Early Treatment Discontinuation Research Articles

P526 Measurement of thiopurine metabolites concentrations after one week of treatment does not predict treatment failure in Inflammatory Bowel Disease patients

Abstract Background Conventional thiopurines such as azathioprine (AZA) and mercaptopurine (MP) remain drugs of choice in maintaining remission and corticosteroid sparing in inflammatory bowel disease (IBD). Early discontinuation of thiopurine therapy occurs frequently, due to slow onset of effect and a relatively high frequency of early adverse drug reactions (ADR). Some ADR such as hepatotoxicity and gastro-intestinal complaints are associated with the thiopurine metabolite concentrations 6-thioguanine nucleotides (6-TGN) or 6-methylmercaptopurine ribonucleotides (6-MMPR), in particular elevated 6-MMPR concentrations or unfavorable 6-MMPR/6-TGN ratios. Early measurement of thiopurine metabolites may help to optimize thiopurine therapy in IBD. The aim of this study was to assess the predictive value of thiopurine metabolite measurement one week after thiopurine therapy initiation on discontinuation during the first three months of therapy. Methods This was a multicenter prospective observational study in the Netherlands. Consecutive IBD patients who initiated thiopurine therapy were included and measurement of thiopurine metabolites was performed after 7 days (6 – 8) of treatment (T1). Patients were monitored for 12 weeks to document occurrence of ADR and early treatment discontinuation. Switching to an alternative thiopurine or adding allopurinol (as co-medication) was also considered as treatment discontinuation (to prevent ADR). 6-MMPR concentrations and 6-MMPR/6-TGN ratios were separately analyzed (Mann-Whitney U-tests) regarding therapy discontinuation within 12 weeks. P-values of ≤0.05 were considered statistically significant. Results In total, 255 patients were included, of which 83 were excluded due to either missing blood samples on T1 (n=54), dose adjustments within 12 weeks (n=25) or a delayed T1 measurement (n=4). Of the remaining 172 patients, 79 patients were male (46%), 102 patients had Crohn’s disease (59%) and 157 patients were treated with MP (91%). In total, 88 (51%) patients continued thiopurine therapy and 84 patients (49%) discontinued therapy within 12 weeks. Median 6-MMPR concentrations (1,295 versus 1,589 pmol x 108 red blood cells) and 6-TGN/6-MMPR ratios (8.8 versus 11.4) did not differ significantly between patients who continued versus discontinued therapy within 12 weeks (Figures 1 and 2). Conclusion In this study thiopurine metabolites at T1 did not relate to discontinuation of thiopurine therapy within 12 weeks. We will conduct additional pharmacodynamic studies to corroborate our hypothesis that early metabolite measurements may be of individual patients’ benefit.

Temporal muscle thickness as an independent prognostic imaging marker in newly diagnosed glioblastoma patients: A validation study.

BackgroundPrevious studies have recognized temporal muscle thickness (TMT) as a prognostic marker in glioblastoma, but clinical implementation is hampered due to studies’ heterogeneity and lack of established cutoff values. The aim of this study was to assess the validity of recent proposed sex-specific TMT cutoff values in a real-world population of genotyped primary glioblastoma patients.MethodsWe measured TMT in preoperative MR images of 328 patients. Sex-specific TMT cutoff values were used to divide patients into “at risk of sarcopenia” or “normal muscle status”. Kaplan-Meier analyses and stepwise multivariate Cox-Regression analyses were used to assess the association with overall survival (OS) and progression-free survival (PFS). The association with occurrence of complications and discontinuation of glioblastoma treatment was investigated using odds ratios (OR).ResultsPatients at risk of sarcopenia had a significantly higher risk of progression and death than patients with normal muscle status, which remained significant in the multivariate analyses (OS HR = 1.437; 95%CI: 1.046–1.973; P = .025 and PFS HR = 1.453; 95%CI: 1.037–2.036; P = .030). Patients at risk of sarcopenia also had a significantly higher risk of early discontinuation of treatment (OR = 2.45; 95%CI: 1.011–5.952; P = .042) and a significantly lower chance of receiving second-line treatment (OR = 0.23; 95%CI: 0.09–0.60; P = .001). There was no association with the occurrence of complications.ConclusionsOur study confirms external validity of the use of proposed sex-specific TMT cutoff values as an independent prognostic marker in newly diagnosed glioblastoma patients. This simple, noninvasive marker could improve patient counseling and aid in treatment decision processes or trial stratification.

