Haematopoietic cell transplantation: Five decades of progress
Authors: Frédéric Baron, Rainer Storb, and Marie-Térèse Little
Current edit date: 2016-02-13
References in Exp Haem format with the addition of all authors
Final sent to H. Mayani, PhD Sept 22-03
Fred Hutchinson Cancer Research Center and the University of Washington,
Seattle, WA USA
This work was supported by grants CA78902, CA18029, CA15704, DK42716, AR050741,
and HL36444 of the National Institutes of Health, Bethesda, MD. Marie-Térèse Little also
received a grant from the MDA-USA. Frédéric Baron is research assistant of the National
Fund for Scientific Research (FNRS) Belgium and supported in part by postdoctoral grants
from the Fulbright Commission.
Running title: allogeneic HCT.
Correspondence to:
Marie-Térèse Little, Ph.D.
Fred Hutchinson Cancer Research Center
1100 Fairview Ave N, D1-100
PO Box 19024
Seattle, WA 98109-1024
Phone: 206-667-4875
Fax: 206-667-6124
E-mail: mlittle@fhcrc.org
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Abstract
During the past 50 years, the role of allogeneic haematopoietic cell transplantation (HCT) has
changed from a desperate therapeutic maneuver plagued by apparently insurmountable
complications to a curative treatment modality for thousands of patients with hematologic
diseases. Now, cure rates following allogeneic HCT with matched siblings exceed 85% for
some otherwise lethal diseases, such as chronic myeloid leukaemia, aplastic anemia or
thalassemia. In addition, the recent development of nonmyeloablative stem cell
transplantation has opened up the way to include elderly patients with a wide variety of
hematologic malignancies. Further progress in adoptive transfer of T cell populations with
relative tumour specificity would make the transplant procedure more effective and would
extend the use of allogeneic haematopoietic cell transplantation (HCT) for treatment of nonhaematopoietic malignancies.
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In the face of heated political controversy about embryonic stem cells, research involving
their adult counterparts, haematopoietic stem cells, has been progressing at an amazing pace
culminating in their clinical use for the treatment of patients with malignant and nonmailgnant
haematologic diseases. Initial enthusiasm of investigators for this approach centered on the
idea that “rescue” of patients with transplantable stem cells allowed increasing the intensity of
cytotoxic anti-cancer therapy far beyond the marrow toxic range. This way, marrow-based
malignancies would be curable. It soon became clear, however, that this tenet was not
universally valid. Rescue by stem cell grafts from twins who were monozygous with the
patients, more often than not, was followed by disease relapse. This finding highlighted the
difficulty in eradicating the last malignant cells even by the most intensive therapy.
Fortunately, while these sobering observations in syngeneic transplants were made, an
exciting new and powerful therapeutic principle was discovered in allogeneic transplants, the
graft-versus-tumour effect. This effect was generated by donor lymphocytes contained in the
graft, which killed recipient tumour cells after recognizing and reacting to disparate minor
histocompatibility antigens. Progress continued to be made in large animal models and
important observations were quickly translated to the clinic. The concept of adoptive
allogeneic immunotherapy forms the basis for modern nonmyeloablative haematopoietic cell
transplants. The low degree of treatment related toxicities associated with these procedures
have allowed the extension of haematopoietic cell transplantation (HCT) to patients
previously deemed ineligible for high-dose conventional approaches due to age or other
comorbidities. In addition, the lack of toxicities has made non-marrow ablative stem cell
transplants attractive for patients with genetic diseases, such as haemoglobinopathies.
Research is continuing to extend these minimal conditioning regimens to eradicate solid
tumours with the same efficacy as noted in some haematological based diseases. In addition,
most recent research has raised the hope that adult haematopoietic stem cells (HSCs) might be
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programmable to differentiate into cells other than those of the haematopoietic system. The
research findings imply that, one day, adult stem cells might not only be useful to treat
diseases of the haematopoietic system but also those of other tissues, example. muscle or even
brain.
To fully appreciate the enthusiasm by researchers, clinicians and patients generated by
recent excitement in the field of nonmyeloablative HCT, it is important to reflect upon how
the field has developed in the last five decades and to document the landmark efforts by
numerous investigators throughout the world who have worked to bring the experimental field
of haematopoietic cell transplantation to a clinical reality.
Early organ and marrow transplants
Studies of transplantation of tissues and organs performed in the first part of this century
set the stage for HCT. In 1912, Alexis Carrel received the Nobel Prize in Medicine for the
technical development of vascular anastomoses and for demonstrating the successful
transplantation of blood vessels and organs such as the kidney. Although autografts were
maintained indefinitely, allografts consistently failed within a few days. This revelation led to
the biological principle that cells or organs transferred from one individual to another would
be recognised as foreign and thus would suffer the fate of rejection. Challenges to this dogma
occurred in the 1940’s when Owen and colleagues (1) noted that vascular anastomoses
between fetal freemartin cattle twins resulted in mutual acceptance, despite the presence of
antigenic distinct cells. Animal studies by Billingham, Brent, and Medawar (2) defining the
immunological basis for graft rejection and demonstrating neonatal tolerance led to Burnet’s
clonal selection theory of acquired immunity (3) both providing the scientific basis for an
understanding of tolerance induced in utero and in newborns. These early studies
demonstrating remarkable insight into the difficulties encountered with transplantation and
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some of the important concepts and themes provided a foundation for transplantation of
haematopoietic tissues and are summarized in three excellent monographs (4-6).
