Supportive Care Agents Research Articles

Treatment of Myelodysplastic Syndromes for Older Patients: Current State of Science, Challenges, and Opportunities.

Myelodysplastic syndromes/neoplasms (MDS) represent a diverse group of pathologically distinct diseases with varying prognoses and risks of leukemia progression. This review aims to discuss current treatment options for elderly patients with MDS, focusing on patients ineligible for intensive chemotherapy or allogenic hematopoietic stem cell transplantation (HSCT). The challenges associated with treatment in this population and emerging therapeutic prospects are also explored. Recent advancements in molecular diagnostics have enhanced risk stratification by incorporating genetic mutations, notably through the molecular International Prognostic Scoring System (IPSS-M). Lower-risk MDS (LR-MDS) treatment ranges from observation to supportive measures and erythropoiesis-stimulating agents (ESAs), with emerging therapies like luspatercept showing promise. High-risk MDS (HR-MDS) is treated with hypomethylating agents (HMAs) or allogenic HSCT, but outcomes remain poor. Elderly MDS patients, often diagnosed after 70, pose challenges in treatment decision-making. The IPSS-M aids risk stratification, guiding therapeutic choices. For LR-MDS, supportive care, ESAs, and novel agents like luspatercept are considered. Treatment of HR-MDS involves HMAs or allogenic HSCT. Emerging treatments, including oral HMAs and novel agents targeting FLT3, and IDH 1/2 mutations, show promise. Future research should refine treatment strategies for this elderly population focusing on quality-of-life improvement.

High Dose Clonidine as a Novel Therapy for Symptomatic Status Dystonicus in a Pediatric Patient (P5-9.009)

<h3>Objective:</h3> To highlight the role of high dose clonidine in the treatment of refractory status dystonicus in children. <h3>Background:</h3> Status dystonicus (SD) is a movement disorder emergency characterized by involuntary sustained dystonia that can result from infections, traumatic brain injuries, hypoxia, or toxins. If under-treated, it can result in respiratory failure and end organ dysfunction. Therefore, it is crucial for SD to be identified and treated early with both supportive care and pharmacologic agents. Common pharmacologic agents include dopamine receptor blockers, baclofen, anticholinergics, and benzodiazepines. However, some patients remain refractory to standard treatments. <h3>Design/Methods:</h3> Case report and literature review. <h3>Results:</h3> A 16-month-old female presented to an outside facility in febrile status epilepticus of &gt;90 minutes duration. She suffered a brief cardiorespiratory arrest, was quickly resuscitated, and then subsequently suffered a second cardiorespiratory arrest and was transferred to our facility. Due to concern for status dystonicus, she was treated with a combination of Baclofen, Diazepam, Clonazepam, Amantadine and Trihexyphenidyl with minimal improvement. MRI showed acute bilateral globus pallidus injury. Extensive infectious, autoimmune, and genetic testing was overall unremarkable. After several days of continued refractory SD with maximized medication therapy, high-dose enteral clonidine was started, increasing dosing over the course of the week from 6 mcg/kg/day to 33 mcg/kg/day, which correlated with significant improvement in symptoms after reaching maximal dose. As she continued to improve with high dose clonidine, she was able to be weaned off of several medications and discharged to acute inpatient rehab. <h3>Conclusions:</h3> Status dystonicus can be a difficult condition to treat, as there are limited pharmaceutical treatment options in pediatric patients. Studies in adult populations have shown effectiveness of high dose clonidine, yet this has not been well described in children. This case suggests that high dose oral clonidine may be a safe and effective treatment option for refractory SD in children. <b>Disclosure:</b> Mr. Woods has nothing to disclose. Dr. Chandler has nothing to disclose. Dr. Barton has nothing to disclose.

ASCO Policy Statement on Biosimilar and Interchangeable Products in Oncology.

