Vegf and bFGF Single-Nucleotide Polymorphisms In Chronic Lymphocytic Leukemia: Impact On Susceptibility

Abstract Background B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease with a highly variable clinical outcome. Recent studies have identified a number of different molecular prognostic markers (including mutational status of the IgVH gene, ZAP70 and CD38 expression) that allow to discriminate patients in prognostic subgroups. However, different expression patterns of angiogenic factors as VEGF, VEGFR1 and bFGF have been related with B-CLL susceptibility and treatment requirements. We have analyzed the polymorphisms: -710 C/T in VEGFR1, rs1109324, rs1547651, rs3025039 (936C/T) and rs833052 in VEGF and rs1449683 (223 C/T) in bFGF in order to determine the possible association with susceptibility in B-CLL. Methods Peripheral blood samples from 230 B-CLL patients and 476 healthy controls were genotyped using probes TaqMan SNP Genotyping Assays. Samples were providing from the Hospital Clinic of Valencia. Four SNPs in the VEGF gene, one SNP in the bFGF gene and one SNP in the VEGFR1 gene were evaluated. Statistical analysis was performed using SNPStats program (Catalan Institute of Oncology) and Fisher's exact test was applied to evaluate the significance. Results We have observed an increased frequency of the T allele in the rs1449683 SNP [OR 1.62 (95% CI: 0.98-2.66) p-value =0.063] and in the rs1547651 SNP [OR 0.72 (95% CI: 0.51-1.03), p-value=0.072] in our B-LLC patients when compared to control subjects. Moreover we observed that T allele carriers of rs3025039 (VEGF) have a significant protective effect concerning this disease [OR 0.59 (95% CI: 0.39-0.89) p-value=0.009]. Conclusion Our data indicate an increased frequency of the T allele in polymorphisms rs1449683 (bFGF) and rs1547651 (VEGF) in the group of patients, which possibly account for the individual susceptibility to develop B-CLL. On the other hand the data provided suggest that the T allele of VEGF rs3025039 is likely important genetic marker of susceptibility to B-CLL. Further studies regarding the role of pro-angiogenic markers in B-CLL would be beneficial to help elucidate pathogenic pathways in this disease. Disclosures: No relevant conflicts of interest to declare.

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Specific Chromosomal IG Translocations Have Different Prognosis In Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v116.21.582.582 ◽

2010 ◽

Vol 116 (21) ◽

pp. 582-582

Author(s):

