scholarly journals Analysis of Clonal Evolution in Chronic Lymphocytic Leukemia from Inactive to Symptomatic Disease Prior Treatment Using Whole-Exome Sequencing

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3206-3206
Author(s):  
María Hernández-Sánchez ◽  
Lenka Radova ◽  
Jana Kotaskova ◽  
David Tamborero ◽  
Ana E Rodriguez ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Inactive Disease ◽  
Driver Mutations ◽  
Clinical Progression ◽  
Cytogenetic Aberration ◽  
First Time ◽  
Time Point

Abstract Clonal evolution is considered as a hallmark of progression in chronic lymphocytic leukemia (CLL). Next-generation sequencing technologies have expanded our knowledge of genetic abnormalities in CLL and enabled to describe marked clonal changes. The acquisition of driver mutations accompanied by selectively neutral passenger changes may be essential to understand the transformation from diagnosis to later more aggressive stages. However, the role of genetic mutations and clonal evolution during the clinical progression prior any therapy is still largely unknown. Longitudinal studies analyzing CLL patients repeatedly before intervening treatment are currently scarce. Patients and methods: We examined the exomes from 35 CLL patients in 2 time-points. Two groups of patients were characterized: (i)patients with progression (n=26) in which we analyzed samples taken from an early stable stage (inactive disease) and during clinical progression (active disease), but before treatment (median of time to first treatment=2.7 years); (ii)patients without progression with a stable inactive disease until last follow-up (n=9) (median follow-up=5.25 years). We also compared patients that gained new cytogenetic aberration detected by FISH in the 2nd time-point with those who did not. Sequencing libraries were prepared using TruSeq Exome Enrichment and sequenced by Illumina HiSeq1000 (84X). Somatic mutation calling was performed by a standardized bioinformatics pipeline. Thereafter, driver mutations were identified using the Cancer Genome Interpreter (https://www.cancergenomeinterpreter.org), a novel tool that identifies variants that are already validated as oncogenic and predicts the effect of the mutations of unknown significance. Results: We identified 397 somatic mutations in 364 different genes, ranging from 4 to 26 mutations per patient. Among them, 58 driver mutations were identified, being SF3B1 (6/35, 17.1%), TP53 (4/35, 11.4%) and NOTCH1 (4/35, 11.4%) the most common mutated genes. Comparing progressive vs. stable group, CLL patients with clinical progression showed a higher intra-tumoral heterogeneity than cases without progression (median of somatic mutations=14[4-26] vs. 9[5-14]). Comparing both tumoral time-points in the same patient, we identified a total of 11 acquired driver mutations and 7 mutations increasing its allele frequency in more than double in the 2nd time-point respect to the 1st one. All of them were detected in patients with clinical progression. Interestingly, TP53 and BIRC3 exhibited recurrently acquired mutations (detected each one in 2 cases). Three driver mutations in cancer genes not yet known for CLL (DHX9, GNAQ and HDAC2) were also acquired. Within CLL progressive patients (n=26), we observed clonal evolution characterized by acquired cytogenetic aberration in 9 cases. In patients with progression but no cytogenetic aberration gained at the 2nd moment (n=17), we detected that almost half of them (7/17) showed clonal evolution by acquired or doubled driver mutations. In the remaining patients with clinical progression but without any clonal evolution (n=10), 6 cases showed a driver mutation of CLL genes associated with bad prognosis (SF3B1, TP53, NOTCH1 or RPS15) already at first time-point. In the stable group (n=9), none acquired or doubled mutation was detected. However, clonal evolution characterized by acquired cytogenetic aberration was observed in 4/9 stable patients: two of them acquired 13q- whereas the other two acquired 11q-. Within stable patients without clonal evolution (n=5), we detected one case with a driver mutation in SF3B1 already at 1st time-point (follow-up=5 years). Conclusion: Clonal evolution represents a central feature of tumor progression in CLL. Our data show that the disease is evolving during time even in stable patients without any clinical signs of disease activity. In progressive patients, the disease evolution is accompanied by new appearance or accumulation of driver mutations and cytogenetic aberrations. Moreover, progressive patients that showed less or no changes during time bore typical CLL drivers at the first time-point. Funding: Seventh Framework Programme (NGS-PTL/2012-2015/no.306242); Ministry of Education, Youth and Sports (2013-2015, no.7E13008; CEITEC 2020 (LQ1601)); AZV-MZ-CR 15-31834A-4/2015 and TACR (TEO2000058/2014-2019); PI15/01471; Junta de Castilla y León (MHS). Disclosures No relevant conflicts of interest to declare.

