Ambulatory Medication Safety: Vaccination and Laboratory Screening for Patients Receiving Immunomodulatory Therapies.

OBJECTIVE: Immunomodulatory therapies improve the management of chronic diseases but can be associated with infectious risk. The present study was undertaken to examine the laboratory screening practices for hepatitis B virus (HBV), hepatitis C virus (HCV), and tuberculosis (TB) and rates of vaccination for pneumococcal and influenza in patients prescribed select immunosuppressive agents at our institution. METHODS: A retrospective analysis was conducted to review patients who were prescribed a select immunosuppressive over 3 years. Data were extracted from electronic health records to identify rates of screening and vaccination prior to initiation or at any time. Logistic regression models were developed to identify predictors of screening and vaccination. RESULTS: We identified 2,396 patients prescribed immunosuppressive medications by rheumatology (52.6%) and non-rheumatology specialties. Rates of screening at any time point were 84.5% (2,025 of 2,396) for HBV, 76.7% (1,838 of 2,396) for HCV, and 71.8% (1,720 of 2,396) for TB. Patients who had either in-system primary care providers (PCPs) or rheumatologists were more likely to receive pneumococcal vaccinations (odds ratio [OR] 1.98 [95% confidence interval (95% CI) 1.55-2.54] and OR 4.08 [95% CI 2.76-6.02], respectively). Patients with dermatologic (OR 1.67 [95% CI 1.14-2.45]) or rheumatologic providers (OR 2.5 [95% CI 1.86-3.36]) were more likely to be vaccinated for influenza. CONCLUSION: More than 70% of patients were screened for either HBV, HCV, or TB at some point. Rates of pneumococcal vaccination were better than rates of influenza vaccination. Patients with in-system PCPs were more likely to be screened and vaccinated. Establishing and executing consistent processes for screening and vaccination prior to immunosuppressive treatment remains a priority in ambulatory settings.

Triazole antifungal use for prophylaxis and treatment of invasive fungal diseases for patients receiving gilteritinib.

Gilteritinib is primarily metabolized via cytochrome P450 (CYP). Therefore, concomitant administration of strong CYP3A4 inducers or inhibitors is not recommended. We evaluated the incidence of gilteritinib-related adverse events (AEs) in 47 patients who received gilteritinib with or without antifungal triazoles which are known inhibitors of CYP3A4. Reasons for coadministration were antifungal prophylaxis or treatment of suspected or confirmed fungal diseases. Gilteritinib-related AEs were similar in the gilteritinib-triazole group compared to the gilteritinib without triazole group (75 % vs. 55.5 %, P = 0.23). Additionally, severity of AEs, gilteritinib dose reductions (15 % vs. 14.8 %) or discontinuation due to AEs (10 % vs. 22.2 %), and 90-day mortality (35 % vs. 11.1 %) were similar in both groups. Thus, concomitant gilteritinib and triazole therapy is feasible and is not associated with clinically meaningful increase in gilteritinib-related AEs.

Cytomegalovirus events in high-risk allogeneic hematopoietic-cell transplantation patients who received letermovir prophylaxis.

