Impact of a Best Practices Program in Patients with Relapsed/Refractory Multiple Myeloma Receiving Selinexor.

Best practice (BP) in cancer care consists of a multifaceted approach comprising individualized treatment plans, evidence-based medicine, the optimal use of supportive care and patient education. We investigated the impact of a BP program in patients with relapsed/refractory multiple myeloma (RRMM) receiving selinexor. Features of the BP program that were specific to selinexor were initiating selinexor at doses ≤80 mg once weekly and the upfront use of standardized antiemetics. Study endpoints included time to treatment failure (TTF), duration of therapy, dose limiting toxicities and overall survival. Comparative analysis on TTF and duration of therapy was conducted using a log-rank test and multivariate Cox proportional hazard regression. Over the ensuing 12-month post-BP period, 41 patients received selinexor-based therapy compared to 68 patients who received selinexor-based therapy pre-BP implementation. Patients treated in the post-BP period had reductions in TTF (hazard ratio [HR] = 0.50; 95% CI: 0.27 to 0.92). Patients in the pre-BP period were four times more likely to stop therapy than those in the post-period (odds ratio [OR] = 4.0, 95% CI: 1.75 to 9.3). The findings suggest a BP program tailored to selinexor could increase the time to treatment failure, increase treatment duration and lower the incidence of drug limiting toxicities.

Diagnosis and management of systemic mastocytosis in a community hematology setting.

BACKGROUND: Systemic mastocytosis (SM) is a rare and potentially severe hematologic disorder characterized by the clonal proliferation of mast cells (MCs) into various organs. The clinical manifestations of advanced SM are caused by the uncontrolled release of cytokines and vasoactive amines from MC and disease-induced organ dysfunction. Patients with SM typically present with symptoms such as flushing, pruritus, diarrhea, and headaches, but outcomes following active treatment have not been well characterized. In this study, the clinical characteristics, treatment patterns, and natural history of an SM patient cohort diagnosed and treated within a community hematology network in the United States is described. METHODS: We identified 105 patients who were diagnosed and managed in one of 19 community hematology clinics up to an index date of 1 October 2022. Data collection included patient and disease characteristics, baseline biochemistry and hematology, SM diagnostic criteria being met, biomarkers tested, CD2 and/or CD25 expression in MCs as well as serum tryptase levels at presentation. Data abstraction also included supportive care drugs and anticancer therapy used, treatment response, reason for discontinuation, and overall survival by disease subtype. RESULTS: A total of 105 SM patients were identified who met the inclusion criteria. The specific SM subtypes were indolent (47.6%), aggressive (9.5%), SM with an associated hematological neoplasm (19.0%), MC leukemia (1.9%), and subtype not documented (21.9%). Regardless of subtype, approximately 62% of patients did not receive SM-directed active therapy. Only 26% of patients with indolent systemic mastocytosis (ISM) received treatment compared to 65.6% with advanced subtypes. Relative to ISM cohort, the relative risk of death in patients with the advanced SM subtypes was approximately 15 times greater (hazard ratio = 15.0; 95% confidence interval: 3.3 to 66.5). CONCLUSIONS: SM patients present with multiple underlying symptoms, within various disease subtypes that are difficult to diagnose in a timely manner. As a result, many patients do not receive active drug therapy for their disease. Therefore, greater disease awareness is required as well as new tools for earlier disease detection.

Fostamatinib or Thrombopoietic Receptor Agonists for the Treatment of Chronic Immune Thrombocytopenia in Adult Patients: A Real-World Assessment of Safety, Effectiveness and Cost.

INTRODUCTION: Chronic immune thrombocytopenia purpura (ITP) in adults is a serious autoimmune disease in which platelets are prematurely destroyed, leaving the patient vulnerable to bruising and bleeding. Initial treatment is with corticosteroids. In patients who become resistant or intolerant to corticosteroids, the thrombopoietic agents (TPOs), consisting of romiplostim (ROM), eltrombopag (ELT) and avatrombopag (AVA) or the spleen tyrosine kinase inhibitor fostamatinib (FOS), are appropriate next lines of therapy. In this study, the comparative safety, effectiveness and cost of care between fostamatinib vs. the TPOs was evaluated in a real-world setting. METHODS: A retrospective analysis from 17 community hematology practices across the United States was conducted to identify adult ITP patients who received one of the four agents. Data collection consisted of patient demographics, disease characteristics, as well as number and type of prior treatments. From the first day until the end of treatment, data were also collected on platelet (PLT) counts, adverse events, the use of rescue IVIG, platelet transfusions and corticosteroids. Multivariable logistic regression analysis was used to compare PLT related endpoints between agents. RESULTS: A sample of 179 ITP patients who had received at least one of the four agents was identified. This resulted in a final sample of 51, 87, 127 and 44 patients who received FOS, ELT, ROM or AVA respectively. At month six, there were no significant differences between FOS vs. the TPOs in terms of the proportion of patients with the PLT count being ≥ 30 x 103/µL, ≥ 50 x 103/µL as well as the proportion of patients whose PLTs levels doubled relative to baseline. The frequency of thromboembolic events (TEs) was 3.9% in FOS patients compared to 9.2%, 4.7% and 11.4% in the ELT, ROM and AVA groups. The mean cost per patient with FOS was $99,209 (95%CI: $59,595 to $115,074) compared to $92,341 (95:CI$68,331 to $115,519), $108,482 (95%CI: $84,782 to $132,182) and $131,050 (95%CI: $83,327 to $179,897) for ELT, ROM or AVA respectively. CONCLUSIONS: In this real-world analysis, FOS was comparable to the TPOs in maintaining PLTs at clinically beneficial levels. Given these findings, the choice of therapy should be based on overall patient safety, preexisting risk factors for TEs and cost effectiveness.

