Publications by authors named "Kelly D Getz"

55 Publications

Risk of bacterial bloodstream infection does not vary by central-line type during neutropenic periods in pediatric acute myeloid leukemia.

Infect Control Hosp Epidemiol 2022 Apr 25:1-8. Epub 2022 Apr 25.

Center for Pediatric Clinical Effectiveness, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Bloodstream infections (BSIs) are a frequent cause of morbidity in patients with acute myeloid leukemia (AML), due in part to the presence of central venous access devices (CVADs) required to deliver therapy.

Objective: To determine the differential risk of bacterial BSI during neutropenia by CVAD type in pediatric patients with AML.

Methods: We performed a secondary analysis in a cohort of 560 pediatric patients (1,828 chemotherapy courses) receiving frontline AML chemotherapy at 17 US centers. The exposure was CVAD type at course start: tunneled externalized catheter (TEC), peripherally inserted central catheter (PICC), or totally implanted catheter (TIC). The primary outcome was course-specific incident bacterial BSI; secondary outcomes included mucosal barrier injury (MBI)-BSI and non-MBI BSI. Poisson regression was used to compute adjusted rate ratios comparing BSI occurrence during neutropenia by line type, controlling for demographic, clinical, and hospital-level characteristics.

Results: The rate of BSI did not differ by CVAD type: 11 BSIs per 1,000 neutropenic days for TECs, 13.7 for PICCs, and 10.7 for TICs. After adjustment, there was no statistically significant association between CVAD type and BSI: PICC incident rate ratio [IRR] = 1.00 (95% confidence interval [CI], 0.75-1.32) and TIC IRR = 0.83 (95% CI, 0.49-1.41) compared to TEC. When MBI and non-MBI were examined separately, results were similar.

Conclusions: In this large, multicenter cohort of pediatric AML patients, we found no difference in the rate of BSI during neutropenia by CVAD type. This may be due to a risk-profile for BSI that is unique to AML patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/ice.2022.82DOI Listing
April 2022

Acute Left Ventricular Dysfunction Following Gemtuzumab Ozogamicin in Two Pediatric AML Patients.

J Pediatr Hematol Oncol 2022 03;44(2):e507-e511

Divisions of Oncology.

Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody-tumor antibiotic conjugate with proven efficacy in pediatric and adult patients with CD33+ acute myeloid leukemia. Adverse effects commonly associated with GO include hyperbilirubinemia, elevated transaminases, and sinusoidal obstruction syndrome. Cardiotoxicity has not been a commonly described adverse event. We describe 2 pediatric patients with relapsed/refractory acute myeloid leukemia who received fractionated GO monotherapy and subsequently developed severe acute left ventricular dysfunction. Both patients achieved remission, recovered cardiac function with medical therapy, and tolerated subsequent stem cell transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000002325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8873989PMC
March 2022

Association between timely targeted treatment and outcomes in patients with metastatic HER2-overexpressing gastroesophageal adenocarcinoma.

Cancer 2022 May 4;128(9):1853-1862. Epub 2022 Feb 4.

Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Timely targeted treatment initiation can be challenging because additional biomarker testing is needed for eligibility. The authors hypothesized that timely targeted treatment improves survival relative to nontimely initiation in metastatic HER2+ gastroesophageal adenocarcinoma (GEA).

Methods: The authors performed a retrospective cohort study of metastatic HER2+ GEA treated with first-line (1L) systemic therapy from January 2011 to December 2017 using a nationwide electronic health record-derived deidentified database. Timely targeted treatment-trastuzumab initiation within 14 days after starting 1L chemotherapy-was assessed as a time-varying exposure. Nontimely targeted treatment included patients who initiated trastuzumab after 14 days or who lacked documentation of receiving trastuzumab. Extended Cox regressions compared overall survival (OS) and progression-free survival (PFS) between timely and nontimely groups.

Results: A total of 320 patients were included; 59.1% received timely trastuzumab. Relative to nontimely initiation, timely trastuzumab was associated with significantly higher OS (2-year OS, 32.1% vs 15.3%; adjusted hazard ratio [HR], 0.67; 95% CI, 0.51-0.88) and PFS (2-year PFS, 9.2% vs 3.7%; adjusted HR, 0.71; 95% CI, 0.55-0.93). Results remained similar in sensitivity analyses 1) using alternative "timeliness" definitions up to 70 days after starting 1L chemotherapy, 2) comparing any trastuzumab, regardless of timing of initiation, to no trastuzumab, and 3) excluding patients lacking documentation of receiving trastuzumab.

Conclusions: Improved survival was observed among metastatic HER2+ GEA patients treated with trastuzumab versus those who were not, regardless of timing of initiation. Although these results reassure clinicians that modest targeted treatment delays may not be detrimental to outcomes, efforts should still ensure that all metastatic HER2+ GEA patients receive trastuzumab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.34117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007872PMC
May 2022

Risk Factors for Treatment Refractory and Relapsed Optic Pathway Glioma in Children with Neurofibromatosis Type 1.

Neuro Oncol 2022 Jan 9. Epub 2022 Jan 9.

Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, PA.

Background: Nearly one-third of patients with neurofibromatosis type 1-associated optic pathway glioma (NF1-OPG) fail frontline chemotherapy; however, little is known about risk factors for treatment failure.

Methods: We performed a retrospective multi-institutional cohort study to identify baseline risk factors for treatment-refractory/relapsed disease and poor visual outcome in children with NF1-OPG. Refractory/relapsed NF1-OPG was defined as requirement of two or more treatment regimens due to progression or relapse.

Results: Of 111 subjects eligible for inclusion, adequate clinical and visual data were available for 103 subjects from 7 institutions. Median follow-up from initiation of first chemotherapy regimen was 95 months (range 13-185). Eighty-four (82%) subjects received carboplatin-based frontline chemotherapy. Forty-five subjects (44%) experienced refractory/relapsed disease, with median time of 21.5 months (range 2-149) from initiation of first treatment to start of second treatment. The proportion of patients without refractory/relapsed disease at 2 and 5 years was 78% and 60%. In multivariable analyses, age less than 24 months at initial treatment, posterior tumor location, and familial inheritance were associated with refractory/relapsed NF1-OPG by 2 years. Both age less than 24 months and posterior tumor location were associated with refractory/relapsed NF1-OPG by 5 years. Subjects with moderate to severe vision loss at last follow-up were more likely to have posterior tumor location, optic disc abnormalities, or abnormal visual acuity at initial treatment.

Conclusion: Young age, posterior tumor location, and optic disc abnormalities may identify patients with the greatest likelihood of refractory/relapsed NF1-OPG and poor visual outcomes, and who may benefit from newer treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noac013DOI Listing
January 2022

Minimizing cardiac toxicity in children with acute myeloid leukemia.

Hematology Am Soc Hematol Educ Program 2021 12;2021(1):368-375

Department of Pediatrics, University of Washington, Seattle Children's Hospital, Seattle, WA.

