An Oncologist’s Perspective on Metformin Use and Acute Lymphoblastic Leukemia Outcomes:

A randomized controlled clinical trial of an intensive insulin regimen in patients with hyperglycemic acute lymphoblastic leukemia (ALL) was terminated early due to futility regarding ALL clinical outcomes, despite improved glycemic control. Of note, a surrogate measure of exogenous insulin usage (molar insulin-to-C [I/C] peptide ratio) was associated with decreased overall survival, whereas metformin and thiazolidinedione treatment was associated with improved progression-free survival. Although there were differences between the 2 cohorts, for example, older and more patients with Philadelphiapositive ALL in the intensive insulin arm, multivariate analysis demonstrated that only age 60 years, glucose levels 180 mg/dL, and high I/C levels predicted overall survival. These data suggest that improved glycemic control alone may not be sufficient to impact ALL outcomes. Although the presence of an unidentified confounding factor antagonizing the beneficial effects of improved glycemic control could have contributed to the poor outcome of insulin-treated patients, another interpretation of these data point to the specific drugs used for glycemic control in these patients as potential culprits. Accumulating experimental data suggest that insulin and metformin exert conflicting effects on ALL cell biology. Metformin and thiazolidinediones may enhance chemosensitivity through their effects on AKT/mammalian target of rapamycin (mTOR) pathways. Metformin appears to exert direct toxic effects on human ALL cell lines and primary patient samples through activation of adenosine monophosphate-activated protein kinase, a regulator of energy homeostasis. Abrogation of metformin-induced apoptosis was seen following treatment with rapamycin, a known mTOR inhibitor. Metformin also induced proviral integrations of Moloney virus 2 (PIM-2) kinase activity in ALL cells, and the combination of metformin and a PIM-1/2 kinase inhibitor synergistically increased cell death. In contrast, insulin and insulin-mediated pathways may contribute to ALL chemoresistance. High exogenous insulin levels may lead to activation of both insulin and insulin-like growth factor 1 (IGF-1) receptors expressed on ALL blasts. IGF-1 signaling has been shown to enhance the proliferation of ALL cell lines and primary patient samples and inhibit dexamethasone-induced (but not chemotherapy mediated) apoptosis, providing a potent growth advantage to malignant cells. In summary, these observations support additional trials exploring the use of metformin to treat hyperglycemia in both diabetic and nondiabetic patients with ALL as a potential means of improving chemotherapy outcomes. Metformin is devoid of negative effects on normal CD34-positive hematopoietic stem cells or proliferating CD4-positive T-lymphocytes from healthy donors and is currently under investigation in a multitude of trials in nondiabetic patients with solid tumor. A recent clinical trial (NCT01324180) is evaluating the clinical and biological effects of metformin in combination with standard systemic chemotherapy in the relapsed ALL setting. The results from this and similar trials are expected to become available shortly.