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

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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Risk Factors for the Development of Skin Cancers in Patients with Chronic Lymphocytic Leukemia: A Retrospective Cohort Study

Blood ◽

10.1182/blood-2020-138961 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Ivan Landego ◽

Shirley Li ◽

Chao Xue ◽

Vincent Poon ◽

Robert C. Clayden ◽

...

Keyword(s):

Risk Factors ◽

Skin Cancer ◽

Chronic Lymphocytic Leukemia ◽

Cell Carcinoma ◽

Lower Incidence ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Skin Cancers ◽

Increased Risk

Introduction: Individuals with chronic lymphocytic leukemia (CLL) are often immunosuppressed and at increased risk of infection and secondary malignancies. The primary aim of this study was to determine the incidence of skin cancer amongst the CLL population at Kingston Health Sciences Centre (KHSC), Ontario, Canada. Secondly, we sought to identify the risk factors associated with the development of skin cancer in CLL patients. Methods: Consecutive patients seen at KHSC with a diagnosis of CLL between 2014 January 1 and 2019 December 31 formed the primary study cohort. KHSC serves a region of ~ 550,000 including a high proportion of older individuals and those living in rural areas. Approval was provided by Queen's University Research Ethics Board. Four independent reviewers conducted retrospective electronic chart review, initially in duplicate with review of any areas of discrepancy to ensure a standardized approach. Data collected included age, sex, CLL date of diagnosis, stage, genetics and treatment; histological diagnoses of other cancers (skin and other), smoking status (ever/never) and date of last follow up or death. The primary outcome was the development of the first skin cancer (squamous cell carcinoma, basal cell carcinoma, melanoma, or sarcoma) confirmed via pathology reports that are available in our local institution. All statistical analysis was performed using SAS Enterprise v. 7.15. Categorical variables were compared using chi-square or Fisher exact tests, medians using Wilcoxon and Mann-Whitney tests, and continuous variables using t-tests. Risk factors for development of skin cancer were assessed using multivarable Cox-proportional hazard models. Results: Of the total cohort of 377 individuals with CLL, 251 (67%) were male. Median age at diagnosis of CLL was 65 years (range 36 - 93 years of age). Median follow-up from the time of CLL diagnosis was 6.5 years (range 0.27 - 30.98). Of these, 80 individuals (21.2%) developed at least one skin cancer after their diagnosis of CLL, with an age-adjusted incidence of 16.96/1000 patient years (95% CI 12.5 - 23). Among the 297 who did not develop skin cancer post-CLL diagnosis, 13 individuals who had documented skin cancer pre-CLL diagnosis only, are included in the non-skin cancer group (Figure 1). Females had a lower incidence of skin cancer compared with males (63 males versus 17 females, p=0.009). There was no difference between the groups based on Rai stage at diagnosis, smoking history, or IGHV /p53 status. Individuals treated with ibrutinib had a lower incidence of skin cancer (3 versus 49, p=0.002). Development of skin cancer was associated with development of other invasive tumours including CLL transformation (p=0.001) (Table 1). Conclusion: Limitations of this study include its small size, and single institution setting. Our data likely reflect a conservative estimate as skin cancers may be diagnosed outside of the institution, and not all CLL is treated at tertiary care centres. Consistent with other studies we found that males with CLL are at increased risk of developing skin cancer, as compared to females. Individuals with CLL and skin cancer were more likely to develop another malignancy or Richter's transformation. The finding of lower incidence of skin cancer with ibrutinib treatment is novel; further investigation in larger populations is needed to determine if it may offer a protective effect. Disclosures Asai: Sanofi Canada: Honoraria, Research Funding; AllerGen NCE: Research Funding; Pfizer: Honoraria, Research Funding; Janssen: Honoraria; Leo Pharma: Honoraria; Eli Lilly: Honoraria; Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Canadian Institutes of Health Research: Research Funding. Hay:Roche: Research Funding; Janssen: Research Funding.

