scholarly journals A Novel Approach to Identifying Septic Shock (SS) in Children with Acute Lymphoblastic Leukemia (ALL) Using Pediatric Health Information System (PHIS) Data: Methods Validation and Incidence Estimation in a National Cohort

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3597-3597
Author(s):  
Viviane C. Cahen ◽  
Yimei Li ◽  
Evanette Burrows ◽  
Caitlin W Elgarten ◽  
Amanda M. DiNofia ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Gold Standard ◽  
Research Funding ◽  
Chart Review ◽  
Lymphoblastic Leukemia ◽  
Medication Administration ◽  
Consensus Conference ◽  
Operating Characteristics ◽  
National Cohort ◽  
Exposure Patterns

Abstract Infectious complications are major contributors to morbidity and mortality in children with leukemia; however, clinical trial reporting is incomplete (Miller 2016 J Clin Oncol). Using administrative data to identify SS events could improve estimates of incidence and clinical impact. However, accurate SS determination is challenging, and the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) definition is often modified for individual studies. ICD-9 codes, assigned at discharge, do not permit precise timing estimates. We hypothesized PHIS resource utilization (RU) codes could identify vasopressor exposures as proxies for IPSCC-defined SS events. We present the operating characteristics of our methods and use the approach to estimate SS incidence for a national cohort. We previously identified and validated a longitudinal cohort of children aged 0-21 with newly diagnosed ALL using PHIS billing and diagnosis codes (Fisher 2014 Med Care), expanded through 12/31/2013. PHIS RU data were used to identify distinct vasopressor exposure patterns hypothesized to represent true SS (Figure 1). Epinephrine alone with asparaginase within ± 3 days was considered anaphylaxis rather than SS. We captured vasopressor patterns occurring ≥7 days from first chemotherapy until the first of: 30 days prior to relapse, 10 days prior to stem cell transplantation, or 3 years from diagnosis. We reviewed charts of all patients with ALL diagnosed from 2004 to 2013 at the Children's Hospital of Philadelphia (CHOP) to establish the SS gold-standard. We assumed true SS events would be associated with blood cultures. Each blood culture triggered a chart review and was classified by IPSCC sepsis criteria. A PHIS RU-defined vasopressor exposure had to be within ±14 days of the chart-defined SS to be considered a true positive. We predicted a patient may meet criteria for a PHIS vasopressor exposure if vasopressors were ordered to the bedside for impending SS but ultimately not administered. For CHOP patients with available electronic medication administration record (MAR) data (1/1/2011-12/31/2013), we assessed whether using vasopressor orders marked as "given" or "given or held at bedside" resulted in different operating characteristics relative to gold standard IPSCC SS events. We calculated sensitivity and positive predictive value (PPV) of PHIS RU exposure patterns for IPSCC SS, then used them to estimate SS incidence for the entire PHIS cohort and for certain risk group subsets. We identified 360 patients common to both PHIS and CHOP chart review cohorts. Chart review revealed 38 events meeting IPSCC SS criteria. PHIS RU data identified vasopressor exposure patterns in 35 of these 38 SS events within ±14 days (sensitivity 92%). PHIS RU data identified an additional 43 vasopressor patterns that did not correlate with a chart review IPSCC SS event (PPV: 35/78, 45%). When considering chart-defined sepsis event of any severity (ie, not restricted to SS), the PPV for PHIS-defined vasopressor events increased to 88%. MAR data were available for 149 patients to delineate whether ordered vasopressors were given or held. Among these 149 patients, 10 SS events met IPSCC criteria by chart review. Restricting RU-identified vasopressor exposure events to patients who actually received vasopressors resulted in sensitivity of 70% and PPV 77%; including orders where vasopressors were given or held, the sensitivity increased to 100% and PPV decreased to 55%. Using PHIS RU vasopressor patterns, we estimated an incidence of 12.6% (95% CI 12.0 - 13.3 %) of patients ever experiencing SS in the PHIS ALL cohort. Infants, children aged ≥10 years, with public insurance, or receiving daunorubicin all had significantly higher SS rates than the cohort baseline (Table 1). PHIS RU-defined vasopressor exposure patterns have a high sensitivity for IPSCC-defined SS but a low PPV. The PPV may be the result of including patients with vasopressors ordered but not given; however, IPSCC-defined SS excludes children with fluid-responsive shock. The low PPV suggests this RU-defined approach results in "overcapture" of SS, but the gold standard definition may be too restrictive. Vasopressor exposure patterns from RU data may identify patients with SS or impending SS that can augment incomplete clinical trial data collection. PHIS RU SS incidence estimates for a national pediatric ALL cohort exceed 12%, with even higher rates in high-risk subgroups. Disclosures Fisher: Merck: Research Funding; Pfizer: Research Funding.

