Kayleigh R. Marx

Isavuconazole: Pharmacology, pharmacodynamics, and current clinical experience with a new triazole antifungal agent

Coinciding with the continually increasing population of immunocompromised patients worldwide, the incidence of invasive fungal infections has grown over the past 4 decades. Unfortunately, infections caused by both yeasts such as Candida and molds such as Aspergillus or Mucorales remain associated with unacceptably high morbidity and mortality. In addition, the available antifungals with proven efficacy in the treatment of these infections remain severely limited. Although previously available second‐generation triazole antifungals have significantly expanded the spectrum of the triazole antifungal class, these agents are laden with shortcomings in their safety profiles as well as formulation and pharmacokinetic challenges. Isavuconazole, administered as the prodrug isavuconazonium, is the latest second‐generation triazole antifungal to receive U.S. Food and Drug Administration approval. Approved for the treatment of both invasive aspergillosis and invasive mucormycosis, and currently under investigation for the treatment of candidemia and invasive candidiasis, isavuconazole may have therapeutic advantages over its predecessors. With clinically relevant antifungal potency against a broad range of yeasts, dimorphic fungi, and molds, isavuconazole has a spectrum of activity reminiscent of the polyene amphotericin B. Moreover, clinical experience thus far has revealed isavuconazole to be associated with fewer toxicities than voriconazole, even when administered without therapeutic drug monitoring. These characteristics, in an agent available in both a highly bioavailable oral and a β‐cyclodextrin–free intravenous formulation, will likely make isavuconazole a welcome addition to the triazole class of antifungals.

Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies

Venetoclax (VEN), a selective BCL2 inhibitor, has single‐agent activity in relapsed and refractory (R/R) acute myeloid leukemia (AML), and efficacy in lower intensity combinations for treatment‐naïve elderly AML patients. VEN treatment combinations in R/R AML have not been previously reported.

Inotuzumab ozogamicin in the treatment of acute lymphoblastic leukemia

ABSTRACT Over 90% of leukemic blasts in patients with acute lymphoblastic leukemia express the marker CD22. Inotuzumab ozogamicin (INO) is a CD22-directed humanized monoclonal antibody conjugated to the potent cytotoxin, calicheamicin, via an acid labile linker. INO has shown high rates of response in the treatment of relapsed and refractory (R/R) ALL in single-agent studies, with fewer adverse effects than traditional cytotoxic chemotherapy. Given this experience, studies are now being done to evaluate INO in combination with low-intensity chemotherapy as frontline treatment for older adults with ALL and patients with R/R disease. Herein we will discuss the use of INO in the treatment of acute lymphoblastic leukemia.

Clinical Outcomes Associated With Linezolid Resistance in Leukemia Patients With Linezolid-Resistant Staphylococcus epidermidis Bacteremia

Abstract Background Coagulase-negative staphylococci, including Staphylococcus epidermidis, are the most common cause of bloodstream infection in cancer patients. Linezolid resistance is increasingly identified in S. epidermidis, but whether such resistance alters the clinical course of S. epidermidis infections is unknown. The purpose of this study was to assess the clinical impact of linezolid resistance in leukemia patients with S. epidermidis bloodstream infection. Methods This was a retrospective, single-center cohort study of all adult leukemia patients with S. epidermidis bacteremia treated with empiric linezolid between 2012 and 2015. The primary end point was adverse clinical outcome on day 3, defined as a composite of persistent bacteremia, fever, intensive care unit admission, or death. Fourteen- and 30-day mortality were also assessed. Results Eighty-two unique leukemia patients with S. epidermidis were identified. Linezolid resistance was identified in 33/82 (40%). Patients with linezolid-resistant S. epidermidis were significantly more likely to have persistent bacteremia (41% vs 7%; adjusted relative risk [aRR], 5.15; 95% confidence interval [CI], 1.63–16.30; P = .005); however, adverse short-term clinical outcomes overall were not more common among patients with linezolid-resistant S. epidermidis (61% vs 33%; aRR, 1.46; 95% CI, 0.92–2.32; P = .108). No differences were observed in 14- or 30-day mortality. Conclusions Leukemia patients with linezolid-resistant S. epidermidis bacteremia who were treated with linezolid were significantly more likely to have persistent bacteremia compared with those with linezolid-sensitive isolates. Interventions to limit the clinical impact of linezolid-resistant S. epidermidis are warranted.

Navigating manuscript assessment: The new practitioner’s guide to primary literature peer review:

For pharmacists, the first years after graduation are spent developing their knowledge base, advancing as a practitioner, and honing their abilities as healthcare providers and drug information experts. New practitioners encounter many challenges during this time, which for many include publishing original research or reviewing manuscripts for colleagues and medical journals. Inexperience navigating the publication process, from submission to receipt of (and response to) peer review commentary, is often cited as a major barrier to timely publication of resident and new practitioner research. Serving as a peer reviewer in turn provides the new practitioner with insight on this process and can be an enlightening experience used to garner confidence in subsequently submitting their own formal manuscripts. A number of publications describing steps for peer review are available, however, many of these articles address more experienced reviewers or critique the peer review process itself. No definitive resource exists for new pharmacy practitioners interested in developing their peer review skills. The information presented in this summative guide should be used in conjunction with practice opportunities to help new practitioners develop proficiency at peer review.