Genomic Analysis of Serial Chronic Lymphocytic Leukemia Samples Suggests That Epigenetic Changes, Rather Than Clonal Evolution, May Drive the Progression of This Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4563-4563
Author(s):  
Emanuela M. Ghia ◽  
Erin Smith ◽  
Christopher DeBoever ◽  
Laura Z. Rassenti ◽  
Sophie Rozenzhak ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Somatic Mutations ◽  
Conflicts Of Interest ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Epigenetic Changes ◽  
Sample Collection ◽  
Aggressive Disease ◽  
Indolent Disease ◽  
Time Point

Abstract Abstract 4563 The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous, with some patients requiring treatment relatively soon after diagnosis and others having indolent disease for many years. Some patients with indolent disease, however may develop more aggressive disease over time that requires therapy. To identify genetic and epigenetic changes that associate with the transition from indolent to aggressive disease, we used genomic methods to analyze sequential samples obtained from 19 CLL patients evaluated at the UC San Diego Moores Cancer Center who ultimately required treatment, as per iwCLL guidelines. For all patients, the first time point sample collection (SC1) was obtained within 1 year post-diagnosis and the second time point sample collection (SC2) was obtained within 1 year before treatment. We performed whole-exome sequencing (Agilent 50Mb capture, 100×) and methylation (450K) array analyses on leukemia cells and germline DNA. Somatic allele frequencies ranged from < 10% to 50%, suggesting heterogeneity within the tumor. When comparing SC1 versus SC2, we observed changes in somatic allele frequency for 6 (32%) of 19 patients, however 13 (68%) of 19 patients did not have evidence for clonal evolution at the somatic level, suggesting that the acquisition of additional somatic mutations did not drive CLL progression and that the clonal population structure remains stable throughout disease progression with multiple clones per patient. Using 450K CpG methylation arrays, we identified 52,409 sites (FDR=0.05) that changed consistently between SC1 and SC2 across 19 patients, suggesting that epigenetic changes were widespread, even without detectable somatic mutations. In summary, our results imply that CLL progression can occur in the absence of somatic mutations, but rather may reflect non-stochastic alterations in the epigenome altering RNA expression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Immunological and genetic kinetics from diagnosis to clinical progression in chronic lymphocytic leukemia

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Isabel Jiménez ◽  
Bárbara Tazón-Vega ◽  
Pau Abrisqueta ◽  
Juan C. Nieto ◽  
Sabela Bobillo ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Ex Vivo ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Clinical Progression ◽  
Molecular Changes ◽  
Main Driver ◽  
Altered Gene

Abstract Background Mechanisms driving the progression of chronic lymphocytic leukemia (CLL) from its early stages are not fully understood. The acquisition of molecular changes at the time of progression has been observed in a small fraction of patients, suggesting that CLL progression is not mainly driven by dynamic clonal evolution. In order to shed light on mechanisms that lead to CLL progression, we investigated longitudinal changes in both the genetic and immunological scenarios. Methods We performed genetic and immunological longitudinal analysis using paired primary samples from untreated CLL patients that underwent clinical progression (sampling at diagnosis and progression) and from patients with stable disease (sampling at diagnosis and at long-term asymptomatic follow-up). Results Molecular analysis showed limited and non-recurrent molecular changes at progression, indicating that clonal evolution is not the main driver of clinical progression. Our analysis of the immune kinetics found an increasingly dysfunctional CD8+ T cell compartment in progressing patients that was not observed in those patients that remained asymptomatic. Specifically, terminally exhausted effector CD8+ T cells (T-betdim/−EomeshiPD1hi) accumulated, while the the co-expression of inhibitory receptors (PD1, CD244 and CD160) increased, along with an altered gene expression profile in T cells only in those patients that progressed. In addition, malignant cells from patients at clinical progression showed enhanced capacity to induce exhaustion-related markers in CD8+ T cells ex vivo mainly through a mechanism dependent on soluble factors including IL-10. Conclusions Altogether, we demonstrate that the interaction with the immune microenvironment plays a key role in clinical progression in CLL, thereby providing a rationale for the use of early immunotherapeutic intervention.

