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Pioglitazone with imatinib in CML may reduce residual disease
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In a phase 2 study of 24 patients with chronic myeloid leukaemia, the addition of a diabetes drug, pioglitazone, to imatinib produced a molecular response (MR) of 4·5 in 13 (56%, 95% CI 37–76) patients. Patients in the study had received imatinib for at least 2 years, and had achieved a major molecular response (MMR), but not MR 4·5 as defined by BCRABL1/ABL1IS RNA concentrations of 0·0032% or less. The study’s primary endpoint was incidence of progression from MMR to MR 4·5 over 12 months. In a parallel cohort of patients not included in the trial who received imatinib alone, the conversion rate to MR from MMR was estimated to be about 23% at 12 months. “Imatinib and other tyrosine kinase inhibitors target the bulk of the disease, but not the residual quiescent chronic myeloid leukaemia cells, which persist in the bone marrow
and blood compartments”, said lead author Philippe Rousselot (Université Versailles Saint-Quentin-en-Yvelines, Le Chesnay, France). “These residual cells are responsible for the lowlevel signal observed in the majority of patients during therapy, and are also the drivers of the molecular relapses observed in patients eligible for a discontinuation [of therapy] attempt.” The study researchers previously found that the STAT5 pathway was able to sensitise the quiescent chronic myeloid leukaemia stem cells to tyrosine kinase inhibitors. Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, in this case pioglitazone, target the STAT5 pathway. Patients received pioglitazone, at 30–45 mg/day, with imatinib at 100–800 mg/day. Adverse effects included weight gain in 12 patients,
and a mean decrease of 0·04 g/L in haemoglobin. Rousselot is conducting two confirmatory studies. “In the past few years, there have been increasing efforts to see if we can deepen MR”, commented Amir T Fathi, (Harvard Medical School, Boston, MA, USA). “This study suggests that it may be possible to do so by adding a drug to TKIs,” he said. “It remains unclear whether piaglitizone is an optimal second drug, because of data linking it to an increased risk of bladder cancer, and data from the current study suggesting that the many patients did not achieve a sustained response to MR 4·5, which has been a prerequisite to treatment cessation,” said Mark Heaney (Columbia University, New York, NY, USA). “Nonetheless, this study could be an important first step”, he said.
Steve Gschmeissner/Science Photo Library
Pioglitazone with imatinib in CML may reduce residual disease
Lancet Oncol 2017 Published Online January 6, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30010-4 For the study by Rousselot and colleagues see Cancer 2016; published online Dec 27. DOI:10.1002/cncr.30490
Vicki Brower
www.thelancet.com/oncology Published online January 6, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30010-4
1
In a phase 2 study of 24 patients with chronic myeloid leukaemia, the addition of a diabetes drug, pioglitazone, to imatinib produced a molecular response (MR) of 4·5 in 13 (56%, 95% CI 37–76) patients. Patients in the study had received imatinib for at least 2 years, and had achieved a major molecular response (MMR), but not MR 4·5 as defined by BCRABL1/ABL1IS RNA concentrations of 0·0032% or less. The study’s primary endpoint was incidence of progression from MMR to MR 4·5 over 12 months. In a parallel cohort of patients not included in the trial who received imatinib alone, the conversion rate to MR from MMR was estimated to be about 23% at 12 months. “Imatinib and other tyrosine kinase inhibitors target the bulk of the disease, but not the residual quiescent chronic myeloid leukaemia cells, which persist in the bone marrow
and blood compartments”, said lead author Philippe Rousselot (Université Versailles Saint-Quentin-en-Yvelines, Le Chesnay, France). “These residual cells are responsible for the lowlevel signal observed in the majority of patients during therapy, and are also the drivers of the molecular relapses observed in patients eligible for a discontinuation [of therapy] attempt.” The study researchers previously found that the STAT5 pathway was able to sensitise the quiescent chronic myeloid leukaemia stem cells to tyrosine kinase inhibitors. Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, in this case pioglitazone, target the STAT5 pathway. Patients received pioglitazone, at 30–45 mg/day, with imatinib at 100–800 mg/day. Adverse effects included weight gain in 12 patients,
and a mean decrease of 0·04 g/L in haemoglobin. Rousselot is conducting two confirmatory studies. “In the past few years, there have been increasing efforts to see if we can deepen MR”, commented Amir T Fathi, (Harvard Medical School, Boston, MA, USA). “This study suggests that it may be possible to do so by adding a drug to TKIs,” he said. “It remains unclear whether piaglitizone is an optimal second drug, because of data linking it to an increased risk of bladder cancer, and data from the current study suggesting that the many patients did not achieve a sustained response to MR 4·5, which has been a prerequisite to treatment cessation,” said Mark Heaney (Columbia University, New York, NY, USA). “Nonetheless, this study could be an important first step”, he said.
Steve Gschmeissner/Science Photo Library
Pioglitazone with imatinib in CML may reduce residual disease
Lancet Oncol 2017 Published Online January 6, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30010-4 For the study by Rousselot and colleagues see Cancer 2016; published online Dec 27. DOI:10.1002/cncr.30490
Vicki Brower
www.thelancet.com/oncology Published online January 6, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30010-4
1