The art and science of blood and marrow transplantation continues to make steady progress. After almost 50 years of experimental and clinical practice, It has been reported that bone marrow transplantation is the most researched procedure in the history of medicine, with thousands of clinical studies and published medical journal articles. It is fairly clear that the use of blood rather than marrow for cell transplantation is more convenient and almost certainly results in superior outcomes in allogenic as well as autologous grafts. Improvements will continue to occur. Results are improving with unrelated donor transplantation and there is an increasing interest on the use of cellular immune therapy. The bone marrow serves as a repository of different classes of stem cells.
Only recently has techniques for the transplantation of highly purified HSC been developed and growing experience of using these cells in determining the optimal cellular compositions and sources for specific types of transplants. According to Solomon and Barrett, from the National Heart, Lung and Blood Institute; concurrently, with the introduction of peripheral blood and umbilical cord blood transplants, there is a growing interest in the use of stem cells from sources other than bone marrow. Just as blood component therapy revolutionized blood banking over 20 years ago, so the time has come to reconsider the issues of cell composition, quality, and dose in order to deliver an optimized transplant to the patients.
As we have seen the beginning of gene therapy and the use of positive and negative cells selection technology, and the cloning and growth of embryonic stem cells , new advances in adult stem cell therapies, mesenchymal , endothelial, GTPs good tissue practices , GMPs good manufacturing practices, new methods of T-cell depletion greater patient safety and better outcomes; cardiac, neurological , and orthopedic applications represent an emerging field of new therapeutic uses for blood and bone marrow stem cell transplantation, it is clear that the field of blood and bone marrow transplantation will continue to prosper intellectually and grow economically, as new advances in efficiency and business models will make this “stem cell rescue” available to millions of more patients. In many of the hospitals, and university medical centers, it is the HSC transplant physician, on the front lines of cellular therapies. The future looks very bright indeed.
Economic considerations of HSCT / BMT
The fact is, HSCT is a very expensive procedure, and it also may be a potentially lucrative business. It has been estimated that approximately 50,000 BMT’s are performed routinely in the USA alone, per year, representing a 10 billion dollar/per year industry. Costs of these procedures are generally estimated to be between $90,000 – $220,000, and are not routinely covered by insurance. According to Glen Balasky , Director of the Zangmeister Center in Columbus Ohio; the prices/fees for bone marrow transplants at OSU James Cancer Center can go as high as 500K. As a humanitarian, one could guess that if the costs of these BMT’s were suddenly dramatically reduced, say 50%, then the availability of these ‘stem cell rescues’, than so many more critically ill people may be saved . This is unfortunately not the case, at present.
We are of the opinion, that new business models must be established , that will allow these BMT procedures , performed outside the hospitals in ambulatory clinic (AC) settings , to critically evaluate ways to substantially reduce the costs, to 30%-50% of current AC’s pricing. The 40 plus years of BMT history has shown, that BMT’s can even be performed safely in the patients home (Herrmann et al 1999). Certainly BMT transplant specialists RN’s , can do as effective jobs as trained transplant doctors, within the out-patient settings, involving peripheral blood donations, and routine re-infusions.
Other economic considerations we observe, involve the new and much needed business model of autologous bone marrow banking, similar to the cord blood banking business model, which is so effectively used today worldwide. We now know, that as we age our cells age and become less potent and in a dangerous future contaminated with incurable diseases, drug resistant virus’s , cancers, and a global pandemic somewhere on the horizon, possibly we should engage in a dialog involving new strategies for contingent certainties that we will all inevitably face. Why not find a way to inexpensively remove these bone marrow stem cells from healthy peripheral blood, years before you will need them, (thereby stopping their aging) and bank them for your own personal medical applications.
Insurance company realities
According to Metha J., Powles R. et al; High –profile, and thus by definition expensive, medical interventions eventually attract close scrutiny. This is beneficial because it insures appropriateness of the intervention. With health care costs skyrocketing, it is inevitable HSCT for other diseases is going to be evaluated stringently by insurance companies, who are responsible for paying for the procedure, and government agencies, either paying for or determining policy and assuring research is done in appropriate fashion (Kalb, Kohler et al 2002).
