Higher tacrolimus concentrations early after transplant reduce the risk of acute GvHD in reduced-intensity allogeneic stem cell transplantation

Abstract

There is significant variability in the serum concentrations of tacrolimus attained early post transplant due to drug interactions and genomic variation. We evaluated whether tacrolimus concentrations early post transplant correlated with incidence of acute GvHD in 120 consecutive patients allografted with a uniform reduced-intensity conditioning regimen. All patients received standard prophylaxis with oral tacrolimus and IV methotrexate. The primary variable of interest was mean weekly tacrolimus concentrations in the initial 4 weeks post transplant. In multivariate analysis, week 1 tacrolimus concentration was an independent predictor of acute grade 2–4 GvHD (hazard ratio (HR), 0.90; 95% confidence interval (CI), 0.84–0.97; P<0.01). This association was driven by a lower risk of acute grade 2–4 GvHD in patients with week 1 tacrolimus concentrations >12 ng/mL (HR, 0.47; 95% CI, 0.25–0.88; P=0.02). Week 1 tacrolimus concentrations were not associated with chronic GvHD, relapse or overall survival. Lower tacrolimus concentrations at weeks 2, 3 and 4 were not associated with a higher incidence of GvHD. In summary, we found that higher tacrolimus concentrations during the first week after allografting with a reduced-intensity conditioning regimen were associated with significantly reduced risk of acute grade 2–4 GvHD without increasing risk of relapse.

Full text

ORIGINAL ARTICLE
Higher tacrolimus concentrations early after transplant reduce
the risk of acute GvHD in reduced-intensity allogeneic stem
cell transplantation
A Ganetsky
1
, A Shah
1
, TA Miano
2
, W-T Hwang
3
,JHe
3
, AW Loren
4
, EO Hexner
4
, NV Frey
4
, DL Porter
4
and R Reshef
5
There is significant variability in the serum concentrations of tacrolimus attained early post transplant due to drug interactions and
genomic variation. We evaluated whether tacrolimus concentrations early post transplant correlated with incidence of acute GvHD
in 120 consecutive patients allografted with a uniform reduced-intensity conditioning regimen. All patients received standard
prophylaxis with oral tacrolimus and IV methotrexate. The primary variable of interest was mean weekly tacrolimus concentrations
in the initial 4 weeks post transplant. In multivariate analysis, week 1 tacrolimus concentration was an independent predictor of
acute grade 2–4 GvHD (hazard ratio (HR), 0.90; 95% confidence interval (CI), 0.84–0.97; Po0.01). This association was driven by a
lower risk of acute grade 2–4 GvHD in patients with week 1 tacrolimus concentrations 412 ng/mL (HR, 0.47; 95% CI, 0.25–0.88;
P= 0.02). Week 1 tacrolimus concentrations were not associated with chronic GvHD, relapse or overall survival. Lower tacrolimus
concentrations at weeks 2, 3 and 4 were not associated with a higher incidence of GvHD. In summary, we found that higher
tacrolimus concentrations during the first week after allografting with a reduced-intensity conditioning regimen were associated
with significantly reduced risk of acute grade 2–4 GvHD without increasing risk of relapse.
Bone Marrow Transplantation (2016) 51, 568–572; doi:10.1038/bmt.2015.323; published online 21 December 2015
INTRODUCTION
The development of reduced-intensity conditioning (RIC) regi-
mens has led to the extended use of allogeneic hematopoietic
stem cell transplantation (HSCT), particularly in patients with
advanced age or those with significant comorbidities. Although
RIC regimens are characterized by reduced toxicity, acute GvHD
remains a leading cause of morbidity and mortality in this type of
transplant.
1
Despite standard prophylactic measures, the rates of
acute GvHD are high, with incidence rates ranging from 25 to
68%.
2–4
Therefore, preventing GvHD without impairing the
graft-versus-tumor effect remains a critical goal for successful
HSCT.
Calcineurin inhibitors (CNIs) are considered to be the backbone
of GvHD prophylaxis in HSCT.
5
Successful administration of CNI is
complicated by their narrow therapeutic index and considerable
intra- and interpatient pharmacokinetic heterogeneity. The
unpredictable pharmacokinetic profile associated with CNI is the
result of drug interactions, genomic variation, hepatic and/or renal
function, and binding capacity to blood and plasma proteins.
