Transcript Slide 1

DoH IVIG Workshop
Update on usage in Transplantation
and outcomes measurement
Haifa Lyster
Consultant Pharmacist – Transplant & VADs
Royal Brompton & Harefield NHS Foundation Trust
Overview
• Changes in Transplant indications in 2nd
edition
– Previously mostly grey indications
• Agreed outomes
Previous classification of
Transplant indications
Updated ‘blue’ INDICATIONS
FOR TRANSPLANTATION
•
•
•
•
Antibody Incompatible Transplants
Antibody Mediated Rejection (AMR)
Viral pneumonitis (eg varicella, RSV,
adenovirus)
T cell mediated rejection (TCR)
–
–
Steroid resistant, or
where steroids are not appropriate
• There are no reports of the
chronic use of IVIg to treat any of
these indications (although
patients may have repeated
episodes of AMR), so IVIg is not
used as a chronic or maintenance
therapy in these conditions
Antibody Incompatible
Transplants
• As adjunctive therapy in conjunction
with
immunoadsorption/plasmapheresis +/rituximab
• Dosage is variable:
– upto 2g/kg to be repeated as per DSA
measurements,
– in renal desensitisation 100mg/kg (8-12 courses)
Jordan SC et al. Evaluation of intravenous
immunoglobulin as an agent to lower allosensitization
and improve transplantation in highly sensitized adult
patients with end-stage renal disease: report of the NIH
IG02 trial. J Am Soc Nephrol. 2004 Dec;15(12):3256-62.
Conclude that IVIG is better than placebo in
reducing anti-HLA antibody levels and
improving transplantation rates in highly
sensitized patients with ESRD. Transplant rates
for highly sensitized patients with ESRD
awaiting kidney transplants are improved with
IVIG therapy
Glotz D et al. Desensitization and
subsequent kidney transplantation of
patients using intravenous
immunoglobulins (IVIg). Am J
Transplant. 2002 Sep;2(8):758-60.
• IVIg therapy allows safe and prompt kidney
transplantation of immunized patients
• These protocols thus demonstrate that the presence
of anti-donor antibody, once an absolute contraindication to transplantation, can, nowadays, be
considered as an immunological hurdle that can be
managed through appropriate immunological
manipulation
Jordan et al. Desensitization therapy with
intravenous gammaglobulin (IVIG): applications
in solid organ transplantation. Trans Am Clin
Climatol Assoc. 2006;117:199-211
• These advancements have enabled
transplantation of patients previously
considered untransplantable and in
concert with new diagnostic techniques
has resulted in new approaches to
management of AMR
N Engl J Med. 2008 Jul 17;359(3):242-51.
Rituximab and intravenous immune globulin
for desensitization during renal
transplantation.
Vo AA et al.
• These findings suggest that the combination of
intravenous immune globulin and rituximab may
prove effective as a desensitization regimen for
patients awaiting a transplant from either a living
donor or a deceased donor. Larger and longer trials
are needed to evaluate the clinical efficacy and safety
of this approach
Tyan DB, Li VA, Czer et al 1994, Intravenous
immunoglobulin suppression of HLA alloantibody in
highly sensitised transplant candidates and
transplantation with a histoincompatible organ.
Transplantation 57(4) 553-562.
More impressively, successive in vivo administration of
IVIG to a sensitized (anti-HLA-A2, A68, A69; B57,
B58) heart transplant candidate resulted in
successful transplantation with an A2+
histoincompatible heart
Danskine AJ, Smith JD, Pottle A, Lyster H, Carby M,
Banner NR, Rose ML, The effect of immunadsorption
therapy on HLA antibody levels and clinical response
after thoracic organ transplantation. 2006 Human
Immunology, 67(suppl 1):S27
• Antibody Incompatible Transplantation,
British Transplantation Society 2006.
www.bts.org.uk
Antibody Incompatible Transplants –
agreed outcome measures
• Thoracic
– Measuring Donor
Specific Antibodies
(DSA) and correlating
to clinical outcomes
– Patient survival
– Length of stay (ITU &
hosp)
– Graft function
(EF/spirometry)
• Renal
– Type of renal
transplant
– HLA class DSA
– Rejection episodes
– Patient survival
– Allograft survival
– Renal function eg
eGFR (MDRD)
Antibody Mediated Rejection (AMR)
• Antibody mediated rejection (AMR) of solid organ
transplants leads to inevitable failure of the transplanted
organ if it is not reversed. There are no reports of
spontaneous recovery from AMR, and graft failure leads to
death in the recipients of life-sustaining grafts (heart, lung,
liver) and return to dialysis with associated significant
decrease in life expectancy and quality in kidney transplant
recipients
• As adjunctive therapy in conjunction with
immunoadsorption/plasmapheresis +/- rituximab
• Dosage is variable:
– upto 2g/kg to be repeated for 2-3 cycles
Jordan SC, Quartel AW, Czer LS et al, 1998
Post-transplant therapy using high-dose
immunoglobulin (intravenous
gammaglobulin) to control acute humoral
rejection in renal and cardiac allograft
recipients and potential mechanism of action.