In fact, payments made by insurance companies in the US are declining, even without adjustment of living or inflation. Unfortunately, few studies have measured the benefits of HSCT in terms of cost per quality-adjusted years. A case in point. The cost implications of the usefulness of one versus two autographs are enormous. If 4,000-6,000 of the 14,000 new cases of myeloma diagnosed in the United States every year are autographed , at $60,000- $90,000 per procedure, (Editors note, allogenic transplantation $90,000 – $225,000) the increased annual cost of therapy with tandem transplantation ( compared with single) would be in the region of $200-500 million, in the United States alone. (Editors notes, these figures only reflect the 4,000-6000 of the 14,000 new cases, and do not appear to include the more than 50,000 total transplants annually, estimated at an annual cost of 10 B U.S. Dollars)
Finally we must remember, that even with all the media propaganda, generated by embryonic stem cell scientists and their supporters, embryonic biology is in its infancy, and we are conservatively projecting 20 years before we will see hospitals routinely using this type of stem cell. It is difficult to imagine that any cellular therapy will be more curative and potent than a persons own , healthy autologous stem cells, which will continue to be the ‘gold standard’ in regenerative medical practices, for at least another generation.
Human stem cell research is in its infancy, biology yields its secrets slowly, and it is possible that a decade or two will pass before a general theory of stem cell biology is fully articulated.
Former Cambridge University surgeon and medical researcher, who is currently at Wake Forest University; Anthony Atala expresses it as follows:
“I have one goal-to cure the patient.”
When asked about whether making customized organs and tissues patient-by-patient will be cost effective. Atala replies,
“You can’t argue with autologous, and is the best way to go, regardless of the cost.”
“Immunosuppressant drugs are nasty things. I think that people who suggest that we can control rejection with better HLA matches haven’t spent much time at the bedside of someone on prednisone.
There are too many immune genes that make us different, and more are discovered every year.”
“I don’t believe that we’ll solve immune rejection in my lifetime or perhaps ever…”
German scientists from Georg-August University’s recent publication in Nature, isolated harvested from the testes of mice, testicular cells, which they have proven behave like embryonic stem cells, and stated that testicular cells would actually precede embryonic cells in the chain of early development.
Paola Vecino of university Miguel Hernandez showed that Sertoli cells, located near sperm stem cells in the body, keep sperm stem cells and teratocarcinoma cells (sperm stem cell cancers) from proliferating. Sertoli cells obviously hold great potential clinical therapy.
Home care for allogenic HSC transplantations
According to Atkinson et al; Initial results in one study using both family member and unrelated donors have been encouraging; 36 patients, 30 of whom received full myeloabatalive conditioning regimen prior to an allograph, elected to be treated at home after the graft was infused. Compared to patients that chose to be treated in the hospital and to a matched control group of patients, those electing home care had fewer days on TPN, less acute GVHD grades II-IV, lower transplant related mortality and lower costs. The two year survival rates were 70% in the home care group versus 51% and 57% in the control groups (Svahn et al, 2002).
Advances in cellular immunotherapy
There remains much interest in conferring antigen specificity on T cells for therapeutic purposes. The introduction of T-cell receptor genes specific for a given antigen. HTL restriction represents a significant hurdle to the wide applicability of this approach. Preclinical observations form the basis for clinical trials using donor-derived CD19-specific T-cell clones to treat or prevent relapse of B-ALL after allogenic HSC transplantation.
Use of CD4+CD25+ cells to inhibit GVHD, in Murine models, resulted in increased GVHD mediated by CD4+ T cells or whole T-cells (Taylor et al, 2002). Administration of ex-vivo activated and expanded CD4+T cells resulted in significant inhibition of rapidly lethal GVHD, raising the possibility of a new modality of cellular therapy for the inhibition of undesirable allogenic responses.
Prospective randomized controlled trials of high-dose chemotherapy and autologous transplantation for high-risk breast patients.
In July 2003, two large perspective randomized controlled trials of high-dose chemotherapy and autologous HSC transplantation in women with stage II or III breast cancer and 10 or more auxiliary lymph nodes involved by tumor were reported (Rodenhuis et al 2003; Tallman et al, 2003) The studies were large, enrolling 885 and 540 patients, respectively, and the medium duration of follow up was 4.8 and 6.1 years. Both studies had similar designs: women were to receive conventional therapy or conventional therapy followed by high-dose chemotherapy and autologous HSC transplant. The Dutch study concluded that high dose therapy improves relapse-free survival among patients with stage II or III breast cancer. The U.S. study concluded that the ‘high-dose therapy ... may reduce the risk of relapse, but did not improve the outcomes; both showed a significant reduction in the relapse rate; from which to explore new and additional methods of reducing relapse further (Elfenbein,2003).
Elfenbein, G. 2003. Stem cell transplantation for high risk breast cancer (editorial) . New England Journal of Medicine, 349, 80-82.