Predictors of Inpatient Treatment Completion and Non Completion in Patients with Alcohol Dependence from a Tertiary Care Centre in Central India

Introduction: In India, millions of individuals are affected by alcohol dependence as evident by a recent national survey. Apart from the serious health consequences, the use of alcohol brings significant social and economic losses to individuals and society as well. The early treatment discontinuation for deaddiction of alcohol is a major challenge, therefore identification of predictors of treatment completion could be of use to reorganize treatment programs effectively. Aim: To study the predictors of inpatient treatment completion of subjects with alcohol dependence in the deaddiction ward of a tertiary care centre and to compare the socio-demographic and clinical variables among completers and non completers. Materials and Methods: The cross-sectional study was conducted at the Department of Psychiatry, MGM Medical College Indore, India. The purposive sample of 100 patients was recruited in a period of one year. Selected inpatients were assessed through semi-structured proforma consisting of sociodemographic variables, clinical variables, and clinical rating scales i.e., Severity of Alcohol Dependence Questionnaire (SADQ), Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar), and Readiness to Change Questionnaire (RCQ). CIWA and SADQ scores were compared with student’s t-test and RCQ categories were compared with Chi-square test. To identify the predictors of treatment completion, binary logistic regression analysis was used. Results: The mean age of participants was 36.5 years. All patients were male. The majority of the enrolled participants were urban 80 (80%) and 20 (20%) were rural. Binary logistic regression was performed to identify the predictors of treatment completion and non completion, so the treatment completers/ non completers were taken as dependent variables and other socio-demographic/clinical variables as independent variables. The analysis showed that the education (p=0.01), occupation (p=0.01), history of substance in family (p=0.037) and complicated withdrawal (p=0.024) were the significant predictors in the study. Conclusion: The current study concludes that the education, occupation, history of substance in family, initiation of substance in younger age and complicated withdrawal, were the significant predictors of treatment completion in context of alcohol dependence. It was found that the stated readiness to change and treatment completion did not display a significantly positive correlation.

Comparative Pharmacotherapy of Hypertension

The purpose of the study. This study aims to review the practice of the utilization of antihypertensive drugs of various pharmacological groups within the condition of the therapeutic hospital in Ukrainian and Egyptian patients, adherence to treatment in patients with hypertension in Ukraine and Egypt. Materials and methods. A study of 120 patients who were treated for hypertension II stage in a therapeutic hospital in Ternopil and Cairo was conducted. All subjects completed a questionnaire that included personal, socio-demographic, and medical data. The number and type of hypotensive drugs or drug combinations were analyzed. Results and discussion. Regarding the pharmacotherapy of hypertension the use of β-blockers among Ukrainian participants did not differ from Egyptian. The use of calcium channel antagonists was a little bit higher among Egyptians than Ukrainians. Diuretics were used more often by Ukrainians than by Egyptians. The use of ACEI/ARBs surpassed the use of all other classes of antihypertensives among both groups. Whereas the ACEI/ARBs use among Egyptians was lower than Ukrainians. In this study we conducted a determination of compliance which was defined as an act of adhering to the regimen of care recommended by the clinician and persisting with it over time. The majority of Ukrainian and Egyptian patients with hypertension do not always perform the doctor's prescription. The reason for the unfull implementation of medical prescriptions with the same frequency was called deficiency of funds and forgetfulness. Near 80% of Ukrainian respondents are ready to complete the prescription with understanding, however, 14% of the patients stated that they were not always ready to fulfill the prescription, and the smallest part of patients did not think it was necessary to follow the regularity of treatment and treatment regimen. We noted no significant difference in the adherence to antihypertensive therapy between Ukrainian and Egyptian participants. Early discontinuation of treatment and suboptimal daily use of the prescribed regimens are the foremost common facets of poor adherence to treatment as well as non-adherence to antihypertensive therapy correlates with a better risk of cardiovascular events. Conclusion. ACEI/ARBs are the most commonly used group of antihypertensive drugs among Ukrainian and Egyptian patients. The majority of Ukrainian and Egyptian participants with hypertension do not always perform the doctor's prescription. Only 50% had an objective reason for insufficient compliance

192. Tolerability Outcomes of Multi-drug Antibiotic Treatment for Pulmonary Nontuberculous Mycobacterial Disease due to Mycobacterium avium Complex in U.S. Medicare Beneficiaries with Bronchiectasis

