Early Switching Research Articles

Practical Issues in Early Switching from Intravenous to Oral Antibiotic Therapy in Children with Uncomplicated Acute Hematogenous Osteomyelitis: Results from an Italian Survey.

Background: The European Society of Pediatric Infectious Diseases (ESPID) guidelines for acute hematogenous osteomyelitis (AHOM) have been published recently. In uncomplicated cases, an early (2–4 days) switch to oral empirical therapy, preferentially with flucloxacillin, is recommended in low methicillin-resistant Staphylococcus aureus settings. We conducted a survey with the aim of evaluating the behaviors of Italian pediatricians at this regard. Methods: An open-ended questionnaire investigating the empiric therapy adopted in uncomplicated AHOM children according to age was sent by email to 31 Italian pediatric clinics taking care of children with infectious diseases, and results were analyzed. Results: The preferred intravenous (IV) regimen was a penicillin plus an aminoglycoside (n = 10; 32.3%) in children aged <3 months, and a combination of a third-generation cephalosporin plus oxacillin (n = 7; 22.6%), or oxacillin alone (n = 6; 19.4%) in those ≥3 months. In every age class, amoxicillin-clavulanate was the first-choice oral antibiotic. Other antibiotics largely used orally included clindamycin, rifampicin, and trimethoprim/sulfamethoxazole. Flucloxacillin was never prescribed. Only 3 centers switched to oral therapy within 7 days in children ≥3 months of age. The most commonly reported reason influencing the time to switch to oral therapy concerned caregivers’ adherence to oral therapy. Conclusion: Adherence to guidelines was poor, and early transition to oral therapy in the clinical practice was rarely adopted. Given the large use of potentially effective, but poorly studied, oral antibiotics such as amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, and rifampicin, our data may stimulate further studies of this regard.

A machine learning model to predict hepatocellular carcinoma response to transcatheter arterial chemoembolization.

Some patients with hepatocellular carcinoma (HCC) are more likely to experience disease progression despite transcatheter arterial chemoembolization (TACE) treatment, and thus would benefit from early switching to other therapeutic regimens. We sought to evaluate a fully automated machine learning algorithm that uses pre-therapeutic quantitative computed tomography (CT) image features and clinical factors to predict HCC response to TACE. Outcome information from 105 patients receiving first-line treatment with TACE was evaluated retrospectively. The primary clinical endpoint was time to progression (TTP) based on follow-up CT radiological criteria (mRECIST). A 14-week cutoff was used to classify patients as TACE-susceptible (TTP ≥14 weeks) or TACE-refractory (TTP <14 weeks). Response to TACE was predicted using a random forest classifier with the Barcelona Clinic Liver Cancer (BCLC) stage and quantitative image features as input as well as the BCLC stage alone as a control. The model's response prediction accuracy rate was 74.2% (95% CI=64%-82%) using a combination of the BCLC stage plus quantitative image features versus 62.9% (95% CI= 52%-72%) using the BCLC stage alone. Shape image features of the tumor and background liver were the dominant features correlated to the TTP as selected by the Boruta method and were used to predict the outcome. This preliminary study demonstrates that quantitative image features obtained prior to therapy can improve the accuracy of predicting response of HCC to TACE. This approach is likely to provide useful information for aiding HCC patient selection for TACE.

Early switching of antibiotic therapy from intravenous to oral using a combination of education, pocket-sized cards and switch advice: A practical intervention resulting in reduced length of hospital stay

To assess the effectiveness of a combined intervention on the timing and rate of switching from intravenous (IV) to oral antibiotic therapy. The study used a historically-controlled prospective intervention design. Interventions consisted of educating physicians, handing out pocket-sized cards and providing switch advice in the electronic patient record (EPR). All patients hospitalized at the surgery department who were treated with IV antibiotics for at least 24 h and who fulfilled the switch criteria within 72 h of IV treatment were included. Outcomes before and during the intervention were compared. An early IV to oral switch took place in 35.4% (35/99) of the antibiotic courses in the baseline period and in 67.7% (42/62) of the antibiotic courses in the intervention period (odds ratio [OR] 3.84, 95% confidence interval [CI] 1.96-7.53). Duration of IV therapy was significantly reduced from 5 to 3 days (P<0.01). Length of hospitalization was reduced from 6 to 5 days (P<0.05). The interventions were effective in promoting an early IV to oral antibiotic switch by shortening the length of IV therapy and hospital stay.

