Real-world drug utilization and treatment patterns in patients with tenosynovial giant cell tumors in the USA.

Aim: Real-world treatment patterns in tenosynovial giant cell tumor (TGCT) patients remain unknown. Pexidartinib is the only US FDA-approved treatment for TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Objective: To characterize drug utilization and treatment patterns in TGCT patients. Methods: In a retrospective observational study using IQVIA's linked prescription and medical claims databases (2018-2021), TGCT patients were stratified by their earliest systemic therapy claim (pexidartinib [N = 82] or non-FDA-approved systemic therapy [N = 263]). Results: TGCT patients treated with pexidartinib versus non-FDA-approved systemic therapies were predominantly female (61 vs 50.6%) and their median age was 47 and 54 years, respectively. Pexidartinib-treated patients had the highest 12-month probability of remaining on treatment (54%); 34.1% of pexidartinib users had dose reduction after their first claim. Conclusion: This study provides new insights into the unmet need, utilization and treatment patterns of systemic therapies for the treatment of TGCT patients.

This database study is the first investigation of how drugs are used to treat patients with tenosynovial giant cell tumor (TGCT) in the real world. We researched adult TGCT patients from IQVIA's prescription and medical claims databases who started treatment with pexidartinib (N = 82) or other non-US FDA-approved systemic therapies (N = 263). The patients included in this analysis were mostly women (61.0 and 50.6%) and their median age was 47 and 54 years for pexidartinib and other non-FDA-approved systemic therapies, respectively. The patients treated with pexidartinib were most likely to remain on treatment (54.0%) at the end of the first year. Most patients (79.3%) started pexidartinib treatment at a total daily dose of 800 mg/day, as per the product label. Only 34.1% of patients had reduced medication dose during follow-up. Of note, this study found that TGCT patients were treated with other systemic therapies which remain unproven to be safe and effective in medical studies of TGCT. Given the unmet need, and with pexidartinib being the only approved systemic treatment in USA, there is an opportunity for the larger population of adult TGCT patients to benefit from its use. Further research is needed to identify barriers for access to pexidartinib and treatment of TGCT patients.

Real-world treatment patterns, healthcare resource utilization and costs among patients with peripheral T-cell lymphoma.

Objective: To evaluate treatment patterns, healthcare resource utilization (HRU) and costs among peripheral T-cell lymphoma (PTCL) patients in the USA. Methods: A retrospective cohort study, using the IQVIA PharMetrics® Plus claims database from 1 April 2011 to 30 November 2021, identified PTCL patients receiving systemic treatments. Three mutually exclusive subcohorts were created based on line of therapy (LOT): 1LOT, 2LOT and ≥3LOT. Common treatment regimens, median time on treatment, all-cause and PTCL-related HRU and costs were estimated. Results: Among 189 PTCL patients identified, 61.9% had 1LOT, 21.7% had 2LOT and 16.4% had ≥3LOT. The most common treatment regimens in the 1LOT were CHOP/CHOP-like, CHOEP/CHOEP-like and brentuximab vedotin; monotherapies were most common in the 2LOT and ≥3LOT. All-cause and PTCL-related hospitalizations and prescriptions PPPM increased with increasing LOT. Nearly 70% of total treatment costs were PTCL related. Conclusion: Higher utilization of combination therapies in the 1LOT and monotherapies in subsequent LOTs were observed, alongside high PTCL-related costs.

Peripheral T-cell lymphomas (PTCL) are a rare and fast-growing form of blood cancer. About 8000­12,000 people in the USA are diagnosed with PTCL every year. As it is a rare disease and has many types, and there is a limited understanding of the patients who have PTCL and the treatments they receive in the real world. The purpose of this study was to evaluate how these patients are treated, what are they treated with and what are the costs of these treatments in the USA. The data collected on these patients was divided into three groups based upon the number of lines of treatment/therapy (LOT) they received: 1LOT, 2LOT and ≥3LOT. This study researched different treatments and their duration in each line of therapy. Among 189 PTCL patients included in the study, the average age of patients was 55 years and 62% were male. Among these patients, 62% had 1LOT, 22% had 2LOT and 16% had ≥3LOT. The most common treatments in the 1LOT were traditional chemotherapy regimens followed by targeted therapies: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-like, CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone) or CHOEP-like, and brentuximab vedotin. Treatment regimens with only one drug were most common in the 2LOT and ≥3LOT. The total cost of PTCL treatment in the USA is very high; 70% of this cost is related to their treatment with various drugs. More research is needed to better understand the treatment and cost of this rare cancer.

