Double IGHV Gene Rearrangements in Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5631-5631
Author(s):  
Benjamin M Heyman ◽  
Alicia D. Volkheimer ◽  
J. Brice Weinberg ◽  
Mark Lanasa
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Clinical Outcomes ◽  
Heavy Chain ◽  
Statistical Difference ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Gene Rearrangements ◽  
Time To Treatment ◽  
Ighv Gene

Abstract Background: Chronic lymphocytic leukemia (CLL) is an incurable cancer of mature B-lymphocytes that infil­trate the bone marrow, secondary lymphoid organs, and blood. Much progress has been made during the past decade in understanding the pathogenesis and prognosis in CLL. Patients with unmutated immunoglobulin gene heavy chain variable region (IGHV) genes have inferior clinical outcomes when compared to patients with mutated IGHV. While there is robust data regarding clinical outcomes in patients with single IGHV rear­range­ments in CLL, there is limited data regarding double IGHV rearrangements. Thus, we investigated the preva­lence of double IGHV rearrangements in our institutional cohort to determine molecular features and the prog­nos­tic significance of CLL cases with double IGHV rearrangements. Methods: Patients with CLL receiving care at Duke University and Durham Veterans Affairs (VA) Medical Centers were enrolled into a longitudinal cohort study between 1999 and 2014. IGHV mutation analysis was performed on DNA from all study patients. Patients were followed clinically for disease progression, need for treatment, and overall survival. The primary end points were time to treatment (TTT) or overall survival (OS). Survival curves were estimated using Kaplan-Meier method. Statistical differences were tested using propor­tional hazards tests for a clinical significance of p < 0.05. CLL cell isolation and IGHV mutational analysis were done as we have previously described (BLOOD 109:1559-1567, 2007). Statistical analysis was performed using SAS enterprise guide 5.1 and JMP Pro 11. Results: A total of 489 CLL patients were studied. Of these, 420 had one IGVH gene rearrangement (single IGHV; 86%). In 69 patients (14%), we amplified two IGHV rearrangements, indicating likely biallelic IGHV. The median TTT for the single IGHV group was 5.4 years, and the median OS for the single IGHV group was 15.3 years. For the double IGHV group, the mean TTT was 6.5 years (p = 0.44), and the median OS was 15.8 years (p = 0.73). Patients with single mutated IGHV (m) had better survival (median OS = 20.1 years) than those with single unmutated IGHV (u) (median OS = 11.3 yrs; p <0.001). There can be three possible combinations in the double IGHV group: double mutated (mm), mutated-unmutated (mu), and double unmutated (uu). The Table displays the differences in TTT and OS for the groups. In our cohort, the median TTT for those with a mutated double IGHV was longer (16.3 years) than for those with an unmutated double IGHV [median = 3.2 years; p < 0.01)]. Similarly, the median OS for those with mutated double IGHV was 33.6 years, while for those without a mutation it was 9.6 years (p < 0.01). In general, the TTT and OS were longer in those patients that had a mutated IGHV versus those without. The number of mutated genes did not make a statistical difference in the patient outcomes. Similarly, when comparing the uu and u groups, there was no statistical difference in survival. Conclusions: This is the largest single center study to date that examines double IGHV gene rearrangements and patient prognosis in CLL. The mutational status of the immunoglobulin heavy chain was a very important predictor of TTT and OS, mutated longer than ummutated. There was no significant survival difference between patients with single or double rearrangements in their IGHV chains. Our data demonstrates that the presence of at least one mutated IGHV gene confers a better prognosis for patients diagnosed with CLL. Thus, patients who have double IGHV rearrangements with at least one that is mutated, should be counseled as if they have a mutated rearrangement. Table: Statistical Analyses for Mutated and Unmutated IGHV for Time to Treatment and Overall Survival Time to Treatment TTT (years) m mu u uu p value (comparison between groups) mm 18.5 0.156 0.168 <.0001 <.0001 m 9.4 0.603 <.0001 0.0001 mu 7.9 0.061 0.007 u 3.0 0.285 uu 3.2 Overall Survival OS (years) m mu u uu p value (comparison between groups) mm 33.6 0.4899 0.623 0.007 0.016 m 20.1 0.612 <.0001 0.001 mu 20.8 0.096 0.053 u 11.3 0.099 uu 9.6 Figure 1 Figure 1. Disclosures Lanasa: MedImmune: Employment.

Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1524-1533 ◽  
Author(s):  
Fiona Murray ◽  
Nikos Darzentas ◽  
Anastasia Hadzidimitriou ◽  
Gerard Tobin ◽  
Myriam Boudjogra ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Germ Line ◽  
Somatic Hypermutation ◽  
Lymphocytic Leukemia ◽  
Chain Gene ◽  
Distinctive Features ◽  
Ighv Gene ◽  
Gene Usage

Abstract Somatic hypermutation (SHM) features in a series of 1967 immunoglobulin heavy chain gene (IGH) rearrangements obtained from patients with chronic lymphocytic leukemia (CLL) were examined and compared with IGH sequences from non-CLL B cells available in public databases. SHM analysis was performed for all 1290 CLL sequences in this cohort with less than 100% identity to germ line. At the cohort level, SHM patterns were typical of a canonical SHM process. However, important differences emerged from the analysis of certain subgroups of CLL sequences defined by: (1) IGHV gene usage, (2) presence of stereotyped heavy chain complementarity-determining region 3 (HCDR3) sequences, and (3) mutational load. Recurrent, “stereotyped” amino acid changes occurred across the entire IGHV region in CLL subsets carrying stereotyped HCDR3 sequences, especially those expressing the IGHV3-21 and IGHV4-34 genes. These mutations are underrepresented among non-CLL sequences and thus can be considered as CLL-biased. Furthermore, it was shown that even a low level of mutations may be functionally relevant, given that stereotyped amino acid changes can be found in subsets of minimally mutated cases. The precise targeting and distinctive features of somatic hypermutation (SHM) in selected subgroups of CLL patients provide further evidence for selection by specific antigenic element(s).

scholarly journals Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5468-5468
Author(s):  
Shuo Ma ◽  
Rebecca J Chan ◽  
Lin Gu ◽  
Guan Xing ◽  
Nishan Rajakumaraswamy ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Dose Reduction ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Treatment Interruption ◽  
Lymphocytic Leukemia ◽  
Hodgkin's Lymphoma ◽  
Advisory Committees

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy >180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy >180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy >180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy >180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT >180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Mutation Status and Immunoglobulin Gene Rearrangements in Patients from Northwest and Central Region of Spain with Chronic Lymphocytic Leukemia

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
I. González-Gascón y Marín ◽  
J. A. Hernández ◽  
A. Martín ◽  
M. Alcoceba ◽  
M. E. Sarasquete ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Central Region ◽  
Lymphocytic Leukemia ◽  
Gene Rearrangements ◽  
Immunoglobulin Gene ◽  
Mutation Status ◽  
Almost All ◽  
Time To First Treatment ◽  
Immunoglobulin Gene Rearrangements

The aim of this study was to investigate the frequency and mutation status of the immunoglobulin heavy variable chain (IGHV) in a cohort of 224 patients from northwest and central region of Spain diagnosed with chronic lymphocytic leukemia (CLL), and to correlate it with cytogenetic abnormalities, overall survival (OS) and time to first treatment (TTFT). 125 patients had mutated IGHV, while 99 had unmutated IGHV. The most frequently used IGHV family was IGHV3, followed by IGHV1 and IGHV4. The regions IGHV3-30, IGHV1-69, IGHV3-23, and IGHV4-34 were the most commonly used. Only 3.1% of the patients belonged to the subfamily IGHV3-21 and we failed to demonstrate a worse clinical outcome in this subgroup. The IGHV4 family appeared more frequently with mutated pattern, similar to IGHV3-23 and IGHV3-74. By contrast, IGHV1-69 was expressed at a higher frequency in unmutated CLL patients. All the cases from IGHV3-11 and almost all from IGHV5-51 subfamily belonged to the group of unmutated CLL.