As the voice of cancer care clinicians and the patients they serve, ASCO has taken steps to elevate awareness about biosimilar products and their use in oncology. In 2018, ASCO released its Statement on Biosimilars in Oncology which was subsequently published in the Journal of Clinical Oncology to serve as an educational tool which highlighted and provided guidance on several topical areas surrounding biosimilars. At the time of its publication, the US Food and Drug Administration (FDA) had approved eight biosimilar products for use in the United States, including one product for use as a supportive care agent in the cancer setting and two products for use in the treatment for cancer. This number has risen dramatically (40 approvals), with a total of 22 cancer or cancer-related biosimilar products approved since 2015. Recently, the FDA also approved the four interchangeable biosimilar products for diabetes, certain inflammatory diseases, and certain ophthalmic diseases. Given the current market dynamics and the regulatory landscape, this ASCO manuscript now seeks to propose several policy recommendations across the scope of value, interchangeability, clinician barriers, and patient education and access. This policy statement is intended to guide ASCO's future activities and strategies and serves to affirm our commitment to providing education to the oncology community on the use of biosimilars in the cancer setting.

Management of the adverse effects of cancer immunotherapy with a focus on the gastrointestinal and hepatic systems

Background: Immunotherapy has become established as a new cancer treatment that enhances patients’ immune systems’ ability to fight cancer. Immune checkpoint inhibitors (ICI) have demonstrated remarkable benefits in the treatment of a range of cancer types. The increasing use of immune-based therapies has exposed a discrete group of immune-related adverse effects. Effective recognition and treatment of ICI-induced toxicities have emerged as essential goals of ICI management.Current Concepts: Gastrointestinal (GI) and hepatic adverse effects of ICI treatment are relatively common. Immune-related GI or hepatic toxicities occur in approximately 30% of patients. The incidence of grade 3 or 4 adverse effects ranges from 0.5% to 2%. The management strategy for immune-related adverse effects depends on their severity. In general, ICI treatment can be continued with close monitoring for mild (grade 1) GI/hepatic toxicities. ICI treatment should be interrupted for most grade 2 to 4 toxicities, and systemic steroid administration is recommended. If steroids are ineffective, immunosuppressive agents such as infliximab may be used. When symptoms and laboratory values revert to grade 1 or less, ICI treatment may be resumed with caution. Grade 4 toxicities warrant permanent discontinuation of ICI treatment.Discussion and Conclusion: Most immune-related GI and hepatic adverse effects are mild to moderate in severity and can be managed with supportive care, steroid therapy, and other immunomodulatory agents. Management of ICI-related toxicities in the GI and hepatic systems requires close collaboration between the patient, the treating oncologist, and other specialists.

Oncology biosimilars: New developments and future directions.

Biologicals have become an integral part of cancer treatment both as therapeutic agents and as supportive care agents. It is important to know that biologics are large, complex molecular entities requiring extensive immunogenicity testing and pharmacovigilance strategies to ensure no immune response is evoked in the body. Oncology's pharmacological market is dominated by biologics; however, their high development and manufacturing costs are burdensome to health care systems. Biologics being the most expensive prescription drugs on the market limit the accessibility for necessary treatment in the case of many patients. As biologics patents expire, the development of biosimilars is underway in an effort to lower costs and enable patients to access new cancer therapies. Regulatory guidelines for biosimilars have now been established and are constantly being revised to address any issues, facilitating their robust development. Moreover, many scientific societies offer guidance to help stakeholders better understand current regulations and biosimilar's safety. Despite the potential cost benefits, lack of knowledge about biosimilars, and the possibility of immunogenicity have created an uncertain environment for healthcare professionals and patients. In this review, we provide an overview of relevant legislation and regulations, pharmacoeconomics, and stakeholder perceptions regarding biosimilars. The article also describes biosimilars in development, as well as the ones currently available on the market.

A RARE CASE OF ANTINEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-NEGATIVE PAUCI- IMMUNE FOCAL NECROTIZING AND CRESCENTIC GLOMERULONEPHRITIS PRESENTING WITH DIFFUSE ALVEOLAR HEMORRHAGE

A RARE CASE OF ANTINEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-NEGATIVE PAUCI- IMMUNE FOCAL NECROTIZING AND CRESCENTIC GLOMERULONEPHRITIS PRESENTING WITH DIFFUSE ALVEOLAR HEMORRHAGE

Turn Up the HETE on Septic Shock.