The modern era of HCT truly began with interests into the biological consequences of
irradiation, with the advent of atomic warfare in World War II, and with the availability of
radioactive isotopes. It was quickly recognised that bone marrow was the most sensitive
organ to radiation and that death associated with low-lethal radiation exposure was due to
marrow failure. In 1949, Jacobsen and colleagues demonstrated that mice could survive
otherwise lethal radiation exposures if the spleen were shielded by a lead foil (7). Similarly,
the same group of investigators demonstrated that a protective effect could be given by
shielding the femur. Lorenz and others described a similar protective phenomenon in
irradiated mice and guinea pigs with the infusion of spleen or marrow cells (8). Although
controversial at the time, many investigators thought that the marrow protective effect was
due to “a substance of noncellular nature” in the spleen or bone marrow that stimulated
recovery (humoral hypothesis) rather than to transplanted stem cells (cellular hypothesis) (9).
However, in 1954 Barnes and Loutit (10) noted that recovery from lethal irradiation and
spleen cell infusions might be due to living cells. A year later, Main and Prehn (11) showed
that allogeneic bone marrow infusions promoted long-term survival of marrow donor skin
grafts consistent with the hypothesis that the established donor’s immune cells now residing
in the recipient were tolerant to the donor skin. Other investigators independently used
various blood genetic markers in the mid-1950s to firmly document that the haematopoietic
recovery after irradiation and infusion of marrow or spleen cells in mice was effected by cells
derived from the donor grafts (12-17).
Researchers and clinicians studying radiation biology, immunology, oncology and
haematology became excited by these recent discoveries suggesting that transplantable
haematopoietic cells could give rise to all haematopoietic lineages. This implied a treatment
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strategy for human patients with life-threatening haematological diseases such as for patients
with acquired lack of marrow function, (for example, severe aplastic anemia), those with
inborn errors, (for example, sickle cell and immunodeficiency diseases) and even those with
haematological malignancies (for example, leukaemia and lymphomas). In the latter case, the
intensity of cytotoxic anticancer drugs could be increased beyond the range that is toxic to the
bone marrow cells, potentially increasing their efficacy. The initial reports confirming the
cellular hypothesis spurred a flurry of successful studies in the mid to late 1950’s aimed at
securing engraftment in mouse models of allogeneic HCT (12,13,15,18-22) .
Haematopoietic cell transplants in humans- Early Success and then Pessimism
It was apparent from the early mouse studies that there was potential application of chemoirradiation and marrow grafting for therapy of leukaemia and other blood diseases. The
notion of a transplantable stem cell from which all haematopoiesis could be generated led to
widespread application of marrow transplantation for haematologic malignancies using
intensive irradiation and intravenous infusion of marrow to protect the recipient from the
inevitable lethal marrow aplasia. In 1955, E.D. Thomas and colleagues pioneered early
studies of human marrow grafting and demonstrated in 1957 that human haematopoietic cell
transplants were for the most part unsuccessful with most patients dying of allograft failure or
progressive disease while only one patient engrafted transiently (23). Despite the poor results,
these early trials importantly demonstrated for the first time that relatively large amounts of
marrow could be safely infused into human patients without dire consequences when grafts
were prepared appropriately. There were indications that haematopoietic cell transplantation
would be a difficult task.
In 1959, three landmark manuscripts were published describing transplantation of marrow
in leukaemic patients and in allogeneic victims of radiation exposure. First, 2 patients with
advanced acute lymphoblastic leukaemia were given high dose (850 R) total body irradiation
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(TBI) followed by syngeneic twin marrow grafts. Although their leukaemia recurred in a few
months, this was the first example of patients given supralethal irradiation who showed
prompt clinical and haematological recovery. Thus, the underlying concept that a human
syngeneic graft could protect against irradiation-induced marrow aplasia was supported by
this observation. Importantly, it was also noted that the irradiation itself did not eliminate the
leukaemia and that additional chemotherapeutic approaches might be needed. Echoing the
early mouse studies of Barnes and colleagues (18), the authors commented on a potential role
of the graft in mounting an immunological reaction against the leukaemia.
Second, Mathé and colleagues (24) reported attempts at rescuing victims of accidental
irradiation exposure with allogeneic marrow infusions. Remarkably, four of the five
recipients survived although the donor engraftment was low and transitory. Granted, these
transplants were performed prior to the knowledge of the importance of histocompatibility
matching, and, in retrospect, the observations of recovery were most likely a result of
autologous reconstitution (25).
Third, McGovern and colleagues (26) reported the first autologous transplantation of a
patient with terminal acute lymphoblastic leukaemia involving treatment with TBI. The
patient achieved remission; however, the leukaemia recurred perhaps seeded by malignant
leukaemic clones harboured in the stored graft or an insufficient graft-versus-leukaemia
effect.
Numerous reports followed these initial transplantation attempts. With the exception of the
serendipitous case of Beilby et al (27) who documented partial engraftment in a Hodgkin’s
disease patient who received a non-identical sibling marrow transplant and inadvertently an
overdose of aminochlorambucil, all of the early clinical transplantation efforts in the late
1950’s and early 1960’s failed. Often patients failed to engraft or, if they engrafted,
developed severe fatal graft-versus-host disease (GVHD). In 1970, Bortin reviewed
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approximately 200 human allogeneic human bone marrow transplantations carried out in the
1950s and 1960s and concluded that none had been successful (28). Indicating that the failure
to secure long-term engraftment was due to the clinical translation from the inbred mouse
model (which do not require histocompatibility typing), it was the opinion of some prominent
haematologists that …”these failures have occurred mainly because the clinical applications
were undertaken too soon, most of them before even the minimum basic knowledge required
to bridge the gap between mouse and patient had been obtained” (6). This caused many
researchers to abandon the idea that bone marrow transplantation could become a clinical
reality and the feasibility of crossing the “allogeneic barrier” in humans was seriously doubted
because it became evident that the GVH reaction in random-bred animals including man was
incomparably more violent than in rodents (6) (Figure 1). Clinical allogeneic marrow
transplantation was declared a dismal failure.
