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Background Cyclin-dependent kinase (CDK) 4 and 6 inhibitors have significantly improved survival in patients with hormone receptor-positive metastatic breast cancer. There are few data regarding the epidemiology of cardiovascular adverse events (CVAEs) with these therapies. Methods and Results Using the OneFlorida Data Trust, adult patients without prior cardiovascular disease who received at least 1 CDK4/6 inhibitor were included in the analysis. CVAEs identified from International Classification of Diseases , Ninth and Tenth Revisions ( ICD-9/10 ) codes included hypertension, atrial fibrillation(AF)/atrial flutter (AFL), heart failure/cardiomyopathy, ischemic heart disease, and pericardial disease. Competing risk analysis (Fine-Gray model) was used to determine the association between CDK4/6 inhibitor therapy and incident CVAEs. The effect of CVAEs on all-cause death was studied using Cox proportional hazard models. Propensity-weight analyses were performed to compare these patients to a cohort of patients treated with anthracyclines. A total of 1376 patients treated with CDK4/6 inhibitors were included in the analysis. CVAEs occurred in 24% (35.9 per 100 person-years). CVAEs were slightly higher in patients who received CKD4/6 inhibitors compared with anthracyclines ( P =0.063), with higher death rate associated with the development of AF/AFL or cardiomyopathy/heart failure in the CDK4/6 group. The development of cardiomyopathy/heart failure and AF/AFL was associated with increased all-cause death (adjusted hazard ratio [HR], 4.89 [95% CI, 2.98-8.05]; and 5.88 [95% CI, 3.56-9.73], respectively). Conclusions CVAEs may be more common with CDK4/6 inhibitors than previously recognized, with increased death rates in these patients who develop AF/AFL or heart failure. Further research is needed to definitively determine cardiovascular risk associated with these novel anticancer treatments.

Abstract: Cardiometabolic disease (CMD) is the most common preventable cause of death in the world. A number of components are included in the spectrum of CMD, such as metabolic syndrome/obesity, hyperglycemia/diabetes, dyslipidemia, and hypertension, which are independently associated with cardiovascular disease risk. These conditions often occur together, and patients with cancer frequently undergo treatments that can generate or worsen CMD. This review highlights and presents mechanistic and epidemiological evidence regarding CMD in 4 categories of anticancer medications, namely, mTOR/PI3K-Akt inhibitors, multitargeted tyrosine kinase inhibitor, immune checkpoint inhibitor therapy, and endocrine therapy. Patients taking these medications need careful monitoring during therapy. There is a role for cardio-oncology and onco-primary care specialists in optimally managing patients at risk to mitigate CMD during treatment with these and other investigational anticancer medications., Competing Interests: N. Agarwal reports consultancy to Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. M. G. Fradley reports research grants with Medtronic and consultancy to Abbott, AstraZeneca and Takeda. None of the above have any relation to the work presented in the manuscript. Other authors declare no conflicts of interests in relation to the work presented in this manuscript., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Along with the fast pace of oncology drug approvals is the heightened opportunity for drug-drug, drug-food, and drug-herbal interactions. Attendees at the JADPRO Live Virtual 2021 conference learned about the pharmacodynamic and pharmacokinetic mechanisms of drug interactions and how to integrate appropriate therapeutic management strategies to optimize patient care and minimize the potential outcomes of severe drug interactions., Competing Interests: The presenter had no conflicts of interest to disclose., (© 2022 Harborside™.)

Introduction : Novel immunotherapeutic agents (e.g. monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engagers) as treatment options for hematologic malignancies continue to emerge. These agents have been used as the standard of care in specific disease states and are associated with high costs. Value assessment of these therapies is of critical importance for coverage and reimbursement decision-making. Areas covered : We identified 15 immunotherapeutic agents through the U.S. FDA approvals for hematologic malignancies until 2018 and systematically reviewed related cost-effectiveness studies. Additionally, we examined whether drug wastage was accounted for in these studies. Expert opinion : We reviewed 51 studies for 14 identified immunotherapeutic agents that met the inclusion criteria for this systematic review. Three studies were observational-based, one study was model-based and incorporated observational data. The remaining studies were model-based with the majority of the model parameters extracted from randomized control trials (RCTs). Among 43 model-based economic evaluations, 13 studies accounted for drug wastage. Most of the studies showed favorable incremental cost-effectiveness ratios of immunotherapeutic agents-containing regimens when compared with no immunotherapeutic agents-containing regimens. Alemtuzumab, brentuximab vedotin, and daratumumab were not considered cost-effective across all the studies. Further investigations are warranted to establish the value of recent immunotherapeutic agents for hematologic malignancies.