Florence Nguyen-Khac ◽

CLaude Lesty ◽

Elise Chapiro ◽

Aurore Grelier ◽

Isabelle Luquet ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Sex Ratio ◽

Conflicts Of Interest ◽

Lymphocytic Leukemia ◽

Rank Test ◽

Exact Test ◽

Kaplan Meier ◽

Trisomy 12 ◽

Binet Stage ◽

The Individual

Abstract Abstract 582 Chromosomal translocations (t) are usually analyzed as one group, and are associated with poor prognosis in chronic lymphocytic leukemia (CLL). Translocations involving immunoglobulin (IG) genes are recurrent, but uncommon (< 5%) in CLL. The two most frequent IG-partners are BCL2 (18q21) and BCL3 (19q13). On the behalf of the Groupe Francophone de Cytogenetique Hematologique (GFCH), we report an extensive analysis of 75 t(14;18)-CLLs, and a comparison to our previously published series of 29 t(14;19)-CLLs (Chapiro et al, Leukemia 2008). The 75 t(14;18)-CLLs or variant BCL2-t have been collected between 1985 and 2009. The morphological and immunological reviews were performed by KM, CS, and HM-B. All karyotypes were reviewed by the GFCH. Fluorescence in situ hybridization analyses were performed to detect IG and BCL2 rearrangements, trisomy 12, and deletions of 11q22 (ATM), 17p13 (TP53), 6q21, 13q14 (D13S319). IGHV mutation analyses were performed by referring laboratories. Statistical analyses were carried out using the Fisher's exact test, and continuous data using the Mann-Whitney test. Overall survival (OS) and treatment free survival (TFS) calculated from diagnosis were estimated using the Kaplan-Meier method, and the statistic significance was determined using log-rank test. Among BCL2-CLL, the sex ratio was 57M/18F, the median age at diagnosis was 66 years; of 68 patients with available data, 63 (93%) presented with Binet stage A; median lymphocytosis was 14.6×109/l. There were 47/75 (63%) “classical” CLL and 28/75 (37%) “atypical” CLL, with more than 10% of lymphoplasmacytoid cells and/or large cells. All tested cases (58/58) were CD10-, 69/73 (94%) were CD5+, and 44/63 (70%) were CD38-; 57/68 (84%) had a Matutes score > 4, 7/68 (10%) a score = 3, 4/68 (6%) a score < 3. We observed 62 t(14;18) and 13 variant translocations [11 t(18;22), 2 t(2;18)]. The karyotype was complex (> 3 abnormalities) in 15/74 (20%) cases, and the BCL2-t was isolated in 25/74 (34%) cases. There were 33/75 (44%) tri12, 32/68 (47%) del13q14, 1/72 (1%) delTP53, 0/72 (0%) delATM, 0/59 (0%) del6q21. Of 42 analyzed cases, 33 (78%) were mutated. Finally, the median time from diagnosis to first therapy was 24 months (m). Comparisons with the BCL3-CLL showed no difference in sex ratio, age, and Binet stages. The lymphocytosis was lower in BCL2-CLL (14.6 vs 24.4 x109/l, p<0.008), and splenomegaly was less frequent (3/61 (5%) vs 13/28 (46%), p<0.0001). There were more “classical” morphologies in BCL2-CLL group (63% vs 9/29 (31%), p<0.005), more Matutes score > 4 (84% vs 5/20 (25%), p<0.001), and more CD38- (70% vs 1/5 (20%), p<0.05). BCL2-t were more frequently single (35% vs 1/28 (3%), p<0.0008). There were less complex karyotypes (20% vs 13/28 (46%), p<0.02), more del13q14 (47% vs 4/27 (15%), p<0.005), and less tri12 (44% vs 20/29 (69%), p<0.03), del6q (0% vs 5/25 (20%), p<0.002) and delTP53 (1% vs 4/23 (17%), p<0.02) in BCL2-CLLs. The IGHV status of BCL2-CLLs was more frequently mutated (78% vs 2/20 (10%), p<0.0001). Finally, the TFS interval was longer in BCL2-CLLs (p<0.0001, median 48 vs 1.2 m,); and the median OS was longer (not reached with 75% alive at 204 m) (p<0.0001). Comparison to common CLL showed that BCL2-CLLs had more tri12 (p<0.00001), and lacked delATM (p<0.0001) and del6q (p<0.05). The majority were CD38-, and mutated (p<0.0001). Finally, even if the median TFS was 48m, the median OS was more than 204m, which is longer than the median OS of the prognostically most favorable subgroup reported by Döhner et al (group with isolated del13q, 133m) (Döhner et al, N Eng J Med, 2000). The presence of BCL2-t remains a favorable marker even in patients who also exhibit markers of intermediate prognosis such as tri12. Compared to BCL3-CLLs, BCL2-CLLs have a much less aggressive behavior, indicating that distinguishing the individual translocations and the cytogenetic partners would allow a better patients' stratification. Disclosures: No relevant conflicts of interest to declare.

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Incidence and Implications of Skin Cancers in Cancercare Manitoba Chronic Lymphocytic Leukemia (CLL) Clinic Patients

Blood ◽

10.1182/blood.v128.22.4359.4359 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4359-4359

Author(s):

Sara Beiggi ◽

Mohammad Pannu ◽

Versha Banerji ◽

Dhali H.S. Dhaliwal ◽

Spencer B. Gibson ◽

...

Keyword(s):