Septic shock is life-threatening organ dysfunction due to a dysregulated response to infection. It is a leading cause of death caused by the excessive release of cytokines and inflammatory mediators in response to bacterial endotoxins. It produces hypotension refractory to vasoconstrictors leading to tissue hypoperfusion and multiple organ failure. Despite intensive investigation, there still are no specific pharmacologic treatments. Current therapy relies on supportive care, including antibiotics, fluid resuscitation, corticosteroids, and pressor agents. This commentary summarizes little-known previous observations that inhibition of vascular 20-hydroxyeicosatetraenoic acid (20-HETE) by nitric oxide plays a key role in sepsis. It also highlights the new and exciting current report by Tunctan et al (2022) in this issue of Journal of Cardiovascular Pharmacology that administration of a 20-HETE mimetic can prevent lipopolysaccharide-induced vascular hyporeactivity, hypotension, and tachycardia in rats by activating the recently discovered GPR75/20-HETE receptor. Overall, these results provide a compelling case for initiating 20-HETE clinical trials to prevent hypotension, multiple organ failure, and death in septic shock.

National Survey on the Effect of Oncology Drug Shortages in Clinical Practice: A Hematology Oncology Pharmacy Association Survey.

Drug shortages are a clear and growing challenge. Prominent shortages included oncology medications and supportive care products essential for the care of patients with cancer. Oncology drug shortages often result in disruptions in the timing of chemotherapy treatments, alterations in the dose or regimen administered, or even missed doses when alternative agents are unavailable. The purpose of this survey was to characterize the impact of oncology drug shortages across the United States, including the experiences of health care organizations, resource implications, and the impact on patient safety, patient care, and clinical trials. A 36-item online survey was distributed to membership of the Hematology/Oncology Pharmacy Association to gather information on shortages of oncology drugs (ie, all drugs essential in the care of patients with cancer, including supportive care agents). Sixty-eight US organizations participated in the survey between December 2019 and July 2020. Sixty-three percent of institutions reported one or more drug shortages per month, with a 34% increase in 2019 from 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents. The most difficult agents to obtain were vincristine, vinblastine, intravenous immunoglobulin, leucovorin, and Bacillus Calmette-Guerin. A survey of US oncology pharmacists indicated that oncology drug shortages occurred frequently in 2020. Shortages led to delays in chemotherapy and changes in treatment or omission, complicated clinical research, and increased risk of medication errors and adverse outcomes.

An evaluation of the results of convalescent plasma therapy applied to pregnant women diagnosed as COVID-19- positive in a pandemic center: A prospective cohort study.

Convalescent plasma (CP) might be an additional treatment modality in COVID-19. The aim of this study was to compare CP-related clinical characteristics and perinatal outcomes in pregnant women with mild or moderate-severe COVID-19. This prospective cohort study included 36 pregnant women (12 mild and 24 moderate-severe), who underwent CP therapy. The CP obtained from recently recovered donors was transfused to patients together with maximum supportive care and antiviral agents. The groups were then compared in respect of clinical characteristics, laboratory parameters, obstetric complications, and neonatal outcomes. Significant differences were determined between the groups in respect of systemic corticosteroids in COVID-19 treatment (41.7%, 87.5%, p = 0.004), oxygen (O2) support (0%, 91.7%, p &lt; 0.001), chest imaging (41.7%, 58.3%, p = 0.02), intensive care unit admission (0%, 20.8%, p = 0.03) and length of hospitalization (5.5 versus 9.5 days, p &lt; 0.001). The O2 saturation levels before and after administration of CP were significantly lower in the moderate-severe COVID-19 group (p &lt; 0.05). The O2 therapy time before and after administration of CP and total O2 therapy time were significantly lower in the mild COVID-19 group (p &lt; 0.05). Platelet, plateletcrit and lymphocyte counts were significantly higher in both the mild and moderate-severe COVID-19 groups after treatment compared to the pretreatment values (p &lt; 0.05). Although data on the results of CP treatment in pregnant women are somewhat limited, it has been suggested that early CP treatment may be associated with improvements in laboratory and ventilatory parameters in pregnant women with mild and moderate-severe COVID-19. Nevertheless, there is a need for further, randomized controlled studies on this subject with the inclusion of greater numbers of patients.