Renewed Hope: Progress in large animal models
Subsequent experiments primarily in dogs and also nonhuman primates renewed a
sense of confidence that allogeneic bone marrow transplantation might become a therapeutic
option for patients with haematological disorders. The outbred nature and the wide genetic
diversity of dogs, predicted the suitability of this animal model for preclinical studies
(reviewed in (29,30)).
In the late 1950’s, Snell documented the existence of major and numerous minor systems
that are involved in murine histocompatibility (31), and it was suggested that these antigens
might be important in haematopoietic transplantation. In 1968, Epstein et al. demonstrated
that dog leukocyte antigen (DLA) compatibility between the donor and the recipient was
crucial and determined the outcome of allogeneic transplantation (32). Although severe
GVHD had been previously documented in mismatched mice and unrelated monkeys, the
canine studies clearly documented that GVHD could occur even across minor
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histocompatibility barriers and thus, effective drug regimens were developed to contain it
(33). Moreover, it was found that immunosuppressive therapy could generally be
discontinued after 3-6 months of treatment because of the establishment of mutual graftversus-host tolerance. These observations encouraged further trials of allogeneic bone marrow
transplantation between matched human siblings.
Conventional High-Dose HCT
Effective supportive care of patients without marrow function including blood
component transfusion technology, parenteral nutrition, vascular access as well as therapies to
prevent or treat bacterial, fungal, and viral infections had already been developed by the late
1960’s. The first successful allogeneic marrow graft in a patient with severe combined
immunological deficiency using a one human leukocyte antigen (HLA)-mismatched sibling
donor was reported by Gati et al. in 1968 (34). This patient did not require
immunosuppressive therapy since he was immunoincompetent due to his underlying disease.
From 1969 to 1975, clinical studies were restricted to patients with severe aplastic anaemia or
refractory advanced leukaemia and with an HLA-matched sibling donor. In 1975, a review
article by the Seattle marrow transplant team described the results of 73 and 37 patients with
leukaemia and aplastic anaemia, respectively, all transplanted after failure of conventional
therapy using a HLA-matched sibling donor (35). Despite the high transplant-related
mortality observed, the demonstration of some long-term disease-free survivors was
encouraging.
In 1977, Thomas et al. reported the long-term survival of 13 of 100 patients who
received transplants for advanced leukaemia and showed that patients in fair condition at the
time of the transplantation had a significant higher disease-free survival (36). These
observations indicated that transplantation should occur earlier in the course of the disease,
while patients were still in good medical condition and had low tumour burdens. In 1979, two
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reports of transplantation for acute myeloid (37) or lymphoblastic (38) leukaemia in first
remission showed greatly improved results. In 1986, two large studies reported that the
majority of patients with chronic myeloid leukaemia (CML) in chronic phase could be cured
by chemo-irradiation and marrow transplantation from a matched sibling donor (39,40). These
promising results lead to the development of allogeneic BMT for patients with genetic
haemoglobin disorders with the first cures of thalassemia major and of sickle cell disease
reported in 1982 (41) and 1984 (42), respectively. Table 2 shows recent results achieved in
some hematologic diseases.
The Conditioning Regimen
When the Seattle team began HLA-compatible sibling marrow transplants, the
conditioning regimen consisted in 1000 rad TBI administered at 7 rad/min. Unfortunately, the
few patients who successfully engrafted showed early recurrence of leukaemia indicating that
irradiation alone was not sufficient to eradicate all leukaemic cells (35). However, the
addition of cyclophosphamide, 60 mg/kg on each of two days before TBI, led to the first longterm disease-free allogeneic recipients. Moreover, it was demonstrated that fractionated TBI
was superior to single-dose irradiation (43).
In 1983, busulfan –an alkylating agent that kills cells by crosslinking DNA- was
shown to be an alternative to irradiation (44). Ten years later, a randomized study including
patients with CML in chronic phase demonstrated comparable results when
cyclophosphamide was combined with TBI or with busulfan (45,46). However, a comparison
of the same two regimens in patients with acute myleloid leukaemia (AML) in first remission
showed the cyclophosphamide/TBI regimen to be superior (47). In 1994, Storb et al. reported
long-term disease-free survival of approximately 90% aplastic anaemia patients conditioned
with a nonmyeloablative regimen combining high-dose cyclophosphamide with
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antithymocyte globulin (48,49). Very similar results were described in patients with other
nonmalignant diseases such as thalassemia major (50,51) or sickle cell disease (52) using
busulfan/cyclophosphamide conditioning. More recently, the pharmacologic targeting of
busulfan in combination with cyclophosphamide or fludarabine was shown to reduce the
transplant-related mortality, particularly in patients older than 50 years of age (53,54).
Graft-versus-host disease
The magnitude of GVHD in humans was not fully appreciated until long-term engraftment
of donor marrow was achieved. As predicted by the dog model, even with a HLA-matched
donor, about 50% of the patients developed GVHD despite the use of postgrafting
immunosuppression with methotrexate (22,33,55). Better prevention and control of GVHD
were achieved by combining the antimetabolite methotrexate with a calcineurin inhibitor such
as cyclosporine (CSP) or tracrolimus (56-59) and the regimen of a short course of MTX
combined with 6 months of cyclosporine (or tacrolimus) became the gold standard.
Another approach of GVHD prophylaxis consisted of T cell depletion of the graft (60-62).
Although the technique was very efficient in term of GVHD prevention, initial trials revealed
a higher incidence of infection, graft rejection and relapse as well as the occurrence of
Epstein-Barr virus (EBV)-induced lymphoproliferative malignancies (60-62). Some of these
complications can now be prevented by the use of new techniques of T cell depletion that also
remove donor B cells or by the use of pre-emptive donor lymphocyte infusion (DLI; reviewed
in (63).
Allogeneic HCT using Unrelated Donors.
