First-line Use Research Articles

Real-World First-Line Use of Pertuzumab With Different Taxanes for Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: A Comparative Effectiveness Study Using US Electronic Health Records.

On the basis of the results from CLEOPATRA, pertuzumab plus trastuzumab and chemotherapy is the first-line standard of care for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, discrepancies have been reported between clinical trial and real-world outcomes. We report real-world outcomes for patients with HER2-positive MBC treated with first-line pertuzumab plus trastuzumab and a taxane in routine clinical practice in the United States. A retrospective analysis was conducted using electronic health record-derived deidentified data from the Flatiron Health database. Patients were grouped according to the first taxane received (paclitaxel/nab-paclitaxel or docetaxel). Median real-world progression-free survival (rwPFS) and overall survival (rwOS) was estimated using Kaplan-Meier methodology. Subgroup analyses were conducted in patients treated with docetaxel who met CLEOPATRA's key eligibility criteria. We included 1,065 patients; 313 patients received paclitaxel/nab-paclitaxel and 752 received docetaxel. Patients who received paclitaxel/nab-paclitaxel were older, had a worse Eastern Cooperative Oncology Group Performance Status, and had more recurrent metastatic disease compared with the docetaxel group. After adjustment for potential confounders, similar median rwPFS (inverse probability of treatment weighted average treatment effect for the treated [IPTW-ATT] hazard ratio [HR], 1.09; 95% CI, 0.9 to 1.3; P = .365) and rwOS (IPTW-ATT HR, 1.23; 95% CI, 0.96 to 1.58; P = .101) was observed between treatment groups. In the subgroup of CLEOPATRA-eligible patients, median rwPFS and rwOS were 16.9 months and 57.8 months, respectively. There was no statistically significant difference in real-world outcomes between patients treated with paclitaxel/nab-paclitaxel and those treated with docetaxel. Selecting patients using key CLEOPATRA eligibility criteria resulted in rwPFS and rwOS similar to those observed in CLEOPATRA, highlighting the importance of ensuring similar patient populations when comparing clinical trial and real-world data.

Abstract 424: Arachidonic Acid Synergizes With Aspirin In Cardioprotection Following Acute Myocardial Infarction

Introduction: Membrane-released arachidonic acid (AA) is metabolized via cyclooxygenase pathway to form prostanoids, including thromboxane, prostacyclin and prostaglandin E2. Aspirin suppresses platelet synthesis of thromboxane, rendering its first-line use for anti-thrombosis in patients with acute myocardial ischemia. We report that endogenous PGE2 protects against myocardial ischemia-reperfusion (MI/R) injury (Nat Commun. 2019;10(1):1888). The impact of AA administration while suppressing thromboxane on MI/R injury is unknown. Methods and Results: C57BL/6J mice were treated intravenously with vehicle, AA, aspirin, or their combination and then subjected to 30min coronary artery ligation and 24hr reperfusion. Cardiac function was assessed by ultrasonography and infraction size quantified by TTC staining. Cardiac microcirculation was assessed by laser doppler flow and vasomotor reactivity determined with isolated coronary arteries. Single treatment with AA at an optimized dose of 0.1mg/Kg, or combined with aspirin at a dose of 10mg/Kg that allowed sufficient suppressing of platelet activation over 24hr, decreased infarct size and improved heart function. Impressively, combination of AA with aspirin provided additional cardioprotection compared with either single treatment. While aspirin, not AA, ameliorated microvascular obstruction following MI/R injury, co-administration of AA and aspirin further increased coronary microcirculatory blood perfusion with improved vascular permeability compared with aspirin alone. MI/R impaired endothelium-dependent dilatation of coronary arteries, and the dual treatment, not AA or ASA alone, increased coronary artery relaxation. Cardiac infiltrated neutrophils and platelet-neutrophil aggregates were also reduced by the combination treatment, consistent with a suppressed leukocyte-ECs adhesion as assessed in vitro. Conclusions: AA and aspirin synergistically protect against MI/R injury and this is attributable to suppressed neutrophil inflammation and improved microvascular obstruction. AA might be used as an adjunct therapy to aspirin in patients with acute myocardial infarction.

Impact on stable chest pain pathways of CT fractional flow reserve

ObjectivesTo evaluate the impact of introducing CT fractional flow reserve (FFRCT) on stable chest pain pathways, concordance with National Institute for Health and Care Excellence (NICE) chest pain guidelines, resource...

Controversies in upper GI oncology: first-line checkpoint inhibitor use in metastatic GEA: guided by PD-L1 CPS or not?

Controversies in upper GI oncology: first-line checkpoint inhibitor use in metastatic GEA: guided by PD-L1 CPS or not?

