Download Mini-review Genetically haploidentical stem cell transplantation for

Bone Marrow Transplantation (2001) 27, 669–676
 2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00
www.nature.com/bmt
Mini-review
Genetically haploidentical stem cell transplantation for acute leukemia
JM Rowe and HM Lazarus
Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center and Bruce Rappaport Faculty of Medicine,
Technion, Haifa, Israel; and Department of Medicine, Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, OH,
USA
Summary:
Genetically haploidentical stem cell transplants have
been performed for several decades, mostly for patients
with advanced acute leukemia. Such transplants are an
option for those patients who do not have a histocompatible sibling donor. The historical data have been disappointing due to graft-versus-host disease, engraftment
failure and delayed immune reconstitution. Recent
modifications and new technological developments have
led to more encouraging clinical results. Haploidentical
transplantation is immediately available to the majority
of patients with acute leukemia and is an acceptable
alternative to matched unrelated donor transplantation.
Bone Marrow Transplantation (2001) 27, 669–676.
Keywords: haploidentical transplantation; acute leukemia
Allogeneic stem cell transplantation – using blood or marrow as the source – provides curative therapy for a substantial number of patients with hematological malignancies
and immunodeficiency syndromes. This procedure is associated with substantial morbidity and mortality, even if performed using an HLA-matched sibling donor. In fact, during the first three decades of bone marrow transplantation
more than 95% of allogeneic transplants were performed
from sibling matched donors. Over the past decade the proliferation of transplant registries for matched unrelated
donors as well as sensitive molecular methods of tissue
typing have provided the opportunity for increasing use of
alternative donors, mostly matched unrelated donors, using
marrow or peripheral blood and also including stem cells
obtained from umbilical cord or fetal liver. Improvements
in the precision of HLA-typing methologies have resulted
in identification of more closely matched donors, which in
principle, will result in a lower incidence and severity of
graft-versus-host disease (GVHD) and improved survival.1,2 A few authors have reported that in some disease
settings, such as chronic myeloid leukemia, unrelated donor
transplant results approach those of sibling-matched alloCorrespondence: Dr JM Rowe, Dept Hematology and Bone Marrow
Transplantation, Rambam Medical Center and Bruce Rappaport Faculty
of Medicine, Technion, Haifa 31096, Israel
grafts.3 However, this procedure has an even greater morbidity and mortality than transplants which utilize sibling
matched donors. Furthermore, unrelated donor transplants
are usually not available to the majority of patients who
require this therapy urgently, due to the long time required
to search for such a donor.
Another potential alternative donor is a genetically haploidentical family member. Such a donor is readily available in 90% of patients and over the past decade significant
strides have been made in increasing the feasibility of such
transplants by overcoming many of the historical barriers
to this procedure. Due to the ease of donor accessibility in
most instances, haploidentical transplants have been
attempted over the past two decades. However, initial
efforts were largely unsuccessful due to the overwhelming
mortality associated with these procedures. The cardinal
problems were those of intractable GVHD4,5 and graft
rejection after transplants in which T cells were depleted
from the donor cells.6,7 It soon became apparent that the
standard conditioning regimen used at that time was not
sufficiently immunosuppressive and failed to eradicate the
cytotoxic T lymphocytes in the recipients, thus allowing
graft rejection to occur unhindered (Table 1).6,8,9
A further major complication of haploidentical transplants has been the slow immune reconstitution that puts
the patient at risk for severe morbidity and mortality for a
Table 1
Major issues in haploidentical stem cell transplantation
Barriers to successful outcome
Current or potential solutions
Graft failure
Megadoses of CD34 donor cells44,46
Immunosuppressive conditioning
regimen41
Selective myeloablative
conditioning regimen32,33
Intractable GVHD
Maximal donor-cell immune
suppression41
T cell depletion19–22
Costimulatory blockade18
Delayed immune reconstitution
Cytokine manipulation53
Adoptive cellular immunotherapy56
Use of non-alloreactive CTL24
↓ GVL
NK cell alloreactivity (KIR epitopemismatching)64,65
Genetically haploidentical SCT for acute leukemia
JM Rowe and HM Lazarus
670
significantly longer period of time when compared to an
HLA-matched sibling donor transplant. This effect remains
even when adequate engraftment has occurred and GVHD
is absent or well controlled, and often leads to viral, fungal
or other opportunistic infections.10–12
Although haploidentical transplantation has been sporadically performed over the past two decades it is only in
the past few years that the emerging data suggest that such
a procedure may have a role in patients other than those in
desperate straits (Table 2). A factor that has confounded
interpretation of the data with haploidentical transplants has
been the inherent advanced disease among recipients of this
procedure.13–18 Inclusion of such a poor-risk patient population must be considered when interpreting the transplantrelated morbidity and mortality as well as the high rate
of relapse.
Over the past decade major attempts have been made to
successfully overcome, or ameliorate, some of these problems enabling haploidentical transplants to be conducted
more safely and with more promising long-term efficacy
(Table 1). These directions will now be summarized.
