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

Christian Ramos-Peñafiel, Irma Olarte-Carrillo, Rafael Cerón-Maldonado, Etta Rozen-Fuller, Juan Julio Kassack-Ipiña, Guillermo Meléndez-Mier, Juan Collazo-Jaloma, Adolfo Martínez-Tovar, Christian Ramos-Peñafiel, Irma Olarte-Carrillo, Rafael Cerón-Maldonado, Etta Rozen-Fuller, Juan Julio Kassack-Ipiña, Guillermo Meléndez-Mier, Juan Collazo-Jaloma, Adolfo Martínez-Tovar

Abstract

Background: In 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.

Methods: A 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.

Results: The 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).

Conclusion: The combined use of metformin with chemotherapy is effective in patients with elevated levels of ABCB1 gene expression. Trial registration NCT 03118128: NCT.

Trial registration: ClinicalTrials.gov NCT03118128.

Keywords: ATP binding cassette subfamily B member 1 (ABCB1); Acute lymphoblastic leukemia (ALL); Quantitative real-time polymerase chain reaction (qRT-PCR).

Figures

Fig. 1
Fig. 1
Treatment scheme used in the two ALL patient treatment groups
Fig. 2
Fig. 2
Global survival (OS) in patients with ALL expressing the ABCB1 gene. OS at 60 months in patients expressing the ABCB1 gene was analyzed. Patients with high levels of ABCB1 gene expression had an OS of 41.5% (19/46) in patients with ALL; patients with low or negative ABCB1 expression had OS values of 70% (14/20) and 69.5% (25/36), respectively (p ≤ 0.030, log-rank test)
Fig. 3
Fig. 3
Global survival (OS) in patients with ALL treated with metformin (metformin users and metformin non-users). OS at 60 months in patients treated with metformin was analyzed, and no significant differences were found between the two groups (p = 0.251, 95% CI)
Fig. 4
Fig. 4
Global survival (OS) in patients with metformin-treated ALL (metformin users) and ALL without metformin treatment (metformin non-users) with elevated levels of ABCB1 gene expression. OS at 60 months in Metformin-treated patients and high levels of ABCB1 expression was analyzed, and metformin had a protective survival benefit (p = 0.025, 95% CI)
Fig. 5
Fig. 5
Global survival (OS) in patients with metformin-treated ALL (metformin users) and ALL without metformin treatment (metformin non-users) with low ABCB1 gene expression levels. No significant changes were observed in OS in the patients with low ABCB1 gene expression levels (p = 0.046, 95% CI)
Fig. 6
Fig. 6
Global survival (OS) in patients with metformin-treated ALL (metformin users) and ALL without metformin treatment (metformin non-users) with negative ABCB1 gene expression levels. No significant changes were observed in OS in the patients with low ABCB1 gene expression levels (p = 0.048, 95% CI)

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