scholarly journals Using Administrative Data to Identify Relapse and Hematopoietic Stem Cell Transplantation (HSCT) in Children with Acute Lymphoblastic Leukemia (ALL): Validation at Two Centers and Incidence Estimation in a National Cohort

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 624-624
Author(s):  
Viviane C. Cahen ◽  
Yimei Li ◽  
Caitlin W Elgarten ◽  
Amanda M. DiNofia ◽  
Jennifer J. Wilkes ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Administrative Data ◽  
Gold Standard ◽  
Research Funding ◽  
Clinical Trial Data ◽  
Trial Data ◽  
National Cohort ◽  
Data Source ◽  
Procedure Codes

Abstract Administrative databases can be used to study outcomes including patients outside of clinical trials and have been used to identify relapse and HSCT in adult and adolescent/young adult leukemia populations. However, there are no published studies using validated billing and diagnostic codes to identify timing of relapse or HSCT in children with ALL. Published approaches are limited to relapses occurring after cessation of therapy, but a substantial proportion of pediatric ALL relapses occur on therapy. We hypothesized HSCT and early and late relapses could be detected accurately in a previously assembled cohort of children with ALL (Fisher 2014 Med Care), using pharmacy billing and ICD-9 diagnosis and procedure codes. We present our methods, validated at two large freestanding children's hospitals, and incidence estimates of relapse or HSCT as first events in a national cohort. The Pediatric Health Information System (PHIS) cohort included patients aged 0-21 admitted between 1/1/2004 and 12/13/2013, previously identified with de novo ALL. We reviewed daily inpatient pharmacy, diagnosis, and procedure codes for patients in the PHIS ALL cohort from the Children's Hospital of Philadelphia (CHOP; 2004-2013) and Texas Children's Hospital (TCH; 2007-2013). Events were captured until the first of 5 years from diagnosis or last day of PHIS data. Relapses were identified using ICD-9 diagnosis/procedure codes and PHIS pharmacy codes (Figure 1A) correlating with relapse regimens. Manual review of daily PHIS data was performed for second-line chemotherapy at any time, reinduction-style chemotherapy365 days after diagnosis, or a relapsed ALL ICD-9 diagnosis code (204.02). HSCTs were identified using ICD-9 procedure and PHIS pharmacy code patterns consistent with conditioning (Figure 1B). We reviewed electronic medical records (EMR) for patients with do novo ALL from CHOP and TCH for all relapses and HSCTs as the gold standard. Demographics were evaluated by hospital and data source using chi-square tests. We calculated sensitivity and positive-predictive value (PPV) of PHIS-defined events compared to the EMR gold standard at the patient level and only considered the first relapse and HSCT per patient. PHIS events were considered valid if the date was within ±14 days of the EMR. We estimated 5-year incidences of relapse and HSCT as first events for the entire PHIS cohort, infants (<1 year at diagnosis), and high-risk ALL (receipt of daunorubicin in Induction). Of 395 patients in the CHOP EMR cohort, 362 matched with the PHIS ALL cohort. The TCH EMR cohort had 410 patients, matching 329 from PHIS. Age, sex, and Down syndrome were similar (Table 1). CHOP patients were more likely to be Black, and race distribution within each hospital was similar by data source. Fewer CHOP patients were Hispanic, and more had missing ethnicity. Fewer TCH patients were missing ethnicity regardless of data source, though PHIS had a higher proportion of missing data. Proportions of children with high- and low-risk B-ALL, T-ALL, infant ALL, and Induction daunorubicin were similar. Government primary insurance in the first admission was more common at TCH. At CHOP, 39 relapses were identified in PHIS, and 45 by EMR (sensitivity 85.7%, PPV 100%). At TCH, 30/31 relapses were correctly identified in PHIS (sensitivity 96.6%, PPV 100%). Our PHIS algorithm identified 38 CHOP patients who underwent HSCT during the study period and 34 at TCH. All matched the EMR, with 100% sensitivity and PPV for both hospitals. Table 2 shows five-year incidences of relapse and HSCT in the entire PHIS ALL cohort (N=10,162), including relapse estimates adjusted for sensitivity. Relapses and HSCTs were higher in infants and in children receiving daunorubicin. We present novel approaches to identify relapse and HSCT events using administrative data, validated at two children's hospitals. Timing of events are matched within ±14 days. Relapse estimates are slightly lower than clinical trial data, but this approach has higher sensitivity than published administrative data reports, and sensitivity-adjusted rates approximate clinical trial data. Detected events are likely to be true based on the 100% PPV. Our relapse identification approach is complex and requires disease-specific clinical expertise to identify relapse-style chemotherapy patterns in children on therapy; however, this approach can capture early relapses in children outside of clinical trials. Disclosures Fisher: Merck: Research Funding; Pfizer: Research Funding.