Cooper, LJN, et al. 2003. T-cell clones can be rendered specific for CD19: toward the selective augmentation of graft-versus-B linage leukemia effect. Blood 101; 1637-44.
Gratwohl, A, et al. 2002. Current trends in hematopoietic stem cell transplantation in Europe. Blood, 100; 2374-86.Kroger, N, et al. 2002. Autologous stem cell transplantation followed by reduced dose allograft reduces high complete remission rate in multiple myeloma. Blood, 100; 755-60.
Svahn, B-M et al. 2002; Home care during the pancytopenic phase after allogenic hematopoietic stem cell transplantation is advantageous compared with hospital care. Blood 100; 4317-24.
Tallman, MS et al. 2003. Conventional adjuvant chemotherapy with or without high dose chemotherapy and autologous stem-cell transplantation in high risk breast cancer. New England Journal of Medicine, 349; 17-26.
Taylor, PA et al. 2002. The infusion of ex-vivo activated and expanded CD4+ CD25+ immune regulatory cells inhibits graft-versus-host disease lethality. Blood, 99; 3493-9.
Umbilical cord blood transplantation
One of the most important advances in the field of allogenic hematopoietic stem cell (HSC) transplantation has been the use of umbilical cord blood transplantation. The principal limitations of allogenic HSC transplantation are the absence of suitable HLA-matched donors and the complications of graft-versus-host disease (GVHD), which are more severe with increasing HLA disparity between donor and recipient. A clinical result have been improving, due to the progress of HLA molecular typing but decreases the probability of finding an identical HLA donor in many specific cases. Despite the increasing number of bone-marrow registries that contain over 8 million bone marrow donors worldwide, some patients cannot be transplanted because of the lack of a suitable donor.
Sense the first successful allogenic umbilical cord blood transplant (UCBT) performed in 1988 to treat a child with Fanconi anemia (Gluckman et al, 1989), the development of cord blood banks and transplants has been an expanding medical enterprise. This discovery has established a new path that has demonstrated that umbilical cord blood could be collected at birth without any harm to the newborn, that umbilical cord blood, could be cryopreserved, thawed and reinfused in the host and permanently engraft. A single umbilical cord blood unit contained enough HSC’s to reconstitute the host’s lympho-hemotopoietic system.
Compared to adult cells, cord blood cells have a distinct biological advantage. The HSC’s have a growth proliferation advantage, and immune cells are less reactive, decreasing the risk of severe allogenic reactions. Compared to adult cells, umbilical cord blood HSC’s grow larger colonies, and are able to expand upon long-term culture in vitro, are able to engraft SCID in the absence of additional human growth factors, and have longer telomeres (Noort & Falkenburg, 2000)
It was realized early on, that it was important to set minimum standards for the safety of the donor and the mother as well as providing the best possible chances to find an appropriate donor for the recipient. In view of this, Netcord was founded in 1998. Netcord has set standards for umbilical cord banking, and currently includes data on large umbilical cord banks in the U.S., Europe, Australia, and Japan. In addition, the Foundation for Accreditation of Cellular Therapy (FACT), has established national and international regulatory standards, and has used internet technology to rapidly locate appropriate umbilical cord blood units according to histocompatibility matching and necessary cell prerequisites. Another international registry operating on behalf of the European Blood and Marrow Transplant (EBMT) group, called Eurocord, has more than 172 transplant centers from 34 countries reporting data.
The main practical advantages of using cord blood as an alternative source of stem cells HSC’s are (1) the relative ease of procurement (2) the absence of risk to donors, (3) the reduced risk of transmitting infection and (4) the availability of cryopreserved cord units to transplant centers.(5) large donor pool (6) increased speed of search (7) the low incidence of GVHD due to the immaturity of the newborn’s immune cells.
Diseases treated by cord blood transplantation (Ballen et al, 2001)
Acute lymphocytic leukemia
Acute myelocytic leukemia
Chronic myelogeneous leukemia
juvenile chronic myelodysplastic syndrome
Globoid cell leukodystrophy
Idiopathic aplastic anemia
Severe combined immune deficiency
X-linked lymphoproliferative syndrome
At the present time, the use of cord blood in the United States is permitted for only certain types of hematopoietic conditions and diseases. This reflects a belief among most scientists, that umbilical cord stem cells are limited to becoming red blood cells and certain immune cells. This is being challenged by a growing body of evidence, involving new clinical studies and scientific journal articles, by prominent physician/researchers. In fact, UCSC’s may improve severe cases of no-option cardiovascular patients; neurodegenerative diseases, including Parkinson’s and the crippling effects of stroke, and spinal cord injuries. As the relentless search for the most immune-compatible allogenically universal stem cell continues, we await the clinical results optimistically, and hopefully a chance of helping patients within our lifetimes.
