Browsing by Author "Orgel, Etan"

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    Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study
    (Elsevier, 2020-03) Myers, Kasiani C.; Furutani, Elissa; Weller, Edie; Siegele, Bradford; Galvin, Ashley; Arsenault, Valerie; Alter, Blanche P.; Boulad, Farid; Bueso-Ramos, Carlos; Burroughs, Lauri; Castillo, Paul; Connelly, James; Davies, Stella M.; DiNardo, Courtney D.; Hanif, Iftikhar; Ho, Richard H.; Karras, Nicole; Manalang, Michelle; McReynolds, Lisa J.; Nakano, Taizo A.; Nalepa, Grzegorz; Norkin, Maxim; Oberley, Matthew J.; Orgel, Etan; Pastore, Yves D.; Rosenthal, Joseph; Walkovich, Kelly; Larson, Jordan; Malsch, Maggie; Elghetany, M. Tarek; Fleming, Mark D.; Shimamura, Akiko; Pediatrics, School of Medicine
    Background: Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies. Methods: We did a multicentre, retrospective, cohort study in collaboration with the North American Shwachman-Diamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients. Findings: We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 [56%] cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9-8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8-not reached) and 0·99 years (95% CI 0·2-2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1-39) for patients with leukaemia and 51% (29-68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia-including the two patients initially diagnosed with myelodysplastic who progressed- two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32-82; n=14) compared with 28% (95% CI 10-50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts. Interpretation: Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome.
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    Levocarnitine for pegaspargase-induced hepatotoxicity in older children and young adults with acute lymphoblastic leukemia
    (Wiley, 2021-11) Schulte, Rachael; Hinson, Ashley; Huynh, Van; Breese, Erin H.; Pierro, Joanna; Rotz, Seth; Mixon, Benjamin A.; McNeer, Jennifer L.; Burke, Michael J.; Orgel, Etan; Pediatrics, School of Medicine
    Background: Pegaspargase (PEG-ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future therapy. Obese and adolescent and young adult (AYA) patients are at high risk. Levocarnitine has been described as potentially beneficial for the treatment or prevention of PEG-ASP-associated hepatotoxicity. Methods: We collected data for patients age ≥10 years who received levocarnitine during induction therapy for ALL, compared to a similar patient cohort who did not receive levocarnitine. The primary endpoint was conjugated bilirubin (c.bili) >3 mg/dl. Secondary endpoints were transaminases >10× the upper limit of normal and any Grade ≥3 hepatotoxicity. Results: Fifty-two patients received levocarnitine for prophylaxis (n = 29) or rescue (n = 32) of hepatotoxicity. Compared to 109 patients without levocarnitine, more patients receiving levocarnitine were obese and/or older and had significantly higher values for some hepatotoxicity markers at diagnosis and after PEG-ASP. Levocarnitine regimens varied widely; no adverse effects of levocarnitine were identified. Obesity and AYA status were associated with an increased risk of conjugated hyperbilirubinemia and severe transaminitis. Multivariable analysis identified a protective effect of levocarnitine on the development of c.bili >3 mg/dl (OR 0.12, p = 0.029). There was no difference between groups in CTCAE Grade ≥3 hepatotoxicity. C.bili >3 mg/dl during induction was associated with lower event-free survival. Conclusions: This real-world data on levocarnitine supplementation during ALL induction highlights the risk of PEG-ASP-associated hepatotoxicity in obese and AYA patients, and hepatotoxicity's potential impact on survival. Levocarnitine supplementation may be protective, but prospective studies are needed to confirm these findings.