National survey on the effect of oncology drug shortages in clinical practice: A Hematology Oncology Pharmacy Association (HOPA) survey.

e13609 Background: Drug shortages are a clear and growing challenge. Prominent shortages included oncology medications and supportive care products essential for the care of cancer patients. Oncology drug shortages often result in disruptions in the timing of chemotherapy treatments, alterations in the dose or regimen administered, or even missed doses when alternative agents are unavailable. The purpose of this survey was to characterize the impact of oncology drug shortages across the United States, including the experiences of health care organizations, resource implications, and the impact on patient safety, patient care, and clinical trials. Methods: A 34-item online survey was distributed to HOPA membership of the Hematology Oncology Pharmacy Association to gather information on shortages of oncology drugs (i.e., all drugs essential in the care of cancer patients, including supportive care agents. Results: Sixty-eight organizations completed the survey; almost all completed by pharmacists, and analysis completed. Sixty-three percent of institutions reported one or more drugs shortages a month, with a 34.33% increase in 2019 from 2018. Sixty four percent of responded had incurred increased costs from oncology drugs shortages, with 7% noting reimbursement issues when switched to brand name therapies due to shortages. Treatment delays, reduced doses or alternative regimens were reported by 74.63% of respondents. The most common disease states which causes a dose delay of treatment included Acute Lymphocytic Leukemia, Lymphoma and Multiple Myeloma with dose reductions noted in 36.36%, 36.36 and 15.91%. The top five oncology drugs on shortage included epirubicin, flutamide, decitabine, mechlorethamine, dactinomycin with the top 5 supportive care drugs on shortage being noted as hydrocortisone, bivalirudin, promethazine, mycophenolate sodium and scopolamine. Respondents noted medication errors related to oncology drug shortages at 4.48%, with noted errors including incorrect conversion from iv to oral etoposide and incorrect EMR drug builds. Oncology Drug shortages impacted clinical trials in 13.4% of respondents in which 54.55% of respondents noting patients not being enrolled in clinical trials. Conclusions: A survey of US oncology pharmacists and technicians indicated that oncology drug shortages occurred frequently in 2020. Shortages led to delays in chemotherapy and changes in treatment or omission, complicated clinical research and increased the risk of medication errors and adverse outcomes.

Effects of filgrastim versus pegfilgrastim on outcomes of DA-R-EPOCH for non-Hodgkin's lymphoma.

Our study aimed to compare the median and average last dose level reached with DA-R-EPOCH, which includes the chemotherapy agents etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab, in patients using filgrastim versus pegfilgrastim as febrile neutropenia primary prophylaxis. A retrospective, single-center chart review from January 1, 2014, to September 30, 2019, at The University of Kansas Health System identified patients > 18 years old who received at least four cycles of DA-R-EPOCH in an inpatient or outpatient setting for any subtype of lymphoma along with at least one dose of filgrastim or pegfilgrastim. Data was collected to compare dosing levels reached, appropriate discontinuation of daily filgrastim when ANC > 5000 cells/mm3, completion of at least twice weekly complete blood count (CBC) monitoring after chemotherapy administration, the incidence of infections, FN, hospitalizations from infections or FN, and bone pain. We hypothesized that patients receiving pegfilgrastim will achieve similar median and average dose levels of DA-EPOCH, event-free survival rates, overall response rates, completion of at least twice weekly CBC monitoring, and incidence of infections, FN, hospitalizations for infections or FN, and bone pain compared to patients receiving filgrastim. The use of pegfilgrastim as a supportive care agent resulted in similar efficacy and safety outcomes compared to filgrastim with DA-R-EPOCH in terms of dose intensity levels and incidence of infections, FN, and bone pain.