Letermovir is approved for the prevention of cytomegalovirus (CMV) reactivation and clinical disease in patients undergoing allogeneic hematopoietic-cell transplantation (HCT). However, there is uncertainty about letermovir's ability to prevent clinical events during the period of prophylaxis as well as after the discontinuation of prophylaxis in the post-transplant setting. We performed a retrospective cohort study in CMV-seropositive allogeneic HCT recipients at high risk of CMV events, who received letermovir for primary prophylaxis from November 2017 through December 2019. We analyzed CMV outcomes for these patients during and after prophylaxis was discontinued. Patient outcomes were followed through June 2020. Sixty patients received letermovir for a median of 13 weeks (range, 1-72 weeks). Thirteen (22%) patients had quantifiable CMV DNAemia (reactivation) during letermovir prophylaxis a median of 9 days (range, 1-59 days) after starting letermovir. Five (8%) of these patients discontinued prophylaxis and received preemptive therapy (PET) with valganciclovir; eight (13%) continued letermovir as prophylaxis and CMV DNAemia resolved without PET. Thirteen patients (22%) had post-prophylaxis CMV reactivation a median of 33 days (range, 14-109 days) after letermovir discontinuation. In four (7%) of these patients, CMV DNAemia resolved without PET, and nine (15%) received PET. No patient developed CMV disease. Patients who developed CMV reactivation during prophylaxis did so shortly after initiation of letermovir, and most patients who developed CMV reactivation post-prophylaxis did so within 60 days after discontinuation of letermovir. Letermovir prophylaxis has changed the presentation of CMV infection in high-risk HCT patients.

Short-Term Surgical Missions: Role of Pharmacist Volunteers.

Health care professionals often participate in short-term surgical missions in underserved areas of the world. Surgical missions often rely on the use of medications to provide health care to these underserved areas in patients with multiple comorbid conditions. The direct role a pharmacist may have in surgical missions is not well described in the literature; however, numerous opportunities exist for pharmacist involvement to improve patient care and operational processes throughout medication planning and delivery of surgical missions. Pharmacists have specialized knowledge in medication acquisition, preparation, and distribution that result in a unique position to contribute positively to the mission's clinical and operational dynamics. Pharmacists may assist in various activities such as medication ordering, accrual, purchasing and preparing during the surgical mission. Pharmacists may also provide clinical support and offer alternative medications in the setting of drug intolerance or allergies. In 2008, Operation Walk Boston, a short-term surgical mission was established to provide hip and knee joint replacements to patients in the Dominican Republic. Pharmacists and pharmacy residents play a crucial role as members of this surgical mission. Based on our experience, this article aims to describe the evolving role of pharmacists as a member of a surgical mission.

Rate of differentiation syndrome in patients based on timing of initial all-trans retinoic acid administration.

All-trans-retinoic acid (ATRA) is the standard of care for the management of acute promyelocytic leukemia (APL), but can be associated with differentiation syndrome (DS). Over a seven-year period, we sought to determine the impact of ATRA initiation time on the development of DS. ATRA administration time had no impact on DS occurrence (p = =0.13), APL risk (p = =0.28) or regimen received (p = =0.1). Patients with higher mean body mass index (BMI) were more likely to develop moderate or severe DS (p = =0.02). Early treatment of APL is essential and maybe strongly considered in patients with elevated BMI.

Evaluating the adverse effects of melphalan formulations.

INTRODUCTION: For multiple myeloma patients who respond to primary therapy, autologous hematopoietic stem cell transplant (HSCT) is considered standard of care with high-dose melphalan for transplant candidates. There are now two different melphalan formulations available, including a propylene glycol containing (PG-MEL) product and a propylene glycol-free (PG-free MEL) product. Although considered bioequivalent, there remains limited literature directly evaluating the adverse events between the two agents. We seek to assess the tolerability and severity of side effects between the two formulations in a real-life practice setting. METHODS: A retrospective, descriptive analysis was conducted of multiple myeloma patients who received autologous stem cell conditioning with either melphalan formulation when dosed at 100 mg/m2/dose for two consecutive doses. The primary outcome was the assessment of tolerability and severity of side effects. Tolerability was split into four major categories including hematologic toxicity, gastrointestinal toxicity, renal toxicity, and highest recorded mucositis grade. RESULTS: There were a total of 78 patients who received a melphalan preparation during the study. The median time to myeloablation and neutrophil engraftment was five and seven days post-HSCT, respectively, for all patients. Patients who received PG-free MEL were less likely to develop mucositis, with 22 (56%) reported highest grade 0, defined by World Health Organization oral toxicity scale, compared to those who received PG-MEL (33%), p = 0.04. CONCLUSION: There were minimal differences in tolerability or side effects observed between PG-free MEL and PG-MEL. These data may assist in better understanding the anticipated adverse effects of a high-dose melphalan conditioning therapy.