L-carnitine and Vitamin B Complex for the Treatment of Pegasparaginase-induced Hyperbilirubinemia

We present 3 cases of severe asparaginase-induced hepatotoxicity, which predominantly manifested as direct hyperbilirubinemia. L-carnitine and vitamin B are mitochondrial cofactors that have been reported to improve hyperbilirubinemia in adult patients treated with asparaginase in the firstline treatment setting. L-carnitine and vitamin B were used to ameliorate severe hyperbilirubinemia due to pegylated-asparaginase administration in the relapsed/refractory, post-allogeneic stem cell transplantation setting. Early intervention and prophylaxis strategies with L-carnitine and vitamin B are worth investigating.

Prophylactic Antibiotic Therapy and Blood Stream Infections in Leukemia Patients Presenting to the Emergency Center

Abstract Background Patients undergoing chemotherapy for leukemia are at high risk for infection and routinely receive antibiotic prophylaxis. The types of breakthrough bloodstream infection (BSI) based on choice of prophylaxis is not well-characterized. Here, we describe antibiotic prophylaxis patterns and the influence of antibiotic choice on BSI epidemiology in leukemia patients presenting to the emergency center (EC) with neutropenic fever (NF). Methods This was a retrospective chart review of patients with leukemia and NF (absolute neutrophil count [ANC] <500 cells/mm3; temperature ≥38.3°C) who presented to the EC at MD Anderson Cancer Center from January 2014 to January 2015. Patients receiving levofloxacin (LEV), ciprofloxacin (CIP), amoxicillin–clavulanate (ACL), or cefpodoxime (CEF) were included. We assessed current antibiotic prophylaxis at presentation to the EC, and correlated with microbiologically proven bloodstream infections (BSI) within the first 48 hours following presentation. Results A total of 284 patients (mean age 56 ± 17 years; 63% male) were assessed. Eighty-four% of patients had neutropenia >7 days in duration and the median ANC at presentation was 0 cells/mm3 (range: 0–490 cells/mm3). Most patients received LEV (42%) followed by CIP (27%), CEF (25%), and ACL (6%). Forty-seven of 284 patients presented with Gram-negative BSI (16%) and 36 (13%) had Gram-positive BSI. Rates of common organisms causing BSI are presented in Table 1. Conclusion In leukemia patients with NF presenting to the EC, rates of BSI differed significantly based on antibiotic prophylaxis choice, with P. aeruginosa BSI more common in patients receiving ACL and E. coli in patients receiving LEV. The epidemiology of breakthrough infections on different prophylactic agents may help guide empiric antibiotic choice.Table 1. Causative organisms of BSI. BSI Type LEV (n = 118) CIP (n = 77) CEF (n = 72) ACL (n = 17) P-value Any Gram-negative (n = 47) 21 (18) 7 (9) 13 (18) 6 (35) 0.05 E. coli (n = 25) 18 (15) 3 (4) 3 (4) 1 (6) 0.02 P. aeruginosa (n = 13) 2 (2) 1 (1) 6 (8) 4 (24) <0.01 Any Gram-positive (n = 36) 18 (16) 10 (13) 7 (10) 0 0.26 Alpha-hemolytic Streptococcus (n = 11) 4 (4) 4 (5) 2 (3) 0 0.90 Enterococcus spp. (n = 5) 0 (0) 2 (3) 3 (4) 0 0.12 All values presented as n (%). Disclosures R. F. Chemaly, Merck & Co., Inc.: Consultant and Investigator, Consulting fee, Research grant and Speaker honorarium

Clinical Experience of Venetoclax Combinations for Relapsed/Refractory Myeloid Malignancies

AML-021 Evaluation of Fluoroquinolone Versus Other Antibiotic Prophylaxis Strategies in Adult Patients with AML Undergoing Induction Chemotherapy Telyssa Anderson, PharmD, Samuel L. Aitken, PharmD, Kayleigh Marx, PharmD, Frank P. Tverdek, PharmD The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Evaluation of Fluoroquinolone Versus Other Antibiotic Prophylaxis Strategies in Adult Patients with AML Undergoing Induction Chemotherapy

AML-021 Evaluation of Fluoroquinolone Versus Other Antibiotic Prophylaxis Strategies in Adult Patients with AML Undergoing Induction Chemotherapy Telyssa Anderson, PharmD, Samuel L. Aitken, PharmD, Kayleigh Marx, PharmD, Frank P. Tverdek, PharmD The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Vosaroxin: innovative anticancer quinolone for the treatment of acute myelogenous leukemia

ABSTRACT Introduction: A first-in-class anticancer quinolone derivative with topoisomerase II activity, mechanistically, vosaroxin is similar to the anthracycline class. However, vosaroxin displays advantageous pharmacokinetic properties such as minimal metabolism, a lack of free radical production, is not a substrate for the P glycoprotein efflux pump, and can exert its antineoplastic activity independently of P53 function. Vosaroxin has shown encouraging results when combined with cytarabine in older patients with relapsed or refractory acute myeloid leukemia (AML) while balancing early toxicity and mortality, making it a compelling novel therapy for acute myelogenous leukemia. Areas covered: Herein, we review the clinical data from published and internationally presented clinical trials utilizing vosaroxin for AML in the elderly, and relapsed and refractory population. Pivotal trials reviewed include the multicenter, phase II, REVEAL-1 study of single-agent vosaroxin in untreated elderly patients and the multicenter, phase III, VALOR study of vosaroxin in combination with intermediate dose cytarabine for patients with relapsed or refractory AML. Expert opinion: Outcomes for older adults with AML, and for patients with relapsed or refractory disease are persistently poor. Improvement in outcomes in the elderly population highlight the utility of this agent in a difficult to treat, often more resistant and intolerant to therapy, group of patients. The expected and observed lack of cardiotoxicity makes this drug particularly suitable for the older population, especially those that may have received prior anthracycline based therapy.