Initial in vivo testing of TPO-receptor agonist eltrombopag in osteosarcoma patient-derived xenograft models by the pediatric preclinical testing consortium

Eltrombopag is a small molecule, thrombopoietin receptor agonist approved for the treatment of patients with aplastic anemia and chronic immune thrombocytopenia. It is also a polyvalent cation chelator and inhibits leukemia cell proliferation via reduction of intracellular iron. The in vivo efficacy of eltrombopag was tested against a panel of six Pediatric Preclinical Testing Consortium osteosarcoma xenografts at doses of 5 mg/kg/day (moderate dose) and 50 mg/kg/day (high dose). Eltrombopag, at moderate doses, failed to significantly improve event-free survival (EFS) in 6/6 models. At high doses, eltrombopag significantly prolonged EFS in 2/2 models, though the effect size was small. All models tested demonstrated progressive disease. While eltrombopag did not meaningfully inhibit osteosarcoma growth, it also did not stimulate tumor growth, suggesting it may be safely investigated as a supportive care agent to enhance platelet recovery post chemotherapy.

Efficacy of Joungal in preventing febrile neutropenia induced by platinum-based doublet chemotherapy in lung cancer.

Myelosuppressive chemotherapy often results in febrile neutropenia (FN) in patients with lung cancer, resulting in infection, prolonged hospitalization, higher economic and labor costs, and increased mortality rate. Colony-stimulating factor (CSF) is used to treat FN, but it exhibits limited efficacy and is often underused. We evaluated Joungal, a traditional Chinese medicine, for treatment of neutropenic complications in patients with lung cancer who received chemotherapy. A total of 795 patients with lung cancer were treated with platinum-based chemotherapy from 2012 to 2017. Of these, 191 received Joungal during chemotherapy. Three hundred eighty-two patients were included in the control group. The primary end point was incidence of FN. The secondary end points were incidence of neutropenia, granulocyte colony-stimulating factor (G-CSF) use, hospitalization duration, and cost. There were no differences in clinicopathological characteristics such as gender, age, smoking status, stage of disease, hemoglobin, or histologic type between two groups. Joungal significantly decreased the incidence of chemotherapy-induced FN (2.1% vs. 9.4%, OR =0.21, P=0.002), grade 2/3/4 neutropenia (29.8 % vs. 55.8%, OR =0.34, P=0.000), and grade 3/4 neutropenia (13.1% vs. 23.8%, OR =0.48, P=0.013) compared with controls. Furthermore, Joungal decreased G-CSF use (0.68 vs. 1.34/patient/cycle, P=0.001), hospitalization duration (2.56 vs. 4.68 day/patient/cycle, P=0.002), and economic burden ($660 vs. $1,580/ patient/cycle, P=0.001). No drug-related toxicity was observed. Joungal safely and effectively decreased the incidence of neutropenia and FN induced by doublet platinum-based chemotherapy in patients with lung cancer, and may have potential as a supportive care agent for patients with lung cancer.

Cost savings of biosimilar pegfilgrastim in a Medicare OCM population.

