The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib

Abstract

The third-generation tyrosine kinase inhibitor (TKI) ponatinib shows activity against all common BCR-ABL1 single mutants, including the highly resistant BCR-ABL1-T315I mutant, improving outcome for patients with refractory chronic myeloid leukemia (CML). However, responses are variable, and causal baseline factors have not been well-studied. The type and number of low-level BCR-ABL1 mutations present after imatinib resistance has prognostic significance for subsequent treatment with nilotinib or dasatinib as second-line therapy. We therefore investigated the impact of low-level mutations detected by sensitive mass-spectrometry before ponatinib initiation (baseline) on treatment response in 363 TKI-resistant patients enrolled in the PONATINIB for Chronic Myeloid Leukemia Evaluation and Ph(+)Acute Lymphoblastic Leukemia trial, including 231 patients in chronic phase (CP-CML). Low-level mutations were detected in 53 patients (15%, including low-level T315I in 14 patients); most, however, did not undergo clonal expansion during ponatinib treatment and, moreover, no specific individual mutations were associated with inferior outcome. We demonstrate however, that the number of mutations detectable by mass spectrometry after TKI resistance is associated with response to ponatinib treatment and could be used to refine the therapeutic approach. Although CP-CML patients with T315I (63/231, 27%) had superior responses overall, those with multiple mutations detectable by mass spectrometry (20, 32%) had substantially inferior responses compared with those with T315I as the sole mutation detected (43, 68%). In contrast, for CP-CML patients without T315I, the inferior responses previously observed with nilotinib/dasatinib therapy for imatinib-resistant patients with multiple mutations were not seen with ponatinib treatment, suggesting that ponatinib may prove to be particularly advantageous for patients with multiple mutations detectable by mass spectrometry after TKI resistance.

Upfront low‐dose ponatinib (15 mg/day) for multi‐TKI resistant chronic myeloid leukemia

“…1 Furthermore, ponatinib might be superior to other 2G-TKIs in terms of its efficacy in patients with ABL1 mutations, in addition to those carrying T315I. 9 This is consistent with the observation that patients failing ponatinib therapy are unlikely to respond to subsequent TKI. 10 The observations from the current study are encouraging regarding the prospect of lower dose ponatinib (15 mg daily) being as effective as the standard dose (45 mg daily).…”

Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression

“…26 The presence of compound mutations describe poor-risk group of chronic phase CML patients, with increased chances of disease progression and acquiring resistance with suboptimal response to second generation TKIs. 16 However, it is expected that each of compound mutant clone retains its own sensitivity against given treatment. 5 Presence of 2 or more mutations in ABL kinase domain impair the binding of Imatinib, resulting in suboptimal treatment outcome and progression of disease.…”

“…Though BCR-ABL compound mutations have been found to be responsible for causing resistance to all tyrosine kinase inhibitors (TKIs) currently in clinical practice 10-15 including ponatinib, 16,17 reports about role of compound ABL mutations in CML progression are lacking. 5,9 In the present study, we studied BCR-ABL kinase domain mutations in imatinib sensitive patients of CML in CP, late CP, AP and BC of the disease using Sanger sequencing.…”

Molecular monitoring in chronic myeloid leukemia—how low can you go?

“…44 Therefore, subclonal diversity could be an important prognostic marker of the capacity of leukemic cells to evolve TKI resistance. Interestingly, using the mass spectrometry sensitive mutation technique, Parker et al 45 demonstrated in chronic-and advancedphase patients treated with ponatinib in the PACE study that the association between multiple low-level mutations and poor outcome was not found with ponatinib therapy. Therefore, ponatinib may be beneficial for patients with multiple mutations after prior TKI.…”