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4. Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921

Author

Apotheek O&O&O, Cancer, Brivio, Erica, Pennesi, Edoardo, Willemse, Marieke E, Huitema, Alwin D R, Jiang, Yilin, van Tinteren, Harm D R, van der Velden, Vincent H J, Beverloo, Berna H, den Boer, Monique L, Rammeloo, Lukas A J, Hudson, Chad, Heerema, Nyla, Kowalski, Karey, Zhao, Huadong, Kuttschreuter, Luke, Bautista Sirvent, Francisco J, Bukowinski, Andrew, Rizzari, Carmelo, Pollard, Jessica, Murillo-Sanjuán, Laura, Kutny, Matthew, Zarnegar-Lumley, Sara, Redell, Michele, Cooper, Stacy, Bertrand, Yves, Petit, Arnaud, Krystal, Julie, Metzler, Markus, Lancaster, Donna, Bourquin, Jean-Pierre, Motwani, Jayashree, van der Sluis, Inge M, Locatelli, Franco, Roth, Michael E, Hijiya, Nobuko, Zwaan, Christian M, Apotheek O&O&O, Cancer, Brivio, Erica, Pennesi, Edoardo, Willemse, Marieke E, Huitema, Alwin D R, Jiang, Yilin, van Tinteren, Harm D R, van der Velden, Vincent H J, Beverloo, Berna H, den Boer, Monique L, Rammeloo, Lukas A J, Hudson, Chad, Heerema, Nyla, Kowalski, Karey, Zhao, Huadong, Kuttschreuter, Luke, Bautista Sirvent, Francisco J, Bukowinski, Andrew, Rizzari, Carmelo, Pollard, Jessica, Murillo-Sanjuán, Laura, Kutny, Matthew, Zarnegar-Lumley, Sara, Redell, Michele, Cooper, Stacy, Bertrand, Yves, Petit, Arnaud, Krystal, Julie, Metzler, Markus, Lancaster, Donna, Bourquin, Jean-Pierre, Motwani, Jayashree, van der Sluis, Inge M, Locatelli, Franco, Roth, Michael E, Hijiya, Nobuko, and Zwaan, Christian M

Published
2024

5. Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia:Results From the Phase I Part of Study ITCC054/COG AAML1921

Author

Brivio, Erica, Pennesi, Edoardo, Willemse, Marieke E., Huitema, Alwin D.R., Jiang, Yilin, Van Tinteren, Harm D.R., Van Der Velden, Vincent H.J., Beverloo, Berna H., Den Boer, Monique L., Rammeloo, Lukas A.J., Hudson, Chad, Heerema, Nyla, Kowalski, Karey, Zhao, Huadong, Kuttschreuter, Luke, Bautista Sirvent, Francisco J., Bukowinski, Andrew, Rizzari, Carmelo, Pollard, Jessica, Murillo-Sanjuán, Laura, Kutny, Matthew, Zarnegar-Lumley, Sara, Redell, Michele, Cooper, Stacy, Bertrand, Yves, Petit, Arnaud, Krystal, Julie, Metzler, Markus, Lancaster, Donna, Bourquin, Jean Pierre, Motwani, Jayashree, Van Der Sluis, Inge M., Locatelli, Franco, Roth, Michael E., Hijiya, Nobuko, Zwaan, Christian M., Brivio, Erica, Pennesi, Edoardo, Willemse, Marieke E., Huitema, Alwin D.R., Jiang, Yilin, Van Tinteren, Harm D.R., Van Der Velden, Vincent H.J., Beverloo, Berna H., Den Boer, Monique L., Rammeloo, Lukas A.J., Hudson, Chad, Heerema, Nyla, Kowalski, Karey, Zhao, Huadong, Kuttschreuter, Luke, Bautista Sirvent, Francisco J., Bukowinski, Andrew, Rizzari, Carmelo, Pollard, Jessica, Murillo-Sanjuán, Laura, Kutny, Matthew, Zarnegar-Lumley, Sara, Redell, Michele, Cooper, Stacy, Bertrand, Yves, Petit, Arnaud, Krystal, Julie, Metzler, Markus, Lancaster, Donna, Bourquin, Jean Pierre, Motwani, Jayashree, Van Der Sluis, Inge M., Locatelli, Franco, Roth, Michael E., Hijiya, Nobuko, and Zwaan, Christian M.

