Do Additional Chromosomal Abnormalities Noted at CML Diagnosis Affect Response and Survival?

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Although cytogenetic abnormalities that arise during the course of CML are prevalent in later stages of the disease and are associated with a poorer prognosis, as many as 10% to 12% of patients exhibi
Although cytogenetic abnormalities that arise during the course of CML are prevalent in later stages of the disease and are associated with a poorer prognosis, as many as 10% to 12% of patients exhibi

Left untreated, patients diagnosed with chronic myeloid leukemia (CML) in the chronic phase (CP) eventually progress to the accelerated (AP) or blast (BP) phase, a transition associated with multiple genetic changes.

Although additional cytogenetic abnormalities (ACAs) that arise during the course of CML are prevalent in later stages of the disease and are associated with a poorer prognosis, as many as 10% to 12% of patients exhibit ACAs at diagnosis, and approximately 5% of patients with CML are Philadelphia chromosome (Ph)-negative, though the disease still expresses BCR-ABL1.1-3

ACAs can be classified as “minor route” or “major route,” depending on the frequency with which they are found, which may or may not correlate with their prognostic value. Major route ACAs include trisomy 8, isochromosome 17q (i17q), trisomy 19, and presence of an extra Ph chromosome.

Minor route ACAs include numerical aberrations (–7, –17, +17), loss of Y chromosome (–Y), and variant translocations that involve other chromosomes in addition to t(9;22), abbreviated as t(v;22). In the large German CML IV study, ACAs frequently found at diagnosis included t(v;22) and –Y.4

A group of researchers from the University of Texas MD Anderson Cancer Center in Houston and Hartford Hospital in Connecticut attempted to stratify ACAs by their prognostic effect. In this study, which evaluated ACAs present at diagnosis as well as those that emerged during treatment, the major and minor route status of individual ACAs did not necessarily correlate with their prognostic significance. Trisomy 8, an extra Ph chromosome, and –Y did not affect survival regardless of whether they were present at diagnosis or as a result of clonal evolution, while i(17q) and –7 were associated with poor risk and negative effects on survival.

In the tyrosine kinase inhibitor (TKI) era, the effect of ACAs present at diagnosis on patients' prognosis is of great interest. A number of studies have attempted to address this issue with some conflicting results. The most recent of these, a study led by Ahmad Alhuraiji, MD, concluded that ACAs at diagnosis have little prognostic value and that testing for them may add little value for patients treated with TKIs.5

Although inconsistent with earlier studies, “this study adds further data to the discussion around precise prognostication at the time of CML diagnosis, and in part how we define CML-AP, said Michael J. Mauro, MD, leader of the Myeloproliferative Neoplasms Program at Memorial Sloan-Kettering Cancer Center in New York, New York. “Given the lack of strong guidelines around initial treatment choice at the time of CML diagnosis, there is continual motivation to clarify expectations from treatment and better ‘triage' of patients into individualized treatment plans based on their individual disease characteristics.”

Dr Alhuraiji's study showed that major route ACAs were present in 41% and minor route in 59% of the evaluated patients with CML. Good risk ACAs were noted in 72% of patients and poor risk ACAs in 28%. None of the patients, however, had i(17q) or 3q26 rearrangements, which are associated with the worst survival outcomes in previous studies. Dr Mauro noted that the majority of patients in this study fell into the “good risk” category, which might limit drawing definitive conclusions. “Studying a heterogeneous problem such as ACA in CML means pooling of different anomalies together,” he said. “Even if stratified between the defined ‘major' and ‘minor' routes with different implications, it is likely that there are certain genetic events that, with a large enough study, would fall out as being more deleterious.”

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