Graft-versus-host disease (GVHD)
Historically, GVHD was one of the overwhelming problems associated with haploidentical transplantation making
the danger of such a procedure almost prohibitive. In one
of the largest early reports4,5 it was clearly shown that the
risk of acute GVHD was significantly increased in patients
receiving marrow grafts from donors incompatible from
one, two, or three HLA loci. In fact, there was a direct
relationship between the degree of HLA incompatibility
and the risk for the development of acute GVHD.2 As a
group, patients receiving marrow grafts from HLA-incompatible donors had a relative risk for the reaction of 3.23
as compared with controls. The risk of severe acute GVHD
was over 80% among patients who were incompatible for
three HLA loci.
Methods to prevent the high rate of GVHD have relied
upon altering the donor graft immunologic capabilities by
removal of, or suppressing the function of all donor T cells
regardless of their immunologic specificity.19–22 (Table 3).
It is clear that the more profound the degree of T cell
depletion the lower the risk for the development of acute
GVHD. Infusion below a threshold of approximately 1–5
⫻ 104 CD3-positive cells per kg is usually sufficient to
prevent the development of GVHD and can often enable
such transplants to be performed without any GVHD
prophylaxis.23,24 However, any relationship linking the
Table 2
grafts
Logistic advantages of haploidentical family member allo-
Immediate donor availability
No racial, ethnic restrictions
Multiple donors: select for gender, age, CMV status
Continued donor access: additional cells for later immunologic
initiatives
Decreased costs: no banking or registration fees, less HLA typing
Bone Marrow Transplantation
degree of T cell depletion to the subsequent development
of GVHD clearly is dependent on many other factors
including the degree to which the patient has been previously treated and, most importantly, the level of immune
suppression afforded by the conditioning regimen. Thus,
the effects, positive and negative, of T cell depletion cannot
be considered in isolation.25
Recently, promising work in this area has demonstrated
that inactivation of a select segment of the alloreactive T
cell repertoire, through blockade of B7-mediated T cell
costimulation, is possible and appears to result in a significant reduction in the risk of GVHD without an excessive
risk for graft failure. Donor bone marrow may be treated
ex vivo by co-culture with irradiated cells from the recipient
in the presence of CTLA-4-Ig – an agent that inhibits
B7:CD28-mediated co-stimulation – to induce anergy to
alloantigens from the recipient with the subsequent relatively low risk of GVHD.18–26 Preliminary clinical data
using this novel approach have been encouraging, albeit in
a small number of patients.
Other approaches to T cell depletion have included selective depletion of CD8⫹ T lymphocytes by ex vivo treatment
of the donor bone marrow with anti-Leu-2 monoclonal antibody and complement.27 However, although this maneuver
may abrogate the severity of GVHD, there are, as yet, no
data in haploidentical transplantation that such manipulation, in itself, would reduce the risk of graft failure
following T cell depletion.28
Graft failure
Strategies designed to reduce the risk for GVHD have not
permitted the safe performance of haploidentical transplants. The cardinal problem lies in the fact that donor T
cells facilitate engraftment, and assist in immunological
reconstitution of the host. These actions prevent opportunistic infections, as well as contribute to the direct anti-tumor
effect of the graft. Thus, T cell depletion of a graft prevents
GVHD but theoretically exacts a prohibitive price. Historically, this effect was certainly true, but advances over the
past 5 years have made major strides in this direction. It
was originally believed that barriers to engraftment could
be overcome by increasing the intensity of the conditioning
regimen especially with higher doses of total body
irradiation (TBI) and/or various combinations of high doses
of myeloablative and immunosuppressive regimens.16,29–31
However, it soon became apparent that such intensive preparative regimens led to major organ toxicity in heavily
pre-treated patients with advanced disease.
A decade ago it was demonstrated that graft failure also
could be mediated by the competition of residual host hematopoietic progenitor cells which survive the conditioning
together with the donor stem cells.32,33 Thus was born the
concept of selective myeloablative therapy using drugs that
are particularly potent stem cell toxins such as melphalan,33
busulphan or thiotepa,34 usually in combination with TBI.
In general, TBI is an integral part of the conditioning regimen for haploidentical transplants, although, in patients
who are unable to receive TBI, successful engraftment also
can be established without this modality.35 Although, his-
Genetically haploidentical SCT for acute leukemia
JM Rowe and HM Lazarus
Table 3
671
Methods of ex vivo T cell depletion of allogeneic donor grafts in clinical trials
Product name
Reagent type
Target
Species
Method
Comments
MAB
MAB
MAB
immunoconjugate
MAB
MAB
MAB
CD2
CD3
CD4
CD5
CD6
CD7
CD8
murine
murine
murine
murine
murine
murine
murine
C⬘ lysis or IM
C⬘ lysis or IM
IM
ricin conjugate
C⬘ lysis or IM
C⬘ lysis or IM
C⬘ lysis or IM
T cells and NK cells
Campath-1G
IgG MAB
CD52
rat
C⬘ lysis
Campath-1M
IgM MAB
CD52
rat
C⬘ lysis
Campath-1H
MAB
CD52
humanized rat
C⬘ lysis
T10B9
SBA
MAB
lectin
TCR␣␤
N-acetyl
galactosamine
CD2
murine
plant
multiple T cell
antigens
pan-T cell
murine
C⬘ lysis
agglutination ⫹
e-rosetting
e-rosetting ⫹
centrifugation
C⬘ lysis or IM
horse
C⬘ lysis
pan-T cell
rabbit
C⬘ lysis
murine
counterflow centrifugal
centrifugation
cell selection device, IM
Orthoclone OKT3
XomaZyme anti-T12
Sheep RBC
MAB combinations
Atgam
Thymoglobulin
cell
MABs
polyclonal
antibody
polyclonal
antibody
sheep
Avanti J centrifuge
(Beckman Coulter)
MAB
CD34
helper T cells
T and B cell subsets
T and NK cell subsets
CD8 T cells and NK cell
subsets
T and B cells and
monocytes
T and B cells and
monocytes
T and B cells and
monocytes
various cocktails of MAB
primarily use in in vivo T
cell depletion
primarily use in in vivo T
cell depletion
requires elutriation rotor
and chamber
‘indirect’ T cell depletion
via positive selection of
CD34 cells
MAB ⫽ monoclonal antibody; SBA ⫽ soybean agglutinin; RBC ⫽ red blood cell; C⬘ ⫽ complement; IM ⫽ immunomagnetic separation; TCR␣␤ ⫽
T cell receptor alpha beta.
