Real-life comparison of posaconazole versus fluconazole for primary antifungal prophylaxis during remission-induction chemotherapy for acute leukemia.

Background: Patients undergoing remission-induction intensive chemotherapy for acute leukemia are at high risk for life-threatening invasive fungal infections (IFIs). Primary antifungal prophylaxis with posaconazole has been shown to reduce the incidence of IFI compared to fluconazole, but real-life data are limited and the effect on mortality remains unclear. Methods: This retrospective cohort study compared fluconazole and posaconazole as primary prophylaxis in real-life practice over a 10-year period, in a Canadian hospital. Results: A total of 299 episodes were included (fluconazole, n = 98; posaconazole, n = 201), of which 68% were first inductions. The underlying hematologic malignancy was acute myeloid leukemia or myelodysplastic syndrome in 88% of episodes and acute lymphoblastic leukemia in 9%. Overall, 20 cases of IFI occurred (aspergillosis, n = 17; candidiasis, n = 3) and 14 were considered as breakthrough IFI. IFI incidence was significantly lower in the posaconazole group (3.5% versus 13.2%; p = 0.001). Empirical or targeted antifungal therapy was also reduced in the posaconazole cohort. Mortality was similar in both groups. Conclusions: In a real-life setting in Canada, primary posaconazole prophylaxis reduces the incidence of IFI during remission-induction chemotherapy, compared to fluconazole.

Historique: Les patients soumis à une chimiothérapie intensive visant à induire la rémission d'une leucémie aiguë sont très vulnérables à des infections fongiques invasives (IFI) au potentiel mortel. Il est démontré qu'une prophylaxie antifongique primaire au posaconazole réduit l'incidence d'IFI davantage que le fluconazole, mais les données sur le terrain sont limitées et l'effet de ce médicament sur la mortalité demeure nébuleux. Méthodologie: La présente étude de cohorte rétrospective a comparé le fluconazole au posaconazole comme prophylaxie primaire sur une période de dix ans dans un hôpital canadien. Résultats: Au total, 299 épisodes ont été inclus (fluconazole, n = 98; posaconazole, n = 201), dont 68 % étaient des premières occurrences. Dans 88 % des épisodes, la leucémie myéloïde était le cancer hématologique sous-jacent, et dans 9 % des cas, il s'agissait plutôt d'une leucémie aiguë lymphoblastique. Dans l'ensemble, 20 cas d'IFI ont été observés (aspergillose, n = 17; candidose, n = 3) et 14 étaient considérés comme des IFI qui avaient percé malgré une médication. L'incidence d'IFI était beaucoup plus faible dans le groupe prenant du posaconazole (3,5 % par rapport à 13,2 %; p = 0,001). Le traitement antifongique empirique ou ciblé était également limité dans cette cohorte. La mortalité était semblable dans les deux groupes. Conclusions: Sur le terrain au Canada, la prophylaxie primaire au posaconazole réduit l'incidence d'IFI davantage que le fluconazole pendant une chimiothérapie visant à induire une rémission.

Opinion, experience and educational preferences concerning pharmacogenomics: an exploratory study of Quebec pharmacists.

Aim: To evaluate the current opinion, experience and educational preferences of pharmacists in Quebec concerning pharmacogenomics. Method: A web-based survey containing 25 questions was sent to all Quebec pharmacists. Results: Most pharmacists were willing to advise patients (81%) and physicians (84%) on treatment choices based on pharmacogenomic test results after proper training. Only 31% had been previously exposed to pharmacogenomic test results, and 91% were favorable to pharmacogenomics training, with e-learning through interactive video sessions (69%). The preferred training session length was between 1 and 3 h (59%). Hospital pharmacists were more often exposed to pharmacogenomic tests (p < 0.0001) and more frequently advised patients on treatment choices (p < 0.001) than community pharmacists. Conclusion: Pharmacists remain favorable toward pharmacogenomics, but its use in clinical practice stays limited. Identifying the educational preferences of pharmacists may help in the development of educational programs to help them integrate pharmacogenomics in their clinical practice.