scholarly journals IGHV-associated methylation signatures more accurately predict clinical outcomes of chronic lymphocytic leukemia patients than IGHV mutation load

Haematologica ◽  
2021 ◽  
pp. 0-0
Author(s):  
Dianna Hussmann ◽  
Anna Starnawska ◽  
Louise Kristensen ◽  
Iben Daugaard ◽  
Astrid Thomsen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Outcomes ◽  
Lymphocytic Leukemia ◽  
Mutation Load ◽  
450K Array ◽  
Mutation Status ◽  
Classification Procedure ◽  
Array Data ◽  
Ighv Gene ◽  
Classification Procedures

Currently, no molecular biomarker indexes are used in standard care to make treatment decisions at diagnosis of chronic lymphocytic leukemia (CLL). We used Infinium MethylationEPIC array data from diagnostic blood samples of 114 CLL patients, and developed a patient stratification procedure based on methylation signatures associated with mutation load of the IGHV gene. This procedure allowed us to predict the time to treatment (TTT) with HR 8.34 (95% CI, 4.54-15.30), as opposed to HR 4.35 (95% CI, 2.60-7.28) for IGHV mutation status. Detailed evaluation of 17 discrepant cases between the two classification procedures showed that these cases were incorrectly classified using IGHV status. Moreover, methylation-based classification stratified patients with different overall survival (OS) (HR, 1.82; 95% CI, 1.07-3.09), which was not possible using IGHV status. Furthermore, we assessed the performance of the developed classification procedure using published HumanMethylation450 array data for 159 patients for which TTT, OS and relapse were available. Despite that 450K array methylation data did not contain all biomarkers used in our classification procedure, methylation signatures again stratified patients with significantly better accuracy than IGHV mutation load regarding all available clinical outcomes. Thus, stratification using IGHV-associated methylation signatures may provide improved prognostic power than IGHV mutation status.

Status of the Immunoglobulin Heavy Chain and Light Chain Genes in Chronic Lymphocytic Leukemia and Related Disorders

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4161-4161
Author(s):  
Hirotaka Nakahashi ◽  
Masamitsu Karasawa ◽  
Akio Saito ◽  
Kohtaro Toyama ◽  
Takeki Mitsui ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Heavy Chain ◽  
Light Chain ◽  
Lymphoproliferative Disorders ◽  
Lymphocytic Leukemia ◽  
Antigen Receptors ◽  
Asian Countries ◽  
Western Countries ◽  
Ighv Gene

