Allogeneic Transfusion Reactions

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Allogeneic Transfusion Reactions

February 18, 2015 by larryhbern

Allogeneic Transfusion Reactions

Writer and Curator: Larry H. Bernstein, MD, FCAP

Introduction

Transfusion Medicine owes much to the discovery of the ABO Blood Groups
by Landsteiner. This was a landmark in the history of immunology.  The next
important discovery was the RhD system in immune hemolytic anemia of the
newborn, which was important in the history of neonatology.  As blood banking
became critical in the preparation, storage, transport, and transfusion of blood
during the Second World War, there was the elucidation of the Kell, MNSs,
Kidd, Duffy, Lewis, and other red cell antigenic systems.  The type and screen
for antibodies, and for red cell compatibility in the crossmatch became routine,
and a formal classification of the antigenic components was created.
Incompatibilities in transfusion mediated reactions were expressed as
allogeneic transfusion reactions.  The red cell was not the only component,
as whole blood was ultimately broken into red cell units, plasma, and platelets,
and eventually a neutrophilic component.  With the development of solid organ
transplantation, the definition of the HLA antigen was a large focus for
compatibility.  Today, the traditional problems of transfusion immuno-compatibility have become displaced in large measure by transplantation
issues.  This piece and that which follows will address allogeneic
transplantation reactions and graft-versus-host disease.

Blood Groups

Although all blood is made of the same basic elements, not all blood is
alike. In fact, there are eight different common blood types, which are
determined by the presence or absence of certain antigens – substances that can trigger an immune response if they are foreign
to the body. Since some antigens can trigger a patient’s immune system
to attack the transfused blood, safe blood transfusions depend on careful
blood typing and cross-matching.

There are four major blood groups determined by the presence or absence
of two antigens – A and B – on the surface of red blood cells:

Group A – has only the A antigen on red cells (and B antibody in the plasma)
Group B – has only the B antigen on red cells (and A antibody in the plasma)
Group AB – has both A and B antigens on red cells (but neither A nor B
antibody in the plasma)
Group O – has neither A nor B antigens on red cells (but both A and B
antibody are in the plasma)

There are very specific ways in which blood types must be matched for a
safe transfusion. See the chart below:

http://www.redcrossblood.org/sites/arc/files/images/ab_top.gif

In addition to the A and B antigens, there is a third antigen called the
Rh factor, which can be either present (+) or absent ( – ). In general,
Rh negative blood is given to Rh-negative patients, and Rh positive blood
or Rh negative blood may be given to Rh positive patients.

O positive is the most common blood type. Not all ethnic groups have the
same mix of these blood types. Hispanic people, for example, have a relatively
high number of O’s, while Asian people have a relatively high number of B’s.
The mix of the different blood types in the U.S. population is:

	Caucasians	African American	Hispanic	Asian
O +	37%	47%	53%	39%
O –	8%	4%	4%	1%
A +	33%	24%	29%	27%
A –	7%	2%	2%	0.5%
B +	9%	18%	9%	25%
B –	2%	1%	1%	0.4%
AB +	3%	4%	2%	7%
AB –	1%	0.3%	0.2%	0.1%

Some patients require a closer blood match than that provided by the ABO
positive/negative blood typing. For example, sometimes if the donor and
recipient are from the same ethnic background the chance of a reaction
can be reduced. That’s why an African-American blood donation may be
the best hope for the needs of patients with sickle cell disease, 98 percent
of whom are of African-American descent.

http://www.redcrossblood.org/learn-about-blood/blood-types

Whether your blood group is type A, B, AB or O is based on the blood types
of your mother and father.

This chart shows the potential blood types you may inherit.

Parent 1

Parent 2

Possible
blood
type
of
child

A blood type (also called a blood group) is a classification of blood based on
the presence or absence of inherited antigenic substances on the surface of
red blood cells (RBCs). These antigens may be proteins, carbohydrates,
glycoproteins, or glycolipids, depending on the blood group system. Some of
these antigens are also present on the surface of other types of cells of
various tissues. Several of these red blood cell surface antigens can stem
from one allele (or very closely linked genes) and collectively form a blood
group system. Blood types are inherited and represent contributions from
both parents. A total of 33 human blood group systems are now recognized
by the International Society of Blood Transfusion (ISBT). The two most
important ones are ABO and the RhD antigen; they determine someone’s
blood type (A, B, AB and O, with +, − or Null denoting RhD status).

Many pregnant women carry a fetus with a blood type which is different from
their own, and the mother can form antibodies against fetal RBCs. Sometimes
these maternal antibodies are IgG, a small immunoglobulin, which can cross
the placenta and cause hemolysis of fetal RBCs, which in turn can lead to
hemolytic disease of the newborn called erythroblastosis fetalis, an illness
of low fetal blood counts that ranges from mild to severe. Sometimes this is
lethal for the fetus; in these cases it is called hydrops fetalis.

ABO_blood_type.svg

http://upload.wikimedia.org/wikipedia/commons/thumb/3/32/ABO_blood_type.svg/824px-ABO_blood_type.svg.png

Blood type (or blood group) is determined, in part, by the ABO blood group antigens

A complete blood type would describe a full set of 30 substances on the surface
of RBCs, and an individual’s blood type is one of many possible combinations
of blood-group antigens. Across the 33 blood groups, over 600 different blood-
group antigens have been found, but many of these are very rare, some being
found mainly in certain ethnic groups.

Almost always, an individual has the same blood group for life, but very rarely
an individual’s blood type changes through addition or suppression of an
antigen in infection, malignancy, or autoimmune disease. Another more
common cause in blood type change is a bone marrow transplant. Bone-marrow transplants are performed for many leukemias and lymphomas,
among other diseases. If a person receives bone marrow from someone
who is a different ABO type (e.g., a type A patient receives a type O bone
marrow), the patient’s blood type will eventually convert to the donor’s type.

Some blood types are associated with inheritance of other diseases; for example,
the Kell antigen is sometimes associated with McLeod syndrome. Certain
blood types may affect susceptibility to infections, an example being the
resistance to specific malaria species seen in individuals lacking the Duffy
antigen. The Duffy antigen, presumably as a result of natural selection, is
less common in ethnic groups from areas with a high incidence of malaria.

The Rh system (Rh meaning Rhesus) is the second most significant blood-
group system in human-blood transfusion with currently 50 antigens.
The most significant Rh antigen is the D antigen, because it is the most
likely to provoke an immune system response of the five main Rh antigens.
It is common for D-negative individuals not to have any anti-D IgG or
IgM antibodies, because anti-D antibodies are not usually produced
by sensitization against environmental substances. However, D-negative
individuals can produce IgG anti-D antibodies following a sensitizing event:
possibly a fetomaternal transfusion of blood from a fetus in pregnancy or
occasionally a blood transfusion with D positive RBCs. Rh disease can
develop in these cases. Rh negative blood types are much less common
in proportion of Asian populations (0.3%) than they are in White (15%).
The presence or absence of the Rh antigens is signified by the + or − sign,
so that for example the A− group does not have any of the Rh antigens.

http://en.wikipedia.org/wiki/Blood_type

Allogeneic blood transfusions: benefit, risks and clinical indications
in countries with a low or high human development index

Carlos Marcucci, Caveh Madjdpour and Donat R. Spahn
Br Med Bull (2004) 70 (1): 15-28. http://dx.doi.org:/10.1093/bmb/ldh023

The risks associated with allogeneic red blood cell (RBC) transfusions differ
significantly between countries with low and high human development indexes
(HDIs). In countries with a low HDI, the risk of infection (HIV, HBV, HCV and
malaria) is elevated. In contrast, in countries with a high HDI, immunological
reactions (hemolytic transfusion reactions, alloimmunization and immuno-suppression) are predominant. Therefore the overall risk associated with RBC
transfusions in low HDI countries is much more significant than that in high HDI
countries. In view of these risks, the limited efficacy of RBC transfusion and its
high costs, this procedure should be used sparingly and rationally.

