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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5212_Библиотеки_им_академика_М_И_Перельмана.pdf
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Minimization of Immunosuppression in Heart Transplantation
David H. Chang and Yosef Manla
14
Abstract
The sequelae of rejection post-heart transplant (HTx) impact the quality of life as well
as short- and long-term survival. The goal
of optimal immunosuppression therapy after
HTx is to achieve a state of immune quiescence, preventing rejection of the donor heart
graft while minimizing immunosuppression
complications. Despite advancements in the
field of immunosuppression, a regimen that
leads to prolonged survival and yet is void
of associated morbidity, including infection,
malignancy, and drug-related toxicities, has
not been identified. Patients without elevated
immunologic risk features may benefit from
minimization of immunosuppression after
HTx. In this chapter, we discuss various
management approaches to minimize immunosuppression for HTx recipients, including
prednisone weaning, calcineurin inhibitors
(CNI) minimization, use of proliferation signal inhibitors (PSI) to reduce or replace CNI,
tacrolimus monotherapy, in addition to leveraging novel assays (e.g., T cell immune
D. H. Chang (*) · Y. Manla
Cedars-Sinai Smidt Heart Institute, Los Angeles,
CA, USA
e-mail: David.chang2@cshs.org
Y. Manla
e-mail: Yosef.manla@cshs.org
function assay), artificial intelligence, and
precision medicine to personalize immunosuppression therapy.
Keywords
Calcineurin inhibition · Anti-metabolite ·
Corticosteroid · Prednisone wean ·
Proliferation signal inhibitor · Precision
medicine · Co-stimulation blockade
Clinical Pearls
• The goal of maintenance immunosuppression
is immune system quiescence and prevention
of allograft rejection and dysfunction.
Three major adverse clinical outcome seque-
•
lae of calcineurin inhibitor (CNI) based
immunosuppression are infection, nephrotoxicity, and malignancy.
• Due to the long-term side effects of CNIs,
CNI-reduced and CNI-free maintenance
immunosuppression regimens are used in
low-risk patients.
• Corticosteroid weaning is a common strategy
of immunosuppression minimization.
• The proliferation signal inhibitors (PSI)
everolimus and sirolimus can be effectively
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2025
J. Kobashigawa (ed.), Clinical Guide to Heart Transplantation, https://doi.org/10.1007/978-3-031-88290-6_14
171
172 D. H. Chang and Y. Manla
used to lower maintenance immunosuppression in select patients.
• Tacrolimus monotherapy can be used with
acceptable outcomes in low-risk heart transplant recipients with severe infection or significant medication intolerance.
Introduction
The sequelae of rejection post-heart transplant (HTx) impact the quality of life as well
as short- and long-term survival [1, 2]. The
goal of optimal immunosuppression therapy
after HTx is to achieve a state of immune quiescence, preventing rejection of the donor
heart graft while minimizing immunosuppression complications [1]. Despite advancements
in the field of immunosuppression, a regimen
that leads to prolonged survival and yet is void
of associated morbidity, including infection,
malignancy, and drug-related toxicities, has not
been identified. Additionally, there is no standard combination of medications for maintenance immunosuppression after HTx, and each
patient’s immunosuppression is individualized.
For maintenance immunosuppression, most
patients are prescribed a combination of calcineurin inhibitor (tacrolimus), anti-metabolite
(mycophenolate mofetil, MMF), and corticosteroid [3–8]. Similarly, there is no set standard
of care with respect to induction therapy at the
time of HTx. Approximately 50% of patients
are treated with induction therapy at the time of
HTx [9]. Induction therapy is generally applied
to patients at higher risk of graft rejection and
patients with renal insufficiency [10]. Patients
at elevated immunologic risk who need heightened surveillance and more intense immunosuppression include patients who are sensitized
pre-transplant, developed post-transplant cardiac
dysfunction, developed de novo donor-specific
antibodies (dn-DSA), and patients with rejection. Patients without these features are considered immunologically low risk and may benefit
from minimization of immunosuppression after
HTx.
