Step-in dosing of bosutinib in pts with chronic phase chronic myeloid leukemia (CML) after second-generation tyrosine kinase inhibitor (TKI) therapy: results of the Bosutinib Dose Optimization (BODO) Study.

The approved dose of bosutinib in chronic phase CML is 400 mg QD in first-line and 500 mg QD in later-line treatment. However, given that gastrointestinal (GI) toxicity typically occurs early after treatment initiation, physicians often tend to start therapy with lower doses although this has never been tested systematically in prospective trials in the Western world. The Bosutinib Dose Optimization (BODO) Study, a multicenter phase II study, investigated the tolerability and efficacy of a step-in dosing concept of bosutinib (starting at 300 mg QD) in chronic phase CML patients in 2nd or 3rd line who were intolerant and/or refractory to previous TKI treatment. Of 57 patients included until premature closure of the study due to slow recruitment, 34 (60%) reached the targeted dose level of 500 mg QD following the 2-weekly step-in dosing regimen. While the dosing-in concept failed to reduce GI toxicity (grade II-IV, primary study endpoint) to < 40% (overall rate of 60%; 95% CI: 45-74%), bosutinib treatment (mean dosage: 403 mg/day) showed remarkable efficacy with a cumulative major molecular remission (MMR) rate of 79% (95% CI: 66 to 88%) at month 24. Of thirty patients refractory to previous therapy and not in MMR at baseline, 19 (64%) achieved an MMR during treatment. GI toxicity did not significantly impact on patient-reported outcomes (PRO) and led to treatment discontinuation in only one patient. Overall, the results of our trial support the efficacy and safety of bosutinib after failure of second-generation TKI pre-treatment. Trial registration: NCT02577926.

Efficacy of vildagliptin for prevention of postpartum diabetes in women with a recent history of insulin-requiring gestational diabetes: A phase II, randomized, double-blind, placebo-controlled study.

OBJECTIVE: Women with insulin-requiring gestational diabetes mellitus (GDM) are at high risk of developing diabetes within a few years postpartum. We implemented this phase II study to test the hypothesis that vildagliptin, a dipeptidyl peptidase-4 inhibitor, is superior to placebo in terms of reducing the risk of postpartum diabetes. METHODS: Women with insulin-requiring GDM were randomized to either placebo or 50 mg vildagliptin twice daily for 24 months followed by a 12-month observation period (EudraCT: 2007-000634-39). Both groups received lifestyle counseling. The primary efficacy outcomes were the diagnosis of diabetes (American Diabetes Association (ADA) criteria) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT). RESULTS: Between 2008 and 2015, 113 patients (58 vildagliptin, 55 placebo) were randomized within 2.2-10.4 (median 8.6) months after delivery. At the interim analysis, nine diabetic events and 28 IFG/IGT events had occurred. Fifty-two women withdrew before completing the treatment phase. Because of the low diabetes rate, the study was terminated. Lifestyle adherence was similar in both groups. At 24 months, the cumulative probability of postpartum diabetes was 3% and 5% (hazard ratio: 1.03; 95% confidence interval: 0.15-7.36) and IFG/IGT was 43% and 22% (hazard ratio: 0.55; 95% confidence interval: 0.26-1.19) in the placebo and vildagliptin groups, respectively. Vildagliptin was well tolerated with no unexpected adverse events. CONCLUSIONS: The study did not show significant superiority of vildagliptin over placebo in terms of reducing the risk of postpartum diabetes. However, treatment was safe and suggested some improvements in glycemic control, insulin resistance, and ß-cell function. The study identified critical issues in performing clinical trials in the early postpartum period in women with GDM hampering efficacy assessments. With this knowledge, we have set a basis for which properly powered trials could be performed in women with recent GDM. TRIAL REGISTRATION NUMBER AT CLINICALTRIALS.GOV: NCT01018602.

The Diabetes Risk Phenotype of Young Women With Recent Gestational Diabetes.

CONTEXT: The pathogenesis of type 2 diabetes (T2D) is still incompletely understood. In-depth phenotyping of young individuals at risk for T2D can contribute to the understanding of this process. OBJECTIVE: The purpose of this study was to metabolically characterize women with recent gestational diabetes (GDM), an at-risk cohort for T2D. STUDY PARTICIPANTS: Participants were 147 women consecutively recruited 3 to 16 months after pregnancy: women who had GDM and women after a normoglycemic pregnancy (control subjects) in a 2:1 ratio. DESIGN: This was a monocenter cross-sectional analysis (Prediction, Prevention and Subclassification of Type 2 Diabetes Study [PPS-Diab]). METHODS: A 5-point oral glucose tolerance test with calculation of the insulin sensitivity index and disposition index (validation by euglycemic clamp and intravenous glucose tolerance test) was performed. In addition, anthropometrics, medical and family history, clinical chemistry and biomarkers, statistical modeling, and a magnetic resonance imaging/magnetic resonance spectroscopy substudy (body fat distribution and liver and muscle fat; n = 66) were obtained. RESULTS: Compared with control subjects, women after GDM had a reduced disposition index, higher levels of plasma fetuin-A, and a lower insulin sensitivity index. A low insulin sensitivity index was also the major determinant of pathological glucose tolerance after GDM. The factors most strongly predictive of low insulin sensitivity were high plasma leptin, body mass index, triglycerides, and waist circumference. Ectopic lipids showed no body mass index-independent associations with having had GDM or low insulin sensitivity in a magnetic resonance imaging substudy. CONCLUSIONS: We found that ß-cell function is already impaired in women with recent GDM, a young at-risk cohort for T2D. In addition, our data suggest that fetuin-A and leptin signaling may be important early contributors to the pathogenesis of T2D, at this disease stage equally or more relevant than ectopic lipids and low-grade inflammation.

Frequency and causes of adrenal crises over lifetime in patients with 21-hydroxylase deficiency.

OBJECTIVE: To study adrenal crisis (AC) in patients with congenital adrenal hyperplasia due to classical 21-hydroxylase deficiency (21-OHD). AC was defined as an acute state of health impairment requiring i.v. glucocorticoid administration and hospital admission. DESIGN AND METHODS: In a cross-sectional study with detailed retrospective assessment, AC was studied following two approaches: i) questionnaire based: 122 adult 21-OHD patients (50 men, 72 women, median age 35 years, range 18-69 years) completed a disease-specific questionnaire; and ii) patient chart based: charts of 67 21-OHD patients (32 males, 35 females, median age 31 years, range 20-66 years) were analyzed from diagnosis to last follow-up with regard to frequency and causes of AC since diagnosis. RESULTS: Evaluation of questionnaires revealed 257 ACs in 4456 patient years (py; frequency 5.8 crises/100 py), while patient charts documented 106 ACs in 2181 py (4.9 crises/100 py). The chart-based evaluation showed that gastrointestinal infections (29%) and salt-wasting crisis (18%) were the main causes of AC. In 14%, the cause remained uncertain. There was no difference in the overall frequency of AC in males and females. AC mostly occurred during childhood, with more than 70% of AC in the first 10 years of life and one-third of AC in the first year of life. Still, 20% of cases of AC were observed in adults (>18 years). CONCLUSION: Our data demonstrate a significant risk of AC in patients with 21-OHD over lifetime. Specific age-adapted and repeated crisis prevention training may help to reduce morbidity due to AC in 21-OHD.