IPD based meta-analysis Powerpoint

Report
Impact of ABO mismatching on
the outcomes of allogeneic BMT:
IPD based meta-analysis
Elianna Saidenberg
November 2009
A brief introduction to HSCT
•
•
•
What is bone marrow?
What are hematopoietic stem cells?
What is the purpose of transplantation?
–
Solid organ transplantation
•
–
For treatment of organ dysfunction or failure
Hematopoietic stem cell transplantation
•
High dose chemotherapy +/- radiation eradicate the
malignant clone or abnormal marrow but also results in
bone marrow ablation. Transplanted marrow repopulates
the marrow with normal cells.
Do these tissues match?
• Major Histocompatibility
Complex (MHC) and Human
Leukocyte Antigens (HLA)
• MHC genes (on chromosome
6) encode human leukocyte
antigens and a variety of cell
surface markers, antigenpresenting molecules, and
other proteins which allow
immune recognition of self and
non-self
• MHC genes are inherited as a
group (haplotype), one from
each parent. Thus, a
heterozygous human inherits
one paternal and one maternal
haplotype, each containing
three class-I (B, C and A) and
three class II (DP, DQ and DR)
loci
• Engraftment
– Resumption of function by the transplanted organ or
tissue
• Rejection
– A problem in solid organ transplant (rarely in BMT)
– Host’s immune system recognizes transplanted organ
as foreign and attacks it
• “Host-versus-graft disease”
• Graft-versus-host disease (GVHD)
– A problem in BMT, never in SOT
– Donor immune system recognizes all host tissues as
foreign and attacks them
• The closer the HLA match the less the risk of
rejection and GVHD
• Graft-versus-tumour effect
– Donor immune system recognizes host’s tumour cells
as foreign and removes them too
You mean there is more than one
kind of bone marrow transplant?
• Syngeneic- From an identical twin
• Allogeneic- From an HLA matched donor
– MRD- Matched related donor
– MUD- Matched unrelated donor
• Autologous- Patients own stem cells are
harvested before high dose chemotherapy and
are later re-infused.
– Not a curative therapy
• Reduced intensity transplantation
– Recipient bone marrow not completely ablated before
transplantation of donor marrow
– Relies on GVT effect
You mean there are even more
kinds of BMT?
• Bone marrow source
– HSC are harvested from a large bone of the donor, through a
large needle that reaches the center of the bone, performed
under general anesthesia
• PBSCT
– Donor stem cells harvested by apheresis procedure after G-CSF
therapy to boost levels of peripheral blood stem cells
• Umbilical cord blood
– Cord blood has a higher concentration of HSC than is normally
found in adult blood. Stem cells are harvested at time of delivery
• Dose of stem cells low, adult cord blood BMTs usually requires 2
cords
• Lesser degree of HLA matching possible compared to other sources
of stem cells
Causes of mortality and morbidity
in BMT
• Treatment related morbidity/mortality (TRM)
– Chemotherapy/ radiation toxicities
• Includes secondary malignancies
– Complications related to cytopenias (infection, bleeding,
anemia)
– Veno-occlusive disease causing severe liver dysfunction
– GVHD
• Acute GVHD occurs in the first 3 months after transplantation and
may involve the skin, intestine, or the liver, and is often fatal.
• Chronic GVHD is the major source of late treatment-related