scholarly journals Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia

Blood ◽  
2013 ◽  
Vol 121 (22) ◽  
pp. 4541-4550 ◽  
Author(s):  
Hanna L. M. Rajala ◽  
Samuli Eldfors ◽  
Heikki Kuusanmäki ◽  
Arjan J. van Adrichem ◽  
Thomas Olson ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Somatic Mutations ◽  
Sh2 Domain ◽  
Lymphocytic Leukemia ◽  
Large Granular Lymphocytic Leukemia ◽  
Key Points ◽  
First Time ◽  
Lgl Leukemia

Key Points Somatic mutations were discovered for the first time in the SH2 domain of the STAT5b gene in LGL leukemia. The mutations are activating and lead to increased phosphorylation and transcriptional activity of STAT5b.

scholarly journals Clinical Relevance of Clonal Hematopoiesis in the Oldest-Old Population: Analysis of the "Health and Anemia" Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 750-750
Author(s):  
Marianna Rossi ◽  
Manja Meggendorfer ◽  
Matteo Zampini ◽  
Mauro Tettamanti ◽  
Emma Riva ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Clonal Evolution ◽  
Oldest Old ◽  
Vascular Diseases ◽  
Employment Equity ◽  
Clonal Hematopoiesis ◽  
Increased Risk ◽  
Equity Ownership ◽  
The Relationship

Abstract Background. Age-dependent clonal expansion of somatic mutations in the hematopoietic system is associated with an increased risk of hematological cancers (including myelodysplastic syndromes, MDS) and other illnesses (coronary heart disease and stroke). However, the presence of clonal hematopoiesis per se in a given individual has only limited predictive power. We hypothesized that the study of oldest-old population can define more specifically the relationship between mutations in the hematopoietic system and risk for MDS, inflammation and vascular diseases. Methods. We analyzed 1004 oldest-old subjects (median age 84.2y, range 80-105) included in the "Health and Anemia" population-based study [Haematologica 2010;95:1849]. Using peripheral blood DNA, we looked for somatic mutations in 47 genes recurrently mutated in hematologic cancers. Results. Clonal mutations were observed in 32.8% of individuals (range 1-5). The majority of variants occurred in 3 genes: DNMT3A (36.4%), TET2 (24.3%) and ASXL1 (6.5%). Mutations in splicing genes, PPM1D and TP53 were found in 7.4%, 5% and 2% of cases, respectively. The mutation frequencies increased with age, up to 50% in individuals aged over 90 years (P=.011). Clonal hematopoiesis was associated with a lower 5-y probability of survival (P=.03), and prognosis was even poorer in patients carrying ≥2 mutations (P=.002) We first focused on the relationship between clonal hematopoiesis and MDS phenotype. Carrying a somatic mutation with a variant allele frequency (VAF) ≥.10, carrying ≥2 mutations, spliceosome gene mutations and co-mutation patterns involving TET2, DNMT3A had a positive predictive value for MDS (from .85 to 1.0). The most frequent early phenotypic changes in patients who developed MDS included an increasing red blood cell distribution width (RDW) and mean corpuscular volume (MCV). Preliminary analyses suggested that the combination of mutations and non-mutational factors (RDW, MCV, after excluding iron/vitamin depletion and thalassemia) may improve the capability to capture individual risk of developing MDS with respect to molecular data alone (P=.01) We studied clonal evolution in 72 patients with multiple samples available over a period of 5y. Clonal hematopoiesis was found at baseline in 22 cases: 2 individuals acquired additional mutations during follow-up, and 5 displayed significant increase in VAF. In 9 subjects without clonal hematopoiesis, mutations were acquired during follow-up. RDW and MCV changes, induction of unexplained cytopenia and overt MDS phenotype were significantly restricted to subjects displaying clonal evolution. We hypothesized that in oldest-old populations MDS could be underdiagnosed (many patients are not considered for bone marrow aspiration because of age). Cytopenia was a common finding in our cohort (20%) the underlying cause remaining unexplained in 27% of cases. In patients with unexplained anemia, carrying a somatic mutation had a positive predictive value for persistent, progressive, multilineage cytopenia (findings consistent with a MDS phenotype) and shorter survival (from .8 to .94). On this basis, 8% of all cytopenias might be undiagnosed MDS. Finally, we investigated the association between clonal hematopoiesis with inflammatory and vascular diseases. Mutations in DNMT3A, TET2, and ASXL1 were each individually associated with risk of coronary heart disease and death, and preliminary analyses suggest that clonal hematopoiesis is also associated with increased risk of rheumatological diseases (P from .03 to.009). We identified mutations in macrophages isolated from synovial fluid of 4/17 patients with rheumatoid arthritis and from atherosclerotic plaques of 3/25 patients with carotid stenosis. Functional studies of macrophages (expression of specific chemokine and cytokine gene patterns) are ongoing. All these findings are under validation in an independent cohort of 800 subjects enrolled in the "Monzino 80-plus" study [Alzheimers Dement 2015;11:258]]. Conclusion. Clonal hematopoiesis was associated with reduced survival in an oldest-old population. Specific mutational profiles define different risks of developing MDS and inflammatory/vascular diseases. Non mutational factors, such as early changes in red blood cell indices, may improve the capability to identify patients at increased risk of developing myeloid cancers. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Bolli:Celgene: Honoraria. Vassiliou:KYMAB: Consultancy, Equity Ownership; Celgene: Research Funding. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

