Ultra-accurate Duplex Sequencing for the assessment of pretreatment ABL1 kinase domain mutations in Ph+ ALL.
Nicholas J ShortHagop KantarjianRashmi Kanagal-ShamanaKoji SasakiFarhad RavandiJorge CortesMarina KonoplevaGhayas C IssaSteven Mitchell KornblauGuillermo Garcia-ManeroRebecca GarrisJake HigginsGabriel PrattLindsey N WilliamsCharles C ValentineVictor M RiveraJustin PritchardJesse J SalkJerald RadichElias JabbourPublished in: Blood cancer journal (2020)
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.
Keyphrases
- chronic myeloid leukemia
- tyrosine kinase
- acute lymphoblastic leukemia
- epidermal growth factor receptor
- bone marrow
- single cell
- peripheral blood
- end stage renal disease
- high resolution
- stem cells
- chronic kidney disease
- ejection fraction
- squamous cell carcinoma
- peritoneal dialysis
- radiation therapy
- locally advanced
- rectal cancer