Search

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-ABL1 decline from baseline, assessed by estimating the number of days over which BCR-ABL1 halved. Patients with BCR-ABL1 halving time <76 days (n = 74) had significantly superior outcomes compared with patients whose BCR-ABL1 values 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-ABL1 decline 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.gov as #NCT00006343. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was registered at http://www.clinicaltrials.gov as #NCT00124748. The Therapeutic Intensification in DE-novo Leukaemia (TIDEL) I trial was registered at http://www.ANZCTR.org.au as #ACTRN12607000614493. The TIDEL II trial was registered at http://www.ANZCTR.org.au as #ACTRN12607000325404., (© 2014 by The American Society of Hematology.)

Recent studies have demonstrated that some patients with chronic myeloid leukemia (CML) can maintain remission after discontinuation of imatinib. A prerequisite is stable, undetectable BCR-ABL1. It is not known how many patients achieve this response or the factors associated with its achievement. We examined 423 de novo imatinib-treated patients to determine the cumulative incidence of achieving the discontinuation criteria as defined in the CML8 study (≥2 years of undetectable BCR-ABL1 [Stable MR(4.5)]), and predictive factors. After 8 years of imatinib, the cumulative incidence of Stable MR(4.5) was 36.5%. Therefore, 9% to 15% of first-line imatinib-treated patients would maintain remission after discontinuation. The BCR-ABL1 level at 3 months and factors at diagnosis were examined for association with Stable MR(4.5): Sokal risk, age, sex, and assigned imatinib dose. The only independent predictors were female sex (54.4% vs 27.2%; P = .018) and the 3-month BCR-ABL1 (P < .001). The highest cumulative incidence of Stable MR(4.5) after 8 years was 78.2% for patients with BCR-ABL1 ≤ 0.10%(IS) at 3 months (n = 38). Time to major molecular response (MMR) influenced the time to reach Stable MR(4.5) (P < .001), suggesting slower dynamics of response with a delayed MMR. The findings justify the focus on rapid reduction of BCR-ABL1 as a strategy to maximize potential suitability for imatinib discontinuation studies. The Iris trial was registered at http://www.clinicaltrials.gov as NCT00006343. The Tops trial was registered at http://www.clinicaltrials.gov as NCT00124748. The TIDEL I trial was registered at www.ANZCTR.org.au as ACTRN12607000614493. The TIDEL II trial was registered at www.ANZCTR.org.au as ACTRN12607000325404.