Efficacy and safety of early switching to an outpatient therapy model using oral arsenic plus retinoic acid based-regimen in newly diagnosed acute promyelocytic leukemia

Realgar-Indigo naturalis formula(RIF)is an oral form of arsenic developed for treatment of acute promyelocytic leukemia (APL). We retrospectively evaluated the efficacy and safety of a novel RIF combined with all-trans retinoic acid (ATRA) based chemotherapy-free approach in newly diagnosed APL patients. Patients received oral ATRA (25 mg/m2/day in 2 divided doses) plus intravenous arsenic trioxide (0.15 mg/kg/day) or oral RIF (60 mg/kg/day in 3 divided doses) as induction chemotherapy, followed by 2 consolidations with ATRA plus RIF and maintenance therapy with intermittent ATRA and RIF. From January 2015 to December 2017, 40 subjects were enrolled. Eighteen subjects were male. Median age was 42 years (range, 14–77 years) and 10 subjects were ≥ 60 years. All subjects achieved a complete morphologic remission after initial induction. Molecular complete remission achieved 100% after second RIF plus ATRA consolidation. Median follow-up of survivors was 27 months (range, 7–43 months). The 2-year event-free survival (EFS) and overall survival (OS) were both 100%. Adverse events were modest and all patients needed only outpatient care during postremission therapy. Compared to our historical RIF plus ATRA with chemotherapy regimen (the Chinese APL07 trial), the inpatient treatment duration was greatly reduced by the RIF plus ATRA regimen. Our data indicates that early switching to RIF plus ATRA based chemotherapy-free approach has yielded encouraging outcomes and might be considered a practicable option to treat patients with newly diagnosed APL.

Highly Aggressive Multiple Sclerosis

Newly introduced disease-modifying therapies offer greater efficacy than previous therapies but also have serious side effects. This article reviews factors useful in identifying those at risk of developing aggressive relapsing multiple sclerosis (MS) and therapies available for treatment. Several factors predict aggressive MS, including demographic factors, relapses, symptom characteristics, MRI activity, and other biomarkers. These can be used to select patients for more aggressive therapies, including natalizumab, alemtuzumab, fingolimod, and ocrelizumab. Additional off-label treatments are available for patients with severe disease. The benefits and side effects of these treatments must be considered when making therapeutic decisions. Selecting patients who are most appropriate for aggressive therapy involves considering risk factors for poor outcomes, early recognition of treatment failure, balancing treatment efficacy and side effects, and sharing the decision with patients to assist them in making optimal treatment choices. Vigilance for signs of treatment failure and early switching to more aggressive therapy are important components in optimal care.

Real-world use of ticagrelor versus clopidogrel in percutaneous coronary intervention-treated ST-elevation myocardial infarction patients: A single-center registry study

ObjectivesThe primary aim was to investigate the efficacy and safety of dual antiplatelet therapy (DAPT) using ticagrelor (T-DAPT) versus clopidogrel (C-DAPT) in a real-world ST-elevation myocardial infarction (STEMI) population. MethodsWe retrospectively analyzed 655 consecutive patients having primary percutaneous coronary intervention (PCI) for STEMI at Liverpool Hospital, Sydney, Australia (from January 2013 to April 2016). Medical and procedural therapies were at clinician discretion. Patient data were retrieved from hospital records and primary clinicians. ResultsT-DAPT (65%) was used more frequently, and in patients with lower mean CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines) score, than C-DAPT (24.6 vs. 32.2; p < 0.0001, respectively). All-cause mortality was 9.0% at 2.7 years follow-up, with fewer deaths for T-DAPT (4.5% vs. 17.2%; p < 0.0001). T-DAPT incurred less BARC (Bleeding Academic Research Consortium) 3–5 major bleeding (5.0% vs. 12.4%; p < 0.0001). Multivariate regression showed that C-DAPT, GRACE (Global Registry of Acute Cardiac Events) score, and renal insufficiency were independently associated with mortality. Intra-aortic balloon pump (IABP) and GRACE score independently predicted BARC 3–5 bleeding. Early DAPT discontinuation (1.7%) and ticagrelor intolerance (7.6%) was rare. Switching DAPT regimen was infrequent (21.7%) and mostly attributed to clinician preference (73.2%). Independent determinants of C-DAPT selection were older age, diabetes, prior PCI, IABP, and higher CRUSADE score. ConclusionTicagrelor was preferred in low bleeding risk patients, which may have contributed to less BARC 3–5 bleeding and lower mortality for T-DAPT. Thus, bleeding mitigation is a clinical priority when selecting DAPT for PCI-treated STEMI patients. Continuation of initial DAPT regimen was typical, but early switching from clopidogrel to ticagrelor shows willingness to optimize DAPT. Patients with very low CRUSADE scores (<21.5) may be appropriate for switching to a potent P2Y12 inhibitor.

B cell-intrinsic MyD88 signaling controls IFN-γ-mediated early IgG2c class switching in mice in response to a particulate adjuvant.

Adjuvants improve the potency of vaccines, but the modes of action (MOAs) of most adjuvants are largely unknown. TLR-dependent and -independent innate immune signaling through the adaptor molecule MyD88 has been shown to be pivotal to the effects of most adjuvants; however, MyD88's involvement in the TLR-independent MOAs of adjuvants is poorly understood. Here, using the T-dependent antigen NIPOVA and a unique particulate adjuvant called synthetic hemozoin (sHZ), we show that MyD88 is required for early GC formation and enhanced antibody class-switch recombination (CSR) in mice. Using cell-type-specific MyD88 KO mice, we found that IgG2c class switching, but not IgG1 class switching, was controlled by Bcell-intrinsic MyD88 signaling. Notably, IFN-γ produced by various cells including Tcells, NK cells, and dendritic cells was the primary cytokine for IgG2c CSR and B-cell intrinsic MyD88 is required for IFN-γ production. Moreover, IFN-γ receptor (IFNγR) deficiency abolished sHZ-induced IgG2c production, while recombinant IFN-γ administration successfully rescued IgG2c CSR impairment in mice lacking B-cell intrinsic MyD88. Together, our results show that Bcell-intrinsic MyD88 signaling is involved in the MOA of certain particulate adjuvants and this may enhance our specific understanding of how adjuvants and vaccines work.