Transplantation 66(6) 800-805.
• IVIG appears to be an effective therapy to control
posttransplant AR episodes in heart and kidney
transplant recipients, including patients who have
had no success with conventional therapies.
Vascular rejection episodes associated with
development of donor-specific cytotoxic antibodies
appears to be particularly responsive to IVIG
therapy.
Montgomery RA, Zachary AA, Racusen LC, et al.
Plasmapheresis and intravenous immune globulin provides
effective rescue therapy for refractory humoral rejection and
allows kidneys to be successfully transplanted into cross-matchpositive recipients. Transplantation 2000; 70: 887-95
• In this study, seven patients for whom the combined
therapies of PP/IVIG were successful in reversing AHR
mediated by Ab specific for donor HLA antigens.
Furthermore, this protocol shows promise for eliminating
DSA preemptively among patients with low-titer positive
antihuman globulin-enhanced, complement-dependent
cytotoxicity (AHG-CDC) cross-matches, allowing the
successful transplantation of these patients using a live
donor without any cases of HAR
Pottle A, Lyster H, Danskine AJ, Rose ML,
Banner NR, The Management of Acute
Antibody-Mediated Rejection after heart
Transplantation. 2007 British journal of
Transplantation 2(1):10-15
• Case report illustrating the many challenges
posed by acute AMR after heart
transplantation. Treatment included IVIG.
• A number of different therapeutic options are
available and a combination of these is often
required.
Antibody Mediated Rejection (AMR)
– agreed outcome measures
• Thoracic
– Measuring Donor
Specific Antibodies (DSA)
and correlating to clinical
outcomes
– Patient survival
– Length of stay (ITU &
hosp)
– Graft function (EF /
Spirometry)
• Renal
– C4d staining, HLA
class DSA, rejection
episodes
– Patient survival
– Allograft survival
– Renal function eg
eGFR (MDRD)
Viral pneumonitis (eg varicella, RSV,
adenovirus)
• Adjunctive therapy (antiviral eg aciclovir,
ribavirin as appropriate)
• Dose: 0.5g/kg for 5 days
• Champlin RE, Whimbey E, Community respiratory virus
infections in bone marrow transplant recipients: The MD
Anderson Cancer Center Experience, Biology of Blood and
Marrow Transplantation 2001, 7 suppl, 8S-10S
– For BMT recipients with respiratory syncytial virus URTIs, treatment
with ribavirin and intravenous immunoglobulin may be helpful in
preventing progression to pneumonia and thus in reducing mortality,
but this approach requires confirmation in controlled clinical trial
Carby M, Jones A, Burke M, Hall A, Banner NR, Varicella
infection after heart and lung transplantation: A singlecenter experience, Journal of Heart and Lung
Transplantation 2007; 26(4):399-402.
• Disseminated varicella-zoster virus infection after organ
transplantation in adults is a rare but serious event causing
significant morbidity and mortality. We describe our 10-year
experience of 13 cases in a single center, including risk factors
for infection, lack of protection from pre-existing antivaricella-zoster virus antibodies, and unusual modes of
presentation, including disseminated intravascular
coagulation. We also report our preliminary observation of
resolution of infection without sequelae in 4 patients with
severe disseminated varicella-zoster virus infection who were
treated with the combination of intravenous acyclovir and
polyspecific intravenous immunoglobulin
Viral pneumonitis (eg varicella, RSV,
adenovirus)– agreed outcome measures
•
•
•
•
•
Virus type
Reversal of radiological change
Length of stay
Survival (30 and 90 days, 1 year)
Lung function - return to baseline? (RFTs,
spirometry)
• Need for respiratory support inc ABGs (CPAP,
NIV, Invasive ventilation)
T cell mediated rejection (TCR) - Renal
• Conventional approach involves the use of corticosteroids and
antiproliferative agents (mycophenolate). Occasionally we may encounter
a patient in which the rejection episode is resistant to steroids or there is a
desire to avoid steroid therapy due to patient co-morbidities.