Only 30% of patients in need of a HCT have a matched related sibling donor;
therefore, this treatment modality is not an option for the majority of patients. Although very
few HLA-matched unrelated transplants were carried out in the 1970s when matched donors
were found fortuitously (64), the heterogeneity of the HLA haplotypes underlined the need for
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large panels of tissue-typed volunteer donors as well as the establishment of donor registries.
The creation of the Anthony Nolan Foundation in England led to the establishment of such
programs in many countries (reviewed in (65)). In addition, advances in immunogenetics of
HLA, especially typing by molecular techniques have made it possible to select unrelated
donors who are matched at the allele level with their respective recipients for HLA-A, B, C,
DRB1 and DQB1. Results with such unrelated transplants have begun resembling those
obtained with HLA-identical sibling grafts (66), at least for young patients (Table 1).
Stem cell source
Other recent developments include the use of alternative sources of stem cells, such as
peripheral blood and cord blood. Prospective randomized studies suggest that the use of stem
cells derived from granulocyte-colony stimulating factor (G-CSF) primed peripheral blood
mononuclear cells (PBMC) instead of marrow is associated with faster haematopoietic
recovery, similar incidence of acute GVHD and perhaps more chronic GVHD and increased
overall survival (67-70).
Similarly, cord blood has been used as a source of transplantable stem cells (71-74).
Potential advantages include more rapid availability and, because cord blood is relatively
deficient in T cells, the possibility that a greater degree of HLA mismatching might be
tolerable. On the other hand, disadvantages are slower engraftment and increased risk of graft
failure. Factors associated with survival after cord blood transplantation are the number of
cells infused per kilogram recipients, the patient age and the degree of match with the donor
(73). Unfortunately, the low cell content of most cord blood units limits the current use of
cord blood transplantation to children and perhaps smaller adults.
Graft-versus-tumour effect
The graft-versus-tumour (GVT) effect was first proposed by Barnes et al. in 1956 on
the basis of murine studies; mice receiving syngeneic transplants after injection of leukaemic
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cell lines and TBI almost uniformly relapsed, whereas mice receiving allogeneic transplants
developed GVHD but had a lower incidence of relapse (18,75). The authors suggested that a
reaction of the donor bone marrow might kill cancer cells. This phenomenon was termed
“adoptive immunotherapy” by Mathé in 1965 (24). The first landmark reports of the GVT
effect in human allograft recipients was reported by Weiden et al. who documented a reduced
relapse rate in patients with acute (76) and/or chronic (77,78) GVHD. The GVT effect was
confirmed by other groups who observed an increased risk of relapse in patients receiving Tcell-depleted grafts (79) and in recipients of syngeneic transplants (80).
Further evidence of the GVT effect came from the observation that single infusion of
donor lymphocytes could induce complete remissions (CR) in patients with haematological
malignancies who have relapsed after transplantation (81-84). Two large randomized studies
have reviewed the results of DLI in more than 300 patients (82,84). In these studies, DLI
induced a complete remission in about 64% of patients with CML and in 20-40% of patients
with multiple myeloma, AML or myelodysplastic syndrome (MDS) (reviewed in (85). It has
been speculated that the response of CML to DLI may be explained by the slow evolution of
the disease (because the time to response after DLI is often prolonged, the GVL reaction may
not have sufficient time to develop in patients with more rapidly progressive disease) and by
the fact that dendritic cells, the most potent antigen-presenting cells, are part of the leukaemic
clone in CML (82). Moreover, several observations suggest that BCR/ABL expression may
increase the susceptibility of leukaemic cells to immune cytolysis (86,87).
Several studies have documented that the response to DLI is associated with conversion
from a mixed chimeric state to complete donor hematopoiesis after DLI (82) and, inversely,
conversion to full donor chimerism has been associated with a GVT effect after DLI (88) .
Moreover, DLI can displace residual host stem cells in case of the recurrence of nonmalignant
disease after allogeneic transplantation (89). Taken together, these observations suggest that
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the GVT reaction is due to the expression of polymorphic minor histocompatibility (mHA)
antigens on both normal and leukaemic marrow cells that trigger the generation of cytotoxic
donor lymphocytes which kill both normal and leukaemic host cells (reviewed in (90,91)).
Nonmyeloablative HCT
Due to regimen-related toxicities, conventional allogeneic HCT is restricted to
younger and medically fit patients. This is unfortunate since the median age for patients with
haematological malignancies susceptible to the GVL effect (such as acute and chronic
leukaemia, lymphomas or multiple myeloma) range from 65 to 70 years (Table 1) (92).
Therefore, several groups have developed the concept of reduced intensity conditioning
regimen (93-95) or true nonmyeloablative HCT (NMHCT) (96-100), in which the main
mechanism of tumour eradication is shifted from high-dose cytotoxic agents to the GVL
effect (101). The following paragraphs review the nonmyeloablative approach that was
developed in the preclinical canine model in Seattle (102-105) and then directly translated
into multi-center clinical studies (97,106-109).
Preclinical Canine Studies
Two immunological barriers must be overcome in allogeneic HCT. One is the
rejection barrier or host-versus-graft (HVG) reaction and the other is graft-versus-host (GVH)
reaction. In the major histocompatibility complex-identical setting, both HVG and GVH
reactions are mediated by T cells. Therefore, it was hypothesized that optimizing postgrafting
immunosuppression could reduce both GVH and HVG reactions, thereby enabling a decrease
in the intensity of the pretransplant conditioning regimen needed for sustained engraftment.