Lessons Learned: Preclinical studies have demonstrated that Src inhibition through dasatinib synergistically enhances the antitumor effects of oxaliplatin. In this phase II, single-arm study, FOLFOX with dasatinib in previously untreated patients with mPC only showed only modest clinical activity, with a progressive-free survival of 4 months and overall survival of 10.6 months. Continued investigation is ongoing to better understand the role of Src inhibition with concurrent 5-fluorouracil and oxaliplatin in a subset of exceptional responders., Background: Src tyrosine kinase activity is overexpressed in many human cancers, including metastatic pancreatic cancer (mPC). Dasatinib is a potent inhibitor of Src family of tyrosine kinases. This study was designed to investigate whether dasatinib can synergistically enhance antitumor effects of FOLFOX regimen (FOLFOX-D)., Methods: In this single-arm, phase II study, previously untreated patients received dasatinib 150 mg oral daily on days 1-14, oxaliplatin 85 mg/m 2 intravenous (IV) on day 1 every 14 days, leucovorin (LV) 400 mg/m 2 IV on day 1 every 14 days, 5-fluorouracil (5-FU) bolus 400 mg/m 2 on day 1 every 14 days, and 5-FU continuous infusion 2,400 mg/m 2 on day 1 every 14 days. Primary endpoint was progression-free survival (PFS) with preplanned comparison to historical controls., Results: Forty-four patients enrolled with an estimated median PFS of 4.0 (95% confidence interval [CI], 2.3-8.5) months and overall survival (OS) of 10.6 (95% CI, 6.9-12.7) months. Overall response rate (ORR) was 22.7% (n = 10): one patient (2.3%) with complete response (CR) and nine patients (20.5%) with partial response (PR). Fifteen patients (34.1%) had stable disease (SD). Nausea was the most common adverse event (AE) seen in 35 patients (79.5%)., Conclusion: The addition of dasatinib did not appear to add incremental clinical benefit to FOLFOX in untreated patients with mPC., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Patients with autoimmune disorders, multiple comorbidities, poor performance status, advanced age, and infection with SARS-CoV-2 (COVID-19) each represent unique subgroups of patients with cancer to whom little is known of the effects, benefits, and complications of checkpoint inhibitor (CPI) therapy. Although prospective trials are lacking in these populations, retrospective data and cohort series suggest that these patients can safely receive and benefit from CPI therapy. Here, we review the relevant data available and offer clinical recommendations in managing these complex patients with CPI therapy, where otherwise indicated., Competing Interests: Jonathan A. ChatzkelTravel, Accommodations, Expenses: Merck, Lilly David DeRemerLeadership: Hematology Oncology Pharmacy Association (HOPA)Honoraria: Bristol-Myers Squibb, Pfizer, Pharmacy Times, Pharmacy Times Thomas J. GeorgeResearch Funding: Bristol-Myers Squibb, Merck, AstraZeneca/MedImmune, Lilly, Bayer, Incyte, Tesaro, Pharmacyclics, Ipsen, Seattle Genetics, GenentechOpen Payments Link: https://openpaymentsdata.cms.gov/physician/321938/summaryNo other potential conflicts of interest were reported.

There have been significant advancements in precision medicine and approaches to medication selection based on pharmacogenetic results. With the availability of direct-to-consumer genetic testing and growing awareness of genetic interindividual variability, patient demand for more precise, individually tailored drug regimens is increasing. The University of Florida (UF) Health Precision Medicine Program (PMP) was established in 2011 to improve integration of genomic data into clinical practice. In the ensuing years, the UF Health PMP has successfully implemented several single-gene tests to optimize the precision of medication prescribing across a variety of clinical settings. Most recently, the UF Health PMP launched a custom-designed pharmacogenetic panel, including pharmacogenes relevant to supportive care medications commonly prescribed to patients undergoing chemotherapy treatment, referred to as "GatorPGx." This tutorial provides guidance and information to institutions on how to transition from the implementation of single-gene pharmacogenetic testing to a preemptive panel-based testing approach. Here, we demonstrate application of the preemptive panel in the setting of an adult solid tumor oncology clinic. Importantly, the information included herein can be applied to other clinical practice settings., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

The Association of Community Cancer Centers (ACCC), Hematology/Oncology Pharmacy Association (HOPA), National Community Oncology Dispensing Association (NCODA), and Oncology Nursing Society (ONS) partnered together to create a resource for providers, and patients and caregivers on oral chemotherapy agents. The patient education sheets include information on medication names and pronunciation, approved uses, dose and schedule, drug and food interactions, the best practice guidelines for safe handling, administration, and disposal of oral chemotherapy agenzts by patients and caregivers; management strategies for the most common side effects; and pregnancy, sexual activity, and contraception information. Each sheet also has an area to list from which pharmacy the patient will receive the medication. The document and the website also provide the link to the individual product website, prescribing information, and product resources, if available.

