Efficacy and tolerability of isocitrate dehydrogenase inhibitors in patients with acute myeloid leukemia: A systematic review of clinical trials.

BACKGROUND: Acute myeloid leukemia (AML) is a hematological malignancy due to anomalous differentiation and proliferation of hematopoietic stem cells with myeloid blast buildup. Induction chemotherapy is considered the first line of treatment in most patients with AML. However, targeted therapy in the form of FLT-3, IDH, BCL-2, and immune checkpoint inhibitors, can be considered as the first line depending on their molecular profile, resistance to chemotherapy, comorbidities, etc. This review aims to assess the tolerability and efficacy of isocitrate dehydrogenase (IDH) inhibitors in AML. METHODS: We searched Medline, WOS, Embase, and clinicaltrials.gov. PRISMA guidelines were followed in this systematic review. 3327 articles were screened, and 9 clinical trials (N = 1119) were included. RESULTS: In randomized clinical trials (RCTs), objective response (OR) was reported in 63-74% of the patients with IDH inhibitors + azacitidine as compared to 19-36 % of the patients with azacitidine monotherapy in newly diagnosed (ND) medically unfit patients. Survival rates were significantly improved with the use of ivosidenib. OR was reported in 39.1-46 % of the patients who relapsed/refractory to chemotherapy. ≥Grade 3 IDH differentiation syndrome and QT prolongation were reported in 3.9-10 % and 2-10 % of the patients, respectively. CONCLUSION: IDH inhibitors (ivosidenib for IDH-1 and enasidenib for IDH-2) are safe and effective in treating ND medically unfit or relapsed refractory patients with IDH mutation. However, no survival benefit was reported with enasidenib. More randomized multicenter double-blinded clinical studies are needed to confirm these results and compare them with other targeting agents.

The utility of the forced oscillation technique in assessing bronchodilator responsiveness in patients with asthma.

OBJECTIVE: To address the utility of the forced oscillation technique (FOT) in assessing bronchodilator responsiveness compared with forced expiratory volume in 1s (FEV(1)). METHODS: This is a retrospective analysis of consecutive 126 patients with a clinical history of asthma without any other lung diseases at a pulmonary function testing laboratory. The following measurements were obtained three times each, before and after two doses of pirbuterol 0.2mg inhalation: the respiratory resistance at 5Hz (Rrs5), the mean respiratory resistance between 5 and 20Hz (Rrs5-20), and the mean respiratory conductance (Grs5-20) by FOT and the FEV(1) by spirometer. These measurements were transformed into dimensionless subject-specific effect-size "d-scores" by dividing them by the estimated pooled within-subject standard deviation. RESULTS: Descriptive statistics for each value were the following [mean baseline value (+/-sd), Delta value (pre- minus post value), and d-score (P value compared to FEV(1))]: Grs5-20 (Ls(-1)kPa(-1)) [1.79+/-0.53, Delta=+0.39, d=2.64 (P<0.001)], Rrs5-20 (kPaL(-1)s) [0.60+/-0.16L, Delta=-0.10, d=2.56 (P=0.001)], Rrs5 (kPaL(-1)s) [0.78+/-0.25, Delta=-0.16, d=2.52 (P<0.001)], and FEV(1) (L) [1.90+/-0.64, Delta=-0.20, d=1.83]. The higher d-score of Grs5-20, Rrs5-20 and Rrs5 compared to FEV(1) indicates that these are better indicators for bronchodilator response than FEV(1). The percentages of subjects exhibiting change in the expected direction after bronchodilator were not significantly different between each value: Rrs5 (85.7%), Rrs5-20 (83.3%), Grs5-20 (83.3%), and FEV(1) (83.3%) [P>0.05]. CONCLUSIONS: Several forced oscillation measures, namely Grs5-20, Rrs5-20 and Rrs5, are more accurate and sensitive for detecting bronchodilator response than FEV(1) in patients with asthma.

Bronchodilator effect of infused B-type natriuretic peptide in asthma.

STUDY OBJECTIVE: To determine the bronchodilator effect of recombinant human B-type natriuretic peptide (BNP; nesiritide) on patients with asthma. DESIGN: A prospective, open-label study. SETTING: Outpatient setting. PATIENTS: Eight adult patients with asthma confirmed by > 12% and > 200 mL increase in FEV1 after bronchodilator inhalation. INTERVENTIONS: An IV nesiritide bolus, 2 microg/kg, followed by continuous infusion for a total of 3 h at escalating doses of 0.01, 0.02, and 0.03 microg/kg/min for 1 h each as tolerated. MEASUREMENTS: Spirometry and forced oscillation technique (FOT) measurements were both obtained at baseline and every 30 min during the infusion. Two doses of albuterol, 90 microg, inhalation via metered-dose inhaler were then administered at the end of nesiritide infusion, followed by repeat spirometry and FOT measurements after 30 min. Primary end points were FEV1 and FVC changes after the nesiritide infusion for 3 h. Wilcoxon signed-ranks tests were used to compare the effects of nesiritide and albuterol. RESULTS: Baseline measurements (mean +/- SD) were as follows: FEV1, 1.89 +/- 0.87 L; FVC, 3.02 +/- 0.99 L; respiratory resistance at 5 Hz (Rrs5), 10.3 +/- 3.85 cm H2O . s/L; and mean respiratory resistance at 5 to 20 Hz, 7.56 +/- 1.92 cm H2O/L/s. Mean baseline serum BNP level was 27 +/- 27 pg/mL. After 180 min of nesiritide infusion, the following measurements showed significant changes: FEV1 increased to 2.41 +/- 0.78 L (mean increase, 520 mL), p = 0.012; FVC increased to 3.65 +/- 1.05 L (mean increase, 630 mL), p = 0.017; and Rrs5 decreased to 8.24 +/- 4.02 cm H2O/L/s, p = 0.017. After albuterol, there were no further significant changes in these measurements. CONCLUSION: IV nesiritide is an effective bronchodilator in patients with asthma.

Relationship between asthma severity and obesity.

The prevalence of both obesity and asthma has risen in recent years. We sought to investigate whether obesity may be related to asthma. We undertook a retrospective medical record review of patient records at an inner-city academic asthma center. Obesity was defined as a body mass index (BMI) greater than 30. Asthma severity was defined by using the National Heart Lung and Blood Institute 1997 guidelines. Adults with a history of cigarette smoking or other lung disease were excluded. A total of 143 individuals aged 18-88 with a mean age of 43.9 met the entry criteria. There were 113 females and 30 males. Seventy-two percent of the sample was obese. The Spearman correlation coefficient showed a linear relationship between asthma severity and BMI (r = 0.40, p < 0.0001). Females with asthma were significantly more overweight than males, mean BMI 35.9 vs. 32.14, respectively (p = 0.01). The prevalence of obesity in the 13 patients on long-term oral corticosteroids was 100%. Prevalence of obesity increases with increasing asthma severity in adults. The association of asthma severity with obesity suggests that obesity may be a potentially modifiable risk factor for asthma or asthma-like symptoms.