BackgroundNontuberculous mycobacteria (NTM), most frequently Mycobacterium avium complex (MAC), cause increasingly common pulmonary infections. Treatment interruptions and early discontinuation are common in MAC therapy, but population-based data on treatment outcomes are severely lacking. We examined tolerability outcomes of guideline-based 3-drug therapies (GBT) targeted for pulmonary MAC infection. MethodsAmong beneficiaries with bronchiectasis (ICD-9-CM 494.0 or 494.1) in U.S. Medicare data (01/2006 – 12/2014), we identified first-time MAC GBT therapy users, excluding those with cystic fibrosis, HIV, or a history of organ transplant. MAC GBT was defined as an overlapping prescription of ≥ 28-day supply of a macrolide, ethambutol and rifamycin. Using Cox regression methods, we compared time-to-regimen change or discontinuation within 12 months of therapy start in the following groups: 1) azithromycin-ethambutol-rifamycin vs. clarithromycin-ethambutol-rifamycin; 2) macrolide-ethambutol-rifampin vs. macrolide-ethambutol-rifabutin; and 3) azithromycin-ethambutol-rifampin vs. clarithromycin-ethambutol-rifabutin.ResultsWe identified 4,626 GBT therapy users (mean 77.9 years [s.d. 6.1], female [77.7%], and non-Hispanic white [87.2%]). Overall, the rate of regimen change or discontinuation was higher in the clarithromycin-based regimens compared to azithromycin-containing regimens, and in rifabutin-containing regimens compared to rifampin-containing regimens. The rate of drug regimen change or discontinuation was 65% greater in the clarithromycin-ethambutol-rifabutin group compared to the azithromycin-ethambutol-rifampin group (adjusted hazard ratio: 1.64, 95% CI: 1.43, 1.64) (Table 1, Figure 1). ConclusionAzithromycin-based regimens and rifampin-containing regimens were less likely to be changed or discontinued within 12 months of therapy compared to clarithromycin-based regimens and rifabutin-containing regimens, respectively. More research is needed to identify factors associated with early treatment change or discontinuation. Disclosures Emily Henkle, PhD, MPH, AN2 (Consultant, Advisor or Review Panel member)Zambon (Advisor or Review Panel member) Theodore K. Marras, MD, Astra Zeneca (Speaker’s Bureau)Insmed (Scientific Research Study Investigator)Novartis (Speaker’s Bureau)RedHill (Consultant)Spero (Consultant) Kevin L. Winthrop, MD, MPH, Insmed (Consultant, Grant/Research Support)Paratek (Consultant)RedHill (Consultant)Spero (Consultant) Kevin L. Winthrop, MD, MPH, Insmed (Consultant, Research Grant or Support)Paratek (Consultant)RedHill Biopharma (Consultant)Spero (Consultant)

Patient-reported treatment toxicity and adverse events in Black and White women receiving chemotherapy for early breast cancer.

It is not known whether chemotherapy-related symptom experiences differ between Black and White women with early breast cancer (Stage I-III) receiving current chemotherapy regimens and, in turn, influences dose delay, dose reduction, early treatment discontinuation, or hospitalization. Patients self-reported their race and provided symptom reports for 17 major side effects throughout chemotherapy. Toxicity and adverse events were analyzed separately for anthracycline and non-anthracycline regimens. Fisher's exact tests and two-sample t-tests compared baseline patient characteristics. Modified Poisson regression estimated relative risks of moderate, severe, or very severe (MSVS) symptom severity, and chemotherapy-related adverse events.Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary.no changes RESULTS: In 294 patients accrued between 2014 and 2020, mean age was 58 (SD13) and 23% were Black. For anthracycline-based regimens, the only significant difference in MSVS symptoms was in lymphedema (41% Black vs 20% White, p = .04) after controlling for axillary surgery. For non-anthracycline regimens, the only significant difference was MSVS peripheral neuropathy (41% Blacks vs. 23% White) after controlling for taxane type (p = .05) and diabetes (p = .05). For all other symptoms, severity scores were similar. Dose reduction differed significantly for non-anthracycline regimens (49% Black vs. 25% White, p = .01), but not for anthracycline regimens or in dose delay, early treatment discontinuation, or hospitalization for either regimen. Except for lymphedema and peripheral neuropathy, Black and White patients reported similar symptom severity during adjuvant chemotherapy. Dose reductions in Black patients were more common for non-anthracycline regimens. In this sample, there were minimal differences in patient-reported symptoms and other adverse outcomes in Black versus White patients.

Evaluating Real-World Effectiveness and Safety of Generic and Brand-Name Imatinib in Chronic Myeloid Leukemia

