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Future considerations in transplantation
Future Considerations in Transplantation Debra Wujci k HE USE OF peripheral blood progenitor/stem cells for hematopoietic reconstitution after high-dose therapy is rapidly increasing. This is due in part to the increased awareness of blood cell transplantation (BCT) as a treatment option and the availability of free-standing community apheresis centers. 1 At the same time, health care reform efforts are exerting financial constraints to decrease or limit use. In addition, a number of issues related to the purity of the stem cells products, definitions of appropriate cell numbers and viability, and the transport of cells across state lines are being raised. Members of the International Society for Hematotherapy and Graft Engineering, The American Society for Blood and Marrow Transplantation, and The Canadian Bone Marrow Transplant Group have joined efforts to form the Foundation for Accreditation of Hematopoietic Cell Therapy. This group has defined standards to ensure the quality of medical and laboratory practice, which will be applied to cells obtained from bone marrow, peripheral blood, and umbilical cord. The standards describe rigorous education and experience requirements for personnel and allow application for accreditation after 10 successful transplants. The assumption is that insurers will identify accredited programs as the "preferred provider." The impact of these standards on the formation of new and existing programs remains to be seen. With the emphasis on a defined and comprehensive program for transplant that includes all aspects of the care, one director, and core facilities with geographic or proximate facilities, it is clear that existing models that include free-standing apheresis facilities will have to be joined more formally with comprehensive programs to ensure ongoing survival. Allogeneic BCT appears to be increasing rapidly although there is little data to support efficacy
T
From Vanderbilt Cancer Center, and Vanderbilt University School of Nursing, Nashville, TN. Debra Wujcik, RN, MSN, AOCN: Clinical Director, Vanderbet Cancer Center, Adjunct Instructor, Vanderbilt University School of Nursing, Nashville, TN. Address reprint requests to Debra Wujcik, RN, MSN, AOCN, 5019 Chaffin Dr, Nashville, TN37221. Copyright © 1997 by W.B. Saunders Company 0749-2081/97/1302-000955.00/0 216
beyond initial hematopoietic recovery. Currently, there are 666 allogeneic BCT recorded in the Autologous Blood and Marrow Transplant Registry (ABMTR). 2 During the recording period 1992 to 1994 there was only 6%, and in 1995 to 1996 there was 94%. The majority (65%) was performed to treat malignant conditions and was from human lymphocyte antigen-related donors (84%). There are a few reports in the literature describing initial experiences with allogeneic BCT. In one comparison of 26 BCT from sibling donors for hematologic malignancy with historic bone marrow transplantation controls, the incidence of acute graft versus host disease (GVHD) was 37% versus 21% and chronic GVHD 53% versus 48% (five to six antigen matched transplants.) Comparable red blood cell transfusions took place in both groups and the BCT group required less platelet transfusions. There was a trend towards shorter recovery as measured by days in hospital. 3 Another report of 19 patients receiving allogeneic BCT from siblings described a similar incidence of acute GVHD (37%) and less chronic GVHD (33%). 4 There is one published report of a matched unrelated donor BCT. 5 The patient with acute myelogenous leukemia was in second complete remission. Although engraftment was evident day + 19 after transplant, the patient died at day +38 of supposed cerebral aspergillus infection. The option for allogeneic donation may increase public interest but issues still to be addressed include the long-term effects of growth factor induced mobilization on healthy donors and alternatives for cell collection that do not require placement of a central venous catheter. Umbilical cord blood (UCB) can provide enough hematopoietic stem cells to provide short- and long-term engraftment after high-dose therapy. 6-8 This finding has led to large scale banking of cord blood for future allogeneic and autologous UCB transplant, in vitro expansion of cells to provide adequate dose for adults, retroviral gene transfer into UCB stem cells for treatment of a variety of diseases, and the study of the immunological properties of fetal and neonatal hematopoiesis. The ABMTR has data from 188 UCB transplants through 1996. Siblings were the donors for 27% of the UCB transplants and the remaining were from