Abstract P4-01-19: Real World Statistics on CDK4/6 Inhibitor Use in Metastatic Hormone Receptor Positive and HER2-Negative Breast Cancer with a Focus on Age

Abstract Background: Combining CDK 4/6 inhibitors with hormone directed therapy using aromatase inhibitors (AI) or selective estrogen receptor down-regulators (SERD) is considered first line therapy for treatment of hormone receptor positive (HR+) human epidermal receptor 2 negative (HER2-) metastatic breast cancer (mBC). Here we aim to evaluate first line CDK 4/6 inhibitor practice patterns both nationally and locally (Wisconsin) in HR+ HER2- mBC patients and evaluate age as a potential factor impacting practice patterns. Methods: A retrospective analysis was performed utilizing IQVIA Anonymized Patient Longitudinal Data. The data base captures 60-85% of cancer patients across all 50 states in the United States and relies on diagnostic coding used in service or treatment claim filing. Patients queried were greater than 18 years old and were identified by a code indicating CDK4/6 inhibitor therapy or a combination of codes indicating mBC, HR+ status and HER- status. First line treatment was categorized as CDK4/6 inhibitor combination therapy, AI monotherapy, SERD, selective estrogen receptor modulator (SERM) monotherapy, chemotherapy, or other. Patients were further filtered by year, location, practice type (academic vs community), and age. Results: A total of 313,978 patients with mBC receiving first-line therapy were identified nationally between 2015 and 2021. The proportion of patients on first line CDK4/6 inhibitor combination therapy nationally significantly improved from 20% in 2015 (N=27,063) when palbociclib was first approved, to 53% in 2021 (N=54,023) (Table 1.) In 2021, first line use of CDK 4/6 inhibitor combination therapy was higher at 59% both in WI and our institution Froedtert Hospital and the Medical College of Wisconsin Cancer Center (Table 2.) At our center in 2021, the use of first line CDK4/6 inhibitor combination therapy in patients greater than age 65 was significantly lower at 35% (N=39) compared to patients less than 65 at 75% (N=64.) Further delineating the age groups at our center (Table 3,) use of CDK4/6 inhibitor combination therapy in patients aged 70-79 was 35% (N=20) and fell to 20% in patients greater than 80 in age (N=8.) Conclusion: Despite significant improvement in long-term outcomes with first line CDK4/6 inhibitor combination therapy in HR+ HER2- mBC patients, overall national usage is suboptimal. At our center, this was particularly apparent in patients older than 70. Identifying barriers to optimal use is critical to improve utilization of this important and effective class of drugs. National Percentages of HR+ HER2- mBC Patients Stratified by First Line Treatment Between 2015-2021 HR+ HER2- mBC patients Nationally treated with first line therapy (N=313,978.) National and Local Percentages of HR+ HER2- mBC Patients Stratified by First Line Treatment in 2021 HR+ HER2- mBC patients treated with first line therapy in 2021 Nationally (N=54,026,) in Wisconsin (N=694,) and at Froedtert Hospital and the Medical College of Wisconsin Cancer Center (N=103.) Local Percentages HR+ HER2+ mBC Patients Stratified by First Line Treatment and Age Group HR+ HER2- mBC patients treated with first line therapy in 2021 at Froedtert Hospital and the Medical College of Wisconsin Cancer Center (N=103.) Citation Format: Kathleen Monahan, Sailaja Kamaraju, Yee Chung Cheng, Janet Retseck, Deepika Sriram, John Burfeind, Christopher Chitambar, Lubna N. Chaudhary. Real World Statistics on CDK4/6 Inhibitor Use in Metastatic Hormone Receptor Positive and HER2-Negative Breast Cancer with a Focus on Age [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-19.

Sustained Virologic Suppression With Dolutegravir/Lamivudine in a Test-and-Treat Setting Through 48 Weeks.

We assessed the efficacy and safety of dolutegravir/lamivudine (DTG/3TC) in a US test-and-treat setting at a secondary 48-week time point of the multicenter, single-arm, phase IIIb STAT study. Participants were eligible adults newly diagnosed with human immunodeficiency virus (HIV)-1 and had started once-daily DTG/3TC within 14 days of diagnosis, before laboratory results were available. Antiretroviral therapy (ART) was modified if baseline testing indicated DTG or 3TC resistance, hepatitis B virus (HBV) coinfection, or creatinine clearance <30 mL/min per 1.73 m2, and these participants remained in the study. A proportion with HIV-1 ribonucleic acid (RNA) <50 copies/mL at Week 48 was calculated among all participants (intention-to-treat-exposed [ITT-E] missing = failure analysis) and those with available data (observed analysis). At Week 48, 82% of all participants regardless of ART (107 of 131; ITT-E missing = failure) and 97% with available data (107 of 110; observed analysis) achieved HIV-1 RNA <50 copies/mL. High proportions of virologic response were seen overall, including in participants with high viral load (≥500 000 copies/mL; 89%) or low CD4+ cell count (<200 cells/mm3; 78%) at baseline. Ten participants had treatment modification (baseline HBV coinfection, n = 5; participant/proxy decision, n = 2; baseline M184V resistance mutation, adverse event [AE; rash], and pregnancy, n = 1 each) before Week 48. Two participants met confirmed virologic failure criteria. No treatment-emergent resistance was observed. Ten participants reported drug-related AEs (all grade 1-2); no serious drug-related AEs occurred. Results demonstrated high proportions of participants with sustained virologic suppression, no treatment-emergent resistance, and good safety over 48 weeks, supporting first-line use of DTG/3TC in a test-and-treat setting.

Initial results of a phase 2 pilot study of radium-223 and radiotherapy in untreated hormone-naïve men with oligometastatic prostate cancer to bone.