Skin Cancer ◽

Chronic Lymphocytic Leukemia ◽

Conflicts Of Interest ◽

Lymphocytic Leukemia ◽

P Value ◽

Close Monitoring ◽

Mutational Status ◽

Skin Cancers ◽

Increased Risk

Abstract Background:We previously conducted a population-based study on chronic lymphocytic leukemia (CLL) in Manitoba, which showed that second cancers are twice as common and skin cancers eight times as common in this disease, as compared to an age- and sex-matched control population and patients with follicular lymphoma. It is postulated that this is related to immunosuppression, secondary to the disease and chemo-immunotherapy. Here we set out to investigate rates and types of skin cancers in CLL patients and how these influence the outcome of CLL patients. Methods: Newly diagnosed CLL patients attending the CancerCare Manitoba CLL Clinic from the January 1st, 2002 until December 31st, 2012 were selected for this study. Patients were followed until December 31, 2014. Cox Proportional Hazard models were constructed to predict hazard's ratios (HR) and 95% confidence intervals (95% CI) for survival as well as risk of non-cutaneous malignancies. Association between skin cancer and CLL prognostic markers were investigated by Fisher's Exact test, Student's t-test and logistic regression analysis. P-value <0.05 was considered statistically significant. Statistical analysis was performed using SAS Studio 3.5. Results: There were 582 CLL patients in this study. The median age was 67 years (range 36-99 years) with a M:F ratio of 1.6:1. This compares with a median age of 71.5 years and a M:F ratio of 1.3:1 in the Manitoba CLL population. The median follow-up for the study was 5.8 years (range 0.1-13.0 years). There were 131 (23%) CLL patients with at least one skin cancer; 73 (56%) had their first skin cancer before the diagnosis of CLL and 58 (44%) after. Rates of first skin cancer diagnoses were constant before CLL diagnosis (5.2 per 1000 CLL cases), but began to increase three years prior to the CLL diagnosis (10.2 per 1000 CLL cases) and continued to increase after the CLL diagnosis (22.7 per 1000 CLL cases). There were a total of 368 skin cancers; 208 (57%) were basal cell carcinomas (BCC), 92 (25%) were squamous cell carcinomas (SCC), 47 (13%) were Bowen's disease, 18 (5%) were melanomas, and three (1%) were Merkel cell carcinomas. Interestingly, multiple skin cancers with varying histologies occurred in almost half the patients. When the total number of skin cancers/year was assessed, the number started to increase seven years before the CLL diagnosis and continued to increase yearly after the CLL diagnosis. Within the follow-up period, 154 (27%) patients died, with the major causes of death being CLL and second malignancies. However, the presence of skin cancers did not appear to influence survival. There were a total of three deaths due to skin cancers; two patients died of melanoma and one from BCC. However, the presence of a skin cancer, in CLL cases without a history of a solid tumor, increased the risk of a non-cutaneous malignancy by seven-fold (HR 7.55, 05% CI 3.92 - 14.53, p<0.0001). The presence of a skin cancer prior to the diagnosis of CLL did not predict CLL aggressiveness at diagnosis, as evaluated by Rai stage, Zap-70 or CD38 status, immunoglobulin levels or IGHV mutational status. However, for those patients developing their first skin cancer after the CLL diagnosis, the risk of developing a skin cancer correlated with the unmutated IGHV status (HR 1.54, 95% CI 1.01 - 2.34, p=0.0462) and baseline CD38 positivity (HR 1.58, 95% CI 1.02 - 2.44, p=0.0405). Interestingly, the risk of developing skin cancer was not increased by chemotherapy. Discussion: In summary, with a median follow-up of 5.8 years, 23% of patients had a skin cancer, half before the diagnosis of CLL and half after the CLL diagnosis. The incidence of skin cancers increased prior to the diagnosis of CLL, indicating that immunosuppression possibly preceded the diagnosis of CLL by years. The increased risk of developing skin cancers in patients with unmutated IGHV and CD38 positivity indicates that CLL patients with a more aggressive disease are more likely to develop skin cancer, probably due to a more pronounced immune deficiency. The diagnosis of skin cancer in CLL patients was associated with a seven-fold increased risk of developing a solid tumour. These results underscore the need for close monitoring and active surveillance of CLL patients for skin and other cancers throughout their disease course, by clinicians experienced in skin and other malignancies. Disclosures No relevant conflicts of interest to declare.