Seminars in Oncology Nursing, Vo113, No 3 (August), 1997: pp 216-218
FUTURE CONSIDERATIONS
217
unrelated donors. 9 The median age for recipients is 6 years with a range from less than 1 year to 46 years. There has also been a rapid increase in UCB transplants performed with 5% in 1988 to 1990, 11% in 1991 to 1993, and 84% in 1994 to 1996. Although the majority (59%) were performed to treat malignant disease, there is potential wide application for nonmalignant disorders such as immunodeficiency states and metabolic disorders. Because of the increasing numbers of UCB transplants worldwide, the International Cord Blood registry has been established. 10 The International Conference Workshop on Cord Blood Transplantation in 1993 reported results from 34 UCB transplants with proven hematopoieric recovery and decreased GVHD when cornparted to BMT. al UCB transplants to date have been from five or six antigen matched donors. Greater antigen disparity has not been evaluated. 12 It is interesting to note the mix of lymphocytes in fetal cells is different than in adult cells. There is a greater percentage of larger granular lymphocytes in UCB. These cells are equivalent to natural killer cells and seem to provide graft versus leukemia effects. It is postulated the decrease in GVHD is due to significantly less cytotoxic T cells (CD8) and a higher ratio of helper cells (CD4).13 A number of issues arise when discussing UCB. Stored UCB for unrelated recipients may save time for recipients and provide more potential donors for underrepresented minorities. However, this may lead to ethical issues related to the rights of the newborn if tissue is released. Should the donor keep cells for potential future need for self or related family member or donate cells to the matched unrelated cell pool? Should insurers pay for the processing and continued storage of the cells? A limitation to UBC transplantation is the number of cells available may not be adequate for adult patients. Use of interleukln-3 (IL-3), IL-6, erythropoietin, granulocyte-macrophage colonystimulating factor, and stern cell factor for in vitro expansion of stem cells is being explored. 14 The best method and minimum number of UBC needed for successful transplant are not yet defined. 9
Another area of research is the collection of fetal tissue from aborted fetuses. The number of cells obtained appears to be directly related to gestational age and the best techniques for obtaining the cells are being developed. 15 Since women appear to be willing to allow this practice, some are concerned that women would be encouraged to abort for economic gain.13 Currently, testing exists to determine early in pregnancy if the fetus is genetically normal and human lymphocyte antigen identical to a sibling affected with genetic disease. A number of genetic diseases such as thalassemia, sickle cell, Fanconi's anemia, and adenonsine deaminase deficiency are potentially treatable by UCB transplants. 16 This leads to issues of having children for the sole purpose of saving the life of a sibling. One report describes 32 pregnancies for this purpose. Six cases allowed UCB collection at delivery, 24 cases were carried to full-term even though the siblings were not HLA matches, and 2 pregnancies were terminated because of a mismatch. 16Issues of moral and financial responsibility of the parents arise. Finally, there is potential use of UBC stem cells as vectors for gene transfer.17 Infusion of fetal UCB cells for in utero transplant has been performed unsuccessfully to treat congenital disease (thalassemia and sickle cell anemia). These two cases indicated UCB transplant is not effective after 12-weeks gestation. However, the investigators speculated that earlier or increased numbers of cells would promote engraftment. 18 Another example is the treatment of human immunodeficiency virus (HIV) infections with allogeneic CD34+ cells that have been transduced by vectors carrying the ribozyme gene, which has been shown to provide resistance against HIV- 1 infection. 19 New relationships must form as these options become more common. The traditional transplant team will be collaborating with the obstetric health care providers who are counseling patients with familial disorders. 2° As cells are collected, processed, and later infused, the teams must work together to provide continuity of care, ensure viability of the cells, and work through the numerous ethical issues that will be encountered, a3