Anthracycline chemotherapy remains an integral component of modern pediatric acute myeloid leukemia (AML) regimens and is often delivered at high doses to maximize cancer survival. Unfortunately, high-dose anthracyclines are associated with a significant risk of cardiotoxicity, which may result in early and/or long-term left ventricular systolic dysfunction and heart failure. Moreover, the development of cardiotoxicity during pediatric AML therapy is associated with lower event-free and overall survival, which may be partially attributable to incomplete anthracycline delivery. A combined strategy of primary cardioprotection and close cardiac monitoring can maximize chemotherapy delivery while reducing the toxicity of intensive AML therapy. Primary cardioprotection using dexrazoxane reduces short-term cardiotoxicity without compromising cancer survival. Liposomal anthracycline formulations, which are under active investigation, have the potential to mitigate cardiotoxicity while also improving antitumor efficacy. Primary cardioprotective strategies may reduce but not eliminate the risk of cardiotoxicity; therefore, close cardiac monitoring is also needed. Standard cardiac monitoring consists of serial echocardiographic assessments for left ventricular ejection fraction decline. Global longitudinal strain has prognostic utility in cancer therapy-related cardiotoxicity and may be used as an adjunct assessment. Additional cardioprotective measures should be considered in response to significant cardiotoxicity; these include cardiac remodeling medications to support cardiac recovery and anthracycline dose interruption and/or regimen modifications. However, the withholding of anthracyclines should be limited to avoid compromising cancer survival. A careful approach to cardioprotection during AML therapy is critical to maximize the efficacy of leukemia treatment while minimizing the short- and long-term risks of cardiotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/hematology.2021000268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8791101PMC
December 2021

Characteristics Associated with Tumor Development in Individuals Diagnosed with Beckwith-Wiedemann Spectrum: Novel Tumor-(epi)Genotype-Phenotype Associations in the BWSp Population.

Genes (Basel) 2021 11 21;12(11). Epub 2021 Nov 21.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Beckwith-Wiedemann Spectrum (BWSp) is the most common epigenetic childhood cancer predisposition disorder. BWSp is caused by (epi)genetic changes affecting the BWS critical region on chromosome 11p15. Clinically, BWSp represents complex molecular and phenotypic heterogeneity resulting in a range of presentations from Classic BWS to milder features. The previously reported tumor risk based on Classic BWS cohorts is 8-10% and routine tumor screening has been recommended. This work investigated the tumor risk and correlation with phenotype within a cohort of patients from Classic BWS to BWSp using a mixed-methods approach to explore phenotype and epigenotype profiles associated with tumor development through statistical analyses with post-hoc retrospective case series review. We demonstrated that tumor risk across BWSp differs from Classic BWS and that certain phenotypic features are associated with specific epigenetic causes; nephromegaly and/or hyperinsulinism appear associated with cancer in some patients. We also demonstrated that prenatal and perinatal factors that are not currently part of the BWSp classification may factor into tumor risk. Additionally, blood testing results are not necessarily synonymous with tissue testing results. Together, it appears that the current understanding from Classic BWS of (epi)genetics and phenotype correlations with tumors is not represented in the BWSp. Further study is needed in this complex population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes12111839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8621885PMC
November 2021

Incidence and risk factors for hypoglycemia during maintenance chemotherapy in pediatric acute lymphoblastic leukemia.

Pediatr Blood Cancer 2022 06 22;69(6):e29467. Epub 2021 Nov 22.

Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Fasting hypoglycemia is a recognized occurrence among pediatric patients with acute lymphoblastic leukemia (ALL) during maintenance therapy. Existing publications describing this finding are limited to small studies and case reports. Our objective was to determine the incidence of hypoglycemia during maintenance chemotherapy and to investigate the association of age, as well as other potential risk factors, with this outcome in pediatric patients with ALL.

Procedure: This retrospective cohort study included individuals 1 to 21 years of age with ALL treated with antimetabolite-containing maintenance chemotherapy at a large children's hospital between January 2011 and December 2014. The primary endpoint was time to first documented episode of hypoglycemia during maintenance therapy, defined as single measurement of plasma glucose <60 mg/dL. Cox regression was used to evaluate the association with age and identify other potential risk factors.

Results: We identified 126 eligible patients, of whom 63% were documented as White, non-Hispanic, 28% as non-White, non-Hispanic, and 9% as Hispanic. Twenty-eight children (22%) had documented hypoglycemia during maintenance therapy. Younger age at the start of maintenance and hepatotoxicity documented during chemotherapy prior to maintenance initiation were associated with hypoglycemia (adjusted HR age = 0.88; 95% CI, 0.78-0.99; adjusted HR prior hepatotoxicity = 3.50; 95% CI, 1.47-8.36).

Conclusions: Nearly one quarter of children in our cohort had hypoglycemia documented during maintenance chemotherapy. Younger age at maintenance initiation and hepatotoxicity during chemotherapy prior to maintenance initiation emerged as risk factors. These findings highlight the importance of counseling about the risk of, and monitoring for, hypoglycemia, particularly in young children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.29467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9038623PMC
June 2022

Center Variation in Indication and Short-Term Outcomes after Pediatric Heart Transplantation: Analysis of a Merged United Network for Organ Sharing - Pediatric Health Information System Cohort.

Pediatr Cardiol 2022 Mar 15;43(3):636-644. Epub 2021 Nov 15.

Division of Oncology, Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

The relationship between center-specific variation in indication for pediatric heart transplantation and short-term outcomes after heart transplantation is not well described. We used merged patient- and hospital-level data from the United Network for Organ Sharing and the Pediatric Health Information Systems to analyze outcomes according to transplant indication for a cohort of children (≤ 21 years old) who underwent heart transplantation between 2004 and 2015. Outcomes included 30-day mortality, transplant hospital admission mortality, and hospital length of stay, with multivariable adjustment performed according to patient and center characteristics. The merged cohort reflected 2169 heart transplants at 20 U.S. centers. The median number of transplants annually at each center was 11.6, but ranged from 3.5 to 22.6 transplants/year. Congenital heart disease was the indication in the plurality of cases (49.2%), with cardiomyopathy (46%) and myocarditis (4.8%) accounting for the remainder. There was significant center-to-center variability in congenital heart disease as the principal indication, ranging from 15% to 66% (P < 0.0001). After adjustment, neither center volume nor proportion of indications for transplantation were associated with 30-day or transplant hospital admission mortality. In this large, merged pediatric cohort, variation was observed at center level in annual transplant volume and prevalence of indications for heart transplantation. Despite this variability, center volume and proportion of indications represented at a given center did not appear to impact short-term outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00246-021-02768-xDOI Listing
March 2022

Medical Outcomes, Quality of Life, and Family Perceptions for Outpatient vs Inpatient Neutropenia Management After Chemotherapy for Pediatric Acute Myeloid Leukemia.

