Tacrolimus (FK506) alone or in combination with methotrexate or

From www.bloodjournal.org by guest on November 7, 2014. For personal use only.
1995 85: 3746-3753
Tacrolimus (FK506) alone or in combination with methotrexate or
methylprednisolone for the prevention of acute graft-versus-host
disease after marrow transplantation from HLA-matched siblings: a
single-center study
RA Nash, R Etzioni, R Storb, T Furlong, T Gooley, C Anasetti, FR Appelbaum, K Doney, P Martin
and J Slattery
Updated information and services can be found at:
http://www.bloodjournal.org/content/85/12/3746.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American
Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.
From www.bloodjournal.org by guest on November 7, 2014. For personal use only.
Tacrolimus (FK506) Alone or in Combination With Methotrexate
or Methylprednisolone for the Prevention of Acute Graft-Versus-Host
Disease After Marrow Transplantation From HLA-Matched Siblings:
A Single-Center Study
By Richard A. Nash, Ruth Etzioni, Rainer Storb, Terry Furlong, Ted Gooley, Claudio Anasetti,
Frederick R. Appelbaum, Kristine Doney, Paul Martin, John Slattery, Keith Sullivan, Richard van der Jagt,
Robert Witherspoon, William J. Jusko, Richard A. Zager, and H. Joachim Deeg
The pharmacokinetics, safety, and efficacy in marrow transplantation of FK506-basedimmunosuppression forgraft-versus-host disease (GVHD) prophylaxis was evaluated in an
open label pilot study of 18 patients. Patients more than12
years of age (median, 35 years; range, 15 t o 50 years) with
advanced hematologic malignancies receiving HLA-matched
sibling marrow grafts were randomized t o receive FK506
alone, FK506and methotrexate(MTX), or FK506 and methylprednisolone. Of 17 evaluable patients, all had evidence of
sustained marrow engraftment. The median time to
an absolute neutrophil count of greater than 500/pL was 15 days
for patientsreceiving FK506 alone or FK506 plus methylprednisolone and 23 days for FK506 plus shortMTX. Pharmacokinetic studiesdid not showany significant difference in clearance of FK506 when administered alone or in combination
with methylprednisolone or MTX. The mean bioavailability
after oral administration in these same three groups was
0.49 f 0.1,0.27 f 0.12, and 0.16 f 0.08, respectively (P=
,003).The decrease in bioavailability may have resulted from
an exacerbation ofradiation-inducedgastroenteritis
by
MTX. The most significant adverse effect associated with
the administration of FK506 was nephrotoxicity, which occurred in 14 of 18 patients (78%). The mean glomerular filtration rate, determined by clearance of (g9v~)DTPA,decreased t o 5640 (?18%) of the pretransplant baseline level
by week 8 (P= .002). Eight of 18 patients (44'70) developed
grades Il-IV acute GVHD, predominantly of the skin and gastrointestinal tract. The actuarial probability of transplantrelated mortality during the first 100 days was 2490. The
actuarial probability of l-year disease-free survival was3990.
In conclusion, although bioavailability of FK506 may be affected in patients receiving MTX, this study suggests that
FK506 may have a role in the management of patients after
allogeneic marrow transplantation.
0 7995 by The American Society of Hematology.
A
of acute GVHD andmay avoid thetoxicities associated with
previously established regimens.
The macrolide FK506 produced by Streptomyces tsukubaensis inhibits T-cell activation by forming a complex with
the FK binding protein- 12 that blocks the serine-threonine
phosphatase activity of calcineurin." This prevents interleukin-2 (IL-2) transcription mediated by NF-AT on the 1L-2
gene promoter. FK506 inhibits certain pathways of T-cell
activationsuchasthosemediated
by theT-cell receptor
CD3complexand by CD2 but did notaffectthe
T-cell
proliferation induced by CD28-specific monoclonal antibodies in the presence ofphorbol12-myristate
13-acetate."."
Clinical studies with FK506 were first performed in liver
transplantation. In this setting, FK506 is effective forprevention of graft rejection and has also been effective as salvage
therapy to control episodes of graft rejection.""' Preclinical
studies of FK506 after marrow transplantation in arat model
that was fully major histocompatibility complex (MHC) and
non-MHC disparate showed that GVHD could be prevented
or treated s u c ~ e s s f u l l y . ' ~In. ' ~a model established to study
GVHD, dogswere grafted with unrelated MHC-nonidentical
marrow after 920 cGy total body irradiation (TBI)." In the
group of dogs thatreceived FK506 incombinationwith
MTX, survival was prolonged when compared with controls
receiving no immunosuppression or FK506 alone. Based on
thesestudies of immunosuppressive activity and because
there werenopreviousreports
of the use of FK506 with
MTX or prednisone for acute GVHD prophylaxis,a pilot
study was conducted in patients with advanced hematologic
malignancies to investigate drug interactions and safety.
CUTE GRAR-VERSUS-HOST disease (GVHD) contributessignificantly tothe morbidity and mortality
associated with allogeneic marrow transplantation.',* Previous studies have shown that the
combination of cyclosporine
(CSP) and four dosesof methotrexate (MTX) is moreeffective than either agent alone in prevention of acute GVHD.',4
Prednisone is an effective agent fortherapy of acute GVHD
and has been studied in combination with CSP for prophylaxis.5-8 In more recentstudies, the combination of CSP,
MTX, and prednisone was more effective
in preventing acute
GVHD than the combination of CSP and prednisone, but
was not more effective than the
combination of CSP and
MTX.9.'0 Although the combination of immunosuppressive
agents has reduced the incidence of GVHD, the use of new
agents (possibly in combination with MTX and prednisone)
may permit a further reduction in the incidence or severity
From the Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, WA; and the
School of Pharmacy, State University of New York at Buffalo, NY.
Submitted October 14, 1994: accepted January 21, 1995.
Supported in part by Grants No. CA-18029, CA-18221, CA-15704,
GM-24211, and HL-36444 awarded by the National Institutes oj
Health, Department of Health and Human Services; and b.y Fujisawa
USA, Inc, Deetjield, IL.
Address reprint requests to Richard A. Nush, MD, Fred Hutchinson Cancer Research Center, 1124 Columbia St. M318, Seattle. WA
98/04-2092,
The publicationcosts of this article were defrayed in purl by page
charge payment. This article must therefre be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1995 by The American Society of Hematology.
0006-4971/95/8512-0006$3.00/0
3746
MATERIALS AND METHODS
Patients. From July 1992 to August 1993, 18 patients were registered on this protocol. Patient characteristics are shown in Table 1 .