Introduction: Generic formulations of imatinib were approved and commercially available in the United States starting in 2016, introducing vast cost savings to the standard treatment of chronic myeloid leukemia (CML). While bioequivalence studies of generic formulations are required for Food and Drug Administration approval, the safety of generic drug supply chains have come into question. There is limited real-world data comparing the effectiveness and safety profiles of generic formulations to the original. This study aimed to evaluate the effectiveness and safety of generic imatinib compared to the branded product.Methods: This retrospective study included patients treated at UNC Medical Centers who were diagnosed with CML and treated with imatinib at any time during their course of treatment. Data was retrieved from the institution's electronic health record and collected over the first 6 months of imatinib treatment to include both safety and effectiveness outcomes. The primary endpoint was to compare generic versus branded product effectiveness, as defined by the European LeukemiaNet (ELN) guidelines (achieving BCR-ABL/ABL ratio of <10% and <1% at 3 and 6 months, respectively). The secondary endpoints included comparisons of generic vs branded product safety, measured via patient adverse drug events (ADEs), all-cause hospitalizations, and early treatment discontinuation. Patients were excluded from primary endpoint evaluation and only included for safety endpoint analysis if they were not treated with imatinib first-line and if duration of imatinib treatment was less than 6 months.Results: Fifty-one CML patients met criteria with no significant differences in age or gender between the generic (n = 23) and brand (n = 28) imatinib groups (Table 1). First-line therapy was composed of 83% of patients on generic imatinib and 29% of patients on brand imatinib. Of those receiving first-line imatinib therapy, there was no difference in molecular responses at 3 and 6 months between generic and brand imatinib (p = 0.71). Brand imatinib was associated with numerically lower CML-related emergency department visits and hospitalizations when compared to generic imatinib, although this difference was not statistically significant (p = 0.12). Rates of discontinuation were numerically lower for brand imatinib although overall time to discontinuation was shorter for generic imatinib (Table 1).Conclusions: This study demonstrates real-world treatment effectiveness and safety of generic and brand imatinib in clinical practice. Generic imatinib appears to be associated with higher rates of CML-related ED visits and hospitalizations although sample size was small and statistical significance was not reached. Further analyses of comparisons and continuation of data collection will provide a more robust assessment to compare the effectiveness and safety of generic and brand imatinib in the real-world setting. [Display omitted] DisclosuresMuluneh: Novartis: Other: Spouse works for Novartis.

Randomized Phase II/III Study of DA-EPOCH-R +/- Venetoclax in Previously Untreated Double Hit Lymphoma: Initial Results from Alliance A051701

Randomized Phase II/III Study of DA-EPOCH-R +/- Venetoclax in Previously Untreated Double Hit Lymphoma: Initial Results from Alliance A051701

Final Results of the Fibromet Trial: An Open Label Phase II Study to Evaluate Metformin Effects on Bone Marrow Fibrosis and Disease Progression in Primary Myelofibrosis Patients

▪Background: Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by myeloid expansion associated with elevation of cytokines involved in fibrosis, angiogenesis, and osteosclerosis, leading to progressive fibrous connective tissue deposition in the bone marrow (BM) and BM failure. Although JAK2, CALR and MPL mutations are frequently seen in PMF, patients' molecular heterogeneity and the lack of an expressive clinical and laboratory response following JAK1/2 inhibitors suggest that other factors, such as unknown protein interactions, additional mutations or epigenetic mechanisms may be involved in the progression of PMF. Metformin (MTF) is an anti-diabetic drug, which has been described to possess anti-cancerous properties through the modulation of the AMPK/TORC1 pathway, thereby causing apoptosis in neoplastic cells. Previous reports demonstrated that MTF significantly reduced Ba/F3 JAK2V617F tumor burden and splenomegaly in Jak2V617F knock-in-induced MPN mice. In this context, our goal was to evaluate the effects of MTF treatment in PMF patients.Aims: To report final results of an open label phase II trial (FIBROMET), which evaluated outcomes of PMF patients after 24mo on MTF treatment.Methods: PMF non-diabetic adults were eligible. Patients received MTF in increasing doses until a maximum of 2500mg PO daily, according to tolerance. Primary endpoint was BM fibrosis reversion. Secondary endpoints included reduction of inflammation and downregulation of the JAK-STAT pathway. Samples were collected at the time points: screening (0), 3mo, 6mo, 12mo, 18mo and 24mo. The extent of collagen deposits in BM biopsies was semi-quantitatively assessed with Masson's trichrome stainings, following the recommendations of the European Consensus on grading of BM fibrosis (grades 0, 1, 2 or 3). The levels of CXCL4, sIL-2Ra, IP-10, VEFG-A, MIG, MCP-1, MIP-1b, FGF-2, IL-1RA, IL-5, IL-6, IL-8, IL-15, IL-18, TNFa and TGFb1 were analyzed in BM samples using multiplex assay. Phosphorylation status of intracellular proteins STAT3 and STAT5 was analyzed by flow cytometry and the percentage of cells was recorded using FlowJo software. This trial was approved by the Institutional and National Review Board; written informed consent was obtained from all subjects. REBEC registry number: RBR-52ty66.Results: 11 patients (aged 40-84y) were included between Aug/2018- Feb/2019. Two subjects had early treatment discontinuation due to non-related causes. One patient had disease progression after 12mo of treatment and was submitted to BM transplantation. The median exposure to MTF was 21 mo (3-24) and the median dose was 2500mg/day (1500-2500mg). The most frequent adverse event was diarrhea. No life threatening event occurred. BM collagen deposits were independently evaluated by two hematopathologists with an overall agreement of 80.64% (grade 0: 100%, grade 1: 62.5%, grade 2: 60.0%, grade 3: 90.0%); discordant cases were submitted to joint review. BM collagen deposits did not change when different time points were compared. After 24mo of MTF treatment, a significant 35.4% reduction in IL-5 levels was observed (p=0.03); a 36% reduction in MCP-1 levels was also observed, however this finding was not statistically significant (p=0.06). Flow cytometry analysis demonstrated a STAT3 phosphorylation decrease when comparing screening samples versus 6, 12, 18 and 24 mo of MTF use (all p<0.05), as well as a STAT5 phosphorylation decrease when comparing screening samples versus 6 and 12 mo (all p<0.05). Mean fluorescence intensity for pSTAT3 was: screening 12.01±2.58, 3mo 7.24±1.19, 6mo 4.40±0.24, 12mo 6.31±0.47, 18 mo 6.89±1.01, 24mo 5.71±1.18; and for pSTAT5: screening 15.32±3.59, 3mo 11.50±3.74, 6mo 4.67±0.45, 12mo 6.25±0.58, 18mo 6.24±0.81, 24mo 4.98±0.72.Conclusions: Final results of the FIBROMET trial demonstrated that, in our study population, metformin was not capable of reversing established bone marrow fibrosis in PMF patients. However, a significant downregulation of the JAK-STAT pathway and reduction of cytokine secretion was observed. Finally, metformin showed to be a safe and well-tolerated drug. Phase III studies are required to confirm our results and to evaluate whether MTF treatment in early PMF phases could delay the progression of BM fibrosis through the downregulation of the JAK-STAT pathway. DisclosuresPagnano: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pintpharma: Other: Lecture; EMS: Other: Lecture; Jansenn: Other: Lecture. OffLabel Disclosure:Metformin for Primary Myelofibrosis treatment.