Discrepancies in ICD-9/ICD-10-based codes used to identify three common diseases in cancer patients in real-world settings and their implications for disease classification in breast cancer patients and patients without cancer: a literature review and descriptive study.

Background: International Classification of Diseases, Ninth/Tenth revisions, clinical modification (ICD-9-CM, ICD-10-CM) are frequently used in the U.S. by health insurers and disease registries, and are often recorded in electronic medical records. Due to their widespread use, ICD-based codes are a valuable source of data for epidemiology studies, but there are challenges related to their accuracy and reliability. This study aims to 1) identify ICD-9/ICD-10-based codes reported in literature/web sources to identify three common diseases in elderly patients with cancer (anemia, hypertension, arthritis), 2) compare codes identified in the literature/web search to SEER-Medicare's 27 CCW Chronic Conditions Algorithm ("gold-standard") to determine their discordance, and 3) determine sensitivity of the literature/web search codes compared to the gold standard. Methods: A literature search was performed (Embase, Medline) to find sources reporting ICD codes for at least one disease of interest. Articles were screened in two levels (title/abstract; full text). Analysis was performed in SAS Version 9.4. Results: Of 106 references identified, 29 were included that reported 884 codes (155 anemia, 80 hypertension, 649 arthritis). Overall discordance between the gold standard and literature/web search code list was 32.9% (22.2% for ICD-9; 35.7% for ICD-10). The gold standard contained codes not found in literature/web sources, including codes for hypertensive retinopathy/encephalopathy, Page Kidney, spondylosis/spondylitis, juvenile arthritis, thalassemia, sickle cell disorder, autoimmune anemias, and erythroblastopenia. Among a cohort of non-cancer patients (N=684,376), the gold standard identified an additional 129 patients with anemia, 33,683 with arthritis, and 510 with hypertension compared to the literature/web search. Among a cohort of breast cancer patients (N=303,103), the gold standard identified an additional 59 patients with anemia, 10,993 with arthritis, and 163 with hypertension. Sensitivity of the literature/web search code list was 91.38-99.96% for non-cancer patients, and 93.01-99.96% for breast cancer patients. Conclusion: Discrepancies in codes used to identify three common diseases resulted in variable differences in disease classification. In all cases, the gold standard captured patients missed using the literature/web search codes. Researchers should use standardized, validated coding algorithms when available to increase consistency in research and reduce risk of misclassification, which can significantly alter the findings of a study.

Elderly patients with acute myeloid leukemia who only receive supportive care in the Surveillance, Epidemiology and End Results-Medicare database: demographics, treatment patterns and outcomes.

Aim: Elderly acute myeloid leukemia (AML) patients are often not treated with antileukemic therapy due to their poor overall health condition, leaving supportive care as the sole treatment option. Objective: To evaluate patient characteristics, treatment patterns and outcomes of elderly patients with AML who are treated with supportive care only. Methods: A retrospective analysis of elderly AML patients included in the Surveillance, Epidemiology and End Results-Medicare database from 2008 to 2015. Results: Of elderly patients with AML (n = 7665), 3209 (41.9%) received supportive care only. Their mean age was 79 years, 50.5% were males; 48.2% died during the first 3 months and 67.3% died during the first 6 months. 82.2% died within the first year; only 13.2% survived >12 months. 77.9% patients died due to leukemia. Conclusion: In elderly AML patients treated with supportive care only, older age, concurrent hypertension, chronic obstructive pulmonary disease, chronic kidney disease and acute myocardial infarction were identified as prognostic factors associated with decreased likelihood of survival. Ideally, these patients should be treated with antileukemic therapy in addition to supportive care, as most of them die from disease progression.

This study analyzed data on elderly patients with acute myeloid leukemia (AML) who were only treated with supportive care. The source of this data was the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Of the 7665 patients diagnosed with AML during 2008­2015, 3209 (41.9%) received supportive care only. Their mean age at index date was 79 years; slightly more than half of these were males (50.5%). Almost half of these patients (48.2%) died within the first 3 months and approximately two-thirds (67.3%) died within the first 6 months. Only a small proportion (13%) of these patients were alive after 1 year. These patients who were alive after one were likely to be in remission (there was decrease in the signs and symptoms of AML). The results of this study showed that elderly AML patients who only received supportive care were more likely to die early if they also had chronic kidney disease, chronic obstructive pulmonary disease, history of acute myocardial infarction or hypertension. As elderly AML patients may be in poor general health and have other diseases (comorbidities), this could be the reason why they may not be treated with antileukemic therapy. Instead of treatment with supportive care only, these patients should ideally receive antileukemic therapy in addition to supportive care. More research should be done to find alternate treatments for these elderly AML patients.