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

Blood ◽

10.1182/blood.v122.21.5287.5287 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5287-5287

Author(s):

Sandra Ballester ◽

Begoña Pineda ◽

Eduardo Tormo ◽

Blanca Navarro ◽

Ariadna Perez ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Conflicts Of Interest ◽

Expression Patterns ◽

Lymphocytic Leukemia ◽

P Value ◽

Nucleotide Polymorphisms ◽

Exact Test ◽

Cd38 Expression ◽

Mutational Status ◽

The Individual

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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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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Increased incidence of non-melanomatous skin cancer in patients with chronic lymphocytic leukemia, an 11-year case-control study

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.19554 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 19554-19554

Author(s):

M. W. Schoen ◽

P. S. Gable ◽

A. M. Reese

Keyword(s):

Skin Cancer ◽

Chronic Lymphocytic Leukemia ◽

Cell Carcinoma ◽

Squamous Cell ◽

Basal Cell ◽

Squamous Cell Carcinomas ◽

Lymphocytic Leukemia ◽

Skin Cancers ◽

Increased Risk ◽

Malignant Lesions

19554 Background: Chronic Lymphocytic Leukemia (CLL) is a disease of B lymphocytes that affects immune tolerance and surveillance. Patients with CLL have an increased risk of basal and squamous cell skin carcinomas, which tend to be aggressive. We report the incidence of non-melanomatous (NM) in a >80% Caucasian cohort of patients with CLL and compared them to normal controls who reside in Southern California. Methods: A retrospective review was conducted of all patients in the Naval Medical Center San Diego tumor registry with CLL diagnosed between Jan 1, 1995 and Dec 31, 2005. The electronic records of 74 CLL patients and 100 control patients from the internal medicine clinic were assessed for skin biopsies performed at our institution revealing NM skin malignancies. Results: Within our CLL population, the average age at diagnosis was 72.2 years. 34% (25/74) had NM skin cancer with an incidence of 11,457 NM skin cancers per 100,000 person-years. The average number of malignant lesions was 3.7 per patient with one patient receiving 17 biopsies. 27% (7/25) of CLL patients with NM skin cancer had only squamous cell carcinoma and 23% (6/25) had only basal cell carcinoma. 42% (11/25) of patients had both squamous and basal cell cancers and one had a Merkel cell carcinoma. In the control population, the average age at diagnosis was 76.4 years. 16% (16/100) had NM skin malignancies with an incidence of 5,333 NM skin cancers per 100,000 person-years. The average number of malignant lesions was 3.7 per patient with one patient receiving 28 biopsies. 63% (10/16) had basal cell carcinomas, only 25% (4/16) had squamous cell carcinomas and 13% (2/16) had both types of cancer. Conclusions: Patients with CLL are at increased risk of developing NM skin cancers, especially squamous cell carcinomas. Patients with CLL have a 2.1 times higher risk of developing NM skin cancer than our control population, who had an incredibly high rate of skin cancer compared to prior publications. CLL patients should be closely screened for cutaneous malignancies in order to excise them before they cause further morbidity. Increased surveillance is especially prudent for elderly patients with fair skin types who have been exposed to a large amount of UV-light. No significant financial relationships to disclose.

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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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Heritable Predisposition To Richter Syndrome In Patients With Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v122.21.2867.2867 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2867-2867 ◽

Cited By ~ 3

Author(s):

Sameer A. Parikh ◽

Susan L Slager ◽

Kari G. Rabe ◽

Neil E. Kay ◽

James R Cerhan ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Research Funding ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Chromosome 18 ◽