Sequelae of Immunosuppression
Immunosuppression side effects and complications can impact morbidity and mortality after
solid organ transplantation. Drug-specific side
effects and morbidity lead clinicians to minimize, as permitted, maintenance immunosuppression to improve patient symptoms and
reduce the impact of maintenance immunosuppression. Three major adverse clinical outcome
sequelae of immunosuppression include infection, renal insufficiency, and malignancy [9, 11,
12]. Infection is the cause of death in ~30% of
HTx recipients from 1 month to 1-year posttransplant and the cause of death in ~10% of
patients from 10 to 15 years post-transplant [9,
11, 12]. Renal insufficiency defined as creati-
nine > 2.5 mg/dL, dialysis or renal transplant
was recorded in 8.6, 18.4, and 29.2% in survivors within 1-, 5-, and 10-years post-transplant
[9, 11, 12]. Malignancy is the long-term leading
cause of death after HTx, accounting for ~20%
of deaths 3 years and afterward post-transplant
[9, 11, 12]. Additionally, immunosuppression, including corticosteroids, contributes to
hypertension and hyperlipidemia. Additional
corticosteroid complications include glucose
intolerance/diabetes, obesity, osteoporosis, avascular necrosis, cataracts, glaucoma, myopathy,
Cushingoid features, and neuropsychiatric issues
[13, 14].
Minimization of Immunosuppression Strategies
Standard Maintenance Immunosuppression
Calcineurin inhibitors (CNI) remain foundational to the maintenance of immunosuppression to prevent allograft rejection, particularly
in the earliest phase after HTx. Trough levels
are assessed and maintained in pre-specified
target levels that are highest in the first month
after transplant and tapered to steady-state
14 Minimization of Immunosuppression in Heart Transplantation
173
levels 3 months after HTx. In our clinical practice, tacrolimus trough levels can be targeted to
10–15 ng/dL in the first month, 8–12 ng/dL in
the second and third months, and 5–10 ng/dL
after month 3. Mycophenolic acid (active metabolite of MMF) trough levels are not commonly
tested as the dose of this medication is based on
tolerance. Common side effects include nausea
and/or diarrhea, leukopenia, anemia, and thrombocytopenia. Optimal target dose (based on
clinical trial data) for MMF is 1500 mg twice
daily [15].
In this chapter, we discuss various manage-
ment approaches to minimize immunosuppression for HTx recipients, including prednisone
weaning, CNI minimization, use of proliferation
signal inhibitors (PSI) to reduce or replace CNI,
tacrolimus monotherapy, in addition to leveraging novel assays (e.g., T Cell Immune function
assay), artificial intelligence, and precision medicine to personalize immunosuppression therapy
(Fig. 14.1).
Prednisone Weaning
A commonly used strategy for minimization
of immunosuppression is corticosteroid weaning. After HTx, high-dose IV steroids, including solumedrol, are routinely administered and
transitioned to oral steroids. Per the most recent
ISHLT guidelines for the care of HTx patients,
corticosteroid withdrawal protocols can be used
3–12 months after HTx in low-risk patients to
minimize steroid side effects [2]. An example of
corticosteroid withdrawal is what follows. After
an oral steroid taper, prednisone 10 mg twice
daily is given for up to 1 month post-HTx. This
dose is slowly weaned such that by 3 months
post-transplant, prednisone is weaned to 10 mg
daily, and by 6 months post-transplant, prednisone is weaned to 5 mg daily. Patients at low
immunologic risk may then reduce prednisone
slowly to off by weaning prednisone by 1 mg
monthly until prednisone is stopped close to a
year after HTx [10]. Asymptomatic rejection is
Fig. 14.1 Management approaches to minimize immunosuppression for heart transplant recipients
174 D. H. Chang and Y. Manla
possible during a prednisone weaning period,
so routine surveillance is recommended either
by endomyocardial biopsy or by non-invasive
diagnostic tests (e.g., genome expression profiling donor-derived cell-free DNA). Patients often
experience symptoms of fatigue, myalgias, and
arthralgias during the process of a prednisone
wean to off protocol. Some studies have effectively directed a more rapid prednisone wean.
In the Tacrolimus In Combination, Tacrolimus
Alone Compared (TICTAC) trial, patients were
weaned off steroids approximately 8–9 weeks
post-HTx with acceptable outcomes [16].