Therapeutic preference for Alzheimer's disease treatments: a discrete choice experiment with caregivers and neurologists.

BACKGROUND: Alzheimer's disease (AD) is a major global health crisis in need of more effective therapies. However, difficult choices to optimize value-based care will need to be made. While identifying preferred therapeutic attributes of new AD therapies is necessary, few studies have explored how preferences may vary between the stakeholders. In this study, the trade-offs among key attributes of amyloid plaque-lowering therapies for AD were assessed using a discrete choice experiment (DCE) and compared between caregivers and neurologists. METHODS: An initial pilot study was conducted to identify the potentially relevant features of a new therapy. The DCE evaluated seven drug attributes: clinical effects in terms of delay in AD progression over the standard of care (SOC), variation in clinical effects, biomarker response (achieving amyloid plaque clearance on PET scan), amyloid-related imaging abnormalities-edema (ARIA-E), duration of therapy, need for treatment titration as well as route, and frequency of drug administration. Respondents were then randomly presented with 12 choice sets of treatment options and asked to select their preferred option in each choice set. Hierarchical Bayesian regression modeling was used to estimate weighted preference attributes, which were presented as mean partial utility scores (pUS), with higher scores suggesting an increased preference. RESULTS: Both caregivers (n = 137) and neurologists (n = 161) considered clinical effects (mean pUS = 0.47 and 0.82) and a 5% incremental in ARIA-E (mean pUS = - 0.26 and - 0.52) to be highly impactful determinants of therapeutic choice. In contrast, variation in clinical effects (mean pUS = 0.12 and 0.14) and treatment duration (mean pUS = - 0.02 and - 0.13) were the least important characteristics of any new treatment. Neurologists' also indicated that subcutaneous drug delivery (mean pUS = 0.42 vs. 0.07) and administration every 4 weeks (mean pUS = 1.0 vs. 0.20) are highly desirable therapeutic features. Respondents were willing to accept up to a 9% increment in ARIA-E for one additional year of delayed progression. CONCLUSIONS: Caregivers and neurologists considered incremental clinical benefit over SOC and safety to be highly desirable qualities for a new drug that could clear amyloid plaques and delay clinical progression and indicated a willingness to accept incremental ARIA-E to achieve additional clinical benefits.

Treatment Preference for Alzheimer's Disease: A Multicriteria Decision Analysis with Caregivers, Neurologists, and Payors.

INTRODUCTION: Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with a high burden of illness. New therapies under development include agents that target amyloid-beta (Aß), a key component in AD pathogenesis. Understanding the decision-making process for new AD drugs would help determine if such therapies should be adopted by society. Multicriteria decision analysis (MCDA) was applied to three key stakeholder groups to assess treatment alternatives for AD based on a multitude of decision trade-offs covering main components of care. METHODS: AD caregivers (n = 117), neurologists (n = 90), and payors (n = 90) from the USA received an online survey. The decision problem was broken down into four decision criterion and 12 subcriteria for two treatment scenarios: an Aß-targeted therapy vs. the standard of care (SOC). Respondents were asked to indicate how much they preferred one option over another on a scale from 1 (equal preference) to 9 (high preference) based on each criterion and subcriterion. The decision criteria and subcriteria were weighted and presented as partial utility scores (pUS), with higher scores suggesting an increased preference for that decision-making component. RESULTS: Caregivers and payors applied the highest value to need for intervention (mean pUS = 0.303 and 0.259) and clinical outcomes (mean pUS = 0.286 and 0.377). In contrast, neurologists placed the highest value on clinical outcomes and types of benefits (mean pUS = 0.436 and 0.248). When decision subcriteria were examined, efficacy (mean pUS = 0.115, 0.219, and 0.166) and the type of patient benefits (mean pUS = 0.135, 0.178, and 0.126) were among the most valued by caregivers, neurologists, and payors. CONCLUSION: All groups placed the highest value on drug efficacy and types of benefit derived by patients. In contrast, cost implications were among the least important aspects in their decision-making.