JAMA Netw Open 2021 10 1;4(10):e2128385. Epub 2021 Oct 1.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Importance: Pediatric acute myeloid leukemia (AML) requires multiple courses of intensive chemotherapy that result in neutropenia, with significant risk for infectious complications. Supportive care guidelines recommend hospitalization until neutrophil recovery. However, there are little data to support inpatient over outpatient management.

Objective: To evaluate outpatient vs inpatient neutropenia management for pediatric AML.

Design, Setting, And Participants: This cohort study used qualitative and quantitative methods to compare medical outcomes, patient health-related quality of life (HRQOL), and patient and family perceptions between outpatient and inpatient neutropenia management. The study included patients from 17 US pediatric hospitals with frontline chemotherapy start dates ranging from January 2011 to July 2019, although the specific date ranges differed for the individual analyses by design and relative timing. Data were analyzed from August 2019 to February 2020.

Exposures: Discharge to outpatient vs inpatient neutropenia management.

Main Outcomes And Measures: The primary outcomes of interest were course-specific bacteremia incidence, times to next course, and patient HRQOL. Course-specific mortality was a secondary medical outcome.

Results: Primary quantitative analyses included 554 patients (272 [49.1%] girls and 282 [50.9%] boys; mean [SD] age, 8.2 [6.1] years). Bacteremia incidence was not significantly different during outpatient vs inpatient management (67 courses [23.8%] vs 265 courses [29.0%]; adjusted rate ratio, 0.73; 95% CI, 0.56 to 1.06; P = .08). Outpatient management was not associated with delays to the next course compared with inpatient management (mean [SD] 30.7 [12.2] days vs 32.8 [9.7] days; adjusted mean difference, -2.2; 95% CI, -4.1 to -0.2, P = .03). Mortality during intensification II was higher for patients who received outpatient management compared with those who received inpatient management (3 patients [5.4%] vs 1 patient [0.5%]; P = .03), but comparable with inpatient management at other courses (eg, 0 patients vs 5 patients [1.3%] during induction I; P = .59). Among 97 patients evaluated for HRQOL, outcomes did not differ between outpatient and inpatient management (mean [SD] Pediatric Quality of Life Inventory total score, 70.1 [18.9] vs 68.7 [19.4]; adjusted mean difference, -2.8; 95% CI, -11.2 to 5.6). A total of 86 respondents (20 [23.3%] in outpatient management, 66 [76.7%] in inpatient management) completed qualitative interviews. Independent of management strategy received, 74 respondents (86.0%) expressed satisfaction with their experience. Concerns for hospital-associated infections among caregivers (6 of 7 caregiver respondents [85.7%] who were dissatisfied with inpatient management) and family separation (2 of 2 patient respondents [100%] who were dissatisfied with inpatient management) drove dissatisfaction with inpatient management. Stress of caring for a neutropenic child at home (3 of 3 respondents [100%] who were dissatisfied with outpatient management) drove dissatisfaction with outpatient management.

Conclusions And Relevance: This cohort study found that outpatient neutropenia management was not associated with higher bacteremia incidence, treatment delays, or worse HRQOL compared with inpatient neutropenia management among pediatric patients with AML. While outpatient management may be safe for many patients, course-specific mortality differences suggest that outpatient management in intensification II should be approached with caution. Patient and family experiences varied, suggesting that outpatient management may be preferred by some but may not be feasible for all families. Further studies to refine and standardize safe outpatient management practices are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2021.28385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554641PMC
October 2021

Interpregnancy interval and prevalence of selected birth defects: A multistate study.

Birth Defects Res 2022 01 21;114(2):69-79. Epub 2021 Oct 21.

Massachusetts Department of Public Health, Center for Birth Defects Research and Prevention, Boston, Massachusetts, USA.

Background: Both short and long interpregnancy intervals (IPIs) have been associated with adverse birth outcomes. We undertook a multistate study to describe the prevalence of selected birth defects by IPI.

Methods: We obtained data from nine population-based state birth defects registries for singleton live births in 2000-2009 among mothers with a previous live birth identified through birth certificates. IPI was calculated as the difference between prior birthdate and start of the current pregnancy (conception date). We estimated prevalence of selected defects per 10,000 live births and prevalence ratios (PRs) with 95% confidence intervals (CIs) overall and stratified by maternal age at previous birth and race/ethnicity. Primary analyses focused on short IPI < 6 months and long IPI ≥ 60 months compared to 18-23 months (referent). Sensitivity analyses limited to active-surveillance states and those with<10% missing IPI.

Results: Among 5,147,962 eligible births, 6.3% had short IPI while 19.8% had long IPI. Compared to referent, prevalence with short IPI was elevated for gastroschisis (3.7, CI: 3.0-4.5 vs. 2.0, CI: 1.6-2.4) and with both short and long IPI for tetralogy of Fallot (short: 3.4, 2.8-4.2 long: 3.8, 3.4-4.3 vs. 2.7, 2.3-3.2) and cleft lip ± palate (short: 9.9, 8.8-11.2 long: 9.2, 8.5-9.8 vs. 8.4, 7.6-9.2). Stratified analyses identified additional associations, including elevated prevalence of anencephaly with short IPI in younger mothers and limb defects with long IPI in those ages 25-34 at prior birth. Sensitivity analyses showed similar results.

Conclusion: In this population-based study, we observed increased prevalence of several birth defects with short and long IPI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bdr2.1960DOI Listing
January 2022

Outcomes of intensification of induction chemotherapy for children with high-risk acute myeloid leukemia: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2021 12 1;68(12):e29281. Epub 2021 Oct 1.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Background: High-risk pediatric acute myeloid leukemia confers a poor prognosis, and alternative strategies are needed to improve outcomes. We hypothesized that intensifying induction on the AAML1031 clinical trial would improve outcomes compared to the predecessor trial AAML0531.

Methods: Patients on AAML0531 received cytarabine (1600 mg/m )/daunorubicin (150 mg/m )/etoposide (ADE) for induction II and patients on AAML1031 received mitoxantrone (48 mg/m )/cytarabine (8000 mg/m ) (MA). Stem cell transplant (SCT) conditioning included busulfan/cyclophosphamide on AAML0531, whereas AAML1031 used busulfan/fludarabine and liberalized donor eligibility. Patients were included in this analysis if they met high-risk criteria common to the two trials by cytogenics or poor disease response after induction I ADE.

Results: MA provided no benefit over ADE at: induction II response (complete response [CR]: 64% vs. 62%, p = .87; measurable residual disease [MRD]+: 57% vs. 46%, p = .34); or intensification I response (CR: 79% vs. 94%, p = .27; MRD+: 27% vs. 20%, p = 1.0). When considered with altered SCT approach, MA did not improve 5-year disease-free survival (24% ± 9% vs. 18% ± 15%, p = .63) or 5-year overall survival (35% ± 10% vs. 38% ± 18%, p = .66). MA was associated with slower neutrophil recovery (median 34 vs. 27 days, p = .007) and platelet recovery (median 29 vs. 24.5 days, p = .04) and longer hospital stay (32 vs. 28 days, p = .01) during induction II.

