Ultra-accurate Duplex Sequencing for the assessment of pretreatment ABL1 kinase domain mutations in Ph+ ALL

Nicholas J. Short, Hagop Kantarjian, Rashmi Kanagal-Shamanna, Koji Sasaki, Farhad Ravandi, Jorge Cortes, Marina Konopleva, Ghayas C. Issa, Steven M. Kornblau, Guillermo Garcia-Manero, Rebecca Garris, Jake Higgins, Gabriel Pratt, Lindsey N. Williams, Charles C. Valentine, Victor M. Rivera, Justin Pritchard, Jesse J. Salk, Jerald Radich, Elias Jabbour

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number61
JournalBlood Cancer Journal
Volume10
Issue number5
DOIs
StatePublished - May 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Oncology

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  • Cite this

    Short, N. J., Kantarjian, H., Kanagal-Shamanna, R., Sasaki, K., Ravandi, F., Cortes, J., Konopleva, M., Issa, G. C., Kornblau, S. M., Garcia-Manero, G., Garris, R., Higgins, J., Pratt, G., Williams, L. N., Valentine, C. C., Rivera, V. M., Pritchard, J., Salk, J. J., Radich, J., & Jabbour, E. (2020). Ultra-accurate Duplex Sequencing for the assessment of pretreatment ABL1 kinase domain mutations in Ph+ ALL. Blood Cancer Journal, 10(5), [61]. https://doi.org/10.1038/s41408-020-0329-y