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V H mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v100.4.1410.h81602001410_1410_1416 ◽

2002 ◽

Vol 100 (4) ◽

pp. 1410-1416 ◽

Cited By ~ 558

Author(s):

Alexander Kröber ◽

Till Seiler ◽

Axel Benner ◽

Lars Bullinger ◽

Elsbeth Brückle ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

Expression Level ◽

Chain Gene ◽

P Value ◽

Prognostic Impact ◽

Survival Times ◽

Mutation Status ◽

Cd38 Expression ◽

Genomic Aberrations

In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (VH) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed VH mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q−, +8q, 11q−, +12q, 13q−, t(14q), 17p−) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of VH mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (Pcor) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was identified at 97% VH homology (95% confidence interval [CI], 96%-98% homology,Pcor <.001) and at 7% CD38 expression (95% CI, 20%-71% expression, Pcor = .02). In univariate analyses, unmutated VH genes and high CD38 expression levels predicted for shorter survival times. The overall incidence of genomic aberrations was similar in theVH unmutated and VHmutated subgroups. High-risk genomic aberrations such as 17p− and 11q− occurred almost exclusively in the VHunmutated subgroup, whereas favorable aberrations such as 13q− and 13q− as single abnormalities were overrepresented in theVH mutated subgroup. In multivariate analysis, unmutated VH, 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of VH mutation status and genomic aberrations to predict outcome in CLL.

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Extensive Intraclonal Diversification in a Subgroup of Chronic Lymphocytic Leukemia Patients with Stereotyped IGHV4-34/IGKV2-30 B cell Receptors: Implications for Ongoing Interactions with Antigen.

Blood ◽

10.1182/blood.v114.22.2337.2337 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2337-2337

Author(s):

Lesley-Ann Sutton ◽

Efterpi Kostareli ◽

Anastasia Hadzidimitriou ◽

Nikos Darzentas ◽

Athanasios Tsaftaris ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Heavy Chain ◽

Conflicts Of Interest ◽

Lymphocytic Leukemia ◽

B Cell Receptors ◽

Valuable Insight ◽

Cell Receptors ◽

Mutational Status ◽

The Impact

Abstract Abstract 2337 Poster Board II-314 Several studies indicate that the development of chronic lymphocytic leukemia (CLL) may be influenced by antigen (Ag) recognition through the clonotypic B cell receptors (BCRs). However, it is still unclear whether Ag involvement is restricted to the malignant transformation phase or whether the putative Ag(s) may continuously trigger the CLL clone. Valuable insight into these issues may be gleaned from the study of intraclonal diversification (ID) within the immunoglobulin (IG) genes through ongoing somatic hypermutation (SHM). Definitive data regarding ID within IG genes in CLL remains limited and conflicting. In the present study we systematically explored the presence of ID within IG genes of CLL, not only at cohort level but also in subgroups defined by BCR stereotypy and IG gene mutational status. We thus conducted a large-scale subcloning study of both IG heavy and light variable genes, in a total of 1496 and 1008 subcloned sequences from 71 and 56 CLL cases, respectively. The analysis was intentionally biased to cases expressing IGHV4-34/IGKV2-30 IGs (subset #4) and IGHV3-21/IGLV3-21 IGs (subset #2) that exhibit distinctive, subset-biased SHM patterns. PCR reactions were run using the high-fidelity Accuprime Pfx polymerase and at least 14 colonies/case were analyzed. All “non-ubiquitous” sequence changes from the germline were evaluated and recorded as follows: (i) unconfirmed mutation (UCM) - a mutation observed in only one subcloned sequence from the same sample (ii) confirmed mutation (CM) - a mutation observed more than once among subcloned sequences from the same sample. Analysis of heavy chain sequences revealed that 40% (28/71) of cases carried intraclonally diversified IGHV-D-J genes with CMs amongst subclones, whilst 32% (23/71) of cases carried only UCMs. The remaining 28% (20/71) of cases carried sets of identical IGHV-D-J subcloned sequences. Although most cases showed no or low levels of ID, an intense and, likely, functionally driven ID was evident in selected cases, especially those belonging to subset #4. The distinct ID in subset #4 was statistically significant when compared to all other groups defined by IGHV gene usage and mutation status, BCR stereotypy or heavy chain isotype. Subsequent analysis of the clonotypic light chains revealed that the impact of ID was generally low, with the outstanding exception again relating to subset #4. In fact, of 22 IGKV-J rearrangements exhibiting CMs, 11 (50%) utilized the IGKV2-30 gene and notably 10/11 (91%) of these were expressed by subset #4 cases. In such cases, the expressed IGKV2-30 gene was affected by an active and precisely targeted ID, analogous to their partner IGHV4-34 gene. These findings suggest that the SHM mechanism may continuously operate in certain subsets of CLL patients, particularly those cases expressing stereotyped IGHV4-34/IGKV2-30 BCRs typical of subset #4. In such cases, the observed ID patterns attest to the very precise targeting of the SHM process and may be considered as evidence for a “stereotyped response” to an active, ongoing interaction with Ag(s). Disclosures: No relevant conflicts of interest to declare.

