Pioglitazone may boost imatinib response

Cancer, January 2017; advance online publication

medwireNews: Phase II trial results suggest that the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone could be used as an add-on therapy for chronic myeloid leukemia (CML) patients who do not achieve a deep molecular response (MR) to the tyrosine kinase inhibitor (TKI) imatinib.

“[T]he results of the ACTIM study reported here suggest that pioglitazone together with imatinib increases the proportion of CML patients who achieve MR^4.5 [BCR–ABL1 ≤0.0032%], further suggesting that the ability of PPAR-γ agonists to erode the CML stem cell pool may be of clinical benefit for CML patients,” the team writes in Cancer.

The ACTIM study included 24 patients who had taken a stable daily dose of imatinib for at least 2 years; 58% had achieved a major molecular response (MMR; BCR–ABL1 <0.1% on the International Scale) and 42% had achieved a molecular response 4 (MR⁴; BCR–ABL1 ≤0.01%), but none had achieved MR^4.5. Patients began pioglitazone at a dose of 30 mg/day with an increase to 45 mg/day after 2 months.

Philippe Rousselot, from Hôpital André Mignot in Le Chesnay, France, and co-investigators did not record any pharmacologic interactions between pioglitazone and imatinib, and patients maintained their imatinib dose. The combined treatment was “well tolerated,” although half of the patients gained weight during the study and there was an average 0.4 g/dL decrease in hemoglobin.

Over 12 months, 54.0% of the patients achieved MR^4.5, including 30.7% of the 13 patients whose previous best response was MMR. At this time point, 29.1% of patients were in MR^4.5 and six patients had fluctuating BCR–ABL1 transcripts around MR^4.5.

Long-term follow-up of 23 patients over a median of 5.1 years showed that 58.3% of patients remained in MR^4.5 at 4 years. And of the 17 patients who continued on imatinib, 88.2% achieved MR^4.5 within 4 years of using pioglitazone.

By comparison, the cumulative incidence of MR^4.5conversions in patients who continue with imatinib alone is estimated to be 23%, the researchers say.

Following the announcement of an associated increased risk of bladder cancer, pioglitazone therapy was limited to 12 months and patient recruitment was halted. Nine patients discontinued pioglitazone within 1 year but five of these patients achieved MR^4.5.

“The corroborating ACTIW randomized trial is currently recruiting to address the questions that remain, such as the optimal duration of the combination and the ideal PPAR-γ agonist to be used,” Rousselot et al conclude.

“Discontinuation of both PPAR-γ agonist and TKI while obtaining a high rate of sustained treatment-free remission is currently being tested and would be the ultimate proof of the possibility of CML eradication and cure using this approach.”

By Lynda Williams, Senior medwireNews reporter

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