Impact of Regulatory Approval Status on CADTH Reimbursement of Oncology Drugs and Role of Real-World Evidence on Conditional Approvals from 2019 to 2021.

Real-world evidence (RWE) is health and outcomes data generated from a patient's journey through the health care system or disease process (i.e., real-world data). RWE is now having an increasingly important role in regulatory/reimbursement decisions. This article examines reimbursement recommendations by the Canadian Agency for Drugs and Technology in Health (CADTH) on oncology drugs approved between 2019 and 2021. Oncology drugs with a Summary Basis of Decision (SBD) for original marketing approvals were used to generate a corresponding list of CADTH final clinical recommendations for review. Of the 45 oncology drugs approved by Health Canada, CADTH granted positive funding recommendations to all 11 drugs that had priority review approvals. Two of the 17 drugs with standard reviews did not file to CADTH and 3 received a negative recommendation. Of the 17 drugs with Notice of Compliance with Conditions (NOCc) status, three were not filed to CADTH and four were under active reviews. Of the ten completed NOCc reviews, all contained RWE from sponsors and six received a negative decision on their first review. No significant differences in review times were found between the three approval statuses. Regulatory approval status appeared to influence reimbursement outcomes in Canada and evaluation of 10 NOCc approvals provided little insight regarding robustness of RWE required for more favorable considerations.

Pre-operative exercise and pyrexia as modifying factors in malignant hyperthermia (MH).

Malignant hyperthermia (MH) is a life-threatening reaction triggered by volatile anesthetics and succinylcholine. MH is caused by mutations in the skeletal muscle ryanodine receptor (RYR1) gene, as is rhabdomyolysis triggered by exertion and/or pyrexia. The discrepancy between the prevalence of risk genotypes and actual MH incidence remains unexplained. We investigated the role of pre-operative exercise and pyrexia as potential MH modifying factors. We included cases from 5 MH referral centers with 1) clinical features suggestive of MH, 2) confirmation of MH susceptibility on Contracture Testing (IVCT or CHCT) and/or RYR1 genetic testing, and a history of 3) strenuous exercise within 72 h and/or pyrexia >37.5 °C prior to the triggering anesthetic. Characteristics of MH-triggering agents, surgery and succinylcholine use were collected. We identified 41 cases with general anesthesias resulting in an MH event (GA+MH, n = 41) within 72 h of strenuous exercise and/or pyrexia. We also identified previous general anesthesias without MH events (GA-MH, n = 51) in the index cases and their MH susceptible relatives. Apart from pre-operative exercise and/or pyrexia, trauma and acute abdomen as surgery indications, emergency surgery and succinylcholine use were also more common with GA+MH events. These observations suggest a link between pre-operative exercise, pyrexia and MH.

A real-world study to evaluate the safety and efficacy of three injectable neurokinin-1 receptor antagonist formulations for the prevention of chemotherapy-induced nausea and vomiting in cancer patients.

BACKGROUND: Three different injectable neurokinin-1 (NK-1) receptor antagonist formulations (CINVANTI® [C] vs. intravenous Emend® [E] vs. generic formulations of fosaprepitant [GFF]) were compared with respect to nausea and vomiting control, use of rescue therapy, and the development of infusion reactions over multiple cycles of chemotherapy. METHODS: A retrospective analysis from 17 community oncology practices across the USA was conducted on patients who received moderately or highly emetogenic chemotherapy. The co-primary endpoints were the control of chemotherapy-induced nausea and vomiting (CINV) from days 1 to 5 over all cycles and the frequency of infusion-related reactions. Propensity score weighted multivariable logistic regression analysis was used to compare complete CINV control, the use of rescue therapy, and the risk of infusion reactions between groups. RESULTS: The study enrolled 294 patients (C = 101, E = 101, GFF = 92) who received 1432 cycles of chemotherapy. Using CINVANTI® as the reference group, comparative effectiveness was suggested in CINV control over all chemotherapy cycles (odds ratio (OR): E vs. C = 1.00 [0.54 to 1.86] and GFF vs. C = 1.12 [0.54 to 2.32]). However, use of rescue therapy was significantly higher in the EMEND® group relative to CINVANTI® (OR = 2.69; 95%CI: 1.06 to 6.84). Infusion reactions were also numerically higher in the EMEND® group, but the difference did not reach statistical significance (OR = 4.35; 95%CI: 0.83 to 22.8). CONCLUSIONS: In this real-world analysis, patients receiving CINVANTI® had a reduced need for CINV rescue therapy and a numerically lower incidence of infusion reactions.

