Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL

Sabah Kadri, Jimmy Lee, Carrie Fitzpatrick, Natalie Galanina, Madina Sukhanova, Girish Venkataraman, Shruti Sharma, Brad Long, Kristin Petras, Megan Theissen, Mei Ming, Yuri Kobzev, Wenjun Kang, Ailin Guo, Weige Wang, Nifang Niu, Howard Weiner, Michael Thirman, Wendy Stock, Sonali M. SmithChadi Nabhan, Jeremy P. Segal, Pin Lu, Y. Lynn Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

96 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)715-727
Number of pages13
JournalBlood Advances
Issue number12
StatePublished - May 9 2017

ASJC Scopus subject areas

  • Hematology


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