Abstract The incidence of chronic lymphocytic leukemia (CLL) is low in Asian countries including Japan, while it is the most common type of leukemia in western countries. It has been evident that the immunoglobulin heavy chain variable region (IGHV) gene mutation status can predict the prognosis in CLL; unmutated IGHV genes correlate with a worse prognosis than mutated genes. Over-representation of selected IGHV genes is noted in western CLL, in particular IGHV1-69, IGHV4-34, IGHV3-7, and IGHV3-21. Although their relative frequencies vary between cohorts, the most frequent gene in western countries is IGHV1-69, which is found in about 10–20% of all CLL patients. Several studies have shown very unusual Ig characteristics in CLL: highly restricted IGHV gene usage and very similar antigen-binding sequences (stereotyped antigen receptors), suggesting a role for antigen selection during the development and maintenance of the disease. For the purpose of clarifying the characteristics of CLL in the Japanese population, we analyzed both IGHV and Ig light chain (κ-chain, IGK and λ-chain, IGL) genes in 81 CLL cases and compared the findings with cases of 52 leukemic chronic lymphoproliferative disorders (CLPD) including 6 hairy cell leukemia (HCL), 1 prolymphocytic leukemia (PLL), 31 indolent lymphoma in leukemic phase (15 mantle cell lymphoma (MCL), 7 follicular lymphoma (FL), 5 splenic marzinal zone lymphoma (SMZL), and 4 lymphoplasmacytic lymphoma (LPL)) and 14 cases that could not be classified further. Of the 81 Japanese CLL patients, 17 (21.3%) had unmutated IGHV, and 63 (78.7%) had mutated IGHV. The number of CLL with mutated IGHV was at a higher frequency compared to previous reports from western countries. It may be partly explained by the fact that the commonly unmutated IGHV1-69 type was rare (1.2%), but the commonly mutated IGHV4-34 type was frequent (27.2%) in the Japanese CLL patients. We previously reported that IGHV1-69 CLL is rare in Japan (1/44), which is confirmed by the present study of newly diagnosed cases (0/37). Moreover, only 1 of 65 CLL patients was reported to use IGHV1-69 in China. These findings suggest that IGHV1-69 is extremely rare in Asia. Similar to reports from Scandinavian countries, IGHV3-21 cases showed biased λ-chain expression (5/6), but were not associated with overuse of IGLV3-21 (V2-14) in our cohort. Recently, studies of B-cell antigen receptors (BCRs) in patients with CLL identified that subsets of cases expressed almost identical BCRs. We also found a pair of CLL patients who had the same IGHV4-39, IGHD6-13, IGHJ5 (heavy chain) and IGKV1-39 (O12), IGKJ1 or 2 segment with remarkably similar H and L CDR3 sequences. The use of IGHV, IGKV and IGLV was significant different when compared between CLL and leukemic CLPD. IGHV4-34, which was the most preferentially used in CLL patients (21/81, 26.0%), was used rarely in CLPD patients (4/52, 7.7%, p = 0.007). Of the 4 CLPD patients with IGHV4-34, 3 were MCL (CD5+) and 1 was unclassified CLPD (CD5 −). As leukemic cells of all CLL cases were CD5+, only 1 of the 25 patients using IGHV4-34 had CD5 negative cells. In normal B-cell development, naive IGHV4-34 B-cells are positively selected and mostly restricted to the follicular mantle zone but these cells are largely excluded from the germinal centers. This mechanism may be relevant to IGHV4-34 usage being underrepresented in CLPD other than MCL, which mainly consisted of GC- or post-GC-derived lymphomas/leukemias. In CLPD patients, only 1 patient with SMZL used the IGHV1-69 gene. Interestingly, IGHV1-69 was associated with IGHD5-24, IGHJ3, IGKV3-20 and IGLKJ1, which have been previously identified to comprise one of the stereotypical BCR gene subsets in patients with CLL. In the CLL patients, IGKV3-11 (L6) and IGLV3-21 (V2-14) were the most frequent IGKV (7/43) and IGLV (11/35), respectively. However, in the CLPD patients, IGKV3-11 and IGLV3-21 were used by none (0/26, p = 0.03) and only 1 MCL patient (1/22, p = 0.002), respectively. To date little data has been obtained on CLL in Japan and other Asian countries, where the susceptibility to CLL is very low. Thus, it is important to investigate genetic and environmental differences between Asian and western countries to identify risk factors that give rise to this disease. In addition, a comparison of the disease features of CLL with other lymphoproliferative disorders will further elucidate the clinical and pathogenetic characteristics of CLL.

Distinct IGHV Repertoire Features In Chinese Chronic Lymphocytic Leukemia Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5279-5279
Author(s):  
Yi Xia ◽  
Wei Xu ◽  
Lei Fan ◽  
Chun Qiao ◽  
Li Wang ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Western World ◽  
Antigenic Difference ◽  
Mutational Status ◽  
Ighv Gene ◽  
Variable Heavy ◽  
Gene Usage