torically, TBI was given at higher total doses than when
used for matched sibling donors,15 more recent clinical
results suggest that this maneuver may not be required.17
Multiple other refinements to conventional conditioning
regimens have been studied, all in an attempt to facilitate
engraftment without excessive GVHD. Fludarabine is now
commonly used in such conditioning regimens17 and other
immunosuppressive manipulations include high-dose
methylprednisolone,36 total nodal irradiation,7 anti-T cell
antibodies37,38 as well as increasing use of antithymocyte
globulin (ATG).17,36,39,40
It is clear that one of the most difficult issues in the
clinical performance of haploidentical transplantation has
been the attempt to balance the necessary degree of myeloablation and immunosuppression with the resulting regimen-related toxicity. Attempts to ameliorate such toxicity
have also focused on careful timing of sequential administration of myeloablative drugs and immunosuppressive
therapy recognizing that procedural morbidity and mortality
may be reduced if such toxic substances are not given simultaneously. Some successful experience has been published by the University of South Carolina.41 With over 210
patients reported, the median time to engraftment was 16
days among patients in whom ATG was added to the TBIbased conditioning regimen.41
Probably one of the most important developments in the
increasing use of haploidentical transplantation has been
reports from the University of Perugia, Italy,17 of the successful use of a relatively nontoxic conditioning regimen
using thiotepa, a single TBI dose of only 800 cGy, fludarabine and antithymocyte globulin. The 30-day treatmentrelated mortality from this conditioning regimen is about
10% and relies on fundamental work that established the
concept that escalation of the stem cell dose directly contributed to the likelihood of the establishment of donor type
chimerism. Cells within the CD34⫹ compartment possess
potent veto activity, which enable cells to neutralize cytotoxic T lymphocyte precursors (CTL-p) directed against
veto cell antigens. The greater the number of CD34 stem
cells, the greater the induction of tolerance.42,43 In humans,
the concept of stem cell dose escalation was tested after
technologies for the collection of peripheral blood progenitor cells became available following mobilization with
cytokines.44,45 Megadoses of CD34 cells, eg, 10 ⫻ 106
cells/kg, could be collected, T cell depleted, and infused
and could successfully ensure engraftment, without the
induction of excess GVHD.46 This method has now become
widely established and probably offers the greatest promise
for current and future studies of haploidentical transplantation.47
Bone Marrow Transplantation
Genetically haploidentical SCT for acute leukemia
JM Rowe and HM Lazarus
672
It appears that T cell-depleted allografts only have a limited capacity to reconstitute marrow mesenchymal cells.48
Such mesenchymal cells not only contribute to the bone
marrow microenvironment, but may also possess immunosuppressive properties. That could attenuate GVHD.49 It
may well be that, ideally, ex vivo generated mesenchymal
cells, capable of long-term functional capacity, need to be
administered as a supplement to T cell-depleted stem cell
allografts to improve marrow stromal reconstitution.48
Delayed immune reconstitution
Having largely overcome the problems of engraftment and
prevention of excessive GVHD, much of the focus for haploidentical transplants has centered on the marked delay in
immune reconstitution in the months and years post transplant. The immune recovery after intensive T cell depletion
that can now be achieved (infusing less than 5 ⫻ 104 CD3
cells per kg) has been associated with a very high risk for
post-transplant viral, fungal and other opportunistic infections.10,50,51 The delay in immunologic reconstitution is the
single most important cause of mortality in adults undergoing haploidentical bone marrow transplantation which may
reach as high as 40% during the months and years post
transplant.17 Following absolute T cell depletion it may take
anywhere from 6 to 18 months for the CD4 cells to recover.
The problem of delayed immunity is not merely due to
the low number of T cells given with the graft. In adults,
the decreased thymic function is of major importance.52
Monocytes and dendritic cells, as well as other antigenpresenting cells, are also vital for the antigen-specific
immunity. IL-12 is known to be a major cytokine in the
initiation of protective Th 1 immunity against opportunistic
infections and viruses. The observation that use of G-CSF
post transplant to speed engraftment blocks IL-12 production by the antigen-presenting cells led to the discontinuation of the routine use of the cytokine post transplant.
