Impact of metformin on tyrosine kinase inhibitor response in chronic myeloid leukemia

Abstract

Objective Oral tyrosine kinase inhibitors (TKIs) are first line therapy for chronic myeloid leukemia (CML). A complete cytogenetic response (CCyR) correlates with increased overall survival, however only 66%–88% of patients achieve CCyR after one year of TKI treatment. Because TKI therapy alone cannot eliminate CML stem cells, strategies aimed at achieving faster and deeper responses are needed to improve long-term survival. Metformin is a widely prescribed glucose-lowering agent for patients with diabetes and in preclinical studies, has been shown to suppress cell viability, induce apoptosis, and downregulate the mTORC1 signaling pathway in imatinib resistant CML cell lines (K562R). This study aims to investigate the utility of metformin added to TKI therapy in patients with CML. Data Sources An observational study at an academic medical center (Salt Lake City, UT) was performed for adults with newly diagnosed, chronic-phase CML to evaluate attainment of CCyR from TKI therapy with or without concomitant metformin use. Descriptive analyses were used to describe baseline characteristics and attainment of response to TKI therapy. Data Summary Fifty-nine patients were evaluated. One hundred percent (5 of 5) in the metformin group and 73.6% (39 of 54) in the non-metformin group achieved CCyR. Approximately 20% of patients in both groups relapsed (defined by a loss of CCyR during study) after a median 34.5 months of follow-up. Conclusions Future research is warranted to validate these findings and determine the utility of metformin added to TKI therapy.

Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review

“…An observational study of patients with newly diagnosed chronic-phase CML showed that the proportion of patients reaching complete cytogenetic response (CCyR) was 100% and 73.6% in the metformin and non-metformin groups, respectively, with similar numbers reaching major molecular response (MMR) and complete molecular response (CMR) between the two groups. The median time for achieving MMR and CMR was shorter in the metformin group compared to the non-metformin group (11.1 months vs. 19.5 months; 37.4 months vs. NR), indicating that metformin used together with TKI therapy may increase the proportion of CML patients achieving CCyR and shorten the time to MMR and CMR [248].…”

Research Progress on the Use of Metformin in Leukemia Treatment

“…In preclinical studies, metformin has been shown to inhibit the viability of imatinib-resistant CML cells (K562R) and BCR-ABL-mutant CML cells, induce apoptosis, and downregulate the mTORC1 signaling pathway [ 82 ]. In a clinical study, metformin and TKIs can increase the proportion of patients with CML to achieve CCyR and shorten the time to reach a major molecular response (MMR) or complete molecular response (CMR) [ 83 ]. Nilotinib is used to treat patients with imatinib-sensitive or drug-resistant CML.…”

Metformin and Cancer, an Ambiguanidous Relationship

“…In a single center observation study, metformin use in combination with a TKI was associated with 100% cytogenetic response (CCyR) compared to only 73.6% of single agent TKI [ 70 ]. Patients receiving a TKI with or without metformin were able to achieve major molecular response (MMR) as well as complete molecular response (CMR), however, metformin users achieved this within a shorter period of time with a median time to response of 11.1 months and 37.4 months, respectively, compared to 19.5 months and not reached in the control group [ 70 ]. Furthermore, CML leukemic stem cells (LSCs) have been shown to have increased mitochondrial oxygen consumption compared to hematopoietic stem cells (HSCs) [ 71 ], which could be specifically targeted by metformin [ 70 ].…”