Abstract Mounting evidence indicates that immunoglobulin variable heavy-chain (IGHV) repertoire and mutational status in chronic lymphocytic leukemia (CLL) patients are prognostically relevant. However, rare data is available in Chinese CLL population. Our group investigated 270 Chinese CLL patients for their IGHV sequences and discovered significant differences between Chinese and European CLL patients. First of all, 169 (62.6%) patients in our group got mutated IGHV and 101 (37.4%) were unmutated, rendering a considerable higher percentage of mutated subgroup compared with European patients (55%) (Figure 1). While IGVH3 is still the most frequently used IGVH gene in Chinese CLL patients (135/270, 50%), discrepancy occurs in the usage of IGVH1 gene, which only presents in 13.7% (37/274) patients in our cohort whereas 23.79% for European (Figure 2). Regarding IGHV subgroups, IGHV3-23 and IGHV4-34 are more often used in Chinese CLL patients (10.7% and 10.4%, respectively). Remarkably, IGHV1-69, the most prevalent IGHV subgroup in European CLL patients (12.81%), only accounts for 5.2% (14/270) Chinese cases.Figure 1Higher percentage of mutated IGHV in Chinese CLL patientsFigure 1. Higher percentage of mutated IGHV in Chinese CLL patientsFigure 2Different IGHV gene usage between Chinese and European CLL patients, with IGVH1 gene accounts for 23.79% of European CLL patients and for only 13.70% of Chinese CLL patients.Figure 2. Different IGHV gene usage between Chinese and European CLL patients, with IGVH1 gene accounts for 23.79% of European CLL patients and for only 13.70% of Chinese CLL patients.Figure 3IGVH1-69 is the most prevalent IGHV gene among European CLL patients(12.81%), however, only 5.20% Chinese CLL patients use VH1-69. IGVH4-39 and IGVH4-59 are more often used in Chinese CLL patients (7.80% vs 3.73% and 5.60% vs 2.75%, respectively).Figure 3. IGVH1-69 is the most prevalent IGHV gene among European CLL patients(12.81%), however, only 5.20% Chinese CLL patients use VH1-69. IGVH4-39 and IGVH4-59 are more often used in Chinese CLL patients (7.80% vs 3.73% and 5.60% vs 2.75%, respectively). We further studied the distribution of stereotyped BCR in our cohort. Thirty-eight patients (14.07%) with stereotyped BCR that belonged to 21 subsets were identified, with 1 to 7 sequences contained each. Among them, subset 1 and subset 8 are the most common types with 6 and 7 cases respectively. Three new subsets were discovered (Table 1). Notably, only 1 case belonged to subset 2, the subset with largest group size in western world. Hence, we conclude that Chinese CLL patients show unique IGHV repertoire features compared to patients from western countries. While the mechanism within remains unknown, the discrepancy might due to antigenic difference in geographically remote areas.Table 1Three new subsets of BCR stereotypy in Chinese CLL patientsNO.IGHVIGHDIGHJM/UMIdentityHCDR3 AA sequenceLengthNovel 1NJ-15IGHV4-59*083-22*016*03UM100,00%ARGNYYDSSGYYYVGYYYYYMDV23NJ-31IGHV4-59*013-22*016*03UM99,65%ARGDYYDSSGYYYVGYYYYYMDV23Novel 2NJ-186IGHV3-23*013-22*014*02M96.60%AKGYRDNYDGDQSSVFDS18NJ-23IGHV3-23*012-21*014*02M96,53%AKGYRDNYDGDQSSVFDS18Novel 3NJ-36IGHV4-34*016-6*015*02M93,33%AKLMAGRPNWFDP13NJ-123IGHV4-34*016-6*015*02M91,67%AKLMAGRPNWFDP13 Disclosures: No relevant conflicts of interest to declare.

Impact Of Clinical and Biological Factors On Outcome In a Cohort Of Unselected Chronic Lymphocytic Leukemia (CLL) Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5275-5275
Author(s):  
Giovanna Piras ◽  
Roberta Murru ◽  
Angelo D. Palmas ◽  
Rosanna Asproni ◽  
Antonella Uras ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tp53 Mutation ◽  
Prognostic Markers ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Fish Analysis ◽  
Line Treatment ◽  
Mutation Status ◽  
Ighv Gene ◽  
Trisomy 12