Preliminary clinical data indicate a more rapid rate of
immune reconstitution, including the recovery of CD4
cells, at 3 months post transplant53 with no adverse effect
on the rate of engraftment.42
A promising method for restoring specific immunity after
transplants, albeit highly specialized and cumbersome,
relies upon adoptive transfer of specific T cell clones. The
potential and clinical use of this approach has been applied
to many infections including candida, aspergillus and toxoplasma.24,54 The most extensive data have come from
investigators at the Fred Hutchinson Cancer Research
Center in Seattle,55,56 who developed a reliable method for
the adoptive transfer of CMV-specific T cell clones. CMVspecific T cells are obtained from the haploidentical donor
and the host T cells may be the target of alloreactivity.
Donor T cells with specific reactivity for CMV antigens
are cloned, a process which is time-consuming and also is
technically complex. Infusion of such cells has resulted in
very specific targeted immunity to CMV. Although not a
routine laboratory procedure, the development of such
adoptive therapy is clearly another promising clinical
avenue to reduce the post-transplant toxicity from infection.
An approach, currently in the experimental design stage,
Bone Marrow Transplantation
involves the use of nonalloreactive T cells generated by
purging IL-2 receptor (CD25) mixed lymphocyte response
(MLR)-reactive T cells.57 Promising clinical data have also
been reported when anergy is induced after incubation with
CTLA-4.18,58,59 These methods for costimulatory blockade
provide a theoretical means to induce tolerance and are
likely to be more extensively studied over the next few
years.
Nevertheless, some authors have urged caution with
these approaches. Induction of tolerance might involve
some risk for the development of severe GVHD by generating committed cytotoxic T lymphocytes (CTLs), should any
of the CTL-p escape deletion or anergy induction. Once
such anti-host CTLs are generated, it is very difficult to
suppress their alloreactivity in vivo.24 Another approach
currently being evaluated is based on earlier studies which
showed that CD8⫹ CTL clones possess extremely high veto
activity.60 Preliminary data from the Weizmann Institute in
Israel have focused on depleting such veto cells of alloreactive activity by generating non-alloreactive anti-third-party
CTL clones. These cells are then evaluated by their
capacity to facilitate engraftment of purified Sca-1⫹ Lin⫺
hematopoietic progenitors in sublethally irradiated mismatched recipients.24,47,61–63 If successful, such an approach
will drastically reduce the morbidity and mortality from
impaired immunity post haploidentical transplantation and
make this transplant approach more commonplace.
Impaired anti-tumor response
T cell depletion carries a high risk of leukemic relapse due
mostly to abrogation of the graft-versus-leukemia effect. It
thus seemed, at first, paradoxical that clinical reports of the
most recent data in patients with advanced AML suggest a
relatively low rate of relapse, especially in patients with
acute myelogenous leukemia.17 However, recent work has
suggested that donor NK cell alloreactivity may play a significant role in graft-versus-leukemia effect.64,65 Donor NK
cell alloreactivity probably is unique to mismatched transplants, as the donor NK cell killer inhibitory receptors
(KIR) do not recognize the MHC allotypes of the recipient
as ‘self’. In this way these donor cells lyse the recipients’
hematopoietic cells. Thus, NK cells originating post transplant from the donor stem cells do not exhibit tolerance
towards the new host and a significant number of donortype NK cells clones are alloreactive against the recipient.65
Whether they exhibit such alloreactivity depends upon the
recognition of a particular epitope shared by specific
HLA allotypes.
In long-term follow-up of 75 high-risk AML patients the
effect of this NK alloreactivity appeared to be impressive.
Only one relapse occurred in 28 patients transplanted from
donors with the potential to transfer anti-recipient NK alloreactivity. In contrast, 14 out of 47 patients relapsed when
transplanted with grafts obtained from donors who could
not transfer anti-recipient NK cell alloreactivity (P ⬍
0.05).66 Thus, these clinical data strongly support the
hypothesis that only in mismatched transplants a graft-versus-leukemia effect, independent of T cell-mediated GVH
reactions, controls leukemia relapse when KIR epitope
Genetically haploidentical SCT for acute leukemia
JM Rowe and HM Lazarus
incompatibility is in the GVHD direction. These authors
therefore suggested that donor-versus-recipient NK cell
alloreactivity may become a major criteria for donor selection in mismatched hematopoietic stem cell transplants.
Clinical perspective
While the performance of sibling-matched allogeneic transplantation has increased over the past four decades, it still
can only be offered to the minority of patients who might
benefit from such a transplant. The majority of individuals
do not have an HLA-matched sibling donor and many are
beyond the age where this can be performed reasonably
safely.
For those subjects who lack an HLA-matched sibling
donor, and are otherwise suitable candidates, a matched
unrelated donor transplant is often performed. Although
success rates are increasing67–69 this procedure carries with
it a high transplant-related mortality (30–40%) and a very
high long-term morbidity. For advanced leukemia it is
rarely successful, as many such patients do not survive the
long waiting period (3–6 months) until a suitable donor can
be found.