Cost Controversies of a "Home Dialysis First" Policy.

Purpose of review:Kidney Failure is highly prevalent and uses a disproportionate amount of health care funding. In Canada (excluding Quebec), 37 647 people were living with kidney failure in 2016. The single-payer Canadian health care system spends approximately 1.2% of their annual budget on kidney failure. In 2016, 58.4% of patients with kidney failure in Canada (excluding Quebec) were on dialysis as opposed to living with a functioning kidney transplant. Home dialysis modalities including peritoneal dialysis (PD) and home hemodialysis (HD) were used by 18.9% and 4.7% of these patients, respectively. In-center HD and home dialysis (PD and home HD) are often considered equally efficacious and have similar impacts on quality of life. Despite cost minimization analyses suggesting that home dialysis offers cost savings over in-center HD, there has been a slow uptake of home dialysis in developed nations over time, suggesting that controversies and barriers to implementation currently exist. The primary objective of this health policy briefing article is to introduce and address some of the major controversies surrounding the cost effectiveness in supporting advocacy for a “Home Dialysis First” policy with a primary focus on single-payer systems in a developed nation such as Canada.Sources of information:Canadian Agency for Drugs and Technologies in Health (CADTH), Canadian and US epidemiologic databases, national/international conference presentations, primary literature review, and discussion with experts within the field of home dialysis.Methods:We have conducted a focused primary literature review alongside individuals with expertise in the field of home dialysis to discuss the cost controversies surrounding the implementation of a “Home Dialysis First” policy.Key findings:First, the primary literature is limited to mostly observational studies which are highly variable in study design and content. Local economic assessments, however, have provided convincing data for home dialysis cost savings in Canada. Second, the cost of delivering dialysis differs significantly throughout the world, explained by differing costs of labor and supplies in developing nations. Third, the indirect patient costs of water, energy, and home modifications are often barriers to implementation and may be overcome by introducing cost reimbursement programs. Fourth, home dialysis requires upfront training costs. We explore the impact of premature switches from home dialysis to in-center HD or a functioning kidney transplant on overall cost savings. Fifth, we discuss the effect of physician financial incentives and program funding on the uptake of home dialysis. Finally, we introduce the controversial topic of comparing the societal value of freedom of modality choice against the societal cost savings of a “Home Dialysis First” policy.Limitations:Narrative reviews, due to their inherently reduced methodological quality in comparison with systematic reviews, may expose our collected literature to selection bias. We have attempted to compose a diverse collection of available literature alongside consensus expertise to provide a fair and concise review of home dialysis cost controversies.Implications:Implementation of a “Home Dialysis First” policy would be a disruptive change to kidney failure care in Canada. To make informed policy decisions, we should recognize the cost savings associated with home dialysis in developed nations, the significance of patient-borne costs as a barrier to implementation, the impact of training costs and early modality switching in home dialysis, the lack of evidence regarding physician financial incentives, and the importance of program funding. Ultimately, we must consider the societal value of freedom of patient modality choice in comparison with the potential cost savings of a “Home Dialysis First” policy.

Early Complete Response after Chemotherapy as A Prognostic Indicator for Final Outcome in High Grade Non-Hodgkin’s Lymphoma Patients

Background: In spite of progress in management of high-grade Non-Hodgkin’s Lymphoma (NHL), more than 30% will ultimately relapse after standard treatment. Aim of study: was to estimate early complete response (CR) as a prognostic factor for final outcome and benefit of early switching to second line chemotherapy for slow responders. Patients and Method: Newly diagnosed patients with high-grade NHL were randomized to either Group A or Group B. All patients received 3 cycles of CHOP/RCHOP while, only patients in the group B who didn't achieve early CR were shifted to second line chemotherapy. Results: The clinicopathological characteristics of patients included in the two groups were comparable. Assessment of treatment results after the 6th cycle showed that 10 patients achieved late CR, 4 patients in group A (40%-4/10) and 6 patients in group B (6/7–85.7%). This difference was statistically significant (p-value 0.04). Out of the early CR group (24 patients), one patient died and another developed CNS relapse thus, both mortality (1/24) and relapse rate (1/23) of early CR group is 4%. Two patients of late CR group relapse (2/10-20%). The difference between the relapse rates of early CR (4%) and late CR (20%) wasn't statistically significant. The remaining 22 patients (22/23-95.7%) achieved early CR and 8 achieved late CR (8/10-80%) were in maintained remission. Regarding toxicity profile, there was no significant difference between both groups. Conclusion: Early shifting to second-line chemotherapy is tolerable and promising. However, studies with larger number of patients are mandatory to identify who may need this approach.