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Analysis of Stereotyped IGHV Distribution In a Series of 1133 Chronic Lymphocytic Leukemia Patients: The Experience of a Multicenter Italian Study Group

Blood ◽

10.1182/blood.v116.21.2423.2423 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2423-2423

Author(s):

Francesco Maura ◽

Giovanna Cutrona ◽

Massimo Gentile ◽

Serena Matis ◽

Monica Colombo ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Heavy Chain ◽

Conflicts Of Interest ◽

Pairwise Alignment ◽

Immunoglobulin Heavy Chain ◽

Lymphocytic Leukemia ◽

Study Group ◽

Data Set ◽

Italian Study ◽

Mutational Status

Abstract Abstract 2423 Chronic lymphocytic leukemia (CLL) is characterized by an extremely variable clinical course. Mutational status of the immunoglobulin heavy-chain variable (IGHV) region defines two disease subsets with different prognosis. A fraction of CLL cases carries highly homologous B-cell receptors (BCR), i.e. characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes and heavy-chain complementarity determining region-3 (HCDR3). We performed sequence analysis to characterize IGHV regions in a panel of 1133 CLL patients investigated by a multicenter Italian study group. A total of 1148 rearrangements were identified; the analysis of stereotyped subsets was performed based on previously reported criteria (Messmer et al, J Exp Med 2004; Stamatopuolos et al, Blood 2007). Specifically, we compared all our sequences with those found in three different publicly available data sets (Stamatopoulos et al, Blood 2007; Murray et al, Blood 2008 and Rossi et al, 2009 Clin Cancer Res). In addition, a pairwise alignment within all sequences was performed in order to discover novel potential subsets (HCDR3 identity > 60%). Based on the 2% cut-off used to discriminate between Mutated (M) and Unmutated (UM) cases, 777 sequences (67.59%) were classified as M, while 371 sequences (32.3%) as UM. The most represented IGHV genes within mutated cases were IGHV4-34 (104/118) and IGHV3-23 (85/96), whereas IGHV1-69 (97/112) was the most frequently used in the UM group. Interestingly, the IGHV3-21 gene, reported to be frequently expressed in CLL patients from Northern Europe, was present in only a small fraction of cases (24; 2.07%), confirming a previous finding reported by Ghia et al (Blood 2005) in a smaller panel. In our series, stereotyped HCDR3 sequences were found in 407/1148 (35.45%) patients, 177 of whom were M and 230 were UM cases. Overall, we observed that stereotyped sequences were significantly associated with UM IGHV status (Fisher's exact test, P<0.0001). Among the 407 stereotyped HCDR3 sequences, 345 belong to the clusters reported by Murray et al and 14 to those described by Rossi et al., 2009 Clin Cancer Res. The most frequent stereotyped subsets identified in our panel were #1 (35 cases), #7 (28 cases), #4 (24 cases), #3 and #9 (16 cases), #28 (13 cases), and #2 (12 cases), together with subsets #5, #8, #10, #12, #13, #16 and #22 (all ranging from 6 to 9 cases). Finally, we were able to identify by auto-matching analysis 48 sequences potentially specific for 23 novel putative stereotype subsets. In our series we identified 407/1148 (35.45%) stereotyped HCDR3 sequences. The percentage was higher than that reported by Stamatopoulos et al and Murray et al. This discrepancy may partially be due to the different approach used in our analysis, namely the matching to a general data set including all published stereotyped subsets instead of the auto-matching performed by those Authors. We demonstrated a significant association between IGHV status and stereotyped sequences and confirmed the finding that #1 is the most frequent subset identified so far. Finally, we were able to identify a series of 23 novel putative subsets that will require further confirmation. Disclosures: No relevant conflicts of interest to declare.

