Discussion
Venetoclax is an orally bioavailable, selective, small-molecule inhibitor of BCL2 that is highly effective for relapsed or refractory CLL; however, TLS is reported to occur as a severe adverse event of venetoclax. The risk of TLS increases with renal dysfunction, and venetoclax use has not been studied in patients with severe renal impairment. In the phase three study, CLL patients with moderate renal impairment (creatinine clearance <50 mL/min) were excluded,2 and the safety of venetoclax for patients with severe CKD (stage 4, GFR<30 mL/min) was not elucidated. To the best of our knowledge, this is the first case in which venetoclax was used for a CLL patient with severe CKD who was not dependent on dialysis. A case report revealed that venetoclax was safely administered in a multiple myeloma patient with renal failure who was dependent on dialysis,5 but this patient had undergone dialysis before venetoclax administration. The clinical situation of that case was completely different from that in this case.
Although we considered the dose and schedule about administration of venetoclax to the patient with severe CKD, we decided to administer venetoclax with no dose reduction and no extension of the treatment schedule because venetoclax and its major metabolite are primarily metabolized by the liver cytochrome P450 3A4 enzyme, and urinary clearance is negligible.6 In addition, a 50% dose reduction for patients with severe liver impairment is recommended,7 but this patient had only mild liver impairment due to CLL, we assessed that no dose reduction for liver function is needed.
Fortunately, venetoclax was safely administered without the onset of TLS in this case. Debulking by rituximab and cyclophosphamide with prednisolone was successful, and it seemed to reduce TLS risk. In addition, intensive prevention of TLS using hydration, febuxostat, and rasburicase as uric acid-reducing agents seemed to be important too. However, TLS is sometime inevitable and dialysis should be initiated without hesitation if TLS is suspected. Thus, strict monitoring of laboratory data also seemed to be important.
In conclusion, we describe the first case of a relapsed CLL patient with severe CKD due to congenital solitary kidney that was successfully treated with venetoclax. Venetoclax was safely administered by intensive prevention, and strict monitoring of TLS. This report may suggest safety and efficacy about using venetoclax in CLL patients with severe CKD, only if proper risk management of TLS is given.