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Haematopoietic cell transplantation: Five decades of progress Authors: Frédéric Baron, Rainer Storb, and Marie-Térèse Little Current edit date: 2022-5-31 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. 1

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Page 1: Fifty years of allogeneic hematopoietic stem cell … · Web viewIn addition, the recent development of nonmyeloablative stem cell transplantation has opened up the way to include

Haematopoietic cell transplantation: Five decades of progress

Authors: Frédéric Baron, Rainer Storb, and Marie-Térèse Little

Current edit date: 2023-5-20

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: [email protected]

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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 non-

haematopoietic 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 chemo-

irradiation 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 graft-

versus-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 long-

term 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 T-

cell-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 long-

term 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 progression-

free 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 regimen-

related 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

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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 0-

22%), 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.

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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 100-

day 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 pre-

emptive 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

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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

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There are now evidence that grafts can create their own marrow space via subclinical graft-

versus-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-213-

labeled 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).

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Other studies examining lower doses of TBI and potential approaches of pre- and post-

transplant 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 post-

transplantation 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).

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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.

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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.

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Table 1. Age of Patients at Diagnoses and at HCT (92).

Median Ages Patient (years)Recent Allogeneic HSCT Recipients

(FHCRC)Disease Related Donor Unrelated Donor At Diagnoses

(SEERS)CML 40 36 67AML 28 33 68NHL 33 35 65MM 45 45 70CLL 51 46 71HD 29 28 34MDS 40 41 68Overall 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.

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Table 2. Effect of TBI dose and postgrafting immunosuppression on engraftment of DLA-identical marrow grafts.

TBI dose (cGy) Postgrafting immunosuppression

Dogs with stable engraftment (%)1/Total transplants

920 None (126) 20/21 (95%)450 None (105) 6/17 (35%)450 CSP2 (105) 7/7 (100%)450 Prednisone3 (105) 0/5 (0%)200 CSP2 (102) 0/4 (0%)200 MTX4 + CSP2 (102) 2/5 (20%)200 MMF5 + CSP2 (102) 11/12 (92%)200 SRL6 + CSP2 (110) 6/7 (86%)100 MMF5 + CSP2 (102) 0/6 (0%)100 SRL6 + CSP2 (110) 0/5 (0%)100 CSP2 (118,119) 2/9 (22%)100 CSP2 + GPBMC7 (118) 5/8 (63%)100 CSP2 + CD3-depleted

GPBMC (118)1/7 (14%)

1Mixed or full chimerism.2Cyclosporine 15 mg/kg p.o. b.i.d. days -1 to 35.3Prednisone 12.5 mg/kg p.o. days -5 to -3 with tapering to day 32.4Methotrexate 0.4 mg/kg i.v. days 1, 3, 6, and 11.5Mycophenolate mofetil 10 mg/kg b.i.d. s.c. days 0-27.6Sirolimus (Rapamycin) 0.05 mg/kg b.i.d. Q.D. days 0-27.7 Granulocyte-colony stimulating factor mobilized peripheral blood mononuclear cells.

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