Characteristics and outcomes of elderly patients with acute myeloid leukemia who receive no treatment in the Surveillance, Epidemiology and End Results-Medicare database.

Background: Without treatment, acute myeloid leukemia (AML) is rapidly fatal. Nevertheless, a large proportion of elderly AML patients do not receive any treatment. Aim: To characterize the demographics, comorbidities, survival and prognostic factors of elderly AML patients who do not receive any AML treatment or supportive care (SC). Methods: A retrospective cohort analysis of the Surveillance, Epidemiology and End Results-Medicare database (2008-2015). Results: Of 7665 AML patients, 2373 (31%) did not receive any AML treatment or SC. The mean age was 80.4 years, 52.8% were males and 79.7% and 95.3% died within the first 60 and 180 days, respectively; 2.1% survived >12 months and only 5.5% of patients had remission or relapse codes populated. Conclusion: Older age, male gender, concurrent depression, ischemic heart disease, chronic kidney disease and benign prostatic hyperplasia were associated with a decreased likelihood of survival. Multiple factors contribute to the complex clinical status of these patients preventing intensive chemotherapy; they should still ideally be treated, at least with the best SC.

An analysis of the data collected in the Surveillance, Epidemiology and End Results-Medicare database from 2008 to 2015 was performed. This database includes data collected by a national cancer registry on people diagnosed with cancer in the United States and those who enroll in Medicare. This study focused on acute myeloid leukemia (AML) patients who did not receive any AML treatment or supportive care (SC). Of 7665 patients with AML, 2373 (31%) did not receive any AML treatment or SC. At the time the data was indexed for each patient in the database, their mean age was 80.4 years and around 53% were males. Within the first 60 days, around 80% of these patients died; over 95% died within the first 180 days. Only 2% of patients survived more than a year without treatment; these patients were likely in remission. Without treatment, AML patients who were older, were male or who also had depression, ischemic heart disease, chronic kidney disease or benign prostatic hyperplasia had a higher chance of dying early. There could be many reasons why these patients are not treated. The main reasons are their poor health condition and the presence of two or more health conditions in a patient at the same time (comorbidities). However, they should still ideally be treated, at least with the best SC. Additional treatment options are urgently needed for elderly AML patients who have comorbidities and are in poor general health.

Health-related quality of life in women with breast cancer: a review of measures.

BACKGROUND: To identify and describe the breast cancer-specific health-related quality of life (HRQoL) instruments with evidence of validation in the breast cancer population for potential use in patients treated for breast cancer (excluding surgery). METHODS: We conducted a systematic literature review using PubMed, Embase, and PsycINFO databases to identify articles that contain psychometric properties of HRQoL instruments used in patients with breast cancer. Relevant literature from January 1, 2009, to August 19, 2019, was searched. Articles published in English that reported psychometric properties (reliability, validity) of HRQoL instruments were identified. RESULTS: The database search yielded 613 unique records; 131 full-text articles were reviewed; 80 articles presented psychometric data for instruments used in breast cancer (including generic measures). This article reviews the 33 full articles describing psychometric properties of breast cancer-specific HRQoL instruments: EORTC QLQ-C30, EORTC QLQ-BR23, FACT-B, FBSI, NFBSI-16, YW-BCI36, BCSS, QuEST-Br, QLICP-BR, INA-BCHRQoL, and two newly developed unnamed measures, one by Deshpande and colleagues (for use in India) and one by Vanlemmens and colleagues (for use among young women and their partners). The articles that described the EORTC QLQ-C30, QLQ-BR23, and FACT-B centered on validating translations, providing additional support for content validity, and demonstrating acceptability of electronic patient-reported outcome administration. Psychometric properties of the measures were acceptable. Several new measures have been developed in Asia with an emphasis on development on cultural relevance/sensitivity. Others focused on specific populations (i.e., young women with breast cancer). CONCLUSIONS: Historically, there have been limited options for validated measures to assess HRQoL of patients with breast cancer. A number of new measures have been developed and validated, offering promising options for assessing HRQoL in this patient population. This review supports the reliability and validity of the EORTC QLQ-C30 and FACT-B; new translations and electronic versions of these measures further support their use for this population.

