TY - JOUR
T1 - Ultra-accurate Duplex Sequencing for the assessment of pretreatment ABL1 kinase domain mutations in Ph+ ALL
AU - Short, Nicholas J.
AU - Kantarjian, Hagop
AU - Kanagal-Shamanna, Rashmi
AU - Sasaki, Koji
AU - Ravandi, Farhad
AU - Cortes, Jorge
AU - Konopleva, Marina
AU - Issa, Ghayas C.
AU - Kornblau, Steven M.
AU - Garcia-Manero, Guillermo
AU - Garris, Rebecca
AU - Higgins, Jake
AU - Pratt, Gabriel
AU - Williams, Lindsey N.
AU - Valentine, Charles C.
AU - Rivera, Victor M.
AU - Pritchard, Justin
AU - Salk, Jesse J.
AU - Radich, Jerald
AU - Jabbour, Elias
N1 - Funding Information:
We are grateful to the supporting laboratory and operational personnel at The University of Texas MD Anderson Cancer Center and TwinStrand Biosciences Inc., who assisted with collecting, coordinating, and preparing these samples. Supported by an MD Anderson Cancer Center Support Grant (CA016672) and SPORE and funding from ARIAD Pharmaceuticals, Inc. Sequencing and analysis partially supported by NIH R44 CA233381 to J.J.S. and J.R. N.J.S. is supported by the K12 Paul Calabresi Clinical Oncology Scholar Award and the American Society of Hematology Junior Faculty Scholar Award in Clinical Research.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Mutations of ABL1 are the dominant mechanism of relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). We performed highly accurate Duplex Sequencing of exons 4–10 of ABL1 on bone marrow or peripheral blood samples from 63 adult patients with previously untreated Ph + ALL who received induction with intensive chemotherapy plus a BCR-ABL1 TKI. We identified ABL1 mutations prior to BCR-ABL1 TKI exposure in 78% of patients. However, these mutations were generally present at extremely low levels (median variant allelic frequency 0.008% [range, 0.004%–3.71%] and did not clonally expand and lead to relapse in any patient, even when the pretreatment mutation was known to confer resistance to the TKI received. In relapse samples harboring a TKI-resistant ABL1 mutation, the corresponding mutation could not be detected pretreatment, despite validated sequencing sensitivity of Duplex Sequencing down to 0.005%. In samples under the selective pressure of ongoing TKI therapy, we detected low-level, emerging resistance mutations up to 5 months prior to relapse. These findings suggest that pretreatment ABL1 mutation assessment should not guide upfront TKI selection in Ph + ALL, although serial testing while on TKI therapy may allow for early detection of clinically actionable resistant clones.
AB - Mutations of ABL1 are the dominant mechanism of relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). We performed highly accurate Duplex Sequencing of exons 4–10 of ABL1 on bone marrow or peripheral blood samples from 63 adult patients with previously untreated Ph + ALL who received induction with intensive chemotherapy plus a BCR-ABL1 TKI. We identified ABL1 mutations prior to BCR-ABL1 TKI exposure in 78% of patients. However, these mutations were generally present at extremely low levels (median variant allelic frequency 0.008% [range, 0.004%–3.71%] and did not clonally expand and lead to relapse in any patient, even when the pretreatment mutation was known to confer resistance to the TKI received. In relapse samples harboring a TKI-resistant ABL1 mutation, the corresponding mutation could not be detected pretreatment, despite validated sequencing sensitivity of Duplex Sequencing down to 0.005%. In samples under the selective pressure of ongoing TKI therapy, we detected low-level, emerging resistance mutations up to 5 months prior to relapse. These findings suggest that pretreatment ABL1 mutation assessment should not guide upfront TKI selection in Ph + ALL, although serial testing while on TKI therapy may allow for early detection of clinically actionable resistant clones.
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U2 - 10.1038/s41408-020-0329-y
DO - 10.1038/s41408-020-0329-y
M3 - Article
C2 - 32457305
AN - SCOPUS:85085323774
VL - 10
JO - Blood Cancer Journal
JF - Blood Cancer Journal
SN - 2044-5385
IS - 5
M1 - 61
ER -