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Imatinib kinetic response similar in children and adults


Haematologica, November 2016; advance online publication

Primary kinetic responses to the tyrosine kinase inhibitor (TKI) imatinib do not differ significantly between children and adults with chronic myeloid leukemia (CML), German study data show.

Ingmar Glauche (Technical University Dresden) and colleagues found that 25 (71%) of 35 pediatric patients and 55 (80%) of 69 adult patients with CML showed the typical biphasic decline in BCR–ABL1 relative to ABL1 transcript levels during treatment with imatinib. The remainder had a uniphasic response.

A bi-exponential regression model applied to patients with a biphasic response showed that the initial rate of decline in average BCR–ABL1/ABL1 transcript levels was 8.0% per month in the pediatric patients, who had a median age of 11.9 years and were mainly boys (64%). For the adults (median age 52.5 years, 73% men), the levels initially fell at a mean rate of 7.3% per month.

During the second, slower phase of decline, the BCR–ABL1/ABL1 transcript levels fell at rates of 0.03% and 0.07% in the pediatric and adult patients, respectively.

When the researchers applied the same regression model to each individual patient, they found that the breakpoint of response kinetics, that is, the point between the first and second slopes, typically occurred between 2 and 11 months, with the BCR–ABL1/ABL1 level generally below 1% at this point.

Glauche and team also note that treatment response did not appear to be affected by age at diagnosis, or by the presence of an e13a2/e14a2 splicing variant in the BCR–ABL1 oncogene, which has previously been associated with an inferior initial response to imatinib.

“However, given the small sample size (which is about a factor 10 smaller as compared to the relevant studies in adult patients) this effect may have been be masked,” they say.

Writing in Haematologica, the researchers point out that although TKI treatment in children inhibits BCR–ABL1 it also exerts many side effects, including dysregulation of bone remodeling, longitudinal growth impairment, impaired vitamin D synthesis, growth hormone deficiency, and other metabolic dysregulations.

They therefore conclude: “As these side effects may become more significant with longer periods of TKI treatment, sophisticated approaches to support the safety of TKI therapy cessation, such as model-based risk estimations, are even more desirable in pediatric cohorts as compared to adult patients.”

By Laura Cowen

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