(18.02) Hyperglycemia in a Novel CDK2 and CDK9 inhibitor-Fadraciclib

Cyclin dependent kinases are drivers of proliferation and have been extensively studied as anti-cancer therapy for the last 2 decades. The novel second generation cyclin dependent kinase inhibitor, Fadraciclib, demonstrates improved selectivity for CDK2 and CDK9, conferring an enhanced efficacy for certain advanced solid tumors and leukemias.

In this case report, we highlight an important adverse event of uncontrolled hyperglycemia, that has not been previously published, and resulted in this patient stopping this therapy.

Based on the mechanism of drug action, there are some theories as to why Fadraciclib causes hyperglycemia.  In animal studies, mice with pancreas specific deletion of CDK2 have hyperglycemia and glucose intolerance due to defects in beta cell mass and metabolism.  This beta cell dysfunction and deterioration of beta cell mass leads to diabetes and potentially severe hyperglycemia (4). In addition, CDK2 also limits beta cell membrane excitability due to loss of ATP sensitive channels (5).  This leads to further beta cell dysfunction resulting in hyperglycemia.  

Case(s) Description :

Our patient was a 76-year-old-male diagnosed with acute myeloid leukemia initially diagnosed in 2018.   

Pt was initially noted to have mild elevations in glucose in June 2020 but was diagnosed with Type 2 Diabetes Mellitus in March 2022 based on persistently elevated sugars without glucocorticoid use.  Prior to initiating treatment with Fadraciclib, patient had overall controlled glucose.  After the first dose of Fadraciclib, he was noted to have severe hyperglycemia.  

Once, hospitalized, the patient received intermittent steroids prior to blood transfusion, but he did not have marked hyperglycemia.  Upon initiation of Fadraciclib, the patient exhibited marked rise of glycemia during the day.  He required up to 176 units of insulin over 24 hours.  During the night, due to fasting and the short half-life of Fadraciclib, he had a steep glucose decline.  

The patient also had frequent episodes of hypoglycemia overnight despite not receiving prandial insulin with dinner.  This was likely due to residual effect of intensive insulin therapy during the daytime and also the short half-life of Fadraciclib.

Due to multiple complications on Fadraciclib therapy, including hyperglycemia and hypoglycemia, the patient was transitioned off Fadraciclib to another clinical trial. 
 

Discussion :

This is the first report published to date of Fadraciclib causing poorly controlled hyperglycemia resistant to treatment with large doses of insulin therapy. The hyperglycemia was compounded by the concurrent use of steroids during his treatment.  Due to the short half-life of the drug, the hyperglycemic effect only persisted for a few hours daily, which presented challenges to glucose management.  It is unclear if patients without diabetes will have a similar response to Fadraciclib therapy, but this case report suggests that frequent monitoring of glucose is imperative for this type of therapy to be successful--especially among our population of patients with diabetes.