156 Background: We hypothesized that treatment with Radium-223 (Ra223) and to ≤5 sites of bony metastases (mets) could safely delay the time to start androgen deprivation therapy (ADT) and maintain quality of life (QoL). Methods: 20 men previously treated with surgery, radiation, or both for M0 PCa later developed ≤5 bone-only mets were eligible for this prospective trial. Inclusion: testosterone ≥ 100 ng/dL and mets on conventional bone scan, validated by a CT, MRI, or PET/CT. Exclusion: LHRH therapies after initial treatment, or N1 disease at diagnosis of bone mets. Therapy was 6 cycles of Ra223 and SBRT (30 Gy in 5 fractions between cycles 1-2). Bone scan was performed at baseline and q3 months. PSA was evaluated monthly during the Ra223 course, and q3 months after. Therapeutic effectiveness was defined as ≥20% of patients meeting the primary endpoint of freedom from ADT (FFAdt) use at 15 months. Discontinuation of study therapy occurred if: PSA rise &gt; 10% if baseline PSA &gt;20ng/ml, PSA&gt;20 if baseline PSA &lt;20 ng/ml, radiographic progression or a skeletal-related event (SRE). All endpoints were timed from the Cycle 1 radium date. Patients were followed for 2 years. Clinically significant changes in patient-reported outcome (PRO) measures were defined as &gt;1/2 standard deviation from the mean baseline value and were censored after the time of ADT use. Continuous and categorical covariates were compared using the Wilcoxon rank sum and Pearson’s Chi2 tests, respectively, and univariate Cox regression. Statistical significance was considered at P&lt;0.05. Results: The median number of Ra223 cycles was 6. 6 patients had &lt;6 cycles (range 2-5) due to progression. FFAdt at 15 and 24 Months was 49.5% and 38.5%, respectively (p&lt;0.001). The median time to ADT was 14.8 months. There were no significant changes from baseline in any PRO QoL domain (physical functioning, anxiety, depression, fatigue, satisfaction with participation in social roles, sleep disturbance, and pain interference). There were 2 patients with Grade 3 SREs (bone fracture, pain). Grade 2+ events attributed as possible or likely to Ra-223 were seen in 4 patients (bone pain, fatigue, fracture, decreased WBC count, and other). Grade 2+ events attributed as possible or likely to EBRT were seen in 2 patients and included fatigue and other pain. were noted for age, baseline PSA, days from primary treatment, NCCN risk group, TNM stage, ISUP grade group, BMI, or # of lesions in those who met or failed the primary endpoint (all p&gt;0.05). Conclusions: First-line use of Ra223 and SBRT to oligomets in hormone-naïve men in this prospective pilot study resulted in a significant delay in ADT use compared to historical control, is well tolerated, and maintains QoL. Clinical trial information: NCT03304418 .

α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer's Disease.

α1-Adrenergic receptors (ARs) are members of the G-Protein Coupled Receptor superfamily and with other related receptors (β and α2), they are involved in regulating the sympathetic nervous system through binding and activation by norepinephrine and epinephrine. Traditionally, α1-AR antagonists were first used as anti-hypertensives, as α1-AR activation increases vasoconstriction, but they are not a first-line use at present. The current usage of α1-AR antagonists increases urinary flow in benign prostatic hyperplasia. α1-AR agonists are used in septic shock, but the increased blood pressure response limits use for other conditions. However, with the advent of genetic-based animal models of the subtypes, drug design of highly selective ligands, scientists have discovered potentially newer uses for both agonists and antagonists of the α1-AR. In this review, we highlight newer treatment potential for α1A-AR agonists (heart failure, ischemia, and Alzheimer's disease) and non-selective α1-AR antagonists (COVID-19/SARS, Parkinson's disease, and posttraumatic stress disorder). While the studies reviewed here are still preclinical in cell lines and rodent disease models or have undergone initial clinical trials, potential therapeutics discussed here should not be used for non-approved conditions.

Transferability of Published Population Pharmacokinetic Models for Apixaban and Rivaroxaban to Subjects with Obesity Treated for Venous Thromboembolism: A Systematic Review and External Evaluations.

Apixaban and rivaroxaban have first-line use for many patients needing anticoagulation for venous thromboembolism (VTE). The pharmacokinetics of these drugs in non-obese subjects have been extensively studied, and, while changes in pharmacokinetics have been documented in obese patients, data remain scarce for these anticoagulants. The aim of this study was to perform an external validation of published population pharmacokinetic (PPK) models of apixaban and rivaroxaban in a cohort of obese patients with VTE. A literature search was conducted in the PubMed/MEDLINE, Scopus, and Embase databases following the PRISMA statement. External validation was performed using MonolixSuite software, using prediction-based and simulation-based diagnostics. An external validation dataset from the university hospitals of Brest and Rennes, France, included 116 apixaban pharmacokinetic samples from 69 patients and 121 rivaroxaban samples from 81 patients. Five PPK models of apixaban and 16 models of rivaroxaban were included, according to the inclusion criteria of the study. Two of the apixaban PPK models presented acceptable performances, whereas no rivaroxaban PPK model did. This study identified two published models of apixaban applicable to apixaban in obese patients with VTE. However, none of the rivaroxaban models evaluated were applicable. Dedicated studies appear necessary to elucidate rivaroxaban pharmacokinetics in this population.

