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

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).

Figure 1.

Flowchart outlining the selection of cases in this study. ACAs, additional chromosomal abnormalities.

Figure 2.

Landscape of CCA/Ph⁻ in patients with chronic-phase chronic myeloid leukemia. (A) Distribution of CCA/Ph⁻ according to the year after treatment start it is first detected. (B) Number of times CCA/Ph⁻ is detected in independent cytogenetic analyses per patient, done every 3 months during the first year, then every 6 to 12 months while on study. (C) Maximum number of metaphases containing CCA/Ph⁻ in a cytogenetic analysis per patient. (D) Distribution of CCA/Ph⁻ by chromosome. Each row represents the chromosomes numbered from 1 to 22 with additional rows for the sex chromosomes and a row labeled “C” for patients with a complex karyotype defined as ≥3 chromosomal abnormalities in 1 metaphase. Each column represents a patient with CCA/Ph⁻. Red. deletion or loss; blue. gain; D, dasatinib; I, imatinib; N, nilotinib; P, ponatinib. Some of the CCA/Ph⁻ metaphases were translocations not shown in this figure. Additional details are provided in supplemental Table 1.

Figure 3.

Survival of patients with chronic phase chronic myeloid leukemia by presence and type of CCA/Ph⁻ metaphases. (A) FFS. (B) EFS. (C) TFS. (D) OS. P value is determined by comparing survival of patients with CCA/Ph⁻ with those without ACAs using the log-rank test. −Y, loss of chromosome Y.