Ibrutinib-associated dermatologic toxicities: A systematic review and meta-analysis.

The scope of dermatologic adverse events to ibrutinib has not been systematically described. We sought to determine the incidence and severity of ibrutinib-associated dermatologic toxicities and provide management recommendations. We conducted a systematic literature search of clinical trials and cohorts investigating ibrutinib monotherapy for cancer or chronic graft-versus-host disease through June 2020. Thirty-two studies with 2258 patients were included. The incidence of all-grade toxicities included cutaneous bleeds (24.8%; 95%CI, 18.6-31.0%), mucocutaneous infections (4.9%; 95%CI, 2.9-7.0%), rash (10.8%; 95%CI. 6.1-15.5%), mucositis (6%; 95%CI, 3.6-8.5%), edema (15.9%; 95%CI, 11.1-20.6%), pruritus (4.0%; 95%CI, 0.0-7.9%), xerosis (9.2%; 95%CI, 5.5-13.0%), nail changes (17.8%; 95%CI, 4.1-31.5%), and hair changes (7.9%; 95%CI, 0.0-21.3%). The incidence of high-grade toxicities included mucocutaneous infection (1.3%; 95%CI, 0.5-2.2%), rash (0.1%; 95%CI, 0.0-0.2%), mucositis (0.1%; 95%CI, 0.0-0.3%), and edema (0.1%; 95%CI, 0.0-0.2%). It is imperative that clinicians familiarize themselves with ibrutinib-associated dermatologic toxicities to learn how to manage them, prevent discontinuation, and improve patient outcomes.

Dermatological Adverse Events in Prostate Cancer Patients Treated with the Androgen Receptor Inhibitor Apalutamide.

PURPOSE: Patients with prostate cancer (PCa) treated with apalutamide frequently develop rash. We aim to characterize apalutamide-related dermatological adverse events (dAEs) and management. MATERIALS AND METHODS: We assessed 303 patients with PCa treated with apalutamide. DAE frequency and time to onset were calculated and clinicopathological features and management described. Associations between dAE occurrence and clinical trial participation, as well as abiraterone/prednisone exposure were detected using logistic regression models. RESULTS: Seventy-one (23.4%) patients had all-grade dAE occurring at a median of 77 (IQR: 30-135) days post-exposure. Twenty (6.6%) dAE-related therapy interruptions included: 8 (2.6%) with dose maintained on rechallenge, 7 (2.3%) with dose reduction and 5 (1.7%) with discontinuation. Common dAEs were maculopapular rashes (33.8%) and xerosis (32.4%). Seven (77.8%) of 9 histological analyses of skin biopsies supported a drug reaction. No significant differences in laboratory hematological, hepatic and renal function were detected between dAE and no dAE cohorts. Most treated grade 1/2 dAEs (29, 40.8%) required topical steroids (14, 19.7%); few required oral steroids (3, 4.2%) ± oral antihistamines. Most grade 3 dAEs (8, 11.3%) required oral/topical steroids (5, 7.0%); few required topical steroids (3, 4.2%) ± oral antihistamines. Clinical trial patients (180, 59.4%) were more likely to report dAEs than those in the off-trial setting (OR=5.1 [95% CI 2.55-10.12]; p <0.001). Of clinical trial patients, concomitant abiraterone/prednisone recipients (109 of 180, 60.6%) were more likely to report dAEs (OR=3.1 [95% CI 1.53-6.17]; p=0.002). CONCLUSIONS: Apalutamide-related dAEs are frequent and can be managed with topical ± oral steroids. With expanded approval of apalutamide, dAE identification and management are essential.

Development of a repeated-measures predictive model and clinical risk score for mortality in ventilated COVID-19 patients.