Patients with cardiac sarcoidosis, for example,
who require HTx, should be maintained on lowdose corticosteroids to prevent recurrent disease
[17, 18].
Calcineurin Minimization
Due to the dose and time-dependent deterioration of renal function with CNI and the longterm risk of malignancy, efforts have been made
to reduce calcineurin exposure or withdraw and
replace the CNI with a different immunosuppressant agent. Predominantly due to the use of
CNI, chronic renal failure [defined as glomerular filtration rate (GFR) < 30 ml/minute or the
development of end end-stage disease (ESRD)]
has been reported in approximately 10% of HTx
recipients over 5 years after transplant [19]. The
overall hazard ratio of 4.5 has been reported for
increased risk of death in patients with chronic
renal failure over the follow-up period [19]. For
patients who undergo induction therapy at the
time of HTx, there are two medications most
commonly used, which include the IL2 receptor
antagonist basiliximab and the polyclonal antithymocyte globulin (ATG). Basiliximab is given
on days 0 and 4 post-HTx, and ATG is dosed at
1.5 mg/kg for 3–7 days post-HTx. Both thera-
pies can allow for the delay of CNI initiation
[20, 21]. ATG may be more potent than basiliximab, but it may carry a higher risk of infection
[22]. Clinical trials have shown that in patients
who receive ATG induction with maintenance
immunosuppression, including cyclosporine and
MMF, lower target cyclosporine levels can be
maintained, resulting in improved renal function
without increased risk of rejection [23, 24].
Use of Proliferation Signal Inhibitors to Reduce or Replace Calcineurin Inhibitors
PSI including sirolimus and everolimus, can be
used as maintenance immunosuppression with
CNI to allow lower target doses of CNI or as an
alternative medication in place of CNI. Clinical
trials of PSI show improvements in cardiac allograft vasculopathy and renal function (in the
absence of CNI). PSI intolerances overlap with
MMF intolerance and include GI disturbance
(nausea and/or diarrhea). Additional PSI intolerances include fluid retention, abdominal bloating, lower extremity edema, and oral aphthous
ulcers. Approximately 10–35% of patients who
trial PSI do not tolerate these medications due to
medication side effects and need to revert back
to prior immunosuppression medical treatments
[25, 26]. Risks of PSI treatment include a higher
risk of fungal infection, deep vein thrombosis/pulmonary embolism (DVT/PE), nephrotic
range proteinuria, pneumonia, and pneumonitis
[25, 26].
PSIs can be used to reduce or replace CNI
in a CNI-free regimen to potentially reduce
long-term nephrotoxicity. PSI may also help
minimize immunosuppression in patients with
post-transplant lymphoproliferative disorder
(PTLD), minimize the severity of malignancies,
including skin cancer, and theoretically reduce
the long-term risk of malignancy [10]. Sirolimus
or everolimus can replace the anti-metabolite
agent (usually MMF) for patients that have had
a history of cytomegalovirus infection (CMV)
or are CMV mismatch patients (donor CMV+/
recipient CMV- status), patients with donorspecific antibodies, or patients with a history of
recurrent treated rejection post HTx [10]. Initial
efforts to replace CNI with the PSI sirolimus
after one year post-HTx showed that in patients
with moderate renal impairment, there was
an improvement in renal dysfunction without
17514 Minimization of Immunosuppression in Heart Transplantation
increased rates of rejection with PSI compared
to patients continued on CNI [27–29]. In the
Nordic Certican (Everolimus) Trial in heart and
lung Transplantation (NOCTET) trial, standard
CNI-based immunosuppression was compared
to everolimus with reduced dose CNI in thoracic transplant patients more than one year after
transplant [30]. 282 patients were randomized in
this multi-center trial. The primary endpoint of
change in mean GFR was met in the everolimus
group without a significant increase in rejection compared to the control CNI-based group.
Infections, including pneumonia, were significantly higher in the PSI group.