Tolerability of bevacizumab and chemotherapy in a phase 3 clinical trial with human epidermal growth factor receptor 2-negative breast cancer: A trajectory analysis of adverse events.

E5103 was a study designed to evaluate the efficacy and safety of bevacizumab. It was a negative trial for the end points of invasive disease-free survival and overall survival. The current work examines the tolerability of bevacizumab and other medication exposures with respect to clinical outcomes and patient-reported outcomes (PROs). Adverse events (AEs) collected from the Common Terminology Criteria for Adverse Events were summarized to form an AE profile at each treatment cycle. All-grade and high-grade events were separately analyzed. The change in the AE profile over the treatment cycle was delineated as distinct AE trajectory clusters. AE-related and any-reason early treatment discontinuations were treated as clinical outcome measures. PROs were measured with the Functional Assessment of Cancer Therapy-Breast + Lymphedema. The relationships between the AE trajectory and early treatment discontinuation as well as PROs were analyzed. More than half of all AEs (57.5%) were low-grade. A cluster of patients with broad and mixed AE (all-grade) trajectory grades was significantly associated with any-reason early treatment discontinuation (odds ratio [OR], 2.87; P = .01) as well as AE-related discontinuation (OR, 4.14; P = .001). This cluster had the highest count of all-grade AEs per cycle in comparison with other clusters. Another cluster of patients with primary neuropathic AEs in their trajectories had poorer physical well-being in comparison with a trajectory of no or few AEs (P < .01). A high-grade AE trajectory did not predict discontinuations. A sustained and cumulative burden of across-the-board toxicities, which were not necessarily all recognized as high-grade AEs, contributed to early treatment discontinuation. Patients with neuropathic all-grade AEs may require additional attention for preventing deterioration in their physical well-being.

Identification of Clinical Predictors of Benefit of Palliative Thoracic Radiotherapy

Palliative thoracic radiotherapy (PTRT) is frequently utilized for relief of pain, obstruction and hemoptysis from lung and bronchial primary tumors and metastatic disease. Historically, the prognosis for these patients has been dismal with radiotherapy (RT) often serving as a last line of therapy. However, with continued advancements in systemic therapies for non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and other malignancies, PTRT may provide increased benefit both in relief of symptoms and prolongation of life for select patients. In this study, we sought to determine clinical predictors of benefit of PTRT in a contemporary cohort of patients with the goal of aiding in appropriate patient selection for escalation or de-escalation of RT in patients with locally advanced or metastatic disease.Patients treated with standard palliative courses of RT, including 8 Gy/1 fx, 20 Gy/5 fx, and 30 Gy/10 fx, to the thoracic cavity between 2014 and 2020 were identified. Clinical information was collected, including age, ECOG PS, histology, stage, presence of brain metastases, presence of lung collapse, lines of previous systemic therapy, neutrophil-lymphocyte ratio (NLR), mutational status, and survival outcomes. Kaplan-Meier analyses were used for survival and sensitivity analyses. Cox regression was performed for multivariate analysis.161 evaluable patients were identified who received PTRT for various indications including dyspnea, SVC syndrome, hemoptysis, pain and obstruction/lung collapse. A majority of patients (61%) had a diagnosis of NSCLC, although SCLC (10%) and other histologies (29%) were also included. 94% of patients were metastatic at the time of receipt of PTRT. Multivariate analysis identified female sex, multi-fraction regimens, better baseline ECOG performance status, presence of an actionable mutation, absence of brain mets, and non-lung histologies as positive predictors of survival following PTRT (P < 0.05). Other factors including age, number of lines of systemic therapy and NLR were not identified as independent predictors in this cohort in either multivariate or univariate analyses. Notably, 14 patients failed to complete prescribed therapy all of whom had ECOG PS of 2 or greater at start of RT.Patients with symptomatic lung disease derive differential benefit from PTRT with ECOG 0-1, absence of brain mets and presence of actionable mutations important clinical predictors of longer-term survival following treatment. Single fraction courses should be strongly considered for poor PS patients who may derive less significant survival benefit from PTRT and are at higher risk for early treatment discontinuation.