Prognostic factors of brain metastasis and survival among HER2-positive metastatic breast cancer patients: a systematic literature review.

BACKGROUND: Patients with breast cancer who overexpress the human epidermal growth factor receptor 2 (HER2) and subsequently develop brain metastasis (BM) typically experience poor quality of life and low survival. We conducted a comprehensive literature review to identify prognostic factors for BM and predictors of survival after developing BM, and the effects of therapies with different mechanisms of action among patients with HER2+ breast cancer (BC). METHODS: A prespecified search strategy was used to identify research studies investigating BM in patients with HER2+ BC published in English during January 1, 2009-to June 25, 2021. Articles were screened using a two-phase process, and data from selected articles were extracted. RESULTS: We identified 25 published articles including 4097 patients with HER2+ BC and BM. Prognostic factors associated with shorter time to BM diagnosis after initial BC diagnosis included younger age, hormone receptor negative status, larger tumor size or higher tumor grade, and lack of treatment with anti-HER2 therapy. Factors predictive of longer survival after BM included having fewer brain lesions (< 3 or a single lesion) and receipt of any treatment after BM, including radiosurgery, neurosurgery and/or systemic therapy. Patients receiving combination trastuzumab and lapatinib therapy or trastuzumab and pertuzumab therapy had the longest median survival compared with other therapies assessed in this review. CONCLUSIONS: More research is needed to better understand risk factors for BM and survival after BM in the context of HER2+ BC, as well as the assessment of new anti-HER2 therapy regimens that may provide additional therapeutic options for BM in these patients.

Use of comorbidity indices in patients with any cancer, breast cancer, and human epidermal growth factor receptor-2-positive breast cancer: A systematic review.

OBJECTIVE: To identify comorbidity indices that have been validated in cancer populations, with a focus on breast cancer and human epidermal growth factor receptor-2-positive (HER2+) breast cancer. STUDY DESIGN AND SETTING: A systematic review of the literature on the use of comorbidity indices in any cancer, breast cancer, and HER2+ breast cancer using Ovid and PubMed. RESULTS: The final data set comprised 252 articles (252 any cancer, 39 breast cancer, 7 HER2+ breast cancer). The most common cancers assessed were hematologic and breast, and the most common comorbidity index used was the Charlson Comorbidity Index (CCI) or a CCI derivative. Most validity testing of comorbidity indices used predictive validity based on survival outcomes. Hazard ratios for survival outcomes generally found that a higher comorbidity burden (measured by CCI) increased mortality risk in patients with breast cancer. All breast-cancer studies that validated comorbidity indices used CCI-based indices. Only one article validated a comorbidity index in HER2+ breast cancer. CONCLUSION: CCI-based indices are the most appropriate indices to use in the general breast-cancer population. There is insufficient validation of any comorbidity index in HER2+ breast cancer to provide a recommendation, indicating a future need to validate these instruments in this population.

Evaluation of patient/caregiver and healthcare provider knowledge, attitudes and behavior for safety and use of pexidartinib.

Aim: Pexidartinib was approved for the treatment of tenosynovial giant cell tumors with a required Risk Evaluation and Mitigation Strategy (REMS) to ensure its safe use. As required by the REMS, a survey was conducted to document the knowledge, attitudes and behavior (KAB) of patients/caregivers and healthcare providers (HCPs) regarding the risk of serious and potentially fatal liver injury due to pexidartinib, the need for liver testing prior to and during treatment and the need for patient counseling about this risk. Patients & methods: The KAB survey was conducted among 40 patients and 18 HCPs enrolled in the pexidartinib REMS. Results: Among patients, 87.5% demonstrated understanding of key risk message (KRM) 1 (risk of serious liver injury), 87.5% demonstrated understanding of KRM2 (liver testing requirement) and 77.5% demonstrated understanding of both KRMs. Among HCPs, 83.3% demonstrated understanding of KRM1, 88.9% demonstrated understanding of KRM2, 100% demonstrated understanding of KRM3 (patient counseling) and 83.3% demonstrated understanding of all three KRMs. Conclusion: The KAB surveys demonstrated that the educational goals of the pexidartinib REMS were being achieved.

