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.

Treatment patterns in patients with tenosynovial giant cell tumors in the USAThis 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.

Evaluation of Quantitative Computed Tomography Cortical Hip Quadrant in a Clinical Trial With Rosiglitazone: A Potential New Study Endpoint.

Quantitative computed tomography (QCT) measurements have been used extensively to ascertain information about bone quality and density due to the 3-dimensional information provided and the ability to segment out trabecular and cortical bones. QCT imaging helps to improve our understanding of the role that each bone compartment plays in the pathogenesis and prognosis of fracture. This study was conducted to explore longitudinal changes in femoral neck (FN) cortical bone structure using both volumetric bone mineral density (vBMD) and cortical shell thickness assessments via QCT in a double-blind, randomized, multicenter clinical trial in postmenopausal women with type 2 diabetes mellitus. This study also examined whether treatment-associated changes in the cortical bone vBMD and thickness in femoral neck quadrants could be evaluated. Subjects were randomized to rosiglitazone (RSG) or metformin (MET) for 52 wk followed by 24 wk of open-label MET. A subset of 87 subjects underwent QCT scans of the hip at baseline, after 52 wk of double-blind treatment, and after 24 wk of treatment with MET using standard full-body computed tomography scanners. All scans were evaluated and analyzed centrally. Cortical vBMD at the FN was precisely segmented from trabecular bone and used to assess a possible therapeutic effect on this bone compartment. QCT analysis showed reductions in adjusted mean percentage change in vBMD and in absolute cortical thickness occurred with RSG treatment from baseline to week 52, whereas changes with MET were generally minimal. The reductions observed during RSG treatment for 1 yr appeared to partially reverse during the open-label MET phase from weeks 52 to 76. The femoral neck quadrant may provide utility as a potential endpoint in clinical trials for the understanding of the therapeutic effect of new entities on cortical bone vs trabecular bone; however, further clinical validation is needed. TRIAL REGISTRATION: The protocol (GSK study number AVD111179) was registered on ClinicalTrials.gov as NCT00679939.

EpiPen4Schools pilot survey: Occurrence of anaphylaxis, triggers, and epinephrine administration in a U.S. school setting.

BACKGROUND: Although epinephrine is the treatment of choice for anaphylaxis, it remains underused. OBJECTIVE: This study was designed to describe anaphylactic events and epinephrine autoinjector (EAI) use in U.S. schools enrolled in the EpiPen4Schools program. METHODS: This exploratory, cross-sectional, Web-based survey of 6019 schools that participated in the EpiPen4Schools program assessed anaphylactic events and EAI use at responding schools during the 2013-2014 school year. RESULTS: A total of 919 anaphylactic events were reported in 607 schools. Of the 852 anaphylactic events with data on those who experienced an event, most 88.8% (n = 757) occurred in students, and 21.9% of events (n = 187) occurred in individuals with no known allergies. Of the 851 events with data on EAI use, 74.7% (n = 636) were treated with EAIs and 8.5% (n = 54) received a second epinephrine injection. Of the 204 individuals not treated with an EAI, 77.0% (n = 157) received antihistamines, 12.7% (n = 26) received another treatment, and 8.3% (n = 17) received no treatment. Of the 850 events with data on hospital transport, 79.6% of individuals (n = 677) were transported to the hospital. Common triggers varied seasonally, with food listed most frequently overall (62.5%). CONCLUSION: More than one in ten schools that participated in the EpiPen4Schools survey reported an anaphylactic event. Approximately 25% of individuals with anaphylactic events were not treated with EAIs, and 20.4% of patients were not taken to the hospital after an anaphylactic event. Analysis of these data supports the value of stocking EAIs and of providing continuing education regarding the recognition and proper treatment of anaphylaxis for school personnel.

Incidence and Risk Factors for Development of Cardiac Toxicity in Adult Patients with Newly Diagnosed Acute Myeloid Leukemia.