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CD1d Expression Is Higher In Chronic Lymphocytic Leukemia Patients With Unfavorable Prognosis

Blood ◽

10.1182/blood.v122.21.5278.5278 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5278-5278

Author(s):

Agnieszka Bojarska-Junak ◽

Iwona Hus ◽

Anna Dmoszynska ◽

Jacek Rolinski

Keyword(s):

B Cells ◽

Chronic Lymphocytic Leukemia ◽

Disease Progression ◽

Conflicts Of Interest ◽

Staining Intensity ◽

Lymphocytic Leukemia ◽

Disease Stage ◽

Inkt Cells ◽

Cd38 Expression

Abstract Chronic lymphocytic leukemia (CLL) is characterized by a very heterogeneous clinical course, which is slow and indolent in most of the patients, however some patient experience rapid disease progression and anticancer therapy is required shortly after the diagnosis. Many issues in CLL development and progression are still unclear. The functional consequences of CD1d expression on tumour cells are not well understood. However, increasing evidence suggests that they may affect iNKT cells.The role of CD1d expression in CLL immunopathogenesis remains undefined. In this study, we investigated the potential role of CD1d in CLL by analyzing the level of CD1d expression on leukemic B cells in peripheral blood of120 patients and assessed its correlation with prognostic markers such as ZAP-70 and CD38 expression, Rai stages and unfavourable cytogenetic changes.Measuring CD1d expression by flow cytometry and qRT-PCR, we showed lower CD1d molecule and CD1d mRNA expression in B cells of CLL patients than of healthy controls. The frequency of CD1d+/CD19+ cells, CD1d staining intensity and CD1d transcript levels increased with the disease stage. CD1d expression was positively associated with ZAP-70 and CD38 expressions as well as with unfavourable cytogenetic changes (17p deletion, 11q deletio),. We established the relationship between high CD1d expression and shorter time to treatment and overall survival. The percentage of CD1d+/CD19+cells inversely correlated with the percentage of iNKT cells. iNKT cells ζ-chain expression was downregulated in the high-CD1d group.These results suggest that high CD1d expression is associated with poor prognosis of CLL and might be involved in disease progression. Disclosures: No relevant conflicts of interest to declare.

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CD38 expression is a poor predictor for VH gene mutational status and prognosis in chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v97.6.1892 ◽

2001 ◽

Vol 97 (6) ◽

pp. 1892-1894 ◽

Cited By ~ 96

Author(s):

Ulf Thunberg ◽

Anna Johnson ◽

Göran Roos ◽

Ingrid Thörn ◽

Gerard Tobin ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

Cd38 Expression ◽

Poor Predictor ◽

Mutational Status ◽

Vh Gene

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New Prognostic Markers in CLL

Hematology ◽

10.1182/asheducation-2006.1.279 ◽

2006 ◽

Vol 2006 (1) ◽

pp. 279-284 ◽

Cited By ~ 46

Author(s):

Emili Montserrat

Keyword(s):

Residual Disease ◽

Daily Practice ◽

Serum Markers ◽

Response To Therapy ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Prognostic Information ◽

Cd38 Expression ◽

Mutational Status ◽

The Individual

Abstract The individual prognosis of patients with chronic lymphocytic leukemia (CLL) is extremely variable. Although clinical stages remain the basis for assessing prognosis in CLL, a number of biological markers, particularly serum markers, cytogenetic abnormalities, IgVH mutations, CD38 and ZAP-70 expression in leukemic cells offer important, independent prognostic information. Before being incorporated into daily practice, however, these markers require standardization and validation in large, prospective trials. Meanwhile, treatment of patients with CLL not included in clinical studies should be decided on the basis of classical NCI/CLL Working Group criteria. An important area of research in CLL prognostication is the identification of markers useful for predicting response to therapy and its duration. Among them, del(17p), reflecting P53 abnormalities, is particularly important. Also relevant is del(11q), which points to ATM defects. There is also some correlation between IgVH mutational status, ZAP-70 and CD38 expression and response to therapy and its duration, although these relationships need further investigation. Finally, there is increasing evidence that response to therapy, particularly in those cases in which minimal residual disease is eradicated, is associated with longer survival.

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Other Cancers in Long-Term Survivors of Chronic Lymphocytic Leukemia: Incidence and Prognostic Relevance

Blood ◽

10.1182/blood.v124.21.3323.3323 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3323-3323 ◽

Cited By ~ 2

Author(s):

Lorenzo Falchi ◽

Michael Keating ◽

Susan Lerner ◽

Xuemei Wang ◽

Kplola Y Elhor Gbito ◽

...