PURPOSE: The COVID-19 pandemic has caused intensive care units (ICUs) to reach capacities requiring triage. A tool to predict mortality risk in ventilated patients with COVID-19 could inform decision-making and resource allocation, and allow population-level comparisons across institutions. METHODS: This retrospective cohort study included all mechanically ventilated adults with COVID-19 admitted to three tertiary care ICUs in Toronto, Ontario, between 1 March 2020 and 15 December 2020. Generalized estimating equations were used to identify variables predictive of mortality. The primary outcome was the probability of death at three-day intervals from the time of ICU admission (day 0), with risk re-calculation every three days to day 15; the final risk calculation estimated the probability of death at day 15 and beyond. A numerical algorithm was developed from the final model coefficients. RESULTS: One hundred twenty-seven patients were eligible for inclusion. Median ICU length of stay was 26.9 (interquartile range, 15.4-52.0) days. Overall mortality was 42%. From day 0 to 15, the variables age, temperature, lactate level, ventilation tidal volume, and vasopressor use significantly predicted mortality. Our final clinical risk score had an area under the receiver-operating characteristics curve of 0.9 (95% confidence interval [CI], 0.8 to 0.9). For every ten-point increase in risk score, the relative increase in the odds of death was approximately 4, with an odds ratio of 4.1 (95% CI, 2.9 to 5.9). CONCLUSION: Our dynamic prediction tool for mortality in ventilated patients with COVID-19 has excellent diagnostic properties. Notwithstanding, external validation is required before widespread implementation.

RéSUMé: OBJECTIF: En raison de la pandémie de COVID-19, les unités de soins intensifs (USI) ont atteint des taux d'occupation nécessitant un triage. Un outil pour prédire le risque de mortalité chez les patients sous ventilation atteints de COVID-19 pourrait éclairer la prise de décision et l'attribution des ressources tout en permettant des comparaisons populationnelles entre les établissements. MéTHODE: Cette étude de cohorte rétrospective a inclus tous les adultes atteints de COVID-19 sous ventilation mécanique admis dans trois USI de centres de soins tertiaires à Toronto, en Ontario, entre le 1er mars 2020 et le 15 décembre 2020. Des équations d'estimation généralisées ont été utilisées pour identifier les variables prédictives de mortalité. Le critère d'évaluation principal était la probabilité de décès à des intervalles de trois jours à partir du moment de l'admission à l'USI (jour 0), avec un nouveau calcul du risque tous les trois jours jusqu'au jour 15; le calcul final du risque a estimé la probabilité de décès au jour 15 et au-delà. Un algorithme numérique a été mis au point à partir des coefficients du modèle final. RéSULTATS: Cent vingt-sept patients étaient éligibles à l'inclusion. La durée médiane de séjour à l'USI était de 26,9 jours (écart interquartile, 15,4 à 52,0). La mortalité globale était de 42 %. Du jour 0 au jour 15, les variables que sont l'âge, la température, les taux de lactate, le volume courant de ventilation et l'utilisation de vasopresseurs ont constitué des prédicteurs significatifs de mortalité. Notre score de risque clinique final avait une aire sous la courbe ROC de 0,9 (intervalle de confiance [IC] à 95 %, 0,8 à 0,9). Pour chaque augmentation de dix points du score de risque, l'augmentation relative des risques de décès était d'environ 4, avec un rapport de cotes de 4,1 (IC 95 %, 2,9 à 5,9). CONCLUSION: Notre outil de prédiction dynamique de la mortalité pour les patients ventilés atteints de COVID-19 possède d'excellentes propriétés diagnostiques. Néanmoins, une validation externe est nécessaire avant sa mise en œuvre généralisée.

Clinical utility of a prediction tool to differentiate between breast cancer patients at high or low risk of chemotherapy-induced nausea and vomiting.

BACKGROUND: A personalized risk model (PRM) that can categorize patients into high or low risk of ≥ grade 2 acute and/or delayed chemotherapy-induced nausea and vomiting (CINV) was previously developed. The current study assessed whether the PMR could accurately stratify patients' risk for other commonly used CINV endpoints. METHODS: Data was pooled from a previously reported trial evaluating CINV in patients with breast cancer (BC) receiving neo/adjuvant anthracycline-cyclophosphamide or carboplatin-based chemotherapy. The predictive ability of the PRM was compared to patient experience of any self-reported significant nausea, any vomiting, complete cycle response, and use of rescue medications, over all cycles of chemotherapy. RESULTS: Data was available from 242 patients over 819 chemotherapy cycles. Irrespective of the chosen antiemetics, significant nausea was common when evaluated across repeated cycles of treatment with an overall incidence of 24.2% in low-risk patients and 34.6% in high-risk patients. Patients identified as high risk of CINV using the PRM were 4.73 (p = 0.011) times more likely to develop significant nausea than those identified as low risk. The PRM did not show any significant statistical differences between both groups in overall vomiting, complete cycle response, or rescue medications use. CONCLUSION: The PRM was able to identify patients at greater risk of significant nausea but not the other CINV endpoints. As nausea remains a pertinent issue for patients with BC, the PRM could be used to identify these patients a priori for innovative treatment strategies.

A Community Hospital-Based Study: A Prespecified Neutrophil Count with Adjuvant mFOLFOX6 Associated with Increased Delays, Increased G-CSF Use, and Reduced Dose Intensity.