Conclusion: Intensification of induction II did not improve treatment response or survival, but did increase toxicity and resource utilization. Alternative strategies are urgently needed to improve outcomes for pediatric patients with high-risk acute myeloid leukemia (trials registered at clinicaltrials.gov NCT01371981, NCT00372593).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.29281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717610PMC
December 2021

Cytarabine dose reduction in patients with low-risk acute myeloid leukemia: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2022 01 2;69(1):e29313. Epub 2021 Sep 2.

Children's Hospital of Philadelphia, Division of Oncology, Philadelphia, Pennsylvania, USA.

Background: The optimal number of chemotherapy courses for low-risk (LR) pediatric acute myeloid leukemia (AML) is not known.

Objective: To compare outcomes for four (21.6 g/m cytarabine) versus five (45.6 g/m cytarabine) chemotherapy courses for LR-AML using data from Children's Oncology Group (COG) AAML0531 and AAML1031.

Methods: We compared relapse risk (RR), disease-free survival (DFS), and overall survival (OS), and the differential impact in LR subgroups for patients receiving four versus five chemotherapy courses. Cox (OS and DFS) and risk (RR) regressions were used to estimate hazard ratios (HR) to compare outcomes.

Results: A total of 923 LR-AML patients were included; 21% received five courses. Overall, LR-AML patients who received four courses had higher RR (40.9% vs. 31.4%; HR = 1.40, 95% confidence interval [CI]: 1.06-1.85), and worse DFS (56.0% vs. 67.0%; HR = 1.45, 95% CI: 1.10-1.91). There was a similar decrement in OS though it was not statistically significant (77.0% vs. 83.5%; HR = 1.45, 95% CI: 0.97-2.17). Stratified analyses revealed the detrimental effects of cytarabine dose de-escalation to be most pronounced in the LR-AML subgroup with uninformative cytogenetic/molecular features who were minimal residual disease (MRD) negative after the first induction course (EOI1). The absolute decrease in DFS with four courses for patients with favorable cytogenetic/molecular features and positive MRD was similar to that observed for patients with uninformative cytogenetic/molecular features and negative MRD at EOI1, though not statistically significant.

Conclusions: Our results support de-escalation of cytarabine exposure through the elimination of a fifth chemotherapy course only for LR-AML patients who have both favorable cytogenetic/molecular features and negative MRD after the first induction cycle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.29313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919970PMC
January 2022

Humanized CD19-Targeted Chimeric Antigen Receptor (CAR) T Cells in CAR-Naive and CAR-Exposed Children and Young Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia.

J Clin Oncol 2021 09 22;39(27):3044-3055. Epub 2021 Jun 22.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: CD19-targeted chimeric antigen receptor (CAR)-modified T cells demonstrate unprecedented responses in B-cell acute lymphoblastic leukemia (B-ALL); however, relapse remains a substantial challenge. Short CAR T-cell persistence contributes to this risk; therefore, strategies to improve persistence are needed.

Methods: We conducted a pilot clinical trial of a humanized CD19 CAR T-cell product (huCART19) in children and young adults with relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (n = 2), treated in two cohorts: with (retreatment, n = 33) or without (CAR-naive, n = 41) prior CAR exposure. Patients were monitored for toxicity, response, and persistence of huCART19.

Results: Seventy-four patients 1-29 years of age received huCART19. Cytokine release syndrome developed in 62 (84%) patients and was grade 4 in five (6.8%). Neurologic toxicities were reported in 29 (39%), three (4%) grade 3 or 4, and fully resolved in all cases. The overall response rate at 1 month after infusion was 98% (100% in B-ALL) in the CAR-naive cohort and 64% in the retreatment cohort. At 6 months, the probability of losing huCART19 persistence was 27% (95% CI, 14 to 41) for CAR-naive and 48% (95% CI, 30 to 64) for retreatment patients, whereas the incidence of B-cell recovery was 15% (95% CI, 6 to 28) and 58% (95% CI, 33 to 77), respectively. Relapse-free survival at 12 and 24 months, respectively, was 84% (95% CI, 72 to 97) and 74% (95% CI, 60 to 90) in CAR-naive and 74% (95% CI, 56 to 97) and 58% (95% CI, 37 to 90) in retreatment cohorts.

Conclusion: HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-ALL, including after failure of prior CAR T-cell therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.03458DOI Listing
September 2021

Neighborhood education status drives racial disparities in clinical outcomes in PPCM.

Am Heart J 2021 08 19;238:27-32. Epub 2021 Apr 19.

Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address:

Background: Peripartum cardiomyopathy (PPCM) disproportionately affects women of African ancestry. Additionally, clinical outcomes are worse in this subpopulation compared to White women with PPCM.  The extent to which socioeconomic parameters contribute to these racial disparities is not known.

Methods: We aimed to quantify the association between area-based proxies of socioeconomic status (SES) and clinical outcomes in PPCM, and to determine the potential contribution of these factors to racial disparities in outcomes. A retrospective cohort study was performed at the University of Pennsylvania Health System, a tertiary referral center serving a population with a high proportion of Black individuals. The cohort included 220 women with PPCM, 55% of whom were Black or African American. Available data included clinical and demographic characteristics as well as residential address georeferenced to US Census-derived block group measures of SES. Rates of sustained cardiac dysfunction (defined as persistent LVEF <50%, LVAD placement, transplant, or death) were compared by race and block group-level measures of SES, and a composite neighborhood concentrated disadvantage index (NDI). The contributions of area-based socioeconomic parameters to the association between race and sustained cardiac dysfunction were quantified.

Results: Black race and higher NDI were both independently associated with sustained cardiac dysfunction (relative risk [RR] 1.63, confidence interval [CI] 1.13-2.36; and RR 1.29, CI 1.08-1.53, respectively). Following multivariable adjustment, effect size for NDI remained statistically significant, but effect size for Black race did not. The impact of low neighborhood education on racial disparities in outcomes was stronger than that of low neighborhood income (explaining 45% and 0% of the association with black race, respectively). After multivariate adjustment, only low area-based education persisted as significantly correlating with sustained cardiac dysfunction (RR 1.49; CI 1.02-2.17).

Conclusions: Both Black race and NDI independently associate with adverse outcomes in women with PPCM in a single center study. Of the specific components of NDI, neighborhood low education was most strongly associated with clinical outcome and partially explained differences in race. These results suggest interventions targeting social determinants of health in disadvantaged communities may help to mitigate outcome disparities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ahj.2021.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8710234PMC
August 2021

Identification of Patient-Reported Outcome Phenotypes Among Oncology Patients With Palliative Care Needs.

JCO Oncol Pract 2021 10 24;17(10):e1473-e1488. Epub 2021 Mar 24.

Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Purpose: Despite evidence-based guidelines recommending early palliative care, it remains unclear how to identify and refer oncology patients, particularly in settings with constrained access to palliative care. We hypothesize that patient-reported outcome (PRO) data can be used to characterize patients with palliative care needs. To determine if PRO data can identify latent phenotypes that characterize indications for specialty palliative care referral.

Methods: We conducted a retrospective study of self-reported symptoms on the Edmonton Symptom Assessment System collected from solid tumor oncology patients (n = 745) referred to outpatient palliative care. Data were collected as part of routine clinical care from October 2012 to March 2018 at eight community and academic sites. We applied latent profile analysis to identify PRO phenotypes and examined the association of phenotypes with clinical and demographic characteristics using multinomial logistic regression.

Results: We identified four PRO phenotypes: (1) Low Symptoms (n = 295, 39.6%), (2) Moderate Pain/Fatigue + Mood (n = 180, 24.2%), (3) Moderate Pain/Fatigue + Appetite + Dyspnea (n = 201, 27.0%), and (4) High Symptoms (n = 69, 9.3%). In a secondary analysis of 421 patients, we found that two brief items assessing social and existential needs aligned with higher severity symptom and psychological distress phenotypes.

Conclusion: Oncology patients referred to outpatient palliative care in a real-world setting can be differentiated into clinically meaningful phenotypes using brief, routinely collected PRO measures. Latent modeling provides a mechanism to use patient-reported data on a population level to identify distinct subgroups of patients with unmet palliative needs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/OP.20.00849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8791824PMC
October 2021

Adherence to and determinants of guideline-recommended biomarker testing and targeted therapy in patients with gastroesophageal adenocarcinoma: Insights from routine practice.

Cancer 2021 07 17;127(14):2562-2570. Epub 2021 Mar 17.

Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Anti human epidermal growth factor receptor 2 (anti-HER2) therapy with trastuzumab improves overall survival in patients with advanced, HER2-positive gastroesophageal adenocarcinoma (GEA) and is now incorporated into national guidelines. However, little is known about adherence to and determinants of timely HER2 testing and trastuzumab initiation in routine practice.

Methods: The authors performed a cross-sectional study of patients who had advanced GEA diagnosed between January 2011 and June 2019 in a nationwide electronic health record-derived database. The annual prevalences of both timely HER2 testing (defined within 21 days after advanced diagnosis) and timely trastuzumab initiation (defined within 14 days after a positive HER2 result) were calculated. Log-binomial regressions estimated adjusted prevalence ratios comparing timely HER2 testing and trastuzumab initiation by patient and tumor characteristics.

Results: In total, the cohort included 6032 patients with advanced GEA of whom 1007 were HER2-positive. Between 2011 and 2019, timely HER2 testing increased from 22.4% to 44.5%, whereas timely trastuzumab initiation remained stable at 16.3%. No appreciable differences in timely testing or trastuzumab initiation were noted by age, sex, race, or insurance status. Compared with patients who had metastatic disease at diagnosis, patients who had early stage GEA who did not undergo surgery were less likely to receive timely HER2 testing and trastuzumab initiation (testing prevalence ratio, 0.69; 95% CI, 0.64-0.75; treatment prevalence ratio, 0.32; 95% CI, 0.18-0.56), as were patients with early stage disease who subsequently developed a distant recurrence (testing prevalence ratio, 0.56; 95% CI, 0.47-0.65; treatment prevalence ratio, 0.61; 95% CI, 0.24-1.55).

Conclusions: In patients with advanced GEA, guideline-recommended HER2 testing and anti-HER2 therapy remain underused. Uptake may improve with universal HER2 testing regardless of stage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249344PMC
July 2021

Broad-Spectrum Antibiotics and Risk of Graft-versus-Host Disease in Pediatric Patients Undergoing Transplantation for Acute Leukemia: Association of Carbapenem Use with the Risk of Acute Graft-versus-Host Disease

Transplant Cell Ther 2021 02 21;27(2):177.e1-177.e8. Epub 2020 Dec 21.

Center for Pediatric Clinical Effectiveness, Children's Hospital of Philadelphia, Philadelphia, PA.

Variation in the gastrointestinal (GI) microbiota after hematopoietic cell transplantation (HCT) has been associated with acute graft-versus-host disease (aGVHD). Because antibiotics induce dysbiosis, we examined the association of broad-spectrum antibiotics with subsequent aGVHD risk in pediatric patients undergoing HCT for acute leukemia. We performed a retrospective analysis in a dataset merged from 2 sources: (1) the Center for International Blood and Marrow Transplant Research, an observational transplantation registry, and (2) the Pediatric Health Information Services, an administrative database from freestanding children's hospitals. We captured exposure to 3 classes of antibiotics used for empiric treatment of febrile neutropenia: (1) broad-spectrum cephalosporins, (2) antipseudomonal penicillins, and (3) carbapenems. The primary outcome was grade II-IV aGVHD; secondary outcomes were grade III-IV aGVHD and lower GI GVHD. The adjusted logistic regression model (full cohort) and time-to-event analysis (subcohort) included transplantation characteristics, GVHD risk factors, and adjunctive antibiotic exposures as covariates. The full cohort included 2550 patients at 36 centers; the subcohort included 1174 patients. In adjusted models, carbapenems were associated with an increased risk of grade II-IV aGVHD in the full cohort (adjusted odds ratio [aOR], 1.24; 95% confidence interval [CI], 1.02 to 1.51) and subcohort (sub hazard ratio [HR], 1.31; 95% CI, 0.99 to 1.72), as well as with an increased risk of grade III-IV aGVHD (subHR, 1.77; 95% CI, 1.25 to 2.52). Early carbapenem exposure (before day 0) especially impacted aGVHD risk. For antipseudomonal penicillins, the associations with aGVHD were in the direction of increased risk but were not statistically significant. There was no identified association between broad-spectrum cephalosporins and aGVHD. Carbapenems, more than other broad-spectrum antibiotics, should be used judiciously in pediatric HCT recipients to minimize aGVHD risk. Further research is needed to clarify the mechanism underlying this association.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946150PMC
February 2021

Presentation acuity, induction mortality, and resource utilization in infants with acute leukemia.

Pediatr Blood Cancer 2021 07 11;68(7):e28940. Epub 2021 Mar 11.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Background: Treatment of infants with acute leukemia remains challenging, especially for acute lymphocytic leukemia (ALL). Infants have shown markedly higher rates of induction mortality compared with noninfants. There are limited data on presentation acuity and supportive care utilization in this age group.

Methods: In retrospective analyses of patients treated for new onset ALL or acute myeloid leukemia (AML) at pediatric hospitals contributing to the Pediatric Health Information System, we compared presentation acuity, induction mortality, and resource utilization in infants relative to noninfants less than 10 years at diagnosis.