Cachexia index as a potential biomarker for cancer cachexia and a prognostic indicator in diffuse large B-cell lymphoma.

BackgroundCancer cachexia is known to adversely affect the clinical course in patients with malignant lymphoma. The cachexia index (CXI) is a potential biomarker of cancer cachexia, and its implications for the prognosis and treatment outcome of lung cancer and aggressive lymphoma has been assessed in previous studies.MethodsA total of 267 patients diagnosed with diffuse large B‐cell lymphoma who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) immunochemotherapy were retrospectively reviewed. The CXI was calculated as the skeletal muscle index (SMI) × serum albumin/neutrophil–lymphocyte ratio (NLR). Although previous studies measured the SMI using the muscles of the L3 vertebral level, the present study used both the L3 vertebral muscles and the pectoralis muscles (PM) at the T4 vertebral level to measure the SMI. Depending on the type of muscles used, the CXI was termed the L3‐CXI or PM‐CXI. Using sex‐specific cutoff values for CXI, the patients were categorized as follows: (i) high‐CXI group (high L3‐CXI and high PM‐CXI), (ii) intermediate‐CXI group (high L3‐CXI and low PM‐CXI), and (iii) low‐CXI group (low L3‐CXI and low PM‐CXI).ResultsComplete responses to R‐CHOP were obtained in 145/173 (83.8%), 25/36 (69.4%), and 27/57 (47.4%) patients in the high‐CXI, intermediate‐CXI, and low‐CXI groups, respectively (P < 0.001). Treatment‐related anaemia (15.6%, 30.6%, and 26.3%, P = 0.038), thrombocytopenia (21.4%, 36.1%, and 43.9%, P < 0.001), febrile neutropenia (23.7%, 44.4%, and 36.8%, P = 0.022), and any nonhaematologic toxicity (31.2%, 44.4%, and 54.4%, P = 0.001) of Grade 3 or more were more common in the lower CXI groups than in the higher‐CXI groups. Early treatment discontinuation for reasons other than lymphoma progression also occurred more frequently in the low‐CXI group (24/57, 42.1%) compared with the intermediate‐CXI (5/36, 13.9%) and high‐CXI (18/173, 10.4%) groups (P < 0.001). Median overall survival in the high‐CXI, intermediate‐CXI, and low‐CXI groups was not reached, 50.6 months, and 14.5 months, respectively (p < 0.001). Multivariable analysis showed that low CXI was an independent negative prognostic factor for overall survival (hazard ratio 2.103, 95% confidence interval 1.278–3.460, P = 0.003).ConclusionsWe suggest that in patients with diffuse large B‐cell lymphoma, the CXI is a biomarker for cancer cachexia that can predict survival, treatment response, treatment‐related toxicity, and compliance with R‐CHOP. Patients were more clearly stratified by this new CXI category compared with the classifications described in previous studies.

The effect of tumor size and metastatic extent on the efficacy of first line pembrolizumab monotherapy in patients with high PD-L1 expressing advanced NSCLC tumors

BackgroundTumor size and metastatic extent may influence tumor response to immunotherapy in non-small cell lung cancer (NSCLC). The aim of this study was to examine the relationship between both baseline sum of longest diameters (bSLD) and number of metastatic organs (NMO) and the tumor response to pembrolizumab. Secondly, we aimed to analyze the association of baseline SLD and NMO with progression-free survival (PFS) and overall survival (OS). MethodsThis retrospective study included patients with high PD-L1 expressing tumors (≥50%) and a good performance score (ECOG ≤ 2) that received first-line pembrolizumab monotherapy. Tumor response was calculated as the ‘SLD-change score’ and ‘early treatment discontinuation’ within 3 months on therapy (ETD). The relationship of both bSLD (based on RECIST v1.1) and NMO with tumor response and survival outcome (PFS, OS) was evaluated. ResultsNo significant differences in SLD-change score could be found using bSLD (OR = 1.010, 95%CI = 0.999–1.021), or using NMO at baseline (OR = 1.608, 95%CI = 0.943–2.743). A bSLD cut-off value of 90 mm was found to be most distinctive for ETD. This cut-off value showed a significant difference for PFS (HR = 2.28, 95%CI = 1.12–4.64, p = 0.023) and OS (HR = 2.99, 95%CI = 1.41–6.34, p = 0.004). NMO also showed a difference for PFS and OS, however, not statistically significant. ConclusionsTumor size and metastatic extent could not discriminate for tumor response, however, a bSLD of 90 mm could differentiate for PFS and OS.

