Acute myeloid leukemia with hepatic infiltration presenting as obstructive jaundice

Walsh, Landis R.; Yuan, Chaofan; Boothe, James T.; Conway, H; Mindiola‐Romero, Andres E.; Barrett-Campbell, Odeth; Yerrabothala, Swaroopa; Lansigan, Frederick

doi:10.1016/j.lrr.2021.100251

Cited by 2 publications

(3 citation statements)

References 9 publications

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“…Because emvododstat and desmethyl emvododstat were metabolized exclusively by the liver, it was assumed that the PKs and hepatic effects of emvododstat and desmethyl emvododstat in patients with AML with normal hepatic function would be similar to those in healthy subjects. Although rare, hepatic infiltration and dysfunction have been reported in patients with AML 25 . Underlying liver conditions and co‐administered drugs may impact hepatic safety of emvododstat in patients with AML, which warrants further investigation and simulations with these specific conditions to inform the liver safety of emvododstat in such cases.…”

Section: Discussionmentioning

confidence: 99%

“…Although rare, hepatic infiltration and dysfunction have been reported in patients with AML. 25 Underlying liver conditions and co-administered drugs may impact hepatic safety of emvododstat in patients with AML, which warrants further investigation and simulations with these specific conditions to inform the liver safety of emvododstat in such cases.…”

Section: Articlementioning

confidence: 99%

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Quantitative Systems Toxicology Modeling Informed Safe Dose Selection of Emvododstat in Acute Myeloid Leukemia Patients

Yang,

Kong,

Spiegel

et al. 2023

Clin Pharma and Therapeutics

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Clinical investigation of emvododstat for the treatment of solid tumors was halted after two patients who were heavily treated with other anticancer therapies experienced drug‐induced liver failure. However, preclinical investigations supported that emvododstat at lower doses might be effective in treating acute myeloid leukemia (AML) and against severe acute respiratory syndrome‐coronavirus 2 as a dihydroorotate dehydrogenase inhibitor. Therefore, a quantitative systems toxicology model, DILIsym, was used to predict liver safety of the proposed dosing of emvododstat in AML clinical trials. In vitro mechanistic toxicity data of emvododstat and its desmethyl metabolite were integrated with in vivo exposure within DILIsym to predict hepatotoxicity responses in a simulated human population. DILIsym simulations predicted alanine aminotransferase elevations observed in prior emvododstat clinical trials in patients with solid tumors, but not in the prospective AML clinical trial with the proposed dosing regimens. Exposure predictions based on physiologically‐based pharmacokinetic modeling suggested that reduced doses of emvododstat would produce clinical exposures that would be efficacious to treat AML. In the AML clinical trial, only eight patients experienced aminotransferase elevations, all of which were mild (grade 1), all resolving within a short period of time, and no patient showed symptoms of hepatotoxicity, confirming the prospective prediction of liver safety. Overall, retrospective DILIsym simulations adequately predicted the liver safety liabilities of emvododstat in solid tumor trials and prospective simulations predicted the liver safety of reduced doses in an AML clinical trial. The modeling was critical to enabling regulatory approval to proceed with the AML clinical trial wherein the predicted liver safety was confirmed.

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Section: Discussionmentioning

confidence: 99%

Section: Articlementioning

confidence: 99%

Quantitative Systems Toxicology Modeling Informed Safe Dose Selection of Emvododstat in Acute Myeloid Leukemia Patients

Yang,

Kong,

Spiegel

et al. 2023

Clin Pharma and Therapeutics

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“…Liver involvement: Though liver involvement as hepatomegaly is lesser than ALL clinically, postmortem studies have demonstrated up to 75% involvement of the liver[ 29 ]. Acute hepatitis may present as conjugated jaundice due to granulocytic sarcoma impeding bile flow or due to myeloid cell infiltration[ 30 ]. Acute liver failure at presentation is rarely reported with pediatric AML posing significant challenges to chemotherapy administration and invariably had poor outcomes in the cases described in the literature[ 31 ].…”

Section: Leukemias In Childrenmentioning

confidence: 99%

Gut and liver involvement in pediatric hematolymphoid malignancies

Devarapalli¹,

Sarma²,

Mathiyazhagan³

2022

WJGO

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Hematolymphoid malignancies are common neoplasms in childhood. The involvement of the gastrointestinal (GI) tract, liver, biliary system, pancreas, and peritoneum are closely interlinked and commonly encountered. In leukemias, lymphomas, and Langerhans cell histiocytosis (LCH), the manifestations result from infiltration, compression, overwhelmed immune system, and chemotherapy-induced drug toxicities. In acute leukemias, major manifestations are infiltrative hepatitis, drug induced gastritis, neutropenic typhlitis and chemotherapy related pancreatitis. Chronic leukemias are rare. Additional presentation in lymphomas is cholestasis due to infiltration or biliary obstruction by lymph nodal masses. Presence of ascites needs a thorough workup for the underlying pathophysiology that may modify the therapy and affect the outcome. Uncommon hematolymphoid malignancies are primary hepatic, hepatosplenic, and GI lymphomas which have strict definitions. In advanced diseases with extensive spread, it may be impossible to distinguish these diseases from the primary site of origin. LCH produces biliary strictures that mimic as sclerosing cholangitis. Liver infiltration is associated with poor liver recovery even after chemotherapy. The heterogeneity of gut and liver manifestations in hematolymphoid malignancies has a clinical impact on their management. Though chemotherapy is the mainstay of therapy in all hematolymphoid malignancies, debulking surgery and radiotherapy have an adjuvant role in specific clinical scenarios. Rare situations presenting as liver failure or end-stage liver disease require liver transplantation. At their initial presentation to a primary care physician, given the ambiguity in clinical manifestations and the prognostic difference with time-bound management, it is vital to recognize them early for optimal outcomes. Pooled data from robust registries across the world is required for better understanding of these complications.

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Acute myeloid leukemia with hepatic infiltration presenting as obstructive jaundice

Abstract: Highlights Acute myeloid leukemia can present as cholestasis with obstructive jaundice. Extramedullary leukemia infiltration of liver can delay initiation of chemotherapy. Hydroxyurea may be employed as a temporizing measure for effects of hyperleukocytosis.

Cited by 2 publications

References 9 publications

Quantitative Systems Toxicology Modeling Informed Safe Dose Selection of Emvododstat in Acute Myeloid Leukemia Patients

Quantitative Systems Toxicology Modeling Informed Safe Dose Selection of Emvododstat in Acute Myeloid Leukemia Patients

Gut and liver involvement in pediatric hematolymphoid malignancies

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