Abstract

PURPOSE Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. Results Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 g h/mL, 2.52 g h/mL, and 2.66 g h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.

Published
2024

6. Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921.

Author

Brivio, Erica, Pennesi, Edoardo, Willemse, Marieke E., Huitema, Alwin D.R., Jiang, Yilin, van Tinteren, Harm D.R., van der Velden, Vincent H.J., Beverloo, Berna H., den Boer, Monique L., Rammeloo, Lukas A.J., Hudson, Chad, Heerema, Nyla, Kowalski, Karey, Zhao, Huadong, Kuttschreuter, Luke, Bautista Sirvent, Francisco J., Bukowinski, Andrew, Rizzari, Carmelo, Pollard, Jessica, and Murillo-Sanjuán, Laura

Published
2024
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7. P676: UPDATED RESULTS FROM THE TRIAL ITCC-054/COG-AAML1921: BOSUTINIB IN NEWLY DIAGNOSED AND RESISTANT/INTOLERANT PEDIATRIC PATIENTS WITH CHRONIC MYELOID LEUKEMIA

Author

Brivio, Erica, primary, Pennesi, Edoardo, additional, Willemse, Marieke, additional, Jiang, Yilin, additional, van der Velden, Vincent, additional, Beverloo, Berna, additional, Hudson, Chad, additional, Kuttschreuter, Luke, additional, van der Sluis, Inge, additional, Brethon, Benoît, additional, Bautista, Francisco, additional, J. Burke, Michael, additional, Heerema, Nyla, additional, Bukowinski, Andrew, additional, Cooper, Stacy, additional, Pollard, Jessica, additional, Nagasubramani, Ramamoorthy, additional, Redell, Michele, additional, Bourquin, Jean-Pierre, additional, Pais, Ray, additional, Frediani, Jamie, additional, Batra, Sandeep, additional, Bertorello, Nicoletta, additional, Boklan, Jessica, additional, Kheradpour, Albert, additional, Kyono, Wade, additional, Kowalski, Karey, additional, Mizukawa, Benjamin, additional, Lancaster, Donna, additional, Murillo-Sanjuán, Laura, additional, Krystal, Julie, additional, Bertrand, Yves, additional, Huitema, Alwin, additional, van Tinteren, Harm, additional, Locatelli, Franco, additional, Roth, Michael, additional, Hijiya, Nobuko, additional, and Zwaan, Michel, additional

Published
2023
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8. Supplementary Data from A Phase I and Surgical Study of Ribociclib and Everolimus in Children with Recurrent or Refractory Malignant Brain Tumors: A Pediatric Brain Tumor Consortium Study

Author

DeWire, Mariko D., primary, Fuller, Christine, primary, Campagne, Olivia, primary, Lin, Tong, primary, Pan, Haitao, primary, Young Poussaint, Tina, primary, Baxter, Patricia A., primary, Hwang, Eugene I., primary, Bukowinski, Andrew, primary, Dorris, Kathleen, primary, Hoffman, Lindsey, primary, Waanders, Angela J., primary, Karajannis, Matthias A., primary, Stewart, Clinton F., primary, Onar-Thomas, Arzu, primary, Fouladi, Maryam, primary, and Dunkel, Ira J., primary

Published
2023
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10. Multicenter study of pediatric Epstein‐Barr virus–negative monomorphic post solid organ transplant lymphoproliferative disorders