Single 6-mg dose of rasburicase: The experience in a large academic medical center.

BACKGROUND: Tumor lysis syndrome is an oncologic emergency due to the release of tumor cell contents, leading to metabolic derangements. Rasburicase, a recombinant urate oxidase, catabolizes uric acid. At our institution, we administer a single 6-mg dose of rasburicase to patients who are at risk for tumor lysis syndrome. We aimed to assess the efficacy of single 6-mg dose of rasburicase and explore risk factors associated with rasburicase failure. METHODS: We report results in 92 adult patients who had a baseline uric acid greater than 7.5 mg/dL and received a single 6-mg dose of rasburicase for the management of tumor lysis syndrome. Responders were defined as those whose uric acid was less than or equal to 7.5 mg/dL within 24-36 h of rasburicase administration. The primary end point was response based on uric acid level. Secondary end points included response to rasburicase in association with lactate dehydrogenase, serum creatinine, calcium, phosphorus, blood pH, and oncologic diagnosis. RESULTS: Median age was 65 years and 70% were men. Most patients had leukemia (32%) or lymphoma (40%). Eighty-seven of 92 patients (95%), who received single 6-mg dose of rasburicase, achieved a uric acid less than 7.5 mg/dL within 24-36h of dosing. Body mass index was similar between responders and non-responders: 28.6 kg/m2 vs. 26.6 kg/m2, respectively, p = 0.6. Baseline lactate dehydrogenase levels were similar between the groups: 756 U/L vs. 892 U/L, respectively, p = 0.33. Blood pH values documented within 24 h of first dose of rasburicase were also similar between the two groups (n = 30; 7.33 vs. 7.34 respectively, p = 0.6). However, median baseline uric acid was lower in responders than non-responders: 12.3 mg/dL vs. 17.3 mg/dL, respectively, p = 0.012. Baseline serum creatinine and creatinine clearance were similar between responders and non-responders (2.2 mg/dL vs. 3.95 mg/dL; p = 0.12 and 29 mL/min vs. 16 mL/min; p = 0.11, respectively). CONCLUSIONS: Higher baseline uric acid levels were observed in patients who did not respond to the first rasburicase dose. In our study, uric acid levels normalized in 95% of patients after a single 6-mg dose of rasburicase indicating that a single 6-mg dose of rasburicase may be sufficient to manage tumor lysis syndrome, for most patients.

Low efficacy and high mortality associated with clofarabine treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes.

Clofarabine, a second-generation nucleoside analog, has clinical activity in relapsed or refractory acute myelogenous leukemia (AML) and higher-risk myelodysplastic syndromes (MDS). However, there are few data evaluating performance of clofarabine in populations of patients not enrolled in clinical trials. We reviewed outcomes for 84 patients treated with clofarabine for relapsed or refractory AML or MDS, either with clofarabine as monotherapy (n=19) or in combination with cytarabine (n=65). Using International Working Group (IWG) response criteria, the overall response rate (ORR) of all treated patients was 21%, with a complete response rate with either complete or incomplete hematopoietic recovery (CRR=CR+CRi) of 14%. For combination therapy, ORR was 22% with CRR of 18%, and monotherapy patients had an ORR of 21% with CRR of 11%. Although limited by small numbers, subgroup analysis did not reveal variation in response rates when comparing different risk factors. The 30-day mortality was 21% and median survival was 3 months; a subset of 12 patients who were able to go to transplant had an 18-month median survival. Clofarabine's efficacy in a "real-world" setting appears to be less than has been reported in clinical trials, and treatment is associated with a high early mortality rate.

An assessment of risk factors associated with ifosfamide-induced encephalopathy in a large academic cancer center.