Lay abstract Pexidartinib is a prescription medicine used to treat adults who have a tenosynovial giant cell tumor that is not likely to improve with surgery. Because of the risk of serious liver problems, pexidartinib is available only through a restricted program called a Risk Evaluation and Mitigation Strategy (REMS) that enrolls both patients and healthcare providers (HCPs). As part of the REMS, information is collected about their knowledge, attitudes and behavior (KAB) regarding the potential for pexidartinib to cause liver problems that may be severe and can lead to death. This KAB survey was conducted among 40 patients and 18 HCPs enrolled in the pexidartinib REMS. The results indicated that among patients, over three-quarters demonstrated understanding of the risk of serious liver injury and the need for regular liver testing. Among HCPs, 83.3­100% demonstrated understanding of the risk of serious liver injury, the need for regular liver testing and the requirement to counsel their patients about this risk. In conclusion, the KAB surveys demonstrated that the educational goals of the pexidartinib REMS were being achieved.

A qualitative evaluation of patient and healthcare provider knowledge, attitudes, and behavior for safety and use of pexidartinib.

Aim: Pexidartinib is approved in the USA for the treatment of symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Due to risk of serious liver injury, a survey of patient and healthcare provider (HCP) knowledge, attitudes, and behavior (KAB) of the risks was required. Materials & methods: Prior to KAB survey execution, structured telephone interviews with 12 patients and 12 HCPs were conducted. Results: The interviews revealed that patients had difficulty with the complexity and wordiness of some of the questions, while HCPs noted that some questions were repetitive with terminology that was not self-explanatory. Of the 15 questions initially in the patient survey, nine were modified for survey inclusion. For the HCP survey, 10 of 18 questions were modified. Conclusion: Qualitative research prior to KAB surveys is recommended to improve comprehension and data quality.

Validated Instruments of Quality of Life (QOL) in Patients With Acute Myeloid Leukemia (AML) and Other Cancers.

INTRODUCTION: Acute myeloid leukemia (AML) can negatively impact quality of life (QOL). Few QOL instruments are specific to and have been validated in AML. This review aims to identify QOL instruments that have been validated in patients with AML and other cancers and summarize their psychometric properties reported in published literature. A literature review search was performed using PubMed and OVID (Biosis, Embase, MEDLINE) databases through June 25, 2020. Search terms included: QOL, health-related QOL, patient-reported outcomes and validity, reliability, validated, tools, instruments, test-retest, and leukemia myeloid acute, leukemia, myeloid, acute, acute myeloid leukemia. Articles were included if they focused on cancer and reported psychometric properties that could be extracted. Abstracts and their references were reviewed for inclusion. RESULTS: Twelve evaluating ten instruments were included. Functional Assessment of Cancer Therapy Leukemia (FACT-Leu) showed internal consistency (IC) of α = 0.86 to >0.9, correlation with EQ-5D-3L of r > 0.50, correlation with European Organisation for Research and Treatment of Cancer (EORTC) QLQ-Leu of ρ = 0.29-0.63, test-retest reliability of κ = 0.861. FACT-F showed correlations with EORTC QLQ-C30 of r = 0.40-0.83. Hematological Malignancy Patient-Reported Outcome (HM-PRO) showed intraclass correlation coefficient (ICC) of 0.94-0.98. EORTC-8D and EQ-5D-3L showed ICC = 0.595, correlations with each other of ρ = 0.137-0.634 and with EORTC QLQ-C30 of r = 0.651-0.917. EORTC QLQ-C30 showed person separation reliability of 0.47 to 0.90 and patient-observer agreement of 0.85. Life Ingredient Profile (LIP) showed IC of α = 0.29-0.77 and test-retest reliability of κ = 0.42-1.0. QOL-E showed correlation with FACT-general of R = 0.71, internal validity of α = 0.7, and test-retest reliability of standardized Cronbach's α = 0.7-0.92. EORTC QLQ-Leu showed IC of α = 0.6-0.79. The Acute Myeloid Leukemia-Quality of Life (AML-QOL) instrument showed IC of α = 0.72, correlations with EORTC QLQ-30 of magnitudes ρ = 0.59-0.72, and test-retest reliability of ICC = 0.52-0.91. CONCLUSION: Although several QOL instruments have been validated, more research is needed to determine the most clinically useful instruments in patients with AML.