The largest recent update of matched unrelated transplants has come from the Fred Hutchinson Cancer Research
Center in Seattle. These investigators reported that the longterm leukemia-free survival for the 81 patients with
relapsed acute myelogenous leukemia was only 7%.70 Furthermore, patient selection or ‘survivability’ greatly affects
these results. A patient must survive the long waiting period
to eventually allow a donor to be identified thereby excluding most of the patients. In fact, there has never been an
intent-to-treat analysis of matched unrelated donor transplants for advanced acute myeloid leukemia (AML).
Haploidentical bone marrow transplantation offers a
ready alternative to matched unrelated donor transplants.
About 90% of patients have a suitable donor and the procedure can be offered within a very short period of time.
The most recent experience published from the University
of Perugia, Italy, suggests that associated morbidity and
mortality do not exceed that reported for matched unrelated
donor transplants; most importantly, in AML, there is not
an excessive risk of relapse.17,47 A further update71 on 111
patients with acute leukemia is shown in Figure 1. The 51.0
year event-free survival for patients with refractory disease
was a disappointing 15%. Such data, however, included all
patients – including those who would never have survived
long enough to wait for an unrelated donor to be found. In
contrast, for 27 patients with very high risk features in first
or second complete remission the 5-year event-free survival
was 45% with a relapse rate of less than 15% (Figure 2).
This same Perugia group has strongly recommended,
with supporting data of reduced transplant-related mortality, the use of the CliniMACS (Miltenyi Biotech,
Bergisch Gladbach, Germany) for positive CD34 cell selection. In sequential studies, using different stem cell columns
for CD34⫹ selection, the transplant-related mortality was
63% using the Isolex (Baxter, Deerfield, IL, USA), 42%
with the Ceprate (CellPro, Bothell, WA, USA) vs only 20%
with the CliniMACS.72 Although these are not prospective
comparisons, and greater patient numbers are required,
these data cautiously support the preferential use of the CliniMACS. With small patient numbers, other groups are
reporting similar data, using the same approach as the Perugia group.73 However, another report with few patients
using this approach – but with the Isolex columns – was
less enthusiastic.74 Other groups are reporting on different
technologies, such as the blockade of B7-mediated T cell
costimulation,18 and others have not yet reported their
experience although this form of transplantation is being
increasingly performed.
Conclusion
Haploidentical bone marrow transplantation clearly is a
viable option for those patients who do not have an HLAcompatible sibling donor. Almost all patients have a genetically haploidentical family member and the procedure can
be performed without delay. Although the clinical experience is limited, recent data are encouraging and suggest
that this procedure is an acceptable alternative to matched
unrelated donor transplantation and, in certain circumstances, may be the preferred option. Much progress has
been made in the control of GVHD without increasing the
rate of non-engraftment. The most encouraging data,
reporting on a rapid rate of engraftment, have followed the
use of ‘mega doses’ of stem cells obtained from the donor
peripheral blood. Of particular note, it appears that in some
Event-free survival
n = 111
0.9
0.8
0.7
Probability
Probability
0.8
High-risk CRI/CRII
n = 27
0.5
0.4
0.3
Relapse/refractory
n = 84
0.2
0.1
0
Relapse
n = 111
1.0
0.9
0.6
0
1
2
Relapse/refractory
n = 84
0.7
0.6
0.5
0.4
0.3
0.2
P < 0.007
High-risk CRI/CRII
n = 27
P < 0.002
0.1
3
4
5
6
7
Years
Figure 1 Event-free survival for 111 patients with acute leukemia who
underwent haploidentical transplantation at the University of Perugia,
Italy, April 1993 to June 2000.
673
0
0
1
2
3
4
5
6
7
Years
Figure 2 Risk for post-transplant relapse of leukemia, April 1993 to
June 2000.
Bone Marrow Transplantation
Genetically haploidentical SCT for acute leukemia
JM Rowe and HM Lazarus
674
T cell-depleted haploidentical transplants, an NK-mediated
graft-versus-leukemia effect may be in place, leading to a
reportedly low rate of relapse.
Post-transplant infectious complications remain the single most important barrier yet to be overcome. New directions in the use of adoptive cellular immunity appear to be
most promising, although such a procedure remains highly
specialized. Preclinical data demonstrating that anti-thirdparty non-alloreactive cytotoxic T lymphocytes may
improve immunologic reconstitution in dramatic fashion,
have yet to be successfully reported in humans.
The use of prospective, multi-center, controlled clinical
trials and companion translational studies will further
improve upon this modality.
References
1 Petersdorf EW, Gooley T, Anasetti C et al. Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and
recipient. Blood 1998; 92: 3515–3520.
2 Sasazuki T, Juji T, Morishima Y et al. Effect of matching of
class I HLA alleles on clinical outcome after transplantation of
hematopoietic stem cells from an unrelated donor. New Engl J
Med 1998; 339: 1177–1185.
3 Lamparelli T, Van Lint MT, Gualandi F et al. Bone marrow
transplantation for chronic myeloid leukemia from unrelated
and sibling donors: single center experience. Bone Marrow
Transplant 1997; 20: 1057–1062.
4 Beatty PG, Clift RA, Mickelson EM et al. Marrow transplantation from related donors other than HLA-identical siblings.
New Engl J Med 1985; 313: 765–771.
5 Anasetti C, Amos D, Beatty PG et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients
with leukemia or lymphoma. New Engl J Med 1989; 320:
197–204.