Impact of GSTA1 Polymorphisms on Busulfan Oral Clearance in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation.

BACKGROUND: Busulfan pharmacokinetics exhibit large inter-subject variability. Our objective was to evaluate the influence of glutathione S-transferase A1 (GSTA1) gene variants on busulfan oral clearance (CLo) in a population of patients undergoing hematopoietic stem cell transplantation. METHODS: This is a quasi-experimental retrospective study in adult patients (n = 87 included in the final analyses) receiving oral busulfan. Pharmacokinetics data (area under the plasma concentration-time curve (AUC) determined from 10 blood samples) were retrieved from patients' files and GSTA1 *A and *B allele polymorphisms determined from banked DNA samples. Three different limited sampling methods (LSM) using four blood samples were also compared. RESULTS: Carriers of GSTA1*B exhibited lower busulfan CLo than patients with an *A/*A genotype (p < 0.002): Busulfan CLo was 166 ± 31, 187 ± 37 vs. 207 ± 47 mL/min for GSTA1*B/*B, *A/*B and *A/*A genotypes, respectively. Similar results were obtained with the tested LSMs. Using the standard AUC method, distribution of patients above the therapeutic range after the first dose was 29% for GSTA1*A/*A, 50% for *A/*B, and 65% for *B/*B. The LSMs correctly identified ≥91% of patients with an AUC above the therapeutic range. The misclassified patients had a mean difference less than 5% in their AUCs. CONCLUSION: Patients carrying GSTA1 loss of function *B allele were at increased risk of overdosing on their initial busulfan oral dose. Genetic polymorphisms associated with GSTA1 explain a significant part of busulfan CLo variability which could be captured by LSM strategies.

Evaluation of Limited Sampling Methods for Oral Busulfan Pharmacokinetic Monitoring in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation.

BACKGROUND: Monitoring busulfan area under the plasma concentration-time curve (AUC) to establish the dose regimen for stem cell transplantation desirable to achieve efficacy while avoiding toxicity. OBJECTIVE: Our objective was to compare AUCs calculated by 18 limited sampling methods (LSMs) from 2 to 5 samples to reference AUCs determined from 10 samples in a retrospective study of 103 adult patients receiving oral busulfan. LSMs using 2 or 3 samples were ineffective. METHODS: Four LSMs using 4 or 5 blood samples that accurately characterized busulfan AUC were identified. The best 2 methods were obtained with sampling at 0.5, 1, 2, 4, and 6 hours and after 1, 1.5, 2, 4, and 6 hours postdose. For these LSMs, the incidence of 20% difference between AUCs from LSMs and reference AUCs was less than 1.3%. CONCLUSIONS: Effective and safe determination of AUC for oral busulfan can be made with strategies using only 4 or 5 concentration timepoints.

Incidence of invasive aspergillosis following remission-induction chemotherapy for acute leukemia: a retrospective cohort study in a single Canadian tertiary care centre.

BACKGROUND: The decision to use universal primary antimould prophylaxis to prevent invasive aspergillosis in patients with acute leukemia depends on the incidence of infection at individual centres. We determined our institution's incidence of invasive aspergillosis among patients who received remission-induction chemotherapy for acute leukemia to evaluate the potential benefits of primary antimould prophylaxis. METHODS: We conducted this retrospective cohort study at a Canadian tertiary care centre. From the central pharmacy registries, we retrieved records for all adult patients for whom remission-induction chemotherapy for acute leukemia was prescribed between 2008 and 2010. We retrieved clinical, microbiologic, pathologic and radiologic data from the patients' medical charts. The primary outcome was a diagnosis of probable or proven invasive aspergillosis up to 180 days after resolution of aplasia. RESULTS: We retrieved records for 123 patients with acute leukemia. Twenty-two of these patients did not receive the prescribed chemotherapy and were excluded from the analysis. Of the 101 patients included, 77 (76.2%) had acute myeloid leukemia. Overall, 136 courses of chemotherapy were administered, with more than 1 course administered to 26 (25.7%) of the 101 patients. In 9 of the patients (8.9%; 95% confidence interval 4.2%-16.2%), invasive aspergillosis was diagnosed (3 proven and 6 probable cases) a median of 19 (range 11-34) days after initiation of chemotherapy. In 7 (78%) of these 9 patients, invasive aspergillosis occurred during the first course of chemotherapy. Three patients died within the first year after diagnosis of invasive aspergillosis. INTERPRETATION: We found a high incidence (8.9%) of invasive aspergillosis at our centre. This finding triggered the introduction of targeted antimould prophylaxis for patients with acute leukemia who were undergoing remission-induction chemotherapy.