REFERENCES
1. Beatty PG: Clinical and societal issues in blood and marrow transplantation for hematologicaldiseases. Biol Blood MarrowTransplant 1:94-114, 1994 2. International Bone Marrow Transplant Registry/Autolo-
gous Blood and Marrow Transplant Registry Statistical Center, MedicalCollegeof Wisconsin, Milwaukee,WI, 1996 3. Russell JA, Brown C, Bowen T, et al: Allogeneic blood cell transplants for haematological malignancy: Preliminary
218
comparison of outcomes with bone marrow transplantation. Bone Marrow Transplant 17:703-708, 1996 4. Rosenfeld C, Collins R, Pineiro L, et al: Allogeneic blood cell transplantation without posttransplant colony-stimulating factors in patients with hematopoietic neoplasm: A phase II study. J Clin Oncol 14:1314-1319, 1996 5. Stockschlader M, Loliger C, Kruger W, et al: Transplantation of allogeneic rhG-CSF mobilized peripheral CD34+ cells from an HLA-identical unrelated donor. Bone Marrow Transplant 16:719-722, 1995 • 6. Wagner JE: Umbilical cord and placental blood transplantation: Analysis of the clinical results. J Hematother 2:265-268, 1993 7. Wagner JE: Umbilical cord blood transplantation: Overview of the clinical experience. Blood Ceils 20:227-233, 1994 8. Harris DT: Analysis of the alloreactive capacity of human umbilical cord blood: Implications for graft-versus-hostdisease. Bone Marrow Transplant 14:545-553, 1994 9. Kogler G, Callejas J, Hakenberg P, et al: Hematopoietic transplant potential of unrelated cord blood: Critical issues. J Hematother 5:105-116, 1996 10. Gluckman E, Thierry D, Traineau R: Blood banking for hematopoietic stem cell transplantation. J Hematother 2:269270, 1993 11. Apperly JF: Umbilical cord blood progenitor cell transplantation. The International Conference Workshop on Cord Blood Transplantation, Indianapolis, November 1993. Bone Marrow Transplant 14:187-196, 1993 12. Wagner JE, Kernan NA, Steinbuch M, et al: Allogeneic
DEBRA WUJCIK
sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease. Lancet 346:214-219, 1995 13. Varadi G, Elchalal U, Shushan JG, et al: Umbilical cord blood for use in transplantation. Obstet Gynecol Surv 50:611617, 1995 14. VanZant G, Rummel SA, Killer MR, et al: Expansion in bioreactors of human progenitor populations from cord blood and mobilized peripheral blood. Blood Cells 20:482-490, 1994 15. Westgren M, Ek S, Bui TH, et al: Establishment of a tissue bank for fetal stem cell transplantation. Acta Obstet Gynecol Scand 73:385-388, 1994 16. Auerbach AD: Umbilical cord blood transplants for genetic disease: Diagnostic and ethical issues in fetal studies. Blood Cells 20:303-309, 1994 17. Hanley ME, Nolta Ja, Parkman R, et al: Umbilical cord blood cell transduction by retroviral vectors: Studies to optimize gene transfer. Blood Cells 20:539-543, 1994 18. Westgren M, Ringden O, Eik-Nes S, et al: Lack of evidence of permanent engraftment after in utero fetal stem cell transplantation in congenital hemoglobinopathies. Transplantation 61:1176-1179, 1996 19. Ho AD, Li X, Yu M, et al: Stem cells as vehicles for gene therapy: Novel strategies for HIV infection. Stem Cells 13:100-105, 1995 (suppl 3) 20. Cetmlo CL, Sbarra A J, Cetmlo CL Jr: Collection and cryopreservation of cord blood for the treatment of hematopoietic disorders: The obstetrician's overview. J Hematother 5:149-151, 1996
T
From Vanderbilt Cancer Center, and Vanderbilt University School of Nursing, Nashville, TN. Debra Wujcik, RN, MSN, AOCN: Clinical Director, Vanderbet Cancer Center, Adjunct Instructor, Vanderbilt University School of Nursing, Nashville, TN. Address reprint requests to Debra Wujcik, RN, MSN, AOCN, 5019 Chaffin Dr, Nashville, TN37221. Copyright © 1997 by W.B. Saunders Company 0749-2081/97/1302-000955.00/0 216
