Prognostic importance of additional cytogenetic anomalies in chronic myeloid leukemia

Abstract

Additional chromosomal abnormalities (ACAs) in Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) are strongly associated with disease progression, but their prognostic impact and effect on treatment response are not clear. While the onset of ACAs in Ph-negative cells during treatment has been described, their origin and clinical significance remain to be clarified. Between January 2008 and January 2011, 105 patients with Ph-positive CML were analyzed. With a median follow-up of 25.5 months, 18 CML patients (17 %) with ACAs in either CP (n = 12) or advanced phases (n = 6) were identified. The median age of the patients was 53.5 years at diagnosis. ACAs were determined in Ph-positive metaphases of 12 patients and in Ph-negative metaphases of 5 patients. One patient showed trisomy 8 both in Ph-positive and in Ph-negative metaphases. The median follow-up after the detection of ACAs was 11.9 months. None of the patients carrying ACAs in their Ph-negative metaphases developed AP or BP; however, 7 out of 12 patients (58 %) having ACAs in their Ph-positive metaphases developed AP/BC at diagnosis or follow-up (p = 0.03). All the patients carrying ACAs in only Ph-negative metaphases achieved optimal response under tyrosine kinase inhibitor (TKI) therapy, whereas only 4 out of 12 patients (25 %) had optimal TKI response in patients with ACAs in Ph-positive metaphases (p = 0.009). The presence of ACAs in Ph-positive cells during TKI therapy may reflect genetic instability and therefore negatively affect OS. Conventional cytogenic analyses remain mandatory during follow-up of patients with CML under TKI therapy.

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

“…To the best of our knowledge, ACAs are associated with CML progression, and they are subdivided into major and minor routes. The major routes have proven to have a negative impact on survival and prognosis, but the minor routes have been less considered.…”

“…Although the use of tyrosine kinase inhibitors (TKIs) has greatly improved the management and prognosis of CML patients, research on CML has never stopped. Current studies have found that the incidence of additional chromosomal abnormalities (ACAs) is approximately 5% in the chronic phase (CP) of CML patients, 30% in the accelerated phase (AP) and 80% in the blast phase (BP) . Hence, ACAs are considered an intrinsic factor in the progression of CML patients with a negative impact on survival and prognosis .…”

“…Current studies have found that the incidence of additional chromosomal abnormalities (ACAs) is approximately 5% in the chronic phase (CP) of CML patients, 30% in the accelerated phase (AP) and 80% in the blast phase (BP) . Hence, ACAs are considered an intrinsic factor in the progression of CML patients with a negative impact on survival and prognosis . ACAs were subdivided into major and minor routes, as initially proposed by Mitelman, based only on the frequencies of the ACAs .…”

Inhibition of nm23-H1 gene expression in chronic myelogenous leukemia cells

“…The constitutive expression of BCR-ABL leads to the unregulated production of mature myeloid cells in the bone marrow and their subsequent release into the blood (9). If untreated, CML will progress from a chronic to an accelerated phase over a number of years, prior to quickly proceeding to a terminal blast crisis phase, reminiscent of acute leukemia (10).…”

Epigenetic Reprogramming and Emerging Epigenetic Therapies in CML

“…Therefore, more targeted therapies are warranted for these patients. Blast phase is typically characterized by the accumulation of additional chromosomal abnormalities (ACAs), but epigenetic regulation is also disrupted (reviewed also in Bozkurt et al, 2013b). While epigenetic changes occurring in CP-CML and in the progression to BP-CML have been studied extensively, changes occurring within the LSC compartment during disease progression are poorly understood and warrant further study.…”