PURPOSE: To look at how the absolute neutrophil count (ANC) is used by community oncologists as the main factor in ordering adjuvant mFOLFOX6 for colorectal cancer. This study reports on how this decision impacts chemotherapy delays, effects received dose intensity (RDI), and increases the use of granulocyte-colony-stimulating factor (G-CSF). METHODS: A retrospective chart review was conducted for all patients receiving adjuvant mFOLFOX6 for colorectal cancer at a two-site community hospital in Toronto, Ontario, Canada, between July 2013 and March 2019. Seven physicians treated 140 patients, who made 1636 clinic visits to receive 1461 cycles of prescribed chemotherapy. RESULTS: The mean ANC per physician associated with a decision to give chemotherapy ranged from 1.05×109/L (95% CI 0.98-1.13×109/L) to 1.5x109/L with a decision to delay if the ANC was lower. Subsequent cycles were then supported by G-CSF with very similar ANC decision levels for dose delay. Physicians were more likely to prescribe chemotherapy with higher pretreatment ANC, r=0.3 (p<0.000). G-CSF was used in 24.6% of cycles and usage had grown to 44.2% by the 12th cycle; physician use ranged from 0.36% to 54.2% of cycles. Secondary prophylaxis was the indication in 94.7% of cases. There was an inverse relationship between the frequency of G-CSF use and the RDI of continuous infusion 5FU, r=-0.26 (p<0.001). There were delays for 8.8% of visits for cycles not supported by G-CSF and, surprisingly, 15.9% of visits for cycles supported by G-CSF. Neutropenia caused 61.6% of delays for chemotherapy cycles not supported by G-CSF and 44.1% for cycles supported by G-CSF. CONCLUSION: Physicians required a pretreatment ANC of 1.05-1.5×109/L before prescribing mFOLFOX6 chemotherapy. When ANC was low, a dose delay and secondary prophylaxis with G-CSF failed to consistently achieve the much sought after ANC. This then caused more delay, reduced RDI and increased expense for both patients and the system. Fewer delays, less G-CSF and increased RDI would have resulted with reduced reliance on ANC and adoption of chemotherapy dose reduction.

Subcutaneous immunoglobulin in allogeneic hematopoietic cell transplant patients: A prospective study of feasibility, safety, and healthcare resource use.

BACKGROUND: We evaluated feasibility, safety, and total resource use of subcutaneous immunoglobulin (SCIG) in a pilot study of patients who underwent allogeneic hematopoietic cell transplant (HCT) over a 6-month period. METHODS: A total of 20 eligible patients were treated with SCIG at 0.1 g/kg/week for up to 6 months. Patients were matched to 20 concurrent intravenous immunoglobulin (IVIG) controls. Clinical outcomes measured included adverse reactions, healthcare resource use, patient satisfaction, and quality of life (QOL). (ClinicalTrials.gov Identifier: NCT03401268.) RESULTS: Groups were comparable in terms of age, weight, sex, transplant indication, donor type, and conditioning intensity. All 20 IVIG patients completed 6 consecutive months of therapy compared with 13/20 (65%) SCIG patients. There were no adverse reactions in IVIG patients, compared with six (30%) SCIG patients. All adverse reactions in SCIG patients were grade I, transient, and required no medical intervention. Median overall cost per patient was lower with SCIG than with IVIG ($9,756 vs. $13,780, p = .046). Among patients who completed 6 months of SCIG, median preference and satisfaction scores were 100%. Over the 6-month period, QOL scores remained stable in SCIG patients. CONCLUSIONS: In a subgroup of patients, SCIG was associated with high patient satisfaction and a reduction in total healthcare costs compared with IVIG in a cohort of HCT patients.

Opioid Prescribing in Canada following the Legalization of Cannabis: A Clinical and Economic Time-Series Analysis.

PURPOSE: On 17 October 2018 recreational cannabis became legal in Canada, thereby increasing access and reducing the stigma associated with its use for pain management. This study assessed total opioid prescribing volumes and expenditures prior to and following cannabis legalization. METHODS: National monthly claims data for public and private payers were obtained from January 2016 to June 2019. The drugs evaluated consisted of morphine, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, oxycodone, tramadol, and the non-opioids gabapentin and pregabalin. All opioid volumes were converted to a mean morphine equivalent dose (MED)/claim, which is analogous to a prescription from a physician. Gabapentin and pregabalin claims data were analyzed separately from the opioids. Time-series regression modelling was undertaken with dependent variables being mean MED/claim and total monthly spending. The slopes of the time-series curves were then compared pre- versus post-cannabis legalization. RESULTS: Over the 42-month period, the mean MED/claim declined within public plans (p < 0.001). However, the decline in MED/claim was 5.4 times greater in the period following legalization (22.3 mg/claim post vs. 4.1 mg/claim pre). Total monthly opioid spending was also reduced to a greater extent post legalization ($Can267,000 vs. $Can95,000 per month). The findings were similar for private drug plans; however, the absolute drop in opioid use was more pronounced (76.9 vs. 30.8 mg/claim). Over the 42-month period, gabapentin and pregabalin usage also declined. CONCLUSIONS: Our findings support the hypothesis that easier access to cannabis for pain may reduce opioid use for both public and private drug plans.