Red blood cell (RBC) transfusions originating from an unrelated donor are known
as allogeneic RBC transfusions. In the West, i.e. in countries with a high human
development index (HDI), which is an index based on life expectancy, literacy,
enrolment in further education and per capita income, >50% of RBC transfusions
are used in trauma and surgery to compensate for major blood loss.

RBC transfusions are certainly beneficial in specific situations, but are accompanied
by many risks and side effects. Several recent studies have suggested that RBC
transfusions are associated with major adverse outcomes and high costs. In addition,
RBC transfusions are a limited resource and blood shortages can occur at times.

The risk of viral transmission via RBC transfusions has decreased considerably
in recent years in high HDI countries, although new transfusion-transmitted
viruses have been discovered.14 In contrast, in countries with medium or low
HDIs, the risk of transmission of infectious diseases may still be extremely high.

Most reviews consider risks on transfusion-transmissible infections and
immunological reactions, associated with RBC transfusions, that are only
applicable to Western countries, i.e. countries with a high HDI. Although 83%
of the global population live in countries with medium and low HDIs, they
have access to only 40% of the global blood supply. Most notably, all blood
donations in high HDI countries are screened for transfusion-transmissible
infections, whereas only 57% of blood donations in medium and low HDI
countries are tested. In addition, the tests used for blood screening are
not always comparable. For example, only four of the 19 countries
participating in the ‘Workshop of the Directors of National Blood Transfusion
Services’, held in Harare, Zimbabwe, in 2000, used p24 antigen testing for
HIV blood screening.18 Moreover, the blood donation rate per 1000 population
is almost 20 times higher in developed countries than in countries with a low HDI.
Regular non-remunerated volunteers, who are the safest donors, provide 98%
of donations in high HDI countries. In contrast, such donors are a minority in
low HDI countries where up to 60% of donated blood comes from relatives of
the anemic patient or from paid donors.

Acute extravascular hemolytic transfusion reaction due to
anti-Kpa antibody missed by electronic crossmatch

Ruth Padmore, Philip Berardi, …, Doris Neurath, Elianna Saidenberg
Transfusion and Apheresis Science 51 (2014) 168–171
http://dx.doi.org/10.1016/j.transci.2014.08.011

Background: Kpa antigen is a low incidence red blood cell antigen within the Kell
system. Anti-Kpa alloantibody may be associated with acute and delayed hemolytic
transfusion reactions.
Case Study: We report a case of a clinically significant acute extravascular
hemolytic transfusion reaction mediated by previously unrecognized (and
undetected) anti-Kpa alloantibody. This reaction occurred in a patient who
met all criteria for electronic crossmatch, resulting in the transfusion of an
incompatible red cell unit.
Results: Post-transfusion investigation showed the transfused red cell unit
was crossmatch compatible at the immediate spin phase but was 3 + incompatible
at the antiglobulin phase.No evidence of intravascular hemolysis was observed
upon visual comparison of the pre and post-transfusion peripheral blood plasma.
Further testing showed the presence of anti-Kpa antibody. The clinical course
of the patient included acute febrile and systemic reaction.
Conclusion: Acute extravascular hemolytic transfusion reaction may occur due
to undetected anti-Kpa alloantibody. Various strategies for crossmatching are
discussed in the context of antibodies to low incidence antigens.

Transfusion-related mortality: the ongoing risks of allogeneic blood
transfusion and the available strategies for their prevention

Eleftherios C. Vamvakas and Morris A. Blajchman
Blood. 2009; 113: 3406-3417
http://dx.doi.org:/10.1182/blood-2008-10-167643

As the risks of allogeneic blood transfusion (ABT)–transmitted viruses were
reduced to exceedingly low levels in the US, transfusion-related acute lung injury
(TRALI), hemolytic transfusion reactions (HTRs), and transfusion-associated
sepsis (TAS) emerged as the leading causes of ABT related deaths. Since 2004,
preventive measures for TRALI and TAS have been implemented, but their
implementation remains incomplete. Infectious causes of ABT-related deaths
currently account for less than 15% of all transfusion-related mortality, but the
possibility remains that a new transfusion-transmitted agent causing a fatal
infectious disease may emerge in the future. Aside from these established
complications of ABT, randomized controlled trials comparing recipients of
non–white blood cell (WBC)–reduced versus WBC-reduced blood components
in cardiac surgery have documented increased mortality in association with
the use of non-WBC–reduced ABT. ABT-related mortality can thus be further
reduced by universally applying the policies of avoiding prospective donors
alloimmunized to WBC antigens from donating plasma products, adopting
strategies to prevent HTRs, WBC-reducing components transfused to patients
undergoing cardiac surgery, reducing exposure to allogeneic donors through
conservative transfusion guidelines and avoidance of product pooling, and
implementing pathogen-reduction technologies to address the residual risk of TAS as well as the potential risk of a transfusion transmitted agent to emerge
in the foreseeable future.

Red blood cell-incompatible allogeneic hematopoietic progenitor cell
transplantation

S D Rowley, M L Donato and P Bhattacharyya
Bone Marrow Transplantation (2011) 46, 1167–1185; http://dx.doi.org:/10.1038/bmt.2011.135

Transplantation of hematopoietic progenitor cells from red cell-incompatible
donors occurs in 30–50% of patients. Immediate and delayed hemolytic
transfusion reactions are expected complications of red cell-disparate
transplantation and both ABO and other red cell systems such as Kidd
and rhesus can be involved. The immunohematological consequences of
red cell-incompatible transplantation include delayed red blood cell recovery,
pure red cell aplasia and delayed hemolysis from viable lymphocytes carried
in the graft (‘passenger lymphocytes’). The risks of these reactions, which
may be abrupt in onset and fatal, are ameliorated by graft processing and
proper blood component support. Red blood cell antigens are expressed on
endothelial and epithelial tissues in the body and could serve to increase
the risk of GvHD. Mouse models indicate that blood cell antigens may
function as minor histocompatibility antigens affecting engraftment. Similar
observations have been found in early studies of human transplantation
for transfused recipients, although current conditioning and immuno-suppressive regimens appear to overcome this affect. No deleterious effects
from the use of red cell-incompatible hematopoietic grafts on transplant
outcomes, such as granulocyte and platelet engraftments, the incidences
of acute or chronic GvHD, relapse risk or OS, have been consistently
demonstrated. Most studies, however, include limited number of patients,
varying diagnoses and differing treatment regimens, complicating the
detection of an effect of ABO-incompatible transplantation. Classification
of patients by ABO phenotype ignoring the allelic differences of these
antigens also may obscure the effect of red cell-incompatible transplantation
on transplant outcomes.

Severe hemolytic transfusion reaction due to anti-A1 following allogeneic
stem cell transplantation with minor ABO incompatibility

Çiğdem Akalın Akkok, Håkon Haugaa, Anders Galgerud, Lorentz Brinch
Transfusion and Apheresis Science 2013; 48(1), Pages 63–66
http://dx.doi.org/10.1016/j.transci.2012.07.006

Blood components should be compatible both with the recipient and the
donor in the ABO incompatible allogeneic stem cell transplantation setting.
A patient with blood type A2 received peripheral blood stem cells from a
blood type O donor. The patient was in critical condition due to treatment-
related toxicity. He had acquired anti-A1 that was unfortunately overlooked.
Following transfusion of A1 red blood cells in error, he developed a severe
hemolytic transfusion reaction. Anti-A1 is rarely clinically significant.
We discuss the role of passenger lymphocytes in development of the anti-A1, and stress the importance of investigating unusual/atypical reactions
in blood typing.

Transfusion Support of Allogeneic Stem Cell Transplant Recipients

Kate Chipperfield MD FRCPC 21 Feb 2012

After this session, the learner will be able to:

Provide an overview of transfusion issues in allogeneic stem cell transplant.
Discuss the potential consequences of ABO mismatch between recipient
and donor.
Understand the rationale for ABO/D group selection of blood product support
peri-stem cell transplant.
Appreciate the special impact of umbilical cord blood stem cell transplant.
Briefly outline variable practices in transfusion support of stem cell
transplantation.

Pre-transplant

Leukocyte Reduction

– reduction in HLA Alloimmunization (TRAP study)

– reduction in CMV infection in seronegative candidates*

Avoidance of directed donations
Irradiation of cellular blood products

– Only from start of SCT conditioning (to end of GVHD prophylaxis or
lymphs >1 x 109/L)

Issues with this

– as soon as identified as potential SCT recipient*

– prevention of microchimerism in intended recipient (donor lymphocytes)

ABO and SCT

Any allogeneic SCT will be one of:

– ABO-Identical

– Major ABO Incompatible

– Minor ABO Incompatible

– Major and Minor incompatible (Bidirectional)

(more not shown)

Major ABO Blood Group Mismatch Increases the Risk for Graft Failure
after Unrelated Donor Hematopoietic Stem Cell Transplantation

Mats Remberger, E Watz, O Ringdén, J Mattsson, A Shanwell, A Wikman
Biology of Blood and Marrow Transplantation 13:675-682 (2007)
http://dx.doi.org:/10.1016/j.bbmt.2007.01.084

Two hundred twenty-four patients with leukemia transplanted with an unrelated
donor between 1991 and 2003 at the Karolinska University Hospital were
analyzed according to association between graft failure and ABO, RhD, MNSs,
and Kidd blood group antigen compatibility. Median age was 29 years
(range: 0-55). Conditioning consisted of total-body irridiation or busulfan-based myeloablative conditioning. A bone marrow graft was given to 152
patients, and 72 patients received peripheral blood stem cells. Most patients
received graft-versus-host disease prophylaxis with cyclosporine and MTX.
Graft failure (GF) was seen in 6 (2.7%) patients. In the multivariate analysis
major ABO mismatch (odds ratio [OR] 14.9, 95% confidence interval
[CI] 2.01-110, P = .008) and HLA-allele mismatch (6.42, 1.19-34.8, P = .03)
was significantly associated to GF. In patients with and without major ABO
mismatch the incidence of GF was 7.5% and 0.6% (P = .02), respectively.
Using an ABO major mismatched graft increases the risk for GF after
unrelated donor hematopoietic stem cell transplantation.

Perioperative transfusion-related acute lung injury: The Canadian
Blood Services experience

Asim Alam, Mary Huang, Qi-Long Yi, Yulia Lin, Barbara Hannach
Transfusion and Apheresis Science 50 (2014) 392–398
http://dx.doi.org/10.1016/j.transci.2014.04.008

Purpose: Transfusion-related acute lung injury (TRALI) is a devastating transfusion-associated adverse event. There is a paucity of data on the incidence and
characteristics of TRALI cases that occur perioperatively. We classified
suspected perioperative TRALI cases reported to Canadian Blood Services
between 2001 and 2012, and compared them to non-perioperative cases
to elucidate factors that may be associated with an increased risk of developing
TRALI in the perioperative setting. Methods: All suspected TRALI cases
reported to Canadian Blood Services (CBS) since 2001 were reviewed by
two experts or, from 2006 to 2012, the CBS TRALI Medical Review Group
(TMRG). These cases were classified based on the Canadian Consensus
Conference (CCC) definitions and detailed in a database. Two additional
reviewers further categorized them as occurring within 72 h from the onset of
surgery (perioperative) or not in that period (non-perioperative). Various
demographic and characteristic variables of each case were collected and
compared between groups. Results: Between 2001 and 2012, a total of
469 suspected TRALI cases were reported to Canadian Blood Services;
303 were determined to be within the TRALI diagnosis spectrum. Of those,
112 (38%) were identified as occurring during the perioperative period.
Patients who underwent cardiac surgery requiring cardiopulmonary bypass
(25.0%), general surgery (18.0%) and orthopedics patients (12.5%) represented
the three largest surgical groups. Perioperative TRALI cases comprised more
men (53.6% vs. 41.4%, p = 0.04) than non-perioperative patients. Perioperative
TRALI patients more often required supplemental O2 (14.3% vs. 3.1%, p = 0.0003),
mechanical ventilation (18.8% vs. 3.1%), or were in the ICU (14.3% vs. 3.7%,
p = 0.0043) prior to the onset of TRALI compared to non-perioperative TRALI
patients. The surgical patients were transfused on average more components
than non-perioperative patients (6.0 [SD = 8.3] vs. 3.6 [5.2] products per patient,
p = 0.0002). Perioperative TRALI patients were transfused more plasma (152
vs. 105, p = 0.013) and cryoprecipitate (51 vs. 23, p < 0.01) than nonperioperative
TRALI patients. There was no difference between donor antibody test results
between the groups. Conclusion: CBS data has provided insight into the
nature of TRALI cases that occur perioperatively; this group represents a
large proportion of TRALI cases.

Platelet allo-antibodies identification strategies forpreventing and
managing platelet refractoriness

Basire, C.Picard
Transfusion Clinique et Biologique 21(2014)193–206
http://dx.doi.org/10.1016/j.tracli.2014.08.140

Platelet refractoriness is a serious complication for patients receiving recurrent
platelet transfusions ,which can be explained by non-immune and immune causes.
Human Leukocyte Antigens (HLA) allo-immunization, especially against HLA
class I, is the major cause for immune platelet refractoriness. To a lesser extent,
alloantibodies against specific Human Platelet Antigen (HPA) are also involved.
Pregnancy, transplantation and previous transfusions can lead to allo-immune reaction against platelet antigens. After transfusion, platelet count
is decreased by accelerated platelet destruction related to antibodies
fixation on incompatible platelet antigens. New laboratory tests for allo-antibodies identification were developed to improve sensibility and specificity,
especially with the LUMINEX® technology. The good use and interpretation
of these antibodies assays can improve strategies for platelet refractoriness
prevention and management with a patient adapted response. Compatible
platelets units can be selected according to their identity with recipient
typing or immune compatibility regarding HLA or HPA antibodies or HLA
epitope compatibility. Prospective studies are needed to further confirm the
clinical benefit of new allo-antibodies identification methods and consensus
strategies for immune platelet refractoriness management.

For Anti-HLA-Specific Donor Antibodies Detection By Flow Cytometry
Cytotoxic Crossmatches Comparison of Methods

Cervelli, F. Pisani, A. Aureli, R. Azzarone, .., A. Famulari, and F. Papola Transplantation Proceedings, 45, 2761e2764 (2013)
http://dx.doi.org/10.1016/j.transproceed.2013.07.023

Anti-HLA-specific donor antibodies induce rapid, irreversible destruction of
the transplant (hyperacute rejection) that today happens rarely due to
immunologic studies prospective crossmatch of patients awaiting the kidney
graft. The usual approach for pretransplant donor/recipient evaluation is
based on 2 methods: (1) the cytotoxic complement crossmatch (CDC) and
(2) the flow cytometric crossmatch  (FCX). The CDC crossmatch is positive
when complement-fixing antibodies are present, an absolute contra-
indication to kidney transplantation. The more sensitive FCX-positive
crossmatch detects low concentrations of unable to fix performed
antibodies complement. It is an  “index” of possible damage due to
accelerated rejection. The target of our study was to develop a cytotoxic
flow cytometry crossmatch (cFCX) that detected cytotoxic antibodies
move sensitively  than the traditional CDC method and also was less
subjective and more standardized for interpretation studying sera from
23 patients; the cFCX showed the requested efficiency characteristics even
in an emergency. In addition, the new method permitted one to calculate a
cutoff for positivity (average value of the negative control at + 2 standard
deviations), assuring an “objective” interpretation of the results that agreed
with the CDC but was more sensitive and accurate allowing solution of
ambiguous results for cases of “doubt”-positive CDC crossmatch.
Furthermore, our aim was to correlate the effect of the strength of the anti-HLA
antibodies determined by mean fluorescence intensity value of LabScreen
Single Antigen beads with results of CDC, cFCX, and FCX methods.

Allogeneic Stem Cell Transplants and Associated Incompatibities

Analysis of Donor and Recipient ABO Incompatibility and Antibody-
Associated Complications after Allogeneic Stem Cell Transplantation
with Reduced-Intensity Conditioning

Emma Watz, Mats Remberger, Olle Ringden, Joachim Lundahl, et al.
Biol Blood Marrow Transplant 20 (2014) 264e271
http://dx.doi.org/10.1016/j.bbmt.2013.11.011

Allogeneic hematopoietic stem cell transplantation (HSCT) can be performed
across the ABO blood group barrier. The impact of ABO incompatibility on
clinical outcome is controversial. A retrospective analysis of 310 patients who
underwent HSCT with reduced-intensity conditioning between 1998 and 2011
was performed to investigate the frequency and clinical implications of anti-RBC
antibodies in passenger lymphocyte syndrome (PLS) after minor ABO mismatch
(mm), persistent or recurring recipient type ABO antibodies (PRABO) after major
ABO mm HSCT, and autoimmune hemolytic anemia (AIHA). Transplantation
characteristics and clinical outcome were analyzed by univariate and multivariate
analysis for groups with or without anti-RBC antibodies. ABO blood group
incompatibility did not affect clinical outcome despite an increased requirement
of blood transfusion. Twelve patients with AIHA, 6 patients with PLS, and 12
patients with PRABO post-HSCT were identified. AIHA did not affect overall
survival (OS) or transplant-related mortality (TRM), but patients with AIHA had
a lower incidence of grades II to IV acute graft-versus-host disease (P < .05).
OS in the PLS group was 0% compared with 61% in the whole group receiving
minor ABO mm transplants (P < .001). Comparing PRABO patients with those
receiving a major ABO mm HSCT, the OS was 17% versus 73% (P <.002) and
TRM was 50% versus 21% (P < .03). At our center, PLS after minor ABO mm
and PRABO antibodies after major ABO mm HSCT are significant risk factors
for decreased OS and TRM. Our results suggest that occurrence of unexpected
ABO antibodies after HSCT warrant a wider investigation individual to find the
underlying cause.

Current Trends in Clinical Studies of Allogeneic Hematopoietic Stem Cell
Transplantation

Sophie Pilon, D Jedrysiak, D Sheppard, CN Bredeson, J Tay, DS Allan
Biol Blood Marrow Transplant 21 (2015) 364e381
http://dx.doi.org/10.1016/j.bbmt.2014.09.014

Allogeneic hematopoietic stem cell transplantation (HSCT) is a specialized
intervention performed at select centers worldwide. The extent to which
specific aspects of care in allogeneic HSCT have been studied and the
types of studies performed for different aspects of care remains incompletely
documented. Studies in allogeneic HSCT were systematically identified from
selected high-profile transplant journals between July 2010 and June 2011
and previously reported in a study addressing the definition of clinical outcomes
in HSCT. All articles were retrieved and assessed for study characteristics and
categorized by specific aspects of care related to allogeneic HSCT. One
hundred sixteen articles were retrieved and reviewed in detail by investigators.
The most studied aspect of care was conditioning regimens. Transfusion
practices were the most understudied aspect of care. Interestingly, most
studies included both adult and pediatric patients. Studies involving all
hematological malignancies were encountered more often than disease-
specific studies. Geographically, most patients described in the published reports
were treated only in North America or only in Europe. Most studies were
retrospective (78), and 25 reported on multicenter registry data. Of the 38
prospective studies, 8 were randomized controlled trials (RCTs) and
predominantly focused on prevention and treatment of graft-versus-host disease
(GVHD) and infections. Median follow-up was longer in retrospective registry
studies (54 months) and shortest in RCTs (32 months). The proportion of
positive outcomes in retrospective and prospective studies was remarkably
high (>80% for all categories) and not significantly different across all aspects
of care (P > .05). When comparing RCTs and registry data studies, this proportion
was similar and high (95% and 100%, respectively, P >.05). Our study highlights
the established and important role of retrospective registry studies for many
aspects of care and suggests RCTs may be most relevant for studies on
infectious complications and GVHD.

Efficacy and Long-Term Outcome of Treatment for Pure Red Cell Aplasia
after Allogeneic Stem Cell Transplantation from Major ABO-Incompatible
Donors

Makoto Hirokawa, T Fukuda, K Ohashi, …, H Sakamaki, for The PRCA
Collaborative Study Group
Biol Blood Marrow Transplant 19 (2013) 1026e1032
http://dx.doi.org/10.1016/j.bbmt.2013.04.004

No standard of care for pure red cell aplasia (PRCA) after major ABO-
incompatible hematopoietic stem cell transplantation (HSCT) has been
established. We conducted a retrospective cohort study to learn the
efficacy and outcome of treatment for PRCA. One hundred forty-five
recipients who showed delayed recovery of erythropoiesis and survived
>100 days after transplantation without early disease progression were
selected from 2846 records of major ABO-incompatible transplantation
in the registry database in Japan, and detailed data of 46 recipients
were collected. Treatment of PRCA, such as rapid tapering of calcineurin
inhibitors, corticosteroids, or additional immunosuppressants, was given
to 22 patients but not to the other 24 patients. The overall response rate
of the treatment group was 54.5%. The number of days from diagnosis of
PRCA to recovery of reticulocytes >1% and the cumulative number of red
blood cell transfusions were not significantly different between the 2 groups.
Infections accounted for the death of 7 of 11 patients in the treatment group.
Univariate analysis identified 5 variables influencing survival, including graft-
versus-host disease, disease progression, and treatment of PRCA; disease
progression remained as the only factor negatively affecting survival by
multivariate analysis. The present study could not provide supportive
evidence for the beneficial effects of treatment for PRCA after major
ABO-mismatched HSCT.

Current therapy of myelodysplastic syndromes

Amer M. Zeidan, Yuliya Linhares, Steven D. Gore
Blood Reviews 27 (2013) 243–259
http://dx.doi.org/10.1016/j.blre.2013.07.003

After being a neglected and poorly-understood disorder for many years, there
has been a recent explosion of data regarding the complex pathogenesis of
myelodysplastic syndromes (MDS). On the therapeutic front, the approval of
azacitidine, decitabine, and lenalidomide in the last decade was a major
breakthrough. Nonetheless, the responses to these agents are limited and
most patients progress within 2 years. Allogeneic stem cell transplantation
remains the only potentially curative therapy, but it is associated with significant
toxicity and limited efficacy. Lack or loss of response after standard therapies
is associated with dismal outcomes. Many unanswered questions remain
regarding the optimal use of current therapies including patient selection,
response prediction, therapy sequencing and combinations, and management
of resistance. It is hoped that the improved understanding of the underpinnings
of the complex mechanisms of pathogenesis will be translated into novel
therapeutic approaches and better prognostic/predictive tools that would
facilitate accurate risk-adaptive therapy.

Donor Selection for Killer Immunoglobulin-like Receptors B Haplotype
of the Centromeric Motifs Can Improve the Outcome after HLA-Identical
Sibling Hematopoietic Stem Cell Transplantation

Huifen Zhou, Xiaojing Bao, …, Miao Wang, Depei Wu, Jun He
Biol Blood Marrow Transplant 20 (2014) 98e105
http://dx.doi.org/10.1016/j.bbmt.2013.10.017

After hematopoietic stem cell transplantation (HSCT), natural killer (NK) cell
alloreactivity in HLA cells of recipients is regulated by killer immunoglobulin-like
receptors (KIRs) on donor NK cells. The effect of KIRs on HSCT outcomes
is controversial, particularly in those undergoing HLA-identical sibling HSCT.
In this study, effects of KIR and HLA genotypes on the HSCT outcome were
investigated in a 5-year retrospective study comprising 219 patient-donor pairs
undergoing HLA-identical sibling HSCT for myeloid and lymphoid malignancies.
We found that 39.7% (87 of 219) of these pairs, which were KIR mismatched,
had better overall survival (OS) and reduced grade III to IV acute graft-versus-
host disease (aGVHD), especially in acute myeloid leukemia (AML) patients.
Bx1 donor KIR genotype with haplotype B on a telomeric region was a risk
factor for the OS and relapse-free survival (RFS). Donor centromeric (c) and
telomeric (t) KIR haplotype analysis showed that donor KIR cB-tA/tB was
associated with improved OS and RFS compared with cA-tA or cA-tB.
Furthermore, donor KIR B haplotype of the centromeric motifs (Cen-B) was
an independent beneficial factor in improving OS and RFS and in protecting
from relapse after HSCT. In AML patients, the occurrence of a GVHD was
significantly lower in HLA-C1 group compared with that in HLA-C2 group,
although such effect was not observed in patients with acute lymphoblastic
leukemia or chronic myelogenous leukemia. Our results suggest that KIR
could impact outcome and donor KIR haplotype with Cen-B confer significant
survival benefits to HLA-identical sibling HSCT.

TEL-AML1 Corrupts Hematopoietic Stem Cells to Persist in the Bone
Marrow and Initiate Leukemia

Jeffrey W. Schindler, D Van Buren, A Foudi, O Krejci, J Qin, SH Orkin, and H Hock
Cell Stem Cell 5, 43–53, July 2, 2009
http://dx.doi.org:/10.1016/j.stem.2009.04.019

The initial steps in the pathogenesis of acute leukemia remain incompletely
understood. The TELAML1 gene fusion, the hallmark translocation in Childhood
Acute Lymphoblastic Leukemia and the first hit, occurs years before the clinical
disease, most often in utero. We have generated mice in which TEL-AML1
expression is driven from the endogenous promoter and can be targeted to
specific populations. TEL-AML1 renders mice prone to malignancy after
chemical mutagenesis when expressed in hematopoietic stem cells (HSCs),
but not in early lymphoid progenitors. We reveal that TEL-AML1 markedly
increases the number of HSCs and predominantly maintains them in the
quiescent (G0) stage of the cell cycle. TEL-AML1+ HSCs retain self renewal
properties and contribute to hematopoiesis, but fail to out-compete normal
HSCs. Our work shows that stem cells are susceptible to subversion by weak
oncogenes that can subtly alter their molecular program to provide a latent
reservoir for the accumulation of further mutations.

Factors Affecting the Outcome of Related Allogeneic Hematopoietic
Cell Transplantation in Patients with Fanconi Anemia

Mouhab Ayas, K Siddiqui, A Al-Jefri, , …, A Al-Musa, A Al-Seraihy
Biol Blood Marrow Transplant 20 (2014) 1599e1603
http://dx.doi.org/10.1016/j.bbmt.2014.06.016

Hematopoietic cell transplantation (HCT) can cure bone marrow failure in
patients with Fanconi Anemia (FA), and it is generally accepted that these
patients should receive low-intensity conditioning because of the underlying
DNA repair defect in their cells. Outcomes for recipients of matched related
HCT have generally been favorable, but only a few studies have scrutinized
the factors that may affect the eventual outcome of these patients. This
retrospective analysis of 94 pediatric patients with FA who underwent related
HCT at King Faisal Specialist Hospital & Research Center was carried out to
attempt to identify factors that may affect outcome. Results showed overall
survival (OS) probabilities of 92.5%, 89%, and 86% at 1, 5, and 10 years,
respectively. In univariate analysis, use of higher dose cyclophosphamide
(CY) (60 mg/kg) conditioning was associated with a better 10-year OS than
lower dose CY (20 mg/kg) conditioning (91% versus 82%, respectively;
P < .035), and use of radiation-containing regimens was associated with a
significantly lower 10-year OS than nonradiation regimens (76% versus 91%,
respectively; P < .005). Of the 4 regimens used in this study, the fludarabine-
based regimen was associated with the highest survival (95.2%; P < .034).
The use of the higher dose CY (60 mg/kg) was associated with a
significantly increased incidence of hemorrhagic cystitis (HC) (20% versus 5.6%
respectively; P < .049). Three patients (3%) developed squamous cell carcinoma
(2 oropharyngeal and 1 genitourinary), at 9.4, 5.4, and 13.3 years after HCT;
2 of them had radiation containing conditioning. In conclusion, our data suggest
that although using a higher dose CY (60 mg/kg)
conditioning regimen may be associated with better survival, it is also associated
with a significantly increased risk of HC. The addition of fludarabine to the low-dose
CY (20 mg/kg) is associated with the best survival. On the other hand, radiation-
containing regimens are associated with significantly lower survival.

Donor Cell Leukemia: A Review

Daniel H. Wiseman
Biol Blood Marrow Transplant 17: 771-789 (2011)
http://dx.doi.org:/10.1016/j.bbmt.2010.10.010

Relapse of acute leukemia following hematopoietic stem cell transplantation
(HSCT) usually represents return of an original disease clone, having evaded
eradication by pretransplant chemo-/radiotherapy, conditioning, or posttransplant
graft-versus-leukemia (GVL) effect. Rarely, acute leukemia can develop
de novo in engrafted cells of donor origin. Donor cell leukemia (DCL) was
first recognized in 1971, but for many years, the paucity of reported cases
suggested it to be a rare phenomenon. However, in recent years, an upsurge
in reported cases (in parallel with advances in molecular chimerism monitoring)
suggest that it may be significantly more common than previously appreciated;
emerging evidence suggests that DCL might represent up to 5% of all post-
transplant leukemia ‘‘relapses.’’ Recognition of DCL is important for several
reasons. Donor-derivation of the leukemic clone has implications when selecting
appropriate therapy, because seeking to enhance an allogeneic GVL effect
would intuitively not have the same role as in standard recipient-derived
relapses. There are also broader implications for donor selection and workup,
particularly given the growing popularity of nonmyeloblative HSCTand
corresponding rising age of the potential donor pool. Identification of DCL
raises potential concerns over future health of the donor, posing ethical
dilemmas regarding responsibilities toward donor notification (particularly
in the context of cord blood transplantation). The entity of DCL is also of
research interest, because it might provide a unique human model for studying
the mechanisms of leukemogenesis in vivo. This review presents and collates
all reported cases of DCL, and discusses the various strategies, controversies,
and pitfalls when investigating origin of posttransplant relapse. Putative etiologic
factors and mechanisms are proposed, and attempts made to address the
difficult ethical questions posed by discovery of donor-derived malignancy
within a HSCT recipient.

Feasible Outcomes of T Cell-Replete Haploidentical Stem Cell
Transplantation with Reduced-Intensity Conditioning in Patients
with Myelodysplastic Syndrome

Seung-Hwan Shin, Jung-Ho Kim, Young-Woo Jeon, …,, Woo-Sung Min,
Yoo-Jin Kim, Je-Hwan Lee
Biol Blood Marrow Transplant 21 (2015) 342e349
http://dx.doi.org/10.1016/j.bbmt.2014.10.031

Even with the recent optimization of haploidentical stem cell transplantation
(SCT), its role for patients with myelodysplastic syndrome (MDS) or acute
myeloid leukemia evolving from MDS (sAML) should be validated. We
analyzed the outcomes of consecutive 60 patients with MDS or sAML
who received T cell-replete haploidentical SCT after reduced-intensity
conditioning with fludarabine, busulfan, and rabbit antithymocyte globuline
800 cGy total body irradiation. Patients achieved a rapid neutrophil
engraftment after a median of 12 days (range, 8 to 23) and an early
immune reconstitution without high incidences of acute graft-versus-host
disease (GVHD) II to IV and chronic GVHD (36.7% and 48.3%, respectively).
After a median follow-up of 4 years, incidence of relapse and nonrelapse mortality
and rate of overall survival and disease-free survival was 34.8%, 23.3%, 46.8%,
and 41.9%, respectively. In multivariate analysis, the disease status at peak was
a significant predictor for relapse (lower-risk MDS versus higher-risk MDS or sAML;
hazard ratio [HR], 5.69; 95% confidence interval [CI], 1.45 to 22.29; P <.013)
and disease-free survival (HR, 4.44; 95% CI, 1.14 to 17.34; P <.032). Chronic
GVHD was an additional significant predictor for relapse (no versus yes; HR,
2.87; 95% CI, 1.03 to 7.51; P <.043). Our T cell-replete haploidentical SCT
may be a feasible option for patients with MDS and sAML without conventional
donors.

Extramedullary Relapse of Acute Leukemia after Allogeneic Hematopoietic
Stem Cell Transplantation: Different Characteristics between Acute
Myelogenous Leukemia and Acute Lymphoblastic Leukemia

Ling Ge, Fan Ye, X Mao, …, C Ruan, Depei Wu, Xiaowen Tang
Biol Blood Marrow Transplant 20 (2014) 1040e1047
http://dx.doi.org/10.1016/j.bbmt.2014.03.030

Extramedullary relapse (EMR) of acute leukemia (AL) after allogeneic
hematopoietic stem cell transplantation (allo-HSCT) is a contributor to post-
transplantation mortality and remains poorly understood, especially the
different characteristics of EMR in patients with acute myelogenous
leukemia (AML) and those with acute lymphoblastic leukemia (ALL).
To investigate the incidence, risk factors, and clinical outcomes of EMR
for AML and ALL, we performed a retrospective analysis of 362 patients
with AL who underwent allo-HSCT at the First affiliated Hospital of Soochow
University between January 2001 and March 2012. Compared with patients
with AML, those with ALL had a higher incidence of EMR (12.9% versus
4.6%; P < .009). The most common site of EMR was the central nervous
system, especially in the ALL group. Multivariate analyses identified the
leading risk factors for EMR in the patients with AML as advanced disease
status at HSCT, hyperleukocytosis at diagnosis, history of extramedullary
leukemia before HSCT, and a total body irradiationebased conditioning
regimen, and the top risk factors for EMR in the patients with ALL as
hyperleukocytosis at diagnosis, adverse cytogenetics, and transfusion
of peripheral blood stem cells. The prognosis for EMR of AL is poor,
and treatment options are very limited; however, the estimated 3-year
overall survival (OS) was significantly lower in patients with AML
compared with those with ALL (0 versus 18.5%; P < .000). The
characteristics of post-allo-HSCT EMR differed between the patients
with AML and those with ALL, possibly suggesting different pathogenetic
mechanisms for EMR of AML and EMR of ALL after allo-HSCT; further
investigation is needed.

French Multicenter 22-Year Experience in Stem Cell Transplantation
for Beta-Thalassemia Major: Lessons and Future Directions

Claire Galambrun, C Pondarré, Yves Bertrand, …,C Badens, I Thuret, for the
French Rare Disease Center for Thalassemia and the French Society of Bone
Marrow Transplantation
Biol Blood Marrow Transplant 19 (2013) 62e68
http://dx.doi.org/10.1016/j.bbmt.2012.08.005

Although hematopoietic stem cell transplantation (HSCT) offers curative
potential for beta-thalassemia major (beta-TM), it is associated with a
variable but significant incidence of graft rejection. We studied the French
national experience for improvement over time and the potential benefit
of antithymocyte globulin (ATG). Between December 1985 and December
2007, 108 patients with beta-TM underwent HSCT in 21 different French
transplantation centers. The majority of patients received a matched sibling
transplant (n = 96) and a busulfan- and cyclophosphamide-based conditioning
regimen (n = 95), also with ATG in 57 cases. Ninety five of the 108 patients
survived, with a median follow-up of 12 years. Probabilities of 15-year survival
and thalassemia-free survival after first HSCT were 86.8% and 69.4%, respectively.
Graft failure occurred in 24 patients, 11 of whom underwent a second HSCT.
The use of ATG was associated with a decrease in rejection rate from 35% to 10%.
Thalassemia-free survival improved significantly with time, reaching 83% in the
54 patients undergoing HSCT after 1994 (median time of HSCT). In view of the
increased risk of graft rejection after matched sibling HSCT, current French
national guidelines recommend, for all children at risk for beta-TM, the systematic
addition of ATG to the myeloablative conditioning regimen and special attention
to optimize transfusion and chelation therapy in the pretransplantation period.

Extramedullary Relapse of Acute Myelogenous Leukemia after
Allogeneic Hematopoietic Stem Cell Transplantation: Better
Prognosis Than Systemic Relapse

Melhem Solh, Todd E. DeFor, Daniel J. Weisdorf, Dan S. Kaufman
Biol Blood Marrow Transplant 18: 106-112 (2012)
http://dx.doi.org:/10.1016/j.bbmt.2011.05.023

Allogeneic hematopoietic cell transplantation (HSCT) is considered a curative
treatment for acute myelogenous leukemia (AML). Extramedullary relapse after
HSCT for AML is a rare event and is less well defined than systemic, hematologic
relapse. We retrospectively studied all patients with AML (n = 436) who underwent
HSCT at the University of Minnesota between 1996 and 2008 who developed
either a bone marrow (BM) or extramedullary (EM) relapse, and examined the
incidence and risk factors for BM and EM relapse. Of 128 patients who relapsed
post-HSCT, 25 had relapse in EM sites, either isolated (n = 13) or with concurrent
BM relapse (n = 12). Relapse sites included bone (n = 1), central nervous system
(n=5 6), gastrointestinal (n=5 4), lymphatic (n = 4), skin (n = 5), genitourinary
(n=5 1), pulmonary (n = 1), and soft tissue (n = 3). The time to relapse was longer
in the EM sites (median, 328 days vs 168 days). Patients with EM relapse were
more likely to have had preceding acute graft-versus-host disease (GVHD) (77%
vs 49%; P = .03) or chronic GVHD (46% vs 15%; P < .02) compared with those
with BM relapse. The 6-month survival post-relapse was significantly better in
patients with isolated EM relapse (69%) compared with those with combined
EM and BM relapse (8%) or those with BM relapse alone (27%) (P <.01).
Compared with local therapy alone, systemic therapy yielded better 6-month
survival in patients with EM relapse. This study suggests differing pathogenesis
of BM relapse versus EM relapse of AML after allogeneic HSCT. GVHD and its
accompanying graft-versus-leukemia effect may better protect BM sites, but
patients with EM relapse have better responses to combined therapy and
improved survival compared with those with BM relapse.

