Current Opinion in Hematology:
Hematopoietic stem cell transplantation: Edited by Andrea Bacigalupo
Trends of hematopoietic stem cell transplantation in the third millennium
Gratwohl, Aloisa; Baldomero, Helenb
aHematology, Department of Medicine, University Hospital, Basel, Switzerland
bTransplant Activity Survey office of the European Group for Blood and Marrow Transplantation (EBMT), University Hospital, Basel, Switzerland
Correspondence to Professor Dr A. Gratwohl, Hematology, University Hospital Basel, CH-4031 Basel, Switzerland Tel: +41 61 265 42 54; fax: +41 61 265 44 50; e-mail: email@example.com
Purpose of review: Hematopoietic stem cell transplantation (HSCT) has evolved into an accepted therapy for many congenital or acquired disorders of the hematopoietic system. It has seen major changes in indications and use of transplant techniques. HSCT is a high cost procedure and requires investments; information on trends is essential for patient counselling and healthcare planning.
Recent findings: HSCT rates have increased worldwide. Increase is constant and predictable; the reasons therefore are manifold. Introduction of reduced intensity conditioning regimens has opened access to patients at older age and with comorbidities. Higher numbers of unrelated volunteer donors and cord blood products give access to HSCT for patients without family donors. For some well defined indications, HSCT has become the most cost efficient therapy in countries with limited resources. Use of HSCT is under discussion for nonhematopoietic indications, as is the use of nonhematopoietic stem cells for organ repair.
Summary: HSCT is likely to continue to increase for currently established indications. Indications and technologies will vary between countries with limited or nonrestricted resources. The most cost effective approach might not be the same everywhere. Novel indications will emerge but time will be needed to confirm their benefit. Close observation of global trends will become an essential tool for healthcare agencies in order to provide the necessary infrastructure in time.
The use of hematopoietic stem cell transplantation (HSCT) has evolved to become the standard of care for many patients with defined congenital or acquired disorders of the hematopoietic system or for chemosensitive, radiosensitive or immunosensitive malignancies. More than fifty years have passed since the first reports of successful bone marrow transplants from human leukocyte antigen (HLA) identical siblings for patients with immune deficiency disorders. After an initially slow evolution, HSCT has seen rapid expansion over the last two decades and major changes in technology use. Bone marrow has nearly completely been replaced as stem cell source by peripheral blood in autologous and, to a vast extent, in allogeneic HSCT. Cord blood has today been accepted as an alternative stem cell source. More than 13 million typed volunteer donors from the many registries or cord blood banks worldwide provide unrelated stem cell products for patients without family donors. Reduced intensity conditioning regimens have expanded the use of HSCT to older patients or to those with comorbidities [1–4].
In this apparently rapidly changing field, the overview might be lost. HSCT remains a high cost, highly specialized procedure. It requires significant infrastructure and a network of specialists from multiple fields of medicine. It is not available on the spot and without preparative work. Hence, information on indication and trends is essential for healthcare agencies in order to prepare the necessary infrastructure.
The European Group for Blood and Marrow Transplantation (EBMT) has introduced an annual activity survey, which gives a snapshot on the current status of HSCT by indication, donor type and stem cell source. Even more, over time, the activity survey can clearly depict trends [5,6••].
The activity survey 2007 of the EBMT [6••] describes in details the increase of transplant teams and numbers of autologous and allogeneic HSCT from 1990 to 2007 (Fig. 1) and illustrates the role of Gross National Income per Capita on the transplant rate in Europe (Fig. 2). It serves as a model to come for all stem cell therapies to come.
This will be of increasing importance, since stem cell therapy has become a treatment vision for many patients with diseases that are not yet amenable to therapy. This might include such a broad spectrum as from Parkinson's disease or diabetes to myocardial failure. Stem cell therapy is considered the treatment option of the 21st century [7,8]. Time will tell whether the promises will hold. There are as yet no series on outcome published. However, results on outcome of HSCT or any form of stem cell therapy will only be available years after initiation of such therapies. Other tools of data collection are therefore warranted. Information on trends presents such an option.