e19362 Background: Pegfilgrastim is a key supportive care agent in oncology patients, providing significant febrile neutropenia prophylaxis for patients on chemotherapy. However, pegfilgrastim also accounts for 5.3% of the total cost of cancer care for all patients in the Oncology Care Model (OCM). Fluctuations in the cost or quantity of pegfilgrastim can have significant impact on a practice’s performance under OCM. One such cost fluctuation is the introduction of biosimilars to the marketplace. This study seeks to understand how CMS reimbursement for pegfilgrastim has been impacted by the introduction of two pegfilgrastim biosimilars into the market. Methods: We tracked average CMS reimbursement for pegfilgrastim (Neulasta, Udenyca and Fulphila) from 7/1/2016 through 6/30/2019. We compared the average reimbursement and the average change in reimbursement before and after the introduction of biosimilars. Results: Prior to the introduction of biosimilars, the Medicare Part B reimbursement (80% of ASP +6%) of pegfilgrastim increased at a steady rate of $292 per year through the first 30 months of the OCM program, resulting in an average reimbursement of $3636 per administration in Q3 2018. However, since the introduction of biosimilars, average pegfilgrastim reimbursement has held steady, averaging $3543 for the time period from 7/1/2018 through 6/30/2019. The change in reimbursement has decreased from $292/year to -$93/year. Conclusions: In 2018, 88,847 Medicare patients received pegfilgrastim, resulting in $1.39 billion in Medicare reimbursement. Assuming that the patterns we’ve detected in our OCM data sample can be applied to the general Medicare population, we have estimated that the introduction of biosimilars resulted in a $4.8 million in savings (1.39%) compared with what the total reimbursement would have been without biosimilars in the market in Q4 2018. This bending of the cost curve is projected to result in savings of $79.1M (5.7%) in 2019 and $157.9M (11.5%) in 2020. Importantly, most of this cost containment is not due to patients utilizing biosimilars. 90.6% of patients in Q2 2019 are still receiving branded pegfilgrastim. However, the introduction of biosimilars has caused even the branded agent to stabilize and possibly even drop net acquisition cost prices. Introduction of biosimilars has created enough pressure on the market to result in significant cost savings, increasing the overall value proposition of pegfilgrastim. This results in significant cost saving to CMS, and also makes it easier for practices participating in OCM to have successful financial outcomes.

Hyper-immune/convalescent plasma: an old option and a valid strategy for treatment of COVID-19?

Currently, there are no approved specific antiviral agents for novel coronavirus disease (COVID-19). Hyper-immune/convalescent plasma derived from recently recovered donors seems to be useful to treat COVID-19 patients, an addition to maximal supportive care and antiviral agents. The endpoints are the improvement of clinical symptoms and laboratory parameters of these patients. However, the efficacy of hyper-immune/convalescent plasma treatment for severe infectious diseases is still controversial. The optimal dose and time point, as well as the clinical benefit of hyper-immune/convalescent plasma therapy, needs further investigation in larger well-controlled trials.

Assessment of the utilization pattern of chemotherapy agents in patients with head and neck cancer in an oncology hospital

The prevalence of head and neck cancers (HNC) is increasing in developing countries, and its pharmacotherapy has become complex. Evaluation of drug utilization patterns (DUPs) of chemotherapy agents is needed to ascertain the rational use of medications in HNC. The aim was to evaluate the DUPs of chemotherapy agents in patients with HNC in an oncology unit. This prospective observational study was designed to review chemotherapy orders for patients with HNC and assess DUPs over a period of 2 years. Cancer patients aged > 18 years who were receiving chemotherapy together with supportive care medications were enrolled. A total of 208 patients met inclusion criteria and were enrolled in the study. The majority of patients were aged 45–75 years (64.4%), were male (81.3%), and used tobacco (54.9%). The most common sites of HNC were pyriform fossa (18.3%), tongue (17.8%), buccal mucosa (13.9%), and tonsils (10.6%). The majority of patients had head and neck squamous cell carcinoma (HNSCC) [93.3%] and were in stage III (32.2%) or stage IV (48.5%). Neoadjuvant chemotherapy (51%) followed by adjuvant chemotherapy (41.4%) were frequently prescribed. Chemotherapy agents prescribed in > 25% of patients included cisplatin (68.8%), paclitaxel (43.8%), and carboplatin (29.8%); supportive care drugs prescribed in > 25% of patients included dexamethasone (51%), metoclopramide (44.2%), chloramphenicol (39.4%), and pantoprazole (27.9%). Platinum analogs and taxanes were highly prescribed chemotherapy agents as they are highly effective in HNSCC. To prevent chemotherapy-induced cytotoxicity, supportive care agents, such as anti-emetics, proton pump inhibitors, anti-infective agents, and colony-stimulating factors, were used along with miscellaneous supplements.