Blood, Vol 85, No 12 (June 15).
1995:
pp 3746-3753
From www.bloodjournal.org by guest on November 7, 2014. For personal use only.
PREVENTIONOF
3747
GVHD AFTER BMT WITHFK506
Table 1. Patient Characteristics
n 1%)
Age (yr)
<35
>35
9 (50)
9 (50)
Diagnosis
Acute leukemia-relapse
Acute leukemia-remission
6 (33)
1 (6)
2 (11)
8 (44)
1 (6)
MDS
Malignant lymphoma in relapse
CML-blast crisis
Conditioning regimen
Cy/TBl (1,575 cGy)
Bu/Cy/TBI (1.200 cGy)
11 (61)
6 (33)
1 (6)
BCV
Patient sex
Male
Female
Donor parity-sedpatient sex
Nonparous femaleflemale
Parous female/female
Male/female
Nonparous female/male
Parous female/male
Male/male
~~~~~
14 (78)
4 (22)
0
0
4 (22)
1 (6)
5 (28)
8 (44)
~
~
The protocol and consent forms were approved by the Institutional
Review Board of the Fred Hutchinson Cancer Research Center. The
risks and benefits of the treatment regimens were explained to each
patient in detail before hospital admission. Patients were sequentially
randomized to one ofthe three regimens of GVHD prophylaxis:
m506 alone, FK506 and MTX, or K 5 0 6 and methylprednisolone.
In this small group of patients, a randomized selection of patients
to each GVHD prophylaxis group allowed a comparison of the pharmacokinetic data.
Conditioning regimens. Before marrow transplantation, patients
with lymphoid malignancies (acute leukemia or lymphoma) received
intravenous cyclophosphamide (60 mgkg body weight) on each of
2 successive days followed by 2.25 Gy to TB1 on each of 7 successive days (1,575 cGy). Patients with myeloid malignancies (acute
leukemia, chronic myeloid leukemia [CML] in blast crisis, or myelodysplasia) received oral busulfan (7 mgkg over 4 days) and
cyclophosphamide (50 mgkg/day over 2 days), followed by 200
cGy of TB1 on each of 6 successive days (1,200 cGy). One patient
received a chemotherapy regimen consisting of BCNU, cyclophosphamide, and VP-16 because of a past history of radiation to the
mediastinum. The radiation was delivered by two opposing “CO
sources at a rate of 6.5 cGy/min. Within 4 hours of the last dose of
TB1 or 36 hours after the last dose of cyclophosphamide, donor
marrow was infused intravenously. The day of marrow infusion was
designated as day 0. Engraftment was defined as thefirst day a
neutrophil count was greater than 500 X lO‘L and was sustained
for 2 days. Eight patients with lymphoid malignancies were treated
with recombinant a-interferon (IFN) when neutrophil counts were
sustained greater than 200 X 106Lfor 3 days as part of an investigational protocol evaluating theriskof relapse after marrow transplantation.
GVHDprophylmis, assessment, and treatment. Postgrafting immunosuppression in all study patients included FK506 alone or in
combination with methylprednisolone or MTX. FK506 was begun
on the day before marrow infusion. In this pilot study, the intravenous dose was 0.03 mgkg/d as a continuous intravenous infusion,
which wasmaintained until the patients had recovered from regimen-
related gastrointestinal toxicity, when oral FK506 (0.15 mgkg/d in
2 divided doses) was substituted. After the seventh patient on study,
the oral dose was reduced to 0.12 mgkgld. The MTX dose was 15
mg/mz on day 1 and then 10 mg/m2 on days 3, 6, and I 1 after
marrow transplantation. Methylprednisolone was started at 0.5 mg/
kg on day 7 and was increased to 1 mgkg from day 15 through day
28 and then tapered through day 72.’.” The full dose of FK506 was
administered until day 60 unless adverse effects or acute GVHD
developed. Generally, if the serum creatinine doubled above baseline
values or increased above 2 mg/dL, the FK506 dose was reduced
or temporarily withheld. After day 60, if the patients had no evidence
of GVHD, the FK506 dose was tapered until the drug was discontinued by day 180. If patients relapsed, FK506 was stopped. FK506
steady-state levels during continuous intravenous infusion or trough
levels during oral treatment were determined by enzyme-linked immunosorbent assay (ELISA).21.22
An attempt was made to maintain
FK506 whole blood levels between 2 and 60 ng/mL.
Donors and recipients were genotypically HLA-identical as determined by serologic histocompatibility typing for HLA-A and B and
the results of HLA-DRB1 DNA analysis based on allelic typing by
polymerase chain reaction (PCR)/sequence-specific oligonucleotide
probe hybridization (SSOP).z3.24
Assessment, grading, and treatment
of acute GVHD have been previously reported? The time period
after stopping FK506 was not evaluated for GVHD if patients had
relapsed or elected to withdraw from the study with no GVHD or
FK506-related toxicity. Acute GVHD was treated with methylprednisolone at 2 mgkg/d for at least 14 days andthentapered over
8 weeks if tolerated. Alternatively, patients were enrolled inan
investigational protocol with oral nonabsorbable beclomethasone if
GVHD was isolated to the upper gastrointestinal tract. Before discharge home, patients were evaluated for chronic GVHD.25-27
Treatment of cGVHD was with FK506 0.12 mgkg/d in two doses 12
hours apart and every other day with prednisone at 1 mgkg. This
regimen is similar to that previously reported with CSP except that
FK506 was administered daily instead of every other day.”
Pharmacokinetics. Whole blood levels of FK506 were determined by a previously described ELISA.Z1~?2
Plasma methylprednisolone and cortisol were measured using the high performance liquid
chromatography (HPLC) method of Ebling et al.?’ Plasma prednisone, prednisolone, and cortisol were measured using the modified
HPLC method ofRose and J u s ~ o . Least-squares
’~
regression calculations related to standard curves were performed using the variance
stabilizing transformation method.” The area under the curve (AUC)
for individual corticosteroid profiles from zero to infinity was calculated using a spline computer program.
In 17 patients, serial blood samples were obtained during continuous intravenous infusion of FK506 on day 1 1 after the administration
of MTX and methylprednisolone for determination of the clearance
of FK506 and methylprednisolone pharmacokinetics. Whole blood
samples were drawn before the morning dose of MTX or methylprednisolone and then at 0.5, 1, 2, 4, 6, 8, and 12 hours after MTX
or methylprednisolone dosing. In the group of patients who received
neither MTXnor methylprednisolone, whole blood samples were
drawn at similar time points in the morning to make them comparable. In 14 patients, a 12-hour pharmacokinetic profile of FK506 was
obtained between weeks 4 and 8 after oral administration of a constant dose for 4 consecutive days. Whole blood samples (3 mL)
were drawn before the morning dose of FK506 and at 0.5, I , 1.5.
