A phase II trial of netupitant/palonosetron for prevention of chemotherapy-induced nausea/vomiting in patients receiving BEAM prior to hematopoietic cell transplantation.

Objective: The purpose of this study was to investigate the efficacy and safety of netupitant/palonosetron (NEPA) for the prevention of chemotherapy-induced nausea and vomiting (CINV) for hematopoietic cell transplantation (HCT) patients receiving BEAM therapy. Study Design: This phase II, prospective, intention-to-treat, single-center, single-arm study involved 43 adult patients who received NEPA and dexamethasone for the prevention of CINV due to BEAM conditioning chemotherapy. An interim analysis, performed after 13 patients, determined utility versus futility, and supported continuation to full enrollment. Descriptive statistics were used to report complete response (CR), complete protection, incidence of emesis, and administration of rescue agents. A Kaplan-Meier curve depicted time to first emesis and first rescue medication. Patients self-reported levels of daily nausea descriptively via a CINV Questionnaire. Results: By study end, 13 of 43 patients achieved a CR with an average of 10.6 emesis-free days (SD 0.95) over the 11-day observation period, with no emetic events in any patient during the acute/chemotherapy phase. Nausea was well-controlled throughout the acute therapy phase (Day 1-6) and increased during the delayed phase (Day 7-11) with a peak mean level of 2.79/10 at Day 10. Aside from lower grade (≤2), headaches, constipation, and diarrhea were the most widely reported adverse effects. Conclusion: The combination of NEPA and dexamethasone is safe and effective for the prevention of CINV in patients receiving BEAM conditioning therapy prior to HCT. The regimen demonstrated greater effectiveness in the acute phase versus the delayed phase, with low levels of nausea throughout the study period and complete emesis prevention during chemotherapy.

Comparative effects of fluconazole, posaconazole, and isavuconazole upon tacrolimus and cyclosporine serum concentrations.

INTRODUCTION: Calcineurin inhibitors are commonly used in hematopoietic stem cell transplant (HSCT) patients to prevent graft versus host disease, but as CYP3A4 substrates they are frequently involved in drug-drug interactions. The purpose of this study is to characterize the effects of isavuconazole, fluconazole, and posaconazole on tacrolimus and cyclosporine serum concentrations and dose adjustments in allogeneic HSCT patients. METHODS: This retrospective study included patients admitted to Oregon Health and Science University between April 2008 and December 2018 who underwent hematopoietic stem cell transplantation and received concomitant tacrolimus or cyclosporine and fluconazole, isavuconazole or posaconazole therapy. Data on patient characteristics, drug dosing, and serum drug concentrations were collected through chart review, and descriptive statistics were used to summarize the results. RESULTS: A total of 139 patients were included in this study. We found fluconazole initiation leads to a 25% reduction in both tacrolimus and cyclosporine doses in order to maintain goal serum concentrations. Posaconazole and isavuconazole initiation requires tacrolimus dose reductions by 53% and 21%, respectively. CONCLUSIONS: Based on our experience, FLC, POS, and ISA initiation may require CNI dose reductions and close monitoring of CNI levels to ensure levels remain within goal serum concentrations. Larger studies are needed to fully quantify the percentage in CNI dose reductions and characterize differences among these antifungals.

Graft-versus-host disease after liver transplantation is associated with bone marrow failure, hemophagocytosis, and DNMT3A mutations.

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.

Clinical Outcomes of Oral Suspension versus Delayed-Release Tablet Formulations of Posaconazole for Prophylaxis of Invasive Fungal Infections.

Posaconazole is used for prophylaxis for invasive fungal infections (IFIs) among patients with hematologic malignancies. We compared the incidence of breakthrough IFIs and early discontinuation between patients receiving delayed-release tablet and oral suspension formulations of posaconazole. This was a retrospective cohort study of patients receiving posaconazole between 1 January 2010 and 30 June 2016. We defined probable or proven breakthrough IFIs using the European Organization for Research and Treatment of Cancer (EORTC) criteria. Overall, 547 patients received 860 courses of posaconazole (53% received the oral suspension and 48% received the tablet); primary indications for prophylaxis were acute myeloid leukemia (69%), graft-versus-host disease (18%), and myelodysplastic syndrome (3%). There were no significant differences in demographics or indications between patients receiving the different formulations. The incidence and incidence rate of probable or proven IFIs were 1.6% and 3.2 per 10,000 posaconazole days, respectively. There was no significant difference in the rate of IFIs between suspension courses (2.8 per 10,000 posaconazole days) and tablet courses (3.7 per 10,000 posaconazole days) (rate ratio = 0.8, 95% confidence interval [CI] = 0.3 to 2.3). Of the 14 proven or probable cases of IFI, 8/14 had posaconazole serum concentrations measured, and the concentrations in 7/8 were above 0.7 µg/ml. Posaconazole was discontinued early in 15.5% of courses; however, the frequency of discontinuation was also not significantly different between the tablet (16.5%) and oral suspension (14.6%) formulations (95% CI for difference = -0.13 to 0.06). In conclusion, the incidence of breakthrough IFIs was low among patients receiving posaconazole prophylaxis and not significantly different between patients receiving the tablet formulation and those receiving the oral suspension formulation.