PURPOSE: Ifosfamide-induced encephalopathy is a neurotoxic adverse effect of ifosfamide chemotherapy. The objective of this study was to determine the incidence of encephalopathy in patients with lymphoma and sarcoma receiving ifosfamide chemotherapy and assess for potential risk factors that influence the incidence of encephalopathy. METHODS: A retrospective study of sarcoma and lymphoma patients receiving ifosfamide chemotherapy was performed at the participating institutions. Enrollment began 1 July 2011 and continued chronologically backwards until 100 sarcoma and 100 lymphoma patients were enrolled. Identification of ifosfamide-induced encephalopathy events was performed by reviewing provider documentation of ifosfamide infusions. Logistic regression was employed to determine associations between risk factors and ifosfamide-induced encephalopathy events. RESULTS: Of the 200 patients enrolled, 29 (14.5%) patients experienced encephalopathy. Ifosfamide-induced encephalopathy occurred more frequently in the sarcoma population than the lymphoma population (24 vs. 5 patients, p < 0.001). In addition to cancer type, prior use of cisplatin, concomitant opioids, and use of CYP2B6 inhibitors remained as significant variables in the multivariate model conferring a 12.47, 2.81, and 5.17 increased odds of experiencing encephalopathy, respectively. The odds of experiencing encephalopathy were 9.0 and 1.37 times higher for a one-unit increase in serum creatinine and hemoglobin, respectively, and 0.15 times lower for a one-unit increase in albumin. CONCLUSIONS: This is the first study to demonstrate that patients with sarcoma experienced ifosfamide-induced encephalopathy more often than those with lymphoma. For all patients, predisposing factors for ifosfamide-induced encephalopathy included previous cisplatin exposure, concomitant opioids and CYP2B6 inhibitors. Laboratory values that increased ifosfamide-induced encephalopathy risk included low serum albumin, increased serum creatinine, and increased hemoglobin.

Denosumab in hypercalcemia of malignancy: a case series.

BACKGROUND: Denosumab is a nuclear factor-kappa ligand monoclonal antibody whose FDA-approved indications include treatment of osteoporosis, bone loss with certain anticancer hormonal agents, and prevention of skeletal-related events in patients with bone metastases from solid tumors. In clinical trials, the incidence of severe hypocalcemia has been reported as 3.1-10.8%. To date, case reports and two clinical trials have reported the use of denosumab in the management of hypercalcemia of malignancy. No reports of denosumab-induced hypocalcemia have been reported for the hypercalcemia of malignancy population. METHODS: We performed a retrospective chart review of all patients who received denosumab for hypercalcemia of malignancy to describe the effects of denosumab on calcium levels at our institution. RESULTS: Seven patients received doses of denosumab for hypercalcemia of malignancy. The most common tumor types were breast cancer (n = 3) and hematologic malignancies (n = 2). All patients had bone involvement. Two patients received single doses of 60 mg. The other five patients received 120 mg. The mean corrected calcium levels were 13.7 mg/dL and 12.24 mg/dL for the days of admission and denosumab administration, respectively (p = 0.1889). The mean corrected calcium level for the last known value was 9.92 mg/dL, while in house (p = 0.0016). Supportive care prior to denosumab included hydration (n = 7), bisphosphonates (n = 6), and calcitonin (n = 5). One patient had a calcium level of 6.6 mg/dL on day 4 after denosumab, requiring calcium supplementation and telemetry. Of the seven patients treated with denosumab for hypercalcemia of malignancy at our institution, six patients were discharged alive. Of these, one patient died two days after discharge. Last-known follow-up was a median of 26 days, range, 3-195, for all patients. CONCLUSIONS: Denosumab helped decrease calcium in patients with hypercalcemia of malignancy. However, symptomatic hypocalcemia may result from denosumab in hypercalcemia of malignancy.

Predictive factors for all-trans retinoic acid-related differentiation syndrome in patients with acute promyelocytic leukemia.