scholarly journals The Observed and Expected Incidence of Cardiovascular (CV) Ischemic Events in Dasatinib (DAS)-Treated Patients (pts) Across a Clinical Trial Program

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4534-4534 ◽  
Author(s):  
Giuseppe Saglio ◽  
Philipp le Coutre ◽  
Jorge E. Cortes ◽  
Jiří Mayer ◽  
Philip A. Rowlings ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Factors ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Phase 3 ◽  
Population Total ◽  
Total N ◽  
Ischemic Events

Abstract Background: The safety profile of each BCR-ABL1– targeted tyrosine kinase inhibitor (TKI) used to treat chronic myeloid leukemia (CML) is unique and should be considered when choosing therapy. Although rare, potentially severe adverse events have been reported in CML pts treated with TKIs, particularly pulmonary arterial hypertension with DAS (Montani, Circulation 2012), peripheral arterial occlusive disease with nilotinib (Kim, Leukemia 2013), and arterial and venous occlusive events with ponatinib (Cortes, N Engl J Med 2013). The incidence of CV ischemic events in DAS-treated pts from clinical trials was assessed. Standardized incidence rates (SIRs) were calculated to determine if the number of observed events was different than expected compared with reference populations. Methods: Incidence of CV ischemic events (Table 1) were assessed in a pooled population of DAS-treated pts with any phase CML or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia from 11 first- and second-line clinical trials (N=2712; median age, 54 years [y]), newly diagnosed CML pts treated with DAS (n=258; median age, 46 y) or imatinib (IM; n=258; median age, 49 y) from the phase 3 DASISION trial only (CA180-056, NCT 00481247), and prostate cancer pts from the phase 3 READY trial treated with DAS or placebo in combination with docetaxel and prednisone (CA180-227, NCT 00744497; N=1518; about 66% of pts were >65 y of age). Reference populations for SIR analyses were a general population (total N=116,000,000; males N=56,000,000), CML pts (N=16,000), and prostate cancer pts (N=530,000) derived from Truven's MarketScan Commercial Claims and Medicare Supplemental database, 2008–2013, narrowed to mimic clinical trial eligibility. SIRs were calculated by dividing the observed number of events in DAS-treated pts by the expected number of events, based on the DAS exposure and reference population event rates. Results: Within the pooled population, 96 pts (4%) had CV ischemic events. In DASISION, 10 DAS- and 4 IM-treated pts had any grade CV ischemic events. In READY, 18 pts in the DAS arm and 9 pts in the placebo arm had any grade CV ischemic events. The majority of pts with a CV event had a history and/or risk factors for atherosclerosis (77/96 [80%] in the pooled population; 8/10 with DAS and 3/4 with IM in DASISION). Time-to-event analysis revealed that, in the pooled population, CV ischemic events occurred in 69/96 pts (72%) within 1 y, 11 pts (11%) in 1–2 y, and 16 pts (17%) in 3–7 y. Over 70% tolerated continued DAS therapy without a recurrent CV event. In DASISION, CV events occurred in 7/10 pts within 1 y of DAS initiation, 2 pts in 1–3 y, and 1 pt after 5 y. Based on SIRs, the observed number of CV events in DAS-treated pts was not higher than expected, given the rates of reference populations (Table 1). SIR results should be interpreted with caution due to the limitations of the indirect comparison between clinical data and claims data (eg, coding differences and surveillance bias). Conclusion: CV ischemic events were reported in 4% of DAS- and 2% of IM-treated pts in DASISION, 4% of DAS-treated pts in the pooled population, and 2% of DAS- and 1% of placebo-treated pts in READY. In all populations, among pts who experienced an event, the majority had a history of arterial ischemic events and/or risk factors for atherosclerosis, and most events occurred early. SIRs suggest that the total number of CV ischemic events among DAS-treated pts was not higher than expected, and in contrast to what has been observed with other TKIs, largely restricted to 1 y after initiating therapy. Disclosures Saglio: Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; BMS: Consultancy, Fees for occasional speeches Other. Off Label Use: Dasatinib is approved for first line use in adults with chronic phase Ph+ CML, and in adult AP- or BP-CML, and Ph+ ALL patients who are resistant or intolerant to prior therapy. le Coutre:ARIAD: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Cortes:Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Mayer:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Mahon:ARIAD: Consultancy, Research Funding; Pfizer : Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Kroog:Bristol-Myers Squibb: Employment. Gooden:Bristol Myers Squibb: Employment. Subar:Bristol Myers Squibb: Employment. Preston:Bristol-Myers Squibb: Employment. Shah:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding.

scholarly journals Simultaneous Kinase Inhibition with Ibrutinib and BCL2 Inhibition with Venetoclax As a Therapeutic Strategy for Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3950-3950
Author(s):  
Christopher A. Eide ◽  
Stephen E Kurtz ◽  
Andy Kaempf ◽  
Nicola Long ◽  
Jessica Leonard ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Advisory Committees ◽  
Equity Ownership

