Adding Pioglitazone to Imatinib May Improve Response Rate in CML

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The addition of pioglitazone to imatinib may increase the proportion of patients with chronic myeloid leukemia in chronic phase (CML-CP).
The addition of pioglitazone to imatinib may increase the proportion of patients with chronic myeloid leukemia in chronic phase (CML-CP).

The addition of pioglitazone, a hypoglycemic agent used to treat type 2 diabetes, to imatinib may increase the proportion of patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieve a complete molecular response, according to a study published in Cancer.1

Previous reports suggest that peroxisome proliferator-activated receptor γ (PPAR-γ) agonists may possess potential therapeutic value in reversing myeloproliferative disorders.

After preclinical studies demonstrated that add-on therapy with pioglitazone may improve molecular response rates in CML, researchers administered pioglitazone to 1 patient with both type 2 diabetes and CML with residual disease after continuous treatment with imatinib. The amount of BCR-ABL transcript detected decreased substantially during the first 3 months of combination therapy; transcript levels were undetectable thereafter until 9 months after therapy.

Researchers therefore evaluated the efficacy and tolerability of pioglitazone and imatinib in a phase 2 proof-of-concept study (ClinicalTrials.gov Identifier: NCT02888964). Investigators enrolled 24 patients with CML who had received imatinib at a stable daily dose for at least 2 years. Patients were included only if they had achieved a major molecular response but a molecular response 4.5.

The cumulative incidence of molecular response 4.5 was 56% (95% CI, 37-76) by 12 months, despite a wide range of treatment duration. In addition, 88% of the 17 evaluable patients who were still receiving imatinib achieved molecular response 4.5 by 48 months.

In contrast, investigators estimated that the cumulative incidence of major molecular to molecular response was 23% (95% CI, 3-55) in a parallel cohort of patients not included in the ACTIM trial with similar characteristics.

The most common adverse event was weight gain, which was observed among 12 patients. One patient reported grade 3 hypokalemia and 1 patient discontinued treatment due to grade 2 edema.

RELATED: Second Generation TKIs Can Be Safely Stopped in CML

To evaluate the optimal duration of imatinib with pioglitazone and the ideal PPAR-γ agonist to be used in this setting, researchers are recruiting patients for the ACTIW randomized trial (ClinicalTrials.gov Identifier: NCT02767063).

Reference

  1. Rousselot P, Prost S, Guilhot J, et al. Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study. Cancer. 2016 Dec 27. doi: 10.1002/cncr.30490 [Epub ahead of print]
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