Clonal evolution in chronic lymphocytic leukemia detected by fluorescence in situ hybridization and conventional cytogenetics after stimulation with CpG oligonucleotides and interleukin-2: A prospective analysis

Brejcha, M; Stoklasová, M.; Brychtová, Yvona; Panovská, Anna; Štěpanovská, Kristina; Vaňková, Gabriela; Plevová, Karla; Oltová, Alexandra; Horká, Kateřina; Pospı́šilová, Šárka; Mayer, Jiřı́; Doubek, Michael

doi:10.1016/j.leukres.2013.10.019

Cited by 14 publications

(13 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CpG mitogen‐stimulated methods increase the sensitivity to detect karyotype abnormalities in CLL (Thompson et al , 2015), and our data provide a strong rationale for considering more routine application of this method, particularly among patients with del(17p). The extent of prior exposure to cytotoxic chemotherapy is associated with clonal evolution to genetically high‐risk disease, including del(17p) and cytogenetic complexity (Brejcha et al , 2014; Malcikova et al , 2015), further suggesting that precision therapeutics should be used earlier in the course of disease. Likewise, the likelihood that patients in this high‐risk group with R/R disease may develop resistance to a single‐agent targeted therapy provides a compelling rationale for combination treatment approaches (Woyach et al , 2014).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

et al. 2018

View full text Add to dashboard Cite

SummaryPatients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) with deletion 17p [del(17p)] have poor outcomes with chemoimmunotherapy. Ibrutinib is indicated for the treatment of CLL/SLL, including del(17p) CLL/SLL, and allows for treatment without chemotherapy. This integrated analysis was performed to evaluate outcomes in 230 patients with relapsed/refractory del(17p) CLL/SLL from three ibrutinib studies. With a median of 2 prior therapies (range, 1–12), 18% and 79% of evaluable patients had del(11q) or unmutated IGHV, respectively. With a median follow‐up of 28 months, overall response rate was 85% and estimated 30‐month progression‐free and overall survival rates were 57% [95% confidence interval (CI) 50–64] and 69% (95% CI 61–75), respectively. Patients with normal lactate dehydrogenase or no bulky disease had the most favourable survival outcomes. Sustained haematological improvements in haemoglobin, platelet count and absolute neutrophil count occurred in 61%, 67% and 70% of patients with baseline cytopenias, respectively. New onset severe cytopenias and infections decreased in frequency over time. Progression‐free and overall survival with ibrutinib surpass those of other therapies for patients with del(17p) CLL/SLL. These results provide further evidence of the robust clinical activity of ibrutinib in difficult‐to‐treat CLL/SLL populations.

show abstract

Section: Discussionmentioning

confidence: 99%

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

et al. 2018

View full text Add to dashboard Cite

show abstract

“…6, [12][13][14] Combined copy number analysis 13,[15][16][17][18][19][20] and NGS 11,12,21 have shown that CLL cases may be composed of heterogeneous tumor cell populations with subclonal mutations that may evolve over the course of the disease and influence its biological behavior. The acquisition and selection of genomic aberrations over the disease course may be critical to understanding the progression and resistance to treatment.…”