2,3,4,6,8, and 12 hours after the dose. These data and the clearance
of FK506 calculated from the pharmacokinetic profile obtained on
day 1 1 were used to assess bioavailability. MTX concentrations were
measured only at 24 hours after the dose. If the 24-hour MTX level
was greater than 0.04 bmol/L, rescue with Leucovorin was started.
Assessment of renalfunction and toxicities. To assess the effects
on renal function, the glomerular filtration rate (GFR) was deter-
From www.bloodjournal.org by guest on November 7, 2014. For personal use only.
3748
NASH ET AL
mined before and during week 8 after marrow transplantation. The
GFR was determined by clearance of technetium-99m (w"Tc)-diethylenetriamine-pentaacetic acid (DTPA) from protein-free ultrafiltered plasma. The DTPAwas injected andblood levels ofDTPA
measured at I hour. The GFR was calculated from this result."'
Nephrotoxicity was defined as a doubling of serum creatinine
greater than baseline or a serum creatinine greater than 2 mg/dL.
This degree of renal dysfunction was defined as significant because doses of nephrotoxic agents such as FK506 were adjusted
at this point. Veno-occlusive disease (VOD) has been previously
described and defined.32 Hypertension was defined as a diastolic
blood pressure greaterthan 90 mm Hg or a systolic blood pressure
greater than 140 mm Hg sustained for more than 3 consecutive
days and requiringtreatment.Hyperglycemiawas
defined as a
serum glucose level greater than 140 mgldL and requiring treatment.Hyperlipidemiawas defined asa serum total cholesterol
concentration 2240 mgldL.
Srurisrics. Cumulative incidence curves and corresponding statistical tests were used to describe acute GVHD and nephrotoxicit^.''.^^ Kaplan Meier curves were used to describe transplant-related
mortality and disease-free survival. The Wilcoxon signed rank test
for matched pairs was used to compare GFR values before and after
transplant. An analysis of variance was used to compare bioavailability and clearance of FK506 among the three different groups of
FK506 alone, FK506 and methylprednisolone, and FK506 and
MTX."
0
0
.
0
0
0
W
0
0
m
Y
L
0-
I
I
I
R506 Only
R506 t Pred.
R506 t Mtx
8
?l
0
0
0
8
RESULTS
Engrafrment. Seventeen of the 18 patients in the FK506
group showed hematopoietic engraftment. The mean time to
recovery of S00 neutrophils per microliter was 15.2 days
(range, 8 to 23 days) in those patients who had received
FK.506 alone or FK506 and methylprednisolone, and 21.7
days (range, 15 to 28 days) in patients who received FK506
and MTX. One patient who received FKS06 plus MTX died
on day 23 after marrow transplantation with a granulocyte
count of 423/pL.
Pharmacokinetics. The mean clearance rates of FK506
on day 11 were similar for patients treated with FK506 by
continuous intravenous infusion, alone or combined with
methylprednisolone or MTX ( P = .61) (0.075 2 0.048 [5
patients], 0.055 f 0.023 [7 patients], and 0.063 2 0.032 L/
hrkg [ S patients], respectively; Fig 1A). The bioavailability
of oral FK506 between weeks 4 and 8 was significantly
different among the same three groups ( P = .003) and was
the lowest in the group that received MTX (0.49 5 0.1 [5
patients], 0.27 2 0.12 [6 patients], and 0.16 It 0.08 [3 patients], respectively [value of l = 100% bioavailability]; Fig
1B). None of the four patients tested had an elevated level
of MTX 24 hours after the dose requiring rescue with folinic
acid. The mean clearance of methylprednisolone (0.5 mg/
kg) on day 11, in 7 patients tested, was 0.27 (50.11) L/min/
kg. Peak concentrations during the first hour after intravenous administration of methylprednisolone ranged from 166
to 278 ng/mL. Methylprednisolone concentrations then followed a typically linear decline. Cortisol was suppressed
(< 10 ng/mL) in all patients except one. On oral prednisone,
betweenweek 3 and 8, conversion to methylprednisolone
was rapid. Prednisolone concentrations peaked at 183 to 676
ng/mL (mean, 379 2 169) between 1 to 4 hours after the
oral dose of prednisone, and cortisol was usually fully sup-
0
0
0
0
FK506 Only
FK506 t Pred.
FK506 t Mtx
fig 1. (AI Clearance of F 6 0 6 during continuous intravenous infusion. IBl Bioavailability of oral n<u)6. Group 1, F K W only; group 2,
FKSO6 and prednisone; group3, FK506 MTX. Tho mean clearance and
bioavailability for each group is indicated by IO).
pressed. The mean clearance of prednisolone was 0.105 Ifr
0.44 Lhrikg.
Adverse effects. Nephrotoxicity (increase of serum creatinine to 2X baseline or greater than 2 mg/dL) was the major
adverse effect associated with GVHD prophylaxis with
FK506-based immunosuppression. The cumulative incidence of nephrotoxicity during the first 100 days was 78%
(Fig 2). Dialysis was required for four patients (22%). In
three of these patients, dialysis occurred during preterminal
acute events, including idiopathic pneumonitis, sepsis, or
systemic Aspergillus infection. The fourth patient had a baseline GFR of 66 W m i n and had an increase in K 5 0 6 levels
to 62 ng/mL during the first 7 days after marrow transplantation, temporally associated with the onset of VOD of the
liver. To further assess renal function in patients on FK506based immunosuppression, GFR measurements were made
before and during week 8 after marrow transplantation. All
patients had GFR studies performed before transplant and
13 patients had GFR studies performed during week 8. All
patients except one had a reduction inGFR (Fig 3). The
mean GFR afte.r at least 8 weeks of FK506 was reduced to
56% ( P = .002 Wilcoxon sign rank test) of the baseline.
Although nephrotoxicity was the most significant adverse
effect, those nephrotoxic events not requiring dialysis, in
From www.bloodjournal.org by guest on November 7, 2014. For personal use only.
