Effect of metformin on the survival of patients with ALL who express high levels of the ABCB1 drug resistance gene

Abstract

BackgroundIn acute lymphoblastic leukemia (ALL), high ABCB1 gene expression has been associated with treatment resistance, which affects patient prognosis. Many preclinical reports and retrospective population studies have shown an anti-cancer effect of metformin. Therefore, the objective of this study was to assess the effect of metformin on the treatment regimen in patients with ALL who exhibited high levels of ABCB1 gene expression and to determine its impact on overall survival.MethodsA total of 102 patients with ALL were recruited; one group (n = 26) received metformin, and the other received chemotherapy (n = 76). Measurement of ABCB1 transcript expression was performed using qRT-PCR prior to treatment initiation. Survival analysis was performed using Kaplan–Meier curves. The impact of both the type of treatment and the level of expression on the response (remission or relapse) was analyzed by calculating the odds ratio.ResultsThe survival of patients with high ABCB1 expression was lower than those with low or absent ABCB1 gene expression (p = 0.030). In the individual analysis, we identified a benefit to adding metformin in the group of patients with high ABCB1 gene expression (p = 0.025). In the metformin user group, the drug acted as a protective factor against both therapeutic failure (odds ratio [OR] 0.07, 95% confidence interval [CI] 0.0037–1.53) and early relapse (OR 0.05, 95% CI 0.0028–1.153).ConclusionThe combined use of metformin with chemotherapy is effective in patients with elevated levels of ABCB1 gene expression. Trial registration NCT 03118128: NCT

Diabetes mellitus among adult survivors of childhood acute lymphoblastic leukemia: A report from the St. Jude Lifetime Cohort Study

“…These data are consistent with previous reports from the CCSS and the Bone Marrow Transplant Survivor Study. 33,34 Early reports from the NCT03118128 study have demonstrated that among patients with ALL who express high levels of the ABCB1 gene, those who receive metformin in combination with conventional chemotherapy had higher survival compared with those who Cancer February 15, 2020 only received conventional chemotherapy (83.33% vs 26.47%; P = .025). 6 This increased risk was associated with receipt of total body irradiation in both the CCSS (OR, 12.6; 95% CI, 6.2-25.3) and the Bone Marrow Transplant Survivor Study (OR, 3.42; 95% CI, 1.55-7.52) cohorts.…”

“…Survivor participants in the CCSS who were treated for ALL during childhood were found to be 1.8 times more likely (95% CI, 1.2-2.6 times) to be diagnosed with diabetes mellitus compared with their siblings. 33 These studies are relevant because they may provide safety data for the potential administration of metformin in children with ALL during therapy. 6,28 In the current study cohort, 23 survivors were treated with total body irradiation, 2 of whom developed T2DM.…”

“…Several ongoing clinical trials currently are investigating the clinical and biological effects (antitumor) of metformin within the setting of high-risk and refractory and/or recurrent ALL (ClinicalTrials.gov identifiers NCT01324180 and NCT03118128). 33,34 Early reports from the NCT03118128 study have demonstrated that among patients with ALL who express high levels of the ABCB1 gene, those who receive metformin in combination with conventional chemotherapy had higher survival compared with those who Cancer February 15, 2020 only received conventional chemotherapy (83.33% vs 26.47%; P = .025). 33 These studies are relevant because they may provide safety data for the potential administration of metformin in children with ALL during therapy.…”

“…33,34 Early reports from the NCT03118128 study have demonstrated that among patients with ALL who express high levels of the ABCB1 gene, those who receive metformin in combination with conventional chemotherapy had higher survival compared with those who Cancer February 15, 2020 only received conventional chemotherapy (83.33% vs 26.47%; P = .025). 33 These studies are relevant because they may provide safety data for the potential administration of metformin in children with ALL during therapy. Although speculative, an additional benefit of metformin in high-risk groups, such as the older children in the current study cohort who were exposed to higher doses of asparaginase, may be to prevent DIDM and perhaps the future development of T2DM during adulthood.…”

Phase I study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer

“…Paclitaxel AUC of cycle 2 was corrected for paclitaxel dose adjustment from cycle 1 to cycle 2 in 1 patient (dose reduction for reason of leukopenia), assuming a linear relationship between dose and AUC escalation scheme used in our study, likely contributed to the relatively high RP2D (3000 mg/day). The characteristics of previous trials can be found in supplementary Table 5 [36][37][38][39][40][41][42][43][44][45][46][47][48].…”