6 Kernan NA, Flomenberg N, Dupont B, O’Reilly RJ. Graft
rejection in recipients of T-cell-depleted HLA-nonidentical
marrow transplants for leukemia. Identification of host-derived
antidonor allocytotoxic lymphocytes. Transplantation 1987;
43: 842–847.
7 Soiffer RJ, Mauch P, Tarbell NJ et al. Total lymphoid
irradiation to prevent graft rejection in recipients of HLA nonidentical T cell-depleted allogeneic marrow. Bone Marrow
Transplant 1991; 7: 23–33.
8 Reisner Y, Ben-Bassat I, Douer D et al. Demonstration for
clonable alloreactive host T cells in a primate model for bone
marrow transplantation. Proc Natl Acad Sci USA 1986; 83:
4012–4015.
9 Butturini A, Seeger RC, Gale RP. Recipient immune competent T lymphocytes can survive intensive conditioning for
bone marrow transplantation. Blood 1986; 68: 954–956.
10 Kook H, Goldman F, Padley D et al. Reconstruction of the
immune system after unrelated or partially matched T-celldepleted bone marrow transplantation in children: immunophenotypic analysis and factors affecting the speed of recovery. Blood 1996; 88: 1089–1097.
11 Ochs L, Shu XO, Miller J et al. Late infections after allogeneic
bone marrow transplantation: comparison of incidence in
related and unrelated donor transplant recipients. Blood 1995;
10: 3979–3986.
12 Sullivan KM, Mori M, Sanders J et al. Late complications of
allogeneic and autologous marrow transplantation. Bone Marrow Transplant 1992; 10: (Suppl. 1) 127–134.
Bone Marrow Transplantation
13 Fleming DR, Henslee-Downey PJ, Romond EH et al. Allogeneic bone marrow transplantation with T-cell-depleted partially matched related donors for advanced acute lymphoblastic leukemia in children and adults: a comparative matched
cohort study. Bone Marrow Transplant 1996; 17: 917–922.
14 Powles RL, Morgenstern GR, Kay HE et al. Mismatched family donors for bone marrow transplantation for treatment for
acute leukaemia. Lancet 1983; i: 612–615.
15 Szydlo R, Goldman JM, Klein JP et al. Results of allogeneic
bone marrow transplants for leukemia using donors other than
HLA-identical siblings. J Clin Oncol 1997; 15: 1767–1777.
16 Henslee-Downey PJ, Abhyankar SH, Parrish RS et al. Use of
partially mismatched related donors extends access to allogeneic marrow transplant. Blood 1997; 89: 3864–3872.
17 Aversa F, Tabilio A, Velardi A et al. Treatment of high risk
acute leukemia with T cell-depleted stem cells from related
donors with one fully mismatched HLA haplotype. New Engl
J Med 1998; 339: 1186–1193.
18 Guinan EC, Boussiotis VA, Neuberg D et al. Transplantation
of anergic histoincompatible bone marrow allograft. New Engl
J Med 1999; 340: 1704–1714.
19 O’Reilly RJ, Collins NH, Kernan N et al. Transplantation of
marrow-depleted T cells by soybean lectin agglutination and
E-rosette depletion: major histocompatibility complex-related
graft resistance in leukemic transplant recipients. Transplant
Proc 1985; 17: 455–456.
20 Ferrara JL, Deeg HJ. Graft-versus-host disease. New Engl J
Med 1991; 324: 667–674.
21 Korngold R, Sprent J. T-cell subsets and graft-versus-host disease. Transplantation 1987; 44: 335–339.
22 Reisner Y, Kapoor N, Kirkpatrick D et al. Transplantation for
severe combined immunodeficiency with HLA-A, B, D, DR
incompatible parental marrow cells fractionated by soybean
agglutinin and sheep red blood cells. Blood 1983; 61: 341–
348.
23 Mackinnon S, Papadopoulos EB, Carabasi MH et al. Adoptive
immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia
responses from graft-versus-host disease. Blood 1995; 86:
1261–1268.
24 Reisner Y, Martelli MF. Transplantation tolerance induced by
‘mega dose’ CD34 ⫹ cell transplants. Exp Hematol 2000; 28:
119–127.
25 Drobyski WR, Ash RC, Casper JT et al. Effect of T-cell
depletion as a graft-versus-host disease prophylaxis on
engraftment, relapse, and disease-free survival in unrelated
marrow transplantation for chronic myelogenous leukemia.
Blood 1994; 83: 1980–1987.
26 Guinan E. Costimulatory Blockade as a Mechanism of
Inducing Tolerance in the allograft setting. Educational Book
of American Society of Hematology 1999, pp 383–388.
27 Champlin R, Ho W, Gajewski J et al. Selective depletion of
CD8⫹ T lymphocytes for prevention of graft-versus-host disease after allogeneic bone marrow transplantation. Blood
1990; 76: 418–423.
28 Lamb L, Gee A, Parrish R et al. Acute rejection of marrow
grafts in patients transplanted from a partially mismatched
related donor: clinical and immunologic characteristics. Bone
Marrow Transplant 1996; 17: 1021–1027.
29 Soderling CC, Cong CW, Blazer BR, Vallera DA. A correlation between conditioning and engraftment in recipients of
MHC mismatched T cell-depleted murine bone marrow transplants. Immunology 1985; 135: 941–946.