Background: In patients with acute lymphoblastic leukemia (ALL), patient outcomes vary considerably by patient age group, specific genetic subtypes, and treatment regimen. Large-scale sequencing efforts have uncovered a spectrum of mutations and gene fusions in ALL, suggesting that combinations of agents will be required to treat these diseases effectively. Previous preclinical studies have shown efficacy of the BCL2 inhibitor venetoclax alone or in combination in ALL cells (Chonghaile et al., Can Disc 2014; Leonard et al, STM 2018), and the multi-kinase inhibitor ibrutinib (approved for patients with chonic lymphoblastic leukemia (CLL)) has also shown potent activity in subsets of ALL (Kim et al., Blood 2017). However, the combination of ibrutinib and venetoclax has not been evaluated to date in patients with ALL. Methods: We used a functional ex vivo screening assay to evaluate the potential efficacy of the combination of ibrutinib and venetoclax (IBR+VEN) across a large cohort (n=808) of patient specimens representing a broad range of hematologic malignancies. Primary mononuclear cells isolated from leukemia patients were plated in the presence of graded concentrations of venetoclax, ibrutinib, or the combination of both FDA-approved drugs. IC50 and AUC values were derived from probit-based regression for each response curve. A panel of clinical labs, treatment information, and genetic features for tested ALL patient specimens was collated from chart review. Single and combination drug treatment sensitivity were compared within groups by Friedman test, across groups by Mann-Whitney test, and with continuous variables by Spearman rank correlation. Results: Consistent with clinical data and previous literature, IBR+VEN was highly effective in CLL specimens ex vivo (median IC50=0.015 µM). Intriguingly, among specimens from 100 unique ALL patients, we also observed that IBR+VEN demonstrated significantly enhanced efficacy by AUC and IC50 compared to either single agent (p<0.001; median IC50=0.018 µM). In contrast, evaluation of this combination on primary mononuclear cells from two healthy donors showed little to no sensitivity. Breakdown of combination sensitivity (as measured by AUC) by a variety of clinical and genetic features revealed no associations with gender or specimen type. Among continuous variables tested, age was modestly correlated with combination AUC (Spearman r = 0.26) and increased blasts in the bone marrow were associated with increased sensitivity to the combination (Spearman r = -0.41; p = 0.0068). More broadly, specimens from patients with B-cell precursor disease (B-ALL) were more sensitive to IBR+VEN than those with T-cell precursor leukemia (T-ALL) (p = 0.0063). Within the B-ALL patient samples, those harboring the BCR-ABL1 fusion were significantly less sensitive to IBR+VEN than other subtypes of B-ALL (p = 0.0031). Within the T-ALL subset, there was a trend toward reduced sensitivity in patients with evidence of mutations in NOTCH1, though statistical significance was not reached. Evaluation of the combination using an expanded 7x7 concentration matrix in human ALL cell lines revealed varying degrees of sensitivity. For example, IBR+VEN showed enhanced efficacy in RCH-ACV B-ALL cells and showed synergy for the majority of drug-pair concentrations by the highest single agent (HSA) method (ibrutinib, venetoclax, and combination IC50: 0.60, 3.4, and 0.28 uM, respectively). Conclusion: Our findings suggest that the IBR+VEN combination, currently approved for patients with CLL, also demonstrates impressive efficacy against primary leukemia cells from ALL patients, warranting further investigation as a treatment strategy in the clinic to continue to improve outcomes for patients. Disclosures Leonard: Amgen: Research Funding. Druker:Cepheid: Consultancy, Honoraria; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Merck & Co: Patents & Royalties: Dana-Farber Cancer Institute license #2063, Monoclonal antiphosphotyrosine antibody 4G10, exclusive commercial license to Merck & Co; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Gilead Sciences: Other: former member of Scientific Advisory Board; Beta Cat: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Patents & Royalties, Research Funding; Pfizer: Research Funding; Aileron Therapeutics: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees , Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Novartis: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Patents & Royalties: Patent 6958335, Treatment of Gastrointestinal Stromal Tumors, exclusively licensed to Novartis, Research Funding; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; Patient True Talk: Consultancy; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Beat AML LLC: Other: Service on joint steering committee; CureOne: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; ICON: Other: Scientific Founder of Molecular MD, which was acquired by ICON in Feb. 2019; Monojul: Other: former consultant; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees. Tyner:Petra: Research Funding; Agios: Research Funding; Array: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Syros: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Array: Research Funding; Aptose: Research Funding; Incyte: Research Funding; Syros: Research Funding; Takeda: Research Funding; Petra: Research Funding; Agios: Research Funding; Constellation: Research Funding; Aptose: Research Funding; Gilead: Research Funding; Incyte: Research Funding; AstraZeneca: Research Funding; Constellation: Research Funding; Janssen: Research Funding; Genentech: Research Funding.