Evidence supports olanzapine for prophylaxis of chemotherapy-induced nausea/vomiting (CINV) for highly emetogenic chemotherapy; however, most studies focus on solid malignancies and single-day regimens. A randomized, double-blinded, placebo-controlled trial was conducted to compare the addition of olanzapine to triplet therapy (fosaprepitant, ondansetron, dexamethasone [FOND-O]) versus triplet therapy alone (FOND) in preventing CINV in hematology patients receiving single-day and multiple-day highly emetogenic chemotherapy and hematopoietic cell transplant (HCT) regimens (NCT02635984). The primary objective of this study was to compare complete response (CR; no emesis and minimal nausea, <25 mm on a 100-mm visual analog scale) during the overall assessment period (chemotherapy days plus 5 days after). Secondary objectives were the number of emesis, number of rescue medications, percent achieving minimal nausea, and percent achieving complete protection (CP; no emesis, rescue antiemetic, or significant nausea), all of which are reported as acute (chemotherapy days), delayed (5 days after chemotherapy), and overall phases. Olanzapine 10 mg or matching placebo were given on each chemotherapy day and 3 days after. Adults with hematologic malignancy receiving HCT regimens of melphalan, BEAM (carmustine, etoposide, cytarabine, melphalan), busulfan (Bu)/cyclophosphamide (Cy), Bu/fludarabine (Flu), Bu/melphalan, FluCy, FluCy-total body irradiation (TBI), etoposide-TBI, and ICE (ifosfamide, carboplatin, etoposide) or 7+3 chemotherapy regimens were included. An estimated 98 patients were required using alpha = .05 and 80% power. No significant differences existed in baseline characteristics between FOND-O (n = 51) and FOND (n = 50) arms. Mean duration of olanzapine was 7.7 days (range, 4 to 11). Discontinuation for possible adverse events occurred in 3 placebo and 0 olanzapine patients. CR was significantly higher for FOND-O in overall (55% versus 26%, P = .003) and delayed (60.8% versus 30%, P = .001) but not acute (P = .13) phases. Significantly more patients receiving FOND-O achieved no more than minimal nausea in overall (P = .001) and delayed phases (P = .0002), as well as fewer overall mean emesis counts (P = .005). CP rates were not different in any assessment phase (P ≥ .05 each). Within the HCT subgroup (n = 64), the CR, CP, and no significant nausea rates were significantly better for FONDO-O in overall and delayed phases (all P < .05). Analysis within the HCT subgroup revealed significant improvement in outcomes in delayed and overall phases with FOND-O in the autologous but not allogeneic cohort. Addition of olanzapine to an NK-1-based triplet antiemetic regimen significantly improved clinically relevant outcomes in the HCT population., (Copyright © 2018. Published by Elsevier Inc.)

Background: Complete remission (CR) in acute myeloid leukemia (AML) is defined as having ≤5% leukemic blast cells in the bone marrow and return of normal hematopoiesis after the first induction cycle. There is a subset of patients, however, who achieve reduction of leukemic blast cells with a subnormal platelet count, designated as CR with incomplete platelet recovery (platelet count, ≤100,000/mcL; normal, 150,000-450,000/mcL), which is associated with inferior outcomes when compared with CR. Furthermore, there is another subset of patients with CR but superior platelet counts (≥400,000/mcL) whose prognostic significance is unclear., Objective: To establish whether CR with superior platelet counts is associated with better outcomes and can be used as a separate entity for prognostication., Methods: A retrospective chart review of 104 cases of AML was conducted. The highest platelet count during days 25-35 from initiation of induction chemotherapy (designated as day 30 platelet count) was documented. A multivariate analysis for other factors such as age, sex, risk categories, day 14+ plasma cell count (average plasma cell percentage at days 14-21), infections, allogeneic bone marrow transplant, and remission status was done., Results: Day 30 platelet count was found to be an independent predictor of survival in AML. On the multivariate analysis, the subgroup with superior platelet counts (≥400,000/mcL) was found to be associated with better outcomes., Limitations: Results need to be validated in a larger cohort., Conclusions: CR with superior platelet recovery (≥400,000/mcL) is a unique subcategory in itself and has prognostic significance. This may help better assess response to chemotherapeutic agents and aid in further decision-making regarding treatment., (©2016 Frontline Medical Communications.)