Early Complete Response after Chemotherapy as A Prognostic Indicator for Final Outcome in High Grade Non-Hodgkin’s Lymphoma Patients

Background: In spite of progress in management of high-grade Non-Hodgkin’s Lymphoma (NHL), more than 30% will ultimately relapse after standard treatment. Aim of study: was to estimate early complete response (CR) as a prognostic factor for final outcome and benefit of early switching to second line chemotherapy for slow responders. Patients and Method: Newly diagnosed patients with high-grade NHL were randomized to either Group A or Group B. All patients received 3 cycles of CHOP/RCHOP while, only patients in the group B who didn't achieve early CR were shifted to second line chemotherapy. Results: The clinicopathological characteristics of patients included in the two groups were comparable. Assessment of treatment results after the 6th cycle showed that 10 patients achieved late CR, 4 patients in group A (40%-4/10) and 6 patients in group B (6/7–85.7%). This difference was statistically significant (p-value 0.04). Out of the early CR group (24 patients), one patient died and another developed CNS relapse thus, both mortality (1/24) and relapse rate (1/23) of early CR group is 4%. Two patients of late CR group relapse (2/10-20%). The difference between the relapse rates of early CR (4%) and late CR (20%) wasn't statistically significant. The remaining 22 patients (22/23-95.7%) achieved early CR and 8 achieved late CR (8/10-80%) were in maintained remission. Regarding toxicity profile, there was no significant difference between both groups. Conclusion: Early shifting to second-line chemotherapy is tolerable and promising. However, studies with larger number of patients are mandatory to identify who may need this approach.

Predictors of contraceptive switching and discontinuation within the first 6 months of use among Highly Effective Reversible Contraceptive Initiative Salt Lake study participants

Nearly half of women will switch or discontinue using their selected contraceptive method in the first year. Research on early switching or discontinuation provides important clinical and public health insights, although few studies have assessed associated factors, particularly among longitudinal cohorts. The current study explores attributes associated with early contraceptive method switching or discontinuation (<6 months of initiation) among participants enrolled in the intervention cohorts of the Highly Effective Reversible Contraceptive Initiative Salt Lake Contraceptive Initiative (Utah, United States). Highly Effective Reversible Contraceptive Initiative Salt Lake participants have access to no-cost contraception for 3 years. This includes both the initial selection and the ability to switch or to discontinue methods without cost. Methods available included the following: nonhormonal behavioral methods (male/female condoms, withdrawal, diaphragms, cervical caps, and fertility awareness); short-acting methods (pill, patch, ring, and injectable); and long-acting methods (intrauterine devices and contraceptive implants). Participants completed surveys at baseline and at 1, 3, and 6 months. We collected data on participant demographics, contraceptive continuation, switching, and discontinuation, as well as factors associated with these changes, including established measures of pregnancy intention and ambivalence and reasons for switching or discontinuing. We conducted descriptive statistics, univariable, and multivariable Poisson regression analyses to assess predictors of both discontinuation and switching. We also conducted χ2 analyses to compare reported reasons for stopping between switchers and discontinuers. At 6 months, 2,583 women (70.0%) reported continuation of their baseline method, 367 (10%) reported at least 1 period of discontinuation, 459 (12.4%) reported switching to a different method, and 279 (7.6%) did not provide 6-month follow-up. Factors associated with discontinuation included selection of a short-acting method (incidence rate ratio [IRR], 2.49; 95% confidence interval [CI], 1.97, 3.12), report of Hispanic ethnicity (IRR, 1.45; 95% CI, 1.12, 1.89) and nonwhite race (IRR, 1.48; 95% CI, 1.08, 2.02), and having any future pregnancy plans, even years out. Participants with some college education were less likely to report discontinuation (IRR, 0.73; 95% CI, 0.57, 0.94). Selecting a short-acting method at baseline was also associated with increased likelihood of method switching (IRR, 2.29, 95% CI, 1.87, 2.80), as was having 2 or more children (IRR, 1.37; 95% CI, 1.08, 1.74). Women were less likely to switch if they were on their parents' insurance (IRR, 0.74; 95% CI, 0.56, 0.99). Among participants who switched methods, 36.9% switched to a long-acting reversible method, 31.7% switched to a short-acting hormonal method, and 31.1% switched to a nonhormonal behavioral method, such as condom use. Of participants providing a reason for stopping, 454 women (73.2%) reported side effects as 1 reason for switching or discontinuing their initial method. Early contraceptive method switching and discontinuation are frequent outcomes of contraceptive use. These changes are common even with removal of contraceptive access barriers.