Results: Analyses included 10 359 children with ALL (405 infants, 9954 noninfants) and 871 AML (189 infants, 682 noninfants). Infants were more likely to present with multisystem organ failure compared to noninfants for both ALL (12% and 1%, PR = 10.8, 95% CI: 7.4, 15.7) and AML (6% vs. 3%; PR = 2.0, 95% CI: 1.0, 3.7). Infants with ALL had higher induction mortality compared to noninfants, even after accounting for differences in anthracycline exposure and presentation acuity (2.7% vs. 0.5%, HR = 2.1, 95% CI: 1.0, 4.8). Conversely, infants and noninfants with AML had similar rates of induction mortality (3.2% vs. 2.1%, HR = 1.2, 95% CI: 0.3, 3.9), which were comparable to rates among infants with ALL. Infants with ALL and AML had greater requirements for blood products, diuretics, supplemental oxygen, and ventilation during induction relative to noninfants.

Conclusions: Infants with leukemia present with higher acuity compared with noninfants. Induction mortality and supportive care requirements for infants with ALL were similar to all children with AML, and significantly higher than those for noninfants with ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283996PMC
July 2021

Short interpregnancy intervals and risks for birth defects: support for the nutritional depletion hypothesis.

Am J Clin Nutr 2021 06;113(6):1688-1699

Department of Epidemiology, Boston University School of Public Health, Boston, MA USA.

Background: Research suggests short interpregnancy intervals increase risks for adverse perinatal outcomes, including some birth defects. A hypothesized cause is nutritional depletion, including folic acid (FA).

Objectives: We evaluated associations between short interpregnancy intervals, alone and in combination with FA intake, and the occurrence of select malformations.

Methods: Data were from the National Birth Defects Prevention Study (US case-control, 1997-2011). Participants included multiparous women whose prior pregnancy resulted in live birth. Cases included 8 noncardiac and 6 cardiac defect groups (n = 3219); controls were nonmalformed live-borns (n = 2508). We categorized interpregnancy interval (<6, 6-11, 12-17, and 18-23 mo) and periconceptional FA intake [no FA supplement use and dietary folate equivalents (DFE) <400 µg/d, no FA supplement use and DFE ≥400 µg/d, or any FA supplement use]. We controlled for age, race/ethnicity, income, pregnancy intention, and study center. ORs <0.8 or >1.2 were considered to represent potentially meaningful associations.

Results: ORs for <6 compared with 18-23 mo were >1.2 for 4/8 noncardiac and 3/6 cardiac malformations. Among participants with any FA supplement use, ORs comparing <6 with 6-23 mo were <1.2 for most defects. Conversely, most ORs were >1.2 for <6 mo + no FA supplement use and DFE <400 µg/d compared with 6-23 mo + any FA supplement use. Magnitude and precision varied by defect.

Conclusions: Short interpregnancy intervals were associated with a trend of higher risks for several defects, notably in the absence of FA supplement use. To our knowledge, our study is the first to provide preliminary empirical support that these etiologies may be related to shorter interpregnancy intervals and possible nutritional deficiencies. Because FA intake is highly correlated with other nutrients, and because our estimates were generally imprecise, more research with larger sample sizes is needed to better understand the role of FA compared with other nutrients in each defect-specific etiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/nqaa436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168364PMC
June 2021

An underappreciated misclassification mechanism: implications of nondifferential dependent misclassification of covariate and exposure.

Ann Epidemiol 2021 06 20;58:104-123. Epub 2021 Feb 20.

Department of Epidemiology, Boston University School of Public Health, Boston University, Boston, MA; Department of Global Health, Boston University School of Public Health, Boston University, Boston, MA. Electronic address:

Misclassification is a pervasive problem in assessing relations between exposures and outcomes. While some attention has been paid to the impact of dependence in measurement error between exposures and outcomes, there is little awareness of the potential impact of dependent error between exposures and covariates, despite the fact that this latter dependency may occur much more frequently, for example, when both are assessed by questionnaire. We explored the impact of nondifferential dependent exposure-confounder misclassification bias by simulating a dichotomous exposure (E), disease (D) and covariate (C) with varying degrees of non-differential dependent misclassification between C and E. We demonstrate that under plausible scenarios, an adjusted association can be a poorer estimate of the true association than the crude. Correlated errors in the measurement of covariate and exposure distort the covariate-exposure, covariate-outcome and exposure-outcome associations creating observed associations that can be greater than, less than, or in the opposite direction of the true associations. Under these circumstances adjusted associations may not be bounded by the crude association and true effect, as would be expected with nondifferential independent confounder misclassification. The degree and direction of distortion depends on the amount of dependent error, prevalence of covariate and exposure, and magnitude of true effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.annepidem.2021.02.007DOI Listing
June 2021

Cardiology Involvement in Patients with Breast Cancer Treated with Trastuzumab.

JACC CardioOncol 2020 Jun 16;2(2):179-189. Epub 2020 Jun 16.

Department of Medicine, Division of Cardiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Background: There is limited evidence regarding the impact of cardiology involvement in the care of cancer patients.

Objectives: We evaluated the impact of cardiology involvement on guideline-adherent cardiovascular monitoring and risk factor management in breast cancer patients treated with trastuzumab.

Methods: In a single-center retrospective cohort study, we evaluated electronic health records from 1,047 breast cancer patients receiving trastuzumab between January 2009 and July 2018. A visit to a cardiology provider beginning from the 3 months prior to cancer therapy initiation until the last contact date defined cardiology involvement. Guideline-adherent monitoring, defined by echocardiography assessment within the 4 months prior to trastuzumab initiation and follow-up echocardiography at least every 4 months during therapy, was compared in patients with and without cardiology involvement prior to treatment initiation. Multivariable associations between cardiology involvement and time-varying risk factors blood pressure (BP) and body mass index (BMI) were assessed using generalized estimating equations.

Results: Cardiology involvement occurred in 293 (28%) patients. A higher proportion of patients with cardiology involvement prior to trastuzumab initiation had guideline-adherent monitoring (76.4% versus 60.1%, p=0.007). Cardiology involvement was associated with an average 1.5mmHg (95% CI -2.9,-0.1, p=0.035) lower systolic BP; which was more pronounced in those with hypertension (-2.7mmHg (95% CI -4.6,-0.7, p=0.007)). Cardiology involvement was associated with a lower BMI in patients with baseline BMI≥25 kg/m (mean difference; -0.5 (95% CI -1.0,-0.1, p=0.027)).

Conclusions: Cardiology involvement in breast cancer patients treated with trastuzumab is associated with greater adherence to cardiovascular monitoring and modest improvements in risk factor control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaccao.2020.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701353PMC
June 2020

Poverty and Targeted Immunotherapy: Survival in Children's Oncology Group Clinical Trials for High-Risk Neuroblastoma.

J Natl Cancer Inst 2021 03;113(3):282-291

Division of Oncology, Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Whether social determinants of health are associated with survival in the context of pediatric oncology-targeted immunotherapy trials is not known. We examined the association between poverty and event-free survival (EFS) and overall survival (OS) for children with high-risk neuroblastoma treated in targeted immunotherapy trials.

