A small but exciting new study is the first to describe gonadotoxicity of immune checkpoint inhibitors (ICIs) based on autopsy findings. Association of ICIs with impaired spermatogenesis is suspected.
Immune checkpoint inhibitors (ICIs) open up new therapeutic opportunities for some patients, but their long-term effects have not yet been investigated in detail. A report published in mid-June in JAMA Oncology (Journal of the American Medical Association) draws attention to an important, as yet unexplored, problem following the use of ICIs: male fertility disorders.1
After an index patient with metastatic melanoma in his early 30s became infertile after treatment with nivolumab and ipilimumab and later died, a group of seven American physicians conducted a retrospective review of similar cases.
They searched the databases of Johns Hopkins Medical Institutions (Baltimore, USA), for men with metastatic melanoma in their medical history who had undergone an autopsy. From more than 10,000 data sets they filtered out melanoma patients who had received ICIs (ipilimumab, nivolumab, pembrolizumab) for at least one month as well as an equivalent number of untreated men who had not received radiotherapy, chemotherapy or immunotherapy.
There were no significant differences between these two groups in terms of age at diagnosis (median 54 years), age at death, and time interval until autopsy. Patients who had undergone systemic chemotherapy or radiotherapy of the thorax, abdomen, pelvis, or lower extremities were excluded. For each patient, demographic characteristics, course of therapy, and type and duration of immunotherapy were recorded.
This Herculean effort provided 13 suitable cases for which testicular tissue was available for retrospective examination. In six of the seven patients (86%) impaired spermatogenesis was detectable after immunotherapy. One man had a focal spermatogenetic residual function, two had hypospermatogenesis and three had Sertoli-cell-only syndrome. Among the patients in the control group, three out of six men (33%) showed abnormalities in spermatogenesis.
The limitation of this report is of course the low availability of autopsy samples and the resulting small sample size. But the data are the first to focus on a potential link between the use of ICIs and impaired testicular function. Prospective surveys would, therefore, be absolutely necessary in order to assess gonadotoxic effects of ICIs and to take this into account in therapy planning.
The 2018 guidelines of the American Society of Clinical Oncology (ASCO) generally recommend that practitioners discuss cryopreservation of sperm with post-pubertal males when oncological therapy is pending.
References:
1. Scovell, J. M. et al. Association of Impaired Spermatogenesis With the Use of Immune Checkpoint Inhibitors in Patients With Metastatic Melanoma. JAMA Oncol (2020) doi:10.1001/jamaoncol.2020.1641.