The Earlier the Better Early Response to Imatinib Predicted Outcomes in Children with CML

While imatinib has been proven effective for the majority of pediatric patients with chronic myeloid leukemia (CML), 13 to 25 percent of children still have a poor response. In a recent study published in Blood, Frédéric Millot, MD, of the Department of Pediatrics, University Hospital, Poitiers, France, and colleagues questioned whether it was possible to predict how patients would respond to treatment and determined, essentially, “the earlier the better.”

An early molecular response to treatment with imatinib — as measured by BCR-ABL1 transcript level and defined as a BCR/ABL ratio of <10 percent at three months post-initiation of imatinib — predicted greater response at one year and improved progression-free survival (defined as absence of accelerated phase, blast crisis, and death from any cause), compared with those children who did not have an early response.

“CML occurs rarely in children and adolescents, and there are scant data available regarding early molecular response in this age range of patients,” Dr. Millot said. The results seen with the current study are similar to those found in adults with CML, in whom a BCR-ABL1/ABL ratio of <10 percent at three months post-initiation of imatinib was associated with improved over-all survival.

Based on the results of this phase IV study, “an alternative treatment, such as a switch for a second-generation tyrosine kinase inhibitor, could be proposed in cases of insufficient decrease in the BCR-ABL1 transcript level,” Dr. Millot told ASH Clinical News.

To address this gap in clinical knowledge, Dr. Millot and investigators enrolled 44 consecutive patients aged ≤18 years with newly diagnosed CML into their study. From March 2004 to December 2008, patients received imatinib 260 mg/m2 daily. Four children were not included in the analysis because they had missing molecular assessment at three months.

Investigators analyzed the BCR-ABL1/ABL ratio at three months following imatinib initiation of the remaining 40 patients:

  • 37 percent of the patients had a ratio of >10 percent
  • 45 percent had a ratio of 1 to 10 percent
  • 18 percent had a ratio of <1 percent

A higher ratio was associated with a larger spleen size and a higher white blood cell count compared with patients with a ratio of ≤10 percent. The dose of imatinib administered was similar between the two groups during the first three months of treatment, “suggesting that treatment exposure was not an independent influencing factor,” Dr. Millot noted.
At one year, compared to patients who had a ratio >10 percent at three months post–imatinib initiation, those who had a ratio ≤10 percent had higher rates of both complete cytogenetic response (76% vs. 47%) and major molecular response (48% vs. 7%).

Furthermore, with a median follow-up of 71 months, a transcript level ≤10 percent correlated with better progression-free survival:

• ≤10% at three months: 100% vs. 92% at 36 months follow-up
• >10% at three months: 100% vs. 61% at 48 months follow-up

Although the results are encouraging, Dr. Millot and colleagues noted that the reliability of this 10 percent cut-off at three months after starting imatinib as a surrogate for one-year response needs to be confirmed in larger cohorts of children.


Reference

Millot F, Guilhot J, Baruchel A, et al. Impact of early molecular response in children with chronic myeloid leukemia treated in the French Glivec phase 4 study. Blood. 2014 August 28. [Epub ahead of print]

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