Keyword(s):

Bladder Cancer ◽

Chronic Lymphocytic Leukemia ◽

Conflicts Of Interest ◽

Observation Time ◽

Lymphocytic Leukemia ◽

P Value ◽

Prognostic Impact ◽

Long Term Survivors

Abstract Introduction. The clinical course of chronic lymphocytic leukemia (CLL) is mostly indolent. About one third of the patients are managed with lifelong watch-and-wait (WW) and those who receive therapy often achieve a durable remission. As a result, the majority of patients with CLL will live with their disease for long periods of time, and be exposed to several complications, including the occurrence of other cancers (OC). Patients with CLL may have an increased incidence in OC. Published reports indicate an incidence of 3-27%, mostly in treated patients, however, very little is known on OC in patients with CLL not requiring therapy. Furthermore, observation time in published studies is limited to <5 years, and the incidence of OC in patients followed for longer than 10 years is unknown. We, therefore, studied the incidence and prognostic impact of OC in treatment-naïve patients with CLL followed for ≥10 years. Methods. We reviewed our database and identified all patients with CLL untreated at the time of referral. We selected long-term survivors (LTS), defined as patients with a follow-up ≥10 years, and analyzed the incidence and prognostic impact of OC in this population. Non-melanoma skin cancers were excluded since these were diagnosed and treated promptly in virtually all cases and felt not to have prognostic impact. Standardized incidence ratios (SIR) were calculated for OC occurring after the diagnosis of CLL that were reportable to the Surveillance, Epidemiology and End Results program.The estimated overall survival (OS) according to the presence of OC was plotted considering OC as a time-dependent covariate. Results. We identified 797 LTS of CLL seen at our institution between 1957 and 2003. Median age was 56 years (24-88). 57% of patients were males. Median follow-up for the entire population is 154 months (120-485). We recorded 383 OC in 286 (36%) patients. 76/286 (26%) patients had >1 OC (62 had 2 OC, 10 had 3, 2 had 4, 1 had 5 and 1 had 6).The firstOC preceded or was diagnosed concomitantly with CLL in 100 patients (35%), while in the remaining 186 (65%) it occurred later during the course of the disease. 570 patients (71%) required treatment for CLL. Median time to treatment was 18 months (0-454). In treated patients, the cumulative frequency of OC was 205/570 (36%) and in WW patients 81/227 (36%). The SIR for all OC was 1.2 (p = .034). Males and patients younger than 60 years had a significantly higher incidence of OC (SIR 1.31 and 1.27, respectively). Among OC types, secondary leukemia, melanoma and head and neck cancers had the highest observed-to-expected ratio. Surprisingly, lung, digestive tract, and bladder cancer had a lower-than-expected incidence (table). 474 patients (59%) are alive. 222/570 (39%) treated patients and 101/227 (44%) WW patients have died. The median OS was longer in patients without OC (279 months) vs. those with OC (189 months). Independent predictors of shorter survival in multivariate analysis included higher creatinine, the presence of OC, and older age. Discussion. This is the first study to address the incidence of OC in LTS of CLL, including WW patients. In our population, the frequency of OC is similar in treated and WW patients. Although the incidence of OC in LTS of CLL is higher compared to matched general population, the incidence of lung, digestive and bladder cancer is lower than expected. Reasons of this finding remain to be identified.The occurrence of OC is an independent predictor of shorter survival, thus constituting a relevant competing risk of mortality in LTS of CLL. Variable Observed Expected Person-years SIR (O/E) 95% CI for O/E P -value Overall 148 123.34 10956 1.20 1.01 – 1.40 0.034 Male 96 73.4 5885 1.31 1.06 – 1.58 0.013 Female 52 49.93 5071 1.04 0.78 – 1.36 0.67 Age ≥60 years 60 54.33 3416 1.10 0.84 – 1.42 0.44 Age <60 years 88 69.02 7540 1.27 1.02 – 1.57 0.027 OC type Prostate 28 25.92 11809 1.08 0.72 – 1.56 0.64 Lung 20 29.08 11942 0.69 0.42 – 1.06 0.04 Breast 19 18.60 11855 1.02 0.62 – 1.59 0.96 Melanoma 16 4.23 11926 3.78 2.16 – 6.14 0.00 Leukemia 15 4.27 12009 3.51 1.96 – 5.79 0.00 Non-Hodgkin lymphoma 6 6.38 11996 0.94 0.34 – 2.05 1.00 Digestive 16 40.4 11937 0.40 0.23 – 0.64 0.00 Colon 8 19.42 11972 0.41 0.18 – 0.81 0.006 Pancreas 2 4.83 12024 0.41 0.05 – 1.49 0.18 Rectal 3 8.69 12011 0.34 0.07 – 1.00 0.05 Bladder 3 11.18 11993 0.27 0.05 – 0.78 0.009 Multiple Myeloma 2 1.98 12012 1.01 0.12 – 3.64 1.00 Lip 3 0.02 12015 150 31.00 – 438.5 0.00 Salivary gland 2 0.03 12026 66.66 8.00 – 240.06 0.00 Disclosures No relevant conflicts of interest to declare.