The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk factors for their occurrence. Among 571 newly diagnosed AML patients, 26 (4.6%) developed fatal cardiac events, and among 525 treated patients, 19 (3.6%) experienced fatal cardiac events (CI: 2% at 6 months; 6.7% at 9 years). Prior heart disease was associated with the development of fatal cardiac events (hazard ratio (HR) = 6.9). The CI of non-fatal cardiac events was 43.7% at 6 months and 56.9% at 9 years. Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4), and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. The 9-year CI of grade 1-2 QTcF prolongation was 11.2%, grade 3 was 2.7%, and no patient had grade 4-5 events. The 9-year CI of grade 1-2 cardiac failure was 1.3%, grade 3-4 was 15%, and grade 5 was 2.1%; of grade 1-2, arrhythmia was 1.9%, grade 3-4 was 9.1%, and grade 5 was 1%. Among 285 intensive therapy patients, median overall survival decreased in those experiencing grade 3-4 cardiac events (p < 0.001). We observed a high incidence of cardiac toxicity associated with significant mortality in AML.

Reductions in biomarkers of cardiovascular risk in type 2 diabetes with rosiglitazone added to metformin compared with dose escalation of metformin: an EMPIRE trial sub-study.

OBJECTIVE: To compare the effects of rosiglitazone added to metformin with dose escalation of metformin on cardiovascular risk biomarkers in type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: Cardiovascular biomarkers were assessed in a sub-population of 122 subjects with type 2 diabetes mellitus (mean age 54.6 and 56.0 years, BMI 34.7 and 32.1 kg/m2; for the rosiglitazone plus metformin and metformin groups, respectively) from the multicenter (63 centers in the USA), double-blind, randomized parallel-group Escalation of Metformin theraPy vs. Initiation of Rosiglitazone Early (EMPIRE) study. Treatment group sizes were slightly imbalanced owing to central, rather than local, randomization. Subjects receiving metformin 1000 mg/day at baseline were randomized to rosiglitazone 4 mg/day plus metformin 1000 mg/day (RSG + MET) or metformin 1500 mg/day (up-titrated MET) for 24 weeks. At 8-weeks, rosiglitazone was increased to 8 mg/day in RSG + MET recipients and metformin to 2000 mg/day in up-titrated MET recipients. RESULTS: Reductions from baseline in HbA1c at week 24 (mean +/- SD) occurred in both groups (RSG + MET: -0.61% +/- 1.16%; up-titrated MET: -0.65% +/- 1.18%). Post-prandial glucose levels (AUC(0-3h)) decreased with RSG + MET (-3.5 mmol/L.h; 95% confidence interval [CI]: -5.2 to -1.8) and up-titrated MET (-1.3 mmol/L.h; 95% CI: -3.8 to 1.1). Homeostasis Model Assessment (HOMA)-estimated insulin sensitivity increased by 37.7% (95% CI: 22.8 to 54.5) in RSG + MET and 6.9% (95% CI: -6.2 to 21.9) in up-titrated MET recipients. RSG + MET reduced C-reactive protein (CRP; -23.9%; 95% CI: -40.4 to -2.8), plasminogen activator inhibitor-1 (PAI-1) activity (-30.1%; 95% CI: -44.5 to -11.9), PAI-1 antigen (-15.5%; 95% CI: -28.3 to -0.3) and matrix metalloproteinase-9 (MMP-9; -13.8%; 95% CI: -25.1 to -0.9), but increased tumor necrosis factor-alpha (TNF-alpha; 27.0%; 95% CI: 6.8 to 50.9). Corresponding values for up-titrated MET were CRP -9.3% (95% CI: -36.9 to 30.2), PAI-1 activity -7.2% (95% CI: -28.2 to 20.0), PAI-1 antigen -1.5% (95% CI: -17.4 to 17.5), MMP-9 29.0% (95% CI: -1.3 to 68.6) and TNF-alpha -6.0% (95% CI: -22.0 to 13.2). CONCLUSIONS: These results suggest that rosiglitazone plus metformin has positive cardiovascular effects against a background of similar glycemic improvements.

