Multiorgan transplant for therapy-associated lung and liver failure in a patient with stage III lung cancer

Anitha Chandrasekhar, Hee Chul Yang, Tarik Demir, Anjana Yeldandi, Chitaru Kurihara, Rade Tomic, Ruli Gao, Jonathan W. Goldman, Satish Nadig, Young Kwang Chae, Ankit Bharat*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Immunotherapy can significantly improve efficacy of cancer treatments. For locally advanced stage III lung cancers, chemoimmunotherapy in the neoadjuvant setting can achieve complete pathological response in about 40% of cases. However, optimal cancer response in patients receiving immunotherapy is sometimes associated with potentially fatal bystander injury to lung and liver. We report a successful combined double lung and liver transplantation for immunotherapy-associated respiratory failure and cirrhosis in a patient with advanced lung cancer. A 68-year-old man with stage IIIA squamous cell lung cancer encountered severe interstitial pneumonitis and nodular regenerative hyperplasia of the liver following systemic anticancer therapy that included immunotherapy and platinum-based chemotherapy. These adverse events culminated into fulminant end-stage pulmonary fibrosis and cirrhosis, which were treated with simultaneous lung and liver transplantation, complete resection of lung cancer, and mediastinal lymphadenectomy. The patient demonstrated promising early outcomes without recurrence of cancer at 12 months. Given that oncologic treatments can induce irreversible solid organ failure despite cancer control, our report suggests that in carefully selected patients without systemic metastasis and in whom complete resection of residual cancer can be performed, organ transplantation can be life-saving.

Original languageEnglish (US)
Pages (from-to)209-214
Number of pages6
JournalAmerican Journal of Transplantation
Volume25
Issue number1
DOIs
StatePublished - Jan 2025

Funding

Immune checkpoint inhibitors (ICIs) are extensively used in treating a variety of cancers. Although effective, ICIs can lead to several adverse effects among which pulmonary and hepatic failure can be fatal.6 Pneumonitis can occur in about 1% to 3% of patients receiving anti-PD1, with grades 3 and 4 being particularly severe.7 Patients with lung cancer are more prone to severe pneumonitis due to factors like smoking history and underlying lung diseases, which further complicate their management.7 Addition of radiotherapy adds to the risk of pneumonitis in these patients. Treatment of adverse effects involves discontinuation of therapy and high-dose steroids although this might only result in partial recovery. Hepatitis can occur in 1% to 9% of patients treated with ICI alone or in combination.8 Our patient developed splenomegaly (Fig 1B), esophageal varices, and ascites, leading to a liver biopsy that revealed NRH (Fig. 3), a relatively rare cause of liver failure and portal hypertension. Despite being on steroids, the biopsy showed inflammatory cell infiltrates and hepatocellular cholestasis, indicative of immune hepatitis.9 Nivolumab was the most likely culprit as the primary cause of pulmonary fibrosis and NRH. Diagnosis of ICI toxicities, as per National Comprehensive Cancer Network guidelines, does not require pathological assessment, and the diagnosis is based on the clinical scenario supported by imaging.10 Our patient revealed typical features on the imaging and posttransplant tissue pathology confirmed the presence of end-organ damage related to the cancer therapy.Both liver and lung transplant have been successfully performed in patients with active malignancies11,12 although transplants are not generally considered for therapy-related organ failure. This case introduces a potentially new paradigm for critically ill patients who develop irreversible and potentially fulminant organ failure because of cancer therapies. To overcome the limitations of defining risk of cancer recurrence using the conventional method of arbitrary follow-ups, we performed rigorous oncological surveillance using multiple contemporary molecular approaches. First, we performed DNA sequencing of the tumor isolated from the explanted lung and identified tumor-specific mutations (Fig. 2B). We then used this genetic information to develop tissue-informed tumor assay and performed liquid biopsies every 12 weeks to detect circulating tumor DNA carrying these mutations using the Signatera test (Natera). A previous study13 has suggested that longitudinal assessments with undetectable tumor DNA through this approach is associated with a \u223C100% 5-year recurrence-free survival whereas a single negative assessment following therapy correlates with recurrence-free survival rate of 73%. In our case, we found that the tumor DNA was lost in the circulation following transplantation, which was indicative of molecular remission. Second, we performed comprehensive genomic profiling using the tissue agnostic NGS liquid biopsy platform (Guardant360) and repeatedly found undetectable circulating tumor DNA, which has a high sensitivity and specificity of long-term progression-free survival and predictive of molecular remission. Third, we performed analysis of circulating tumor cells using CellSearch assay (Menarini Silicon Biosystems), which strongly predicts long-term survival.14 During follow-up, mutations identified in liquid NGS were categorized as clonal hematopoiesis-associated mutations, attributed to the absence of overlap in tissue-based NGS (Fig. 2B).15 This molecular approach of identifying and predicting tumor recurrence is now standard of care in the management of non-small-cell lung cancer and used routinely in patients with liver cancer post-liver transplant.16,17 Although transplantation was necessary owing to the complications of systemic therapy, it achieved tumor downstaging (ypT1aN0), which available published data would support as reasonable to consider for lung transplantation.

Keywords

  • immune-related adverse event
  • liver transplantation
  • lung transplantation
  • nivolumab

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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