Review of Survival, Safety, and Clinical Outcomes in HER2+ Metastatic Gastric Cancer Following the Administration of Trastuzumab.

BACKGROUND: Therapies targeting human epidermal growth factor receptor 2 (HER2) have become a focus for improving treatment outcomes in patients with gastric cancer. This literature review sought to assesses clinical outcomes, including safety, survival, and treatment outcomes, of patients who received trastuzumab for the treatment of HER2+ metastatic gastric cancer. METHODS: Searches were conducted in PubMed and Embase to identify observational research studies investigating the clinical outcomes of trastuzumab and combination therapies for the treatment of HER2+ metastatic gastric cancer, published January 1, 2014-August 22, 2019. Article screening was a two-phase process, and the results of each screening level were documented in accordance with PRISMA. RESULTS: Twenty articles met the selection criteria for data extraction. Studies focused on treatment patterns or survival, safety, and clinical outcomes, as well as the natural history of disease. In the combined HER2+ patient populations included in this review, tumors were located in the stomach (33.7%), gastroesophageal junction (GEJ, 14.2%), unspecific GEJ or stomach (50.3%), or esophagus (1.9%). Studies observed increases in both overall survival and progression-free survival with the use of trastuzumab-based chemotherapy compared with chemotherapy treatment alone. Additionally, trastuzumab-based chemotherapy appeared to improve survival and clinical outcomes regardless of the presence of multi-organ metastases or tumor location. CONCLUSIONS: Trastuzumab-treated patients have longer survival times than those not treated with trastuzumab and tolerate treatment well, with few serious adverse events. New treatments for second- and subsequent-line therapies would increase regimen options. MINI-ABSTRACT: The treatment patterns and clinical outcomes observed in this literature review suggest patients treated with trastuzumab have longer survival times compared with chemotherapy treatment alone and tolerate treatment.

Achievement of red blood cell transfusion independence in red blood cell transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes correlates with serum erythropoietin levels.

In the randomized, phase 3, MDS-005 study (NCT01029262), lenalidomide-induced red blood cell transfusion independence (RBC-TI) in 27% of transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes (MDS) ineligible for or refractory to erythropoiesis-stimulating agents. To determine the influence of erythropoietin (EPO) level on response, 155 patients treated with lenalidomide in MDS-005 were categorized into four groups by baseline EPO level. The EPO >500 mU/mL group had higher RBC transfusion burden and the lowest proportion of patients with ring sideroblasts ≥15% versus lower EPO groups. Achievement of RBC-TI ≥8 weeks inversely correlated with EPO level, ranging from 42.5 to 15.5%. EPO level did not affect erythroid hematologic improvement response (36.2-44.4%). This analysis suggests patients with lower EPO levels experience the strongest benefit from lenalidomide. Although meaningful improvements were observed in some patients with EPO level >500 mU/mL, new treatments are needed for this population.

Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care.

Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m2/day x7 days (n = 240) or conventional care regimens (CCR; n = 245): intensive chemotherapy, low-dose cytarabine, or best supportive care only. Overall survival (OS) was assessed for patients with common (occurring in ≥10% of patients) cytogenetic abnormalities and karyotypes, and for patients with recurring gene mutations. There was a significant OS improvement with azacitidine vs CCR for patients with European LeukemiaNet-defined Adverse karyotype (HR 0.71 [95%CI 0.51-0.99]; P = 0.046). Azacitidine-treated patients with -5/5q-, -7/7q-, or 17p abnormalities, or with monosomal or complex karyotypes, had a 31-46% reduced risk of death vs CCR. The most frequent gene mutations were DNMT3A (27%), TET2 (25%), IDH2 (23% [R140, 15%; R172, 8%]), and TP53 (21%). Compared with wild-type, OS was significantly reduced among CCR-treated patients with TP53 or NRAS mutations and azacitidine-treated patients with FLT3 or TET2 mutations. Azacitidine may be a preferred treatment for older patients with AML with Adverse-risk cytogenetics, particularly those with chromosome 5, 7, and/or 17 abnormalities and complex or monosomal karyotypes. The influence of gene mutations in azacitidine-treated patients warrants further study.

Azacitidine in Lower-Risk Myelodysplastic Syndromes: A Meta-Analysis of Data from Prospective Studies.