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    Practice patterns in the diagnosis and management of chemotherapy-induced peripheral neuropathy in adolescents and young adults with cancer: a survey of oncologists
    (Springer, 2025-04-04) Belsky, Jennifer A.; Dupuis, L. Lee; Sung, Lillian; Carter, Allie; Leisinger, Audrey; Orgel, Etan; Parsons, Susan K.; Roth, Michael; Pediatrics, School of Medicine
    Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) affects > 78% of oncology patients and causes detrimental side effects. There may be practice heterogenicity in CIPN management amongst oncologists treating pediatric, adolescent young adult (AYA), and adult patients with cancer. We sought to evaluate the practice patterns of oncologists regarding their management of CIPN in AYAs with cancer. Methods: A survey was developed and sent to pediatric and medical oncologists from across the United States. Scenarios included an 18-year-old receiving vincristine (VCR) with mild neuropathy (Scenario 1) and moderate/severe neuropathy (Scenario 2). Respondents were asked how they would manage each patient. Differences between pediatric and medical oncologists' management were assessed. Results: A total of 179 responses were submitted by 132 (73.7%) pediatric, 44 (24.6%) medical oncologists, and 3 (1.6%) oncologists who care for both pediatric and adult patients. Over half of respondents for Scenario 1 would refer the patient to physical therapy (PT) (56.8%), 38.1% would prescribe a pharmacologic agent, and 27.8% would dose reduce/omit vincristine. For Scenario 2, most (81.8%) would dose reduce/omit vincristine, 69.3% would refer for PT, and 44.9% would start a pharmacologic agent. On multivariable analyses, medical oncologists were more likely to dose reduce/omit vincristine for Scenario 1 (OR, 7.68; 95% CI, 3.24-18.22) and Scenario 2 (OR, 5.52; 95% CI, 1.37-22.18, and less likely to refer to PT for Scenario 1 (OR, 0.12; 95% CI, 0.05-0.31) and Scenario 2 (OR, 0.18; 95% CI, 0.08-0.41). Conclusion: Our survey suggests a broad spectrum of CIPN management in AYAs with cancer. The heterogenicity in practices and significant differences between pediatric and medical oncologists underscores an urgent need to better understand the source of heterogeneity in CIPN management practices and barriers to evidence-based care delivery.
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    Prospective External Validation of the Esbenshade Vanderbilt Models Accurately Predicts Bloodstream Infection Risk in Febrile Non-Neutropenic Children With Cancer
    (American Society of Clinical Oncology, 2024) Zhao, Zhiguo; Patel, Pratik A.; Slatnick, Leonora; Sitthi-Amorn, Anna; Bielamowicz, Kevin J.; Nunez, Farranaz A.; Walsh, Alexandria M.; Hess, Jennifer; Rossoff, Jenna; Elgarten, Caitlin; Myers, Regina; Saab, Raya; Basbous, Maya; Mccormick, Meghan; Aftandilian, Catherine; Richards, Rebecca; Nessle, C. Nathan; Tribble, Alison C.; Sheth Bhutada, Jessica K.; Coven, Scott L.; Runco, Daniel; Wilkes, Jennifer; Gurunathan, Arun; Guinipero, Terri; Belsky, Jennifer A.; Lee, Karen; Wong, Victor; Malhotra, Megha; Armstrong, Amy; Jerkins, Lauren P.; Cross, Shane J.; Fisher, Lyndsay; Stein, Madison T.; Wu, Natalie L.; Yi, Troy; Orgel, Etan; Haeusler, Gabrielle M.; Wolf, Joshua; Demedis, Jenna M.; Miller, Tamara P.; Esbenshade, Adam J.; Pediatrics, School of Medicine
    Purpose: The optimal management of fever without severe neutropenia (absolute neutrophil count [ANC] ≥500/µL) in pediatric patients with cancer is undefined. The previously proposed Esbenshade Vanderbilt (EsVan) models accurately predict bacterial bloodstream infections (BSIs) in this population and provide risk stratification to aid management, but have lacked prospective external validation. Materials and methods: Episodes of fever with a central venous catheter and ANC ≥500/µL occurring in pediatric patients with cancer were prospectively collected from 18 academic medical centers. Variables included in the EsVan models and 7-day clinical outcomes were collected. Five versions of the EsVan models were applied to the data with calculation of C-statistics for both overall BSI rate and high-risk organism BSI (gram-negative and Staphylococcus aureus BSI), as well as model calibration. Results: In 2,565 evaluable episodes, the BSI rate was 4.7% (N = 120). Complications for the whole cohort were rare, with 1.1% (N = 27) needing intensive care unit (ICU) care by 7 days, and the all-cause mortality rate was 0.2% (N = 5), with only one potential infection-related death. C-statistics ranged from 0.775 to 0.789 for predicting overall BSI, with improved accuracy in predicting high-risk organism BSI (C-statistic 0.800-0.819). Initial empiric antibiotics were withheld in 14.9% of episodes, with no deaths or ICU admissions attributable to not receiving empiric antibiotics. Conclusion: The EsVan models, especially EsVan2b, perform very well prospectively across multiple academic medical centers and accurately stratify risk of BSI in episodes of non-neutropenic fever in pediatric patients with cancer. Implementation of routine screening with risk-stratified management for non-neutropenic fever in pediatric patients with cancer could safely reduce unnecessary antibiotic use.