Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline

• Published in: Blood Vol. 124; no. 4; pp. 511 - 518
• Main Authors: Branford, Susan, Yeung, David T., Parker, Wendy T., Roberts, Nicola D., Purins, Leanne, Braley, Jodi A., Altamura, Haley K., Yeoman, Alexandra L., Georgievski, Jasmina, Jamison, Bronte A., Phillis, Stuart, Donaldson, Zoe, Leong, Mary, Fletcher, Linda, Seymour, John F., Grigg, Andrew P., Ross, David M., Hughes, Timothy P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.07.2014
• Subjects: Antineoplastic Agents - therapeutic use; Benzamides - therapeutic use; Female; Follow-Up Studies; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - mortality; Male; Middle Aged; Piperazines - therapeutic use; Prognosis; Pyrimidines - therapeutic use; Remission Induction; Survival Rate; Time Factors
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-03-566323

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. •Among patients with >10% BCR-ABL1, at 3 months, the poorest-risk group can be distinguished by the rate of BCR-ABL1 decline from baseline.•Patients with BCR-ABL1 values on a constant downward trajectory may rapidly reach the level considered optimal with additional follow-up.