scholarly journals Orthopedic Toxicity Among Adolescents and Young Adults Treated on DFCI ALL Consortium Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-32
Author(s):  
Yannis K. Valtis ◽  
Kristen E. Stevenson ◽  
Andrew E. Place ◽  
Lewis B. Silverman ◽  
Lynda M. Vrooman ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Chart Review ◽  
Total Joint Replacement ◽  
Massachusetts General Hospital ◽  
Lymphoblastic Leukemia ◽  
Advisory Board ◽  
Competing Risk ◽  
Adolescent And Young Adult ◽  
Adequate Information

Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. These regimens, which rely heavily on corticosteroids and asparaginase (asp), are known to increase the risk of osteonecrosis (ON). In children older than 10 years (yrs), reported rates of symptomatic ON range from 5-25% (Mattano JCO 2000, Mattano Lancet Onc 2012, Toft Eur J Haematol 2016, Larsen JCO 2016). In adults, the frequency of ON and fractures (fx) are not well described including among those treated on pediatric regimens. In the recently reported C10403 trial (Stock Blood 2019), a 4% rate of ON was reported among patients aged 17-39 yrs. Here, we describe the orthopedic toxicities of AYA pts treated on sequential Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Methods: Pts aged 1-50 yrs were treated on four sequential multi-center DFCI ALL Consortium protocols between 2000 and 2018. Additional pts treated as per these protocols at DFCI, Massachusetts General Hospital (MGH), and Boston Children's Hospital (BCH) were identified by chart review. Earlier pts were enrolled on parallel Pediatric 00-001 (2000-2004) and Adult 01-175 (2002-2008) trials while later pts were enrolled on parallel Pediatric 05-001 (2005-2011) and Adult 06-254 (2007-2011) trials. Protocol 00-001 randomized pts between dexamethasone (dex) and prednisone (pred) during consolidation, while the other three trials used dex (all trials used pred during induction). Both 00-001 and 01-175 used native E.Coli asp, while later protocols (05-001, 06-254) used PEG asp for some (05-001, randomized) or all (06-254) pts. All pts were intended to receive 30 weeks of asp during consolidation. Pts aged 15-50 yrs were included in this study. Orthopedic toxicities were extracted from case report forms for trial pts and by chart review for those not on trial. Additional chart review was performed on all pts treated at DFCI, MGH, and BCH to identify surgical events. All pts were combined in the modeling based on the treatment backbone. The 5-yr cumulative incidences (CIs) of ON and fx were estimated and compared using the Gray test. Univariate and multivariable competing risk regression models were constructed with death as a competing risk. Results: A total of 367 pts with a median age of 23 yrs (68% &lt; 30 yrs) were identified. The majority (61%) of pts were male and the median BMI was 24.5 kg/m2 (46% overweight or obese). The median follow-up for pts remaining alive was 5 yrs (range, 0.01-14.1). In total, 60 pts experienced ON (5-yr CI 17%, [95% CI 13-22]) and 40 pts experienced fx (5-yr CI 12%, [8-15]). The median time to develop ON was 1.6 yrs (range, 0.5-7.7). The median time to fx was 1.4 yrs (range, 0.2-5.2). Pts &lt; 30 yrs were significantly more likely to be diagnosed with ON (21%, [16-27]) compared to those aged 30-50 yrs (8%, [4-14], univariate HR 2.77 [1.35-5.65]; p=0.005). Pts treated on PEG-asp based protocols were significantly more likely to be diagnosed with ON (5-yr CI 24% [18-30]) compared to those treated on earlier trials with native E.coli asp (5-yr CI 5% [2-10], HR 5.28 [95% CI 2.24-12.48], p&lt;0.001). These results remained statistically significant in multivariate analysis including treatment backbone, age, BMI, and sex. BMI and sex were not associated with orthopedic toxicity, although there was a trend toward fewer fx in male pts (HR 0.55, [0.29-1.02]). Of the 54 ONs for which adequate information was available, surgery was performed in 25 (46%) and total joint replacement in 18 (33%). Of the 9 fx with adequate information, 3 (33%) required surgery. Conclusions: In a large cohort of AYA ALL pts aged 15-50 yrs treated on a pediatric regimen, orthopedic toxicities were common (17% for ON, 12% for fx at 5 yrs). Younger pts (&lt; 30 yrs) experienced higher rates of ON, as well as pts treated on later-generation PEG-asp protocols which combined dex and PEG asp. Increased rates of orthopedic toxicity in later generation protocols may be driven by the pharmacokinetic drug interaction between PEG asp and dex, leading to higher dex exposure (Yan JCO 2008, Panetta Clin Pharmacol Ther 2009). Increased awareness may be useful in early identification of orthopedic toxicities. Future efforts should focus on further understanding the pathophysiology and risk factors for orthopedic toxicity in ALL AYA regimens and developing prophylactic interventions. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board. Brunner:Acceleron Pharma Inc.: Consultancy; Biogen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Forty Seven, Inc: Consultancy; Jazz Pharma: Consultancy; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Xcenda: Consultancy; GSK: Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding. DeAngelo:Blueprint Medicines Corporation: Consultancy, Research Funding; Forty-Seven: Consultancy; Jazz: Consultancy; Incyte Corporation: Consultancy; Novartis: Consultancy, Research Funding; Shire: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy; Autolos: Consultancy; Agios: Consultancy; Pfizer: Consultancy.

