GLUCOSE AND LIPID METABOLISM ABNORMALITIES DURING NILOTINIB TREATMENT AND COMPARISON WITH IMATINIB AND DASATINIB THERAPY ? RESULTS FROM ENIGMA 2 STUDY
(Abstract release date: 05/19/16)
EHA Library. Racil Z. 06/11/16; 135189; S433
Prof. Dr. Zdenek Racil
Contributions
Contributions
Abstract
Abstract: S433
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 11:45 - 12:00
Location: Hall A2
Background
Our pilot study on 10 CML patients demonstrated fast development of hyperinsulinaemia, peripheral insulin resistance, hypoadiponectinaemia and hypercholesterolemia during nilotinib (NILO) therapy.
Aims
The aim of this multicenter ENIGMA 2 study was to confirm these results and to compare data obtained during NILO therapy with control groups of patients treated with imatinib (IMA) and dasatinib (DASA).
Methods
Patients received intensive laboratory workup before the start of tyrosine kinase inhibitor (TKI), after 3 and 12 months of therapy. This included oral glucose tolerance test, fasting insulin, glucose, adiponectin and serum lipid concentration. Patients with diabetes mellitus, TKI treatment interruption for >2 weeks (start-month 3) or > 4 weeks (month 4-12) or TKI dose reduction for > 25% were excluded.
Results
Between 2/2011-11/2015 87 CML patients in 6 centers initiated TKI therapy – 48 NILO (1st line - 25; 2nd line - 23), 24 with IMA (all 1st line) and 15 with DASA (1st line - 5; 2nd line - 10). After 3 months of NILO treatment patients evolved significant hyperinsulinaemia and hyperglycaemia (presented in 75% of patients) as result of fast development of peripheral insulin resistance. This was proved by significant increase in HOMA-2 index during this period (appeared in 73% of patients). Moreover, total and LDL cholesterol concentration significantly increased already after this short NILO treatment (developed in 92% and 87% of patients, respectively). All these abnormalities were significant also after 12 months of therapy (Table). A separate analysis of patients treated with NILO either 1st or 2nd line confirmed these metabolic changes after 3 months of treatment. On the contrary – none of these abnormalities were detected in the control group of patients treated with IMA and DASA, including any change in insulin resistance measured by HOMA-2 index.Interestingly, previously described decrease in adiponectin (major insulin sensitizer) concentration during NILO administration was confirmed subsequently when all NILO treated patients were analyzed together. However, in separate analysis decrease in adiponectin was proved only in patients with the 2nd line NILO therapy (median concentration at baseline vs. month 3 – 14.3 vs. 7.1 mg/l, p<0.001; at baseline vs. month 12 – 14.3 vs. 10.5 mg/l, p<0.001), but not in the 1st line NILO patients (median concentration at baseline vs. month 3 – 7.3 vs. 7.3 mg/l, p = 0.875; at baseline vs. month 12 – 7.3 vs. 7.8 mg/l, p = 0.917). While in the control IMA group (but not DASA) adiponectin concentration was significantly and persistently increased. Thus hypoadiponectineamia observed in the whole NILO group was caused by spontaneous decrease in adiponectin after the stop of IMA in the subgroup of the 2nd line NILO-treated patients.
Conclusion
We proved fast and persisting development of peripheral insulin resistance during NILO therapy as underlying cause of glucose and lipid metabolism impairment during NILO treatment. This was not proved for patients treated with IMA and DASA. IMA administration significantly increases serum adiponectin (major insulin sensitizer) concentration, which spontaneously declines after discontinuation of IMA and start of 2nd line NILO therapy.Supported by the CELL – the Czech Leukemia Study Group – for life.
Session topic: Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, Metabolic syndrome, Tyrosine kinase inhibitor
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 11:45 - 12:00
Location: Hall A2
Background
Our pilot study on 10 CML patients demonstrated fast development of hyperinsulinaemia, peripheral insulin resistance, hypoadiponectinaemia and hypercholesterolemia during nilotinib (NILO) therapy.
Aims
The aim of this multicenter ENIGMA 2 study was to confirm these results and to compare data obtained during NILO therapy with control groups of patients treated with imatinib (IMA) and dasatinib (DASA).
Methods
Patients received intensive laboratory workup before the start of tyrosine kinase inhibitor (TKI), after 3 and 12 months of therapy. This included oral glucose tolerance test, fasting insulin, glucose, adiponectin and serum lipid concentration. Patients with diabetes mellitus, TKI treatment interruption for >2 weeks (start-month 3) or > 4 weeks (month 4-12) or TKI dose reduction for > 25% were excluded.