Richter Syndrome ◽

Increased Risk ◽

Translocation Breakpoints

Abstract Background Approximately 2-8% patients with chronic lymphocytic leukemia (CLL) will transform to diffuse large B-cell lymphoma (DLBCL, Richter syndrome [RS]). Clinical characteristics and molecular markers at the time of CLL diagnosis are associated with the risk of RS; however, there are no data regarding germline genetic variations and the risk of RS. Genomewide association studies (GWAS) have shown several single-nucleotide polymorphisms (SNPs) that are associated with a higher risk of familial CLL. It is not known whether any of these polymorphisms also predispose to RS. Methods Since 2002, all consecutive patients with newly diagnosed (<9 months diagnosis) CLL at Mayo Clinic were offered enrollment into a prospective genetic epidemiology study. Patients completed extensive epidemiologic questionnaires and baseline clinical, laboratory, and biologic data were abstracted using a standard protocol. Genotyping of germline tissue at diagnosis was performed using an Illumina iSelect panel and Affymetrix 6.0 SNP chip. All patients were prospectively and longitudinally followed at defined time-points with systematic collection of data on treatments, second cancers, and RS. All patients with biopsy-proven DLBCL during follow-up were considered to have undergone transformation into RS. Time to RS was calculated from CLL diagnosis date until RS or until last follow-up date for those with no RS. SNPs were modeled in two ways: ordinal and dominant. Cox regression was used to estimate hazard ratio (HR) for individual SNPs with time to transformation. Results Thirteen of the GWAS-discovered SNPs associated with risk of developing CLL were available and genotyped on 620 CLL patients. Median age at diagnosis of CLL was 62 years (range 27-88), and 428 (69%) were male. Three hundred and ten (51%) patients were low (0) Rai stage, 271 (45%) were intermediate (I-II) Rai stage, and 22 (4%) were advanced (III-IV) Rai stage. The immunoglobulin heavy chain gene was unmutated in 189 (40%) patients; 157 (32%) patients expressed ZAP-70, 163 (29%) expressed CD38 and 104 (31%) expressed CD49d. Fluorescence in-situ hybridization (FISH) revealed that 210 (41%) patients had del13q, 90 (18%) patients had trisomy 12, 37 (7%) had del11q, 23 (5%) had del17p and 141 (28%) had no detectable FISH abnormalities. As of last follow-up, 239 (39%) patients received therapy for CLL. After a median follow-up of 5.9 years (range 0-11), 15 (2.4%) patients developed biopsy-proven RS. The median time to RS in these 15 patients was 4.5 years (range 1.0-8.7 years). The ordinal HR for the 13 SNPs tested, their corresponding genes, and p-values are shown in Table 1. Germline polymorphisms in a single SNP, rs4987852, encoding for BCL2 (chromosome 18), was significantly associated with an increased risk of RS (ordinal HR=3.9; 95% CI=1.6-9.8; p-value=0.004). This allele was present in 48/605 (8%) non-transformed CLL patients compared to 4/15 (27%) of patients with RS. Time to RS according to the Kaplan-Meier analysis for rs4987852 is shown in Figure 1. This SNP is located in a region in which t(14;18) translocation breakpoints commonly occur in follicular lymphoma and overexpression of BCL2 leads to an increased incidence of B-cell lymphomas in mice. Conclusion Our results suggest that inherited genetic polymorphisms predispose CLL patients to develop RS. Specifically, SNP (rs4987852) present on the BCL2 gene on chromosome 18 in CLL is associated with an increased risk of transformation to RS. These observations require replication in other CLL cohorts. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.

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Risk Factors Associated with Richter's Transformation in Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-112442 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1697-1697 ◽

Cited By ~ 1

Author(s):

Yasmin Ben-Dali ◽

Mariam Hussein Hleuhel ◽

Michael Asger Andersen ◽

Christian Brieghel ◽

Erik Clasen-Linde ◽

...

Keyword(s):

Risk Factors ◽

Chronic Lymphocytic Leukemia ◽

Incidence Rate ◽

Cumulative Incidence ◽

Research Funding ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Increased Risk ◽