scholarly journals Development of an Electronic Algorithm to Identify Inappropriate Antibiotic Prescribing for Pediatric Pharyngitis

2020 ◽  
Vol 41 (S1) ◽  
pp. s188-s189
Author(s):  
Jeffrey Gerber ◽  
Robert Grundmeier ◽  
Keith Hamilton ◽  
Lauri Hicks ◽  
Melinda Neuhauser ◽  
...  
Keyword(s):  
Predictive Value ◽  
Gold Standard ◽  
Antibiotic Stewardship ◽  
Chart Review ◽  
Antibiotic Use ◽  
Audit And Feedback ◽  
Urgent Care ◽  
Antibiotic Prescribing ◽  
Tract Infections ◽  
The Impact

Background: Antibiotic overuse contributes to antibiotic resistance and unnecessary adverse drug effects. Antibiotic stewardship interventions have primarily focused on acute-care settings. Most antibiotic use, however, occurs in outpatients with acute respiratory tract infections such as pharyngitis. The electronic health record (EHR) might provide an effective and efficient tool for outpatient antibiotic stewardship. We aimed to develop and validate an electronic algorithm to identify inappropriate antibiotic use for pediatric outpatients with pharyngitis. Methods: This study was conducted within the Children’s Hospital of Philadelphia (CHOP) Care Network, including 31 pediatric primary care practices and 3 urgent care centers with a shared EHR serving >250,000 children. We used International Classification of Diseases, Tenth Revision (ICD-10) codes to identify encounters for pharyngitis at any CHOP practice from March 15, 2017, to March 14, 2018, excluding those with concurrent infections (eg, otitis media, sinusitis), immunocompromising conditions, or other comorbidities that might influence the need for antibiotics. We randomly selected 450 features for detailed chart abstraction assessing patient demographics as well as practice and prescriber characteristics. Appropriateness of antibiotic use based on chart review served as the gold standard for evaluating the electronic algorithm. Criteria for appropriate use included streptococcal testing, use of penicillin or amoxicillin (absent β-lactam allergy), and a 10-day duration of therapy. Results: In 450 patients, the median age was 8.4 years (IQR, 5.5–9.0) and 54% were women. On chart review, 149 patients (33%) received an antibiotic, of whom 126 had a positive rapid strep result. Thus, based on chart review, 23 subjects (5%) diagnosed with pharyngitis received antibiotics inappropriately. Amoxicillin or penicillin was prescribed for 100 of the 126 children (79%) with a positive rapid strep test. Of the 126 children with a positive test, 114 (90%) received the correct antibiotic: amoxicillin, penicillin, or an appropriate alternative antibiotic due to b-lactam allergy. Duration of treatment was correct for all 126 children. Using the electronic algorithm, the proportion of inappropriate prescribing was 28 of 450 (6%). The test characteristics of the electronic algorithm (compared to gold standard chart review) for identification of inappropriate antibiotic prescribing were sensitivity (99%, 422 of 427); specificity (100%, 23 of 23); positive predictive value (82%, 23 of 28); and negative predictive value (100%, 422 of 422). Conclusions: For children with pharyngitis, an electronic algorithm for identification of inappropriate antibiotic prescribing is highly accurate. Future work should validate this approach in other settings and develop and evaluate the impact of an audit and feedback intervention based on this tool.Funding: NoneDisclosures: None