Dasatinib Versus Imatinib in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Have Not Achieved an Optimal Response to 3 Months of Imatinib Therapy: Dascern

Introduction: Treatment with dasatinib, a second-generation tyrosine kinase inhibitor (TKI), has resulted in high rates of cytogenetic and molecular responses for pts with CML-CP, both as initial therapy and after failure of other therapies. A reduction in BCR-ABL1 transcript levels to ≤ 10% on the International Scale (IS) at 3 mo is associated with an improved probability of deep molecular responses and superior progression-free and overall survival (PFS and OS). In DASISION, considerably more pts treated with dasatinib achieved BCR-ABL1 ≤ 10% IS compared to imatinib. BCR-ABL1 ≤ 10% IS at 3 mo is considered an optimal response by international guidelines; however, approximately one-third of pts with CML-CP on first-line (1L) imatinib will not achieve this threshold. Clinical studies exploring the potential benefit of early switching to dasatinib in pts with less than optimal responses on initial imatinib treatment have not been reported.Methods: DASCERN (NCT01593254) is a randomized, open-label, international phase 2b trial in adult pts with CML-CP who had achieved complete hematologic response (CHR) but who had BCR-ABL1 > 10% IS at 3 mo after initial treatment with 400 mg imatinib once daily (QD). Imatinib must have been started within 6 mo of the initial CML-CP diagnosis. Pts were randomized 2:1 to receive 100 mg dasatinib QD or continue imatinib at ≥ 400 mg daily with the option for dose escalation. Pts initially randomized in the imatinib cohort who met European LeukemiaNet 2013 failure criteria after randomization and without dasatinib-resistant mutations were crossed over to the dasatinib arm. The primary endpoint in DASCERN is the rate of MMR (BCR-ABL1 < 0.1% IS) at 12 mo after day 1 initiation of 1L imatinib (9 mo after randomization). Secondary endpoints include time to MMR, OS, and PFS (progression was defined as transformation to accelerated/blast phase or death). Tertiary endpoints include safety and tolerability profile of both treatment arms and cytogenetic response over time.Results: All 260 randomized pts (dasatinib: n = 174; imatinib: n = 86) had a minimum follow-up of ≥ 12 mo from the last pts 1st visit (Sokal scores: 28% low, 30% intermediate, 24% high, 18% unknown; median age 37 y [range 18-82, 95% were < 65 y]; 78% male; 73% Asian). All pts had e13a2 or e14a2 transcript types. At the time of analysis, 84% of pts were continuing in the study. Median daily dose was 100 mg QD (range 26-142) for dasatinib and 400 mg QD (range 129-825) for imatinib. Median treatment duration was 111 wk (774 d) in the dasatinib arm and 68 wk (477 d) in the imatinib arm; 42 (49%) imatinib-randomized pts crossed over to dasatinib. Rate of MMR at 12 mo in the intent-to-treat population was 29% (95% confidence interval [CI] 22, 36) for dasatinib and 13% (95% CI 7, 22) for imatinib (P = 0.005); median time to MMR was 14 mo (range 12-18) for dasatinib vs 20 mo (range 14-26) for imatinib (P = 0.053). No differences in the rate of progression or OS were observed between treatment arms. No new safety signals were observed for either treatment arm and the early switch to dasatinib did not increase the toxicity rate. Treatment-emergent pleural effusion (PE; any grade) occurred in 11 (6%) pts randomized to dasatinib and 3 (7%) imatinib-randomized pts who crossed over to dasatinib; treatment-emergent PE grade 3/4 occurred in 1 (1%) pt randomized to dasatinib and 2 (5%) pts randomized to imatinib who crossed over to dasatinib. Hematologic toxicity was similar between treatment arms: neutropenia grade 3/4 occurred in 18 (11%) pts randomized to dasatinib and 12 (29%) pts randomized to imatinib who crossed over to dasatinib; thrombocytopenia grade 3/4 occurred in 18 (11%) pts randomized to dasatinib and in 7 (17%) pts randomized to imatinib who crossed over to dasatinib. Two dasatinib-treated pts discontinued due to hematologic toxicity (1 neutropenia, 1 thrombocytopenia).Conclusions: Early results from DASCERN show that pts with suboptimal responses to imatinib at 3 mo who switched to dasatinib had a significantly increased rate of MMR at 12 mo compared to pts who remained on imatinib. Longer follow-up is required to assess the impact of early switching on PFS and OS, and achievement of deep molecular responses. DisclosuresCortes:Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Takeda: Research Funding. Kim:BMS: Research Funding; Ilyang: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Martin Regueira:Bristol-Myers Squibb: Employment, Equity Ownership. Sy:Bristol-Myers Squibb: Employment. Gurnani:Bristol-Myers Squibb: Employment.