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98% IGHV Gene Identity Is Still the Optimal Cutoff to Predict the Prognosis of Chronic Lymphocytic Leukemia Patients in China

Blood ◽

10.1182/blood-2018-99-118141 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5545-5545

Author(s):

Yi Xia ◽

Ke Shi ◽

Qian Sun ◽

Chun Qiao ◽

Huayuan Zhu ◽

...

Keyword(s):

Prognostic Factor ◽

Chronic Lymphocytic Leukemia ◽

Conflicts Of Interest ◽

Somatic Hypermutation ◽

Lymphocytic Leukemia ◽

Study Cohort ◽

Optimal Cutoff ◽

Entire Cohort ◽

Mutational Status ◽

Significant Difference

Abstract Background: Immunoglobulin heavy chain variable region (IGHV) has been an important prognostic factor for chronic lymphocytic leukemia (CLL) for decades. 98% being a cut-off value for IGHV is a mathematical choice and researches on the best cut-off value have never been stopped. Chinese CLL patients are known to differ from Caucasian CLL patients on both clinical and genetical features. However, the optimal cutoff for IGHV mutational status has not yet been studied in this particular ethnic group. Method: We carried out a study on 595 Chinese CLL patients in order to find out whether 98% is the best cut-off value for IGHV in Chinese CLL patients. Genomic DNA from peripheral blood or bone marrow was subjected to PCR amplification following the IGH Somatic Hypermutation Assay v2.0 protocol (InVivoScribe). Sequences were aligned to ImMunoGeneTics/V-QUEry and Standardization (IMGT/-VQUEST) database. Result: 600 sequences were received after IGHV rearrangement sequencing. IGHV3-23, IGHV4-34, IGHV3-7, IGHV4-39 and IGHV1-69 were the most frequently used IGHV genes. 352 (58.7%) cases were IGHV-mutated while 248 (41.3%) cases were IGHV-unmutated if the classical 98% classification by ERIC was used. In order to determine the optimal cut-off value, we used 1% as the interval to divide the entire cohort into 7 groups according to the mutational rate, which were <95%, 95%-95.99%, 96%-96.99%, 97%-97.99%, 98%-98.99%, 99%-99.99% and 100% respectively. Binet A patients had a relatively indolent course of disease and cases with different IGHV mutational rates had no significant differences in time to first treatment (TTFT) apart from truly unmutated (100%) cases. For the whole study cohort, significant difference appeared at 98% interval (P<0.001 and P=0.005 for TTFT and OS respectively) while intervals less than 98% had no significant difference compared with the <95% group. Similarly, there was no clear dissimilarities among 98%, 99% and 100% intervals (Table 1a and b). All the other prognostic factors including del(17p), del(11q), TP53 mutation, MYD88 mutation, NOTCH1 mutation, SF3B1 mutation, CD38, ZAP-70, Binet staging, gender, β2-microglobulin and EBV-DNA were differently distributed between group <98% and group ³98%, but not among subgroups in ³98%. In multivariate analysis, the 98% IGHV was also an independent prognostic factor for TTFT and OS. Conclusion: 98% is the optimal cutoff value for IGHV mutational status to predict the prognosis of CLL patients in China. Table 1. Table 1. Disclosures No relevant conflicts of interest to declare.

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