6–9
This constellation of factors leads to significant variability in CNI
concentrations attained within the first week after HSCT, which
may affect outcomes as preclinical models have demonstrated
that the critical sequence of immunologic events that lead to
acute GvHD occurs within the first few days after
transplantation.
10
Therefore, a delay in achieving therapeutic CNI
concentrations within the first week post transplant may result in
a higher risk of acute GVHD.
Given these findings, we hypothesized that CNI concentrations
attained early after transplant would affect clinical outcomes in
RIC HSCT recipients. Previous studies have shown conflicting
results regarding the associations between CNI concentrations
and GVHD, possibly due to significant variability in the studied
populations with respect to conditioning intensity, GVHD prophy-
laxis regimens, graft sources and CNI route of administration.
11–14
To overcome some of these limitations and inform the
management of immunosuppression early after RIC HSCT, we
analyzed a uniform and large cohort of consecutive patients who
received oral tacrolimus (TAC) after peripheral blood stem cell
transplantation with fludarabine+busulfan conditioning. The goal
of this analysis was to evaluate whether early TAC concentrations
correlated with incidence of GvHD, disease relapse and survival.
MATERIALS AND METHODS
Study population
We conducted a retrospective cohort study of 120 consecutive adult
patients undergoing first allogeneic HSCT for a malignant hematologic
disorder at the University of Pennsylvania between January 2009 and
January 2014. All patients received a uniform RIC regimen of fludarabine
(120 mg/m
2
) and busulfan (6.4 mg/kg), followed by infusion of T-cell
replete, G-CSF-mobilized peripheral blood stem cells from either a related
1
Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, PA, USA;
2
Center for Pharmacoepidemiology Research and Training, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA, USA;
3
Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA, USA;
4
Blood and Marrow Transplantation Program, Abramson Cancer Center and the Division of Hematology and
Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA and
5
Blood and Marrow Transplantation Program and Columbia Center for
Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA. Correspondence: Dr R Reshef, Blood and Marrow Transplantation
Program and Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, BB-1701C, 650 West 168th Street, New York,
NY 10032, USA.
Email: ran.reshef@columbia.edu
Received 1 September 2015; revised 12 November 2015; accepted 14 November 2015; published online 21 December 2015
Bone Marrow Transplantation (2016) 51, 568–572
© 2016 Macmillan Publishers Limited All rights reserved 0268-3369/16
www.nature.com/bmt

or unrelated donor. All patients received standard GvHD prophylaxis with
oral TAC (0.06 mg/kg per day) in two divided doses starting 3 days before
HSCT and IV methotrexate at a dose of 15 mg/m
2
on day 1 and 10 mg/m
2
on days 3, 6 and 11. Antithymocyte globulin was not used in any of
the patients. The dose of TAC was adjusted to a target trough level of
5–15 ng/mL and was continued through 100 days post HSCT and then
tapered. The standard at our institution is to obtain the first TAC trough
concentrations 1 day before HSCT and then at least twice weekly and at
least 72 h after any dosage change to allow drug levels to achieve
steady state. TAC whole-blood concentrations were measured by liquid
chromatography–mass spectrometry. The study was approved by the
Institutional Review Board of the University of Pennsylvania.
Clinical outcomes
The primary outcome of interest was the correlation between mean
weekly TAC concentrations and acute grade 2–4 GvHD. We calculated
the mean TAC concentration for each of the first 4 weeks post HSCT by
adding all of the available TAC concentrations from initiation of therapy
until the last day of the given week and dividing the sum by the total
number of available measurements. Secondary end points included acute
grade 3–4 GvHD, chronic GVHD, relapse, overall survival (OS), relapse-free
survival (RFS) and acute kidney injury (AKI). Acute GvHD was graded
according to the modified Glucksberg criteria and guidelines for data
collection recently published by the MAGIC Consortium.
15,16
Chronic GvHD
was graded according to the National Institutes of Health Consensus
Criteria.
17
Disease relapse was defined as morphological, cytogenetic
or radiological evidence of disease demonstrating pre-transplant
characteristics. We used the Disease Risk Index (DRI) stratification system
to classify patients according to disease type and disease status.
18
OS was
defined as the time interval between date of HSCT and death from any
cause or censored at last follow-up. RFS was defined as the time from date
of HSCT to death or relapse/progression, whichever came first or censored
at last follow-up. AKI was defined as at least a twofold increase in serum
creatinine or a reduction in glomerular filtration rate by 450% from
baseline, as per the Risk, Injury, Failure, Loss and End-stage kidney disease
criteria.