Results
Between 2/2011-11/2015 87 CML patients in 6 centers initiated TKI therapy – 48 NILO (1st line - 25; 2nd line - 23), 24 with IMA (all 1st line) and 15 with DASA (1st line - 5; 2nd line - 10). After 3 months of NILO treatment patients evolved significant hyperinsulinaemia and hyperglycaemia (presented in 75% of patients) as result of fast development of peripheral insulin resistance. This was proved by significant increase in HOMA-2 index during this period (appeared in 73% of patients). Moreover, total and LDL cholesterol concentration significantly increased already after this short NILO treatment (developed in 92% and 87% of patients, respectively). All these abnormalities were significant also after 12 months of therapy (Table). A separate analysis of patients treated with NILO either 1st or 2nd line confirmed these metabolic changes after 3 months of treatment. On the contrary – none of these abnormalities were detected in the control group of patients treated with IMA and DASA, including any change in insulin resistance measured by HOMA-2 index.Interestingly, previously described decrease in adiponectin (major insulin sensitizer) concentration during NILO administration was confirmed subsequently when all NILO treated patients were analyzed together. However, in separate analysis decrease in adiponectin was proved only in patients with the 2nd line NILO therapy (median concentration at baseline vs. month 3 – 14.3 vs. 7.1 mg/l, p<0.001; at baseline vs. month 12 – 14.3 vs. 10.5 mg/l, p<0.001), but not in the 1st line NILO patients (median concentration at baseline vs. month 3 – 7.3 vs. 7.3 mg/l, p = 0.875; at baseline vs. month 12 – 7.3 vs. 7.8 mg/l, p = 0.917). While in the control IMA group (but not DASA) adiponectin concentration was significantly and persistently increased. Thus hypoadiponectineamia observed in the whole NILO group was caused by spontaneous decrease in adiponectin after the stop of IMA in the subgroup of the 2nd line NILO-treated patients.
Conclusion
We proved fast and persisting development of peripheral insulin resistance during NILO therapy as underlying cause of glucose and lipid metabolism impairment during NILO treatment. This was not proved for patients treated with IMA and DASA. IMA administration significantly increases serum adiponectin (major insulin sensitizer) concentration, which spontaneously declines after discontinuation of IMA and start of 2nd line NILO therapy.Supported by the CELL – the Czech Leukemia Study Group – for life.
Session topic: Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, Metabolic syndrome, Tyrosine kinase inhibitor
Abstract: S433
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 11:45 - 12:00
Location: Hall A2
Background
Our pilot study on 10 CML patients demonstrated fast development of hyperinsulinaemia, peripheral insulin resistance, hypoadiponectinaemia and hypercholesterolemia during nilotinib (NILO) therapy.
Aims
The aim of this multicenter ENIGMA 2 study was to confirm these results and to compare data obtained during NILO therapy with control groups of patients treated with imatinib (IMA) and dasatinib (DASA).
Methods
Patients received intensive laboratory workup before the start of tyrosine kinase inhibitor (TKI), after 3 and 12 months of therapy. This included oral glucose tolerance test, fasting insulin, glucose, adiponectin and serum lipid concentration. Patients with diabetes mellitus, TKI treatment interruption for >2 weeks (start-month 3) or > 4 weeks (month 4-12) or TKI dose reduction for > 25% were excluded.
Results
Between 2/2011-11/2015 87 CML patients in 6 centers initiated TKI therapy – 48 NILO (1st line - 25; 2nd line - 23), 24 with IMA (all 1st line) and 15 with DASA (1st line - 5; 2nd line - 10). After 3 months of NILO treatment patients evolved significant hyperinsulinaemia and hyperglycaemia (presented in 75% of patients) as result of fast development of peripheral insulin resistance. This was proved by significant increase in HOMA-2 index during this period (appeared in 73% of patients). Moreover, total and LDL cholesterol concentration significantly increased already after this short NILO treatment (developed in 92% and 87% of patients, respectively). All these abnormalities were significant also after 12 months of therapy (Table). A separate analysis of patients treated with NILO either 1st or 2nd line confirmed these metabolic changes after 3 months of treatment. On the contrary – none of these abnormalities were detected in the control group of patients treated with IMA and DASA, including any change in insulin resistance measured by HOMA-2 index.Interestingly, previously described decrease in adiponectin (major insulin sensitizer) concentration during NILO administration was confirmed subsequently when all NILO treated patients were analyzed together. However, in separate analysis decrease in adiponectin was proved only in patients with the 2nd line NILO therapy (median concentration at baseline vs. month 3 – 14.3 vs. 7.1 mg/l, p<0.001; at baseline vs. month 12 – 14.3 vs. 10.5 mg/l, p<0.001), but not in the 1st line NILO patients (median concentration at baseline vs. month 3 – 7.3 vs. 7.3 mg/l, p = 0.875; at baseline vs. month 12 – 7.3 vs. 7.8 mg/l, p = 0.917). While in the control IMA group (but not DASA) adiponectin concentration was significantly and persistently increased. Thus hypoadiponectineamia observed in the whole NILO group was caused by spontaneous decrease in adiponectin after the stop of IMA in the subgroup of the 2nd line NILO-treated patients.