Phase II open label pilot trial of aprepitant and palonosetron for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic FOLFOX chemotherapy for the treatment of colorectal cancer.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) causes significant morbidity among colorectal cancer patients, receiving fluorouracil, oxaliplatin, and leucovorin (FOLFOX) chemotherapy even with standard antiemetic prophylaxis. The purpose of this study is to determine if the addition of aprepitant to standard antiemetic therapy improves CINV in these patients. METHODS: Patients receiving FOLFOX for colorectal cancer were given antiemetic prophylaxis with aprepitant 125 mg orally on day 1 and 80 mg on days 2 and 3. Palonosetron 0.25 mg was given IV push on day 1 only. Dexamethasone 12 mg was administered orally on day 1 and 8 mg each morning on days 2 through 4. Assessments including emetic events, rescue doses, nutritional intake, and appetite were recorded in a patient diary which was returned to study personnel in the following cycle. RESULTS: Of the 53 patients screened, 50 were evaluable and had a complete dataset for cycle 1. For the first cycle, 74% of patients achieved a complete response (CR), 22% achieved a major response and 4% experienced treatment failure. The percentage of patients achieving a CR remained high throughout each cycle at 83, 83, and 86% for cycles 2, 3, and 4, respectively. Appetite and nutritional status remained largely unchanged throughout treatment. Adverse events occurring in more than 10% of patients included diarrhea (13.6%), fatigue (12.6%), and neutropenia (11%). CONCLUSIONS: Aprepitant added to standard antiemetic therapy appears to be an effective and safe regimen for prevention of CINV in patients receiving FOLFOX.

Posaconazole Tablet Formulation at 400 Milligrams Daily Achieves Desired Minimum Serum Concentrations in Adult Patients with a Hematologic Malignancy or Stem Cell Transplant.

We describe our experience using the posaconazole 400-mg delayed-release tablet formulation once daily in 20 patients with hematologic malignancy or hematopoietic stem cell transplant who were unable to attain prespecified target minimum serum (trough) concentrations for treatment or prophylaxis of invasive fungal infection. The higher dose allowed the majority of patients to achieve prespecified target trough concentrations without incurring additional toxicities.

Comparison of posaconazole serum concentrations from haematological cancer patients on posaconazole tablet and oral suspension for treatment and prevention of invasive fungal infections.

Posaconazole tablet formulation (PTF) was developed to optimise bioavailability. This study compared posaconazole levels between patients on the PTF and oral suspension formulation (OSF). We also examined factors that may impact posaconazole levels. The primary and secondary objectives were analysed by comparing trough levels and attainment of target level between the formulation groups. For the 86 patients on PTF and 176 on OSF, the mean first levels was 1.32 µg ml-1 (SD = 0.69) and 0.81 µg ml-1 (SD = 0.59), P < 0.0001 respectively. PTF group was more likely to achieve levels ≥0.7 µg ml-1 than OSF group (OR 7.97 [95 CI; 3.75-16.93], P < 0.0001). Levels from patients on PTF and with presence of acid suppression, GI GVHD, mucositis or diarrhoea were not statistically different from those without these factors. For PTF, no correlation was found between patient's weight (kg) and levels (R2 = 0.0536, P = 0.035). The incidences of elevation in ALT/AST or Tbili were similar between the formulation groups. In conclusion, PTF should be considered the preferred formulation because it demonstrated better absorption than the OSF. Patients on PTF for prophylaxis are more likely to attain target level and may not routinely require therapeutic drug monitoring during prophylaxis.

Evaluation and implementation of chemotherapy regimen validation in an electronic health record.

