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Clonal chromosomal abnormalities appearing in Philadelphia chromosome–negative metaphases during CML treatment

Ghayas C. Issa, Hagop M. Kantarjian, Graciela Nogueras Gonzalez, Gautam Borthakur, Guilin Tang, William Wierda, Koji Sasaki, Nicholas J. Short, Farhad Ravandi, Tapan Kadia, Keyur Patel, Raja Luthra, Alessandra Ferrajoli, Guillermo Garcia-Manero, Mary Beth Rios, Sara Dellasala, Elias Jabbour and Jorge E. Cortes

Key Points

  • Clonal chromosomal abnormalities in Ph metaphases not including –Y predict decreased FFS, EFS, TFS, and OS in patients with CML.

  • They affect TFS independently of baseline variables, although this is abrogated by inclusion of early response in multivariate models.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

Clonal chromosomal abnormalities in Philadelphia chromosome-negative (CCA/Ph) metaphases emerge as patients with chronic phase chronic myeloid leukemia (CP-CML) are treated with tyrosine kinase inhibitors (TKIs). We assessed the characteristics and prognostic impact of 598 patients with CP-CML treated on clinical trials with various TKIs. CCA/Ph occurred in 58 patients (10%); the most common were −Y in 25 (43%) and trisomy 8 in 7 patients (12%). Response to TKI therapy was similar for patients with CCA/Ph and those without additional chromosomal abnormalities (ACAs). We further categorized CCA/Ph into those in which –Y was the only clonal abnormality, and all others. We found that patients with non –Y CCA/Ph had worse failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) compared with those without ACAs with the following 5-year rates: FFS (52% vs 70%, P = .02), EFS (68% vs 86%, P = .02), TFS (76% vs 94%, P < .01), and OS (79% vs 94%, P = .03). In a multivariate analysis, non –Y CCA/Ph increased the risk of transformation or death when baseline characteristics were considered with a hazard ratio of 2.81 (95% confidence interval, 1.15-6.89; P = .02). However, this prognostic impact was not statistically significant when achieving BCR-ABL <10% at 3 months was included in the analysis. In conclusion, non –Y CCA/Ph are associated with decreased survival when emerging in patients with chronic-phase CML across various TKIs. This trial was registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, and #NCT00050531 (imatinib); #NCT00254423 (dasatinib); #NCT00129740 (nilotinib); and NCT01570868 (ponatinib).

  • Submitted July 9, 2017.
  • Accepted August 15, 2017.
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