A small preliminary study showed that adding pioglitazone to imatinib therapy might have a favorable impact on residual disease in chronic myeloid leukemia, as measured by conversion to molecular response 4.5.
A small preliminary study showed that adding pioglitazone to imatinib therapy might have a favorable impact on residual disease in chronic myeloid leukemia (CML), as measured by conversion to molecular response 4.5 (MR4.5).
“Residual CML disease remains detectable above the level of MR4.5 in 40% to 90% of patients in spite of sustained imatinib therapy,” wrote study authors led by Philippe Rousselot, MD, PhD, of HÃ´pital AndrÃ© Mignot in Le Chesnay, France. Recent preclinical work has shown that PPAR-Î³ agonists such as pioglitazone can erode the CML leukemia stem cell pool, potentially sensitizing quiescent CML stem cells to imatinib.
The new study was a phase II trial including 24 patients with CML; all patients had been treated with the tyrosine kinase inhibitor (TKI) imatinib for at least 2 years at a stable daily dose and had achieved a major molecular response (MMR), but not MR4.5 (defined as BCR-ABL/ABL1IS RNA levels at or below 0.0032%). Patients received pioglitazone at a dose of 30 to 45 mg/day along with imatinib. The results were published online ahead of print in Cancer.
During a 12-month follow-up period, 13 patients (54%) achieved MR4.5. Of 13 patients who began the study in MMR but not in MR4, four (30.7%) achieved MR4.5 by 12 months. At the 12-month mark, seven patients (29.1%) remained in MR4.5 while six patients had BCR-ABL1 fluctuations around that level.
Twenty-three of the 24 patients were followed long-term as well (median period of 5.1 years); one patient died of multiple myeloma diagnosed 4.5 years after inclusion in this study. At 48 months from inclusion in the trial, 14 patients (58.3%) maintained MR4.5. Further, of 17 patients who never switched to a different TKI, 15 reached MR4.5 by 48 months after pioglitazone treatment; this included patients who were nonresponders at the 12-month point.
The addition of pioglitazone was generally well tolerated; there were no cases of bladder carcinoma, and only one grade 3 adverse event (hypokalemia) was recorded.
Though the authors noted this would require a prospective trial to firmly evaluate, they also compared these results with an estimated rate of MMR-to-MR4.5 conversion in a parallel cohort of CML patients treated with imatinib alone. The cumulative incidence of MR4.5 conversions over a 12-month period in this group was estimated at 23%, well below the rate seen in this trial.
The authors concluded that the results suggest “pioglitazone together with imatinib increases the proportion of CML patients who achieve MR4.5, further suggesting that the ability of PPAR-Î³ agonists to erode the CML stem cell pool may be of clinical benefit for CML patients.”