Purpose: The pharmacology, pharmacokinetics, clinical efficacy, and safety and tolerability of brentuximab vedotin are reviewed., Summary: Brentuximab vedotin is a potent antibody-drug conjugate composed of the monoclonal antibody cAC10, which targets the CD30 antigen on Hodgkin lymphoma and systemic anaplastic large-cell lymphoma (sALCL) cells; a highly stable valine-citrulline linker; and a potent chemotherapeutic agent monomethyl auristatin E, which inhibits microtubule polymerization. Brentuximab is indicated for patients with relapsed Hodgkin lymphoma after autologous stem-cell transplantation (ASCT), for patients who are not candidates for ASCT who have not responded to at least two multiagent chemotherapy regimens, and for patients with ALCL who have not responded to at least one multiagent chemotherapy regimen. In a Phase II, single-group, multicenter study, brentuximab produced an overall response rate of 75% in relapsed or refractory Hodgkin lymphoma. In another Phase II study, brentuximab demonstrated clinical benefit in sALCL, with 86% of patients achieving a response and 57% of patients achieving complete remission. Adverse events most commonly reported included nausea, fatigue, diarrhea, neutropenia, and peripheral sensory neuropathy. A Phase III study is currently ongoing in patients at high risk for residual Hodgkin lymphoma after ASCT., Conclusion: Brentuximab vedotin, a novel antibody-drug conjugate combining a cytotoxic agent with a selective monoclonal antibody, is a therapeutic option for patients with relapsed or refractory Hodgkin lymphoma and sALCL. Phase I and II studies have shown brentuximab to have a manageable toxicity profile.

Peripheral blood progenitor cell mobilization with intermediate-dose cyclophosphamide (ID-CY) and granulocyte colony-stimulating factor (G-CSF) has been shown to be more efficacious, albeit more toxic, than low-dose cyclophosphamide (LD-CY) mobilization regimens in patients with multiple myeloma treated with conventional therapies. However, the relative importance of cyclophosphamide dose intensity in peripheral blood progenitor cell mobilization after novel induction regimens is not known. Here we report mobilization outcomes of 123 patients who underwent transplantation within 1 year of starting induction chemotherapy with novel agents. We compared consecutive patients undergoing mobilization with ID-CY/G-CSF (3-4 g/m(2)) at one institution (n = 55) with patients receiving LD-CY/G-CSF (1.5 g/m(2)) at a different transplantation center (n = 68). At baseline, the 2 groups were well balanced, except for more frequent previous lenalidomide use in the ID-CY group (P = .04). Compared with LD-CY, ID-CY use was associated with higher median peak PB CD34(+) cell count (35/μL versus 160/μL; P < .001), CD34(+) cell yield on day 1 of collection (2.6 × 10(6)/kg versus 11.7 × 10(6)/kg, P ≤ .001), and total CD34(+) cell yield (7.5 × 10(6)/kg versus 16.6 × 10(6)/kg; P ≤ .001). Six patients in the LD-CY group had mobilization failure, compared with no patients in the ID-CY group. A significantly higher proportion of patients in the LD-CY group (P < .001) were unable to collect ≥5 × 10(6)/kg and ≥10 × 10(6)/kg CD34(+) cells. Neutrophil and platelet engraftment were significantly faster in the ID-CY group, likely because of higher infused CD34(+) cell doses. In conclusion, compared with LD-CY, ID-CY produced a more robust peripheral blood progenitor cell mobilization and significantly reduced the rates of mobilization failure. These data caution against the use of LD-CY-containing mobilization strategies in patients with multiple myeloma undergoing stem cell collection after novel induction regimens., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The combination of filgrastim (G-CSF) and plerixafor is currently approved for mobilizing peripheral blood progenitor cells in patients with non-Hodgkin lymphoma and multiple myeloma undergoing autologous peripheral blood hematopoietic cell transplantation. However, chemotherapy and G-CSF-based mobilization remains a widely used strategy for peripheral blood progenitor cell collection. In this paper we describe our experience from two North American transplant centers in a series of patients who received salvage plerixafor while failing chemotherapy and G-CSF mobilization. Patients received a median of two doses of plerixafor salvage upon failure to mobilize adequate number of peripheral blood progenitor cells at neutrophil recovery. The use of plerixafor was associated with a 2.4-fold increase in peripheral blood CD34+ cell count and 3.9-fold increase in total CD34+ cell yield. All patients were able to collect ≥2 × 10(6) CD34+ cells/kg with this approach. These results were more pronounced in patients with a higher CD34+ cell count at the time of the first plerixafor dose. Interestingly, peripheral blood white blood cell count was not shown to correlate with a response to plerixafor. Our results provide safety and efficacy data for the use of plerixafor in patients who are destined to fail chemomobilization.