Initial efforts to replace CNI with PSI early
post-HTx were not successful and were terminated. The Heart Save the Nephron multicenter
randomized trial examined CNI withdrawal and
replacement with sirolimus at 12 weeks. MMF
and steroids were also used in maintenance of
immunosuppression. The trial was terminated
early as more than half of the seven patients randomized to PSI experienced significant cellular
rejection, including one patient with hemodynamic compromise [31]. The Scandinavian HTx
everolimus de novo study with early calcineurin
inhibitor avoidance (SCHEDULE) trial included
115 patients and was a subsequent attempt at
early conversion to a PSI-based regimen in
patients after HTx [32]. In this randomized,
open-label trial, ATG induction was used in all
patients. Patients were randomized to low-dose
everolimus (3–6 ng/ml) with low-dose cyclosporine in addition to MMF and corticosteroids
or to a control group of standard-dose cyclosporine, MMF and corticosteroids. Between 7
and 11 weeks, cyclosporine was withdrawn, and
everolimus was adjusted to target a trough level
of 6–10 mg/ml in the everolimus group. The primary endpoint of GFR at 1-year post-transplant
was significantly increased in the everolimus
group. Intravascular ultrasound (IVUS) data
at 1-year cardiac catheterization showed a significantly lower incidence of cardiac allograft
vasculopathy (CAV) in the everolimus group.
However, biopsy-proven rejection was higher
in the everolimus arm at 1-year post-HTx but
left ventricular function was similar between
the two groups. There were higher rates of cellular rejection in the everolimus group but similar left ventricular ejection fraction between the
two groups. The frequency of adverse and serious adverse events was higher in the everolimus
group. There were more deaths in the CNI group
compared to the PSI group. The SCHEDULE
trial demonstrated that early CNI withdrawal
is possible with everolimus with favorable
effects on GFR and CAV, but rejection rates
were higher in the PSI arm but did not lead to
increased morbidity/mortality (compared to the
CNI arm). Long-term follow-up data from the
SCHEDULE trial showed similar improvements
in GFR and CAV in the everolimus group [33].
The optimal time frame to attempt to include
PSI in chronic maintenance immunosuppression
after a HTx is unknown. Recent ISHLT guidelines indicate that PSI use with CNI-reduced
based maintenance immunosuppression can be
considered cautiously if done after 3 months of
HTx [2]. For low-risk patients with chronic kidney disease, substitution of PSI for CNI can be
considered to reduce CNI-related nephrotoxicity. Due to the risk of proteinuria with PSI-based
chronic immunosuppression, regular assessment of proteinuria should be completed [34].
PSI-based regimens (CNI-free) have shown
increased rates of cellular rejection in clinical
trials, so doses of MMF < 500 mg BID should
be minimized, and patients in CNI-free maintenance immunosuppression regimens should have
close monitoring of rejection [35].
Tacrolimus Monotherapy to Minimize Immunosuppression
A different approach to immunosuppression
minimization shown to be feasible is to use tacrolimus as monotherapy. In the TICTAC trial,
150 adult de novo HTx recipients were enrolled
in a prospective, randomized, controlled, openlabel study [16]. Induction therapy was, for the
most part, not utilized. All patients received tacrolimus and MMF immediately after HTx. In
the tacrolimus alone arm, MMF was weaned to
off by 2 weeks post HTx. All patients received
176 D. H. Chang and Y. Manla
steroids post-transplant, which were weaned off
by 8–9 weeks post-transplant. Tacrolimus trough
levels were targeted in the 8–10 mg/dL range.
MMF target dose was 1000 mg twice daily if
tolerated. There were no significant differences
in a composite biopsy score at 6 months, CAV
by angiography and IVUS, or survival at 3 years.
Angiography was completed at 3–6 months and
yearly thereafter. Recently published long-term
outcomes of the TICTAC trial revealed comparable post-transplant survival rates at 5, 10, and
15 years in the Tacrolimus monotherapy group
and patients randomized to tacrolimus / MMF
(84.5, 66.9, and 52.7, and 94.4, 78.2% and 56.1,
respectively, p = 0.19 log-rank). Similar rates
of CAV and kidney failure were also recorded
[36]. The TICTAC trial showed that tacrolimus
without MMF or steroids was feasible in the prespecified tacrolimus target range. Tacrolimus
monotherapy can be considered in patients
with intolerable side effects with anti-metabolic
agents, severe infection, or significant corticosteroid side effects [37]. In the TACTFUL trial,
Pearston et al. evaluated the outcomes among
patients converted to tacrolimus monotherapy
compared with those maintained on combination immunosuppression. Leukopenia, infection,
and gastrointestinal distress were the most common reasons for conversion. No differences in
mortality or acute cellular rejection rates were
noticed between groups [38].