Efficiency of CMV serodiagnosis during pregnancy in daily laboratory routine

BackgroundMaternal acute primary cytomegalovirus (CMV) infection during the first trimester may cause severe long-term sequelae in newborns. For risk assessment, serological screening is routinely performed in pregnant women based on IgM, IgG and avidity tests using whole-virus antigen. A recent study evaluated the diagnostic value of recombinant protein-based ELISAs as second-line tests in pregnancy CMV screening, including anti-p52 IgM and anti-gB IgG as markers defining the early and late phase of infection, respectively. In the present study, these recombinant ELISAs were used as first-line screening tests in daily laboratory routine and compared to lysate-based assays with respect to [i] the number of conclusive results obtained with the initial sample and [ii] the underlying workload. Methods553 unselected routine serum samples from pregnant women were tested for anti-CMV IgM and IgG antibodies using lysate-based ELISAs and avidity testing. Anti-CMV IgM antibodies against recombinant p52 and anti-CMV IgG antibodies against recombinant glycoprotein B (gB) were also determined by ELISA. All assays were performed and interpreted according to the manufacturer’s instructions. ResultsFor lysate-based IgM, IgG and avidity testing, 84.6 % of samples yielded conclusive results in a total of 1156 tests, while 15.4 % needed follow-up testing of a consecutive sample. Anti-p52 CMV IgM and anti-gB CMV IgG testing produced conclusive results for 92.8 % of samples in a total of 1026 tests, while 7.2 % samples required follow-up testing. ConclusionsThe first-line use of ELISAs measuring anti-p52 CMV IgM and anti-gB CMV IgG antibodies to test for maternal CMV infection increases the number of conclusive results derived from an initial serum sample while requiring a considerably lower number of tests compared to the lysate-based approach. For day-to-day routines in a diagnostic laboratory, this high efficiency of the recombinant testing approach has significant practical relevance.

Impact of Frailty on Outcomes of First-Line Pembrolizumab Monotherapy in a Real-World Population with Advanced Non-Small Cell Lung Cancer

ICIs have been able to improve overall survival in advanced-stage lung cancer. The benefit of this therapy is limited in patients with poor ECOG PS. However, this scale is imprecise and can be influenced by different factors, such as frailty. Cancer patients have a high risk of frailty independently of age. In this observational, single-center, retrospective study, we investigated the effect of frailty on the effectiveness of pembrolizumab in first-line use in a cohort of 101 patients with metastatic NSCLC. Frailty was determined using a frailty score system developed by Sakakida et al. Univariate and multivariate analysis was performed to determine the prognostic role of frailty on OS and PFS. Median OS was significantly higher in patients with low frailty compared with intermediate and high frailty (23.8 vs. 7.0 and 1.8 months, respectively; p < 0.001). Median PFS was also significantly higher in patients with low frailty compared with intermediate and high frailty (10.5 vs. 3.9 and 1.6 months; p < 0.001, respectively). Frailty was the only variable that showed significant differences in OS and PFS. Multivariate analysis confirms frailty as an independent predictor of OS and PFS. Frailty assessment could help to select which patients are candidates for ICIs in NSCLC.

Graves' Disease in Children: An Update.

Graves' disease (GD) is the most common cause of hyperthyroidism in children. A common GD symptom is a goiter. The usual biochemical profile in children with GD is a decreased thyroid hormone stimulating hormone (TSH) level and high free thyroxine (FT4) and free triiodothyronine (FT3) concentrations. The presence of thyroid receptor antibodies (TRAb) is the most important specific immunological sign for diagnosing GD. The treatment choices for pediatric GD are anti-thyroid drugs (ATDs), radioiodine, and thyroidectomy, but the risks and benefits of each modality are different. Management recommendations include the first-line use of a prolonged course of ATDs for at least 3 years and potentially 5 years or more. Rituximab and Teprotumumab are new novel alternative medications for the treatment of adult patients with GD and Graves' orbitopathy respectively, but evidence of the efficacy and safety of these drugs in pediatric patients with GD is lacking.

Impact of first-line use of caplacizumab on treatment outcomes in immune thrombotic thrombocytopenic purpura

BackgroundThe von Willebrand factor–directed nanobody caplacizumab has greatly changed the treatment of immune thrombotic thrombocytopenic purpura (iTTP) in recent years. Data from randomized controlled trials established efficacy and safety. ObjectivesThis study aims to address open questions regarding patient selection, tailoring of therapy duration, obstacles in prescribing caplacizumab in iTTP, effect on adjunct treatment, and outcomes in the real-world setting. MethodsWe report retrospective, observational cohorts of 113 iTTP episodes treated with caplacizumab and 119 historical control episodes treated without caplacizumab. We aggregated data from the caplacizumab phase II/III trials and real-world data from France, the United Kingdom, Germany, and Austria (846 episodes, 396 treated with caplacizumab, and 450 historical controls). ResultsCaplacizumab was efficacious in iTTP, independent of the timing of therapy initiation, but curtailed the time of active iTTP only when used in the first-line therapy within 72 hours after diagnosis and until at least partial ADAMTS13-activity remission. Aggregated data from multiple study populations showed that caplacizumab use resulted in significant absolute risk reduction of 2.87% for iTTP-related mortality (number needed to treat 35) and a relative risk reduction of 59%. ConclusionCaplacizumab should be used in first line and until ADAMTS13-remission, lowers iTTP-related mortality and refractoriness, and decreases the number of daily plasma exchange and hospital stay. This trial is registered at www.clinicaltrials.gov as #NCT04985318.