Using the canine pretransplant model, a dose response relationship with respect to TBI
and allogeneic engraftment (Table 2) has been demonstrated. A single TBI dose of 920 cGy
was sufficiently immunosuppressive to allow engraftment of DLA-identical littermate marrow
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in 95% of dogs transplanted. When the dose was decreased to 450 cGy, only 41% of dogs had
stable engraftment. The others rejected their grafts and either died of marrow aplasia (23%) or
survived with autologous recovery (36%). When dogs were given 450cGy TBI followed by
DLA-identical littermate marrow with the addition of prednisone, given at 12.5 mg/kg b.i.d.
orally on days -5 to 3, with tapering through day 32, the engraftment rate was not enhanced
(105). However, the addition of postgrafting CSP, given at 15 mg/kg b.i.d. orally for 5 weeks,
led to engraftment in all 7 animals studied (105). When the TBI dose was further decreased to
200 cGy, postgrafting immunosuppression either with CSP alone or with a combination of
CSP and methotrexate resulted in graft rejection with autologous recovery in the majority of
the dogs (102). On the other hand, a postgrafting immunosuppressive regimen combining
CSP and mycophenolate mofetil (MMF, a purine synthesis inhibitor given at 10 mg/kg b.i.d.
s.c. from day 0 to day 27) lead to the development of stable mixed chimerism in 10 of 11 dogs
studied (102). However, when the TBI dose was further decreased to 100 cGy, stable longterm engraftment did not occur, exemplifying the delicate balance between host and graft
cells (102). More recently, the combination of Rapamycin (Sirolimus) and CSP was found to
be as effective as MMF/CSP in dogs given DLA-identical marrow followed by 200cGy TBI
(Figure 2) (110). These observations in the preclinical canine model were a prelude to the
development of the Seattle consortium’s clinical nonmyeloablative HCT approach discussed
below.
Clinical Trials
The clinical trials were carried out jointly by a group of collaborators located at the Fred
Hutchinson Cancer Research Center, University of Washington, Children’s Hospital and
Regional Medical Center, and Veterans Administration Medical Center, all in Seattle, WA,
USA; Stanford University, Palo Alto, CA, USA; City of Hope National Medical Center,
Duarte, CA, USA; University of Leipzig, Germany; University of Colorado, Denver, CO,
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USA; University of Torino, Italy; University of Arizona, Tucson, AZ, USA; Baylor
University, Dallas, TX, USA; University of Utah, Salt Lake City, UT, USA; Oregon Health
Sciences University, Portland, OR, USA; and, more recently, the Medical College of
Wisconsin, Milwaukee, WI, USA; and Emory University, Atlanta, GA, USA. Candidates for
NMHCT have been exclusively patients with haematological diseases treatable by allogeneic
HCT who were ineligible for conventional allogeneic HCT because of age (older than 50
years) and/or concomitant diseases or preceding extensive therapies, such as failed autologous
or allogeneic HCT (Figure 3).
NMHCT from HLA-identical siblings
Results of the first 212 patients have been recently reviewed (111). Conditioning regimen
were 200 cGy TBI only (n=102) or 90 mg/m2 fludarabine plus 200 cGy TBI (n=110). Patient
diagnoses were multiple myeloma (n=66), acute leukaemia or myelodysplastic syndrome
(n=58), chronic leukaemia (n=43), lymphomas (n=41) and other haematological malignancies
(n=4). Median patient age was 55 (range 18 to 73) years old. The declines in blood counts
were generally modest (Figure 3). The incidence of nonfatal graft rejection was 16% in
patients conditioned with TBI only versus 3% for patients conditioned with TBI and
fludarabine. The incidence of grade II-IV acute GVHD and chronic GVHD were 44% and
65%, respectively. With a median follow-up of 11.5 (3-42) months, overall and progressionfree survival were 63% and 52%, respectively. Typically, remissions occurred over an
extended period of time, and some patients achieved complete remission more than 1 year
after the transplant.
A more detailed analysis of the first 45 patients receiving 200 cGy TBI only as
conditioning regimen was published in Blood in 2001 (97). No patients experienced regimenrelated painful mucositis, pulmonary toxicity, cardiac toxicity, veno-occlusive disease of the
liver, hemorrhagic cystitis or new onset alopecia. Fifty-three percent of eligible patients were
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treated entirely in the outpatient department, with others having relatively short
hospitalization (median 8 days). The incidence of graft rejection was 20% and was
significantly less frequent in patients who have received intensive prior therapy (defined by
prior autograft, prior intensive chemotherapy for acute leukaemia or more than 3 cycles of a
fludarabine-containing regimen) as well as in patients with high (>50%) donor T cell
chimerism on day 28 after the transplant. Unfortunately, DLIs given at 1 x 107 CD3+ cells/kg
from day 56 were unable to prevent progression to complete graft rejection. Twenty-nine of
36 patients with sustained engraftment had measurable disease before NMHCT, and 19 (66%)
achieved CR sometime after HCT. With median follow-up of 417 days, survival was 66.7 %,
relapse mortality 26.7% and nonrelapse mortality 6.7%.
NMHCT from HLA-matched or mismatched unrelated donors
Fifty-two elderly or medically infirm patients with haematological diseases have been
recently reported (106). Median patient age was 48 years (range, 6-65 years). Diseases were
acute leukaemia or myelodysplastic syndrome (n=20), chronic leukaemia (n=15), multiple
myeloma (n=8), lymphoma (n=7), or other haematological malignancies (n=2). Most patients
(88%) were high-risk candidates as defined by relapse after preceding HCT (38%) or by
refractory/advanced disease. Conditioning regimen was 200 cGy TBI and fludarabine 90
mg/m2. Compared to HLA-matched related recipients, postgrafting immunosuppression with
cyclosporine and MMF was extended to 100 and 40 days, respectively. Of donor-recipient
pairs, 29% were HLA mismatched and 71% were matched at the antigen level. Stem cell
source was PBSC (n=39) or BM (n=13). Median hospital stay for the 22 patients eligible for
outpatient therapy was 16 days (range, 0 to 56 days). The incidence of graft rejection was
12%. Factors predictive of graft rejection in univariate analysis were low T-cell contents in
the grafts and diagnosis of myelodysplastic syndrome. The incidence of grade II, III and IV
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acute GVHD and the incidence of chronic GVHD requiring systemic immunosuppressive
therapy were 42%, 8%, 13% and 30%, respectively. The 100-day transplant related mortality
(TRM) was 11%. Complete remissions, including molecular remissions, were seen in 45% of
patients with measurable disease before transplantation. With a median follow-up of 19.3
months (range, 15.3-28.1 months), overall 18 of the 52 patients (35%) were alive and 25%
were in remission. Eight patients (15%) died from complications associated with either acute
or chronic GVHD.