30 Sondel TM, Bozdech MJ, Trigg ME et al. Additional immunosuppression allows engraftment following HLA-mismatched T
Genetically haploidentical SCT for acute leukemia
JM Rowe and HM Lazarus
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
cell-depleted bone marrow transplantation for leukemia.
Transplant Proc 1985; 17: 460–462.
Champlin RE, Ho WG, Mitsuyasu R et al. Graft failure and
leukemia relapse following T lymphocyte-depleted bone marrow transplants: effect of intensification of immunosuppressive conditioning. Transplant Proc 1987; 19: 2616–2619.
Lapidot T, Singer TS, Reisner Y. Transient engraftment of T
cell depleted allogeneic bone marrow in mice improves survival rate following lethal irradiation. Bone Marrow Transplant 1988; 3: 157–164.
Lapidot T, Terenzi A, Singer TS et al. Enhancement by dimethyl myleran of donor type chimerism in murine recipients of
bone marrow allografts. Blood 1989; 73: 2025–2032.
Terenzi A, Lubin I, Lapidot T et al. Enhancement of T-cell
depleted bone marrow allografts in mice by thiotepa. Transplantation 1990; 50: 717–720.
Godder K, Pati AR, Abhyankar S et al. Partially mismatched
related donor transplants as salvage therapy for patients with
refractory leukemia who relapse post-BMT. Bone Marrow
Transplant 1996; 17: 49–53.
Kernan NA, Emanuel D, Castro-Malaspina H et al. Posttransplant immunosuppression with antithymocyte globulin and
methylprednisolone prevents immunologically mediated graft
failure following a T-cell depleted marrow transplant. Blood
1989; 74: 123a.
Fischer A, Griscelli C, Blanche S et al. Prevention of graft
failure by an anti-HLFA-1 monoclonal antibody in HLA-mismatched bone marrow transplantation. Lancet 1986; ii:
1058–1061.
Henslee-Downey PJ, Parrish RS, Macdonald JS et al. Combined ex-vivo and in-vivo T-lymphocyte depletion for the control of graft-versus-host disease following haplo-identical marrow transplant. Transplantation 1996; 61: 738–745.
Malilay GP, Sevenich EA, Condie RM, Filipovich AH. Prevention of graft rejection in allogeneic bone marrow transplantation: I. Preclinical studies with antithymocyte globulins.
Bone Marrow Transplant 1989; 4: 107–112.
Henslee-Downey PJ. Allogeneic related partially mismatched
transplantation. In: Barrett J, Treleaven J (eds). The Clinical
Practice of Stem-Cell Transplantation. Isis Medical Media:
Oxford, 1998, p 391.
Henslee-Downey PJ, Godder K, Abhyankar S et al. Sequential
immuno-modulation to achieve engraftment and control graftversus-host disease across mismatched MHC barriers. Educational Book of American Society of Hematology 1999,
pp 389–394.
Reisner Y, Martelli MF. Tolerance induction by ‘megadose’
transplants of CD34⫹ stem cells: a new option for leukemia
patients without an HLA-matched donor. Curr Opin Immunol
2000; 12: 536–541.
Rachmim N, Gan J, Segall R et al. Tolerance induction by
‘megadose’ hematopoietic transplants: donor-type human
CD34 stem cells induce potent specific reduction of host antidonor cytotoxic T lymphocyte precursors in mixed lymphocytes culture. Transplantation 1998; 65: 1386–1393.
Aversa F, Tabilio A, Terenzi A et al. Successful engraftment
of T cell-depleted haploidentical ‘three-loci’ incompatible
transplants in leukemia patients by addition of recombinant
human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum.
Blood 1994; 84: 3948–3955.
Reisner Y, Martelli MF. Bone marrow transplantation across
HLA barriers by increasing the number of transplanted cells.
Immunol Today 1995; 16: 437–440.
Bachar-Lustig E, Rachamim N, Li HW et al. Megadose of T
cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice. Nature Med 1995; 1: 1268–1273.
47 Reisner Y, Aversa F, Bachar-Lustig E et al. The role of megadose CD34 haploidentical transplantation: potential application to tolerance induction. Educational Book of American
Society of Hematology 1999, pp 376–382.
48 Cilloni D, Carlo-Stella C, Falzetti F et al. Limited engraftment
T capacity of bone marrow-derived mesenchymal cells following T-cell-depleted hematopoietic stem cell transplantation.
Blood 2000; 96: 3637–3643.
49 Lazarus HM, Koc ON. Culture-expanded human marrowderived mesenchymal stem cell transplantation. Graft 2001
(in press).
50 Lamb LS, Szafer F, Henslee-Downey et al. Characterization
of acute bone marrow graft rejection in T cell-depleted, partially mismatched related donor bone marrow transplantation.
Exp Hematol 1995; 23: 1595–1600.
51 Lamb LS, Gee AP, Henslee-Downey PJ et al. Phenotypic and
functional reconstitution of peripheral blood lymphocytes following T cell-depleted bone marrow transplantation from partially mismatched related donors. Bone Marrow Transplant
1998; 21: 461–471.
52 Roux E, Dumont-Girard F, Starobinski M et al. Recovery of
immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood 2000; 96:
2299–2303.