BACKGROUND: After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients with lower-risk myelodysplastic syndromes (LR-MDS). Optimal choice of these agents as front-line therapy in non-del(5q) LR-MDS is unclear. Because azacitidine clinical data mainly describe experience in higher-risk MDS, we performed a meta-analysis of patient-level data to evaluate azacitidine in patients with red blood cell (RBC) transfusion-dependent LR-MDS. MATERIALS AND METHODS: We searched English-language articles for prospective phase II and III azacitidine clinical trials and patient registries published between 2000 and 2015, and Embase abstracts from 2015 conferences. Patient-level data from identified relevant studies were provided by investigators. Meta-analyses followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Efficacy endpoints were RBC transfusion independence (TI) and Clinical Benefit (RBC-TI, erythroid response, and complete or partial remission, per International Working Group 2006 criteria for MDS). RESULTS: Data for 233 patients from 6 clinical studies and 1 registry study met criteria for inclusion in analyses. Overall, 90.3% of patients had non-del(5q) LR-MDS. Pooled estimates from random-effects models of RBC-TI and Clinical Benefit were 38.9% and 81.1%, respectively; for the ESA-refractory subgroup, they were 40.5% and 77.3%; and for patients with isolated anemia, they were 41.9% and 82.5%. In multivariate analyses, planned use of ≥6 azacitidine treatment cycles was significantly predictive of response. CONCLUSION: Azacitidine effects in these patients, most with non-del(5q) LR-MDS, were promising and generally similar to those reported for lenalidomide in similar patients. The choice of initial therapy is important because most patients eventually stop responding to front-line therapy and alternatives are limited. IMPLICATIONS FOR PRACTICE: Lower-risk myelodysplastic syndromes (LR-MDS) are primarily characterized by anemia. After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients. This meta-analysis of 233 azacitidine-treated red blood cell (RBC) transfusion-dependent patients with LR-MDS (92.3% non-del[5q]) from 7 studies showed 38.9% became RBC transfusion-independent. There is no clear guidance regarding the optimal choice of lenalidomide or hypomethylating agents for patients with non-del(5q) LR-MDS following ESA failure. Clinical presentation (e.g., number of cytopenias) and potential outcomes after hypomethylating agent failure are factors to consider when making initial treatment decisions for LR-MDS patients.

Assessment of the Cardiovascular Risk of Olmesartan Medoxomil-Based Treatment: Meta-Analysis of Individual Patient Data.

INTRODUCTION: Results from two long-term studies (ROADMAP and ORIENT) indicated a numerical imbalance in the number of cardiovascular deaths between the olmesartan medoxomil (OM) and placebo groups. OBJECTIVE: Our objective was to conduct an individual patient data meta-analysis to provide more complete information regarding OM-associated cardiovascular risks and/or benefits. METHODS: We created an integrated database based on 191 clinical trials from the OM development program. Events were identified and adjudicated by an independent, blinded clinical events committee. The incidence of major cardiovascular events and total mortality for OM versus placebo/active control were evaluated, and the effect of OM on cardiovascular mortality (main endpoint of interest) and morbidity was calculated using a two-stage approach (Tian method). RESULTS: A total of 46 studies (~27,000 patients) met the US FDA-specified inclusion criteria (phase II-IV randomized, double-blind, placebo- or active-controlled studies [OM-based monotherapy or combination, double-blind period ≥28 days] and adult patients). The incidence of known adjudicated endpoints in the analysis of all studies combined was low among OM (0.11-0.53 %) and placebo/active control (0.08-0.76 %) groups. For cardiovascular mortality, the estimated risk difference (OM vs. control) was 0.00070 (95 % confidence interval [CI] -0.0011 to 0.0024; p = 0.60); the risk difference for each endpoint was <1/1000, with no statistically significant difference between groups. Results were similar with and without ROADMAP and ORIENT. DISCUSSION: The results from this meta-analysis did not show a clinically meaningful or statistically significant difference in cardiovascular risk between OM and the placebo/active control groups, and thus did not corroborate the numerical imbalance observed in ROADMAP and ORIENT.

CHADS2 and CHA2DS2-VASc risk factors to predict first cardiovascular hospitalization among atrial fibrillation/atrial flutter patients.