scholarly journals Development of an Electronic Algorithm to Target Outpatient Antimicrobial Stewardship Efforts for Acute Bronchitis

2020 ◽  
Vol 41 (S1) ◽  
pp. s32-s32
Author(s):  
Ebbing Lautenbach ◽  
Keith Hamilton ◽  
Robert Grundmeier ◽  
Melinda Neuhauser ◽  
Lauri Hicks ◽  
...  
Keyword(s):  
Antimicrobial Stewardship ◽  
Predictive Value ◽  
Gold Standard ◽  
Chart Review ◽  
Acute Bronchitis ◽  
Antibiotic Use ◽  
Antibiotic Prescribing ◽  
Diagnostic Codes ◽  
Icd 10 ◽  
The Impact

Background: Antibiotic resistance has increased at alarming rates, driven predominantly by antibiotic overuse. Although most antibiotic use occurs in outpatients, antimicrobial stewardship programs have primarily focused on inpatient settings. A major challenge for outpatient stewardship is the lack of accurate and accessible electronic data to target interventions. We sought to develop and validate an electronic algorithm to identify inappropriate antibiotic use for outpatients with acute bronchitis. Methods: This study was conducted within the University of Pennsylvania Health System (UPHS). We used ICD-10 diagnostic codes to identify encounters for acute bronchitis at any outpatient UPHS practice between March 15, 2017, and March 14, 2018. Exclusion criteria included underlying immunocompromising condition, other comorbidity influencing the need for antibiotics (eg, emphysema), or ICD-10 code at the same visit for a concurrent infection (eg, sinusitis). We randomly selected 300 (150 from academic practices and 150 from nonacademic practices) eligible subjects for detailed chart abstraction that assessed patient demographics and practice and prescriber characteristics. Appropriateness of antibiotic use based on chart review served as the gold standard for assessment of the electronic algorithm. Because antibiotic use is not indicated for this study population, appropriateness was assessed based upon whether an antibiotic was prescribed or not. Results: Of 300 subjects, median age was 61 years (interquartile range, 50–68), 62% were women, 74% were seen in internal medicine (vs family medicine) practices, and 75% were seen by a physician (vs an advanced practice provider). On chart review, 167 (56%) subjects received an antibiotic. Of these subjects, 1 had documented concern for pertussis and 4 had excluding conditions for which there were no ICD-10 codes. One received an antibiotic prescription for a planned dental procedure. Thus, based on chart review, 161 (54%) subjects received antibiotics inappropriately. Using the electronic algorithm based on diagnostic codes, underlying and concurrent conditions, and prescribing data, the number of subjects with inappropriate prescribing was 170 (56%) because 3 subjects had antibiotic prescribing not noted based on chart review. The test characteristics of the electronic algorithm (compared to gold standard chart review) for identification of inappropriate antibiotic prescribing were the following: sensitivity, 100% (161 of 161); specificity, 94% (130 of 139); positive predictive value, 95% (161 of 170); and negative predictive value, 100% (130 of 130). Conclusions: For outpatients with acute bronchitis, an electronic algorithm for identification of inappropriate antibiotic prescribing is highly accurate. This algorithm could be used to efficiently assess prescribing among practices and individual clinicians. The impact of interventions based on this algorithm should be tested in future studies.Funding: NoneDisclosures: None

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