Personalizing Immunosuppression
T Cell Immune Function Assay
To further individualize maintenance immunosuppression, the T cell immune function assay
(ImmuKnow, Viracor Eurofins, Lee’s Summit,
MO, USA) is approved by the Food and Drug
Administration (FDA) of the United States for
monitoring [39]. Lymphocytes are isolated,
stimulated with phytohemagglutinin, lysed, and
adenosine triphosphate (ATP) release measured
via spectroscopic analysis. An overall sense of
immune function can be quantified. The test is
less reliable in patients with leukopenia. Per the
manufacturer’s guidelines, low values (<200 ng/
ml) suggest higher risk of infection [40]. One
study showed elevated early ImmunKnow values were associated with increased plaque progression by intravascular ultrasound, consistent
with increased risk for cardiac allograft vasculopathy [40, 41]. A validation study demonstrated that a score of 380 ATP ng/ml reflected
the intersection of the odds ratio curves for
infection and rejection with 200–550 ATP ng/
ml representing a therapeutic range for overall
immunosuppression [42]. Immunosuppression is
adjusted primarily with low T cell immune function values; one can individualize immunosuppression to each patient and consider lowering
the dose of an immunosuppressant agent particularly in patients with infections and malignancies. Of note, immunosuppression trough
levels do not correlate well with ImmunKnow
values, supporting the concept that additional
data can be used to refine our immunosuppressive management of individual patients.
Role of Precision Medicine
and Articial Intelligence to Minimize
Maintenance Immunosuppression
The potential for personalized precision medicine could further refine and minimize each
HTx recipient’s immunosuppression. Currently,
patients have their maintenance immunosuppression adjusted based on a pre-dose trough
concentration level (C
Monitoring of cyclosporine levels 2 h postadministration (C2) was observed to allow lower
CNI dosing while maintaining adequate immunosuppression in stable HTx recipients over
a year post-HTx and in de novo HTx patients
with basiliximab induction [43, 44]. However,
the timing of obtaining C2 blood samples is not
always practical. There is the possibility for further precision medicine refinements in this area
in the future [45]. Pharmacogenetic testing of a
HTx recipient’s cytochrome p450 system, specifically CYP3A5 and CYP3A4 can influence
) of individual drugs.
0
17714 Minimization of Immunosuppression in Heart Transplantation
initial tacrolimus dosing to facilitate earlier
time to therapeutic tacrolimus levels after HTx.
Novel pharmacodynamic biomarkers, including nuclear factor of activated T cells (NFAT)regulated gene expression and intracellular
gamma-interferon, may be useful to guide CNI
dosing and therapy. Furthermore, using evolutionary algorithms, neural networks, and other
artificial intelligence (AI) techniques that have
been trained in predicting drug levels and outcomes in transplant patients can play a potential role in predicting and adjusting dosages of
immunosuppressive agents [46].
Future Directions to Minimize Immunosuppression
Future directions to minimize and optimize
maintenance immunosuppression after HTx
may include other T cell-directed therapies and
non-T cell maintenance immunosuppression
with novel therapeutics. Belatacept is a selective T-cell co-stimulation blocker formed by
the fusion of the Fc component of human IgG1
to the extracellular portion of human CTLA-4.
Based on the use of belatacept in renal transplant patients and limited experience in HTx
recipients, there are ongoing clinical trials with
belatacept in HTx recipients [47, 48]. Non-T
cell targets of immunosuppression include
aspects of both the innate and adaptive immune
systems. Complement inhibition with the use of
eculizumab in addition to ATG induction allows
for HTx in highly sensitized HTx recipients with
acceptable outcomes (49). Until more novel
therapeutics are developed, there will continue
to be a number of competing interests in individualizing and minimizing maintenance immunosuppression for each HTx recipient.
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