All-trans retinoic acid (ATRA) used for the treatment of APL can lead to the development of differentiation syndrome (DS), a potentially life threatening complication. Since ATRA is metabolized by cytochrome P450 (CYP) enzymes, we sought to identify drug interactions that might be associated with a higher risk for the development of DS in addition to other predictive factors related to the incidence of DS. We identified 60 consecutive patients with APL treated at our institution with ATRA from May 2004 until January 2010. Of the 60 patients identified, 29 (48%) developed DS within a median of 5 days (range 1-31) of ATRA initiation. We did not find any difference in overall incidence of DS whether patients were on concurrent CYP 2C8, 2C9 or 3A4 inhibitors, inducers or substrates. In multivariable analysis, higher peripheral blood blast counts on admission (p=0.04) as well as higher body mass index (p=0.003) were associated with developing DS. Out of the 29 patients with DS, there were 4 early deaths of which 2 were attributed to DS compared to no early deaths in the patients who did not develop DS (p=0.05). Regarding disease-related outcomes, only CR rate was different between patients developing DS versus those who did not develop DS.

Evaluation of caspofungin or micafungin as empiric antifungal therapy in adult patients with persistent febrile neutropenia: a retrospective, observational, sequential cohort analysis.

BACKGROUND: Caspofungin is approved in the United States for empiric antifungal therapy for persistent febrile neutropenia (FN). There are limited data about the use of other echinocandins in this setting. OBJECTIVE: After a formulary change, we retrospectively evaluated the safety and effectiveness of caspofungin and micafungin as empiric antifungal therapy for FN at Brigham and Women's Hospital (Boston, Massachusetts). METHODS: This was a retrospective, observational, sequential cohort study. We identified patients who had received >or=2 doses on concurrent days of either caspofungin (between November 2005 and October 2006) or micafungin (between November 2006 and October 2007) for empiric FN therapy. Patients were included for analysis if they were neutropenic (absolute neutrophil count <500 cells/microL) and febrile (temperature >or=100.5 degrees F [>or=38 degrees C]). Patients without previous exposure to an echinocandin were included; those included in the caspofungin cohort were excluded from the micafungin cohort. Those who had previously received another systemic antifungal agent for FN therapy (except fluconazole for mucosal candidiasis) were excluded. Patients were followed through hospital discharge. Outcomes analyzed were successful treatment of baseline invasive fungal disease (IFD), incidence of breakthrough IFD, overall mortality, and discontinuation because of adverse events (AEs). IFD was diagnosed and classified according to current European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group Consensus Group criteria. RESULTS: Three hundred twenty-three patients met inclusion criteria (caspofungin, n = 149; micafungin, n = 174). Median age was 49 years in both the caspofungin and micafungin groups; 80 (53.7%) and 99 (56.9%) patients in each group, respectively, were men. Fluconazole prophylaxis had been administered to 30 patients (20.1%) treated with caspofungin and 21 patients (12.1%) treated with micafungin. Caspofungin was administered at 70 mg for one dose, followed by 50 mg daily; micafungin was administered at 100 mg daily. The median duration of therapy and of hospitalization were 10 days and 29 days, respectively, with caspofungin, and 9 days and 28 days with micafungin (both, P = NS between groups). Twelve patients (8.1%) in the caspofungin cohort and 13 (7.5%) in the micafungin cohort died during the study period (P = NS). There were 3 cases (2.0%) of baseline IFD in the caspofungin cohort and 6 (3.4%) in the micafungin cohort (P = NS); 6 were successfully treated (caspofungin, 2 [1.3% of entire group]; micafungin, 4 [2.37% of entire group]; P = NS). Breakthrough IFD was diagnosed in 16 patients (10.7%) receiving caspofungin and 21 (12.1%) receiving micafungin (P = NS). AEs requiring echinocandin discontinuation were uncommon (caspofungin, 2 cases of rash and 1 anaphylactoid infusion reaction [2.0%]; mica-fungin, 1 liver function test elevation >or=5 times the upper limit of normal and 1 maculopapular rash [1.1%]; P = NS). CONCLUSION: Micafungin, as empiric antifungal therapy for persistent FN, did not appear to differ significantly from caspofungin in terms of safety profile or efficacy in the adult patients included in this sequential cohort analysis at one institution. ClinicalTrials.gov identifier: NCT00723073.