3149
PREVENTION OF GVHD AFTER BMT WITH FK506
1.00
r
0.75
1
r
1
0.75
:
p
-
-
,
0
0
20
40
80
60
100
Fig 2. The cumulative incidence of nephrotoxicity in patients receiving FK506done or in combination with MTX or prednisone was
78%. A patient was defined as developing nephrotoxicity
if there was
a doubling of serum creatinine over baseline or an increase over 2
mg/dL at any time in the first 100 days aftermarrow transplantation
(n = 18).
general, occurred later in the period after transplantation,
appeared more directly related to the toxic effects of FK506,
and improved on dose reduction in all cases.
Seven patients (39%) developed VOD as previously defined by McDonald et al.32Four patients had mild-moderate VODwith complete resolution of signs and symptoms.
One patient with pre-existing mild liver disease before
marrow transplantation developed severe VOD associated
with significant ascites and a coagulopathy. Two patients
who died before day 28
had clinical evidence of mildmoderate VOD but pulmonary complications secondary
to systemic Aspergillus or toxicity from the conditioning
regimen were found at autopsy. No association was observed between changes in bilirubin levels with FK506
dose adjustment. Other adverse effects were hypertension
and hyperglycemia in nine and 10 patients, respectively.
Sixpatients had hypercholesterolemia. All six patients
developed hypercholesterolemia while on glucocorticoids
and FK506 for prophylaxis or treatment of GVHD. One
r
1
1
1
1
1 2 3 4
1
1
1
1
1
1
1
1
25
50
75
100
Days after Transplant
Days after Transplant
300
0
1
1
,
1
1
1
5 6 7 8 9 10 11 121314151617 18
Patients
Fig 3. Glomerular filtration rates for patients on FK506 before (01
and 8 weeks (0)after marrow transplantation.Thirteenpatientswere
evaluable after marrow transplantation.The mean GFR was reduced
to 56% of the pretransplant values ( P = .002).
Fig 4. The cumulative incidence of acute GVHD (grades Il-IV) in
patients receiving FK506 alone or
in combination with MTX or prdnisone was 44% at 100 days (n = 18).
of these also had hyperkalemia and required treatment
with both fiudrocortisone acetate and gemfibrozil. These
problems resolved after FK506 and prednisone were tapered. Neurologic adverse effects were noted in one patient who experienced delirium at the time FK506 whole
blood levels were between 20 and 30 ng/mL. This resolved
when the FK506 was held and other drugs were reduced
in dose or discontinued. A burning discomfort in the extremities (hands and feet) or severe headaches during intravenous infusion occurred in 11 patients
but improved
or resolved after reducing the rateof the intravenous infusion or changing to oral FK506. Two patients required
additional narcotic analgesia to control this discomfort.
GVHD. The cumulative incidence of grades 11-IV acute
GVHD was 44% (8/18; Fig 4). Skin GVHD occurred in six
patients. In addition, six patients had GVHD of the gastrointestinal tract. Two patients were considered to have GVHD
of the liver, but both of these patients also had moderatesevere hepatic VOD. Four of six patients receiving FK506
alone, one of seven patients receiving FK506 plus methylprednisolone, and three of five patients receiving FK506 plus
MTX developed overall grades 11-IV GVHD. Six of the eight
patients were treated with 2 mgkg of methylprednisolone
for 2 to 3 weeks and then received tapered doses. Four of
these patients had a complete response. Two of the eight
patients had biopsy-proven GVHD of the upper GI tract
only, manifested by anorexia and vomiting. One patient was
treated with prednisone at 1 mgkg and the other with oral
nonabsorbable beclomethasone (investigational drug). Both
patients had responses and did not require second-line therapy. Only one patient received second-line treatment with
ATG for an increasing serum bilirubin after FK506 had been
discontinued. However, this patient also had VOD with ascites and a gram-negative bacteremia that likely contributed
to the changes that led tothis intervention. Three of the eight
patients who developed grades 11-IV GVHD were receiving
IFN at the time of onset but there was no obvious correlation
of administration of IFN to the development of acute GVHD.
Nine patients in hematologic remission were evaluable for
chronic GVHD (cGVHD). One patient was treated for subclinical cGVHD (positive lip and skin biopsies with an abnormal Schirmer's test) with FK506 and prednisone. Two
From www.bloodjournal.org by guest on November 7, 2014. For personal use only.
3750
NASH ET AL
transplant patients can developliver and gastrointestinal tract
complications, all of which possibly could affect clearance
or bioavailability. Drug interactions might also affect these
parameters. Prednisolone inhibits FKS06 metabolism and another agent, such as FKS06, which is a substrate of cytochrome P-450 3A, cyclosporineA, can decrease the metabolism of prednis~lone.~'"Delays in MTX elimination have
I
I
l
I L
been observed during the concomitant administration of ke0.25
6
toprofen and a macrolide-like antibiotic, Pristinarnycin."'.''
Clearance of FKS06 was similarinall
threegroups.The
0
100
200
I
300
400
1
differences observed inbioavailability
among the three
Days after Transplant
groups might have resulted from the exacerbation of the
radiation-induced gastroenteritis by MTX. The range of valFig 5. The actuarial probability of nonrelapse mortality at l year
ues for both clearance and bioavailability of FKS06 in our
for the FK508 study group was 0.24, 1 year after the marrow transstudy were similar to results obtained after liver and small
plantation. Tick marks indicate relapse or
time of last contact for
surviving patients.
bowel transplantation. All studies have shown large interindividual ~ariability:~-~~ Because number
the
of patients studied here were small, the differencesobserved in the bioavailother patients developed cGVHDafter successfully tapering
ability of FK506 among thethree groups will need to be
off FKS06 at day 180 and were therefore treated with CSP
confirmed. No major effect of FKS06 on clearance of methand prednisone as previously described.2h
ylprednisolone or prednisolone wasfound, althoughthe
Survival. Theactuarial probability of transplant-related
clearance of methylprednisolone and prednisolone may have
mortality during the first 100 days was 24% (Fig 5). Only
been slightly decreased compared with results reported for
1 of 16 patients in the study (without myelodysplastic synhealthyindividuals.50,5' Therewasno
apparenteffect
of
drome [MDS]) were in remission at the time of transplant.