Binet Stage

Abstract Background Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). Roughly, 2-10 % of patients with CLL develop RT most often as diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL). Aim This study aimed to assess the incidence rate and risk factors for RT for patients with CLL in a nationwide cohort. Furthermore, we want to assess prognostic risk factors for patients with RT. Methods All patients diagnosed with CLL in Denmark between 2008 and 2016 were included in this study. Clinical data was retrieved from the Danish National CLL Registry (DCLLR), whereas all histologically verified DLBCL, HL and/or transformation diagnoses for patients with CLL were retrieved from the Danish National Pathology Registry. Patients were followed from date of CLL diagnosis until date of RT, death or end of follow-up, whichever came first. The time to RT was estimated as cumulative incidence considering death as a competing risk. Stepwise Cox analysis with backward elimination was applied to identify independent risk factors for RT in patients with CLL. Results A total of 3771 CLL patients were identified, and followed for 14165 person-years. With a median follow-up of 4.3 (IQR (2.4;6.6)) years, 120 (3%) CLL patients had a transformation diagnosis, of which 4 patients were excluded due to misdiagnosis. DLBCL accounted for 78/116 (67%) cases, HL for 15/116 (13%) cases and one patient presented with both DLBCL and HL. In the remaining 22/116 (19%) cases the subtype of the transformation was either unspecified or unclassified RT. The median time to RT was 3.4 (IQR (1.8;5.7)) years from CLL diagnosis and the median overall survival (OS) after development of RT was 4.9 (IQR (0.7;8.4)) years. The cumulative incidence of RT, calculated by Aalen-Johansen estimator, at 5 and 8 years post-CLL diagnosis were 3.3% and 7.9% respectively (Figure 1). The annual crude incidence rate of RT was approximately 0.7% per year for all CLL patients. In all, 918 (24%) patients received CLL-related treatment, of whom 59 (6.4%) patients developed RT, resulting in a cumulative incidence of RT of 7% after 5 years and 11% after 8 years. At the time of CLL diagnosis, patients treated for CLL prior to RT diagnosis had a worse median OS (1.49 years) compared to RT patients who were untreated for CLL (6.16 years). In the univariate analysis, RT was significantly associated with male gender, advanced Binet stage (B or C), unmutated IGHV status (CLL-U), elevated beta-2-microglobulin (>3.5 mg/L) and elevated lactate dehydrogenase (>205 U/L). Of cytogenic aberration, deletion 13q (del(13q)) had a protective effect on the risk of RT, whereas deletion 11q (del(11q)) and deletion 17p (del(17p)) increased the risk. In the multivariable model, advanced Binet stage (HR 2.86 (1.82;4.51), p<0.001), del(17p) ((HR 3.74 (2.12;6.61), p<0.001) and CLL-U ((HR 2.30 (1.46;3.63), p<0.001) showed an independent correlation with development of RT. ZAP70 and CD38 were excluded from statistical analyses due to incomplete data and high inter-laboratory variation. Among RT patients, CLL-U, trisomy 12 and del(17p) at CLL diagnosis as well as ECOG Performance Status (PS) (i.e. PS≥1) at time of RT diagnosis correlated with poor OS in univariate analysis. Both del(17p) and PS≥1 were independently associated with an increased risk of death in a multivariable analysis (HR 2.9, (1.1;7.7), p=0.04 and HR 3.0, (1.0;3.1), p=0.05, respectively). Conclusions To the best of our knowledge, we here report the largest study on RT assessing nationwide data of consecutive patients diagnosed with CLL. The incidence of RT in this unselected population was 3.3% after 5 years while the median OS for patients from time of RT was 4.9 years. Advanced Binet stage, del(17p) and CLL-U were significantly and independently associated with an increased risk of RT. Del(17p) at CLL diagnosis and PS≥1 at RT diagnosis were significant predictors for death for patients with RT. For patients diagnosed with RT prior to any CLL treatment, a less severe disease course with a median OS of 6.16 years was demonstrated. Contrary, the median OS for patients receiving prior CLL treatment was 1.49 years. Thus, assessment of different treatment options for patients developing RT based on whether they have received prior CLL treatment or not is warranted. Figure 1. Figure 1. Disclosures Ben-Dali: Rigshospitalet: Research Funding. Hleuhel:Rigshospitalet: Research Funding. Brieghel:Arvid Nilson's Fund: Research Funding; Rigshospitalet, Denmark: Research Funding. Niemann:Danish Cancer Society: Research Funding; Novo Nordisk Foundation: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy.