Abstract Introduction Chronic Lymphocytic Leukemia (CLL) is a heterogeneous disease with a variable clinical course. Therapeutic decisions are based mainly on clinical grounds. Several prognostic markers based on genetic, phenotypic and molecular lesions have emerged in the past decade as relevant, alone or in combination with each other, in order to predict the clinical course and the best treatment option for CLL patients. Among these, NOTCH1 and TP53 mutation, have been described as new prognostic markers and predictive of survival in CLL. In this study, a real-life cohort of 165 CLL patients from Sardinia (Italy), was retrospectively analyzed for clinical, laboratory data (including NOTCH-1, TP53 mutation), first line treatment and followed up for survival. Methods Patients (99 males, 66 females, age ranged 31-89 y, 24% <55 y, Binet A 60%, Binet B/C 40%) were diagnosed with CLL between 1988-2012 by standard criteria. First-line treatment: 34% patients received no therapy, 30% fludarabine based regimens (+/-Rituximab), 32% alkylating agents based regimens (+/- Rituximab), 4% other regimens. Cytogenetic analysis was performed on peripheral blood cultured in the presence of the immunostimulatory CpG-oligonucleotide DSP30/Interleukin-2. FISH analysis on interphase nuclei was done using conventional 4-probe panel. The presence of NOTCH1 c.7544_7545delCT was investigated by ARMS PCR approach. The TP53 exons 4-11 were amplified in 33 patients and direct sequenced. Data from chromosome banding analysis (n=73), CD38 expression (n=133), IGHV mutation status (n=110) were also available. Categorical variables were compared by chi-squared test and Fisher exact test when appropriate. Statistical significance was defined as P value= 0,05. Kaplan-Meier curves and log rank test were used to determine overall survival and Cox regression analysis to calculate hazardous ratios using the R statistical program. Results Survival curve for the entire cohort ofpatients showed a median survival time of 195 months (95% CI 185-303). Patient stratification based on 1st line-treatment regimens did not show any significant difference in clinical outcome. FISH analysis detected trisomy 12 in 16% (24/154) patients, 13q14 deletion in 45/154 (29%), 17p deletion in 6% (10/154) and 11q deletion in 3%(5/154). Abnormal karyotype was present in 37% (27/73) of samples including 6 cases which resulted negative at the FISH test. Presence of 17p deletion was associated with the worse overall survival in univariate analysis (81 months, 95%CI 56-117, p value=0.0001). NOTCH1 c.7544_7545delCT was present in 8% (7/99), in 21% of trisomy 12 cases and in 16,6% of patients with no other genetic prognostic markers. The presence of NOTCH1 mutation had no impact on outcome. Comparing baseline characteristics between patients with or without mutations, no significant differences were found for age, sex, stage, B symptoms, blood cell counts, LDH, ß2-microglobulin. TP53 mutations were found in 2 out of 33 patients (6%). TP53p.R181P and p.249_251del10ins3 were present in two cases with 17p deletion detected by FISH. Thirtynine patients (35%) displayed an unmutated IGHV status, 68 cases (61%) had a mutated IGHV gene while 4 cases had a borderline IGHV mutation status. Unmutated IGHV status was an indipendent prognostic factor for worse overall survival (median survival 110 months 95%CI 85-303, p value= 0,02). The IGHV gene family usage within the mutated group was VH4>VH3>VH2>VH1>VH7, whereas IGHV 3 was the most frequently used in the unmutated group, being expressed in 13 patients. IGHV 1-69 genes were present in 3 CLL patients overall (2 unmutated). Correlation between cytogenetic categories and mutation status showed that the poor prognostic marker 17p deletion was present in 4/36 (11,0%) of unmutated CLLs and in 2/55 (3,6%) of mutated cases while 13q14 deletion was statistically associated with the 45% of mutated cases (p=0.0089). Conclusion In our cohort of unselected patients NOTCH1 mutation didn’t affect outcome of CLL patients, while TP53 deletion/mutation and IGHV mutational status maintain a strong prognostic negative impact. Treatment heterogeneity is likely the reason of absence of difference in outcome in our study. In current clinical practice prognostic markers need yet to be validated in large clinical trials, not biased by stringent selection criteria. Disclosures: No relevant conflicts of interest to declare.

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