Maris et al reported the results of 89 patients transplanted from unrelated donors matched
for HLA-A, -B and –C antigens and -DRB1 and -DQBI alleles (109). Median patient age was
53 years. Diseases were acute leukaemia or myelodysplastic syndrome (n=38), chronic
leukaemia (n=19), multiple myeloma (n=7), lymphoma (n=17), or other haematological
malignancies (n=8). Stem cell source was marrow (n=18) or PBSC (n=71). Durable
engraftment was observed in 85% of PBSC and 56% of marrow recipients (p=0.007).
Cumulative probabilities of grades II, III and IV acute GVHD were 42%, 9%, and 2%,
respectively. Non-relapse mortality at day 100 and one year were 11% and 16%, respectively.
One-year overall and progression free survival were 57% and 44% for PBSC recipients and
33% (p=0.13) and 17% (p=0.02), respectively, for marrow recipients. Grades II-IV acute
GVHD (p=0.02) and chronic GVHD (p=0.04) were associated with a decreased risk of
relapse.
NMHCT for AML in CR1
Feinstein et al. reported outcomes of 18 patients with de novo (n=13) or secondary
(n=5) AML in CR1 who received NMHCT from HLA-identical sibling donors (108). Median
age was 59 years (range, 36 to 73 years) and patients were declared ineligible to a
conventional HCT because of age (n=15), hepatitis C (n=2) or abnormal pulmonary function
testing (n=1). Conditioning regimen were 200 cGy TBI only (n=10) or 200 cGy TBI and
18
fludarabine (n=8). Two rejections were observed in patients not given fludarabine and 1 died
with relapse. At a median follow-up of 766 days (range, 188-1141 days) seven patients
remain in CR. The 1-year estimates of TRM, overall survival (OS) and progression-free
survival (PFS) were 17% (95% CI 0–35%), 54% (95% CI 31–78%) and 42% (95% CI 19–
66%), respectively. For the 13 patients older than 55 years, the figures were 8% (95% CI 022%), 68% (95% CI 43–94%) and 59% (95% CI 31–87%), respectively. These results are
promising since the 1-year PFS for AML patients older than 55 years is around 35% with
conventional chemotherapy.
NMHCT for patients who failed a previous conventional HCT
Conventional allogeneic HCT administered after a failed previous transplant is
associated with a high incidence of TRM and poor outcomes. Feinstein et al. recently
reported outcomes of 55 patients who received NMHCT as a treatment after a failed
autologous (n=49), syngeneic (n=2) or allogeneic (n=4) HCT (107). Diagnoses were
lymphoma (n=32), MDS (n=9), multiple myeloma (n=8), chronic leukaemia (n=3) and acute
leukaemia (n=3). Donors were HLA-matched related (n=31) or HLA-matched unrelated
(n=24). Conditioning regimens were 200 cGy TBI only (n=7) or 200 cGy TBI plus
fludarabine (n=48). The 1-year estimates of TRM, OS and PFS were 20% (95% CI, 9-31%),
49% (95% CI, 35-62%) and 28% (95% CI, 16-41%), respectively. Previous TBI (hazard ratio
[HR] 0.3; p=0.08) was associated with increased hazards of TRM and untreated disease at the
time of NMHCT (HR 2.4; p=0.04) was associated with increased risk of death. Causes of
death without progression included multiple organ failure (n=9), infection (n=7), GVHD
(n=5) and suicide (n=1) with 7 of 12 patients having more than 1 cause of death.
19
Comparison of NMHCT with conventional allogeneic HCT
Retrospective studies have been carried out to compare some issues after conventional
or nonmyeloablative allogeneic HCT. Weissinger et al. compared the platelet and red blood
cell (RBC) transfusion requirements in 40 NMHCT recipients (NMHCT group) with those of
67 conventional transplant recipients (control group), transplanted during the same time
interval for equivalent diseases (112). The incidences of platelet and RBC transfusion
requirement were 23% and 63% in the NMHCT group versus 100% (p<0.001) and 96%
(p<0.001) in the control group, respectively. The median number of platelet and RBC units
transfused were 0 (range, 0-214) and 2 (range, 0 to 50) in the NMHCT group versus 24
(range, 4 to 358) (p<0.001) and 6 (range, 0 to 34) (p<0.001) in the control group, respectively.
Junghanss et al. analyzed the incidence of posttransplantation cytomegalovirus (CMV)
infection in 56 NMHCT recipients (113). Each NMHCT recipient was matched to 2 controls
who were treated by conventional HCT during the same time period. Matching criteria
included CMV risk group, HSC source, donor type, age and underlying disease. CMV disease
occurred in neither low- and intermediate-risk CMV NMHCT or control patients. The 100day incidence of CMV disease for high-risk CMV patients (defined as recipient serologically
positive for CMV) was 9% in the NMHCT group versus 19% (p=0.08) in the control group.
However, the 1 year probability of CMV disease for high-risk CMV patients was similar in
the two groups (p=0.87). The onset of CMV disease was significantly delayed in the NMHCT
group compared to the control group (median 130 versus 52 days, p=0.02). These results
emphasize that NMHCT patients should receive CMV surveillance beyond day 100 and preemptive ganciclovir treatment similar to that routinely given to recipients of a myeloablative
regimen.
