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Imatinib molecular response depth determines impact of fluctuation


Br J Haematol, February 2017; advance online publication

: Research suggests that the relationship between a fluctuating response to imatinib and the likelihood of developing resistance to the tyrosine kinase inhibitor (TKI) depends on the depth of molecular response (MR) achieved by the chronic myeloid leukemia (CML) patient.

“Our results clearly demonstrate that unstable MR3 [BCR–ABL1 ≤0.1% on the International Scale] is associated with increased probability of developing resistance to imatinib, whereas long-term fluctuation of a deeper MR does not influence the outcome”, says the team from Sapienza University in Rome, Italy.

“These results, which require further confirmation in larger prospective series of patients, may prompt haematologists to switch early from imatinib to a second- or third-generation TKI in patients who undergo molecular fluctuations within defined ranges of MR”, the authors suggest in the British Journal of Haematology.

Massimo Breccia and co-workers assessed MR instability in 208 CML patients who had used imatinib for a median of 7 years. They defined stable MR as a persistant response in three consecutive evaluations, and fluctuation as the achievement and subsequent loss of an International Scale cutoff of 0.1%.

Within 3 months of initiating imatinib, 7.2% of patients had achieved MR3, rising to 62.0% at 12 months, with a cumulative incidence of MR3 at 7 years of 64.4%.

In all, 17 (12.6%) patients had a least one fluctuation of MR3 response; 76% of these patients lost their MR3 response and 17.6% developed secondary resistance to imatinib. By contrast, just 2.5% of the 117 patients without molecular fluctuation lost their MR and developed secondary resistance.

Failure-free survival (FFS) at 7 years was estimated to be 82.4% and 93.2% in patients who did and did not have a MR3 fluctuation, with corresponding overall survival (OS) rates of 94.6% and 94.0%.

The cumulative incidence of MR4.0 (BCR–ABL1 ≤0.01%) was 51.0% after a median of 3.8 years and for MR4.5 (BCR–ABL1 ≤0.0032%), 34.6% after 5.4 years. Fluctuations were reported for seven (6.5%) patients with MR4.0, four of whom lost their response, although none developed secondary resistance. And 25.0% of MR4.5 patients had fluctuations but none developed secondary resistance or progression.

Loss of MR4.0 response was attributed to poor adherence to treatment in five of the seven patients, the researchers observe.

Among patients with MR4.0 or MR4.5,the FFS and OS of patients with fluctuations did not significantly differ from those of patients with a stable deep response, at 100% versus 99.4% and 98.2% versus 97.8%, respectively.

Thus, patients with unstable MR3 are more likely to experience an event than those who achieve unstable MR4.0 or MR4.5, the researchers say.

“Low compliance to treatment cannot be excluded in patients with molecular fluctuation and subsequent loss of response, but we believe that cannot justify the increased relapse rate observed only at MR3 cut-off and not at deep MR cut-off”, the team comments.

“Other factors (i.e. immunological compartment) should be investigated in patients with molecular fluctuations.”

By Lynda Williams, Senior medwireNews reporter

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