Anaphylaxis Triggers and Treatments by Grade Level and Staff Training: Findings from the EPIPEN4SCHOOLS Pilot Survey.

This pilot survey was designed to evaluate the characteristics of anaphylactic events and epinephrine autoinjector (EAI) use in children in U.S. schools. A cross-sectional, web-based, pilot survey of schools participating in the EPIPEN4SCHOOLS® program (Mylan Specialty L.P., Canonsburg, PA) assessed characteristics of anaphylactic events and EAI use during the 2013-2014 academic year. Respondents reported 757 anaphylactic events experienced by students; student grade level was noted for 724 events. Of these events, 32.3% (234/724) were experienced by students in grade school, 18.6% (135/724) by students in middle school, and 49.0% (355/724) by students in high school. Frequency of food-related triggers was consistently high across grade levels. However, many events experienced by students in high school (22.3%, 79/355), middle school (15.0%, 20/135), and grade school (14.1%, 33/234) had an unknown trigger. In 36.0% of schools (2008/5579), only the school nurse and select staff received training to recognize anaphylaxis; most staff or all staff received training in 28.9% (1610/5579) and 30.9% (1722/5579) of schools, respectively. In a majority of schools (54.2%, 3003/5544), only the school nurse and select staff were permitted to administer epinephrine, whereas most staff or all staff were permitted to administer epinephrine in 15.8% (876/5544) and 21.9% (1212/5544) of schools, respectively. Risk of anaphylaxis may be particularly high during adolescence, and some students encounter staff members who are untrained in anaphylaxis recognition or management, or both. These findings support the need for continued anaphylaxis training for the protection of all students, staff, and visitors.

Bone mineral density changes following discontinuation of ronacaleret treatment: off-treatment extension of a randomized, dose-finding phase II trial.

CONTEXT: Parathyroidectomy in patients with hyperparathyroidism can produce subsequent increases in bone mineral density (BMD). Ronacaleret, a selective calcium-sensing receptor antagonist that stimulates endogenous parathyroid hormone release, induced mild hyperparathyroidism. OBJECTIVE: The aim of this study is to evaluate whether BMD changes after cessation of ronacaleret treatment. DESIGN: Observational, off-treatment, extension of a randomized, placebo-controlled, dose-ranging phase II trial. SETTING: Fifteen academic centers in seven countries. PATIENTS: Postmenopausal women with low BMD; 171 out of 569 women in the parent study were enrolled in the extension study. INTERVENTIONS: Subjects were treated with ronacaleret 100mg (n=16), 200mg (n=38), 300mg (n=35), or 400mg (n=32) once daily, alendronate 70mg (n=17) once weekly, or matching placebo (n=33) for 10-12months; BMD was measured after discontinuation of ronacaleret or alendronate treatment. MAIN OUTCOME MEASURE: Mean percent change in lumbar spine areal BMD by dual-energy X-ray absorptiometry at 6-12months after discontinuing ronacaleret or alendronate compared with the 10- to 12-month BMD measurement of the parent study. RESULTS: At the lumbar spine, all doses of ronacaleret resulted in gains in BMD while on treatment. These increases in BMD were maintained or increased after discontinuation of ronacaleret. All doses of ronacaleret caused bone loss at the total hip while on active treatment. However, there was an attenuation of this loss in the off-treatment extension study. CONCLUSION: The gain in BMD at the lumbar spine was maintained post-treatment and the loss of BMD at the total hip was attenuated. We hypothesize that there may have been some bone remineralization after cessation of ronacaleret.

Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia.

BACKGROUND: X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH. METHODS: Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003-0.3 mg/kg i.v. or 0.1-1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days. RESULTS: KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P<0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8-15 days) compared with that seen with i.v. dosing (0.5-4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8-12 days after i.v. administration and 13-19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine. CONCLUSION: KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674. Funding. Kyowa Hakko Kirin Pharma, Inc.

Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus.

CONTEXT: Postmenopausal status and type 2 diabetes mellitus (T2DM) are independent risk factors for fractures. An increased fracture risk has been observed with rosiglitazone (RSG), a thiazolidinedione, in patients with T2DM. DESIGN AND SETTING: This was a randomized, double-blind study in postmenopausal women with T2DM. A 52-week double-blind phase (RSG or metformin [MET]) was followed by a 24-week open-label phase, during which time all patients received MET. MAIN OUTCOME MEASURES: The primary endpoint was to assess the mean percentage change in bone mineral density (BMD) at the femoral neck (FN) by dual-energy x-ray absorptiometry from baseline to week 52 in the RSG treatment group. Key secondary objectives included assessment of changes in BMD at the total hip, trochanter, and lumbar spine and to evaluate RSG effects on bone turnover markers. RESULTS: From baseline to week 52, RSG was associated with a reduction in FN BMD by dual-energy x-ray absorptiometry (-1.47%). During the open-label phase (weeks 52-76), no further loss in FN BMD was observed. A decrease in BMD occurred at the total hip during RSG or MET treatment at 52 weeks (-1.62 and -0.72%, respectively). Total hip BMD loss by RSG was attenuated after switching to MET and was similar between treatment groups at the end of the open-label phase. From baseline to week 52, bone turnover markers significantly increased with RSG compared with MET, but decreased significantly during the open-label phase. CONCLUSIONS: RSG for 52 weeks in postmenopausal women with T2DM was associated with small reductions in FN, total hip, and lumbar spine BMD and increased bone turnover markers. These effects are attenuated after cessation of RSG treatment.

Mechanism of action study to evaluate the effect of rosiglitazone on bone in postmenopausal women with type 2 diabetes mellitus: rationale, study design and baseline characteristics.

OBJECTIVES: Post-hoc analyses have shown an increase incidence of fractures among type 2 diabetes (T2DM) patients treated with thiazolidinediones (TZDs). The mechanisms by which TZDs may be associated with increased fracture risk is not well understood. This article describes the study design and baseline characteristics for a prospective, randomized, double-blind, active-controlled trial to evaluate the effects of rosiglitazone on changes in measures of skeletal structure, surrogates of bone strength and metabolism. METHODS: Postmenopausal women without osteoporosis and diagnosed with T2DM were randomized in a double-blind design to either rosiglitazone or metformin for 52 weeks, then all subjects received open-label metformin for 24 weeks. Study endpoints included changes in bone mineral density (BMD), quantitative computed tomography (QCT), digitized hip radiography (HXR) and high resolution magnetic resonance imaging (hrMRI). Serum markers of bone metabolism and indices of glycemic control were assessed within and between treatment groups. RESULTS: A total of 226 subjects were randomized. Baseline characteristics included: age 63.8 ± 6.5 years; years postmenopausal 16.9 ± 8.4; duration of diabetes 3.5 (1.8-7.8) years; body mass index (BMI) 31.4 ± 5.9 kg/m(2); and glycated hemoglobin (HbA1c) 6.4 ± 0.65%. At baseline, mean T-scores were -0.95 ± 0.91 at the femoral neck, -0.02 ± 0.97 at the total hip and -0.55 ± 1.25 at the total spine. Since there are no well recognized techniques to determine bone mass and structure at the distal limbs (cortical bone sites where fractures were reported in RSG subjects), using the femoral neck as a surrogate for these areas may be a potential limitation of the study. CONCLUSION: This is the first randomized trial utilizing multiple techniques to evaluate bone mass, structure, serum markers of bone remodeling, and potential reversibility of changes after discontinuation of rosiglitazone. This study will provide information about RSG bone effects in a population of postmenopausal women at risk for bone loss and subsequent fracture. CLINICALTRIALSGOV NUMBER: NCT00679939.