FKS06 in delaying the elimination of MTX, as determined
Seven patients relapsed during the first year after transplant.
by serumlevels 24 hours afterdosing.During
thispilot
The actuarial probability of disease-free survival was 39%
study of FKS06, we wereattempting to maintain whole blood
at 1 year after transplant.
levelsbetween 2 and 60 ng/mL. More recently, for other
studies, we have reduced the upper limit and increased the
DISCUSSION
lower limit of this range of whole bloodFKS06 levels. These
pharmacokinetic
results confirm that (1) althoughthe associPatients with advancedhematologic malignancies were
ation betweenwholebloodFKS06levels
and toxicity or
selected for this study of acute GVHD prevention because
acute GVHD is currently unclear, the high degree of interinthe efficacy and safety of FKS06 as an immunosuppressive
dividual variability in clearance and bioavailability resulting
agent after marrow transplantation was unknown. If these
from multiple factors, requires routine monitoring and adpatients with a high risk of relapse had a higher incidence
justments of dose; and (2) FKS06 does not have any signifiof acute GVHD asa result ofusing this new agentthan what
cant interactions onotherimportantimmunosuppressive
otherwise might have been expected, the overall survivalof
agents now used after marrow transplantation.
the group mightnot have been affected because of the graftThe major adverse effect associated with the administraversus-leukemia
During
this
period,
patients
with
tion of FKS06 was nephrotoxicity. Renal tubular celldamage
advanced hematologicmalignancies received more intensive
and glomerular thrombosis have
been associated with FKS06
conditioning regimens at this center, either with higher doses
nephrotoxicity." FKS06 has been reported to be cytotoxic
of TB1 (1,575 cGy) or intensified chemotherapy (combinafor tubular cells in vitro,inducingultrastructural
changes
tion of busulfan andcyclophosphamide with TBI).More
and delayed regeneration. Moreover, release of endothelin
intensified conditioning regimens,especially with intensified
from renal tubular cells may perturb renal hemodynamics,
TBI, have been associated with an increased incidence of
decreasing
GFR and renal plasma flow and increasing renal
acute GVHD.2*38339
This may occur becauseof a potentiating
vascular
Sodium depletion experimental
in an
effect of TB1 on acute GVHD. Another reason for the inrat model potentiates FKS06 nephrotoxicity." The incidence
creased incidence of acute GVHD might be an inability to
of severe nephrotoxicity requiring hemodialysis was similar
administer effective dosesof immunosuppressive agents beto what has been previouslyreported after marrowtranscause of the increased regimen-relatedtoxicity. The inciplantationwithCSP-basedregimens
of GVHDprophydence of acute GVHD reported in this study is comparable
laxis.sh In thefour patients of thisstudy of FKS06 who
to what has been
reported in previous studies ofpatients
requiredhemodialysis,nephrotoxicity
was associatedwith
receiving conditioning regimens of higher in tens it^.^*,^^ In
hepatic VOD or serious infections. Although it is likely that
this study, an increased risk of acute GVHD was not obFKS06was contributory, the limitedobservations in this
served with I F N administration!"
study would confirm what has been previously reported with
FKS06 is a highly lipophilic macrolide with a
large volCSP, thatin patients earlyafter marrow transplantation, other
ume ofdistribution. The drug is primarily eliminated by
complicationssuchasVOD,
sepsis, hypotension,andthe
hepatic metabolism(P-4503A),with
less than 1% of an
use ofAmphotericin B more closelycorrelate with the develintravenous or an oral dose appearing in the urine. Marrow
3
c
OP'
I
From www.bloodjournal.org by guest on November 7, 2014. For personal use only.
3751
PREVENTION OF GVHD AFTER BMT WITH FK506
opment of acute renal failure requiring hem~dialysis.~~
After
liver transplantation, nephrotoxicity observed in the FK506
group was also described as the major adverse effect, OCcurring in 37% to 54% of patients, similar to the incidence
observed in patients treated with CSP.57-59
Because both the
immunosuppressive and nephrotoxic effects of FK506 may
be linked to the ability of the FK506-binding protein-12
complex to inhibit the phosphatase activity of calcineurin,
a degree of nephrotoxicity may be unavoidable to achieve
adequate [email protected]’ The incidence of VOD has
previously been determined to be 54% and severe VOD was
seen in 15% of patients after marrow tran~plantation.~~
The
incidence of VOD in this study of FK506 in patients who
were at higher risk of developing this complication because
of the higher-dose regimen of cytoreductive therapy is comparable to the previous experience.
Hypertension and hyperglycemia were common but manageable adverse effects. After marrow transplantation with
CSP for GVHD prophylaxis, a 60% incidence of hypertension was reported, similar to what was obtained in this study
of FK506.61 In a prospective randomized trial comparing
FK506 to CSP after liver transplantation, hypertension was
less frequent in the group receiving FK506.6*Hyperglycemia
has been observed in 17% to 20% of patients treated with
FK506 after liver and kidney tran~plantation.~~’~~
Preclinical
studies in rats, dogs, and primates have indicated that one
of the mechanisms for the development of hyperglycemia
was a reduction in insulin secretion during treatment.”@
Seizures, delirium, dysarthria, or coma occurred in 8.4% of
liver transplant patients treated with FK506.57These complications were associated with toxic FK506 levels and responded to dose reduction in all but one case. The spectrum
of FK506-related complications observed after marrow
transplantation is similar to that observed after solid organ
transplantation.
FK506-based immunosuppression after marrow transplantation has an acceptable safety profile and has immunosuppressive activity that appears to be effective for prophylaxis of acute GVHD. No significant interactions were
observed between FK506, MTX, or prednisone that affected
clearance, although because bioavailability of oral FK506 in
patients receiving MTX may be reduced, blood levels should
be carefully monitored. In another recent phase I1 study of
FK506 alone for GVHD prophylaxis after marrow transplantation from HLA-matched siblings, the incidence of
grades 11-IV acute GVHD in 27 patients was 41%.67Based
on phase I1 clinical studies in marrow transplantation and
on the preclinical study of GVHD in dogs showing that
FK506 in combination with MTX significantly decreased
the incidence of acute GVHD compared with FK506 alone,
further studies are indicated to compare FK506 and MTX
with CSP and MTX in patients receiving marrow grafts from
HLA-matched siblings.
