association between CLL and myeloid malignancies (CML, acute myeloid leukemia and MDS, myelodysplastic syndrome) is rare. In literature documenting CLL and CML in same patients, occur either simultaneously or CML is preceded by CLL.