Section: Introductionmentioning

confidence: 99%

Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia

Nadeu

Delgado

Royo

et al. 2016

Blood

291

328

View full text Add to dashboard Cite

Key Points• Clonal and subclonal mutations of NOTCH1 and TP53, clonal mutations of SF3B1, and ATM mutations in CLL have an impact on clinical outcome.• Clonal evolution in longitudinal samples occurs before and after treatment and may have an unfavorable impact on overall survival.Genomic studies have revealed the complex clonal heterogeneity of chronic lymphocytic leukemia (CLL). The acquisition and selection of genomic aberrations may be critical to understanding the progression of this disease. In this study, we have extensively characterized the mutational status of TP53, SF3B1, BIRC3, NOTCH1, and ATM in 406 untreated CLL cases by ultra-deep next-generation sequencing, which detected subclonal mutations down to 0.3% allele frequency. Clonal dynamics were examined in longitudinal samples of 48 CLL patients. We identified a high proportion of subclonal mutations, isolated or associated with clonal aberrations. TP53 mutations were present in 10.6% of patients (6.4% clonal, 4.2% subclonal), ATM mutations in 11.1% (7.8% clonal, 1.3% subclonal, 2% germ line mutations considered pathogenic), SF3B1 mutations in 12.6% (7.4% clonal, 5.2% subclonal), NOTCH1 mutations in 21.8% (14.2% clonal, 7.6% subclonal), and BIRC3 mutations in 4.2% (2% clonal, 2.2% subclonal). ATM mutations, clonal SF3B1, and both clonal and subclonal NOTCH1 mutations predicted for shorter time to first treatment irrespective of the immunoglobulin heavy-chain variable-region gene (IGHV) mutational status. Clonal and subclonal TP53 and clonal NOTCH1 mutations predicted for shorter overall survival together with the IGHV mutational status. Clonal evolution in longitudinal samples mainly occurred in cases with mutations in the initial samples and was observed not only after chemotherapy but also in untreated patients. These findings suggest that the characterization of the subclonal architecture and its dynamics in the evolution of the disease may be relevant for the management of CLL patients. (Blood. 2016;127(17):2122-2130

show abstract

“…Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia of the Western world, and an incurable disease of remarkable genetic and clinical heterogeneity [1,2]. The identification of patients with indolent versus progressive disease remains a challenge of critical importance, and relies on clinical staging systems [3,4] in addition to molecular and cytogenetic markers, guiding the necessity, timing, and type of chemotherapeutic intervention [5].…”

Section: Introductionmentioning

confidence: 99%

FISHing in the dark: How the combination of FISH and conventional karyotyping improves the diagnostic yield in CpG‐stimulated chronic lymphocytic leukemia

et al. 2016

View full text Add to dashboard Cite

Despite significant advances in molecular genetic approaches, fluorescence in situ hybridization (FISH) remains the gold standard for the diagnostic evaluation of genomic aberrations in patients with chronic lymphocytic leukemia (CLL). Efforts to improve the diagnostic utility of molecular cytogenetic testing have led to the expansion of the traditional 4-probe CLL FISH panel. Not only do these efforts increase the cost of testing, they remain hindered by the inherent limitations of FISH studies -namely the inability to evaluate genomic changes outside of the targeted loci. While array-based profiling and next generation sequencing (NGS) have critically expanded our understanding of the molecular pathogenesis of CLL, these methodologies are not routinely used by diagnostic laboratories to evaluate copy number changes or the mutational profile of this disease. Mitogenic stimulation of CLL specimens with CpG-oligonucleotide (CpG-ODN) has been identified as a reliable and reproducible means of obtaining a karyotype, facilitating a low-resolution genomewide analysis. Across a cohort of 1255 CpG-ODN-stimulated CLL specimens, we describe the clinical utility associated with the combinatorial use of FISH and karyotyping. Our testing algorithm achieves a higher diagnostic yield (~10%) through the detection of complex karyotypes, well-characterized chromosomal aberrations not covered by the traditional CLL FISH panel and through the detection of concurrent secondary malignancies. Moreover, the single cell nature of this approach permits the evaluation of emerging new clinical concepts including clonal dynamics and clonal evolution. This approach can be broadly applied by diagnostic laboratories to improve the utility of traditional and molecular cytogenetic studies of CLL.

show abstract

Clonal evolution in chronic lymphocytic leukemia detected by fluorescence in situ hybridization and conventional cytogenetics after stimulation with CpG oligonucleotides and interleukin-2: A prospective analysis

Cited by 14 publications

References 22 publications

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia

FISHing in the dark: How the combination of FISH and conventional karyotyping improves the diagnostic yield in CpG‐stimulated chronic lymphocytic leukemia

Contact Info

Product

Resources

About