Impact of Early Switching to Nilotinib As Second Line TKI in Patients with Chronic Myeloid Leukemia Who Were Intolerant to, Suboptimal to and Failed Imatinib: The Thai Multi-Centered Study

Introduction: To date, the ELN recommendation and NCCN guidelines are the principle mile stones to follow up the treatment response and to make the decision of TKIs switching. However, in real life practice, many factors influence changing the real switching date from the date had an indication. This study aims to analyze the impact of early switching to second line TKI, nilotinib, in real life practice, for the CML patients who failed, had sub-optimal response or were intolerant to imatinib.Methods: This prospective study was conducted through 7 medical centers in Thailand between 1st of September 2009 and 31st of August 2011. Adult CML patients of age ≥ 18 years old, in chronic and accelerated phase, who had failure, suboptimal response or intolerance to imatinib, based on ELN 2009 guideline, were included and were eligible with nilotinib 400 mg twice daily. Prospective data collection for 24 months of each patient was performed. The main objective was to identify the impact of early switching to nilotinib on major molecular response (MMR). The other objectives were to observe the efficacy of nilotinib including overall survival, progression free survival and the safety. The survival results were presented as Kaplan-Meier survival curves. For the comparison of the treatment groups, the Kaplan-Meier estimator with the corresponding log-rank test for equality of survivor functions across treatment group was applied.Results: The final 108 cases were analysed. The median age was 47 (17-79) years with the proportion of male to female of 1.4:1 respectively. The median duration of the prior imatinib treatment was 18 months (2-142 months). The median duration between the date of indication and the date of real switching was 3.1 months (0-62.8 months) with 50% changing less than 3 months, 26.9% between 3 months and 12 months, and 23.1% changing longer than 12 months. The indication of switching included 63.6% failure to imatinib, 29% intolerance to imatinib and 7.4% suboptimal to imatinib. On the nilotinib switching, 70.4% completed 24 months follow-up, and 29.6% discontinued treatment mostly because of unsatisfactory results or adverse events.Evaluation was made every 3 months based on 2009 ELN recommendation. At 3 months, 57%, 20%, and 8% of the patients achieved CHR, CCyR and MMR, respectively. Those who did not achieve CHR at 3 months never achieved MMR, while 86 % of those who achieved CCyR at 3 months achieved MMR. All CML achieving MMR at 3 months had sustained MMR throughout the study period (24 months). Imatinib suboptimal response had better outcome than imatinib failure and imatinib intolerance groups.A preliminary analysis of BCR-ABL mutation was performed on 90 cases, and mutations were found on 21 cases. Two of them were T315I which were excluded from the study. The cases with mutation had poorer response to treatment than those without mutation. There was one case with initial G250E mutation developing T315I mutation after treatment with nilotinib. At 24 months, one case progressed to accelerated phase and 3 cases progressed to blastic transformation. The 2-year overall survival and 2-year progression-free survival and were 98.9% and 96.9% (figure 1 and 2), respectively. The interquatile analysis was done to identify the groups of cumulative MMR according to the duration between the date of indication and the date of real switching to nilotinib. The patients who switched to nilotinib within 12 months after date of indication could have a greater chance to achieved MMR than those who switched treatment later than 12 months (p(log-rank) = 0.002) (figure 3).Skin rash, musculoskeletal pain, and infection were the three most common non-hematologic adverse events, However, most of them were grade 1-2, except for 4 cases with grade 3-4 infections. Grade 3-4 hematologic adverse events included thrombocytopenia (12%), neutropenia (11%), anemia (5%) and leucopenia (4%), and most of them were manageable. Although biochemical abnormalities were commonly found, most of them were mild.Conclusions: Nilotinib, as a second line treatment showed excellent efficacy and tolerability. Indication for nilotinib treatment, initial mutation status and depth of response at 3 months after treatment can predict outcomes of the patients. However, the patients will have a greater chance to achieve MMR if they switched to nilotinib within 12 months after the date of indication for changing. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Switching Between Antibiotics Among Danish Children 0-4 Years of Age: A Nationwide Drug Utilization Study.

In Denmark, the use of amoxicillin is widespread among children, despite phenoxymethylpenicillin being recommended as first-line therapy. The reason for this apparent discrepancy is not fully understood. We aimed at evaluating prescribing patterns of antibiotics among Danish children 0-4 years of age, with emphasis on incidence of treatment episodes, choice of initial antibiotic treatment and switching patterns between different types of antibiotics. We identified all children ≤4 years of age who filled a prescription of antibiotics from 2000 to 2015 according to the nationwide Danish National Prescription Registry. We estimated the incidence rate of episodes treated with antibiotics and the choice of initial antibiotic treatment over time. Further, we assessed the cumulative risk of switching within 0-3 days after initiating therapy. We identified 3,481,684 antibiotic treatment episodes issued to 0- to 4-year-olds from 2000 to 2015. The incidence rate was stable until 2011 both among children 0-1 years of age (approximately 880/1000) and among children 2-4 years of age (approximately 610/1000), after which it dropped. Phenoxymethylpenicillin and, increasingly, amoxicillin were most frequently used as initial treatments (39% vs. 44%). Few switched from amoxicillin (1%) or phenoxymethylpenicillin (4.7%) within the first 3 days. Of those who switched from phenoxymethylpenicillin, 64% received amoxicillin as second-line treatment. The incidence of episodes treated with antibiotics among Danish children 0-4 years of age has decreased considerably since 2011. In contrast to guideline recommendations, amoxicillin is the most frequently used initial treatment. Early switching between antibiotics is uncommon. Initiatives should address the extensive use of amoxicillin.