scholarly journals Monosomy 7 As the Initial Hit Followed By Sequential Acquisition of SETBP1 and ASXL1 Driver Mutations in Childhood Myelodysplastic Syndromes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 105-105 ◽  
Author(s):  
Victor Pastor Loyola ◽  
Pritam Kumar Panda ◽  
Sushree Sangita Sahoo ◽  
Enikoe Amina Szvetnik ◽  
Emilia J. Kozyra ◽  
...  
Keyword(s):  
Deep Sequencing ◽  
Myelodysplastic Syndromes ◽  
Somatic Mutations ◽  
Clonal Evolution ◽  
Driver Mutations ◽  
Common Denominator ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Clonal Architecture ◽  
Over Time

Abstract Childhood myelodysplastic syndromes (MDS) account for less than 5% of pediatric hematologic malignancies and differ from their adult counterpart in terms of biology, genetics, and cure rates. Complete (-7) or partial loss (del7q) of chromosome 7 constitutes the most common cytogenetic abnormality and is associated with more advanced disease typically requiring timely hematopoietic stem cell transplantation (HSCT). Previously, we and others established a link between -7 and germline GATA2 mutations in pediatric MDS (37% of MDS/-7 cases are GATA2-deficient) as well as constitutional SAMD9/9L disorders where -7 is utilized as an escape mechanism from the growth-restrictive effect of SAMD9/9L mutations. To date, comprehensive sequencing studies have been performed in 96 children with primary MDS, as reported by Pastor et al, Leukemia 2017 and Schwartz et al, Nature Comm 2017. This work established mutations in SETBP1, ASXL1, PTPN11, RUNX1 and RAS pathway genes as common somatic drivers. However, little is known about the clonal development of -7 and the role of additional somatic mutations. The knowledge about clonal hierarchies is essential for the understanding of disease progression on molecular level and for mapping potential drug targets. The rationale for the current study was to i) define the most common somatic drivers in a large cohort of patients with childhood MDS, ii) identify clonal/subclonal mutations, iii) infer clonal architecture of monosomy 7 and track the changes over time. We studied a cohort of 576 children and adolescents with primary MDS diagnosed between 1998 and 2016 in Germany, consisting of 482 (83%) patients with refractory cytopenia of childhood (RCC) and 94 (17%) MDS with excess blasts (EB). All patients underwent deep sequencing for 30 genes relevant to pediatric MDS and additional WES was performed in 150/576 patients. Using 20 computational predictors (including CADD and REVEL), population databases and germline testing, we identified the most likely pathogenic mutations. First, we excluded germline predisposing mutations in GATA2, SAMD9/SAMD9L and RUNX1 detected in 7% (38/576), 8% (43 of 548 evaluable) and 0.7% (4/576) of patients, respectively. Then we focused on the exploration of somatic aberrations. Most common karyotype abnormalities were monosomy 7 (13%, 77/576) and trisomy 8 (3%, 17/576). A total of 104 patients carried somatic mutations, expectedly more prevalent in the MDS-EB group as compared to RCC (56%, 53/94 vs 10.6%, 51/482; p<0.0001). The most recurrent somatic hits (≥ 1% frequency within 576 cases) were in SETBP1 (4.2%), ASXL1 (3.8%), RUNX1 (3.3%), NRAS (2.9%), KRAS (1.6%), PTPN11 (1.4%) and STAG2 (1%). We next focused on the -7 karyotype as a common denominator for the mutated group. Mutations were found in 54% (43/79), and the mutational load was significantly higher in -7 vs. non-7 (1.1 vs. 0.1 mutations per patient; p<0.001). In 11 patients with -7 and concomitant SETBP1/ASXL1 driver mutations, SETBP1 surpassed ASXL1 hits (median allelic frequency: 38% vs. 24%, p<0.05), while mutations in other genes were subclonal. Notably, these clonal patterns were independent of the underlying hereditary predisposition (4/11 GATA2; 3/11 SAMD9L). To explore the clonal hierarchy in MDS/-7 we performed targeted sequencing of several hundreds of single bone marrow derived colony forming cells (CFC) in 7 patients with MDS/-7. In all cases, the -7 clone was the founding clone followed by stepwise acquisition of mutations (i.e. -7>SETBP1>ASXL1; -7>SETBP1>ASXL1>PTPN11; -7>SETBP1>ASXL1>CBL, -7>EZH2>PTPN11). Finally, we tracked clonal evolution over time in 12 cases with 2-12 available serial samples using deep sequencing complemented by serial CFC-analysis. This confirmed that SETBP1 clones are rapidly expanding, while ASXL1 subclones exhibit an unstable pattern with clonal sweeping, while additional minor clones are acquired as late events. In 2 of 11 transplanted patients who experienced relapse, the original clonal architecture reappeared after HSCT. In summary, the hierarchy of clonal evolution in pediatric MDS with -7 follows a defined pattern with -7 aberrations arising as ancestral event followed by the acquisition of somatic hits. SETBP1 mutations are the dominant driver while co-dominant ASXL1 mutations are unstable. The functional interdependence and potential pharmacologic targetability of such somatic lesions warrants further studies. Disclosures Niemeyer: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Anticipating High-Risk Chromosome Clonal Evolution in Chronic Lymphocytic Leukemia: A Next Generation Sequencing and Longitudinal FISH Combined Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3305-3305
Author(s):  
Ana Maria Hurtado ◽  
Chahinez Hamedi ◽  
Bartlomiej P Przychodzen ◽  
Ana I. Anton ◽  
Maria Dolores Garcia-Malo ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Next Generation ◽  
Mutational Hotspots ◽  
Generation Sequencing ◽  
11Q Deletion