1764. Accuracy of Penicillin Allergy Risk Severity Documentation in Surgical Patients

Abstract Background Clinical guidelines for antimicrobial prophylaxis recommend use of cefazolin for most surgical procedures. Patients who are labeled penicillin (PCN) allergic are often prescribed second line agents, though cross-reactivity is less than 1%. PCN allergic patients have significantly higher rates of readmissions and healthcare-associated infections. Allergy documentation in the medical record is often incomplete or inaccurate, and many allergies can be de-labeled through history alone. Our study aimed to investigate accuracy of allergy risk assessment in PCN allergic patients and the impact on surgical antibiotic prophylaxis for quality improvement. Methods This was a retrospective observational cohort study among adult patients with a reported PCN allergy who underwent a surgical procedure from 3/2019-2/2020 at a single academic institution. The primary outcome was incidence of appropriate documentation of allergy risk severity. Secondary outcomes included receipt of beta-lactam for surgical prophylaxis and incidence of documentation to reflect tolerance. Allergy risk classification was considered appropriate if it aligned with institutional guidelines (Table 1). Results Of 2647 patients who underwent surgical procedures, 330 (12%) reported PCN allergy. Allergy risk severity was appropriately documented in 136 (41%) patients. 150 (45%) were mislabeled as “high” or “unknown” risk compared to reported reaction. 191 (58%) patients with reported PCN allergies received beta-lactam antibiotics peri-operatively. Allergy history had been updated to reflect tolerance in only 6% of patients who received cefazolin for surgical prophylaxis and in 21% who had received beta-lactams previously (Table 2). Table 2:Primary and Secondary Outcomes Conclusion Inaccurate documentation of allergy risk results in decreased first-line antimicrobial use in patients with reported PCN allergies. Documented PCN allergy risk severity was often incorrect and over 100 additional patients could have been labeled “low risk” based on reported reaction. 72% of patients could have received first-line beta-lactam prophylaxis per institutional guidelines. Interventions targeting allergy history documentation alone could positively impact antibiotic selection. Disclosures All Authors: No reported disclosures.

A Systematic Review and Indirect Treatment Comparison of Ferric Carboxymaltose Versus Iron Isomaltoside in Correcting Iron Deficiency Anemia

Background: Iron deficiency anemia (IDA) is a global public health concern. It is estimated 1.24 billion people with IDA and responsible for about 800,000 deaths per year. Intravenous iron therapy is one of the treatment options and in recent years has been promoted for first-line use in correcting IDA. Currently in the literature, there is a lack of direct evidence of comparative effectiveness between ferric carboxymaltose (FCM) and iron isomaltoside (IIM) in correcting IDA. Available indirect evidence is far from conclusive. With more evidence emerging from the literature, the aim of the current study was to conduct an indirect treatment comparison (ITC) of FCM versus IIM in correcting IDA. Method: To address potential heterogeneity, two separate ITC analyses were proposed: one via iron sucrose (IS) and the other via oral iron (OI) and focused on non-chronic-kidney-disease (non-CKD) patients. A systematic literature review, searching PubMed, EMBASE, and Cochrane Library, was conducted to identify relevant randomized controlled trials (RCTs). The data cut-off date was 2022.03.31. The risk of bias for each involved study was assessed based on the Cochrane review criteria. Bucher's ITC method and random-effects model for meta-analysis were applied to compare outcomes. The efficacy outcomes included the response rate, mostly defined as 2 g/dL increase from baseline or hemoglobin (Hb) level normalized, and hemoglobin level change from baseline. The safety outcome was adverse drug reactions (DARs) and drug-related serious adverse events (SAEs). When feasible, subgroup analyses by underlying disease were also conducted. Results: For ITC via IS, 8 RCTs (7 FCM vs IS and 1 IIM vs IS) were included. Most of the studies presented with the low risk of bias. The total number of patients in FCM and IIM RCTs were 1471 and 1512, respectively. The distribution of baseline characteristics between two groups were: the proportion of female (84.8 vs 89.2%), age (35.7 vs 44.0), baseline Hb level (8.7 vs 9.2 g/dL) and serum ferritin level (10.3 vs 13.6 ug/mL) . The ITC result indicated that FCM had a statistically significant better response rate with a risk ratio (RR) of 1.34 (95% CI: 1.03 - 1.75), compared to IIM. FCM also resulted in a significantly larger increase from baseline Hb level in comparison to IIM, with a mean difference of +0.87 g/dL (95% CI: 0.40 - 1.34). For safety as measured by DARs, FCM showed no significant difference with IIM (RR of 0.80, 95% CI: 0.40 - 1.57). Due to a high number of zero event reported in the studies and different SAE definitions, indirect comparison of SAE was not conducted. For ITC via OI, 17 RCTs (15 FCM vs OI and 2 IIM vs OI) were included. The total number of patients in FCM and IIM RCTs were 3428 and 677, respectively. Between the two groups, the average age (38.1 vs 45.5 years), proportion of female (88.0 vs 65.9 %) and baseline Hb level (9.8 vs 9.9 g/dL) were similar. In the IIM group, half of patients were cancer patients with chemotherapy. The results of the ITC via OI were similar to those via IS. FCM had a non-significant better response rate (RR 1.18, 95% CI: 0.96 - 1.45) and a statistically significant larger increase from baseline Hb level (+0.81 g/dL, 95% CI: 0.37 - 1.25) in comparison to IIM. For safety, there was no significant difference between the two (RR of 1.23, 0.27 - 5.57). Subgroup analysis was conducted in IBD patients (3 FCM and 1 IIM RCT, 486 vs. 327 patients). The result also indicated that FCM had a significantly larger increase from baseline hemoglobin (+0.99 g/dL, 0.86 - 1.13) in comparison to IIM. Conclusion: Based on the current evidence, both indirect treatment comparison analyses indicated that in non-chronic-kidney-disease patients ferric carboxymaltose has better efficacy outcomes than iron isomaltoside and no difference in terms of adverse drug reactions. Future head-to-head trials might be needed to confirm the current findings.