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

A country level analysis measuring the impact of government actions, country preparedness and socioeconomic factors on COVID-19 mortality and related health outcomes.

BACKGROUND: A country level exploratory analysis was conducted to assess the impact of timing and type of national health policy/actions undertaken towards COVID-19 mortality and related health outcomes. METHODS: Information on COVID-19 policies and health outcomes were extracted from websites and country specific sources. Data collection included the government's action, level of national preparedness, and country specific socioeconomic factors. Data was collected from the top 50 countries ranked by number of cases. Multivariable negative binomial regression was used to identify factors associated with COVID-19 mortality and related health outcomes. FINDINGS: Increasing COVID-19 caseloads were associated with countries with higher obesity (adjusted rate ratio [RR]=1.06; 95%CI: 1.01-1.11), median population age (RR=1.10; 95%CI: 1.05-1.15) and longer time to border closures from the first reported case (RR=1.04; 95%CI: 1.01-1.08). Increased mortality per million was significantly associated with higher obesity prevalence (RR=1.12; 95%CI: 1.06-1.19) and per capita gross domestic product (GDP) (RR=1.03; 95%CI: 1.00-1.06). Reduced income dispersion reduced mortality (RR=0.88; 95%CI: 0.83-0.93) and the number of critical cases (RR=0.92; 95% CI: 0.87-0.97). Rapid border closures, full lockdowns, and wide-spread testing were not associated with COVID-19 mortality per million people. However, full lockdowns (RR=2.47: 95%CI: 1.08-5.64) and reduced country vulnerability to biological threats (i.e. high scores on the global health security scale for risk environment) (RR=1.55; 95%CI: 1.13-2.12) were significantly associated with increased patient recovery rates. INTERPRETATION: In this exploratory analysis, low levels of national preparedness, scale of testing and population characteristics were associated with increased national case load and overall mortality. FUNDING: This study is non-funded.

Economic Evaluation of Single versus Combination Immuno-Oncology Therapies: Application of a Novel Modelling Approach in Metastatic Melanoma.

BACKGROUND: Existing economic model frameworks may not adequately capture the atypical treatment response patterns in immuno-oncology (I-O) compared with conventional therapies and thus may fail to represent the full clinical value associated with disease dynamics and improved survival. OBJECTIVE: A cost-effectiveness analysis (CEA) of the I-O Regimen (nivolumab/ipilimumab) versus ipilimumab alone in advanced melanoma was carried out by applying a 5-state partitioned survival model (PSM) as a case study, to explore the I-O treatment response and clinical outcomes. The findings were compared with those of a conventional 3-state PSM. MATERIALS AND METHODS: The case study extends the conventional 3-state PSM, by separating the pre-progression state into non-responders and responders, and the post-progression state into normal and I-O progression to account for delayed treatment effects preceding clinical response. Model states were populated using patient-level data (where possible), mapping from the best overall response (BOR), and survival analysis with flexible and traditional parametric methods. Survival functions were applied to progression-free survival (PFS) and overall survival (OS) endpoints across treatment arms using the 4-year follow-up data (data available at the time of the research; since then 5-year follow-up data have been published) from the CheckMate 067 trial. Information on BOR was used as a means of differentiating the I-O treatment response in addition to the outcomes of progression-free and progressed disease. A UK National Health Service and personal social services (NHS/PSS) perspective over a lifetime horizon was used with outcomes discounted at 3.5% annually. RESULTS: The 5-state PSM generated an increase in quality adjusted life years (QALYs) in both treatment arms and gave a more granular description of patients' health profiles compared with the traditional 3-state PSM. The incremental QALY increased by 13% (from 2.62 to 2.95 QALYs) and the incremental cost decreased by 12% (£29,125 to £25,678) with the 5-state model. In both models, the Regimen had an incremental cost-effectiveness ratio (ICER) relative to ipilimumab alone within the lower bound of the National Institute for Health and Care Excellence (NICE) reference range (£20,000 per QALY gained). CONCLUSION: A 5-state economic model, incorporating relevant I-O health states, can be more informative to gain insight into treatment response and progression differences that are not commonly captured in existing economic models. Clinical trial endpoints, including those relating to treatment response, which are not directly reported in ongoing I-O trials, can be mapped on to the proposed modelled health states (although assumptions are required to do so). Improvements in reporting treatment response in future I-O clinical trials could help to further validate and improve the proposed model framework.