complication. Can lead to the development of fibrosis causing
functional disability
• High-dose corticosteroids are the mainstay of treatment but
increase risk of infection
– Drug side effects
• Drugs needed to prevent GVHD include cyclosporine, MMF
• All have serious side effects (ie HTN, ARF. TTP)
• Disease relapse
ABO incompatibility in BMT
• Genes for ABO groups and for HLA are
inherited independently
• ABO incompatibility may occur in 20-40%
of HLA-matched allogeneic SCT
• ABO incompatibility between donor and
recipient is NOT considered a
contraindication to transplantation
Major ABO Incompatibility
• Donor ABO antigens are not compatible with
recipient’s immune system
– Example: Donor is group A, recipient is group B or
group O and hence has anti-A in his or her serum
• Can have acute hemolysis due to lysis of incompatible RBCs
contained in the graft
– Purge grafts of RBCs
– Plasmapheresis may be effective in reducing the anti-donor
hemagglutinin in the recipient plasma with a goal to reduce the titer to
1:16 or lower
• Known complications
– Pure red cell aplasia
– Delayed donor RBC engraftment
• Anti-A and anti-B remain demonstrable in the recipient’s plasma for
some months
Minor ABO Incompatibility
• Recipient ABO antigens are not compatible
with donor’s immune system
– Hence, the donor’s B cells capable of making
antibodies directed at recipient’s RBCs
• Hemolysis may develop 1-2 weeks after transplant
– Due to lysis of ABO-incompatible recipient cells as the donor
lymphocytes engraft
– Reactions are most common and most severe when the donor is group
O and the recipient group A
Bidirectional Incompatibility
• Recipient isohemagglutinins directed against
donor RBCs and contrariwise
– Occurs in 3-5% of alloSCT
– Example: Donor is group A, recipient is group B
– Potential complications
•
•
•
•
Hemolysis of RBCs in graft
Hemolysis of recipient RBCs by passively transfused antibody,
Hemolysis of RBCs produced by graft
PRCA
• Special considerations in ABO incompatible
transplant:
– During preparatory regimen transfused blood should
be compatible with both donor and recipient
• In bidirectional incompatibility (major-minor) only group O
cells should be transfused
• It may be prudent to give plasma reduced platelet
transfusions
• IVIg should be avoided during the post-transplant period as it
contains variable titres of red cell antibodies (esp anti-A)
Recipient blood
group
Donor
Transfused
RBCs
Transfused
Platelets
Transfused
FFP
A
B
O
Any
AB
A
O
O
Any
A
A
AB
O,A
Any
AB
B
A
O
Any
AB
B
O
O
Any
B
B
AB
O,B
Any
AB
O
A
O
Any
A
O
B
O
Any
B
O
AB
O
Any
AB
AB
A
O,A
Any
AB
AB
B
O,B
Any
AB
AB
O
O
Any
AB
Rh pos
Rh neg
Rh neg
Rh neg
N/A
Rh neg
Rh pos
Rh pos
Rh pos
N/A
The Trial
• Individual patient data (IPD) meta-analysis of 6
published and one unpublished cohort of donorrecipient ABO mismatched allogeneic stem cell
transplants
• Primary end-point: Overall survival
– OS compared among transplants with major, minor
and bi-directional mismatch
• Other end-points:
– TRM
– GVHD-related mortality
– Engraftment or reticulocytes, neutrophils and platelets
Study Selection
• Inclusion criteria:
– Original articles published in English after
1995
– Study endpoints included difference in OS
between ABO matched and mismatched
transplants
• Exclusion criteria
– ≤80 subjects
– Median follow up <6 months
11 articles eligible

