| Autor: |
Short, Nicholas J., Kantarjian, Hagop, Kanagal-Shamanna, Rashmi, Sasaki, Koji, Ravandi, Farhad, Cortes, Jorge, Konopleva, Marina, Issa, Ghayas C., Kornblau, Steven M., Garcia-Manero, Guillermo, Garris, Rebecca, Higgins, Jake, Pratt, Gabriel, Williams, Lindsey N., Valentine III, Charles C., Rivera, Victor M., Pritchard, Justin, Salk, Jesse J., Radich, Jerald, Jabbour, Elias |
| Předmět: |
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| Zdroj: |
Blood Cancer Journal; May2020, Vol. 10 Issue 5, p1-9, 9p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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