5.19 A Literature Review: Racial and Ethnic Disparities in the Diagnosis and Treatment of ADHD

ADHD is a neurodevelopmental disorder characterized by symptoms of inattention, hyperactivity, and impulsivity. ADHD has a prevalence rate of approximately 5% in children and responds well to therapeutic interventions. If untreated, ADHD can cause impairment in academic and social functioning. This review aims to study the current literature to identify disparities in diagnoses and treatment among non-Hispanic White and ethnic and racial minority patients. A literature review was conducted among studies from the last 10 years from PubMed and PsycINFO. The search terms used in PsycINFO were “treat/intervention or diagnosis/assess or clinical decision” and “ADHD and racial bias/racial or ethnic differences.” The search terms used in PubMed were “ADHD,” “ADHD and racial disparity,” and “ADHD, treatment and racial disparities.” Combined, 36 studies were imported for screening from 2 sources with 9 duplicates, leaving 27 studies. Of these, 5 were considered irrelevant by authors. A full-text review was done for 22 studies. Nearly all studies showed that ethnic and racial minority children, mainly African Americans and Latinx, were less likely to be diagnosed with ADHD when compared to the non-Hispanic White youth. These disparities remained even after various environmental and sociocultural confounding factors were statistically controlled for by logistic regression. Furthermore, minority children were also less likely to receive care and were at risk of early discontinuation of treatment. Two recent studies have shown increasing rates of diagnosis and treatment of ADHD in Black children; however, the disparity remains. Although ethnic and racial minority children exhibit the same severity of ADHD symptoms when compared to non-Hispanic White youth, they are less likely to be diagnosed with ADHD and have decreased odds of receiving appropriate psychopharmacologic and other treatment modalities. Barriers to care included minority status, less parental education, and lack of insurance, which decreased the chances of getting a comprehensive evaluation and which also decreased the odds of identifying comorbidities associated with ADHD. When ethnic minority children receive less comprehensive evaluations, there may be more opportunities for unconscious bias to impact diagnosis and treatment.

How Antibiotics Stewardship Can Be Safely Implemented in Patients with Septic Shock?

In critically ill patients with sepsis and septic shock, the need for prompt and adequate antibiotic therapy is balanced by the risk of excessive antibiotic exposure that leads to emergence of multidrug-resistant pathogens. As such, antibiotic stewardship programs propose a set of operating rules from antibiotic treatment initiation to de-escalation and finally cessation. In this review, we will describe the rationale for early antibiotic treatment in septic patients, how to optimize initial antibiotic treatment, rules for early treatment discontinuation in pathogen-negative sepsis, and optimal duration of antimicrobial therapy.

Patient Factors Influencing Outpatient Retention in Patients with Affective and Anxiety Disorders: A Retrospective Study.

ObjectiveThe aim of the present study is to identify the factors that affect retention in outpatients with psychiatric disorders as indicators of treatment adherence, including Minnesota Multiphasic Personality Inventory (MMPI) scores.MethodsThe medical records of 146 patients diagnosed with major depressive disorder, bipolar disorder, or anxiety disorder for at least 10 years and discharged were retrospectively reviewed in the present study. The subjects were categorized based on the duration of outpatient treatment as < 6 months (L6) or ≥ 6 months (M6) groups and reclassified as < 36 months (L36) and ≥ 36 months (M36) groups. The demographic, clinical, and personality characteristics of the groups were compared.ResultsPatients in M6 and M36 groups were more likely to have a higher educational level compared with those in the L6 and L36 groups, respectively. Patients in the M6 group showed significantly lower hypomania (Ma) scores on the MMPI test than did patients in the L6 group.ConclusionThe association between high Ma score on the MMPI test and early discontinuation of treatment suggests that impulsivity, hostility, and disinhibition confer higher risk of nonadherence.