53 Volpi I, Perruccio K, Ruggeri L et al. G-CSF blocks IL-12
production by antigen presenting cells: implications for
improved immune reconstitution after haploidentical hematopoietic transplantation. Blood 1999; 10 (Suppl. 1): 2841a.
54 Perruccio K, Tosti A, Posati S et al. Transfer of functional
immune responses to aspergillus and CMV after haploidentical hematopoietic transplantation. Blood 2000; 96: 2383a.
55 Walter EA, Greenberg PD, Gilbert MJ et al. Reconstitution
of cellular immunity against cytomegalovirus in recipients of
allogeneic bone marrow by transfer of T-cell clones from the
donor. New Engl J Med 1995; 333: 1038–1044.
56 Riddell SR, Greenberg PD. Adoptive immunotherapy with
antigen-specific T cells. In: Thomas ED, Blume KJ, Forman
SJ (eds). Hematopoietic Cell Transplantation. Blackwell
Science: Oxford, 1999, 327–341.
57 Cavazzana-Calvo M, Stephan JL, Sarnacki S et al. Attenuation
of graft-versus-host disease and graft rejection by ex-vivo
immunotoxin elimination of alloreactive T cells in an H-2
haplotype disparate mouse combination. Blood 1994; 83:
288–298.
58 Boussiotis VA, Gribben JG, Freeman EJ, Nadler LM. Blockade of the CD 28 co-stimulatory pathway: a means to induce
tolerance. Curr Opin Immunol 1994; 6: 797–807.
59 Gribben JG, Guinan EC, Boussiotis VA et al. Complete blockade of B7 family-mediated costimulation is necessary to
induce human alloantigen-specific anergy: a method to ameliorate graft-versus-host disease and extend the donor pool.
Blood 1996; 87: 4887–4893.
60 Sambhara SR, Miller RG. Programmed cell death of T cells
signaled by the T-cell receptor and the a3 domain of class I
MHC. Science 1991; 252: 1424–1427.
61 Reisner Y, Bachar-Lustig E, Li HW et al. Purified Sca-1⫹Linstem cells can tolerize fully allogeneic host T cells remaining
after sublethal TBI. Blood 1997; 90: 563a.
62 Bachar-Lustig E, Li HW, Marcus H, Reisner Y. Tolerance
induction of megadose stem cell transplants: synergism
between Sca-1⫹Lin cells and non-alloreactive T-cells. Transplant Proc 1998; 30: 4007–4008.
63 Bachar-Lustig E, Li HW, Gur H et al. Induction of donortype chimerism and transplantation tolerance across major histocompatibility barriers in sublethally irradiated mice by Sca1 (⫹)Lin (⫺) bone marrow progenitor cells: synergism with
675
Bone Marrow Transplantation
Genetically haploidentical SCT for acute leukemia
JM Rowe and HM Lazarus
676
64
65
66
67
68
non-alloreactive (Host x donor)F (1) T cells. Blood 1999; 94:
3212–3221.
Lee LA, Sergio JJ, Sykes M. Natural killer cells weakly resist
engraftment of allogeneic, long-term, multilineage-repopulating hematopoietic stem cells. Transplantation 1996; 61:
125–132.
Ruggeri L, Capanni M, Casucci M et al. Role of natural killer
cell alloreactivity in HLA-mismatched hematopoietic stem
cell transplantation. Blood 1999; 94: 333–339.
Ruggeri L, Capanni M, Urbani E et al. KIR epitope incompatibility in their GvH direction predicts control of leukemia
relapse after mismatched hematopoietic transplantation. Blood
2000; 96: 2059a.
Davies SM, Kollman C, Anasetti C et al. Engraftment and
survival after unrelated-donor bone marrow transplantation: a
report from the National Marrow Donor Program. Blood 2000;
96: 4096–4102.
McGlave PB, Shu XO, Wen W et al. Unrelated donor marrow
transplantation for chronic myelogenous leukemia: 9 year’s
experience of the national marrow donor program. Blood
2000; 95: 2219–2225.
Bone Marrow Transplantation
69 Anasetti C. Transplantation of hematopoietic stem cells from
alternate donors in acute myelogenous leukemia. Leukemia
2000; 14: 502–504.
70 Sierra J, Storer B, Hansen JA et al. Unrelated donor marrow
transplantation for acute myeloid leukemia: an update of the
Seattle experience. Bone Marrow Transplant 2000; 26: 397–
404.
71 Aversa F, Martelli MF. Haploidentical stem cell transplantation in leukemia. Blood Rev 2001 (in press).
72 Aversa F, Tabilio A, Velardi A et al. Advances in full-haplotype mismatched transplants in acute leukemia. Blood 1999;
94 (Suppl. 1): 2522a.
73 Bunjes D, Duncker C, Wiesneth M et al. CD34⫹ selected
cells in mismatched stem cell transplantation: a single centre
experience of haploidentical peripheral blood stem cell transplantation. Bone Marrow Transplant 2000; 25 (Suppl. 2): 9–
11.
74 Passweg JR, Kuhne T, Gregor M et al. Increased stem cell
dose, as obtained using currently available technology, may
not be sufficient for engraftment of haploidentical stem cell
transplants. Bone Marrow Transplant 2000; 26: 1033–1036.