The same authors similarly analyzed the incidence of bacterial infection the first 100
days and of fungal infection the first year posttransplantation (114). The 30- and 100-day
20
incidence of bacteriema were 9% and 27% in the NMHCT group versus 27% (p=0.01) and
41% (p=0.07) in the control group, respectively. Invasive aspergillosis occurred at a similar
rate (15% in the NMHCT group versus 9% in the control group, NS). Multivariate analyses
identified neutropenia and CMV disease as the major factors associated with bacteremia and
aspergillosis, respectively.
Mielcarek et al. compared GVHD in 44 NMHCT and 52 conventional HCT recipients
(control group) (115). All HCT were performed from related or unrelated donors who were
serologically matched for HLA-A,-B and -C and allele-matched for HLA-DRB1 and -DQB1.
The median patient age was 56 (range, 50 to 65) years in the NMHCT group versus 54 (range,
50 to 64) years in the control group. Postgrafting immunosuppression was cyclosporine and
MMF in the NMHCT group and cyclosporine plus methotrexate (MTX) (n=48) or
cyclosporine and MMF (n=4) in the control group. One patient in the NMHCT group and no
patient in the control group received DLI. For related transplant recipients, the 100-day
cumulative incidence of grade II-IV acute GVHD was 62% in the NMHCT group versus 77%
(p=0.02) in the control group. For unrelated transplant recipients, the figures were 65% versus
95% (p=0.01), respectively. There was no difference in the cumulative incidences of grades
III-IV acute GVHD between the two groups. The cumulative incidence of chronic GVHD
requiring treatment was 73% in the NMHCT group versus 71% in the control group (NS).
However, peaks of skin and gastrointestinal morbidities occurred between 6 and 12 months in
the NMHCT group instead of during the first month in the control group, and 7 out of 10
NMHCT patients who required steroids treatment for cutaneous GVHD after day + 80 had
acute inflammatory changes, as observed in acute GVHD (“late onset acute GVHD”). This
late-onset acute GVHD syndrome should be taken into consideration in NMHCT studies.
Perspectives
Allogeneic HCT without cytotoxic therapy
21
There are now evidence that grafts can create their own marrow space via subclinical graftversus-host reactions. First, dogs conditioned only with 450 cGy irradiation targeted to
cervical, thoracic and upper abdominal lymph nodes and post-grafting immunosuppression
with CSP and MMF achieved long-term mixed haematopoietic chimerism as well as in the
lymph nodes and bone marrow spaces that were shielded from irradiation (103). Secondly,
allografts have been successfully carried out with only postgrafting immunosuppression with
CSP and MMF as conditioning regimen in some human patients with T cell deficiencies other
than severe combined immunodeficiency disease (SCID) (116). Thirdly, sustained
engraftment has been accomplished in dogs after selective T-cell ablation with bismuth-213labeled anti TCRαβ and postgrafting immunosuppression with CSP and MMF (117). Thus, it
may be possible to reduce or suppress the pre-transplant TBI dose below 200cGy by
maximizing the immunosuppressive regimen.
Storb et al. noted that stable mixed chimerism can be achieved after only 100 cGy TBI
by reducing the intensity of host immune responsiveness with help of the fusion peptide,
CLLA4-Ig, which blocks T cell costimulation through the B7-CD28 signal pathway (104).
Recipients T cells were activated with intravenous (i.v.) injection of donor PBMC on days -7
to -1 before 100 cGy TBI with concurrent i.v. administration of CTLA4Ig. Four out of 6
evaluable dogs showed persistent mixed chimerism.
Zaucha et al further demonstrated the addition of granulocyte colony stimulating factor
PBMC (G-PBMC) to marrow grafts allowed to reduce the pre-transplant TBI to 100 cGy and
to omit MMF (118). This effect was due to donor CD3 cells contained in G-PBMC, because
the addition of the CD3-depleted fraction of G-PBMC resulted in sustained engraftment in
only 1 of 7 recipients. In another study, they also found that substituting G-PBMC for marrow
did not increase stable allogeneic engraftment whereas increasing the duration of
immunosuppression with CSP from 35 to 100 days did (119).
22
Other studies examining lower doses of TBI and potential approaches of pre- and posttransplant immunosuppression are ongoing to develop more elegant and minimally toxic HCT
regimens in the future.
Directing donor cytotoxic T cells toward specific tumour target
Donor-derived cytotoxic T lymphocytes (CTL) have been successfully used to restore
immunity against cytomegalovirus and Epstein-Barr virus after allogeneic HCT (91).
Remarkably, neither significant toxicity nor GVHD were observed with this early posttransplantation cell immunotherapy. Thus, the infusion of specific donor CTL directed against
recipient haematopoietic cells could induce strong GVT effect without GVHD. Typical
examples of good target candidates for a specific GVT effect are mHA (90). mHA are
polymorphic antigens that are inherited independently from HLA antigens. Some mHA, such
as the H-Y antigen, HA-3, HA-4, HA-6, HA-7 and HA-8 are ubiquitously expressed and are
target molecules in both GVHD and GVL reactions, whereas the expression of others, such as
HA-1 and HA-2, seems restricted to the haematopoietic system. Recently, the emergence of
HA-1 and HA-2-specific CD8+ T cells has been demonstrated in the blood of 3 HA-1 and/or
HA-2 positive recipients 5-7 weeks after DLI from their HA-1 and/or HA-2 negative donors
(120). The appearance of these CTL was followed by complete remission of the disease.
Thus, the in vitro generation of CTL recognizing hematopoiesis-restricted mHA may induce a
relative specific immune response against malignant haematopoietic recipient cells without
the induction of GVHD.