Author

Afify, Zeinab A. M., primary, Taj, Mary M., additional, Orjuela‐Grimm, Manuela, additional, Srivatsa, Kavitha, additional, Miller, Tamara P., additional, Edington, Holly J., additional, Dalal, Mansi, additional, Robles, Joanna, additional, Ford, James B., additional, Ehrhardt, Matthew J., additional, Ureda, Tonya J., additional, Rubinstein, Jeremy D., additional, McCormack, Sarah, additional, Rivers, Julie M., additional, Chisholm, Karen M., additional, Kavanaugh, Madison K., additional, Bukowinski, Andrew J., additional, Friehling, Erika D., additional, Ford, Maegan C., additional, Reddy, Sonika N., additional, Marks, Lianna J., additional, Smith, Christine Moore, additional, and Mason, Clinton C., additional

Published
2022
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11. Burkitt lymphoma after solid‐organ transplant: Treatment and outcomes in the paediatric PTLD collaborative

Author

Afify, Zeinab, primary, Orjuela‐Grimm, Manuela, additional, Smith, Christine Moore, additional, Dalal, Mansi, additional, Ford, James B., additional, Pillai, Pallavi, additional, Robles, Joanna M., additional, Reddy, Sonika, additional, McCormack, Sarah, additional, Ehrhardt, Matthew J., additional, Ureda, Tonya, additional, Alperstein, Warren, additional, Edington, Holly, additional, Miller, Tamara P., additional, Rubinstein, Jeremy D., additional, Kavanaugh, Madison, additional, Bukowinski, Andrew J., additional, Friehling, Erika, additional, Rivers, Julie M., additional, Chisholm, Karen M., additional, Marks, Lianna J., additional, and Mason, Clinton C., additional

Published
2022
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12. Pediatric EBV-negative monomorphic post–solid organ transplant lymphoproliferative disorders [EBV(-)M-PTLD]: Characteristics, treatment, and outcome from 11 pediatric academic centers.

Author

Afify, Zeinab A.M., primary, Taj, Mary, additional, Srivatsa, Kavitha, additional, Miller, Tamara P., additional, Edington, Holly, additional, Dalal, Mansi, additional, Robles, Joanna, additional, Ford, James, additional, Ehrhardt, Matthew J., additional, Ureda, Tonya., additional, Rubinstein, Jeremy, additional, McCormack, Sarah, additional, Rivers, Julia M., additional, Chisholm, Karen M., additional, Kavanaugh, Madison., additional, Bukowinski, Andrew J., additional, Friehling, Erika, additional, Marks, Lianna, additional, Smith, Christine Moore, additional, and Mason, Clinton, additional

Published
2022
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13. Multicenter study of pediatric Epstein‐Barr virus–negative monomorphic post solid organ transplant lymphoproliferative disorders.

Author

Afify, Zeinab A. M., Taj, Mary M., Orjuela‐Grimm, Manuela, Srivatsa, Kavitha, Miller, Tamara P., Edington, Holly J., Dalal, Mansi, Robles, Joanna, Ford, James B., Ehrhardt, Matthew J., Ureda, Tonya J., Rubinstein, Jeremy D., McCormack, Sarah, Rivers, Julie M., Chisholm, Karen M., Kavanaugh, Madison K., Bukowinski, Andrew J., Friehling, Erika D., Ford, Maegan C., and Reddy, Sonika N.

