2 Case Presentation
An 88-year-old man treated with imatinib for CML was admitted to our
hospital because of dyspnea and malaise. His current medical history was
congestive heart failure, hypertension, type 2 diabetes, and chronic
kidney disease G5A3. The patient underwent left nephrectomy for left
renal cancer in November 2010. At discharge, decreased renal function
was observed with blood urea nitrogen (BUN) 23 mg/dL and creatinine (Cr)
1.5 mg/dL. He was then regularly followed by his family doctor. In
February 2014, a routine follow-up blood test revealed white blood cell
(WBC) count of 32.6×103/μL, and he was referred to our
hematology department in March 2014. At that time, renal function
deterioration was recognized, with BUN 46 mg/dL and Cr 4.7 mg/dL, and he
was clinically diagnosed with chronic phase Philadelphia-positive CML,
which was later confirmed by blood tests, bone marrow examination, and
imaging findings. In April of the same year, imatinib was started at a
dose of 100 mg. After 3 weeks, the dose was increased to 200 mg. Blood
test during outpatient visits showed gradual deterioration of renal
function, and he was scheduled to consult a nephrology department. In
May of the same year, he complained of dyspnea and malaise and consulted
his family doctor. However, he was unable to go the local hospital
because of poor physical condition, and was transported to the emergency
department of our hospital and was admitted. On the day of admission
(day 1), BUN was 54 mg/dL and Cr was 5.1 mg/dL, indicating impaired
renal function. A plain chest radiograph suggested pulmonary edema.
Therefore, he was admitted to the Department of Nephrology of our
hospital for initiation of dialysis and treatment of respiratory
failure. Imatinib was suspected to have caused the rapid decline in
renal function, and administration was discontinued on the same day. He
had dyspnea and was poorly oxygenated; SpO2 was 90%
with oxygen administration at 10 L/min. Pleural effusion and pulmonary
edema observed on chest radiograph were considered to be flooding due to
exacerbation of chronic renal failure. A flexible double-lumen (FDL)
catheter was inserted through the right internal jugular vein and
emergency dialysis was started. Blood pressure at admission was as high
as 182/98 mmHg, and nitroglycerin was administered at 2 mL/h and human
atrial natriuretic peptide (hANP) at 0.75 mL/h. Respiratory distress
gradually improved with administration of nitroglycerin and hANP, and
water removal by dialysis. On day 7, 2 L/min of oxygen delivered via
nasal cannula improved SpO2 to 98%, and administration
of nitroglycerin and hANP was terminated. The patient was taking 5 mg of
oral amlodipine at admission, and the dose was increased to 10 mg due to
high blood pressure, and returned to 5 mg when blood pressure decreased
by water removal. On day 8, SpO2 was maintained at 98%
without oxygen administration, and oxygen therapy was terminated on the
same day. Chronic changes in the kidney were observed based on the
increase of Cr before admission and CT findings at admission, and
maintenance dialysis was considered necessary in the future. Therefore,
on day 10, a shunt was built in the left forearm, and maintenance
dialysis became possible. After dialysis was initiated, a hematologist
re-administered oral imatinib on day 10. A nephrologist consulted us
regarding dosage regiment of imatinib and removal rate of imatinib by
dialysis in patients with chronic kidney disease. Our search found no
clear guidelines regarding the dose of imatinib for dialysis patients.
Since imatinib is metabolized in the liver, and 67% is excreted in
feces and 13% in urine, dosage reduction is not recommended even in
patients with renal failure. However, several reports indicated that the
same dose for patients with normal renal function is used in patients
with renal failure, and that adverse effects were severe in dialysis
patients due to high blood imatinib concentration, necessitating dose
reduction.16 Therefore, we suspected that the blood
concentration of imatinib was increased to some extent in this patient.
We proposed to measure the plasma concentration of imatinib to examine
the imatinib removal rate by dialysis. The dose used to start
re-administration was 200 mg/day, the same as that before treatment
suspension. At the time of TDM (day 10), WBC was
27.1×103/μL, PLT was 423×103/μL, BUN
was 40.7 mg/dL, and Cr was 5.0 mg/dL. Plasma concentration was
determined by a high performance liquid chromatographic method as
described previously.17 Using this method, the plasma
concentration of imatinib was 1667 ng/mL (Figure 1) at the
8th day of re-administration. This value was higher
than the mean trough concentration of 1002 ng/mL reported to be
effective in treating CML by Picard et al.18 After
confirming the TDM results, the attending physician decided to continue
prescribing the same dose. After resuming imatinib, WBC counts declined
markedly to 14.65×103/μL on day 20. On day 37 (27 days
after resuming administration), steady-state blood concentration was
confirmed. The trough plasma concentration of imatinib was 2514 ng/mL
(Figure 1). This value was lower than the mean trough concentration of
3180 ng/mL reported to be associated with a higher frequency of grade
3/4 adverse events such as neutropenia.19 Renal
function did not exacerbate, and no other adverse events were observed.
At that time, WBC was 10.24×103/μL, PLT was
155×103/μL, BUN was 48.0 mg/dL, and Cr was 6.0 mg/dL.
After confirming the TDM results and no adverse events, the attending
physician decided to continue prescribing the same dose. On day 44,
complete hematologic response
(CHR) was achieved with normalization of peripheral blood data and
extramedullary lesions. CHR was achieved within 3 months after the start
of treatment, corresponding to the criteria of optimal response to TKI
treatment.20 On day 49, the patient’s condition was
stable with dialysis and imatinib therapy, and he was transferred to
another hospital.