INTRODUCTION: Computerized provider order entry of chemotherapy regimens is quickly becoming the standard for prescribing chemotherapy in both inpatient and ambulatory settings. One of the difficulties with implementation of chemotherapy regimen computerized provider order entry lies in verifying the accuracy and completeness of all regimens built in the system library. Our goal was to develop, implement, and evaluate a process for validating chemotherapy regimens in an electronic health record. METHODS: We describe our experience developing and implementing a process for validating chemotherapy regimens in the setting of a standard, commercially available computerized provider order entry system. The pilot project focused on validating chemotherapy regimens in the adult inpatient oncology setting and adult ambulatory hematologic malignancy setting. RESULTS: A chemotherapy regimen validation process was defined as a result of the pilot project. Over a 27-week pilot period, 32 chemotherapy regimens were validated using the process we developed. Results of the study suggest that by validating chemotherapy regimens, the amount of time spent by pharmacists in daily chemotherapy review was decreased. In addition, the number of pharmacist modifications required to make regimens complete and accurate were decreased. Both physician and pharmacy disciplines showed improved satisfaction and confidence levels with chemotherapy regimens after implementation of the validation system. CONCLUSION: Chemotherapy regimen validation required a considerable amount of planning and time but resulted in increased pharmacist efficiency and improved provider confidence and satisfaction.

Daptomycin pharmacokinetics in adult oncology patients with neutropenic fever.

Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant Staphylococcus aureus. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means +/- standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (C(max)) was 49.04 +/- 12.42 microg/ml (range, 21.54 to 75.20 microg/ml), the 24-h plasma concentration was 6.48 +/- 5.31 microg/ml (range, 1.48 to 29.26 microg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 +/- 523.53 microg.h/ml (range, 164.64 to 3155.11 microg.h/ml), the volume of distribution at steady state was 0.18 +/- 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 +/- 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 +/- 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 +/- 20.66 h (range, 7.00 to 121.73 h), and the median time to C(max) was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 +/- 0.02. All patients achieved C(max)/MIC and AUC from time zero to 24 h (AUC(0-24))/MIC ratios for a bacteriostatic effect against Streptococcus pneumoniae. Twenty-seven patients (93%) achieved a C(max)/MIC ratio for a bacteriostatic effect against S. aureus, and 28 patients (97%) achieved an AUC(0-24)/MIC ratio for a bacteriostatic effect against S. aureus. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for S. pneumoniae and 90% of patients for S. aureus. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.

Optimal prevention of seizures induced by high-dose busulfan.

High-dose busulfan is frequently used in a variety of conditioning regimens for hematopoietic cell transplantation. In this setting, busulfan has marked neurotoxicity, specifically causing seizures that generally are tonic-clonic in character. Phenytoin has been the preferred drug to treat busulfan-induced seizures, but this practice should be reexamined in light of newer antiepileptic drugs being preferentially used by neurologists. Characteristics of ideal seizure prophylaxis include lack of overlapping toxicity with the conditioning regimen, lack of interference with engraftment of donor cells, and minimal potential for pharmacokinetic drug interactions. Based on these criteria, phenytoin is suboptimal due to possible toxicities and is especially ill suited because of its ability to induce busulfan metabolism. It is postulated that this induction adversely affects efforts to update methods for targeting busulfan doses to individual patients, based on recent developments in the understanding of the pharmacogenomics of busulfan metabolism. The existing clinical data support the use of benzodiazepines, most notably clonazepam and lorazepam, to prevent busulfan-induced seizures. The second-generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for busulfan-induced seizures, and early data of its efficacy are promising, although further study is needed.

Prevention and management of prostate cancer chemotherapy complications.

Prevention and management of the adverse effects of prostate cancer chemotherapy depend on skilled regimen selection, dose adjustment, use of supportive care strategies, and a thorough understanding of the patient- and regimen-related factors that determine the risk for toxicity. Urologists, radiation oncologists, and primary care providers can play an important role before chemotherapy is prescribed by judicious use of treatments that impair bone marrow and other vital organ function. The current role of chemotherapy in prostate cancer is palliative. Successful palliation depends on reducing cancer-related suffering without introducing treatment-related suffering. Thus prevention and management of toxicity is central to the success of chemotherapy in advanced prostate cancer.

Neutropenia after single-dose clindamycin for dental prophylaxis.

A 68-year-old man with stable chronic myelogenous leukemia received a single dose of clindamycin before having a tooth extracted. He was neutropenic 6 days later, with an absolute neutrophil count of 945 cells/mm3. His neutrophil count returned to normal within 2 weeks. Clindamycin has been implicated in drug-induced neutropenia; however, a review of the literature produced only three reports of this reaction. Only one provided the duration of the neutropenia. To our knowledge, this case report is only the second that provides the duration of the clindamycin-induced neutropenia. Clinicians should be made aware of this potential adverse event.

Trends in opioid use over time: 1997 to 1999.