Conclusion
We proved fast and persisting development of peripheral insulin resistance during NILO therapy as underlying cause of glucose and lipid metabolism impairment during NILO treatment. This was not proved for patients treated with IMA and DASA. IMA administration significantly increases serum adiponectin (major insulin sensitizer) concentration, which spontaneously declines after discontinuation of IMA and start of 2nd line NILO therapy.Supported by the CELL – the Czech Leukemia Study Group – for life.
Session topic: Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, Metabolic syndrome, Tyrosine kinase inhibitor
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 11:45 - 12:00
Location: Hall A2
Background
Our pilot study on 10 CML patients demonstrated fast development of hyperinsulinaemia, peripheral insulin resistance, hypoadiponectinaemia and hypercholesterolemia during nilotinib (NILO) therapy.
Aims
The aim of this multicenter ENIGMA 2 study was to confirm these results and to compare data obtained during NILO therapy with control groups of patients treated with imatinib (IMA) and dasatinib (DASA).
Methods
Patients received intensive laboratory workup before the start of tyrosine kinase inhibitor (TKI), after 3 and 12 months of therapy. This included oral glucose tolerance test, fasting insulin, glucose, adiponectin and serum lipid concentration. Patients with diabetes mellitus, TKI treatment interruption for >2 weeks (start-month 3) or > 4 weeks (month 4-12) or TKI dose reduction for > 25% were excluded.
Results
Between 2/2011-11/2015 87 CML patients in 6 centers initiated TKI therapy – 48 NILO (1st line - 25; 2nd line - 23), 24 with IMA (all 1st line) and 15 with DASA (1st line - 5; 2nd line - 10). After 3 months of NILO treatment patients evolved significant hyperinsulinaemia and hyperglycaemia (presented in 75% of patients) as result of fast development of peripheral insulin resistance. This was proved by significant increase in HOMA-2 index during this period (appeared in 73% of patients). Moreover, total and LDL cholesterol concentration significantly increased already after this short NILO treatment (developed in 92% and 87% of patients, respectively). All these abnormalities were significant also after 12 months of therapy (Table). A separate analysis of patients treated with NILO either 1st or 2nd line confirmed these metabolic changes after 3 months of treatment. On the contrary – none of these abnormalities were detected in the control group of patients treated with IMA and DASA, including any change in insulin resistance measured by HOMA-2 index.Interestingly, previously described decrease in adiponectin (major insulin sensitizer) concentration during NILO administration was confirmed subsequently when all NILO treated patients were analyzed together. However, in separate analysis decrease in adiponectin was proved only in patients with the 2nd line NILO therapy (median concentration at baseline vs. month 3 – 14.3 vs. 7.1 mg/l, p<0.001; at baseline vs. month 12 – 14.3 vs. 10.5 mg/l, p<0.001), but not in the 1st line NILO patients (median concentration at baseline vs. month 3 – 7.3 vs. 7.3 mg/l, p = 0.875; at baseline vs. month 12 – 7.3 vs. 7.8 mg/l, p = 0.917). While in the control IMA group (but not DASA) adiponectin concentration was significantly and persistently increased. Thus hypoadiponectineamia observed in the whole NILO group was caused by spontaneous decrease in adiponectin after the stop of IMA in the subgroup of the 2nd line NILO-treated patients.
Conclusion
We proved fast and persisting development of peripheral insulin resistance during NILO therapy as underlying cause of glucose and lipid metabolism impairment during NILO treatment. This was not proved for patients treated with IMA and DASA. IMA administration significantly increases serum adiponectin (major insulin sensitizer) concentration, which spontaneously declines after discontinuation of IMA and start of 2nd line NILO therapy.Supported by the CELL – the Czech Leukemia Study Group – for life.
Session topic: Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, Metabolic syndrome, Tyrosine kinase inhibitor
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