19
Statistical analysis
Baseline and treatment characteristics were analyzed with descriptive
statistics. Associations between covariates and the cumulative incidence of
acute grade 2–4 GVHD were determined using Fine and Gray proportional
hazards regression. Death was considered a competing event. Associations
of covariates with OS and RFS were analyzed using Cox regression models.
Mean weekly TAC levels were included in the analyses as continuous
variables and then divided into tertiles. The following variables were
examined as potential covariates: patient and recipient age, patient and
recipient sex, disease type, donor source, DRI, degree of HLA match, and
presence or absence of CMV. Multivariable analysis was performed on
variables with a univariate P-valueo0.1. A two-sided P-value of ⩽05 was
considered significant for all other analyses. Competing risks regression
analyses were also conducted to identify predictors of relapse, allowing for
death as a competing event. Patients were censored at the time of donor
lymphocyte infusion for GvHD analyses. The associations between TAC
concentrations and AKI were conducted using t-tests.
RESULTS
Patient and transplant characteristics of the 120 subjects are
presented in Table 1. The median follow-up was 14.3 months
(range 0.7–66.3 months). The mean weekly TAC concentrations at
weeks 1, 2, 3 and 4 were 10.2 (range 2.8–19.4), 10.6 (range
3.9–23.9), 12.7 (range 4.2–24.1) and 11.9 (range 2.9–29.2) ng/mL,
respectively (Figure 1). Within this cohort, 115/120 (95.8%)
patients had complete TAC concentration data available for all
4 weeks of the analysis. In the remaining five patients, the missing
TAC concentration values were confined to weeks 3 (n=1) and 4
(n= 4) of the study period. The majority of patients (111/120;
92.5%) received all four scheduled methotrexate doses.
GvHD
The primary outcome of interest was acute grade 2–4 GvHD.
The cumulative incidence of acute grade 2–4 GvHD was 21.3%
(95% confidence interval (CI), 14.9–29.9%) at day 100 and 42.8%
(95% CI, 34.3–52.4%) at day 180 post HSCT. To assess whether
early TAC concentrations were predictive of acute grade 2–4
GvHD, we analyzed mean weekly TAC concentrations as
continuous variables up to 4 weeks post HSCT. We first examined
the effect of TAC concentrations at each week independently, and
then constructed a multivariable model for predicting risk of acute
grade 2–4 GvHD. The hazard ratios (HRs) reflect the increased or
decreased risk of acute grade 2–4 GvHD for each 1 ng/mL of
difference in mean TAC concentration.
In univariable analysis, week 1 TAC concentrations were
inversely associated with acute grade 2–4 GvHD (HR, 0.92; 95%
CI, 0.85–0.99; P= 0.03). Other variables associated with a higher
risk of acute grade 2–4 GvHD that met our threshold for modeling
were the presence of a single-allele HLA mismatch (HR, 2.14; 95%
CI, 1.20–3.84; Po0.01) and lymphoid malignancies as opposed to
Table 1. Patient and transplant characteristics (N=120)
Characteristic Value
Recipient age, median in years (range) 62 (28–72)
Recipient sex, male/female (n) 70/50
Donor age, median in years (range) 44 (18–72)
Donor sex, male/female (n) 64/56
Sex mismatch, n(%) 55 (46)
Female donor to male recipient transplant, n(%) 28 (24)
Diagnosis, n(%)
Acute myeloid leukemia 49 (41)
Myelodysplastic syndromes 33 (27)
Non-Hodgkin lymphoma 22 (18)
Acute lymphoblastic leukemia 8 (7)
Other
a
8 (7)
Donor source, n(%)
Matched sibling 53 (44)
Matched unrelated 50 (42)
Single-allele mismatched unrelated 17 (14)
Disease Risk Index, n(%)
Low 10 (8)
Intermediate 80 (67)
High/very high 30 (25)
a
Other includes: chronic myeloid leukemia (n=2), Hodgkin lymphoma
(n=2), multiple myeloma (n=1), myelodysplastic/myeloproliferative neo-
plasm (n=1) and myelofibrosis (n=2).
30
25
20
15
10
5
0
Week 1 Week 2 Week 3 Week 4
Week after transplant
Mean tacrolimus concentration (ng/mL)
N=120 N=120 N=119 N=116
Figure 1. Significant variability in TAC concentrations attained early
after RIC HSCT. Box-and-whisker plot showing the distribution of
mean weekly TAC concentrations during the first 4 weeks after
transplantation.
