Clinical impact of low-burden BCR-ABL1 mutations detectable by amplicon deep sequencing in Philadelphia-positive acute lymphoblastic leukemia patients

Although the prognosis of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has significantly improved upon the advent of tyrosine kinase inhibitors (TKIs) targeting the deregulated BCR-ABL1 tyrosine kinase activity, disease recurrence remains a major problem.1 The long-term stability of responses is frequently undermined by the selection of BCR-ABL1 mutants that can survive TKI treatment and trigger relapse.2 Imatinib-resistant Ph+ ALL patients frequently harbor the T315I mutation,2 against whom second-generation TKIs (2GTKIs; dasatinib and nilotinib) are ineffective. Even in imatinib-resistant patients who have 2GTKI-sensitive mutants, responses may be short-lived because of the high genetic instability fostering the acquisition of additional mutations, often in a ‘compound’ form (that is, two mutations gained by the same clone).2 Recently, however, effective salvage options for T315I mutation-positive or multi-TKI-resistant cases have become available—including the third-generation TKI ponatinib,3 as well as monoclonal antibodies such as blinatumomab.4 To prevent hematologic relapse with timely and rational therapeutic intervention, minimal residual disease (MRD) monitoring by real time quantitative polymerase chain reaction (RQ-PCR) and BCR-ABL1 mutation screening of patients who do not achieve MRD negativity can thus be expected to have an important role.