Substantial resources have been spent to improve pain control for dying patients, and increased opioid administration has been presumed. Oregon has been a consistent leading state in per capita use for morphine for the past 10 years, as recorded by the Automation of Reports and Consolidated Orders System (ARCOS). Health policy experts, extrapolating from World Health Organization methods, have suggested these data are indicative of the quality of end-of-life care in Oregon. To determine whether trends in opioid prescription at the state and national levels reflect increased opioid use for inpatients during the final week of life, chart reviews were conducted to record all opioid medications administered in the last week of life to 877 adult inpatients who died from natural causes between January 1, 1997 and December 31, 1999. Inpatient morphine use did not increase significantly for dying patients from 1997 to 1999. However, overall morphine use for both Oregon and the United States as measured by ARCOS data increased significantly. Comparisons revealed no significant difference between linear trends for Oregon and U.S. morphine use, but both were significantly greater than the dying inpatients. This pattern was also found for all other opioids. These findings suggest that ARCOS data do not necessarily provide information about opioid use for specific subpopulations of patients and raise questions about the meaning of observed increases in ARCOS data.

A pilot study of the efficacy and safety of empiric daptomycin therapy in oncology patients with fever and severe neutropenia.

OBJECTIVES: Patients with extended periods of time spent with low or absent absolute neutrophil counts (ANCs) are at risk for bacterial infections. Febrile neutropenia is a complication in this patient population, requiring administration of antibiotics. The use of daptomycin in treating patients with febrile neutropenia is not well described. Our objective was to describe the clinical course of febrile neutropenic patients that received daptomycin therapy. METHODS: This was an open-labeled, pilot study of 30 patients with documented febrile neutropenia treated with empiric daptomycin. Eligible patients received daptomycin 6 mg/kg/day, in addition to concomitant broad-spectrum antimicrobials. The Kaplan-Meier method was used to estimate the median days to reach an afebrile state and negative bacterial cultures. RESULTS: A total of 30 febrile neutropenic patients were enrolled and received daptomycin as part of an empiric antimicrobial regimen. All patients had severe neutropenia with ANC <100 cells/mm(3). Two patients were removed from study due to the development of pneumonia. Clinically, 87% patients improved on daptomycin in combination with Gram-negative coverage, with 73% of patients succeeding therapy. A total of 18 of 19 (95%) subjects with positive blood cultures had microbiological eradication, with the median time to reach an afebrile state of 4.3 days (range 1-13). Four patients were discontinued from daptomycin due to a suspected related adverse event or to clinical failure. CONCLUSIONS: This pilot study supports future evaluation of the use of empiric daptomycin therapy in combination with Gram-negative coverage compared with vancomycin in patients with neutropenic fever in a large, randomized controlled trial.

Aprepitant pharmacokinetics and assessing the impact of aprepitant on cyclophosphamide metabolism in cancer patients undergoing hematopoietic stem cell transplantation.

Aprepitant, a neurokinin antagonist, is an effective antiemetic agent in chemotherapy for delayed nausea and vomiting. The study objective was to evaluate the pharmacokinetics of aprepitant and concurrent cyclophosphamide (CY), often a component of hematopoietic stem cell transplant (HSCT) conditioning regimen, in cancer patients undergoing HSCT. Forty subjects were randomized to either aprepitant or placebo in addition to standard antiemetics. Aprepitant or placebo was started 1 hour before the first chemotherapy or radiation dose for HSCT conditioning and administered daily until 4 days after infusion of the hematopoietic cell graft (for a total of 10-12 days). Serial blood samples were collected for aprepitant and CY plus 2 important CY metabolites. The results indicate that aprepitant is well absorbed and does not auto-induce its metabolism. No significant drug interaction was observed with CY or its metabolites. A significant portion of the patients had subtherapeutic aprepitant concentrations; however, chemotherapy-induced nausea and vomiting were effectively managed. No dosage adjustment was necessary, and administration of aprepitant in HSCT at the prescribed dosage of 125 mg orally on day 1 and 80 mg orally on each consecutive day through day +4 after HSCT was well tolerated with no significant changes in CY pharmacokinetic parameters.

Effects of docetaxel on pain due to metastatic androgen-independent prostate cancer.

Bone pain commonly plagues patients with metastatic androgen-independent prostate cancer. Studies of mitoxantrone demonstrated that chemotherapy can substantially reduce this debilitating symptom. Two of the available studies examining the use of docetaxel with and without estramustine for treatment of androgen-independent prostate cancer include a detailed prospective analysis of pain and quality of life. One study required patients to have pain at entry and demonstrated significant improvement in pain. The second study enrolled patients with low prevalence and intensity of pain and did not demonstrate pain relief. The available results, although preliminary, suggest that patients with significant bone pain due to androgen-independent prostate cancer can experience substantial pain relief with docetaxel-based therapy. Larger randomized studies targeting patients with sufficient prevalence and intensity of pain are needed to refine our understanding of the contribution of docetaxel to pain control in this patient population.