Jeong, JA, et al. Rapid neural differentiation of human cord blood-derived mesenchymal stem cells. Neuroreport 15 ;( 11) 2004; 1731-1734.
Kogler, G, et al. A new human somatic stem cell from placental blood with intrinsic pluripotent differentiation potential. J Exp Med 2004; 223-235.
Bicknese, AR. et al. Human umbilical cord blood cells can be induced to express markers for neurons and glia. Cell Transplant 11 ;( 3) 2002; 261-264.
Hao, SG et al. Studies on the dynamics of biological characteristics of CD133+ cells from human umbilical cord blood during short term culture. Zhongguo Shi Yan Xue Ye Xue Za Zhi 11(6)2003; 569-575.
Baal, N, et al. Expression of transcription factor Oct-4 and other embryonic genes in CD133 positive cells from human umbilical cord blood. Thromb Haemost 92(4) 2004; 767-775.
Fu, YS, et al. Transformation of human umbilical mesenchymal cells into neurons in vitro. J Biomed Sci 11(5) 2004; 652-660.
Walczak P, et al. Do hematopoietic cells exposed to a neurogenic environment mimic properties of endogenous neural precursors. J Neurosci Res 76(2) 2004; 244-254.
McGuckin CP, et al. Umbilical cord blood stem cells can expand hematopoietic and neuroglial progenitors in vitro. Exp Cell Res 295(2) 2004; 350-359.
Hou L, et al. Induction of umbilical cord blood mesenchymal stem cells into neuron-like cells in vitro. Int J Hematol 778(3) 2003; 256-261.
Discussions and conclusions
Registry-based analyses confirm reported results that support the concept of establishing cryopreserved cord blood banks for clinical uses. Several questions have been answered while others remain to be investigated. Engraftment has been a major concern, as studies have shown that neutrophil and platelet recoveries were delayed, while long-term engraftment is similar to BMT. This result was expected, as it has been shown that that the number of cells infused predicted the outcomes of UCBT. This will be potentially overcome by the expansion of the cord blood stem cells, which, studies indicate are moderately easy to expand in-vitro. The regulatory issues, created by expanded umbilical cord blood stem cells , is another FDA accreditation process , involving numerous safety and efficacy testing over years of experience. We report that, in fact, several clinical studies are currently on-going, involving expanded UCB cells, in aspects of cardial regeneration and an experimental new blood substitute, supported by DARPA, is in clinical studies. We cannot report on these studies due to confidentiality and non-disclosure agreements as well as exploring the clinical potential aspects of expanded non-mobilized blood stem cells, are not within the objectives of this review.
Whether current approaches being explored to speed recovery after cord blood transplantation, such as ex-vivo expansion, will result in accelerated reconstitution is unknown. Other approaches include , the co-infusion of mesenchymal stem cells, and or the co-infusion of related HLA-mismatched PBSC’s( Fernandez et al, 2001) ; or the ex vivo expansion of cord blood progenitors to improve short term engraftment (Kogler et al. 1999; Pecora et al . 2000). Another area of research has involved the use of multiple cord blood units to increase cell counts, but several tiny studies have suggested that one unit apparently fails to graft. (Editors note; research if studies were funded by medical insurance companies). Let me share a brief thought with you. In 1973, doctors at Memorial Sloan-Kettering Cancer Center in New York City performed the first bone marrow transplant in which marrow from an unrelated donor was given to a five-year-old child with severe combined immunodeficiency syndrome (SDID), a rare, usually fatal, genetic disorder in which the body cannot defend itself against germs. The child was given seven successive graft infusions of marrow, six of which did not fully take. The seventh finally resulted in engraftment.
Recommendations for the use of cord blood cells may be given. However, the best results are obtained when patients are treated at an early stage of the disease, indicating that cord blood should be given as soon as possible (ASAP). According to established procedures, the first criterion of choice in selecting a cord blood unit should be the number of cells collected, the second ABO compatibility, and the third HLA compatibility. In addition, a combination of class I and class II mismatches , or more than 2 HLA mis-matches, should be avoided unless there is no other possible donor and the cell count numbers are greater than 2 x 10(7)/kg.
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