Cohort versus patient level simulation for the economic evaluation of single versus combination immuno-oncology therapies in metastatic melanoma.

Background: Model structure, despite being a key source of uncertainty in economic evaluations, is often not treated as a priority for model development. In oncology, partitioned survival models (PSMs) and Markov models, both types of cohort model, are commonly used, but patient responses to newer immuno-oncology (I-O) agents suggest that more innovative model frameworks should be explored. Objective: A discussion of the theoretical pros and cons of cohort level vs patient level simulation (PLS) models provides the background for an illustrative comparison of I-O therapies, namely nivolumab/ipilimumab combination and ipilimumab alone using patient level data from the CheckMate 067 trial in metastatic melanoma. PSM, Markov, and PLS models were compared on the basis of coherence with short-term clinical trial endpoints and long-term cost per QALY outcomes reported. Methods: The PSM was based on Kaplan-Meier curves from CheckMate 067 with 3-year data on progression free survival (PFS) and overall survival (OS). The Markov model used time independent transition probabilities based on the average trajectory of PFS and OS over the trial period. The PLS model was developed based on baseline characteristics hypothesized to be associated with disease as well as significant mortality and disease progression risk factors identified through a proportional hazards model. Results: The short-term Markov model outputs matched the 1-3 year clinical trial results approximately as well as the PSMs for OS but not PFS. The fixed (average) cohort PLS results corresponded as well as the PSMs for OS in the combination therapy arm and PFS in the monotherapy arm. Over the lifetime horizon, the PLS produced an additional 5.95 quality adjusted life years (QALYs) associated with combination therapy relative to ipilimumab alone, resulting in an incremental cost-effectiveness ratio (ICER) of £6,474 per QALY, compared with £14,194 for the PSMs which gave an incremental benefit of between 2.2 and 2.4 QALYs. The Markov model was an outlier (∼ £49,000 per QALY in the base case). Conclusions: The 4- and 5-state versions of the PSM cohort model estimated in this study deviate from the standard 3-state approach to better capture I-O response patterns. Markov and PLS approaches, by modeling state transitions explicitly, could be more informative in understanding I-O immune response, the PLS particularly so by reflecting heterogeneity in treatment response. However, both require a number of assumptions to capture the immune response effectively. Better I-O representation with surrogate endpoints in future clinical trials could yield greater model validity across all models.

Low-molecular-weight heparins for the prevention of recurrent venous thromboembolism in patients with cancer: A systematic literature review of efficacy and cost-effectiveness.

BACKGROUND: Patients with cancer have an elevated risk of venous thromboembolism. Importantly, patients with cancer, who have metastatic disease, renal insufficiency, or are receiving anticancer therapy, have an even higher risk of a recurrent event. Similarly, the risk of recurrent venous thromboembolism is higher than the risk of an initial event. To reduce the risk, extended duration of prophylaxis for up to six months with low-molecular-weight heparins such as dalteparin, enoxaparin, nadroparin, and tinzaparin is recommended by international guidelines. In this paper, the clinical and economic literature is reviewed to provide evidenced based recommendations based on clinical benefit and economic value. METHODS: A systematic review of major databases was conducted from January 1996 to October 2016 for randomized controlled trials evaluating the four distinct low-molecular-weight heparins against a vitamin K antagonists control group for the prevention of recurrent venous thromboembolism in patients with active cancer. This was then followed by the application of the National Institute of Health and Clinical Excellence guidance to assess the quality of all trials that met the inclusion criteria. Finally, the cost-effectiveness literature supporting the value proposition of each product was reviewed. RESULTS: Six randomized trials met the inclusion criteria. There were one, two, and three trials that compared dalteparin, tinzaparin, and enoxaparin to a vitamin K antagonists control group. However, there were no trials for nadroparin in the setting of secondary venous thromboembolism prevention. In addition, only the dalteparin and one of the tinzaparin trials were of high quality and adequately powered. Of the two studies, only the dalteparin trial reported a statistically significant benefit in terms of venous thromboembolism absolute risk reduction when compared to a vitamin K antagonists control group (HR = 0.48; p = 0.002). In addition, there was robust pharmacoeconomic data from Canada, the Netherlands, France, and Austria supporting the cost-effectiveness of dalteparin for this indication. There were no such studies for any of the other agents. CONCLUSIONS: The totality of high-quality clinical and cost-effectiveness data supports the use of dalteparin over other low-molecular-weight heparins for preventing recurrent venous thromboembolism in patients with cancer.