A risk mitigation strategy was implemented to determine if a higher prophylactic voriconazole dosage in patients with CYP2C19 rapid metabolizer neutropenic acute myeloid leukemia (AML) reduces the incidence of subtherapeutic trough concentrations. Patients with AML (n = 263) were preemptively genotyped for CYP2C19*2, *3, and *17 alleles as part of a single‐center prospective, interventional, quality improvement study. CYP2C19 rapid metabolizers (CYP2C19*1/*17) were recommended to receive interventional voriconazole 300 mg twice daily, ultrarapid metabolizers (CYP2C19*17/*17) were recommended to avoid voriconazole, and all others received the standard prophylactic dosage of 200 mg twice daily. In this real‐world setting, 202 patients (76.8%) were prescribed prophylactic voriconazole, and of these patients 176 (87.1%) received CYP2C19‐guided prophylactic dosing. Voriconazole trough concentrations were obtained for 41 of the 58 (70.7%) CYP2C19 rapid metabolizers prescribed prophylactic voriconazole. Interventional voriconazole resulted in higher plasma trough concentrations (median 2.7 μg/mL) compared with the standard prophylactic dosage (median 0.6 μg/mL; P = 0.001). Subtherapeutic concentrations were avoided in 83.8% of CYP2C19 rapid metabolizers receiving interventional dosage compared to 46.2% receiving standard dosage (P = 0.02). CYP2C19 genotyping to preemptively guide prophylactic voriconazole dosing is feasible and may be a potential strategy for reducing the risk of subtherapeutic trough concentrations that potentiate breakthrough fungal infections.

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The model, based on the robust literature of clinical and economic data, predicts that proactive genotype-guided voriconazole prophylaxis is likely to yield modest cost savings while improving patient outcomes. The primary driver of savings is the avoidance of expensive antifungal treatment and extended hospital stays, costing $30 952 per patient, in patients succumbing to fungal infection.

BackgroundBlinatumomab is an anti-CD19 immunotherapy approved for relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) with significantly increased survival rate. While blinatumomab showed lower rates of infection, neutropenia and mucosal barrier injury versus chemotherapy, its infection risks are not well described.MethodsAll patients who received blinatumomab for ≥ seven days at an academic cancer center from May 2015 to April 2017 were included. Patient characteristics pertinent to infectious risks and complications were examined.ResultsTwenty patients with refractory (25%), relapsed (70%), or remitted (5%) B-ALL who received a total of 35 cycles were included. Ten of the 35 cycles were interrupted, none of which were due to infections. Twenty-six infections (n) were observed with lower respiratory (9), gastrointestinal (6) and bacteremia (5) being most common. Compared to patients without nodular, possible mold pneumonia (n=16), patients with nodular pneumonia (n=4) had significantly lower baseline absolute neutrophil count (ANC) (2319 v. 208/μL, p=0.011). There were no differences in baseline characteristics including ANC between bacteremic and non-bacteremic patients. One patient was discharged with no antibacterial prophylaxis since ANC recovered to >500cells/μL, but developed Pseudomonal bacteremia within a week with ANC ~100cells/μL.ConclusionDespite blinatumomab’s relatively modest myelosuppression and the lack of mucotoxicity, host factors (e.g., duration and degree of neutropenia/lymphopenia) play a key role and should be considered when choosing anti-microbial prophylaxis. In relapsed/refractory disease, the ANC should be monitored closely post blinatumomab since neutropenia can unexpectedly develop after treatment which may be compounded by the underlying disease and recent chemotherapy effects.

Questions relating to drug use, dosing, and related issues in oncology are presented in this regular feature. Pharmacokinetics Due to poor aqueous solubility, the absolute bioavailability of thalidomide is unknown. Time to maximal concentration (T max) ranged from 2.9 to 5.7 hours in patients with Hansen's disease and healthy volunteers. 3 A similar range of 2 to 7.1 hours was seen in elderly prostate cancer patients. 32 The volume of distribution in prostate cancer patients varied by dose level: 66.93 ± 34.27 L (200 mg/day) and 165.81 ± 84.18 L (1,200 mg/day). 32 The extent of plasma protein binding is unknown. 3 Significant hepatic metabolism has not yet been identified 3 ; however, the presence of an antiangiogenic active metabolite is anticipated. 30 Thalidomide does not induce or inhibit its own metabolism. 3 Renal elimination is minor, with 0.7% of the dose excreted unchanged in the urine. 3 The major route of elimination appears to be non-enzymatic hydrolysis. 3 The elimination half-life is reported to be 5 to 7 hours, based on Hansen's disease patients who rarely receive more than 400 mg/day. 3 Half-life was shown to be dose-related in prostate cancer patients: 6.52 ± 3.81 hours (200 mg/day) and 18.25 ± 14.08 hours (1,200 mg/day). 32 However, overall clearance was comparable between the two groups (7.41 ± 2.05 L/h and 7.21 ± 2.89 L/h, respectively). 32 Renal dysfunction would be expected to have minimal effects on thalidomide's pharmacokinetics. Hepatic dysfunction may not produce a major effect on the elimination of thalidomide itself, but it could affect the production of the presumed antiangiogenic metabolite. Contraindications and Precautions Several side effects, particularly severe human teratogenicity, are associated with thalidomide therapy and thus have limited its use in specific populations. Some of the adverse effects are listed in Table 1, and a summary of the indications and contraindications of thalidomide use are presented in Table 2. Chemical structure of thalidomide.