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.