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A Ganetsky et al
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© 2016 Macmillan Publishers Limited Bone Marrow Transplantation (2016) 568 –572

myeloid malignancies (HR, 0.56; 95% CI, 0.30–1.03; P= 0.06). When
incorporating these covariates into a multivariable model, higher
week 1 TAC concentrations remained independently associated
with a lower risk of acute grade 2–4 GvHD (HR, 0.90; 95% CI,
0.84–0.97; Po0.01), as shown in Figure 2. We found no
correlations between lower TAC concentrations at weeks 2, 3 or
4 and increased incidence of acute grade 2–4 GvHD. In addition,
TAC concentrations on the day before HSCT were not associated
with acute grade 2–4 GVHD.
To further characterize the relationship between week 1 TAC
concentrations and acute grade 2–4 GVHD, we examined the
effect of week 1 TAC concentrations categorized in tertiles ( o8.5,
8.5–12 and 412 ng/mL). Interestingly, the inverse association
between week 1 TAC concentrations and acute grade 2–4 GVHD
was driven by a lower risk in the upper tertile (412 ng/mL), as
shown in Figure 3. Patients in the upper tertile had a lower risk of
acute grade 2–4 GVHD compared with those in the lower tertile
(HR, 0.47; 95% CI, 0.25–0.88; P= 0.02). There was no difference in
risk of acute grade 2–4 GVHD when comparing the intermediate
and lower tertiles (HR, 1.1; 95% CI, 0.60–1.93; P= 0.80).
We then analyzed the effect of week 1 TAC concentrations on
acute grade 2–4 GvHD in recipients of grafts from related and
unrelated donors separately. The cumulative incidence of acute
grade 2–4 in related donor HSCT at day 100 and day 180 was
11.3% (95% CI, 2.5–20.1%) and 32.1% (19.1–45.1%), respectively.
Week 1 TAC concentrations were not predictive of acute grade
2–4 GVHD following related donor HSCT (adjusted HR, 0.96; 95%
CI, 0.85–1.07; P= 0.46). In recipients of grafts from unrelated
donors, the cumulative incidence of acute grade 2–4 GVHD at day
100 was 31.3% (95% CI, 19.9–42.7%) and at day 180 was 50.7%
(38.3–63.1%). In unrelated donor HSCT, higher week 1 TAC
concentrations were associated with a lower risk of acute grade
2–4 GvHD (adjusted HR, 0.88; 95% CI, 0.81–0.96; P= 0.003).
Furthermore, we evaluated whether TAC concentrations
within the first month post HSCT impacted the risk of acute
grade 3–4 GVHD. The cumulative incidence of acute grade 3–4
GVHD was 6.8% (95% CI, 3.2–10.4%) at day 100 and 16.6% (95% CI,
10.2–23.0%) at day 180 post HSCT. We found no association
between TAC concentrations and this outcome (data not shown).
We then examined the associations between TAC concentrations
and acute grade 3–4 GVHD when recipients of related and
unrelated grafts were analyzed separately. In related donor HSCT,
the cumulative incidence of acute grade 3–4 at day 100 was 5.8%
(95% CI, 0.6–11.0%) and 15.2% (5.8–24.6%) day 180. The
cumulative incidence of acute grade 3–4 GvHD in recipients of
grafts from unrelated donors was 7.9% (2.9–12.9%) at day 100 and
18.9% (10.1–27.7%) at day 180. Week 1 TAC concentrations were
not predictive of acute grade 3–4 GVHD when patients were
analyzed separately according to donor source. Similar analyses
were conducted for chronic GvHD and no associations were found
(data not shown).
Relapse
Because the pathogenesis of GvHD is closely intertwined with
the graft-versus-tumor effect, we examined whether early TAC
concentrations after RIC HSCT influenced risk of disease relapse.
The cumulative incidence of disease relapse was 29.2% (95% CI,
21.8–37.9%) at day 180 and 38.3% (95% CI, 30.1–47.3%) at 1 year.
In univariable analyses, disease relapse was not associated with
mean TAC concentrations at week 1 (HR, 0.98; 95% CI, 0.89–1.06;
P= 0.58), week 2 (HR, 0.98; 95% CI, 0.91–1.05; P= 0.52), week 3
(HR, 0.97; 95% CI, 0.91–1.03; P= 0.29) or week 4 (HR, 1.04; 95% CI,
0.98–1.11; P= 0.15). We also analyzed the relationship between
TAC concentrations and risk of relapse with adjustment for the
DRI and found no significant associations (data not shown).
In addition, mean TAC concentrations did not correlate with
donor–recipient whole-blood or T-cell chimerism levels at days 30,
60 and 100, and 1 year after RIC HSCT.
RFS and OS
The 2-year estimated rates of RFS and OS were 25.8% (95% CI,
18.8–34.4%) and 34.2% (95% CI, 26.3–43.0%), respectively. In
univariable analysis, higher week 3 TAC concentrations were
associated with improved RFS (HR, 0.95; 95% CI, 0.90–1.00;
P= 0.06) but did not meet our threshold for statistical significance.
With adjustment for the DRI, this correlation remained
non-significant (HR, 0.95; 95% CI, 0.90–1.01; P= 0.08). TAC
concentrations at weeks 1, 2 and 4 were not predictive of RFS.
We conducted a similar analysis to identify associations
between early TAC concentrations and OS. In univariable analysis,
higher week 3 TAC concentrations were associated with improved
OS (HR, 0.95; 95% CI, 0.89–1.00; P= 0.07) but did not reach
statistical significance. With adjustment for disease type, recipient
age and DRI, the relationship between higher week 3 TAC
concentrations and improved OS remained non-significant
(HR, 0.94; 95% CI, 0.89–1.00; P= 0.06). TAC concentrations at
weeks 1, 2 and 4 were not associated with OS.
Week 1 TAC
Week 2 TAC
Week 3 TAC
Week 4 TAC
0.5 1 2
Adjusted hazard ratio
P<0.01
P=0.16
P=0.66
P=0.52
Figure 2. Significant association between week 1 TAC concentra-
tions and acute grade 2–4 GvHD. Multivariable analysis showing
adjusted hazard ratios (aHRs) for acute grade 2–4 GvHD based on
mean TAC concentrations at weeks 1, 2, 3 and 4 after RIC HSCT. The
aHRs reflect the increased or decreased risk of acute grade 2–4
GVHD for each 1 ng/mL of difference in mean TAC concentration.
Mean week 1 TAC levels
<8.5 ng/mL (low)
8.5-12 ng/mL (intermediate)
>12 ng/mL (high)
1.0
0.8
0.6
0.4
0.2
0.0
0123456
Cumulative incidence
Time from transplant (months)
Figure 3. Lower risk of acute grade 2–4 GvHD in patients with
mean week 1 TAC412 ng/mL. Cumulative incidence plots showing
acute grade 2–4 GvHD according to mean week 1 TAC concentra-
tions. Patients in the lower tertile ( o8.5 ng/mL), middle tertile
(8.5–12 ng/mL) and upper tertile (412 ng/mL) are represented by
the dashed, dotted and solid lines, respectively.
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Kidney injury
As nephrotoxicity is a commonly reported complication of TAC,
we examined whether TAC concentrations early post transplant
were predictive of AKI in this cohort. Renal impairment, defined by
the Risk, Injury, Failure, Loss and End-stage kidney disease criteria,
which is a standard criterion in pharmacological studies, occurred
in 20 (16.7%) patients during the first 4 weeks after RIC HSCT.
Week 1 TAC concentrations were higher in patients who
developed AKI by week 2 post transplant compared with those
who did not (12.7 vs 10.0 ng/mL; P= 0.01). We did not observe an
association between TAC concentrations at any other time points
and AKI within the first month post transplant. No patients
required hemodialysis within the first 4 weeks after HSCT. We also
examined whether TAC concentrations early after RIC HSCT were
associated with chronic renal impairment. Of the 71 patients alive
at 1 year after HSCT, no one had a serum creatinine 42 mg/dL.
DISCUSSION
In this study, we demonstrated that there is significant variability
in the serum concentrations of TAC attained early post-RIC
HSCT. In addition, we found that higher TAC concentrations
during the first week after RIC HSCT were associated with
significantly reduced risk of acute grade 2–4 GvHD without
increasing risk of relapse. For each 1 ng/mL increase in TAC
concentration, there was a 10% decrease in risk of acute grade 2–4
GvHD. Importantly, this association was driven by a lower risk of
acute grade 2–4 GvHD in patients with mean week 1 TAC
concentrations 412 ng/mL. To the best of our knowledge, this
study is the first to characterize the importance of achieving
higher therapeutic TAC concentrations within the first week after
RIC HSCT.