Multicenter analysis of geriatric fitness and real-world outcomes in older patients with classical Hodgkin lymphoma

AbstractWe performed a multicenter retrospective analysis across 10 US academic medical centers to evaluate treatment patterns and outcomes in patients age ≥60 years with classic Hodgkin lymphoma (cHL) from 2010-2018. Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 96% had Eastern Cooperative Oncology Group performance status (PS) 0-2, and 12% had documented loss of ≥1 activity of daily living (ADL). Medical comorbidities were assessed by the Cumulative Illness Rating Scale–Geriatric (CIRS-G), where n = 44 (18%) had total scores ≥10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; hazard ratio [HR] 2.13, P = .007) and overall survival (OS; HR 2.52, P = .02). Most patients (n = 203, 83%) received conventional chemotherapy regimens, including doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P = .0007) and OS (HR 0.31, P = .0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs ≥70: PFS HR 0.88, P = .63; OS HR 0.73, P = .55. Early treatment discontinuation due to toxicity was more common with CIRS-G ≥10 (28% vs 12%, P = .016) or documented geriatric syndrome (28% vs 13%, P = .02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, P = .02) and higher mortality from causes other than disease or treatment with high CIRS-G or geriatric syndromes. This study suggests conventional chemotherapy regimens remain a standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward.

Treatment Persistence of Renin-Angiotensin-Aldosterone-System Inhibitors Over Time in Heart Failure with Reduced Ejection Fraction

Clinical practice guidelines support sustained use of renin-angiotensin-aldosterone-system (RAAS) inhibitors over time in heart failure with reduced ejection fraction, yet few data are available regarding the frequency, timing or predictors of early treatment discontinuation in clinical practice. Among prevalent or new users of angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), and mineralocorticoid receptor antagonists (MRAs) in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry, we estimated the frequency and independent predictors of treatment discontinuation during follow-up. Among sites with > 5 users of a given RAAS inhibitor, we evaluated practice variation in the proportion of patients with treatment discontinuation. Over median follow-up of 18 months, frequency of drug discontinuation of ACEis/ARBs, ARNIs and MRAs was 12.7% (444 of 3509 users), 10.4% (140 of 1352 users), and 20.4% (435 of 2129 users), respectively. An additional, 149 (11.0%) of ARNI users were switched to ACEis/ARBs, and 447 (12.7%) of ACEi/ARB users were switched to ARNIs during follow-up. Across sites, the median proportion of discontinuation of ACEis/ARBs, ARNIs and MRAs was 12.5% (25th-75th percentiles 6.9%-18.9%), 18.8% (25th-75th percentiles 12.5%-28.6%), and 19.6% (25th-75th percentiles 10.7%-27.0%), respectively. Chronic kidney disease was the only independent predictor of increased risk of discontinuation of each of the RAAS inhibitor classes (P < 0.02 for all). Higher Kansas City Cardiomyopathy Questionnaire overall summary scores independently predicted lower risk of discontinuation of ACEis/ARBs and ARNIs (both P < 0.001) but not of MRAs. Investigator clinical experience was predictive of lower risks of discontinuation of ACEis/ARBs and MRAs (P < 0.02) but not of ARNIs. All other independent predictors of discontinuation were unique to individual therapeutic classes. One in 10 patients discontinue ACEis/ARBs or ARNIs, and 1 in 5 discontinue MRAs in routine clinical practice of heart failure with reduced ejection fraction. Unique patient-level and clinician/practice-level factors are associated with premature discontinuation of individual RAAS inhibitors, which may help to guide structured efforts to promote treatment persistence in clinical care.

C-Reactive Protein, Interleukin-6, and Procalcitonin in Diagnosis of Late-Onset Bloodstream Infection in Very Preterm Infants.

Late-onset bloodstream infection (LOBSI) is common in very preterm infants. Early and accurate diagnosis is crucial for prognosis and outcome. We aimed to analyze the accuracy of routinely used inflammatory biomarkers in the diagnosis of LOBSI as compared to uninfected controls. In this single-center, retrospective case-control study, interleukin-6 (IL-6), procalcitonin (PCT), and C-reactive protein (CRP) were routinely measured, when infection was clinically suspected. The definition of LOBSI was based on positive blood culture, clinical signs of infection, and onset more than 72 hours after birth. Among 285 enrolled infants, 66 developed LOBSI. IL-6 was superior to other markers, and levels greater than 100 ng/L had a sensitivity of 94% and a specificity of 99% for the presence of LOBSI. Receiver operating characteristic curve of IL-6 had area under the curve of 0.988 (95% CI = 0.975-1.00, P < .001). The negative predictive value of IL-6, CRP, and PCT for optimal cutoff values was 99%, 95%, and 93%, respectively. The logistic regression model of IL-6 > 100 ng/L or CRP > 10 mg/L were successfully predicted LOBSI in 97.9% of cases. The combination of IL-6 and CRP seems to have great potential in routine rapid diagnosis of LOBSI development. High negative predictive value of all tested markers could encourage the early discontinuation of antibiotic treatment.

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival

BackgroundSeveral therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab...