review
Ten years of cord blood transplantation: from bench to bedside Eliane Gluckman Hospital Saint Louis APHP, University Paris VII, IUH (Institut Universitaire d’He´matologie), Paris, France
Summary Cord blood is an unlimited source of haematopoietic stem cells for allogeneic haematopoietic stem cell transplant. Since the first human cord blood transplant, cord blood banks have been established worldwide for collection and cryopreservation of cord blood for allogeneic haematopoietic stem cell transplant. More than 400 000 cord blood units are now available for international exchange. Results of unrelated allogeneic cord blood transplants in malignant and non-malignant diseases, in adults and children, show that, compared to human leucocyte antigen (HLA)-matched unrelated bone marrow transplant, cord blood has several advantages, including prompt availability of the transplant, decrease of graft-versus-host disease and better long-term immune recovery resulting in a similar long term survival. Several studies have shown that the number of cells is the most important factor for engraftment while some degree of HLA mismatches is acceptable. Progress is expected to facilitate engraftment and reduce transplantrelated mortality and includes reduced intensity conditioning regimen, intra bone injection of cord blood cells and double cord blood transplants. In addition to haematopoietic stem cells, cord blood and placenta contain a high number of nonhaematopoietic stem cells that explains the increasing interest of using cord blood for developing regenerative medicine. Keywords: cord blood, banking, clinical results. Haematopoietic stem cell transplantation (HSCT) can be curative in a large variety of selected malignant and nonmalignant diseases. Umbilical cord blood transplantation (UCBT) has extended the availability of allogeneic HSCT to patients who would not otherwise be eligible for this curative approach because of the lack of a human leucocyte antigen (HLA) identical bone marrow (BM) or granulocyte colonystimulating factor mobilized peripheral blood haematopoietic stem cell (PBSC) donor. The first UCBT was performed in a patient with Fanconi Anaemia, in 1988, (Gluckman et al, 1989). This patient had a healthy HLA-identical sibling who was shown by prenatal testing to be unaffected by the disorder
Correspondence: Professor E. Gluckman, Eurocord, Hospital Saint Louis, 1 Avenue Claude Vellefaux, 75475 Paris cedex10, France. E-mail:
[email protected]
doi:10.1111/j.1365-2141.2009.07780.x
and to have a normal karyotype. Her cord blood was collected at birth, cryopreserved and, after thawing, used for transplantation. Currently, this patient is doing well with complete haematological donor chimaerism and complete recovery of his blood counts. This first success opened the way to a new field in the domain of allogeneic HSCT as it showed that: a single unit of umbilical cord blood (UCB) contained enough haematopoietic stem cells to reconstitute definitely the host lympho-haematopoietic compartment; an UCB unit could be collected at birth without any harm to the new-born infant, and UCB haematopoietic stem cells could be cryopreserved and transplanted in a host after thawing without losing their repopulating capacity. Since then, our knowledge on the biological characteristics of UCB cells has increased, emphasizing the advantages of using UCB stem cells for transplantation. Compared to other sources of haematopoietic stem cells, UCB has many theoretical advantages, due to the immaturity of newborn cells. UCB haematopoietic progenitors are enriched with primitive stem/progenitor cells able to produce in vivo long-term repopulating stem cells. The properties of UCB cells should compensate the relatively low number of cells contained in a single UCB unit and, through rapid expansion, reconstitute myeloablated patients. Despite the capacity for UCB cell expansion, clinical results showed that haematopoietic recovery was delayed after UCBT; engraftment was associated with the number of nucleated and CD34+ cells infused and the number of HLA differences (Gluckman et al, 1997, 2004; Wagner et al, 2002). As acute graft-versus-host disease (GVHD) is an early event after allogeneic bone marrow transplantation (BMT) and is partly triggered by cytokine release, it is reasonable to postulate that UCBT induces less frequent and less severe acute and chronic GVHD than adult HSCT which contain a higher number of activated T cells. These properties should lead to less stringent criteria for HLA donor-recipient selection. In comparison with other sources of allogeneic HSCT, UCB offers substantial logistic and clinical advantages such as: significantly faster availability of banked cryopreserved UCB units with patients receiving UCB transplantation in a median of 25–36 days earlier than those receiving BM (Barker et al, 2002); extension of the donor pool due to tolerance of 1–2 HLA mismatches out of six (higher HLA mismatched is associated with lower probability of engraftment); lower incidence and severity of GVHD; lower
ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 147, 192–199
Review risk of transmitting infections by latent viruses; lack of donor attrition; lack of risk to the donor and, finally higher frequency of rare haplotypes compared to bone marrow donor registries, as it is easier to target ethnic minorities.
