Renal Adverse Events in Chronic Myeloid Leukemia: Can the Exposure to One TKI be the Culprit?

Introduction

Tyrosine kinase inhibitors (TKIs) have revolutionized prognosis and survival of chronic myeloid leukemia (CML). This expanding use of TKIs has raised concerns regarding the management of their associated toxicities, particularly nephrotoxicity, for which the optimal measures are yet to be determined, given the lack of established guidelines. This systematic review aimed to provide guidance for this population by summarizing the literature on the effects of renal impairment on TKI therapy and the renal adverse reactions (ADRs) associated with the use of one or more TKIs in CML. Herein, the preliminary findings on the renal ADRs associated with the exposure to only one TKI in CML patients are described.

Methods

A comprehensive literature review was conducted using PubMed and EMBASE, limited to human studies published in English until April 2024. The utilized search terms focused on FDA-approved TKIs and renal impairment in CML patients. All publication types were allowed except for book chapters, reviews, and those reporting TKI use in non-CML cases. Data collected included the study details, type of TKI, population characteristics, and renal ADRs.

Results

A total of 37 studies met the inclusion criteria. Of these studies, 15 explicitly reported the use of a single TKI and are reported here (7 case reports/series, 6 observational cohort studies, 1 meta-analysis of FDA Adverse Events Reporting System (FAERS) reports, and 1 post-marketing surveillance study). The full-text article will report the results of the remaining studies (pharmacokinetics of TKIs in renal impairment and the renal ADRs reported with the use of two or more TKIs).

Overall, imatinib was the most commonly reported TKI to have incidence of renal ADRs (n=11) when compared to dasatinib (n=2) or nilotinib (n=2). Findings suggested that long-term imatinib use is significantly associated with a progressive, albeit likely reversible, decline in the estimated glomerular filtration rate (eGFR) as described by Celestino (2023), Singh (2023), Moura (2019), Sakurai (2016), and Rüžičková (2015). New-onset chronic kidney disease (CKD) as well as deterioration of pre-existing kidney dysfunction, were also frequently reported with imatinib use. Three cases reported imatinib-induced progression of baseline CKD, leading to dialysis initiation (Nakahara, 2021) and subsequent mortality in 2 of the 3 cases (Mestroni, 2011) and (Kitiyakara, 2002). Nakahara (2021); however, reported successful rechallenging with imatinib during dialysis with the use of therapeutic drug monitoring (TDM). Moreover, the imatinib-induced decline in eGFR was significantly correlated with a reduction in hemoglobin levels over time (Singh, 2023) and (Sakurai, 2016). Teuma (2016) also reported renal vein thrombosis and subsequent nephrotic syndrome during imatinib therapy. Conversely, no significant renal deterioration was observed in a CKD patient who underwent a second kidney transplant while on imatinib (Thiem, 2021).

Post-marketing renal ADRs with nilotinib were rare (Ahn, 2022), and were described to be secondary to tumor lysis syndrome (TLS) in a case series (Hua, 2013), thereby emphasizing the need for appropriate TLS prevention and dose titration upon treatment initiation. Dasatinib was associated with a markedly higher incidence of nephrotic syndrome compared to other TKIs in the FAERS analysis (Calizo, 2019). A case report also described dasatinib-induced glomerulosclerosis and secondary nephrotic syndrome (Loi, 2018).

In general, potential risk factors for developing renal events include older age, baseline hypertension and diabetes, TLS, and concomitant nephrotoxic medications. Interventions for managing renal ADRs encompassed the temporary or permanent discontinuation of TKI, hydration, diuresis, corticosteroids (nephrotic syndrome), initiation of dialysis, and TDM (imatinib).

Conclusion

In conclusion, TKIs remain the cornerstone of CML treatment; however, the monitoring for renal ADRs is crucial. In particular, the progressive decline in eGFR with imatinib, nephrotic syndrome with dasatinib and TLS with nilotinib should be monitored. Furthermore, evidence surrounding the incidence of renal ADRs with following the exposure to multiple TKIs is under analysis. This will provide evidence-based guidance for clinicians to optimize the use of TKIs in patients with CML, while minimizing the risk of nephrotoxicity.

Cortes:Novartis: Consultancy, Research Funding; Syndax: Consultancy; Sun Pharma: Consultancy, Research Funding; Nerviano: Consultancy; Rigel: Consultancy; AbbVie: Research Funding; Ascentage: Research Funding; Biopath Holdings: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy; Pfizer: Consultancy. Saglio:Hikma: Speakers Bureau; Ascentage Pharma: Consultancy; Novartis: Consultancy, Speakers Bureau.