A case report of vanishing bile duct syndrome after exposure to pexidartinib (PLX3397) and paclitaxel

Piawah, Sorbarikor; Hyland, Colby J.; Umetsu, Sarah E.; Esserman, Laura J.; Rugo, Hope S.; Chien, Amy Jo

doi:10.1038/s41523-019-0112-z

Cited by 20 publications

(20 citation statements)

References 37 publications

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“…Over the ensuing 13 months, her liver enzymes remained abnormal (ALT/AST 150 to 200 U/L; ALP 350 to 400 U/L; TBIL 20 to 25 mg/dL; R value <2: cholestatic), and she eventually required liver transplantation. Following successful transplant, her liver tests normalized and her performance status vastly improved [26].…”

Section: Resultsmentioning

confidence: 99%

Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors

et al. 2020

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Background Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib. Materials, and Methods Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow‐up from initial pexidartinib treatment was 39 months (range, 32–82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288. Results In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1–76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low‐grade dose‐dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1–7 months following pexidartinib discontinuation. Five patients from the non‐TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases. Conclusion This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long‐term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury. Implications for Practice This is the first long‐term pooled analysis to report on the long‐term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.

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Section: Resultsmentioning

confidence: 99%

Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors

et al. 2020

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“…One potential advantage of using preclinical models is to improve therapeutic regimens that very often lead to serious adverse events in patients that might be irreversible and cause long-lasting damage (33). Accordingly, we coupled our low dose CTX with a lower dose of PXB and still observed a dramatic regression of primary tumors with this combination therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, we used reduced (3.3 X lower dose) of PXB in combination with CTX as Csf1r inhibitors may elicit liver toxicity (33). The low-dose combination treatment also yielded a significant survival benefit for primary tumors as compared to single agent treated T12 tumors ( Fig S1j).…”

Section: P53 -/-Syngeneic Tnbc Gem Recapitulate Human Tnbc Subtypes Amentioning

confidence: 99%

Chemotherapy coupled to macrophage inhibition leads to enhanced T and B cell infiltration and durable triple negative breast cancer regression

Singh

Lee

Bado

et al. 2021

Preprint

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Immunosuppressive elements within the tumor microenvironment such as Tumor Associated Macrophages (TAMs) can present a barrier to successful anti-tumor responses by cytolytic T cells. We employed preclinical syngeneic p53 null mouse models of TNBC to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose chemotherapy coupled with the pharmacologic inhibition of TAMs. Combination therapy was used to successfully treat several highly aggressive, claudin-low murine mammary tumors and lung metastasis. Long-term responders developed tertiary lymphoid structures co-infiltrated by T and B cells at the treatment site. Mechanistically, CD86+ antigen-experienced T cells exhibited polyclonal expansion and resulted in exceptional responses upon tumor rechallenge. Combination treatment also eliminated lung metastases. High dimensional transcriptomic data for CD45+ immune cells lead to the identification of an aberrant developmental trajectory for TAMs that were resistant to treatment. Signatures derived from these TAM populations were predictive of patient response to our therapy. This study illustrates the complexity of tumor infiltrating myeloid cells and highlights the importance of personalized immuno-genomics to inform therapeutic regimens.

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“…Implicated classes of agents comprise antineoplastic drugs, macrolide antibiotics, penicillins, sulfonamides, fluoroquinolones, antifungals, NSAIDs, phenothiazines, tricyclics antidepressants, naproxen and aromatic anticonvulsants ( Flynn and Demling 1982 ; Bethesda 2012 ; Li et al, 2019 ). Drugs related to VBDS reported in the past two years include amoxicillin and clavulanate potassium ( Li et al, 2019 ), ibuprofen ( Park et al, 2020 ), atovaquone/guanine ( Abugroun et al, 2019 ), pembrolizumab ( Doherty et al, 2017 ; Thorsteinsdottir et al, 2020 ), infliximab ( Shah et al, 2019 ), pesidatinib (PLX3397) + paclitaxel ( Piawah et al, 2019 ), meropenem ( Zubarev et al, 2020 ), efavirenz ( Nwaesei et al, 2019 ), trimethoprim/sulfamethoxazole ( Kathi et al, 2020 ) and temozolomide ( Bethesda 2012 ) ( Table 3 ), which provides a clue for the early detection of VBDS in clinical practice.…”

Section: Clinical Manifestationmentioning

confidence: 99%

Chronic Drug-Induced Liver Injury: Updates and Future Challenges

et al. 2021

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Chronic drug-induced liver injury (DILI), defined as DILI with persistent liver injury more than one year after the first onset by the latest European guidelines, is a notable challenge globally with big issues of defining causality and establishing effective treatment. About 20% of patients with DILI develop into chronic DILI. Chronic DILI manifests as persistent or repeated inflammatory or diminishing bile ducts, even progresses to cirrhosis and needs liver transplantation eventually. However, research on chronic DILI over the last decades is still lacking, and the incidence, phenotypes, mechanisms, risk factors, and treatment have not been fully understood. In this paper, we reviewed the definition of chronic DILI, updated clinical studies in terms of incidence, special manifestations, and promising risk factors of chronic DILI, along with the recent progress and challenges in glucocorticoid therapy.

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A case report of vanishing bile duct syndrome after exposure to pexidartinib (PLX3397) and paclitaxel

Cited by 20 publications

References 37 publications

Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors

Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors

Chemotherapy coupled to macrophage inhibition leads to enhanced T and B cell infiltration and durable triple negative breast cancer regression

Chronic Drug-Induced Liver Injury: Updates and Future Challenges

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