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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-ABL1mutations 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.

In chronic myeloid leukemia (CML) patients, a breakpoint cluster region–Abelson (BCR-ABL1) value >10% at 3 months of therapy is statistically associated with poorer outcome, yet many of these patients still achieve satisfactory outcomes. We investigated 528 first-line imatinib-treated patients to determine whether patients with the poorest outcome can be better discriminated at 3 months. All outcomes were significantly superior for the 410 patients with BCR-ABL1≤10% at 3 months (P< .001). However, the poorest outcomes among the 95 evaluable patients with BCR-ABL1>10% at 3 months were identified by the rate of BCR-ABL1decline from baseline, assessed by estimating the number of days over which BCR-ABL1halved. Patients with BCR-ABL1halving time <76 days (n = 74) had significantly superior outcomes compared with patients whose BCR-ABL1values did not halve by 76 days (n = 21; 4-year overall survival, 95% vs 58%, P= .0002; progression-free survival, 92% vs 63%, P= .008; failure-free survival, 59% vs 6%, P< .0001; and major molecular response, 54% vs 5%, P= .008). By multivariate analysis, the halving time was an independent predictor of outcome in this poor risk group. Our study highlighted that the rate of BCR-ABL1decline may be a critical prognostic discriminator of the patients with very poor outcome among those >10% at 3 months. The International Randomized IFN vs STI571 (IRIS) trial was registered at http://www.clinicaltrials.govas #NCT00006343. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was registered at http://www.clinicaltrials.govas #NCT00124748. The Therapeutic Intensification in DE-novo Leukaemia (TIDEL) I trial was registered at http://www.ANZCTR.org.auas #ACTRN12607000614493. The TIDEL II trial was registered at http://www.ANZCTR.org.auas #ACTRN12607000325404.