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%, = .02), EFS (68% vs 86%, = .02), TFS (76% vs 94%, < .01), and OS (79% vs 94%, = .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; = .02). However, this prognostic impact was not statistically significant when achieving <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).

Outcomes of 219 chronic myeloid leukaemia patients with additional chromosomal abnormalities and/or tyrosine kinase domain mutations

“…Moreover, −Y was associated with increased survival in CML patients. 25 In this research, two patients with −Y maintain complete remission (CR).…”

How I investigate Clonal cytogenetic abnormalities of undetermined significance

“…Isolated CCA detected in Ph‐ cells in the absence of morphologic evidence of MDS does not require a change in therapy . In a recent study by Issa et al, it is noteworthy that CCA in Ph‐ cells was not commonly associated with the development of secondary myeloid neoplasms, but these patients showed inferior event‐free survival, transformation‐free survival, and overall survival …”

“…Most of the CCAs observed in these patients show structural or numerical changes that are typically associated with MDS or AML, with −Y, +8, −7/del(7q), and del(20q) being the most common . Interestingly, most CCAs in Ph− cells are transient, lasting only for a limited time interval, and are of undetermined significance; less than 10% of patients may develop a secondary MDS/AML, and the latter group is composed mainly of patients with monosomy 7 or a complex karyotype . Del(5q), a cytogenetic abnormality highly associated with myeloid neoplasms, also can be observed occasionally in Ph‐ cells.…”

“…In CML, it is believed that Philadelphia chromosome‐negative (Ph−) hematopoiesis is normal and derived from nonleukemic hematopoietic stem cells. However, in 2%‐15% of CML patients who undergo imatinib (first generation TKI) treatment, CCAs have been detected in Ph− cells (CCA/Ph−) . Most of the CCAs observed in these patients show structural or numerical changes that are typically associated with MDS or AML, with −Y, +8, −7/del(7q), and del(20q) being the most common .…”

“…[18][19][20] Interestingly, most CCAs in Ph− cells are transient, lasting only for a limited time interval, and are of undetermined significance [20][21][22] ; less than 10% of patients may develop a secondary MDS/AML, and the latter group is composed mainly of patients with monosomy 7 or a complex karyotype. 18,20,22,23 Del(5q), a cytogenetic abnormality highly associated with myeloid neoplasms, also can be observed occasionally in Ph-cells. In our previous study, 24 4 patients were found to have del(5q) in their BM during TKI therapy and, with 8-to 59-month follow-up, none of these patients developed secondary myeloid neoplasms.…”