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The Combination of Complex Karyotypes' Subtypes and IGHV Mutational Status Provides Prognostic and Predictive Information in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-114721 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1844-1844

Author(s):

Andrea Visentin ◽

Laura Bonaldi ◽

Gian Matteo Rigolin ◽

Francesca Romana Mauro ◽

Annalisa Martines ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Research Funding ◽

Board Member ◽

Advisory Board ◽

Lymphocytic Leukemia ◽

Rank Test ◽

Predictive Information ◽

Excellent Outcome ◽

Mutational Status

Abstract INTRODUCTION. Complex karyotype (CK), defined by the presence of at least 3 chromosomal abnormalities, is a heterogeneous cytogenetic category associated with adverse prognosis in several hematologic malignancies. Recently, Rigolin et al. provided evidence that CK with major structural abnormalities (CK2) at chronic lymphocytic leukemia (CLL) diagnosis negatively impact on the time to first treatment (TTFT) and overall survival (OS) (Rigolin GM, BJH 2018). However, it is unknown whether the prognostic strength of CK could be implemented when combined with stable markers such as the IGHV mutational status. In the present study, we assessed the prognostic and predictive role of the combination of CK subtypes and IGHV status in a large CLL series. METHODS. Stimulated cytogenetics with CpG+IL2 was performed in 736 CLL patients in 3 referenced Italian hematological centers. According to Rigolin et al, CK2 cases included unbalanced translocations, addition, insertion, derivative and marker chromosomes. All other CK were classified as type 1 (CK1). An IGHV gene sequence homology >98% was considered as unmutated (U-IGHV), as opposed to mutated (M-IGHV). Treatment was initiated according to the iwCLL guidelines. TTFT and OS were calculated from diagnosis to first treatment or death, respectively, or last known follow-up. Survival curves were compared with the log-rank test and p<.05 was considered as significant. Harrell concordance index (c-index) was used to compare our prognostic model with Dohner's and FISH-IGHV models. RESULTS. We focused on 520 out of the 736 patients with cytogenetic and IGHV status assessed within 12 months from diagnosis. The median age at diagnosis was 63 years, 322 (62%) were males, 68% at Binet A stage, 45% U-IGHV, 48 harbored TP53 abnormalities, 99 a CK (28 CK1 and 71 CK2), 232 received at least one line of therapy (31% FCR, 16% BR, 8% ibrutinib, 5% chlorambucil-antiCD20, 40% other treatments) and 80 died over a median follow-up of 5.8 years. 71 (14%) harbored CK2, 214 (41%) CK1 or U-IGHV and 235 (45%) M-IGHV without CK2. The former group were characterized by a higher prevalence TP53 (38% vs 8% vs 3%, p<0.0001) and cytogenetics abnormalities but lower cases with low-risk FISH (i.e. 13q or normal; 38% vs 54% vs 91%, p<0.0001) as compared with others two groups. We observed that subjects with CK2 had a shorter TTFT (median years 1.97, 3.40 and 19.1, p<0.0001) and 5 years OS (67%, 85%, 93%, p<0.0001) compared to cases with CK1/U-IGHV, or M-IGHV without CK. These data were confirmed in multivariate analysis. The worse prognosis of CK2 patients was independent of TP53 status (p values 0.0770 and 0.8122 for TTFT and OS, respectively). The c-indexes for our model were 69% and 68% for TTFT and OS, respectively, and were not inferior to those calculated with Dohner's (64% and 61%) and FISH-IGHV (69% and 63%) models. The combination of these two markers also provides predictive information after first-line therapy (p<0.0001 for both TTFT and OS). In particular, among 107 patients treated with FCR or BR just one of the M-IGHV cases relapsed but none died after a median follow-up of 43 months as compared with the other two subgroups (3-year PFS 92%, 69% and 23%, p<0.0001; 3-year OS: 100%, 94%, 62%, p<0.0001). CONCLUSIONS. In this study, we demonstrated that the combination of CK subtypes and IGHV status provides important prognostic and predictive data in CLL. Moreover, our model was not inferior to other commonly used prognostic scores. While patients with M-IGHV without any subtypes of CK showed an excellent outcome with chemoimmunotherapy, new alternative therapies should be explored for patients with CK2. Disclosures Visentin: janssen: Consultancy, Honoraria. Rigolin:Gilead: Research Funding. Mauro:abbvie: Other: board member; janssen: Other: board member. Foà:JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; NOVARTIS: Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau. Cuneo:Roche: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Trentin:Gilead: Research Funding; Janssen: Research Funding; Abbvie: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees.

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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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