Effects of switching ticagrelor to clopidogrel on cardiovascular outcomes in patients with acute coronary syndrome

Present study was to evaluate whether switching ticagrelor to clopidogrel would impact platelet reactivity and cardiovascular outcomes in acute coronary syndrome (ACS) patients after percutaneous coronary intervention (PCI).A total of 202 ACS patients after PCI were enrolled and prescribed ticagrelor. Before discharge, 138 (68%) patients were switched to clopidogrel. Peripheral blood was obtained before switching and at 48 hours after switching to measure platelet reactivity. Patients were followed for 30 days to evaluate cardiovascular events.Compared to ticagrelor group, patients in clopidogrel group were more likely to be male (69.6% vs 65.6%), smokers (34.1% vs 31.3%) and had higher prevalence of hypertension (75.4% vs 71.9%). The frequency of right coronary artery lesion was significantly higher in ticagrelor group (34.4% vs 30.4%). There were no significant differences in baseline platelet reactivity (37.6 ± 5.2% vs 38.4 ± 4.9%). Forty-eight hours after switching to clopidogrel, platelet reactivity in clopidogrel group was significantly higher (46.3 ± 5.6% vs 38.1 ± 5.0%, P <.05). Patients in clopidogrel group had significantly higher incidence of cardiovascular events (3.6% vs 1.6%, P <.05). However, after further adjusted for platelet reactivity at 48 hours of switching, clopidogrel switching was not significantly associated with composite outcomes, with hazard ratio 1.08 (95% confidence interval 0.98–1.21, P = .063), indicating that platelet reactivity was a critical mediator between antiplatelet drug switching and cardiovascular outcomes.ACS patients after PCI treatment, early switching ticagrelor to clopidogrel results in increased platelet reactivity and higher incidence of short-term cardiovascular events.

Successful switching from insulin to sulfonylurea in a 3-month-old infant with diabetes due to p.G53D mutation in KCNJ11.

Permanent neonatal diabetes mellitus is most commonly caused by mutations in the ATP-sensitive potassium channel (KATP) subunits. Prompt initiation of sulfonylurea treatment can improve glycemic control in children with KCNJ11 mutation. In this report, we present a case of permanent neonatal diabetes caused by a mutation in the KCNJ11 gene that was successfully treated via early switching of insulin to sulfonylurea treatment. A 53-day-old female infant presented with diabetic ketoacidosis. Insulin was administered for the ketoacidosis and blood glucose regulation. At 3 months of age, using genomic DNA extracted from peripheral lymphocytes, direct sequencing of KCNJ11 identified a heterozygous mutation of c.158G>A (p.G53D) and confirmed the diagnosis of permanent neonatal diabetes mellitus. Subsequently, treatment with sulfonylurea was initiated, and the insulin dose was gradually tapered. At 4 months of age, insulin therapy was discontinued, and sulfonylurea (glimepiride, 0.75 mg/kg) was administered alone. At 6 months after initiation of administration of sulfonylurea monotherapy, blood glucose control was stable, and no hypoglycemic events or developmental delays were reported. C-peptide levels increased during treatment with sulfonylurea. Early switching to sulfonylurea in infants with permanent diabetes mellitus owing to a KCNJ11 mutation could successfully help regulate glycemic control, which suggests the need for early genetic testing in patients presenting with diabetes before 6 months of age.

Modulation of dynamic modes by interplay between positive and negative feedback loops in gene regulatory networks.

A positive and a negative feedback loop can induce bistability and oscillation, respectively, in biological networks. Nevertheless, they are frequently interlinked to perform more elaborate functions in many gene regulatory networks. Coupled positive and negative feedback loops may exhibit either oscillation or bistability depending on the intensity of the stimulus in some particular networks. It is less understood how the transition between the two dynamic modes is modulated by the positive and negative feedback loops. We developed an abstract model of such systems, largely based on the core p53 pathway, to explore the mechanism for the transformation of dynamic behaviors. Our results show that enhancing the positive feedback may promote or suppress oscillations depending on the strength of both feedback loops. We found that the system oscillates with low amplitudes in response to a moderate stimulus and switches to the on state upon a strong stimulus. When the positive feedback is activated much later than the negative one in response to a strong stimulus, the system exhibits long-term oscillations before switching to the on state. We explain this intriguing phenomenon using quasistatic approximation. Moreover, early switching to the on state may occur when the system starts from a steady state in the absence of stimuli. The interplay between the positive and negative feedback plays a key role in the transitions between oscillation and bistability. Of note, our conclusions should be applicable only to some specific gene regulatory networks, especially the p53 network, in which both oscillation and bistability exist in response to a certain type of stimulus. Our work also underscores the significance of transient dynamics in determining cellular outcome.