Expanding hematopoietic stem cell transplantation to countries with limited resources
Until recently, HSCT was largely limited to high-income countries. Numbers in other areas were negligible. This has rapidly changed just over the last 2 or 3 years. The complexity behind these changes was summarized by the report from the Eastern Mediterranean Blood and Marrow Transplant Group EMBMT (www.EMBMT.org), which was formally founded in 2008 [9••].
The EMRO report was followed by representations from individual countries [9••,10–29].
Differences relate primarily to indications, donor type and specific comorbidities. In brief, focus in these countries is on indications that are highly prevalent in their region and for which HSCT might provide cure. Then, HSCT might represent the most cost effective form of treatment. This list of indications includes diseases that are more frequent in countries with a high degree of consanguinity, such as severe combined immunodeficiency, or with a historically high prevalence such as thalassemia or sickle cell anemia. It includes acquired diseases with a high prevalence because of endogenous viruses or toxins, such as aplastic anemia. HSCT represents the sole form of curative treatment for patients with severe combined immunodeficiency. HSCT is more cost effective than routine erythrocyte transfusions and life-long iron chelation therapy in young patients with thalassemia major in countries where costs of a stem cell transplant might not be higher than one year of medical treatment. Similar considerations explain the use of HSCT early after diagnosis for patients with chronic myeloid leukemia, in countries where annual costs of imatinib therapy might exceed costs for a transplant .
Cost considerations explain as well why use of an HLA identical sibling donor is preferred choice in countries with limited resources. Import of an unrelated stem cell product, be it from a living unrelated donor or cord blood, might exceed total costs of HSCT. In addition, specific HLA requirements might not be met for a genetically distinct but diverse population within the large established unrelated donor pools or cord blood banks. Current donor pools still represent primarily a Caucasian population. The need for local cord blood banks and unrelated donor registries in these emerging countries has repeatedly been stressed [31–34,35••,36,37].
Countries with limited resources are confronted with yet another obstacle. Hepatitis or parasitic infections are endemic in some of these countries. Consequently, many patients or their respective family donors are affected by hepatitis or malaria. Preexisting liver damage increases the likelihood of posttransplant hepatic complications. A limited noninfectious donor pool for transfusions of blood products is available [12,17]. Preparation for a transplant and management of a transplant patient might differ in such situations form the ‘routine approach’ in countries with unrestricted resources and without endemic blood-borne diseases. The need for regionally or locally adapted transplant management guidlelines is imperative. Risk adapted treatment strategies include therefore adaptation to the risk of the patient (his or her disease), the donor (EBMT risk score) and the country (specific requirements/possibilities).
New indications for hematopoietic stem cell transplantation
Until recently, HSCT was limited to congenital immunodeficiency disorders, bone marrow failure syndromes, malignancies of the hematopoietic system and some rare solid tumors. These indications still remain the main categories, but some trends are evolving. Thalassemia major and sickle cell disease are two hemoglobinopathies with an established history in HSCT. Still, numbers were relatively low, compared with the incidence of the disease even in countries with established stem cell transplant networks. Transplant related mortality was considered to be too high compared with the immediate toxicity and morbidity with continuous red cell transfusion support and iron chelation therapy [38–41,42••].
Similar consideration takes place for other congenital disorders without immediate mortality but considerably shortened life span, when a missing enzyme can be produced and substituted by normal donor derived hematopoietic cells. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is one example. Successful application of HSCT has been reported. It remains to be shown that long-term correction is possible and that organ damage can be reverted. If the preliminary data are indeed confirmed, this rare indication MNGIE might serve as an example of other congenital mitochondrial disorders or other congenital metabolic diseases [43,44].
A clearer view emerges on the use of HSCT for autoimmune diseases. Animal data and incidental cases of patients with HSCT for a malignancy but with a concomitant autoimmune disorder had shown that HSCT could arrest an ongoing therapy refractory autoimmune disease. Early trials were initiated about 10 years ago [45,46••].
Finally, HSCT might be used in the near future in increasing numbers as a tool for tolerance induction in the setting for organ transplantation. Indeed, any organ might be transplanted from a stem cell donor without the need for immunosuppression, if full donor type chimerism is achieved. Interestingly, tolerance induction might also be favored, by use of transient chimerism or microchimerism. Hematopoietic stem cells are routinely applied as a tool to ease tolerance in the setting of face or limb transplantation. Admittedly, comparative studies are lacking [47,48••].