Palifermin: role in the prevention of chemotherapy- and radiation-induced mucositis.

OBJECTIVE: To assess the efficacy, toxicity, and potential cost benefit of palifermin in the prevention of chemotherapy- and radiation-induced mucositis. DATA SOURCES: MEDLINE and PubMed database searches were conducted (1966-May 2006) using the following search terms: palifermin, human keratinocyte growth factor, fibroblast growth factor, mucositis, and stomatitis. STUDY SELECTION AND DATA EXTRACTION: All published clinical trials and abstracts examining the use of palifermin, as well as information from the manufacturer, were included. DATA SYNTHESIS: Severe mucositis resulting from anticancer therapies increases healthcare expenditures and negatively impacts patients' quality-of-life. Radiation therapy to the head and neck, as well as stem cell transplant conditioning regimens, have the highest incidence of severe mucositis. Consequences include prolonged hospitalization, need for parenteral nutrition, increased risk of infection, and severe pain. Palifermin is a recombinant human keratinacyte growth factor indicated in patients with hematologic malignancies who are undergoing stem cell transplant. In a randomized, placebo-controlled, Phase III trial, palifermin significantly reduced the incidence and duration of severe mucositis and days of parenteral nutrition and opioid analgesics in patients undergoing autologous stem cell transplant. The most common adverse effects of palifermin were rash, pruritus, cough, and taste alterations. Data in patients with solid tumors are limited, and there is a theoretical risk of stimulating tumor growth. CONCLUSIONS: Treatment with palifermin appears to decrease the severity and duration of severe mucositis following autologous stem cell transplant. Use in these patients appears justified; however, use in non-stem cell transplant patients should be discouraged until more efficacy and toxicity data are available.

Single-dose rasburicase 6 mg in the management of tumor lysis syndrome in adults.

Rasburicase is currently approved at a dosage of 0.15-0.2 mg/kg once/day for 5 days in pediatric patients with cancer to lower plasma uric acid concentrations and manage tumor lysis syndrome (TLS). Information on rasburicase dosing in adults is limited, with some data on using rasburicase as a single dose instead of multiple daily doses. Therefore, we evaluated the efficacy of a single dose of rasburicase for preventing or managing TLS in adults. We collected retrospective data for 11 adults with hematologic malignancies who received a single 6-mg dose of rasburicase. All patients received intravenous hydration with urinary alkalinization and allopurinol; however, due to adverse reactions, two patients received short courses of allopurinol. Only patients at high risk for TLS (e.g., large tumor burden, increasing uric acid concentration) or those with TLS received rasburicase. The single dose of rasburicase 6 mg resulted in a median 0.0773-mg/kg dose (range 0.0232-0.1361 mg/kg). The single 6-mg dose rapidly lowered uric acid concentrations in 10 of the 11 patients. The median uric acid concentration of 11.7 mg/dl (range 7.4-17.4 mg/dl) declined to 2.0 mg/dl (range 0.5-15.4 mg/dl) within a day after rasburicase administration (p=0.022). In these 10 patients, uric acid concentrations remained low despite subsequent chemotherapy, and none required additional rasburicase doses. The only patient who did not respond to the single 6-mg rasburicase dose was a morbidly obese man (259 kg, body mass index 87 kg/m2) who subsequently responded to an additional dose of rasburicase 12 mg. These results warrant further investigation of a single 6-mg dose of rasburicase in adults with TLS or at high-risk for developing TLS.