REFERENCES
1. StorbR, Thomas ED: Graft-versus-host disease in dog and
man: The Seattle experience. Immunol Rev 88:215, 1985
2. Nash RA, Pepe MS, Storb R, Longton G, Pettinger M, Anasetti
C, Appelbaum FR, Bowden RA, Deeg HJ, Doney K, Martin PJ,
Sullivan KM, Sanders J, Witherspoon RP: Acute graft-versus-host
disease: Analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate. Blood
80:1838, 1992
3. Storb R, Deeg HJ, Farewell V, Doney K, Appelbaum F, Beatty
P, Bensinger W, Buckner CD, Clift R, Hansen J, Hill R, Longton
G, Lum L, Martin P, McGuffin R, Sanders J, Singer J, Stewart P,
Sullivan K, Witherspoon R, Thomas ED: Marrow transplantation
for severe aplastic anemia: Methotrexate alone compared with a
combination of methotrexate and cyclosporine for prevention of
acute graft-versus-host disease. Blood 68: 119, 1986
4. Storb R, Deeg HJ, Whitehead J, Appelbaum FR, Beatty P,
Bensinger W, Buckner CD, Clift R, Doney K, Farewell V, Hansen
J, Hill R, Lum L, Martin P, McGuffin R, Sanders J, Stewart P,
Sullivan K, Witherspoon R, Yee G, Thomas ED: Methotrexate and
cyclosporine compared with cyclosporine alone for prophylaxis of
acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 314:729, 1986
5 . Martin PJ, Schoch G, Fisher L, Byers V, Anasetti C, AppelBeatty PG, Doney K, McDonald GB, Sanders JE, Sullivan
baum
KM, Storb R, Thomas ED, Witherspoon RP, Lomen P, Hannigan J,
Hansen JA: A retrospective analysis of therapy for acute graft-versus-host disease: Initial treatment. Blood 76:1464, 1990
6. Martin PJ, Schoch G, Fisher L, Byers V, Appelbaum FR, McDonald GB, Storb R, Hansen JA: A retrospective analysis of therapy
for acute graft-versus-host disease: Secondary treatment. Blood
77:1821, 1991
7. Santos GW, Tutschka PJ, Brookmeyer R, Sara1 R, Beschomer
WE, Bias WB, Hayden GB, Bums WH, Farmer ER, Hess AD,
Kaizer H, Mellits D, Sensenbrenner LL, Stuart R,YeagerAM:
Cyclosporine plus methylprednisolone versus cyclophosphamide
plus methylprednisolone as prophylaxis for graft-versus-host disease: A randomized double-blind study in patients undergoing allogeneic marrow transplantation. Clin Transplant 1:21, 1987
8. Tutschka PJ, Copelan EA, Klein JP: Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide
regimen. Blood 70:1382, 1987
9. Chao NJ, Schmidt GM, Niland JC, Amylon MD, Dagis AC,
Long GD, Nademanee AP, Negrin RS, O’Donnell MR, Parker PM,
Smith EP, Snyder DS, Stein AS, Wong RM, Blume KG, Forman
SJ: Cyclosporine, methotrexate, and prednisone compared with
cyclosporine and prednisone for prophylaxis of acute graft-versushost disease. N Engl J Med 329:1225, 1993
IO. Storb R, Pepe M, Anasetti C, Appelbaum
Beatty P, Doney
K, Martin P, Stewart P, Sullivan KM, Witherspoon R, Bensinger
W, Buckner CD, Clift R, HansenJ, Longton G, Loughran T, Petersen
FB, Singer J, Sanders J, Thomas ED: What role for prednisone in
prevention of acute graft-versus-host disease in patients undergoing
marrow transplants? Blood 76:1037, 1990
11. Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I,
Schreiber SL: Calcineurin is a common target of cyclophilincyclosporine A and FKBP-FK506 complexes. Cell 66:807, 1991
12. Baumann G, Geisse S, Sullivan M: Cyclosporine A and FK506 both affect DNA binding of regulatory nuclear proteins to the
human interleukin-2 promoter. New Biol 3:270, 1991
13. Bierer BE, Schreiber SL, Burakoff SJ: The effect of the immunosuppressant FK-506 on alternate pathways of T cell activation.
Eur J Immunol 21:439, 1991
14. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R,
Jain A: FK 506 for liver, kidney, and pancreas transplantation. Lancet 2:1000, 1989
15. Klintmalm GBG, Goldstein R, Gonwa T, Wiesner RH, Krom
RAF, Shaw BW Jr, Stratta R, Ascher NL, Roberts JW, Lake J,
Busuttil RW, McDiarmid S, Esquivel CO, Nakazato P, March JW,
Woodle ES, KalayogluM, D’Alessandro AM, Pirsch JD, Miller
FR.
FR.
From www.bloodjournal.org by guest on November 7, 2014. For personal use only.
3752
C, Schwartz M, Lewis WD, Monaco AP, Jenkins RL, Emend JC,
Thistlethwaite JR, Whitington PF, Steinmuller DR, Fitzsimmons
506 for the prevention of recurrent
WE, Lawrence I: UseofFK
allograft rejection after successful conversion from cyclosporine for
refractory rejection. U.S. Multicenter FK 506 Liver Study Group.
Transplant Proc 25:635, 1993
16. Jordan ML, Shapiro R, Vivas CA, Scantlebury VP, Darras
FS, Carrieri G, McCauley J, Demetris AJ, Randhawa P, Jensen C,
Hakala TR, Fung JJ, Starzl TE: FK 506 salvage of renal allografts
with ongoing rejection failing cyclosporine immunosuppression.