Although mHAs are rational targets for separating GVT from GVHD, an alternative
approach is to identify antigens associated with the malignant phenotype. These targets could
be mutational antigens (such as BCR/ABL) or normal proteins overexpressed in leukaemia
progenitors such as proteinase 3 (PR3) (121) or Wilm’s tumour-suppressor (WT1) (122).
23
NMHCT for solid tumours
In September 2000, Childs et al. reported the results of NMHCT combining
cyclophosphamide (120 mg/kg) and fludarabine (125 mg/m2) in 19 patients with metastatic
renal cell carcinoma (RCC). Ten of the 19 patients enjoyed objective responses, including 3
with sustained complete response (CR), occurring 3-6 months after the transplant (99).
Although the conditioning regimen was nonmyeloablative, the neutrophil count fell to less
than 0.1 x 109/L in all patients. Two preliminary reports studied the feasibility of NMHCT
with 200 cGy TBI and fludarabine in patients with solid tumours. Baron et al. reported the
successful engraftment of 7 metastatic RCC patients (123). Patients experienced much less
toxicity than patients reported by Childs et al. and one of the seven patients achieved a partial
response after GVHD occurrence. Hentschke et al reported 18 patients with RCC (n=10),
colon adenocarcinoma (n=6), breast cancer (n=1) and cholangiocarcinoma (n=1) (124).
Donors were HLA-identical sibling (n=12) or HLA-identical unrelated (n=6). The
conditioning regimen consisted of 90 g/m2 fludarabine and 200 cGy TBI for sibling recipients
and 200 cGy TBI, 150 mg/m2 fludarabine and thymoglobulin for unrelated donor graft
recipients. Post-grafting immunosuppression was carried out with CSP and MMF. Twelve
patients achieved full donor chimerism but 2 patients rejected their graft. Regression of
metastases occurred in 4 patients (2 patients with RCC and 2 with colon cancer). Although
some complete responses occurred, they seem quite infrequent. However, as observed in the
leukaemia setting, it is presumed that results would be better if the HCT was done earlier in
the patient’s disease course, while they had low tumour burden. Moreover, progress in the
identification of tumour antigens could allow post-transplant tumour vaccination or the
adoptive transfer of tumour-reactive T-cell populations from the donor and could increase the
efficacy of NMHCT for solid tumours.
24
In conclusion, the role of allogeneic HCT has changed from a desperate therapeutic
manoeuvre plagued by apparently insurmountable complications to a curative treatment
modality for thousands of patients with hematologic diseases. Now, cure rates following
allogeneic HCT with matched siblings exceed 85% for some otherwise lethal diseases, such
as chronic myeloid leukaemia, aplastic anaemia or thalassemia. In addition, the recent
development of nonmyeloablative stem cell transplantation has opened up the way to include
elderly patients with a wide variety of hematologic malignancies. Progress continues in the
large animal canine model to eliminate the need for TBI and in the area of adoptive
immunotherapy. Further progress in adoptive transfer of T cell populations with relative
tumour specificity would make the transplant procedure more effective and would extend the
use of allogeneic HCT to the therapy of non-haematopoietic malignancies. This more specific
approach could be facilitated by the development of new techniques, such as gene microarray
analyses (125), that would allow the identification of additional new candidates antigens for
many tumour types.
25
Table 1. Age of Patients at Diagnoses and at HCT (92).
Disease
Median Ages Patient (years)
Recent Allogeneic HSCT Recipients
(FHCRC)
Related Donor
Unrelated Donor
At Diagnoses
(SEERS)
CML
40
36
67
AML
28
33
68
NHL
33
35
65
MM
45
45
70
CLL
51
46
71
HD
29
28
34
MDS
40
41
68
Overall
40 (n=1428)
35 (n=1277)
Abbreviations: HCT = hematopoietic cell transplantation; FHCRC = Fred Hutchinson Cancer
Research Center; SEERS = surveillance, Epidemiology and End Results; CML = chronic
myeloid leukemia; AML = acute myeloid leukemia; NHL = non-Hodgkin lymphoma; MM =
multiple myeloma; CLL = chronic lymphocytic leukemia; HD = Hodgkin disease; MDS =
myelodysplastic syndrome.
26
Table 2. Effect of TBI dose and postgrafting immunosuppression on engraftment of DLAidentical marrow grafts.
TBI dose (cGy)
920
450
450
450
200
200
200
200
100
100
100
100
100
Postgrafting
immunosuppression
None (126)
None (105)
CSP2 (105)
Prednisone3 (105)
CSP2 (102)
MTX4 + CSP2 (102)
MMF5 + CSP2 (102)
SRL6 + CSP2 (110)
MMF5 + CSP2 (102)
SRL6 + CSP2 (110)
CSP2 (118,119)
CSP2 + GPBMC7 (118)
CSP2 + CD3-depleted
GPBMC (118)
1
Dogs with stable
engraftment (%)1/Total
transplants
20/21 (95%)
6/17 (35%)
7/7 (100%)
0/5 (0%)
0/4 (0%)
2/5 (20%)
11/12 (92%)
6/7 (86%)
0/6 (0%)
0/5 (0%)
2/9 (22%)
5/8 (63%)
1/7 (14%)
Mixed or full chimerism.
Cyclosporine 15 mg/kg p.o. b.i.d. days -1 to 35.
3
Prednisone 12.5 mg/kg p.o. days -5 to -3 with tapering to day 32.
4
Methotrexate 0.4 mg/kg i.v. days 1, 3, 6, and 11.
5
Mycophenolate mofetil 10 mg/kg b.i.d. s.c. days 0-27.
6
Sirolimus (Rapamycin) 0.05 mg/kg b.i.d. Q.D. days 0-27.
7
Granulocyte-colony stimulating factor mobilized peripheral blood mononuclear cells.
2
27
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