Milestones in the development of UCBT 1 First HLA-identical sibling cord blood transplant in a patient with Fanconi Anaemia (Gluckman et al, 1989). 2 Optimization of UCB collection and storage (Rubinstein et al, 1993, 1995). 3 Development of cord blood banks (CBB) for related and unrelated transplants (Paris, Dusseldorf, New York, Milan) (Wernet, 2004). 4 First unrelated mismatched cord blood transplant in children (Kurtzberg et al, 1996). 5 First unrelated cord blood transplant in adults (Gluckman et al, 1997). 6 Creation of the Eurocord Netcord network (Wernet, 2004). 7 Demonstration that, in HLA-identical sibling transplants, cord blood gave delayed engraftment, less graft-versus-host effect and same survival Rocha et al (2000). 8 Description of criteria of donor choice based on number of cells and possibility of using mismatched cord blood (Wagner et al, 1995, 1996, 2002; Rubinstein et al, 1998; Laughlin et al, 2001; Gluckman et al, 2004). 9 Demonstration that, compared to matched unrelated bone marrow, mismatched cord blood gave similar long term leukaemia-free survival in children (Rocha et al, 2001; Eapen et al, 2007) and in adults (Laughlin et al, 2004; Rocha et al 2004; Takahashi et al, 2007). 10 Improvement of results mostly in adults by double cord blood transplants and non-myeloablative conditioning regimens (Hwang et al, 2007). 11 Isolation of non-haematopoietic stem cells form cord blood as a first step for regenerative medicine (Kogler et al, 2004).
(more than 437 transplants centres in 47 countries), all performing either related (n = 499) or unrelated cord blood transplants (n = 4655). It works in close collaboration with EBMT and Netcord banks to collect clinical data and follow patients transplanted in or outside Europe with Netcord units. During the last 3 years, the number of unrelated UCBT reported to Eurocord has increased as a result of: the increased number of cord blood units stored, the expansion of indications to all diagnoses curable by allogeneic haematopoietic stem cell transplant, publication of criteria of donor choice, the increasing number of adult transplants that use double cord blood units to overcome the problem of the cell dose, and the use of reduced intensity conditioning in older patients or with disabilities (Figs 1–3). Overall results have improved with time due to better choice of indications and better quality of the cord blood unit transplanted (Figs 4 and 5). In order to promote education and information, Eurocord has recently launched a new European Online Cord Blood Learning Portal, an on-line curriculum on cord blood technology and transplantation, which aims to provide a learning tool for the scientific, technical, clinical and regulatory
800
Related
700
Unrelated n = 4655
600
n = 499
*Still collecting data *
500 400 300 200 100 0
88
91
94
97
2000
2003
2006
2009
Fig 1. Eurocord registry data: number of related and unrelated cord blood transplants reported yearly.
Development of cord blood banks (CBB) Umbilical CBB have been established for related or unrelated UCBT. The progress in the field of UCBT has paralleled the huge interest in establishing and developing CBB worldwide. Today, more than 400 000 cord blood grafts are available in more than 50 CBB (http://www.bmdw.org and http:// www.wmda.org). This development is due to the organization of international registries for outcome data collection, named Eurocord (http://www.eurocord.org) and the Center for International Blood and Marrow Transplant Research (CIBMTR; http://www.cibmtr.org), and of a CBB networks, named Netcord (http://www.netcord.org) and National Marrow Donor Program (NMDP; http://www.nmdp.org). Eurocord is an international registry which operates on behalf of the European Blood and Marrow Transplant group (EBMT), and includes European and non-European centres
450
*Still collecting data
400 350
Children n = 2522
300
Adults n = 2041
*
250 200 150 100 50 0
94
96
98
2000
2002
2004
2006
2008 2009
Fig 2. Eurocord registry data: number of adult and paediatric cord blood transplant.
ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 147, 192–199
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Review Double unrelated CBT/ year reported to eurocord n = 572
(A) 200
200
*Still collecting data
180
Reduced intensityconditioning CBT/year reported to eurocord n = 882
(B) 180
160
160
140
140
120
120
100
100
*
80
80
60
60
40
40
20
20
*
0
0 99 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
94
96
98
2000
2002
2004
2006
2008 2009
Fig 3. Eurocord registry data: number of patients receiving a double cord transplant (panel A); number of patients receiving a reduced intensity conditioning (panel B).
Overall survival (children with malignant disease) 1·0 1994–1998 1999–2000 2001–2003 2004–2008
0·8
n = 276 n = 234 n = 347 n = 459
2-year OS 42 ± 3% 2-year OS 43 ± 3% 2-year OS 43 ± 3% 2-year OS 47 ± 3%
0·6 0·4 0·2 0·0
0
6
12 Months
18
24
Fig 4. Overall survival according to the period of cord blood transplantation in children.
Overall survival (adults with malignant disease) 1·0 0·8
1994–1998 1999–2000 2001–2003 2004–2008
n = 62 n = 100 n = 233 n = 787
2-year OS 23 ± 5% 2-year OS 31 ± 5% 2-year OS 36 ± 3% 2-year OS 38 ± 2%
0·6 0·4 0·2 0·0 0·00
6·00
12·00 Months
18·00
24·00
Fig 5. Overall survival according to the period of cord blood transplantation in adults.
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aspects of cord blood that is easily accessible at a time and language convenient for users (http://www.eurocord-ed.org). The Netcord group was established in 1998 to provide good practises in UCB storage, facilitate donor search, improve the quality of the grafts, standardize excellence criteria on an international scale and, importantly, establish procedures for bank accreditation in collaboration with FACT (Foundation on Accreditation in Cell Therapy). National regulatory agencies and transplant centres are aware of the need of international standards for cord blood collection, processing, testing, banking, selection and release. All the practical aspects of cord blood banking, such as mother informed consent, collection techniques, labelling and identification, infectious disease and genetic disease testing, HLA typing, methodology of cell processing, cryopreservation, transportation and release have been extensively published. All these aspects are detailed in the last version of the NetcordFACT Standards (http://www.factwebsite.org).
Clinical experience with related and unrelated umbilical cord blood transplantation In a CIBMTR-Eurocord study, comparing paediatric BM and UCBT from an HLA identical sibling, UCBT was associated with delayed granulocyte and platelet engraftment, reduced acute and chronic GVHD and the same survival. This was the first analysis to demonstrate, unambiguously, that acute and chronic GVHD was reduced when CB cells were used instead of BM even when the BM was provided by children (Rocha et al, 2000). This first study was the basis for advocating the use of mismatched UCBT and triggered the development of unrelated CBB. The second step was the demonstration that unrelated UCBT could be used in all current indications of allogeneic HSCT, including malignant and non-malignant diseases in
ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 147, 192–199
Review children and adults and compared favourably to matched unrelated BM or PBSC transplants. In children with malignant diseases, two studies compared the outcome of unrelated UCBT and BMT. Eurocord published a study comparing the outcome of matched unrelated BMT (HLA six out of six), either unmanipulated or T depleted, to mismatched UCBT: the results showed that after UCBT, engraftment was delayed, GVHD was reduced similarly to T-cell–depleted BMT and that relapse and leukaemia-free survival (LFS) were the same (Rocha et al, 2001). Eapen et al (2007) compared outcomes of 503 children with acute leukaemia given an unrelated mismatched UCBT with 282 unrelated BM transplant recipients (116 HLA alleles matched eight out of eight). HLA allele-mismatched BM recipients had more acute and chronic GVHD without reducing LFS. Importantly, they found that even using an allele-matched BM donor, LFS was not statistically different from one or two HLA disparate UCBT and that an HLAmatched UCBT recipient had better outcomes compared to HLA allele-matched BM recipients. However, an increased transplant-related mortality was observed in children transplanted with a low CB cell dose (