Effectiveness of convalescent plasma therapy in severe COVID-19 patients.

Currently, there are no approved specific antiviral agents for novel coronavirus disease 2019 (COVID-19). In this study, 10 severe patients confirmed by real-time viral RNA test were enrolled prospectively. One dose of 200 mL of convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents. The primary endpoint was the safety of CP transfusion. The second endpoints were the improvement of clinical symptoms and laboratory parameters within 3 d after CP transfusion. The median time from onset of illness to CP transfusion was 16.5 d. After CP transfusion, the level of neutralizing antibody increased rapidly up to 1:640 in five cases, while that of the other four cases maintained at a high level (1:640). The clinical symptoms were significantly improved along with increase of oxyhemoglobin saturation within 3 d. Several parameters tended to improve as compared to pretransfusion, including increased lymphocyte counts (0.65 × 109/L vs. 0.76 × 109/L) and decreased C-reactive protein (55.98 mg/L vs. 18.13 mg/L). Radiological examinations showed varying degrees of absorption of lung lesions within 7 d. The viral load was undetectable after transfusion in seven patients who had previous viremia. No severe adverse effects were observed. This study showed CP therapy was well tolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases. The optimal dose and time point, as well as the clinical benefit of CP therapy, needs further investigation in larger well-controlled trials.

Drug-Drug Interactions of 257 Antineoplastic and Supportive Care Agents With 7 Anticoagulants: A Comprehensive Review of Interactions and Mechanisms.

Data on drug–drug interactions (DDI) of antineoplastic drugs with anticoagulants is scarce. We aim to evaluate factors associated with DDI of antineoplastic and supportive care drugs with anticoagulants resulting in modification of pharmacokinetics of these last mentioned. A literature review on DDI databases and summaries of products characteristics (SmPC) was done. Drug–drug interactions of 257 antineoplastic and supportive care drugs with direct oral anticoagulants (DOACs), warfarin, enoxaparin, or fondaparinux were categorized as no clinically significant expected DDI, potentially weak DDI, potentially clinically significant DDI, and recommendation against coadministration. Logistic regression models were performed to analyze the association between the dependent variable potentially clinically significant interaction/recommendation against coadministration and the mechanisms of DDI. Of the 1799 associations, 84.4% were absence of DDI, 3.6% potentially weak DDI, 10.2% potentially clinically relevant DDI, and 2.0% recommendation against coadministration. Warfarin has higher DDI potential than other anticoagulants. Enoxaparin and fondaparinux have fewer DDI than others. There was no difference between DOACs. Drug–drug interactions with apixaban and rivaroxaban was independently associated with the absence of CYP3A4 competition, P-glycoprotein inhibition, CYP3A4 induction, and drug class of tyrosine kinase inhibitors. Drug–drug interactions with dabigatran and edoxaban was associated with inhibition of P-glycoprotein and tyrosine kinase inhibitors. Warfarin, induction of CYP3A4, and inhibition of CYP2C9. Enoxaparin and fondaparinux, only tyrosine kinase inhibitors. Direct oral anticoagulants did not differ regarding DDI with antineoplastic agents. Warfarin presented more DDI than other anticoagulants. P-glycoprotein inhibition and CYP3A4 induction were independently associated with DDI of antineoplastic agents with DOACs.