Use of hematopoietic stem cells for nonhematopoietic use and use of nonhematopoietic stem cells for tissue and organ repair
The use of nonhematopoietic stem cells for nonhematopoietic use and the use of nonhematopoietic stem cells has gained rapid interest over the last few years [5,6••]. As published by the EBMT activity survey, more than 200 such procedures were performed in Europe in 2007. These novel efforts for data collection will continue between the different organizations involved in these procedures. Institutions are urged to contribute their activity information in order to arrive at a comphrehensive overview. Results on outcome are scarce.
Bone marrow or adipose tissue derived mesenchymal stromal cells have both immunomodulatory and multilineage potential. They are increasingly used for immunosuppression in patients with severe treatment refractory graft-versus-host disease and for treatment of severe autoimmune disorders. Early phase II data are encouraging, conclusive results are still missing; prospective trials are planned or ongoing.
Mesenchymal stromal cells are also tested as a tool to induce organ repair, for a broad variety of diseases. It is likely that such treatments will increase in the near future. All donor types will be used; autologous and allogeneic cells are used. The optimal donor type remains a key issue of debate. Best stem cell source for mesenchymal stromal cells and nonhematopoietic stem cells is under discussion. Cord blood is a source of both. Trends indicate that cord blood will be intensively investigated for its potential role in organ and tissue repair [5,6••,49,50••,51–55].
Donor aspects have long been neglected by the transplant community. In contrast to patient outcome, there is no established network for collecting systematically outcome of donors outside the unrelated donor registries. Specifically, no systematic donor follow-up exists for sibling donors. The importance for such a broad information network was stressed by the recent EBMT report. Severe donor events are rare, but they can occur: in addition, there is a clear trend for an increasing age of HLA-identical peripheral blood stem cell sibling donors (Fig. 3). This is explained by the increasing age of patients. These elderly patients are more likely to be treated with reduced intensity conditioning transplants for which peripheral blood is the preferred choice [56••].
To give any predictions on trends in the third millennium concerning stem cell transplantation is a challenging, fascinating but impossible task. Who had envisaged yet 30 years ago that HSCT would become a routine procedure for many diseases, when the bone marrow transplant program was stopped at the National Institutes of Health in the United States because of a too high failure rate  or when even in the early eighties a technology assessment conference at the same institution concluded that the development of unrelated volunteer donor registries would be a too expensive and fruitless task? A little more than 20 years later, more than 12 million donors are typed and available for a stem cell product and numbers of unrelated donor allogeneic HSCTs were for the first time higher than HLA-identical sibling donor transplants last year in Europe.
Still, a few points can clearly be predicted. HSCT has given proof of principle that a failed organ, the hematopoietic system, can be replaced by the use of stem cell therapy. Admittedly, the function of the bone marrow appears less complex than that of a liver or pancreas; its organization and even its three dimensional structure is nevertheless complex. It appears only a matter of time until other organ function can be restored by the use of stem cells.
The second clear statement is, that for the time being, HSCT will remain an important tool with increasing tendancy on a global level. HSCT will increase for currently accepted indications because of a falling age limit, increasing donor availability and increasing access to HSCT for patients and regions without such access so far. HSCT will also expand to novel indications, mainly autoimmune disorders and congenital enzyme deficiency disorders. The trend is only likely to be reversed when single small molecule drugs such as imatinib for chronic myeloid leukemia become introduced for other diseases and are similarly as effective as HSCT in function and costs [1–3,29,58–64].
The last clear prediction is that the ‘old concept’ donor = transplant, no donor = no transplant, will soon belong to the past. The therapeutic algorithm will become more complex. Continuous risk assessment from diagnosis, relating to the risk of the disease, the patient, the donor [56••], the transplant procedure and the economic environment will become mandatory and decisions might differ between two patients with the same disease. The idea of one-size-fits-all is gone. It is evident that in such a rapidly changing and evolving field international collaboration on a global level and between ‘stem cell therapists’ from all fields of medicine will be a most essential part [65,66].
All current trends indicate that stem cell transplantation will play an important role in the future for treatment of single organ failure.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 524).
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