Authors contacted

6 authors agreed

Kyoto University (study centre) provided
previously unanalysed SCT database
Data Collection
• IPD exclusion criteria:
– Patients who did not meet minimum data
requirements
– SCT for conditions other than hematologic
malignancies
– Cord blood grafts, combined PB and BM grafts
– Known previous SCT or no info re prior SCT history

Excluded patients enrolled in other pooled cohort studies
Data Collection -2
Defined required variables (age, sex, diagnosis,
stem cell source, MRD or MUD, survival status,
# days survival post-BMT, donor-recipient blood
types) and additional variables (HLA matching,
conditioning regimen, GVHD prophylaxis
regimen, cause of death, disease status at SCT,
#days to engraftment of all blood cells)

Asked authors to complete data collection forms

Ambiguous results discussed and resolved
Patients
1424 patients

133 did not meet minimum data requirements or had SCT
for diseases other than heme malignancies

28 received cord blood grafts or both PB and BM grafts

6 enrolled in other pooled studies

49 prior SCT or SCT history not known

1208 transplants
697 ABO-matched
202 major ABO mismatch
228 minor ABO mismatch
81 bidirectional ABO mismatch
Patients-2
• Western centres
– 709 MRD
– 184 MUD
• Asian centres
– 214 MRD
– 101 MUD
• No significant differences between matched and
mis-matched groups for any category except
type of donors and centres of transplantation
– More MRD than MUD
– Among MUD fewer HLA-mismatched
Results- Overall Survival
• Unadjusted probability of survival at 5
years:
– ABO-matched: 48%
– Major mismatch: 48%
– Minor mismatch: 45%
– Bidirectional mismatch: 37%
Results- Overall Survival
The Subgroups
• MRD
– No difference in OS between ABO-matched
and mismatched groups
• Consistent across each stratified group
• MUD
– Minor and bi-directional mismatch associated
with poorer OS when adjusted for age and
sex
• Strongly observed in some stratified categories:
acute leukemia, SCT after 1998, Asian centres
Results- Secondary Endpoints
• TRM
– Cumulative incidences of overall TRM was not
significantly different between ABO matched and
unmatched groups
• Engraftment
– No impact of ABO matching on engraftment in any
cell line among patients who had MRD grafts
– Marginally significant impact of minor and bidirectional mismatch on MUD grafts on delayed
reticulocyte engraftment as compared to matched
grafts
The Authors’ Conclusion
• “Our IPD-based meta-analysis
demonstrated no adverse association
between any type of ABO mismatching
and survival in allogeneic SCTs for
hematologic malignancies, although the
possible association of minor or bidirectional ABO mismatching with lower
OS was observed among recipients of
unrelated SCTs”
Intro to IPD
• A Systematic Review and meta-analysis
based on Individual Patient Data (IPD)
involves collecting original individual
patient data from trials included in the
systematic review, and using this data to
undertake meta-analysis.
• http://www.liv.ac.uk/medstats/ipd.htm
• As of 2005 IPD represented <5% of total
meta-analysis literature
Conventional vs IPD meta-analysis
• Conventional meta-analysis extracts
aggregated data
– Analysis requires calculating a weighted average for
effect across trials
• Limitations:
• Risk of publication bias
• Heterogeneity in trial results
• Inability to perform intention-to-treat analyses when relevant
data are excluded/ missing
• Limited methodological quality of source studies
• Sub-group analysis generally not possible
– Subgroup or meta-regression analysis using study level
covariates can lead to questionable conclusions
Differences between conventional
and IPD meta-analysis
• Advantages:
– Enables detailed statistical analysis including time-toevent and subgroup analysis with adjustment for
important baseline differences among patients
– Enables intention-to-treat analysis
• A necessary prerequisite for this is that all randomized
patients, including those excluded from trialists’ analyses,
must be included
– Can use common definitions, coding and cutpoints
– May be able to address questions not addressed in
original publication
– Can assess adequacy of randomization
– Can check data, update data and check analyses
• Limitations
– Biased pooling of data
• If IPD investigators do not include ALL databases or explain
why some studies were not included
• IPD investigators should also indicate how missing data was
handled
– Presently no standardized method for IPD data
analysis
• A review of 44 IPD analyses found that clear reporting of
statistical methods was rare and little reporting on why
particular methods were chosen (Simmonds et al Clinical
Trials 2005)
Why would someone ever want to
do this?
• According to the Cochrane Collaboration,
IPD analysis is desirable when:
– Reporting of trials is selective, inadequate or
ambiguous
– Long term or time-to-event outcomes are
considered
– More detailed analyses are planned
– Subgroup effects are of primary interest
Some helpful tips from Sud and
Douketis (EBM August 2009)
• Analysis should occur as per an a priori
statistical plan that accounts for across study
and within study variation
– “Prespecifying hypotheses and analytic methods is
essential to prevent data dredging”
• Important details to ascertain when looking at
IPD analyses:
– Any missing studies?
• Do missing studies differ from those included in the IPD?
– Any missing patients? Were statistical methods used
that account for missing patient data and variability of
patient characteristics
How did our trial do?
No pre-specification of sub-group analyses
Missing data
 Publications in languages other than English not
considered
 Databases other than PubMed not checked
 Only 6 of 11 possible studies used
 Inclusion of 1 previously unanalysed data set
Insufficient detail on choice of statistical methods
 Missing patients
Ex: Data on (i) primary cause of death available for only 85% of
patients, (ii) engraftment available for 24-55% of patients
Does IPD have a role in transfusion
medicine?
• According to the Cochrane Collaboration, IPD analysis is
desirable when:
– Reporting of trials is selective, inadequate or ambiguous
• Off label use of rFVIIa and thrombo-embolic complications
– Long term outcomes are considered
• ESAs- and risk of cancer relapse/ metastasis
– Time-to-event outcomes are considered
• Red cell to plasma ratios in massive transfusion
– More detailed analyses are planned
• Effect of platelet transfusion dose
– Subgroup effects are of primary interest
• ICU and perio-operative transfusion triggers in special groups (ie
cardiac patients)

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