We evaluated the frequency of invasive fungal infections (IFI), the frequency of empirical antifungal use (EAFU), and the efficacy of fluconazole prophylaxis on IFI and EAFU after high-dose cytarabine (HiDAC) consolidations. Twenty-seven acute myelogenous leukemia patients in their first complete remission received 76 cycles of HiDAC (median cycle: n = 3). Fluconazole prophylaxis was administered following 44 cycles (fluconazole group) and not given in 32 cycles (control group). IFI (2 episodes) + EAFU (11 episodes) was observed in 13 of 76 cycles (17%); there was no difference between the fluconazole group and the control group (p = 0.469). Neutropenia duration was <13 days in 89% of the 76 cycles and was similar in the fluconazole and control groups (p = 0.845). Neutropenic fever was observed in 34 of the 76 cycles (45%) and was similar in the fluconazole group and the control group (p = 0.43). Although HiDAC cycle 1 was associated with a shorter neutropenia duration, there was no association between HiDAC cycle numbers and neutropenic fever or IFI + EAFU. HiDAC consolidations resulted in a high rate of neutropenic fever, the lack of an appreciable benefit from EAFU, and rare IFI. Most likely because of the low incidence of IFI, use of fluconazole or another antifungal is not warranted in this setting., (Copyright © 2010 S. Karger AG, Basel.)

The present study was designed to test the hypothesis that a 60 Hz electromagnetic field could affect the influx of calcium ions across the plasma membrane through the so-called capacitative calcium entry system. Recordings of cytosolic calcium-ion concentrations in SV40-transformed Swiss 3T3 cells were obtained in real time during exposure to magnetic fields ranging from 0.3-50 mT or to sham conditions using the calcium-sensitive photoprotein aequorin. This was done for cell populations whose capacitative entry system was activated by either bradykinin or thapsigargin under a variety of experimental conditions. No effects of the magnetic field were observed on bradykinin-induced calcium transients and, with the exception of a small but statistically significant increase observed in experiments performed at 50 mT, no effects of the fields were observed on baseline calcium levels prior to or after such transients. The magnetic fields also had no effects on the size or kinetics of any of the thapsigargin-induced calcium transients. Overall, the data fail to support the hypothesis tested in this work.

The purpose of this study was to evaluate the presence of chemical-shift artifacts on cranial MR and to illustrate the interrelationship among chemical-shift artifacts, variable acquisition parameters, and field strength. Measurements of chemical-shift artifacts were performed on scans obtained from a volunteer imaged in a 1.5-T General Electric system at bandwidths of 8, 16, and 32 kHz, using a 24-cm field of view and an 8-kHz bandwidth with a 48-cm field of view. Chemical-shift displacements at 8 kHz were 6.6 and 14.2 mm at the respective fields of view. Retrospective review was also performed in 77 cases of cranial MR performed on a 1.4-T Technicare unit for the presence and source of chemical-shift artifact on spin-density and T2-weighted images. Most data reviewed showed no significant interference of chemical-shift artifacts on cranial images. An artifactual subdural fluid collection was a common artifact (n = 30/77). When present, this was due to shift of fat signal from subcutaneous tissues onto the brain in patients younger than 10 years old (n = 4/10) and correlated with the distance between brain and subcutaneous fat of less than the linear value of the chemical shift. When this artifact was present in adults (n = 25/67), it was due to shift of the medullary fat signal across the inner table of the skull. The latter also occurred in one child under 10. Apparent location shifts, consistent with the displacement expected from the chemical-shift artifact, were noted in five of five cases of intracranial lipoma. In one of these, the chemical-shift artifact disguised the presence of a large associated vessel. The method of calculating the linear displacement of chemical-shift artifact is reviewed, and the interrelationship of machine parameters and chemical-shift artifact is illustrated. Chemical-shift artifact increases proportionally with field strength and field of view. Increasing the bandwidth to decrease chemical-shift artifact has a resultant penalty in signal to noise but allows a lower time to echo. A lower time to echo can also be accomplished without increasing the bandwidth if asymmetric sampling is used. Awareness of the relationships among chemical-shift artifacts, acquisition parameters, and field strengths can result in a more tailored examination when the chemical-shift artifact is going to be a significant factor. In addition, interpreter error can be avoided by awareness of these relationships when reviewing images from outside institutions.