Subjects
LYMPHOPROLIFERATIVE disorders, TRANSPLANTATION of organs, tissues, etc., DIFFUSE large B-cell lymphomas, CHILDHOOD cancer, CHILD patients, LACTATE dehydrogenase
Abstract

Background: Pediatric Epstein‐Barr virus–negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(−)M‐PTLD] comprises approximately 10% of M‐PTLD. No large multi‐institutional pediatric‐specific reports on treatment and outcome are available. Methods: A multi‐institutional retrospective review of solid organ recipients diagnosed with EBV(−)M‐PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data. Results: Thirty‐six patients were identified with EBV(−)M‐PTLD. Twenty‐three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(−)M‐PTLD, and interval from transplant to PTLD were 2.2 years (0.1–17), 14 years (3.0–20), and 8.5 years (0.6–18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B‐cell lymphoma (n = 31 [86.1%]) and B–non‐Hodgkin lymphoma (B‐NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B–NHL‐specific regimen (n = 13 [36.1%]) and low‐dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow‐up from diagnosis was 3.0 years (0.3–11.0 years). Three‐year event‐free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease. Conclusions: EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B‐NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi‐institutional registry to design prospective studies. Plain Language Summary: Pediatric Epstein‐Barr virus–negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(−)M‐PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B‐cell lymphoma in immunocompetent pediatric patients.The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes.The impact of treatment regimen on relapse risk could not be assessed because of small numbers.In the intensive pediatric B–non‐Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years. No consensus exists about treatment and outcomes of pediatric Epstein‐Barr virus–negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(−)M‐PTLD]. Retrospective evidence suggests that EBV(−)M‐PTLD has comparable outcomes to published results in EBV(+) PTLD, but inferior to diffuse large B‐cell lymphoma in immunocompetent pediatric patients. [ABSTRACT FROM AUTHOR]

Published
2023
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14. Burkitt lymphoma after solid‐organ transplant: Treatment and outcomes in the paediatric PTLD collaborative.

Author

Afify, Zeinab, Orjuela‐Grimm, Manuela, Smith, Christine Moore, Dalal, Mansi, Ford, James B., Pillai, Pallavi, Robles, Joanna M., Reddy, Sonika, McCormack, Sarah, Ehrhardt, Matthew J., Ureda, Tonya, Alperstein, Warren, Edington, Holly, Miller, Tamara P., Rubinstein, Jeremy D., Kavanaugh, Madison, Bukowinski, Andrew J., Friehling, Erika, Rivers, Julie M., and Chisholm, Karen M.

Subjects
TREATMENT effectiveness, LYMPHOPROLIFERATIVE disorders, LYMPHOMAS, PEDIATRICS, TRANSPLANTATION of organs, tissues, etc.
Abstract

Summary: Burkitt lymphoma arising in paediatric post‐solid‐organ transplantation‐Burkitt lymphoma (PSOT‐BL) is a clinically aggressive malignancy and a rare form of post‐transplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT‐BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1–14) and age at PSOT‐BL diagnosis was 8.0 years (range: 1–17). All but one patient had late onset of PSOT‐BL (≥2 years post‐transplant), with a median interval from transplant to PSOT‐BL diagnosis of 4.0 years (range: 0.4–12). Heart (n = 18 [51.4%]) and liver (n = 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatment‐related mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma‐specific French–American–British/Lymphomes Malins B (FAB/LMB), n = 13 (37.1%), and a low‐intensity regimen consisting of cyclophosphamide, prednisone and rituximab (CPR) n = 12 (34.3%). Median follow‐up was 6.7 years (range: 0.5–17). Three‐year event‐free and overall survival were 66.2% and 88.0%, respectively. Outcomes of PSOT‐BL patients receiving BL‐specific intensive regimens are comparable to reported BL outcomes in immunocompetent children. Multi‐institutional collaboration is feasible and provides the basis of prospective data collection to determine the optimal treatment regimen for PSOT‐BL. [ABSTRACT FROM AUTHOR]

Published
2023
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15. Mixed phenotype acute leukemia in a child associated with a NUP98‐NSD1 fusion and NRAS p.Gly61Arg mutation

Author

Ganapathi, Shireen S., Raikar, Sunil S., Yatsenko, Svetlana A., Djokic, Miroslav, and Bukowinski, Andrew

