OBJECTIVES. In acute lymphoblastic leukemia (ALL), high levels ABCB1 gene expression have been associated with treatment resistance. Metformin has been reported to decrease the level of ABCB1 gene expression. The objective of this study was to evaluate the effect of metformin on the treatment regimen in patients with ALL who exhibit high levels of ABCB1 gene expression and 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. A total of 102 patients with B-immunophenotype-free ALL were enrolled and divided into two groups: metformin users (n = 25) and metformin non-users (n = 76). The mean for the Metformin User group was 31 (range of 18-61), with 93 x 103/mcl leukocytes (range of 1.2-870 x 103/mcl). Regarding the Metformin Non-User group, the mean age was 35 years (range 18-78), most of the patients were women 52.6% (n = 40), and the patients had a lower mean leukocyte level of 45.1 x 103/mcl (range 0.4-251 x 103/mcl).

When analyzing the relative ABCB1 gene expression levels prior to initiation of treatment in the 102 patients, 45.1% (46/102) had high expression levels, 19.6% (20/102) had low levels, and only 35.2% (36/102) did not express the gene. The proportions of patients with high expression were similar in the two treatment groups (in the metformin User group and in the metformin Non-User group)

The effect of expression levels of the ABCB1 gene on Global Survival (OS) at 60 months demonstrated that high levels of ABCB1 gene expression were associated with a lower OS of 41.5% (19/46) in ALL patients; low and negative expression had OS values of 70% (14/20) and 69.5% (25/36), respectively. The results indicated a significant decrease in survival in patients with high levels of ABCB1 gene expression, similar to our previously reported findings ( p ≤ 0.030, log-rank test)

However, when evaluating the two treatment groups (metformin users and metformin non-users), there were no significant differences between the groups (p = 0.251, 95% confidence interval [CI]), confirming that no therapeutic benefit was evident in the OS in 102 patients, without considering ABCB1 gene expression levels. Therefore, we analyzed only those patients who reported high levels of ABCB1 gene expression (46/102) and its effect on OS. In these patients, increased survival was observed in the metformin user group (83.3%, 10/12) compared with the metformin non-user group (26.6%, 9/34), decreasing the risk of therapeutic failure (p = 0.025, 95% CI). No significant changes were observed in OS in patients with low or negative levels of ABCB1 gene expression.

These findings suggest that the use of metformin and steroids in the pre-induction stage depletes the energy reserves of ATP that could be required by the pg170-kDa transporter and increases the chemosensitivities of different chemotherapeutic drugs, increasing their efficacy only in patients with high levels of ABCB1 gene expression.

When assessing the type of risk in the two treatment groups, in terms of refractoriness, only patients with high levels of ABCB1 gene expression demonstrated an increased risk of therapeutic failure (odds ratio [OR] 7.48; 95% CI, 0.3638-153.79) compared with other clinical variables, such as age over 35 years (OR 2.25, 95% CI, 0.3044-16.632) and white blood cell count (OR 6.00, 95% CI, 0.5626-63.987). Regarding relapse, high levels of ABCB1 gene expression were also associated with an increased risk of relapse (OR 2.91, 95% CI, 0.2808-30.299) compared with clinical variables such as age greater than 35 years (OR 3.42, 95% CI, 0.4944-23.775) and leukocyte count (OR 8.57, 95% CI, 0.8251- 89.043). In the metformin user group, metformin functioned as a protective factor against both therapeutic failure and early relapse (OR 0.07, 95% CI, 0.0037-1.538) and (OR 0.05; 95% CI, 0.0028-1.153)

Survival of those patients with high ABCB1 expression was lower than those with low or absent gene expression (p = 0.030).

CONCLUSIONS. The combined use of metformin with chemotherapy is effective in patients with elevated levels of ABCB1 gene expression

graphic
View largeDownload slide
Disclosures

No relevant conflicts of interest to declare.

Topics:
abcb1 gene, metformin, chemotherapy regimen, p-glycoprotein, acute lymphocytic leukemia, antineoplastic agents, disease remission, immunophenotyping, membrane transport proteins, polymerase chain reaction

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2017 by The American Society of Hematology
2017
Sign in via your Institution