A Real-World Analysis of Acquired Thrombotic Thrombocytopenic Purpura: Comparing Clinical Outcomes of Early Versus Late Responders to Plasma Exchange

INTRODUCTION: Acquired thrombotic thrombocytopenic purpura (TTP) is a rapidly fatal thrombotic microangiopathy mediated by autoantibodies targeting ADAMTS-13. The main pillars of acquired TTP management include therapeutic plasma exchange (PLEX) and immunosuppression with glucocorticoids and rituximab. PLEX is initiated in all patients with a presumptive clinical/confirmed diagnosis of TTP and is continued until platelet count recovery. The platelet response to PLEX is quite variable, with some patients having rapid recovery (early responders [ERs]) within 4-7 days, and others requiring a longer duration (late responders [LRs]) of PLEX. Although rapid platelet count recovery is reassuring to the treating physician, it is unclear whether there is a significant difference in outcomes between ERs and LRs to PLEX. We performed a single-center retrospective study of survival outcomes of ERs vs those of LRs with acquired TTP. METHODS: We performed a retrospective analysis of adult patients (≥18 years old) with acquired TTP who were treated at our institution between January 1, 2005, and May 1, 2020. Baseline demographic and clinical data and laboratory values at the time of diagnosis were collected. Patients were ERs if platelet recovery (platelet count >150,000/µL for 2 consecutive days) occurred within 7 days of starting PLEX, whereas LRs had delayed platelet recovery (≥7 days) after initiation of PLEX. Refractory disease was defined as recurrent thrombocytopenia (platelet count <150,000/µL) following an initial response between days 1 and 30 after last PLEX. Relapses were defined as thrombocytopenia and elevated LDH occurring >30 days after last PLEX. We analyzed survival outcomes and the relapse risk in ERs versus LRs. RESULTS: A total of 61 patients fulfilled the diagnostic criteria for acquired TTP (ER = 34 patients, LR = 27 patients). Patient demographics, laboratory studies, and treatment details are shown in Table 1. The mean age of ER and LR patients was 45 and 38 years, respectively. About 56% of patients in each group identified as Black. About 18% of ERs and 9% of LRs had a diagnosis of HIV. No statistically significant difference was noted in the baseline laboratory findings of the two groups. Involvement of ≥2 affected organ systems was seen in 79% of ERs and 93% of LRs (p=0.2757). All LRs (100%) and 88% of ERs had severe TTP at presentation (ADAMTS-13 level ≤10). The mean number of PLEX was 6.11 and 24.96 in ERs and LRs (p<0.0001), respectively. The mean number of PLEX to platelet recovery was 4.27 and 19.27 (p<0.0001). Glucocorticoids were given to 97% of ERs and 100% of LRs. First-line rituximab was given to 52% (n=14) of LRs, versus only 9% (n=3) of ERs (p=0.0004). About 15% of LRs went on to receive additional immunosuppressive agents, whereas no ERs did so (p=0.0336). The relapse rate among ERs and LRs was 55.56% and 44.44%, respectively (p > 0.9999). The 30-day mortality rate was 6% in ERs and 0% in LRs. Cardiovascular diseases were the common cause of early deaths. Overall survival (OS) at 6 months was 79% in ERs and 96% in LRs (p=0.0665). The OS at 1 year was 74% in ERs and 96% in LRs (p=0.03). The 2-year OS was available for 24 ER patients (83%) and LR 17 patients (89%) (p>0.9999). Among the 19 patients who received front-line rituximab, the OS at 1 year was 100%. CONCLUSIONS: More LRs than ERs received rituximab and glucocorticoids for immunosuppression as first-line therapy. LRs were found to have a statistically significant greater OS at 1 year. ERs were less likely to receive adequate immunosuppression than LRs. This may indicate that the time to response to PLEX should not be used as a surrogate for risk of relapse. Immunosuppression is the cornerstone of the management of acquired TTP, and first-line use of rituximab is critical in the reducing relapse rate and improving OS. Larger studies in the prospective setting are needed to evaluate the impact of duration of PLEX on OS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Longitudinal, Real-World Data Reveal Treatment Effectiveness in Idiopathic Multicentric Castleman Disease and Support Current Treatment Guidelines