Abstract Background: Chronic lymphocytic leukemia (CLL), the most common leukemia of adults in Western countries, is clinically characterized by a variable clinical outcome, ranging from indolent to agressive cases. The acquisition of new 17p and/or 11q chromosomal lesions during the disease course (high-risk chromosomal clonal evolution), detected either by FISH or conventional cytogenetics has been shown to confer an adverse prognosis. In a high proportion of these patients, a concomitant p53 and ATM mutation can be found in the remaining allele. Next Generation Sequencing (NGS) of tumors is now an affordable, rapid and comprehensive technology for detecting somatic coding mutations and its depth-sensitivity enables reliable detection of subclonal mutations not detectable by classic methods. The aim of this study was to assesed whether the presence of a detectable p53 or ATM mutation by NGS might anticipate a high risk chromosomal clonal evolution during the follow up. Methods: To this end, we performed targeted NGS sequencing of blood samples from 168 CLL patients at diagnosis who did not present a 17p and/or 11q deletion by FISH and did not meet criteria for active treatment. We designed a TruSeq Custom Amplicon panel (TSCA, Illumina) targeting 12 genes recurrently mutated in CLL, including p53 and ATM. In genes with well-defined mutational hotspots only these regions were targeted; otherwise the entire coding sequence of the gene was sequenced. The panel covers a total of 46605 base pairs with 305 amplicons. Libraries prepared from 250 ng DNA were subjected to 250 bp paired-end sequencing. A second FISH was perfomed in the course of the disease if progression data fullfilling criteria for starting therapy was observed or during of the third year of disease follow up otherwise. Results: With a median age of 71 y.o. (range, 43-95) and a slight male predominance (56%), the median follow up time of our cohort was 43 months (24-104). Median absolute lymphocyte count at baseline was 17660/uL (interquartile range, 7300-25250), with a 49% and 33% of ZAP70 and CD38 positive cases, respectively. At baseline, 52% of patients presented a 13q deletion and 13% a trisomy 12.Twenty-eight percent of patients presented, at least, a panel mutation, being NOTCH1 the gene most frequenly mutated (n=14).Thirteen patients (9%) developed a high risk chromosomal clonal evolution during the follow up: 8 patients acquired a 17p deletion and 5 cases a 11q deletion. In eight out of these cases, a p53/ATM mutation could be found in the baseline simple, with a clonal size ranging from 4% to 50% (median=9%). The presence of a p53/ATM mutation was associated with de development od a high-risk chromosomal clonal evolution (p=0.02) Conclusions: Our study shows, in a clinical setting, that the use of targeted next-generation sequencing technology can anticípate the high-risk chromosomal clonal evolution during the follow up in a subset of patients with chronic lymphocytic leukemia, Disclosures No relevant conflicts of interest to declare.

Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms

Blood ◽  
2014 ◽  
Vol 123 (14) ◽  
pp. 2220-2228 ◽  
Author(s):  
Pontus Lundberg ◽  
Axel Karow ◽  
Ronny Nienhold ◽  
Renate Looser ◽  
Hui Hao-Shen ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Myeloproliferative Neoplasms ◽  
Clonal Evolution ◽  
Great Majority ◽  
Leukemic Transformation ◽  
Clinical Correlates ◽  
Key Points ◽  
New Mutations

Key Points The total number of somatic mutations was inversely correlated with survival and risk of leukemic transformation in MPN. The great majority of somatic mutations were already present at MPN diagnosis, and very few new mutations were detected during follow-up.

scholarly journals Driver Mutations and Single Copy Number Abnormalities Identify Binet Stage A Patients with Chronic Lymphocytic Leukemia with Aggressive Progression

2020 ◽  
Vol 9 (11) ◽  
pp. 3695
Author(s):  
Ana P. Gonzalez-Rodriguez ◽  
Angel R. Payer ◽  
Juan J. Menendez-Suarez ◽  
Christian Sordo-Bahamonde ◽  
Seila Lorenzo-Herrero ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Copy Number ◽  
Statistical Significance ◽  
Single Copy ◽  
Lymphocytic Leukemia ◽  
Driver Mutations ◽  
Genetic Characteristics ◽  
Risk Of Progression ◽  
Binet Stage

The correlation between progression and the genetic characteristics of Binet stage A patients with chronic lymphocytic leukemia (CLL) detected by whole exome sequencing (WES) was analyzed in 55 patients. The median follow-up for the patients was 102 months. During the follow-up, 24 patients (43%) progressed. Univariate Cox analysis showed that the presence of driver mutations, the accumulation of two or more mutations, the presence of adverse mutations, immunoglobulin heavy chain genes (IGHV) mutation status and unfavorable single copy number abnormalities (SCNAs) were associated with a higher risk of progression. Particularly, the occurrence of an adverse mutation and unfavorable SCNAs increased the risk of progression nine-fold and five-fold, respectively. Nevertheless, only the occurrence of adverse mutations retained statistical significance in the multivariate analysis. All patients carrying an unfavorable mutation progressed with a median progression-free survival (PFS) of 29 months. The accumulation of two or more mutations also increased the risk of progression with a median PFS of 29 months. The median PFS of patients with unfavorable SCNAs was 38 months. Combining mutations and SCNAs, patients may be stratified into three groups with different prognostic outcomes: adverse (17% probability of five-year PFS), protective (86% probability of five-year PFS) and neither (62% probability of five-year PFS, p < 0.001). Overall, the analysis of the mutational status of patients with CLL at an early stage of the disease may allow the identification of patients with a high risk of progression. The feasibility of an early therapeutic intervention in these particular patients requires further investigation.

scholarly journals Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia

Blood ◽  
2017 ◽  
Vol 129 (11) ◽  
pp. 1469-1479 ◽  
Author(s):  
Inhye E. Ahn ◽  
Chingiz Underbayev ◽  
Adam Albitar ◽  
Sarah E. M. Herman ◽  
Xin Tian ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clonal Evolution ◽  
High Sensitivity ◽  
Lymphocytic Leukemia ◽  
Resistance Mutations ◽  
Clinical Progression ◽  
Sensitivity Testing ◽  
Key Points ◽  
Ibrutinib Resistance

Key Points Most cases of ibrutinib-resistant CLL were due to mutations in BTK and/or PLCG2 and often composed of multiple independent subclones. High sensitivity testing identified resistance mutations up to 15 months before manifestation of clinical progression.

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