Elevated liver function tests in a patient on palbociclib and fulvestrant

These trials also monitored the number of AEs as secondary aims. The most commonly reported AEs in the PALOMA trials for those patients in the palbociclib group were hematologic, with neutropenia being the most common, followed by leukopenia, anemia, and thrombocytopenia. The most common nonhematologic AEs reported in the palbociclib-fulvestrant group were fatigue, nausea, and headache. Elevated liver function tests were a rare but reported AE in 7.2% of the palbociclib-treated patients in the PALOMA-1 study.⁷ In the PALOMA-2 study, ALT and AST elevations were reported as AEs (all grades) in 9.9% and 9.7% of palbociclib-treated patients, respectively.⁵ In the PALOMA-3 study, there was 1 fatal serious AE of hepatic failure with grade 5 disease progression in the palbociclib group; however, the patient’s medical history included progressive liver metastasis and disease progression.⁶ A pooled safety analysis conducted across all PALOMA studies demonstrated that grade 3/4 AST and ALT elevations occurred in 3.3% and 2.3% of palbociclib-treated patients, respectively, again highlighting a reported but rare occurrence.⁸

The patient described in the present case report started on combination fulvestrant and palbociclib after her disease showed progression on letrozole. She developed an increase in transaminases after completing 3 cycles of palbociclib. Liver function tests increased nearly 12 weeks after beginning her first cycle of the CDK 4/6 inhibitor. Staging scans of the patient demonstrated fatty liver. It is not known if her fatty liver contributed to her transminitis; however, her baseline labs showed normal liver function tests, and they did not increase until after therapy with fulvestrant–palbociclib was started. It might have been that her fatty liver caused her to be at higher risk of transaminitis with administration of palbociclib, although we cannot be certain. Her lab results remained normal while she was on fulvestrant alone, and the liver function test results increased only after palbociclib was started, making this drug the more likely culprit.

Both events of increased liver enzymes occurred within a week of the last palbociclib dose; however, we note that hepatotoxicity developed at a faster rate when the patient was rechallenged with palbociclib at a lower dose, with elevated liver function tests increasing 1 week after restarting treatment as opposed to the first episode that occurred after 3 cycles of the palbociclib. After discontinuation of the medication, liver function tests again normalized, suggesting that palbociclib was most likely the causative agent. In addition, the degree of elevated liver enzymes was less severe on re-exposure at the lower dose of 100 mg, which raises the possibility that there could be a dose-dependent association between palbociclib and hepatotoxicity. There have been few case reports of increased liver enzymes associated with palbociclib, and it is only recently that this association has been more recognized. A meta-analysis by Zaw and colleagues has demonstrated that CDK 4/6 inhibitor–based regimens are associated with a higher risk of elevated AST and ALT; however, their relation with dose dependence was not described. In particular, they found that CDK 4/6 inhibitors increased the risk of high-grade, elevated ALT with a relative risk of 4.33 (95% confidence interval, 2.15-8.71; P < .0001). The meta-analysis also included other CDK 4/6 inhibitors such as abemaciclib and ribociclib, which have been more commonly associated with liver toxicity than palbociclib has.⁹ Our case report highlights the specific association between palbociclib and elevated liver enzymes.

In conclusion, this case report illustrates that our patient’s elevated liver enzymes were likely related to palbociclib. This is further supported by the fact that this AE occurred twice, both times after palbociclib exposure. In each instance, liver enzymes normalized after discontinuation of palbociclib. One cannot entirely rule out that fulvestrant might have been the culprit medication, but the patient’s normal hepatic panel for several months after starting fulvestrant suggests that is less likely. This case report is indicative of an uncommon complication in the treatment of metastatic breast cancer, one that is starting to gain more recognition, and we must think of palbociclib as a possible cause of drug-induced liver injury when targeted CDK 4/6–based regimens are used.