Methods: We conducted a retrospective cohort study of 371 children with high-risk neuroblastoma treated with GD2-targeted immunotherapy in the Children's Oncology Group trial ANBL0032 or ANBL0931 at a Pediatric Health Information System center from 2005 to 2014. Neighborhood poverty exposure was characterized a priori as living in a zip code with a median household income within the lowest quartile for the cohort. Household poverty exposure was characterized a priori as sole coverage by public insurance. Post hoc analyses examined the joint effect of neighborhood and household poverty using a common reference. All statistical tests were 2-sided.

Results: In multivariable Cox regressions adjusted for disease and treatment factors, household poverty-exposed children experienced statistically significantly inferior EFS (hazard ratio [HR] = 1.90, 95% confidence interval [CI] = 1.28 to 2.82, P = .001) and OS (HR = 2.79, 95% CI = 1.63 to 4.79, P < .001) compared with unexposed children. Neighborhood poverty was not independently associated with EFS or OS. In post hoc analyses exploring the joint effect of neighborhood and household poverty, children with dual-poverty exposure (neighborhood poverty and household poverty) experienced statistically significantly inferior EFS (HR = 2.21, 95% CI = 1.48 to 3.30, P < .001) and OS (HR = 3.70, 95% CI = 2.08 to 6.59, P < .001) compared with the unexposed group.

Conclusions: Poverty is independently associated with increased risk of relapse and death among neuroblastoma patients treated with targeted immunotherapy. Incorporation of social and environmental factors in future trials as health-care delivery intervention targets may increase the benefit of targeted therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djaa107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936051PMC
March 2021

Identifying relapses and stem cell transplants in pediatric acute lymphoblastic leukemia using administrative data: Capturing national outcomes irrespective of trial enrollment.

Pediatr Blood Cancer 2021 09 11;68(9):e28315. Epub 2020 May 11.

Center for Childhood Cancer Research, Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Introduction: Our objectives were to design and validate methods to identify relapse and hematopoietic stem cell transplantation (HSCT) in children with acute lymphoblastic leukemia (ALL) using administrative data representing hospitalizations at US pediatric institutions.

Methods: We developed daily billing and ICD-9 code definitions to identify relapses and HSCTs within a cohort of children with newly diagnosed ALL between January 1, 2004, and December 31, 2013, previously assembled from the Pediatric Health Information System (PHIS) database. Chart review for children with ALL at the Children's Hospital of Philadelphia (CHOP) and Texas Children's Hospital (TCH) was performed to establish relapse and HSCT gold standards for sensitivity and positive predictive value (PPV) calculations. We estimated incidences of relapse and HSCT in the PHIS ALL cohort.

Results: We identified 362 CHOP and 314 TCH ALL patients in PHIS and established true positives by chart review. Sensitivity and PPV for identifying both relapse and HSCT in PHIS were > 90% at both hospitals. Five-year relapse incidence in the 10 150-patient PHIS cohort was 10.3% (95% CI 9.8%-10.9%) with 7.1% (6.6%-7.6%) of children underwent HSCTs. Patients in higher-risk demographic groups had higher relapse and HSCT rates. Our analysis also identified differences in incidences of relapse and HSCT by race, ethnicity, and insurance status.

Conclusions: Administrative data can be used to identify relapse and HSCT accurately in children with ALL whether they occur on- or off-therapy, in contrast with published approaches. This method has wide potential applicability for estimating these incidences in pediatric ALL, including patients not enrolled on clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28315DOI Listing
September 2021

Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients With Acute Myeloid Leukemia: A Report From the Children's Oncology Group.

J Clin Oncol 2020 07 28;38(21):2398-2406. Epub 2020 Apr 28.

Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens.

Patients And Methods: This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children's Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF < 28% or EF < 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure.

Results: A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% 45.1%; = .534) and OS (65.0% 61.9%; = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% 12.7%; = .068).

Conclusion: Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.02856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367546PMC
July 2020

Changes in Cardiovascular Biomarkers With Breast Cancer Therapy and Associations With Cardiac Dysfunction.

J Am Heart Assoc 2020 01 21;9(2):e014708. Epub 2020 Jan 21.

Department of Medicine Division of Cardiology Perelman School of Medicine at the University of Pennsylvania Philadelphia PA.

Background We examined the longitudinal associations between changes in cardiovascular biomarkers and cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer treated with cardotoxic cancer therapy. Methods and Results Repeated measures of high-sensitivity cardiac troponin T (hs-cTnT), NT-proBNP (N-terminal pro-B-type natriuretic peptide), myeloperoxidase, placental growth factor, and growth differentiation factor 15 were assessed longitudinally in a prospective cohort of 323 patients treated with anthracyclines and/or trastuzumab followed over a maximum of 3.7 years with serial echocardiograms. CTRCD was defined as a ≥10% decline in left ventricular ejection fraction to a value <50%. Associations between changes in biomarkers and left ventricular ejection fraction were evaluated in repeated-measures linear regression models. Cox regression models assessed the associations between biomarkers and CTRCD. Early increases in all biomarkers occurred with anthracycline-based regimens. hs-cTnT levels >14 ng/L at anthracycline completion were associated with a 2-fold increased CTRCD risk (hazard ratio, 2.01; 95% CI, 1.00-4.06). There was a modest association between changes in NT-proBNP and left ventricular ejection fraction in the overall cohort; this was most pronounced with sequential anthracycline and trastuzumab (1.1% left ventricular ejection fraction decline [95% CI, -1.8 to -0.4] with each NT-proBNP doubling). Increases in NT-proBNP were also associated with CTRCD (hazard ratio per doubling, 1.56; 95% CI, 1.32-1.84). Increases in myeloperoxidase were associated with CTRCD in patients who received sequential anthracycline and trastuzumab (hazard ratio per doubling, 1.28; 95% CI, 1.04-1.58). Conclusions Cardiovascular biomarkers may play an important role in CTRCD risk prediction in patients with breast cancer who receive cardiotoxic cancer therapy, particularly in those treated with sequential anthracycline and trastuzumab therapy. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01173341.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.119.014708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033834PMC
January 2020

Unintended consequences of evolution of the Common Terminology Criteria for Adverse Events.

Pediatr Blood Cancer 2019 07 9;66(7):e27747. Epub 2019 Apr 9.

Center for Pediatric Clinical Effectiveness, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Adverse events (AEs) on Children's Oncology Group (COG) trials are reported manually by clinical research assistants (CRAs). The Common Terminology Criteria for Adverse Events (CTCAE) was developed to provide standardized definitions for identifying and grading AEs. The CTCAE has expanded significantly over its five versions, but the impact of CTCAE definitional changes has not been examined.

Procedure: This study compared AE number and ascertainment among the first four CTCAE versions using a case vignette. Each CTCAE version was used to create a list of AEs and grades by two separate CRAs.