Subjects
mTOR inhibitors, Adolescent, Oncogene Proteins, Fusion, Biopsy, Hematopoietic Stem Cell Transplantation, Membrane Proteins, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Case Report, NRAS, Case Reports, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Neoplasms, Complex and Mixed, Neoadjuvant Therapy, GTP Phosphohydrolases, mixed phenotype acute leukemia (MPAL), Leukemia, Myeloid, Acute, Fatal Outcome, Bone Marrow, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Mutation, Humans, NUP98‐NSD1, Female, RC254-282
Abstract

Background Mixed phenotype acute leukemia (MPAL) is a rare subset of acute leukemia in the pediatric population associated with genetic alterations seen in both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Case We describe a patient with MPAL with a NUP98 (nucleoporin 98)‐NSD1 gene fusion (nuclear receptor binding SET domain protein1) and NRAS (neuroblastoma RAS viral oncogene homolog mutation) p.Gly61Arg mutation who was treated with upfront AML‐based chemotherapy, received hematopoietic stem cell transplant (HSCT), but unfortunately died from relapsed disease. Conclusion This case highlights the challenges faced in choosing treatment options in MPAL patients with complex genomics, with predominant myeloid features.

Published
2021

17. A Phase I Study of Entinostat in Children and Adolescents with Recurrent or Refractory Solid Tumors, Including CNS Tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN)()

Author

Bukowinski, Andrew, Chang, Bill, Reid, Joel M., Liu, Xiaowei, Minard, Charles G., Trepel, Jane B., Lee, Min-Jung, Fox, Elizabeth, and Weigel, Brenda J.

Subjects
Adult, Male, Adolescent, Maximum Tolerated Dose, Pyridines, Antineoplastic Agents, Sarcoma, Article, Central Nervous System Neoplasms, Young Adult, Neoplasms, Benzamides, Humans, Female, Neoplasm Recurrence, Local, Child
Abstract

BACKGROUND: Entinostat is an oral small molecule inhibitor of Class I Histone Deacetylases (HDAC) which has not previously been evaluated in pediatrics. We conducted a phase 1trial to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), toxicity profile, pharmacokinetics (PK), and pharmacodynamics (PD) of entinostat in children with relapsed or refractory solid tumors including central nervous systems malignancies. METHODS: A rolling six dose escalation design evaluated two dose levels. Entinostat oral tablet formulation was administered once per week, four doses per 28 day cycle. PK and PD studies were performed. RESULTS: Twenty-one eligible patients median (range) age 14 (6–20). Six subjects were treated at 3mg/m(2) dose level and fifteen were treated in 4mg/m(2) dose level. The study included patients with CNS tumors (n=12), sarcomas (n=6), or other solid tumors (n=3). Eight patients were not fully evaluable for toxicity due to progression of disease prior to receiving the required percentage of protocol therapy. No cycle one dose limiting toxicity (DLT) was observed at either dose level. A threefold higher Area Under the Curve (AUC) was achieved in our cohort compared to adults using a similar dosing schedule. The PD studies showed increase in acetylated lysine in peripheral blood leukocytes at both doses. CONCLUSIONS: Entinostat was well tolerated with no DLT observed. All patients experienced progression within the first two cycles except one patient with ependymoma with stable disease. Based on pharmacokinetics and pharmacodynamics, the R2PD in pediatric patients with solid tumors is 4mg/m(2) orally administered once weekly.

Published
2021

19. A Phase I and Surgical Study of Ribociclib and Everolimus in Children with Recurrent or Refractory Malignant Brain Tumors: A Pediatric Brain Tumor Consortium Study

Author

DeWire, Mariko D., primary, Fuller, Christine, additional, Campagne, Olivia, additional, Lin, Tong, additional, Pan, Haitao, additional, Young Poussaint, Tina, additional, Baxter, Patricia A., additional, Hwang, Eugene I., additional, Bukowinski, Andrew, additional, Dorris, Kathleen, additional, Hoffman, Lindsey, additional, Waanders, Angela J., additional, Karajannis, Matthias A., additional, Stewart, Clinton F., additional, Onar-Thomas, Arzu, additional, Fouladi, Maryam, additional, and Dunkel, Ira J., additional

