TY - JOUR
T1 - Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL
AU - Kadri, Sabah
AU - Lee, Jimmy
AU - Fitzpatrick, Carrie
AU - Galanina, Natalie
AU - Sukhanova, Madina
AU - Venkataraman, Girish
AU - Sharma, Shruti
AU - Long, Brad
AU - Petras, Kristin
AU - Theissen, Megan
AU - Ming, Mei
AU - Kobzev, Yuri
AU - Kang, Wenjun
AU - Guo, Ailin
AU - Wang, Weige
AU - Niu, Nifang
AU - Weiner, Howard
AU - Thirman, Michael
AU - Stock, Wendy
AU - Smith, Sonali M.
AU - Nabhan, Chadi
AU - Segal, Jeremy P.
AU - Lu, Pin
AU - Wang, Y. Lynn
N1 - Publisher Copyright:
© 2017 by The American Society of Hematology
PY - 2017/5/9
Y1 - 2017/5/9
N2 - 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.
AB - 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.
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U2 - 10.1182/bloodadvances.2016003632
DO - 10.1182/bloodadvances.2016003632
M3 - Article
C2 - 29296715
SN - 2473-9529
VL - 1
SP - 715
EP - 727
JO - Blood advances
JF - Blood advances
IS - 12
ER -