2. with tacrolimus. Eight months after starting mycophenolate she
developed fever and severe neutropenia. The blood counts were as
follows: white blood count (WBC), 1.25 ϫ 103
; neutrophils, 0.125 ϫ
103
; platelets, 134 ϫ 103
; and hemoglobin, 12 g/dL. She was
admitted to the hospital, mycophenolate was discontinued, and
GCSF was administered to raise the white cell count. The neutro-
penia developed at a time when the trough level of mycophenolate
was elevated (7 g/dL). The neutrophil count returned to normal
after 5 days. She remains well at 20 months after transplantation.
Case 2
A 53-year-old woman underwent orthotopic liver transplantation
for cirrhosis secondary to hepatitis B and C. She received immu-
nosuppression with tacrolimus and methylprednisolone along with
nystatin, cotrimoxazole, and norfloxacin. Fifteen days posttrans-
plant she developed renal failure and mycophenolate therapy was
initiated in association with tacrolimus, to reduce the serious toxic
side effects of the CNIs. Four months after starting mycophenolate
she developed neutropenia without clinical effects (0.537 ϫ 103
).
Hemoglobin and platelet count remained normal. Neutropenia
developed at a time when the level of mycophenolate was in the
therapeutic range. Discontinuation of MMF was followed by a
spontaneous rise of the neutrophils in 2 months. The patient
remains well at 17 months after transplantation.
Case 3
A 45-year-old woman received a liver transplant for primary
sclerosing cholangitis secondary to ulcerative colitis. She received
immunosuppression with tacrolimus and methylprednisolone along
with nystatin, cotrimoxazole, and norfloxacin. Twenty days post-
transplant she developed an episode of grade 2 acute rejection that
responded to pulses of IV methylprednisolone. Mycophenolate was
associated with the tacrolimus treatment and 2 months later she
developed moderate neutropenia, which did not respond despite
MMF dose reduction. The blood counts were as follows: WBC,
1.32 ϫ 103
; neutrophils, 0.753 ϫ 103
; platelets, 165 ϫ 103
; and
hemoglobin, 11 g/dL. Mycophenolate was discontinued. Within 30
days the neutrophil level rose to normal. In this patient, the plasma
level of MMF was in the therapeutic range. She died 1 year after
liver transplantation due to chronic rejection.
Case 4
A 62-year-old-man received a liver transplant for HCV cirrhosis
plus hepatocellular carcinoma. Immunosuppression was induced
with tacrolimus and methylprednisolone. Tacrolimus treatment
was discontinued for severe renal failure a few days after surgery.
One week after transplantation, mycophenolate therapy was initi-
ated (2 g/d). Four months after starting mycophenolate he devel-
oped anemia, leukopenia, and thrombocytopenia. The blood
counts were as follows: WBC, 1.13 ϫ 103
; neutrophils, 0.700 ϫ 103
;
platelets, 45 ϫ 103
; and hemoglobin, 9 g/dL. His other medications
were cotrimoxazole, nystatin, norfloxacin, and gancyclovir for
CMV infection. Despite discontinuing mycophenolate, cotrimox-
azole, and gancyclovir, the blood count did not improve immedi-
ately. Blood loss, vitamin or iron deficiencies, as well as hemolysis
were excluded. A bone marrow biopsy showed a normocellular
bone marrow. Six months after discontinuing medications, the
patient is well, with no CMV infection. His blood counts are as
follows: WBC, 2.66 ϫ 103
; neutrophils, 1.65 ϫ 103
; platelets, 64 ϫ
103
; and hemoglobin, 11 g/dL.
DISCUSSION
Mycophenolate mofetil, the pro-drug of mycophenolic acid
inhibits inosine monophosphate dehydrogenase. It is a
potent and safe agent in orthotopic liver transplant recipi-
ents for rescue therapy in acute and chronic rejection.
MMF helps to reduce the serious toxic side effects of
calcineurin inhibitors (CNIs).1–3
Most of our patients receive
mycophenolate for renal failure in combination therapy for
primary immunosuppression. Recognized side effects of the
drug include leukopenia, anemia, and thrombocytopenia,
which may necessitate drug withdrawal. Leukopenia affects
as many as 5% to 11% of patients.2,4,5
Of 18 liver transplant patients we studied, 4 (22%)
developed neutropenia while receiving mycophenolate. In
all four the neutropenia resolved after drug discontinua-
tion. Therapeutic monitoring of levels is preferable in
patients receiving MMF, although it is questionable
whether a valid therapeutic range can be defined. A dose of
2 g/d yields trough concentrations of 1 to 3.5 g/mL.
Concentrations between 2 and 4 g/mL appear to maximize
efficacy and minimize adverse effects.6,7
Neutropenia devel-
oped when the plasma level of mycophenolate was in the
therapeutic range in all our patients but one. The measured
level of the drug in plasma may not accurately reflect the
amount that is biologically available.4
The mean time from
starting MMF until development of neutropenia is variable:
in our cases it was 4 months.
In conclusion, we have reported four cases of neutro-
penia in liver transplant patients, considered to be second-
ary to the use of MMF. In the last patient three hematologic
cells were affected; other medications could have been
implicated. Interactions between MMF and valacyclovir
have been suspected, which may increase the latter drug up
to hematotoxic levels.8
We recommend caution when using
MMF as well as monitoring levels and cell counts during
treatment; in addition, the impact of other etiologic drugs
must also be evaluated.
REFERENCES
1. Pfitzmann R, Klupp J, Langrehr JM, et al: Mycophenolate
mofetil for immunosuppression after liver transplantation: a follow-up
study of 191 patients. Transplantation 76:130, 2003
2. Cohen SM: Current immunosuppression in liver transplanta-
tion. Am J Ther 9:119, 2002
Table 1. Characteristics of Patients
Case 1 Case 2 Case 3 Case 4
Age (years) 59 53 45 62
Gender Female Female Female Male
Start dose of MMF D30 D15 D30 D7
Cessation of MMF Month 8 Month 4 Month 2 Month 7
Neutrophil count (ϫ103
) 0.125 0.537 0.753 0.700
Hematologic
improvement after
cessation MMF
Day 5 Month 2 Month 1 Month 4
MMF levels (g/mL) Elevated Normal Normal Normal
1510 NOGUERAS, ESPINOSA, MANSILLA ET AL
3. 3. Benerjee R, Halil O, Bain BJ, et al: Neutrophil dysplasia
caused by mycophenolate mofetil. Transplantation 70:1608, 2000
4. Engelen W, Verpooten GA, Van der Plaken M, et al: Four
cases of red blood cell aplasia in association with the use of
mycophenolate mofetil in renal transplant patients. Clin Nephrol
60:119, 2003
5. Cox VC, Ensom MH: Mycophenolate mofetil for solid organ
transplantation: does the evidence support the need for clinical
pharmacokinetic monitoring? Ther Drug Monit 25:137, 2003
6. Wong SHY: Therapeutic drug monitoring for immunosup-
pressants. Clin Chim Acta 313:241, 2001
7. Squifflet JP, Backman L, Claesson K, et al: Dose optimization
of mycophenolate mofetil when administered with a low dose of
tacrolimus in cadaveric renal transplant recipients. Transplantation
72:63, 2001
8. Royer B, Zanetta G, Berard M, et al: A neutropenia suggesting
an interaction between valacyclovir and mycophenolate mofetil. Clin
Transplant 17:158, 2003
MMF-INDUCED NEUTROPENIA 1511