• There is one randomized controlled trial comparing steroid resistant TCR
with a more conventional therapy – the anti-T cell antibody muromonab,
OKT3, [Casadei et al. Transplantation 2001]. It showed identical graft
survival in both groups [11/15 in IVIG receiving vs 13/15 in OKT3 receiving;
p0.79] with no difference in creatinine or patient survival. IVIG was better
tolerated in this study, and although not reported has not been associated
with infections or increased long term malignancy risk as with polyclonal
antibodies [Bustami RT, Ojo AO et al. AJT 2004; 4(1): 87].
• IVIG has been shown to be useful when high dose steroids are
contraindicated [Moger V et al. Transplantation 2004. 77(9): 1455] due to
co-morbidities
T cell mediated rejection (TCR) – Renal
Dosage & outcomes measures
Dosage: 2 doses of 1g/kg
administered post plasma exchange
Outcomes:
–Patient survival
–Allograft survival
–Renal function eg eGFR (MDRD)
Single centre experience
(cardiothoracic transplantation)
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14
12
10
8
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2
0
AMR
Viral
Pneumonitis
AIT
Draft immunoglobulin measures
Options
9
10
11
12
Measure
100% of patients receiving
immunoglobulin for
designated short term
conditions must be reregistered on the national
database if retreatment is
required
Patients receiving
immunoglobulin for
designated short term
conditions should have
their outcomes reported on
the national database
Patients who are receiving
immunoglobulin for a long
term condition should have
their dose and/or dosing
frequency reviewed on an
at least annual basis
100% of patients receiving
immunoglobulin for
designated grey and grey
unlisted indications should
have been reviewed and
approved by a
multidisciplanary panel
before commencing on
immunoglobulin therapy
Measurement definition
Number of patients receiving
immunoglobulin for designated
short term conditions who are reregistered on the national
database
Number of patients receiving
immunoglobulin for designated
short term conditions who have
outcomes reported on the national
database
Numerator
Number of patients receiving
immunoglobulin for
designated short term
conditions who are reregistered on the database
Number of patients receiving
immunoglobulin for
designated short term
conditions whose outcomes
are documented on the
national database during the
quarter when outcomes
should be documented
Number of patients who are
Number of patients who are
receiving immunoglobulin for a
receiving immunoglobulin for
long term condition who have
a long term condition who
documented evidence of dose
have documented evidence
reduction and/or increased dosing of a dose reduction and/or
interval
increased dosing interval
Patients receiving immunoglobulin Patients receiving
for designated grey and grey
immunoglobulin for
unlisted indications who have
designated grey and grey
been reviewed and approved by a unlisted indications who have
multidisciplanary panel before
been reviewed and approved
commencing on immunoglobulin by a multidisciplanary panel
therapy
that is documented on the
national database before
immunoglobulin therapy is
commenced
Denominator
Number of patients
receiving
immunoglobulin for
designated short term
conditions who require
retreatment
Number of patients
receiving
immunoglobulin for
designated short term
conditions whose
outcomes are due to be
documented during the
quarter
Number of patients who
are receiving
immunoglobulin for a
long term condition
Patients receiving
immunoglobulin for
designated grey and
grey unlisted indications
who have been
registered on the
national database
Draft immunoglobulin measures
Options
13
14
15
Measure
100% of patients receiving
immunoglobulin for
designated grey and grey
unlisted indications have
had their panel
recommendation confirmed
for funding by the relevant
commissioner before
commencing on
immunoglobulin therapy
Measurement definition
Numerator
Denominator
Number of patients receiving
Number of patients receiving Number of patients
immunoglobulin for designated grey immunoglobulin for designated receiving immunoglobulin
and grey unlisted indications who grey and grey unlisted
for designated grey and
have had their panel
indications who have
grey unlisted indications
recommendation confirmed for
documented evidence that the
funding by the relevant
panel recommendation has
commissioner before commencing received confirmation for
on immunoglobulin therapy
funding by the relevent
commissioner before
commencing on
immunoglobulin therapy
Patients on long term
Number of patients who are on long Number of patients who are on Number of patients who
therapy for PID should have term immunoglobulin therapy for
long term immunoglobulin
are on long term
trough immunoglobulin
PID who have quarterly trough
therapy for PID who have
immunoglobulin therapy
levels measured on a
immunoglobulin levels measured quarterly trough
for PID
quarterly basis
immunoglobulin levels
documented
Patients on long term
Number of patients on long term
Number of patients on long
Number of patients on
immunoglobulin therapy for immunoglobulin therapy for a
term immunoglobulin therapy long term immunoglobulin
a neurological condition
neurological condition who have
for a neurological condition
therapy for a neurological
should have objective
objective measures of improvement who have objective measures condition
improvement measured on documented
of improvement documented
an annual basis
10 minutes to comment on draft measures
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