1620 Pneumatosis Intestinalis Associated With Clostridium difficile Colitis in Crohn’s Disease

INTRODUCTION: Pneumatosis intestinalis (PI) or pneumatosis cystoides intestinalis is defined as the presence of extraluminal bowel gas that is confined within the bowel wall. Characterized by intramural gas in the gastrointestinal tract, PI represents an alarming radiographic sign rather than a specific diagnosis. PI is associated with a wide spectrum of underlying pathological processes such as bowel ischemia, mechanical trauma, inflammatory/autoimmune bowel disease, intestinal neoplasms, bacterial infections like C. Diff, drug-induced including immunosuppression therapy. Differentiating these causes is critical in directing an appropriate care plan and specific treatment is best directed at the underlying disease process. Described here is a case of pneumatosis intestinalis associated with Clostridium Difficile infection in the setting of Inflammatory Bowel Disease (IBD). CASE DESCRIPTION/METHODS: 11-year-old white male with Crohn's Disease on remission on Remicade and Methotrexate, presented with severe periumbilical pain radiating to right lower quadrant associated with fever, multiple episodes of loose stools and vomiting. Denied recent travel, sick contacts or recent exposure to antibiotics. On exam he had significant right lower quadrant abdominal tenderness with no guarding or rebound. Lab data only revealed mild elevation of CRP. US abdomen showed poorly visualized appendix. Subsequent CT abdomen revealed pneumatosis of ascending colon without wall thickening. Following, he was admitted and considering his stable clinical conditions and lab assays, he was treated conservatively with IV antibiotics and bowel rest. A day later, stool studies returned positive for C. Diff toxins. He was started on oral Vancomycin. Serial abdominal X-rays revealed disappearance of PI. Patient began to show clinical improvement, tolerating feeding advances gradually over the next four days. DISCUSSION: IBD is a rare cause of PI. Concurrently, patients with IBD are at increased risk of developing C. Difficile infection. C. Diff infections have a different and often more severe clinical course in patients with IBD. PI patients should be carefully evaluated for possible surgery due to the risk of severe complications. However, management decisions should be made on combined clinical, lab findings and underlying etiology. As in the above case, supportive care and appropriate antibacterial agents sufficed to alleviate symptoms and resolve the pneumatosis.

Evaluation of the TPO-receptor agonist Eltrombopag in the Pediatric Preclinical Testing Consortium osteosarcoma in vivo models.

e22502 Background: Eltrombopag (EP) is a small molecule, thrombopoietin receptor (TPO-R) agonist indicated for the treatment of patients with chronic immune thrombocytopenia and severe aplastic anemia. EP is a polyvalent cation chelator and inhibits leukemia cell proliferation via depletion of intracellular iron. Recent studies show EP inhibits the proliferation of osteosarcoma cells lines via depletion of polyvalent cations. The in vivo effects of EP were studied in osteosarcoma patient derived xenograft models by the Pediatric Preclinical Testing Consortium (PPTC). Methods: The in vivo anticancer effects of EP were assessed in a panel of six osteosarcoma PPTC PDX models with limited MPL mRNA expression (OS2, OS9, OS31, OS33, OS36, OS60). EP was administered at an oral dose of 5 mg/kg/day given for 5 days each week with planned treatment period of 4 weeks. High dose EP (50mg/kg/day) was also tested in 2 PDX models (OS2, OS9) on the same schedule. A control cohort that received vehicle was included for each PDX model. Tumor volumes were measured and responses defined utilizing the PPTC statistical analyses. Results: EP at 5 mg/kg failed to inhibit tumor growth or induce significant differences in event-free survival (EFS) in any of the 6 osteosarcoma PDX models. At the higher dose of 50 mg/kg a significant prolongation in time to event in the EP-treated group was observed, but the effect was small with the ratio of the median time to event for treated versus control animals (EFS T/C) being only 1.2 in the 2 OS PDX models tested. No objective responses were observed with EP at either dose, with all models demonstrating progressive disease. Conclusions: EP did not exhibit significant antitumor activity against the PPTC osteosarcoma PDX panel. However, EP also did not enhance tumor growth. EP’s lack of anti-tumor activity against the OS PDX models suggests leukemia and osteosarcoma cells likely have different dependencies on intracellular polyvalent cations. Given EPs effect on stimulating platelet production, and the demonstration that EP does not stimulate in vivo growth of osteosarcoma, EP may be considered in patients with osteosarcoma as a supportive care agent in supporting platelet recovery.