An evaluation of pharmacists' expectations towards pharmacogenomics.

BACKGROUND: Given their expertise in pharmacotherapy, pharmacists are well positioned to play a leading role in the implementation of pharmacogenomics in clinical practice. However, little is known about the opinions of pharmacists towards pharmacogenomics or their willingness to integrate this new field in their practice. METHODS: We conducted a survey of 284 pharmacists practicing in the province of Québec (Canada) to describe the opinions, expectations and concerns of pharmacists toward pharmacogenomics. RESULTS: Pharmacists were very hopeful regarding the potential role of pharmacogenomics. Moreover, more than 95% of responders would be willing to recommend pharmacogenomic testing. Nevertheless, only 7.7% of pharmacists currently felt comfortable advising patients based on pharmacogenomic test results. Accordingly, the majority of responders (96.6%) indicated that they would like to undertake continuing education related to pharmacogenomics. CONCLUSION: Pharmacists are extremely hopeful towards pharmacogenomic testing. Furthermore, a vast majority is willing to integrate these tests as part of their clinical practice. Proper education will be required if the integration of pharmacogenomics in patient care is to be optimal.

Safe handling of oral chemotherapeutic agents in clinical practice: recommendations from an international pharmacy panel.

Although there has been a significant increase in the availability and use of oral chemotherapeutic agents, the guidelines around their safe handling are still evolving. Although oral chemotherapy is associated with ease of administration, it has the same exposure risks to health care practitioners, patients, and their caregivers as intravenous formulations, and because it is administered in the home, to the families of patients. However, the general misconception appears to be that exposure risk is low and therefore oral chemotherapeutic agents present little risk and are safer to handle. In a series of three roundtable meetings, a team of international pharmacists from North America and Europe reviewed existing guidelines and identified gaps in recommendations that we believe are important for safe handling. The present article is a compilation of these gaps, especially applicable to manufacturers and distributors, storage and handling, and patient education regarding safe handling. These recommendations, on the basis of our experience and of best practices, provide an international perspective and can be adapted by institutions and practices for development of standardized procedures specific to their needs for the safe handling of oral chemotherapeutic agents.

Pharmacogenetics of intravenous and oral busulfan in hematopoietic cell transplant recipients.

Kinetics-based dose targeting is often conducted in hematopoietic cell transplant (HCT) patients conditioned with intravenous (IV) or oral busulfan to lower rates of rejection, nonrelapse mortality, and relapse. Using the candidate gene approach, the authors evaluated whether busulfan clearance was associated with polymorphisms in the genes regulating the predominant metabolizing enzymes involved in busulfan conjugation, specifically glutathione S-transferase (GST) isoenzymes A1 (GSTA1) and M1 (GSTM1). Busulfan clearance was estimated after the morning dose on days 1, 2, and 3; each patient's average clearance was used for analyses. The average (± standard deviation) busulfan clearance was 3.2 ± 0.56 mL/min/kg in the separate population of 95 patients who received oral busulfan and 103 ± 24 ml/min/m(2) in the 57 patients who received IV busulfan. Oral busulfan clearance was associated with GSTA1 (P = .008) but not GSTM1 (P = .57) genotypes. However, among the GSTA1 haplotypes (ie, *A*A, *A*B, *B*B), there was significant overlap in the observed oral busulfan clearance and similar rates of achieving the target busulfan exposure. Clearance of IV busulfan was not associated with GSTA1 (P = .21) or GSTM1 (P = .99). These data suggest that personalizing either IV or oral busulfan dosing cannot be simplified on the basis of GSTA1 or GSTM1 genotype.