Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL
- 2 May 2017
- journal article
- Published by American Society of Hematology in Blood Advances
- Vol. 1 (12), 715-727
- https://doi.org/10.1182/bloodadvances.2016003632
Abstract
Ibrutinib has generated remarkable responses in patients with chronic lymphocytic leukemia (CLL), including those with an unfavorable cytogenetic profile. However, patients develop resistance, with poor outcomes and no established treatment options. Mutations in BTK and PLCG2 have emerged as main mechanisms of drug resistance, but not all patients carry these mutations. Further understanding of mechanisms of resistance is urgently needed and will support rational development of new therapeutic strategies. To that end, we characterized the genomic profiles of serial samples from 9 patients with ibrutinib-relapsed disease, including 6 who had Richter transformation. Mutations, indels, copy-number aberrations, and loss of heterozygosity were assessed using next-generation sequencing and single-nucleotide polymorphism array. We found that 18p deletion (del(18p)), together with del(17p)/TP53 mutations, was present in 5 of 9 patients before ibrutinib therapy. In addition to BTKC481, we identified BTKT316A, a structurally novel mutation located in the SH2 domain of BTK. Minor BTK clones with low allele frequencies were captured in addition to major BTK clones. Although TP53 loss predisposes patients for relapse, clone size of TP53 loss may diminish during disease progression while mutant BTK clone expands. In patients who had Richter transformation, we found that the transformed cells were clonal descendants of circulating leukemia cells but continued to undergo evolution and drifts. Surprisingly, transformed lymphoma cells in tissue may acquire a different BTK mutation from that in the CLL leukemia cells. Collectively, these results provide insights into clonal evolution underlying ibrutinib relapse and prompt further investigation on genomic abnormalities that have clinical application potential.Keywords
This publication has 41 references indexed in Scilit:
- Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndromeThe Journal of Experimental Medicine, 2013
- Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndromeBlood, 2013
- Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell LymphomaNew England Journal of Medicine, 2013
- Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell MalignanciesJournal of Clinical Oncology, 2013
- Integrative Genomics Viewer (IGV): high-performance genomics data visualization and explorationBriefings in Bioinformatics, 2012
- Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencingProceedings of the National Academy of Sciences of the United States of America, 2012
- The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformationBlood, 2011
- Integrative genomics viewerNature Biotechnology, 2011
- The Sequence Alignment/Map format and SAMtoolsBioinformatics, 2009
- Gene Expression Omnibus: NCBI gene expression and hybridization array data repositoryNucleic Acids Research, 2002