31. OPTIMISE-ING THE TREATMENT OF FIRST-EPISODE SCHIZOPHRENIA

Overall : Even if there have been effective antipsychotic treatments for more than fifty years, the implementation of these treatments in clinical practice is still far from optimal, and a significant amount of patients with schizophrenia show poor outcomes. It is unquestionable that antipsychotics remain the first treatment option for patients with first-episode schizophrenia (FES). However, several questions still demand answer in the field. It is unclear how long we should wait before changing an antipsychotic that has not been fully effective, how long we have to wait before starting clozapine in FES, whether we can identify who will respond better to current treatments using biological markers including neuroimaging, and how to improve adherence and functional prognosis after clinical remission is achieved.OPTiMiSE (‘Optimisation of Treatment and Management of Schizophrenia in Europe’) is an European Consortium funded under the VII Framework Program that addressed these questions in a sample of nearly 500 patients with FES or schizophreniform psychosis and minimal prior exposure to antipsychotics recruited across Europe and Israel. Within an integrative framework, the Consortium aimed at combining clinical, neuroimaging, genetic and biochemical data in a large representative sample to provide answers to these clinically relevant questions and prepare the field for personalised medication strategies as drugs with novel mechanisms of action become available. Results from this study have not yet been published and most of them will be presented for the first time in a Congress.Based on previous results from the EUFEST study, all patients received amisulpride as a first step. For those not achieving remission after 4 weeks, OPTiMiSE compared in a randomised double-blind fashion the option of staying on amisulpride or moving to a drug with a different receptor-binding profile, olanzapine. In those not achieving remission after 6 weeks, clozapine was started. OPTiMiSE thus constitutes the first systematic, large-scale testing of the potential benefits of early switching to an antipsychotic with different characteristics in patients not achieving remission, and the application of clozapine in non-remitting patients within the first 10 weeks of treatment. OPTiMiSE also provides information on the added value of psychosocial interventions to improve treatment adherence, reduce relapses and improve functional outcomes after remission is achieved, through a 1-year follow-up randomised controlled trial testing a web-based program comprising a motivational intervention package, psychoeducation, and electronic medication alerts and updates.OPTiMiSE also collected blood samples for patients participating in the clinical trial and a systematic sample of more than 200 standardised, high-quality, magnetic resonance imaging (MRI) images. Based on this information, OPTiMiSE examined the clinical utility and cost-effectiveness of MRI for screening of underlying organic conditions in FES. In addition, OPTiMiSE also offers novel information on how MRI alterations, genetic and biochemical markers at first presentation of schizophrenia can predict the response to subsequent treatment. For this, OPTiMiSE used two broad strategies—a combination of technology-driven (pharmacogenetics, proteomics, and metabolomics) and hypothesis-driven (neuroimaging, neurochemical, and immune-related) markers.This symposium offers an overview of the main results obtained in the project in all these areas, with special focus on their clinical and research implications.

Switching Anti-Vascular Endothelial Growth Factors in Refractory Neovascular Age-Related Macular Degeneration.

Anti-vascular endothelial growth factor (VEGF) therapy is the treatment of choice for cases with neovascular age-related macular degeneration (AMD). Switching to an alternate anti-VEGF has been suggested as a possible option for resistant cases. The purpose of this review is to evaluate whether the timing of switching affects treatment outcomes. A review of published literature was performed looking at all studies where patients with refractory neovascular AMD were switched to an alternative anti-VEGF. Studies were then stratified based on the timing of switching into early (< 12 previous injections) and late (> 12 previous injections). A total of 38 studies were identified: 18 where patients were switched early and 20 where they were switched late. Both subgroups showed anatomic improvement after switching, with limited visual gains. There are insufficient data to recommend early versus late switching. However, both groups showed a reduction of fluid on optical coherence tomography and visual gains in 25% to 30% of patients. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:166-170.].

Predictive factors for 6 vs 12 cycles of Folfiri-Bevacizumab in metastatic colorectal cancer.

Early switching to de-intensified maintenance regimen is still a matter of debate in metastatic colorectal cancer (mCRC).The MARTHA trial, a S.I.C.O.G. phase III randomized trial, compared FOLOFIRI+bevacizumab (B) for 12 cycles (6 months) followed by B for up to 12 months (FOLFIRI +B*12 arm) vs FOLFIRI+B for 6 cycles (3 months) followed by capecitabine+B for 4 cycles followed by B for up to 12 months (FOLFIRI+B*6 arm). Chemotherapy-naïve mCRC patients were randomized, primary endpoint was progression free survival (PFS), with overall survival (OS) as a secondary endpoint. A novel analysis, the Death Pace Analysis (DPA), was performed to identify patients who benefited from a specific treatment.No PFS difference was seen in 198 enrolled patients (101 in FOLFIRI+B*12, 97 in FOLFIRI+B*6). A non-significant superior OS was observed for FOLFIRI+B*6 (HR 0.74, p 0.098). The DPA demonstrated that 14% of patients were identifiable as FOLFIRI+B*6-benefiting patients. According to a logistic regression analysis including 23 clinicopathological variables, baseline Hb was the only independent predictor of DPA-defined FOLFIRI+B*6-benefit status. Among patients with Hb ≤ 11.1 gr/dL a statistically significant prolonged OS was observed for FOLFIRI+B*6 over FOLFIRI+B*12 (median OS: 20.7 vs 12.6 months, respectively, HR 0.54, p 0.048). No survival difference was observed between arms in patients with Hb > 11.1.mCRC patients with low baseline Hb levels are better treated with FOLFIRI+B*6 first-line strategy. Possible biological explanations for this finding are being investigated.