Hematopoietic Cell Transplantation for Thalassemia: A Global
Perspective BMT Tandem Meeting 2013

Parinda A. Mehta, Lawrence B. Faulkner
Biol Blood Marrow Transplant 19 (2013) S70eS73
http://dx.doi.org/10.1016/j.bbmt.2012.10.025

Hematopoietic cell transplantation (HCT) remains the sole available curative
option for patients with β-thalassemia major. Expanded and improved supportive
therapies for thalassemia now routinely extend the life span of affected individuals
well into adulthood. Consequently, in regions of the world where this care is
readily available, HCT has been pursued infrequently, in part owing to concerns
about an expected lack of balance between risks and benefits. More recently,
however, recognition of significant health problems in older patients with
thalassemia, along with recognition of increased risks of graft-versus-host
disease (GVHD), graft rejection, and impaired organ function leading to inferior
HCT outcomes in this particular group, seem to be turning the wheels and tipping
the balance again in the direction of consideration for earlier HCTs. In contrast,
in countries where thalassemia is most prevalent (>100,000 new children born
each year in Middle East and southeast Asia), lack of supportive care standards
together with often insufficient access to dedicated health care facilities, results
in the majority of these children not reaching adulthood, further supporting the
need for expanded access to HCT for these patients. The cost of HCT is equivalent
to that of a few years of noncurative supportive care, such that HCT in low-risk
young children with a compatible sibling is justified not only medically and ethically
but also financially. International cooperation can play a major role in increasing
access to safe and affordable HCT in countries where there is a considerable
shortage of transplantation centers. In this article, we review the current status
of bone marrow transplantation for thalassemia major, with particular emphasis
on a global prospective.

Hematopoietic Stem Cell Transplantation in Autoimmune Diseases: The
Ahmedabad Experience

AV Vanikar, PR Modi, RD Patel, KV Kanodia, VR Shah, VB Trivedi, HL Trivedi
Transplantation Proceedings, 39, 703–708 (2007)
http://dx.doi.org:/10.1016/j.transproceed.2007.01.070

Introduction. Autoimmune disease represents a (AD) breakdown of natural
tolerance against autoreactive antigens leading to a high mortality and morbidity.
The reaction is usually polyclonal; T- and B-cell components of the hematopoietic
system are responsible for disease progression. Allogeneic/ autologous
hematopoietic stem cell transplantation (HSCT) are the current modalities
for treating drug-resistant AD. Patients and Methods. We present a single-
center retrospective evaluation of allogeneic HSCT with nonmyelo-ablative,
low-intensity conditioning in nine patients (five males, four females) with
pemphigus vulgaris (PV) and 27 patients with systemic lupus erythematosus
(SLE; 3 males, 24 females). The mean follow-up period was 4.24 years for PV
and 4.9 years for SLE. Cytokine-mobilized HSC from unmatched related donors,
with mean dose of 21.3108 nucleated cells/kg body weight (BW; mean CD34⁺
count, 6 x 10⁶/kg BW) was administered in to the thymus as well as the portal and
peripheral circulations of recipients. Cyclosporine (4 + 1 mg/kg BW per day) and
prednisolone (10 mg/kg BW per day) were administered for 6 months to protect
mixed chimerism. A subset of patients with cross-gender donors were analyzed
for peripheral blood chimerism at 1 month post-HSCT and every 3 months
thereafter. Results. Sustained clinical remission with peripheral lymphohemato-
poietic chimerism of 0.7 + 0.3% was observed in PV, whereas SLE relapsed after
mean of 7.35 months of disease-free interval associated with fall in chimerism
from 5 + 3% to 0.08 + 0.03%. Conclusion. HSCT was effective to achieve early
clinical remission of PV; and in SLE relapsed after a 7.35-month disease-free
interval accompanied by a fall in mixed lymphohematopoietic chimerism.

Hematopoietic Stem Cell Transplantation in Children and Young Adults
with Secondary Myelodysplastic Syndrome and Acute Myelogenous
Leukemia after Aplastic Anemia

Ayami Yoshimi, B Strahm, I Baumann, I Furlan, S Schwarz, …, CM Niemeyer
Biol Blood Marrow Transplant 20 (2014) 421-434
http://dx.doi.org/10.1016/j.bbmt.2013.11.031

Secondary myelodysplastic syndrome and acute myelogenous leukemia
(sMDS/sAML) are the most serious secondary events occurring after immuno-
suppressive therapy in patients with aplastic anemia. Here we evaluate the
outcome of hematopoietic stem cell transplantation (HSCT) in 17 children
and young adults with sMDS/sAML after childhood aplastic anemia. The
median interval between the diagnosis of aplastic anemia and the development
of sMDS/sAML was 2.9 years (range, 1.2 to 13.0 years). At a median age of
13.1 years (range, 4.4 to 26.7 years), patients underwent HSCT with bone
marrow (n = 6) or peripheral blood stem cell (n = 11) grafts from HLA-
matched sibling donors (n = 2), mismatched family donors (n = 2), or
unrelated donors (n = 13). Monosomy 7 was detected in 13 patients. The
preparative regimen consisted of busulfan, cyclophosphamide, and melphalan
in 11 patients and other agents in 6 patients. All patients achieved neutrophil
engraftment. The cumulative incidence of grade II-IV acute graft-versus-host
disease (GVHD) was 47%, and that of chronic GVHD was 70%. Relapse
occurred in 1 patient. The major cause of death was transplant-related
complication (n = 9).Overall survival and event-free survival at 5 years after
HSCT were both 41%.In summary, this study indicates that HSCT is a curative
therapy for some patients with sMDS/sAML after aplastic anemia. Future
efforts should focus on reducing transplantation-related mortality.

Hematopoietic stem cells: An overview

Youssef Mohamed Mosaad
Transfusion and Apheresis Science 51 (2014) 68–82
http://dx.doi.org/10.1016/j.transci.2014.10.016

Considerable efforts have been made in recent years in understanding the
mechanisms that govern hematopoietic stem cell (HSC) origin, development,
differentiation, self-renewal, aging, trafficking, plasticity and trans-differentiation.
Hematopoiesis occurs in sequential waves in distinct anatomical locations during
development and these shifts in location are accompanied by changes in the
functional status of the stem cells and reflect the changing needs of the
developing organism. HSCs make a choice of either self-renewal or committing
to differentiation. The balance between self-renewal and differentiation is
considered to be critical to the maintenance of stem cell numbers. It is still
under debate if HSC can rejuvenate infinitely or if they do not possess ‘‘true”
self-renewal and undergo replicative senescence such as any other somatic
cell. Gene therapy applications that target HSCs offer a great potential for the
treatment of hematologic and immunologic diseases. However, the clinical
success has been limited by many factors. This review is intended to
summarize the recent advances made in the human HSC field, and will
review the hematopoietic stem cell from definition through development
to clinical applications.

HLA epitope based matching for transplantation

René J. Duquesnoy
Transplant Immunology 31 (2014) 1–6
http://dx.doi.org/10.1016/j.trim.2014.04.004

As important risk factors for transplant rejection and failure, HLA antibodies
are now recognized as being specific for epitopes which can be defined
structurally with amino acid differences between HLA alleles. Donor–recipient
compatibility should therefore be assessed at the epitope rather than the
antigen level. HLA Matchmaker is a computer algorithm that considers each
HLA antigen as a series of small configurations of polymorphic residues
referred to as eplets as essential components of HLA epitopes. It includes
epitopes on antigens encoded by all HLA-A, B, C, DR, DQ and DP loci as
well as MICA. HLA epitopes have two characteristics namely antigenicity, i.e.
the reactivity with antibody and immunogenicity, i.e. the ability of eliciting
an antibody response. This article addresses the relevance of determining
epitope-specificities of HLA antibodies, the effect of epitope structure on
technique-dependent antibody reactivity and the identification of acceptable
mismatches for sensitized patients considered for transplantation. Permissible
mismatching for non-sensitized patients aimed to prevent or reduce HLA
antibody responses could consider epitope loads of mismatched antigens and
the recently developed nonself-self paradigm of epitope immunogenicity.

Impact of HLA Mismatch Direction on the Outcome of Unrelated Bone
Marrow Transplantation: A Retrospective Analysis from the Japan
Society for Hematopoietic Cell Transplantation

Junya Kanda, T Ichinohe, S Fuji, Y Maeda, K Ohashi, …, Y Atsuta,
Y Kanda, on behalf of the HLA Working Group of the Japan Society
for Hematopoietic Cell Transplantation
Biol Blood Marrow Transplant 21 (2015) 305e311
http://dx.doi.org/10.1016/j.bbmt.2014.10.015

The relative desirability of an unrelated donor with a bidirectional 1-locus
mismatch (1MM-Bi), a 1-locus mismatch only in the graft-versus-host direction
(1MM-GVH), or a 1-locus mismatch only in the host versus-graft direction
(1MM-HVG) is not yet clear. We analyzed adult patients with leukemia or
myelodysplastic syndrome who received a first allogeneic stem cell transplant
from an HLA-A, -B, -C, and -DRB1 matched or 1-allele mismatched unrelated
donor in Japan. The effects of 1MM-Bi (n = 1020), 1MM-GVH (n = 83), and
1MM-HVG (n = 83) compared with a zero mismatch (0MM) (n = 2570)
were analyzed after adjusting for other significant variables. The risk of
grades III to IV acute graft-versus-host disease (GVHD) was higher with
marginal significance in the 1MM-GVH group than in the 0MM group
(hazard ratio, 1.85; P = .014). However, there was no significant difference
in overall or nonrelapse mortality between the 1MM-GVH and 0MM groups.
There was no significant difference in acute GVHD or overall or nonrelapse
mortality between the 1MM-HVG and 0MM groups. The risks of acute
GVHD and overall mortality were significantly higher in the 1MM-Bi group
than in the 0MM group. These findings indicate that unrelated donors with
1MM-GVH and 1MM-HVG are both good candidates for patients without an
HLA-matched unrelated donor in a Japanese cohort.

ABO incompatibility between donor and recipient and clinical
outcomes in allogeneic stem cell transplantation

James Goldman, Jane Liesveld, Diane Nichols, Joanna Heal, Neil Blumberg
Leukemia Research 27 (2003) 489–491 PII: S0145-2126(02)00259-X

We performed a retrospective, cohort study to evaluate the impact on recipient
survival of ABO incompatibility between recipient and donor after allogeneic
stem cell transplantation, primarily involving marrow-derived cells. No
statistically significant difference was noted in survival for 153 patients
with acute or chronic leukemia or myelodysplastic syndrome receiving
ABO identical or ABO mismatched allografts. Five patients who had
allografts that were bidirectionally incompatible (both donor cells and
plasma incompatible) did have significantly poorer survival than the other
recipients, similar to the experience reported in one other cohort study.
However, these patients had other risks for mortality, including being
older and receiving transplants from matched, unrelated donors. Our
data do not support a significant role for ABO donor–recipient matching in
allogeneic stem cell transplantation.

Allogeneic Hematopoietic Cell Transplantation Outcomes in
Acute Myeloid Leukemia: Similar Outcomes Regardless of
Donor Type

Erica D. Warlick, RP de Latour, R Shanley, …, Gerard Socie
Biol Blood Marrow Transplant 21 (2015) 357e363
http://dx.doi.org/10.1016/j.bbmt.2014.10.030

The use of alternative donor transplants is increasing as the transplantation-
eligible population ages and sibling donors are less available. We
evaluated the impact of donor source on transplantation outcomes for
adults with acute myeloid leukemia undergoing myeloablative (MA) or
reduced-intensity conditioning (RIC) transplantation. Between January 2000
and December 2010, 414 consecutive adult patients with acute myeloid
leukemia in remission received MA or RIC allogeneic transplantation from
either a matched related donor (n = 187), unrelated donor (n = 76), or
umbilical cord blood donor (n = 151) at the University of Minnesota or
Hôpital St. Louis in Paris. We noted similar 6-year overall survival
across donor types: matched related donor, 47% (95% confidence interval
[CI], 39% to 54%); umbilical cord blood, 36% (95% CI, 28% to 44%);
matched unrelated donor, 54% (95% CI, 40% to 66%); and mismatched
unrelated donor, 51% (95% CI, 28% to 70%) (P < .11). Survival differed
based on conditioning intensity and age, with 6-year survival of 57% (95% CI,
47% to 65%), 39% (95% CI, 28% to 49%), 23% (95% CI, 6% to 47%), 47%
(95% CI, 36% to 57%), and 28% (95% CI, 17% to 41%) for MA age 18 to 39,
MA age 40þ, or RIC ages 18 to 39, 40 to 56, and 57 to 74, respectively
(P < .01). Relapse was increased with RIC and lowest in younger patients
receiving MA conditioning (hazard ratio, 1.0 versus 2.5 or above for all RIC
age cohorts), P <.01. Transplantation-related mortality was similar across
donor types. In summary, our data support the use of alternative donors as
a graft source with MA or RIC for patients with acute myeloid leukemia
when a sibling donor is unavailable.

A Novel Reduced-Intensity Conditioning Regimen for Unrelated Umbilical
Cord Blood Transplantation in Children with Nonmalignant Diseases

Suhag H. Parikh, A Mendizabal, CL Benjamin, KV Komandur, J Antony, et al.
Biol Blood Marrow Transplant 20 (2014) 326e336
http://dx.doi.org/10.1016/j.bbmt.2013.11.021

Reduced-intensity conditioning (RIC) regimens have the potential to decrease
transplantation-related morbidity and mortality. However, engraftment
failure has been prohibitively high after RIC unrelated umbilical cord blood
transplantation (UCBT) in chemotherapy-naïve children with nonmalignant
diseases (NMD). Twenty-two children with a median age of 2.8 years, many
with severe comorbidities and prior viral infections, were enrolled in a novel RIC
protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and
thiotepa followed by single UCBT. Patients underwent transplantation for
inherited metabolic disorders (n = 8), primary immunodeficiencies (n = 9),
hemoglobinopathies (n = 4) and Diamond Blackfan anemia (n = 1). Most
umbilical cord blood (UCB) units were HLA-mismatched with median infused
total nucleated cell dose of 7.9 107/kg. No serious organ toxicities were
attributable to the regimen. The cumulative incidence of neutrophil engraftment
was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20
days, with the majority sustaining > 95% donor chimerism at 1 year. Cumulative
incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV
by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%),
respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95%
CI, 0% to 20.8%). The primary causes of death were viral infections (n ¼ 3), acute
GVHD (n = 1) and transfusion reaction (n ¼ 1). One-year overall and event-free
survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6%
to 83.4%) with 31 months median follow-up. This is the first RIC protocol
demonstrating durable UCB engraftment in children with NMD. Future risk-
based modifications of this regimen could decrease the incidence of viral
infections. (www.clinicaltrials.gov/NCT00744692).