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Painful Eruptions in a Patient With Cholangiocarcinoma Treated With Fibroblast Growth Factor Receptor Inhibitor

Educational Objective
Based on this clinical scenario and the accompanying image, understand how to arrive at a correct diagnosis.
1 Credit CME

A 65-year-old woman with locally advanced, unresectable intrahepatic cholangiocarcinoma being treated with pemigatinib, a fibroblast growth factor receptor inhibitor (FGFRi), presented with a painful eruption on the bilateral lower extremities. Pemigatinib treatment was initiated 2 months prior to the skin findings. Laboratory evaluation demonstrated a mildly elevated D-dimer level at 578 ng/mL fibrinogen-equivalent units, prolonged prothrombin time of 12.7 seconds, elevated phosphorus level at 6.8 mg/dL (of note, phosphorus was 3.1 mg/dL 1 month prior), and normal calcium level and kidney function. Other laboratory tests to note include cryoglobulin and cryofibrinogen, which both had negative results. Within weeks, there was rapid progression with skin necrosis despite treatment initiation with rivaroxaban. Physical examination revealed retiform purpura with areas of necrosis involving the bilateral lower extremities (Figure, A and B). A punch biopsy specimen from the right calf was obtained for histopathologic analysis (Figure, C and D).

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B. Calciphylaxis

Cholangiocarcinoma is a rare malignant neoplasm that arises from intrahepatic and/or extrahepatic bile ducts. Treatment options include targeted systemic therapy, localized radiation therapy, and surgery. Treatments are based on tumor stage and location within the biliary tract. Standard-of-care first-line therapy for either locally advanced or metastatic cholangiocarcinoma is gemcitabine and cisplatin.1 In the era of next-generation sequencing, targetable alterations have been identified in cholangiocarcinoma. One such alteration is FGFR2 fusions, which is identified in 15% of patients with intrahepatic cholangiocarcinoma.2,3 In April 2020, the US Food and Drug Administration granted accelerated approval for pemigatinib, an oral inhibitor of FGFR1, FGFR2, and FGFR3. Common adverse effects affecting more than 30% of patients receiving oral therapy include alopecia, dysgeusia, diarrhea, and fatigue.4 Overall, the most common adverse effect of pemigatinib is hyperphosphatemia, which develops in approximately 60% of patients.2

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Article Information

Corresponding Author: Natasha S. Wylie, DNP, APRN, Division of Hematology and Medical Oncology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 (wylie.natasha@mayo.edu).

Published Online: October 28, 2021. doi:10.1001/jamaoncol.2021.5578

Conflict of Interest Disclosures: Dr Starr reported receiving honoraria for consulting from Natera, Pfizer, TerSera Therapeutics, Ipsen, and Advanced Accelerator Applications outside the submitted work. No other disclosures were reported.

Additional Contributions: We thank the patient for granting permission to publish this information.

References
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Valle  J , Wasan  H , Palmer  DH ,  et al; ABC-02 Trial Investigators.  Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.   N Engl J Med. 2010;362(14):1273-1281. doi:10.1056/NEJMoa0908721 PubMedGoogle ScholarCrossref
2.
Abou-Alfa  GK , Sahai  V , Hollebecque  A ,  et al.  Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.   Lancet Oncol. 2020;21(5):671-684. doi:10.1016/S1470-2045(20)30109-1 PubMedGoogle ScholarCrossref
3.
Ross  JS , Wang  K , Gay  L ,  et al.  New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing.   Oncologist. 2014;19(3):235-242. doi:10.1634/theoncologist.2013-0352 PubMedGoogle ScholarCrossref
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Pemazyre (pemigatinib). Package insert. Incyte Corporation; 2020.
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Nigwekar  SU , Thadhani  R , Brandenburg  VM .  Calciphylaxis.   N Engl J Med. 2018;378(18):1704-1714. doi:10.1056/NEJMra1505292 PubMedGoogle ScholarCrossref
6.
Macklis  P , Chung  C , Kaffenberger  B .  Calciphylaxis associated with the fibroblast growth factor receptor inhibitor erdafitinib.   JAAD Case Rep. 2020;7:125-127. doi:10.1016/j.jdcr.2020.11.022 PubMedGoogle ScholarCrossref
7.
Lacouture  ME , Sibaud  V , Anadkat  MJ ,  et al.  Dermatologic adverse events associated with selective fibroblast growth factor receptor inhibitors: overview, prevention, and management guidelines.   Oncologist. 2021;26(2):e316-e326. doi:10.1002/onco.13552 PubMedGoogle ScholarCrossref
8.
Arudra  K , Patel  R , Tetzlaff  MT ,  et al.  Calcinosis cutis dermatologic toxicity associated with fibroblast growth factor receptor inhibitor for the treatment of Wilms tumor.   J Cutan Pathol. 2018;45(10):786-790. doi:10.1111/cup.13319 PubMedGoogle ScholarCrossref
9.
McCarthy  JT , El-Azhary  RA , Patzelt  MT ,  et al.  Survival, risk factors, and effect of treatment in 101 patients with calciphylaxis.   Mayo Clin Proc. 2016;91(10):1384-1394. doi:10.1016/j.mayocp.2016.06.025PubMedGoogle ScholarCrossref
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