Results: The CTCAE expanded from 9 categories and 49 AEs in v1.0 to 26 categories and 790 AEs in v4.0. CRAs independently selected different approaches to AE ascertainment-comprehensive and parsimonious. The number of AEs identified in the parsimonious approach was stable with 10-14 in each CTC version. The comprehensive approach identified 9, 20, 29, and 37 AEs in CTC versions 1.0, 2.0, 3.0, and 4.0, respectively. Only approximately 65% of AEs were conclusively graded in versions 2.0 to 4.0 using the comprehensive approach.

Conclusions: CTCAE has increased in complexity. Although this increased complexity allows for more granular AE reporting, these data demonstrate potential unintended negative consequences of increasing CTC AE complexity, including the risk of varying approaches to AE capture. A comprehensive evaluation of CTC AE definitions and CRA reporting practices across COG institutions and AEs are needed to improve the accuracy and efficiency of AE reporting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681806PMC
July 2019

Disparities in pediatric acute myeloid leukemia (AML) clinical trial enrollment.

Leuk Lymphoma 2019 09 7;60(9):2190-2198. Epub 2019 Feb 7.

Division of Oncology, The Children's Hospital of Philadelphia , Philadelphia , PA , USA.

Equal access to clinical trial enrollment is important to ensure that findings are generalizable to the broader population. This study aimed to evaluate disparities in enrollment on pediatric oncology clinical trials. We assessed the relationship between patient characteristics and enrollment on COG trial AAML1031 in a cohort of pediatric patients with AML in the Pediatric Health Information System. The associations of enrollment with outcomes were evaluated. Non-Hispanic Black patients, infants, and patients from zip codes with a lower proportion of poverty were less likely to enroll (30% vs. 61%,  = .004; 34% vs. 58%,  = .003; 46% vs. 58%,  = .02). On-therapy mortality was similar among enrolled and nonenrolled patients (7.3% vs. 8.9%,  = .47). Differences in early mortality were more pronounced among nonenrolled patients compared to enrolled patients (3.0% vs. 0.5%,  = .03). Understanding the etiology of these disparities will inform strategies to ensure balanced access to clinical trials across patient populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2019.1574002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685754PMC
September 2019

Comparable on-therapy mortality and supportive care requirements in Black and White patients following initial induction for pediatric acute myeloid leukemia.

Pediatr Blood Cancer 2019 04 26;66(4):e27583. Epub 2018 Dec 26.

Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

Background: Black patients with acute myeloid leukemia (AML) are more likely to present with high acuity and consequently experience higher rates of induction mortality than white patients. Given the consistently identified racial disparities in overall survival (OS) among patients with AML, we aimed to evaluate whether there were sustained on-therapy racial differences in inpatient mortality, intensive care unit (ICU) requirements, or supportive care beyond initial induction.

Procedure: Within a retrospective cohort of 1239 children diagnosed with AML between 2004 and 2014 in the Pediatric Health Information System (PHIS) database who survived their initial course of induction chemotherapy, we compared on-therapy inpatient mortality, ICU-level care requirements, treatment course duration, cumulative length of hospital stay (LOS), and resource utilization after induction I by race.

Results: Over the period from the start of induction II through completion of frontline chemotherapy, there were no significant differences in mortality (adjusted odds ratios [OR], 1.01; 95% confidence intervals [CI], 0.41-2.48), ICU-level care requirements (adjusted OR, 0.93; 95% CI, 0.69-1.26), LOS (adjusted mean difference, 3.2 days; 95% CI, -2.3-9.6), or supportive care resource utilization for black patients relative to white patients. Course-specific analyses also demonstrated no differences by race.

Conclusion: Although black patients have higher acuity at presentation and higher induction mortality, such disparities do not persist over subsequent frontline chemotherapy treatment. This finding allows interventions aimed at reducing disparities to be directed at presentation and induction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386601PMC
April 2019

Mortality, Resource Utilization, and Inpatient Costs Vary Among Pediatric Heart Transplant Indications: A Merged Data Set Analysis From the United Network for Organ Sharing and Pediatric Health Information Systems Databases.

J Card Fail 2019 Jan 25;25(1):27-35. Epub 2018 Nov 25.

Division of Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Merging United Network for Organ Sharing (UNOS) and Pediatric Health Information Systems databases has enabled a more granular analysis of pediatric heart transplant outcomes and resource utilization. We evaluated whether transplant indication at time of transplantation was associated with mortality, resource utilization, and inpatient costs during the first year after transplantation.

Methods And Results: We analyzed transplant outcomes and resource utilization from 2004 to 2015. Patients were categorized as congenital (CHD), myocarditis, or cardiomyopathy based on UNOS-defined primary indication. CHD complexity subgroup analyses (single-ventricle, complex, and simple biventricular CHD) were also performed. Of 2251 transplants (49% CHD, 5% myocarditis, 46% cardiomyopathy), CHD recipients were younger (2 [IQR 0-10], 6 [IQR 0-12], and 7 [IQR 1-14] years, respectively; P < .001) and less likely to have a ventricular assist device (VAD) at transplantation (3%, 27%, and 13%, respectively; P < .001). Patients with single-ventricle CHD had the longest time on the waitlist and were least likely to receive a VAD before transplantation. After adjusting for patient-level factors, transplant recipients with single-ventricle CHD had the greatest mortality during transplantation admission and within 1 year (odds ratio [OR] 11.8 [95% confidence interval (CI) 5.9-23.6] and OR 6.0 [95% CI 3.6-10.2], respectively, vs cardiomyopathy). Mortality was similar between patients with myocarditis and cardiomyopathy. Post-transplantation length of stay (LOS) was longer in transplant recipients with CHD than myocarditis or cardiomyopathy (25 [interquartile range [IQR] 15-45] vs 21 [IQR 12-35] vs 16 [IQR 12-25] days; P < .001), related in part to longer duration of intensive care unit-level care (ICU LOS 8 [IQR 4-20] vs 6 [IQR 4-13] vs 5 [IQR 3-8] days; P < .001). Similarly, patients with CHD had higher median post-transplantation costs than myocarditis or cardiomyopathy ($415K [IQR $201K-503K] vs $354K [IQR $179K-390K] vs $284K [IQR $145K-319K]; P < .001) that persisted after adjusting for patient-level factors (adjusted cost ratio 1.4 [95% CI 1.4-1.5], CHD vs cardiomyopathy) and was primarily driven by longer LOS. More than 50% were readmitted during the first year after transplantation, although readmission rates were similar across transplant indications (P = .42).

Conclusions: Children with CHD, particularly single-ventricle patients, require substantially greater hospital resource utilization and have significantly worse outcomes during the first year after heart transplantation compared with other indications. Further work is aimed at identifying modifiable pre-transplantation risk factors, such as pre-transplantation conditioning with VAD support and cardiac rehabilitation, to improve post-transplantation outcomes and reduce resource utilization in this complex population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cardfail.2018.11.014DOI Listing
January 2019
-->