Transplant Proc 25:638, 1993
17. Markus PM, Cai X, Ming W, Demetris AJ, Fung JJ, Starzl TE:
Prevention of graft-versus-host disease following allogeneic bone
marrow transplantation in rats using FK506. Transplantation 52:590,
1991
18. Markus PM, Cai X, Ming W, Demetris AJ, Fung JJ, Starzl
TE: FK 506 reverses acute graft-versus-host disease after allogeneic
bone marrow transplantation in rats. Surgery 110:357, 1991
19. Storb R, Raff RF, Applebaum FR, Deeg HJ, Fitzsimmons W,
Graham TC, Pepe M, Pettinger M, Sale G, van der Jagt R, Schuening
FG: FK-506 and methotrexate prevent graft-versus-host disease in
dogs given 9.2 Cy total body irradiation and marrow grafts from
unrelated dog leukocyte antigen-nonidentical donors. Transplantation 56:800, 1993
20. Santos GW, Tutschka PJ, Brookmeyer R, S a r d R, Beschorner
WE, Bias WB, Braine HG, Burns WH, Farmer ER, Hess AD, Kaizer
H, Mellits D, Sensenbrenner LL, Stuart R, Yeager AM: Cyclosporine
plus methylprednisolone versus cyclophosphamide plus methylprednisolone as prophylaxis for graft-versus-host disease: A randomized
double-blind study in patients undergoing allogeneic marrow transplantation. Clin Transplant 1:21, 1987
21. Tamura K, Kobayashi M, Hoshimoto K, Kojima K, Nagese
K, Iwasaki K, Kaizu T, Tanaka H, Niwa M: A highly sensitive
method to assay FK506 levels in plasma. Transplant Proc 19:23,
1987
22. Jusko WJ, D'Ambrosio R: Monitoring FK506 concentrations
in plasma and whole blood. Transplant Proc 23:2732, 1991
23. Beatty PG, Anasetti C, Hansen JA, Longton GM, Sanders JE,
Martin PJ, Mickelson EM, Choo SY, Petersdorf' EW, Pepe MS,
Appelbaum FR, Bearman SI, Buckner CD, Clift R A , Petersen FB,
Singer J, Stewart PS, Storb RF, Sullivan KM, Tesler MC, Witherspoon RP, Thomas ED: Marrow transplantation from unrelated
donors for treatment of hematologic malignancies: Effect of mismatching for one HLA locus. Blood 81:249, 1993
24. Petersdorf EW, Smith AG, Haase AM, Martin PJ, Hansen
JA: Polymorphism of HLA-DRw52-associated DRB I genes as defined by sequence-specific oligonucleotide probe hybridization and
sequencing. Tissue Antigens 38: 169, 1991
25. Sullivan KM, Shulman HM, Storb R, Weiden PL, Witherspoon RP, McDonald GB, Schubert MM, Atkinson K, Thomas
ED: Chronic graft-versus-host disease in 52 patients: Adverse natural
course and successful treatment with combination immunosuppression. Blood 57:267, 1981
26. Sullivan KM, Witherspoon RP, Storb R, Deeg HJ, Dahlberg
S, Sanders JE, Appelbaum FR, Doney KC, Weiden P, Anasetti C,
Loughran TP, Hill R, Shields A, Yee G, Shulman H, Nims J, Strom
S, Thomas ED: Alternating-day cyclosporine and prednisone for
treatment of high-risk chronic graft-versus-host disease. Blood
72:555, 1988
27. Loughran TP Jr, Sullivan K, Morton T, Beckham C, Schubert
M, Witherspoon R, Sale G, Sanders J, Fisher L, Shulman H, Thomas
ED, Storb R: Value of day 100 screening studies for predicting the
development of chronic graft-versus-host disease after allogeneic
bone marrow transplantation. Blood 76:228, 1990
28. Ebling WF, Szefler SJ, Jusko WJ: Analysis of cortisol, meth-
NASH ET AL
ylprednisolone, and methylprednisolone hemisuccinate. Absence of
effects of troleandomycin on ester hydrolysis. J Chromatogr 305:27 I.
1984
29. Rose JQ, Jusko WJ: Corticosteroid analysis in biological fluids by high-performance liquid chromatography. J Chromatogr
I62:273, 1979
30. McLean AM, Ruggirello DA, Banfield C, Gonzalez MA,
Bailer M: Application of a variance-stabilizing transformation approach to linear regression of calibration lines. J Pharm Sci 79: 1005.
I990
3 1. Goates J J , Morton KA, Whooten WW, Greenberg HE, Datz
FL, Handy JE, Scuderi AJ, Haakenstad AO, Lynch RE: Comparison
of methods for calculating glomerular filtration rate: Technetium99m-DTPA scintigraphic analysis, protein-free and whole-plasma
clearance of technetium-99m-DTPA and iodine-l 25-iothalamate
clearance. J Nucl Med 31:424, 1990
32. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford
JL, Banaji M, Hardin BJ, Shulman HM, Clift RA: Veno-occlusive
disease of the liver and multiorgan failure after bone marrow transplantation: A cohort study of 355 patients. Ann Intern Med 118:255.
I993
33. Pepe MS, Mori M: Kaplan-Meier, marginal or conditional
probability curves in summarizing competing risks failure time data?
Stat Med 12:737, 1993
34. Pepe MS, Longton G, Pettinger M, Mori M, Fisher LD, Storb
R: Summarizing data on survival, relapse, and chronic graft-versus
host disease after bone marrow transplantation: Motivation for and
description of new methods. Br J Haematol 83:602, 1993
35. Snedecor GW, Cochran WG: Statistical Methods (ed 7).
Ames, IA, Iowa State, 1980
36. Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A,
Buckner CD, Storb R: Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med
300: 1068, 1979
37. Sullivan KM, Weiden PL, Storb R, Witherspoon RP. Fefer
A, Fisher L, Buckner CD, Anasetti C, Appelbaum FR, Badger C,
Beatty P. Bensinger W, Berenson R, Bigelow C, Cheever MA, Clift
R, Deeg HJ, Doney K, Greenberg P, Hansen JA, Hill R, Loughran
T, Martin P, Neiman P, Petersen FB, Sanders J, Singer J, Stewart
P, Thomas ED: Influence of acute and chronic graft-versus-host
disease on relapse and survival after bone marrow transplantation
from HLA-identical siblings as treatment of acute and chronic lenkemia. Blood 73:1720, 1989
38. Clift RA, Buckner CD, Appelbaum FR, Petersen FB, Fisher
LD. Anasetti C, Beatty P, Bensinger WI, Doney K, Hill R, McDonald G, Martin P, Sanders J, Singer J, Stewart P, Sullivan KM, Witherspoon R, Storb R, Hansen J, Thomas ED: Allogeneic marrow
transplantation in patients with acute myeloid leukemia in first remission. A randomized trial of two irradiation regimens. Blood 76: 1867,
1990
39. Clift RA, Buckner CD, Appelbaum FR, Bryant A, Bearman
SI, Petersen FB, Fisher LD, Anasetti C, Beatty P, Bensinger WI,
Doney K, Hill RS, McDonald GB, Martin P, Meyers J, Sanders J,
Singer J, Stewart P, Sullivan K M , Witherspoon R, Storb R, Hansen
JA, Thomas ED: Allogeneic marrow transplantation in patients with
chronic myeloid leukemia in the chronic phase. A randomized trial
of two irradiation regimens. Blood 77:1660, 1991
40. Meyers JD, Flournoy N, Sanders JE, McGuffin RW, Newton
BA, Fisher LD, Lurn LC, Appelbaum FR, Doney K, Sullivan KM,
Storb R, Buckner CD, Thomas ED: Prophylactic use of human leukocyte interferon after allogeneic marrow transplantation. Ann Intern
Med 107:809, 1987
41. lwasaki K, Matsuda H, Nagase K, Shiraga T, Tokuma Y,
Uchida K: Effects of 23 drugs on the metabolism of FK506 by
From www.bloodjournal.org by guest on November 7, 2014. For personal use only.
