Circulating tumour DNA reflects treatment response and clonal evolution in chronic lymphocytic leukaemia

Several novel therapeutics are poised to change the natural history of chronic lymphocytic leukaemia (CLL) and the increasing use of these therapies has highlighted limitations of traditional disease monitoring methods. Here we demonstrate that circulating tumour DNA (ctDNA) is readily detectable in patients with CLL. Importantly, ctDNA does not simply mirror the genomic information contained within circulating malignant lymphocytes but instead parallels changes across different disease compartments following treatment with novel therapies. Serial ctDNA analysis allows clonal dynamics to be monitored over time and identifies the emergence of genomic changes associated with Richter's syndrome (RS). In addition to conventional disease monitoring, ctDNA provides a unique opportunity for non-invasive serial analysis of CLL for molecular disease monitoring.

[1]  Sigrid Stroobants,et al.  Revised response criteria for malignant lymphoma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  T. Kipps,et al.  Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. , 2016, The New England journal of medicine.

[3]  A. Børresen-Dale,et al.  The Life History of 21 Breast Cancers , 2012, Cell.

[4]  Georgina L Ryland,et al.  A simple consensus approach improves somatic mutation prediction accuracy , 2013, Genome Medicine.

[5]  Dirk C. Keene.  Acknowledgements , 1975 .

[6]  Juthamas Sukbuntherng,et al.  Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. , 2013, The New England journal of medicine.

[7]  D. Rossi.  Venetoclax: a new weapon to treat high-risk CLL. , 2016, The Lancet. Oncology.

[8]  Z. Szallasi,et al.  Sequenza: allele-specific copy number and mutation profiles from tumor sequencing data , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[9]  J. Byrd,et al.  Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. , 2014, The New England journal of medicine.

[10]  Gisela Mir Arnau,et al.  UV-Associated Mutations Underlie the Etiology of MCV-Negative Merkel Cell Carcinomas. , 2015, Cancer research.

[11]  Michael Hallek,et al.  Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. , 2008, Blood.

[12]  Jeffrey A Jones,et al.  Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. , 2014, Blood.

[13]  C. Nabhan,et al.  Minimal residual disease in chronic lymphocytic leukaemia: is it ready for primetime? , 2007, British journal of haematology.

[14]  M Hummel,et al.  Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936 , 2003, Leukemia.

[15]  A. McKenna,et al.  Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia , 2012, Cell.

[16]  Jiajie Zhang,et al.  PEAR: a fast and accurate Illumina Paired-End reAd mergeR , 2013, Bioinform..

[17]  Laurens P. Kil,et al.  Targeting Bruton's tyrosine kinase in B cell malignancies , 2014, Nature Reviews Cancer.

[18]  S. Pileri,et al.  The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. , 2011, Blood.

[19]  Martin A. Nowak,et al.  Mutations driving CLL and their evolution in progression and relapse , 2015, Nature.

[20]  K. Kinzler,et al.  IgH gene rearrangements as plasma biomarkers in Non-Hodgkin's Lymphoma patients , 2011, Oncotarget.

[21]  E. Montserrat,et al.  Improving efficiency and sensitivity: European Research Initiative in CLL (ERIC) update on the international harmonised approach for flow cytometric residual disease monitoring in CLL , 2013, Leukemia.

[22]  P. Smolewski,et al.  Emerging immunological drugs for chronic lymphocytic leukemia , 2015, Expert opinion on emerging drugs.

[23]  Ash A. Alizadeh,et al.  Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. , 2015, Blood.

[24]  J. Byrd,et al.  Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. , 2014, The New England journal of medicine.

[25]  Kenneth D. Doig,et al.  Assessing the clinical value of targeted massively parallel sequencing in a longitudinal, prospective population-based study of cancer patients , 2015, British Journal of Cancer.

[26]  L. Larocca,et al.  Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis , 2011, International journal of cancer.

[27]  Juliane C. Dohm,et al.  Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia , 2011, Nature.

[28]  E. Giné,et al.  Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia , 2011, Nature Genetics.

[29]  Luca Laurenti,et al.  Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. , 2012, Blood.

[30]  Pieter Wesseling,et al.  DNA copy number analysis of fresh and formalin-fixed specimens by shallow whole-genome sequencing with identification and exclusion of problematic regions in the genome assembly , 2014, Genome research.

[31]  J. Byrd,et al.  Entering the era of targeted therapy for chronic lymphocytic leukemia: impact on the practicing clinician. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  Simon Tavaré,et al.  multiSNV: a probabilistic approach for improving detection of somatic point mutations from multiple related tumour samples , 2015, Nucleic acids research.

[33]  L. Lam,et al.  ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets , 2013, Nature Medicine.

[34]  A. Sivachenko,et al.  SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. , 2011, The New England journal of medicine.

[35]  J. Byrd,et al.  International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia , 2007, Leukemia.

[36]  Jeffrey A Jones,et al.  Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. , 2015, JAMA oncology.

[37]  Catherine J. Wu,et al.  Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia. , 2015, Blood.

[38]  H. Döhner,et al.  Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  A. Zelenetz,et al.  Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. , 2014, The New England journal of medicine.

[40]  L. Staudt,et al.  Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. , 2015, The Lancet. Oncology.

[41]  S. Halgamuge,et al.  Inferring copy number and genotype in tumour exome data , 2014, BMC Genomics.

[42]  S. Ferrari,et al.  Author contributions , 2021 .

[43]  Carlos Caldas,et al.  Analysis of circulating tumor DNA to monitor metastatic breast cancer. , 2013, The New England journal of medicine.