Solid Organ Transplant Rejection Associated with the Use of the Immunomodulatory Drugs (IMIDs)
Authors: Nadeau Nguyen Michelle , Nayernama Afrouz , Jones Steven Christopher , Kasamon Yvette L. , Waldron Peter E. 
Published: November 2019

Introduction: IMIDs are a cornerstone of multiple myeloma treatment and have a recently expanded role in the treatment of selected lymphomas. However, the safety of chemotherapeutic regimens containing IMIDs in patients with a history of solid organ transplantation (SOT) is uncertain. Recently, several published case reports have described SOT rejection (SOTr) among patients taking IMIDs.
Methods: To investigate a potential association between IMID exposure and SOTr, we evaluated postmarketing adverse event reports submitted to the FDA Adverse Event Reporting System (FAERS) and published in the literature. We descriptively characterized the clinical outcomes and severity of SOTr and utilized the World Health Organization-Uppsala Monitoring (WHO-UMC) scale to assess drug causality.
Results: We identified 22 cases of SOTr associated with the use of lenalidomide (n=16), pomalidomide (n=3), or thalidomide (n=3) from FAERS and the literature. After IMID initiation, the median time to onset of SOTr was 39 days (range 3-70 days) with 89% of cases occurring by 60 days. Notably, SOTr occurred within 2 weeks of lenalidomide and pomalidomide administration in 5 cases, including 2 patients with a distant history of SOT (lenalidomide, n=1; pomalidomide, n=1). The most commonly affected organs were the kidney (n=13) and heart (n=10), with 3 of these cases involving rejection of both organs. In 12 cases, rejection was confirmed with biopsy findings of acute T-cell mediated rejection. Notably, 6 of these 12 cases provided baseline biopsy findings prior to IMID initiation that indicated stable organ function and showed no signs of rejection. All cases were complicated by serious outcomes including 7 deaths described as related to graft rejection. Other serious clinical manifestations included surgical excision of the original transplanted organ (n=2), requirement of a second transplant (n=3), and dialysis (n=4), including 2 cases that required long-term renal replacement therapy.
We determined the causality as probable (no confounding factor identified) in 6 cases and possible (confounding factor identified) in the remaining 16 cases. The most frequently reported confounding factor was concomitant change of the baseline immunosuppressive regimen with the initiation of the IMID (n=7). Notably, 5 of the 7 cases with fatal outcome had immunosuppression reduced at IMID therapy initiation, including 2 cases with a distant history of SOT and stable graft function.
Conclusion: To our knowledge, this is the largest case series describing SOTr with the IMIDs. These cases are characterized by serious events including death and reduced long-term survival of the graft. Although this analysis is limited by the quality of spontaneous adverse event reporting, the strong temporal relationship and the histologic findings of T-cell mediated rejection provide reasonable evidence of a contributory role of IMIDs to SOTr. This risk is plausible because IMIDs induce T-cell proliferation, enhance interleukin-2 and interferon-gamma production, and inhibit regulatory T-cell function. Increased surveillance for early signs of acute rejection is warranted for SOT recipients receiving IMID therapy. The US prescribing information is currently being revised to reflect the risk of SOTr across all IMIDs.

Disclosures
No relevant conflicts of interest to declare.