Background: Idiopathic multicentric Castleman disease (iMCD) is an immunologic disorder with unknown etiology that is diagnosed in approximately 1200 individuals in the US annually. Presentation is heterogeneous - ranging from mild/moderate constitutional symptoms to severe multi-organ dysfunction. Treatment guidelines were developed by an international expert panel in 2017 based on the review of a limited number of clinical trials and small case series. Siltuximab, a monoclonal antibody against interleukin-6 (IL6) approved for the treatment of iMCD, is recommended first-line based on evidence from its phase II trial. High-dose steroids and cytotoxic chemotherapy are recommended for patients with severe disease who progress on anti-IL6 therapy. For patients with mild/moderate disease not responding to IL6 blockade, rituximab +/- immunomodulators is recommended. While concurrent steroids are recommended in some cases, steroid monotherapy is discouraged. Limited data exist on the effectiveness of these agents beyond siltuximab. Herein, we evaluate treatment regimens administered to a cohort of 83 iMCD patients with longitudinal treatment and response data. Methods: A review of cases in the ACCELERATE natural history registry by a panel of experts led to the identification of 83 patients with confirmed iMCD. Longitudinal treatment and response data were abstracted from medical records. Durable treatment response was defined as the best response according to the change in the proportion of abnormal clinical/laboratory criteria sustained for at least 1 year. Severity at the time of treatment initiation was defined as ≥2 of renal failure, fluid accumulation, severe anemia, pulmonary involvement, or hospitalization. Survival analysis for time-to-next-treatment, a proxy for time to treatment failure, was performed on regimens categorized in the guidelines: siltuximab +/- best supportive care (BSC), tocilizumab +/- BSC, rituximab +/- BSC, chemotherapy +/- other agents, and steroid monotherapy. BSC includes steroids, transfusions, and other supportive modalities. Log rank test was used to determine differences across treatment regimens, and pairwise comparisons were Bonferroni corrected. Results: Approximately half (47%) of the patients were female, with a mean (SD) age at diagnosis of 35.9 (16.2). A total of 261 regimens were administered across the cohort. Of the 41 patients who received siltuximab +/-BSC, 44% (N=18) achieved a durable response. Durable response rates to other treatments included: tocilizumab +/-BSC: 41% (7/17); rituximab +/-BSC: 23% (6/26); chemotherapy +/-BSC: 38% (8/21); steroid monotherapy: 6% (2/32). Steroid monotherapy was significantly less likely to induce a durable response than siltuximab +/-BSC (p=0.02). Notably, response rates were significantly lower across modalities in severe compared to mild/moderate disease (p=0.004). We also found that the treatment regimen significantly predicts time-to-next-treatment (p<0.0001, Figure 1). Median time-to-next-treatment for siltuximab +/-BSC is 742 days (95% CI: 1.26, no upper limit), tocilizumab +/-BSC is 689 days (234, no upper limit), rituximab +/- BSC is 153 days (116, 399), chemotherapy +/- other agents is 463 days (107, 791), and steroid monotherapy is 64 days (36,129). Pairwise comparison demonstrated that siltuximab +/-BSC, tocilizumab +/-BSC, and chemotherapy each have a significantly longer time-to-next-treatment compared with steroids (p<0.05). Further, siltuximab +/- BSC also had a significantly longer time-to-next-treatment than rituximab +/-BSC (p=0.02). There were no other differences between regimens. Discussion: Though guidelines were developed in 2017, this is the first systematic assessment of iMCD treatment regimens included in these guidelines. We found differences in durable response rates and in time-to-next-treatment between regimen approaches. Patients on steroids alone require additional drug-intervention a median of 2 months after treatment start, while patients treated on siltuximab +/-BSC remained on treatment for a median of 2 years before additional interventions were added. Our results support current recommendations to administer siltuximab first-line and limit steroid monotherapy use. These results also demonstrate that additional agents are needed for refractory patients, who have few options and are at risk of death due to progression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Treatment Patterns and Outcomes of Daratumumab Retreatment in Multiple Myeloma in the United States