As expected, we observed a direct association between week 1
TAC concentrations and incidence of AKI occurring by day 14 post
transplant. The incidence of AKI has been previously reported to
be proportionally related to TAC concentrations in HSCT
recipients.
20
AKI was reversible and long-term renal complications
were not observed.
The results of our study show the critical importance of
achieving therapeutic TAC concentrations within the first week
after RIC HSCT to optimally attenuate donor alloreactivity.
This association is consistent with preclinical studies that
demonstrated that the initiating events of acute GvHD occur very
early after transplant.
10,21
It was observed that alloreactive T-cell
activation, proliferation and migration to GvHD target organs
occur within several days after stem cell infusion. In addition,
ex vivo analyses of gastrointestinal tract tissue have shown
alloreactive CD4+ donor lymphocyte infiltration of Peyer’s patches
and mesenteric lymph nodes as early as 12 h after HSCT.
10
The
importance of inhibiting alloreactivity within the first week after
RIC HSCT has been further characterized with the emergence of
novel approaches to GvHD prophylaxis, including proteasome
inhibition with bortezomib and post-transplant cyclophospha-
mide. The efficacy of both of these novel strategies is critically
dependent on the early timing of drug administration after
HSCT.
22,23
Taken together, our findings imply that achieving a
mean TAC concentration 412 ng/mL during the first week after
RIC HSCT potentially mitigates the intense alloreactivity that
occurs immediately after stem cell infusion and thereby reduces
the risk of developing acute GvHD. In a subset analysis, this
association appeared to be driven by the group of recipients of
unrelated donor grafts, although the analysis in recipients of
related grafts may have been inadequately powered due to a
smaller sample size.
The optimal target concentration of CNI early after HSCT
has been previously examined with conflicting results.
11–14
The varying results are likely due to heterogeneity in studied
populations, inclusion of multiple GvHD prophylaxis regimens,
different routes of TAC administration and heterogeneity in
conditioning regimens and graft sources. To overcome these
limitations, our analysis focused on a homogeneous patient
population consisting of patients undergoing first allogeneic
HSCT who were allografted with fludarabine/busulfan, the most
commonly used RIC regimen according to the Center for
International Blood and Marrow Transplant Research.
1
In addition,
all patients received a uniform GVHD prophylaxis regimen and
received peripheral blood stem cells. Another retrospective study
that reported on a uniform patient population that underwent RIC
HSCT found no associations between TAC concentrations and
acute grade 2–4 GvHD, although week 2 TAC concentrations
o10.5 ng/mL were associated with a higher risk of acute grade
3–4 GvHD. In contrast to our findings, there was no correlation
between week 1 TAC concentrations and acute GvHD.
11
Several
differences between this report and our study, including the use
of non-myeloablative conditioning (low-dose TBI ± fludarabine)
and the use of mycophenolate mofetil and not methotrexate,
could potentially explain the different results of these studies.
Our data highlight the importance of developing novel
methods to optimize the initial dosing of TAC in RIC HSCT
recipients. One approach that may aid in achieving higher
therapeutic concentrations rapidly is to incorporate a patient’s
genotype into the formula for determining the initial starting dose
rather than using the standard weight-based fixed-dose strategy.
TAC is primarily metabolized by cytochrome P450 3A4 and 3A5,
both highly polymorphic isoenzymes. In addition, a number
of other enzymes responsible for TAC metabolism possess
gene variants that have the propensity to influence TAC
pharmacokinetic.
24
Identifying patient-specific genotypes prior
to initiating TAC may reduce the time it takes to achieve
therapeutic concentrations of TAC and thereby reduce the
incidence of acute GvHD.
In summary, we conclude that achieving higher TAC con-
centrations, and in particular levels 412 ng/mL within the first
week of RIC HSCT, may significantly reduce the risk of acute grade
2–4 GvHD without impairing the graft-versus-tumor effect.
Although post-transplant AKI is more commonly seen in patients
with high TAC concentrations, long-term renal complications are
rare. These data highlight the importance of optimizing the initial
dosing of TAC in RIC HSCT recipients. Prospective confirmation of
our findings is warranted.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
This work was supported by a Career Development Award from the Conquer Cancer
Foundation (RR); Amy Strelzer Manasevit Award from the National Marrow Donor
Program (RR); National Institutes of Health grants K23-CA178202 (RR) &
U01-HL069286 (DLP), and the Margie and Andy Rooke Fund for Leukemia Research
(RR and DLP). We thank Oren Litvin for help with preparation of the figures.
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