Limited data exist concerning risk factors for cardiovascular (CV) hospitalization in patients with atrial fibrillation (AF) or atrial flutter (AFL). The aim of this retrospective cohort evaluation was to assess whether patient characteristics and risk factors, including CHADS(2) (congestive heart failure, hypertension, age ≥75 years, type 2 diabetes, and previous stroke or transient ischemic attack [doubled]) and CHA(2)DS(2)-VASc (congestive heart failure; hypertension; age ≥75 years [doubled]; type 2 diabetes; previous stroke, transient ischemic attack, or thromboembolism [doubled]; vascular disease; age 65 to 75 years; and sex category) scores, identified patients with AF or AFL at risk for CV hospitalization. Claims data (January 2003 to June 2009) were evaluated to identify patients aged ≥40 years with ≥1 inpatient or ≥2 (within 30 days of each other) outpatient diagnoses of AF or AFL and an absence of diagnosis codes related to cardiac surgery within 30 days of AF or AFL diagnosis. Risk factors for first CV hospitalization in the 2-year period after diagnosis were assessed using univariate and multivariate analyses. Overall, 377,808 patients (mean age 73.9 ± 12.1 years) were identified, of whom 128,048 had CV hospitalizations. CHADS(2) and CHA(2)DS(2)-VASc scores were the top 2 predictors of first CV hospitalization after AF or AFL diagnosis. Hospitalization risk was increased 2.3- to 2.7-fold in patients with CHADS(2) scores of 6 and approximately 3.0-fold in patients with CHA(2)DS(2)-VASc scores of 9 compared to patients with a score of 0. These increases were maintained essentially unchanged throughout the 2-year follow-up period. In conclusion, CHADS(2) and CHA(2)DS(2)-VASc scores were predictive of first CV hospitalization in patients with AF or AFL and may be helpful in identifying "at-risk" patients and guiding therapy.

Adverse drug events associated with yohimbine-containing products: a retrospective review of the California Poison Control System reported cases.

BACKGROUND: Herbal supplements are classified as foods rather than drugs and are not required to undergo premarketing review by the Food and Drug Administration. Yohimbine is an alpha(2)-antagonist available in both prescription and herbal supplement products. OBJECTIVE: To determine the prevalence and severity of yohimbine-related adverse drug events (ADEs) reported to the California Poison Control System (CPCS). METHODS: A retrospective review of the CPCS electronic database of cases within a 7-year period (2000-2006) was conducted. Cases involving adults aged 18 and older who were symptomatic following exposure to a yohimbine-containing product, with a causality rating of possible or better on the Naranjo scale, were included. RESULTS: A total of 238 cases were identified. There was a substantial increase in the annual prevalence of yohimbine-associated ADEs reported to the CPCS between 2000 and 2006; specifically, the prevalence (per 10,000 total adult exposures) increased from 1.8 cases in 2000 to 8.0 cases in 2006). The majority (98.7%) of cases involved herbal (vs prescription) yohimbine products. Common reasons for use included sexual enhancement (27.7%), weight loss (9.2%), and stimulant effects (7.6%). Common ADEs reported included: gastrointestinal distress (46%), tachycardia (43%), anxiety/agitation (33%), and hypertension (25%). Yohimbine exposures were associated with a significantly greater proportion of severe outcomes and were more likely to require management at a health-care facility than the average substance exposure reported to the CPCS (odds ratios [95% CIs] were 5.81 [4.43 to 7.64] and 2.35 [1.82 to 3.04], respectively). CONCLUSIONS: A substantial increase in the prevalence of ADEs associated with yohimbine herbal products was seen between 2000 and 2006. These ADEs were associated with significantly more serious outcomes than the average exposures reported to the CPCS. A reexamination of whether yohimbine should be considered a "safe" dietary supplement under the Dietary Supplement Health and Education Act is warranted.

Maternal influenza infection is likely to alter fetal brain development indirectly: the virus is not detected in the fetus.

Epidemiological studies have shown that maternal infection can increase the risk for mental illness in the offspring. In a mouse model of maternal respiratory infection with influenza virus, the adult offspring display striking behavioral, pharmacological and histological abnormalities. Although influenza primarily infects the respiratory system, there are reports of viral mRNA and protein in the fetus of infected pregnant animals. To determine the extent of viral spread following maternal respiratory infection, we used RT-PCR to assay various maternal and fetal tissues for influenza A mRNAs coding for neuraminidase, non-structural protein 2, nuclear protein and matrix protein. While infected maternal lungs exhibit uniformly very strong signals, placentae are only rarely positive, and viral RNAs are not detectable in fetal brains from infected mothers. Thus, the effects of maternal infection on fetal brain development are likely to be indirect, probably involving the maternal inflammatory response.