Background: Daratumumab (Dara) combination therapy is approved in transplant ineligible newly diagnosed multiple myeloma (MM), and ongoing trials evaluating Dara in transplant eligible newly diagnosed MM may result in increased first-line (1L) use. Because Dara combinations are also approved in relapsed/refractory MM, patients may receive Dara retreatment in subsequent lines of therapy (LOTs); however, data regarding optimal sequencing and benefit of Dara retreatment are lacking. Here, we present a real-world evaluation of treatment patterns and effectiveness of retreatment with Dara-based regimens. Methods: This retrospective observational study utilized deidentified electronic health records data from the Concert AI Patient360 database, representing primarily United States community-based oncology centers. The analysis included adult patients who met the following inclusion criteria: diagnosed with MM on or after January 1, 2011 through December 31, 2021, received ≥1 LOT postdiagnosis, had no prior stem cell transplantation, and had no other primary cancer diagnosis at baseline. Within this population, patients who received treatment with Dara (1L and beyond) and subsequent retreatment with Dara (second line [2L] and beyond) were identified. 1L was defined as all MM medications used within 35 days of MM-related medication initiation. Advancement of LOT was based on regimen change and documented progression events or stem cell transplant. The primary objective was to determine the proportion of MM patients initially treated and retreated with Dara-based regimens overall and by LOT. Key secondary objectives were to determine duration of treatment (DOT) and time to next treatment (TTNT) using the Kaplan-Meier method. A maximum follow-up date was determined for each patient using activity dates from multiple data files to identify the last active date of any medical encounter. Patients without subsequent LOT or death dates were censored at the maximum follow-up. Data were reported for the overall group and by the LOT in which initial Dara treatment was received. Results: Among 2367 patients with MM who met the inclusion criteria, 713 (30%) were treated with a Dara-based regimen, of which 97 (4%) were retreated with Dara and included in the analysis. Among the 97 patients analyzed, 21 (22%) started initial Dara treatment in 1L, 38 (39%) in 2L, 23 (24%) in third line (3L), and 15 (15%) in fourth or later line (4L+). Median age at diagnosis was 61-68.5 years across these groups, and 35%-50% of patients were male. Most patients had a baseline ECOG performance status of 1-2 (61%-65% for 1L, 2L, and 3L) with the exception of 4L+ (33%), and stage 2 (20%-42%) or 3 (27%-48%) disease at diagnosis. Patients were mostly treated at community (67%-81%) vs academic centers (19%-33%). Initial treatment regimens were Dara + immunomodulatory drug (IMiD) ± proteasome inhibitor (PI) (67%), Dara + PI (21%), or Dara monotherapy (12%). Dara retreatment occurred in the LOT subsequent to the initial Dara treatment episode for 90%-100% of patients; the most common retreatment regimen was Dara + IMiD (43%), followed by Dara + IMiD + PI (33%) and Dara + PI (15%). The Table shows clinical outcomes for initial Dara treatment and retreatment episodes in the same set of patients, with data by LOT indicating the line in which initial Dara treatment was received. Among 95 Dara retreated patients who had a maximum follow-up date, median DOT was 254 days and 196 days for initial Dara treatment and retreatment episodes, respectively. Median DOT by LOT for initial Dara treatment episodes ranged from 173 days (4L+ initiation) to 288 days (1L initiation). Median DOT by LOT for Dara retreatment episodes ranged from 149 days (4L+ initiation) to 304 days (1L initiation). Median TTNT was 308 days and 457 days for initial Dara treatment and retreatment episodes, respectively. Median TTNT by LOT for initial Dara treatment episodes ranged from 286 days (4L+ initiation) to 434 days (1L initiation). Median TTNT by LOT for Dara retreatment episodes ranged from 256 days (3L initiation) to not yet reached (1L initiation). Conclusion: This analysis of real-world data from adult patients diagnosed with MM showed that DOT and TTNT for Dara retreatment episodes were reasonably long and aligned with clinical expectations for subsequent therapy, suggesting that patients continue to receive meaningful clinical benefit with Dara retreatment despite prior exposure. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Spontaneous pneumomediastinum: a surrogate of P-SILI in critically ill COVID-19 patients

Spontaneous pneumomediastinum (SP) has been described early during the COVID-19 pandemic in large series of patients with severe pneumonia, but most patients were receiving invasive mechanical ventilation (IMV) at the time of SP diagnosis. In this retrospective multicenter observational study, we aimed at describing the prevalence and outcomes of SP during severe COVID-19 with pneumonia before any IMV, to rule out mechanisms induced by IMV in the development of pneumomediastinum.Among 549 patients, 21 patients (4%) developed a SP while receiving non-invasive respiratory support, after a median of 6 days [4–12] from ICU admission. The proportion of patients requiring IMV was similar. However, the time to tracheal intubation was longer in patients with SP (6 days [5–13] vs. 2 days [1–4]; P = 0.00002), with a higher first-line use of non-invasive ventilation (n = 11; 52% vs. n = 150; 28%; P = 0.02). The 21 patients who developed a SP had persisting signs of severe lung disease and respiratory failure with lower ROX index between ICU admission and occurrence of SP (3.94 [3.15–5.55] at admission vs. 3.25 [2.73–4.02] the day preceding SP; P = 0.1), which may underline potential indirect signals of Patient-self inflicted lung injury (P-SILI).In this series of critically ill COVID-19 patients, the prevalence of SP without IMV was not uncommon, affecting 4% of patients. They received more often vasopressors and had a longer ICU length of stay, as compared with their counterparts. One pathophysiological mechanism may potentially be carried out by P-SILI related to a prolonged respiratory failure, as underlined by a delayed use of IMV and the evolution of the ROX index between ICU admission and the day preceding SP.

Impact of First-Line Use of Caplacizumab on Treatment Outcomes in Immune Thrombotic Thrombocytopenic Purpura: News From the REACT-2020 Cohort

Impact of First-Line Use of Caplacizumab on Treatment Outcomes in Immune Thrombotic Thrombocytopenic Purpura: News From the REACT-2020 Cohort