PREVENTION OF GVHD AFTER BMT WITH FK506
human liver microsomes. Res Commun Chem Path01 Pharmacol
82:209, 1993
42. Egfjord M, Daugaard H, Olgaard K: The effect of
cyclosporine A on the hepatic clearance rate of prednisone in isolated
perfused livers of normal and uremic rats. Transplant Proc 20549,
1988 (suppl 2)
43. KLintmalm G: High dose methylprednisolone increases
plasma cyclosporin levels in renal transplant recipients. Lancet
1:731, 1984
44. Ost L: Effects of cyclosporin on prednisolone metabolism.
Lancet 1:451, 1984
45. Thyss A, Milan G, Kubar J, Namer M, Schneider M: Clinical
and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen. Lancet 1:256, 1986
46. Thyss A, Milano G, Renee N, Cassuto-Viguier E, Jambou P,
Soler C: Severe interaction between methotrexate and a macrolidelike antibiotic. J Natl Cancer Inst 85582, 1993
47. Venkataramanan R, Jain A, Cadoff E, Warty V, Iwasaki K,
Nagase K, Krajack A, Imventarza 0, Todo S , Fung JJ, Starzl T E
Pharmacokinetics of FK 506: Preclinical and clinical studies. Transplant Proc 2252, 1990
48. Jain AB, Abuelmagd K, Abdallah H, Warty V, Fung J, Todo
S , Starzl TE, Venkataramanan R Pharmacokinetics of FK506 in
liver transplant recipients after continuous intravenous infusion. J
Clin Phannacol 33:606, 1993
49. Jain A, Venkataramanan R, Todo S, Abu-Elmagd K, Fung J,
Warty V, Tzakis A, Reyes J, Alessiani M, Starzl TE: Intravenous,
oral pharmacokinetics, and oral dosing of FK 506 in small bowel
transplant patients. Transplant Proc 24:1181, 1992
50. Rose JQ, Yurchak AM, Jusko WJ: Dose dependent pharmacokinetics of prednisone and prednisone in man. J Pharmacokinet Biopharm 9:389, 1981
51. Dunn TE, Ludwig EA, Slaughter RL, Camara DS, Jusko WJ:
Pharmacokinetics and pharmacodynamics of methylprednisolone in
obesity. Clin Pharmacol Ther 49536, 1991
52. Demetris AJ, Banner B, Fung J, Shapiro R, Jordan M, Starzl
TE: Histopathology of human renal allograft rejection under FK
506: A comparison with cyclosporine. Transplant Proc 23:944, 1991
53. Moutabarrik A, Ishibashi M, Fukunaga M, Kameoka H, Kawaguchi N, Takano Y, Kokado Y, Sonoda T, Onishi S , Takahara
S, Okuyama A: FK506-induced kidney tubular cell injury. Transplantation 54:1041, 1992
54. Kumano K, Wang G, Endo T: FK506-induced nephrotoxicity
in rats. Transplant Proc 23512, 1991
55. Andoh TF, Burdmann EA, Lindsley J, Houghton DC, Bennett
WM: Enhancement of FK506 nephrotoxicity by sodium depletion
in an experimental rat model. Transplantation 57:483, 1994
56. Zager RA, O'Quigley J, Zager BK, Alpers CE, Shulman HM,
Gamelin LM, Stewart P, Thomas ED: Acute renal failure following
3753
bone marrow transplantation: A retrospective study of 272 patients.
Am J Kidney Dis 13:210, 1989
57. Alessiani M, Cillo U, Fung JJ, Irish W, Abu-Elmagd K, Jain
A, Takaya S, Van Thiel D, Starzl TE: Adverse effects of FK 506
overdosage after liver transplantation. Transplant Proc 25:628, 1993
58. Porayko MK, Textor SC, Krom RAF, Hay JE, Gores GJ,
Wahlstrom HE, Sanchez-Urdazpal L, Richards T, Crotty P, Beaver
S, Wiesner RH: Nephrotoxicity of FK 506 and cyclosporine when
used as primary immunosuppression in liver transplant recipients.
Transplant Proc 25:665, 1993
59. Distant DA, Bonwa TA, Jennings L, Backman L, Eisenstein
C, Renard T, Levy M, Goldstein R, Husberg BS, Klintmalm G:
Long-term renal function after liver transplantation: An analysis of
600 patients on cyclosporine or FK506 immunosuppression. American Society of Transplant Surgeons 12th Annual Meeting, Houston,
TX, 1993, p 123 (abstr 72)
60. Dumont FJ, Staruch MJ, Koprak SL, Siekierka JJ, Lin CS,
Harrison R, Sewell T, Kindt VM, Beattie "R,Wyvratt M, Sigal NH:
The immunosuppressive and toxic effects of FK-506 are mechanistically related: Pharmacology of a novel antagonist of FK-506 and
rapamycin. J Exp Med 176:751, 1992
61. Loughran TP Jr. Deeg HJ, Dahlberg S, Kennedy MS, Storb R,
Thomas ED: Incidence of hypertension after marrow transplantation
among 112 patients randomized to either cyclosporine or methotrexate as graft-versus-host disease prophylaxis. Br J Haematol 59547,
1985
62. Pirsch J: Renal and metabolic effects of liver transplantation
(Tx): Comparison of FK506 to CyA with respect to GFR, hypertension, hyperlipidemia, hyperglycemia and hyperkalemia. American
Society of Transplant Physicians 12th Annual Meeting, Houston,
TX, 1993, p 153 (abstr 102)
63. Scantlebury V, Shapiro R, Fung 3, Tzakis A, McCauley J,
Jordan M, Jensen C, Hakala T, Simmons R, Starzl TE: New onset
of diabetes in FK 506 vs cyclosporine-treated kidney transplant recipients. Transplant Proc 23:3169, 1991
64. Tze WJ, Tai J, Murase N, Tzakis A, Starzl TE: Effect of FK
5 0 6 on glucose metabolism and insulin secretion in normal rats.
Transplant Proc 23:3158, 1991
65. Strasser S , Alejandro R, Shapiro ET, Ricordi C, Todo S,
Mintz DH: Effect of FK506 on insulin secretion innormal dogs.
Metabolism 4 1: 6 4 , 1992
66. Ericzon BG, Wijnen RM, Kubota K, Kootstra G, Groth CG:
FK506-induced impairment of glucose metabolism in the primateStudies in pancreatic transplant recipients and in nontransplanted
animals. Transplantation 54:615, 1992
67. Fay JW, Weisdorf DJ, Wingard JR, Antin JH, Collins RH,
Blazar BR, Sara1R, Bierer BE, Przepiorka D, Fitzsimmons WE:
FK506 monotherapy for prevention of graft versus host disease after
histocompatible sibling marrow transplantation. Bone Marrow
Transplant 80:135a, 1992 (abstr, suppl 1)