Published
2021
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20. A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase‐Clinical Trial Network (PEP‐CTN)

Author

Bukowinski, Andrew, primary, Chang, Bill, additional, Reid, Joel M., additional, Liu, Xiaowei, additional, Minard, Charles G., additional, Trepel, Jane B., additional, Lee, Min‐Jung, additional, Fox, Elizabeth, additional, and Weigel, Brenda J., additional

Published
2021
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21. EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIB AND EVEROLIMUS IN CHILDREN WITH RECURRENT OR REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN TUMOR CONSORTIUM INTERIM REPORT

Author

DeWire, Mariko, primary, Fuller, Christine, additional, Campagne, Olivia, additional, Lin, Tong, additional, Pan, Haitao, additional, Young-Pussaint, Tina, additional, Baxter, Patricia, additional, Hwang, Eugene, additional, Bukowinski, Andrew, additional, Dorris, Kathleen, additional, Hoffman, Lindsey, additional, Waanders, Angela, additional, Karajannis, Matthias, additional, Steward, Clinton, additional, Onar-Thomas, Arzu, additional, Dunkel, Ira, additional, and Fouladi, Maryam, additional

Published
2020
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27. Novel Urinary Biomarkers of Acute Kidney Injury to Detect Toxicity and Predict Clearance in Pediatric Oncology Patients Treated with High Dose Methotrexate

Author

Bukowinski, Andrew

Subjects
Surgery, Methotrexate, Pediatrics, Kidney Injury Molecule-1, Delayed Clearance, Oncology, Neutrophil Associated Lipocalin
Abstract

High-dose methotrexate (HD-MTX) is a critical component of therapy for pediatric malignancies. The ability to identify patients at risk for delayed MTX clearance and acute kidney injury (AKI) is limited. Kidney Injury molecule-1 (KIM-1) is a urinary biomarker which is an early indicator of tubular injury. The current study evaluates associations between urinary KIM-1, delayed MTX clearance, and MTX exposure. Methods: 47 patients (31 male, 16 female; median age 9.5 years, range 3-31) received 1-12 g/m2 HD-MTX over 4 or 24 hours for a total of 96 courses of MTX. Diagnoses included: leukemia/lymphoma (42 pts), osteosarcoma (5 pts). Data was collected on up to 4 courses of HD-MTX. Serum creatinine (SCr) and MTX were measured per standard clinical practice. Urine samples were obtained prior to the infusion and at 12, 24, and 36-48 hours after start. KIM-1 was measured by enzyme linked immunosorbent assay and normalized to urine creatinine. Delayed methotrexate clearance (DC) was defined by plasma MTX levels exceeding “high risk” concentrations in standard oncology treatment regimens, failure to clear MTX within 72 hours, or a 50% rise in SCr. Toxicity data was collected by chart review. Univariate analyses were conducted using Wilcoxon Rank sum testing. MTX area under the curve (AUC) was calculated with MW/Pharm software using Bayesian estimation. Results: Patients with DC had higher AUC levels (p < 0.05). Kim-1 at 12 hours correlated with AUC (p < 0.04) in leukemia patients receiving 1st course of HD-MTX. KIM-1 is associated with DC at 12 and 24 hours for 1st and 2nd courses of HD-MTX (p < 0.05). Prior to infusion KIM-1 is associated with previous DC (p < 0.05). Conclusions: Increased KIM-1 is associated with both MTX AUC and DC and is indicative of renal tubular injury. This association is most pronounced in course 1 and may be due to attrition of patients with severe toxicity, or dose reduction and enhanced supportive care in subsequent courses. KIM-1 provides an early indication of kidney injury from HD-MTX and with additional evaluation may be a target for enhanced supportive care strategies

Published
2015

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