beyond initial hematopoietic recovery. Currently, there are 666 allogeneic BCT recorded in the Autologous Blood and Marrow Transplant Registry (ABMTR). 2 During the recording period 1992 to 1994 there was only 6%, and in 1995 to 1996 there was 94%. The majority (65%) was performed to treat malignant conditions and was from human lymphocyte antigen-related donors (84%). There are a few reports in the literature describing initial experiences with allogeneic BCT. In one comparison of 26 BCT from sibling donors for hematologic malignancy with historic bone marrow transplantation controls, the incidence of acute graft versus host disease (GVHD) was 37% versus 21% and chronic GVHD 53% versus 48% (five to six antigen matched transplants.) Comparable red blood cell transfusions took place in both groups and the BCT group required less platelet transfusions. There was a trend towards shorter recovery as measured by days in hospital. 3 Another report of 19 patients receiving allogeneic BCT from siblings described a similar incidence of acute GVHD (37%) and less chronic GVHD (33%). 4 There is one published report of a matched unrelated donor BCT. 5 The patient with acute myelogenous leukemia was in second complete remission. Although engraftment was evident day + 19 after transplant, the patient died at day +38 of supposed cerebral aspergillus infection. The option for allogeneic donation may increase public interest but issues still to be addressed include the long-term effects of growth factor induced mobilization on healthy donors and alternatives for cell collection that do not require placement of a central venous catheter. Umbilical cord blood (UCB) can provide enough hematopoietic stem cells to provide short- and long-term engraftment after high-dose therapy. 6-8 This finding has led to large scale banking of cord blood for future allogeneic and autologous UCB transplant, in vitro expansion of cells to provide adequate dose for adults, retroviral gene transfer into UCB stem cells for treatment of a variety of diseases, and the study of the immunological properties of fetal and neonatal hematopoiesis. The ABMTR has data from 188 UCB transplants through 1996. Siblings were the donors for 27% of the UCB transplants and the remaining were from
Seminars in Oncology Nursing, Vo113, No 3 (August), 1997: pp 216-218
FUTURE CONSIDERATIONS
217
unrelated donors. 9 The median age for recipients is 6 years with a range from less than 1 year to 46 years. There has also been a rapid increase in UCB transplants performed with 5% in 1988 to 1990, 11% in 1991 to 1993, and 84% in 1994 to 1996. Although the majority (59%) were performed to treat malignant disease, there is potential wide application for nonmalignant disorders such as immunodeficiency states and metabolic disorders. Because of the increasing numbers of UCB transplants worldwide, the International Cord Blood registry has been established. 10 The International Conference Workshop on Cord Blood Transplantation in 1993 reported results from 34 UCB transplants with proven hematopoieric recovery and decreased GVHD when cornparted to BMT. al UCB transplants to date have been from five or six antigen matched donors. Greater antigen disparity has not been evaluated. 12 It is interesting to note the mix of lymphocytes in fetal cells is different than in adult cells. There is a greater percentage of larger granular lymphocytes in UCB. These cells are equivalent to natural killer cells and seem to provide graft versus leukemia effects. It is postulated the decrease in GVHD is due to significantly less cytotoxic T cells (CD8) and a higher ratio of helper cells (CD4).13 A number of issues arise when discussing UCB. Stored UCB for unrelated recipients may save time for recipients and provide more potential donors for underrepresented minorities. However, this may lead to ethical issues related to the rights of the newborn if tissue is released. Should the donor keep cells for potential future need for self or related family member or donate cells to the matched unrelated cell pool? Should insurers pay for the processing and continued storage of the cells? A limitation to UBC transplantation is the number of cells available may not be adequate for adult patients. Use of interleukln-3 (IL-3), IL-6, erythropoietin, granulocyte-macrophage colonystimulating factor, and stern cell factor for in vitro expansion of stem cells is being explored. 14 The best method and minimum number of UBC needed for successful transplant are not yet defined. 9
Another area of research is the collection of fetal tissue from aborted fetuses. The number of cells obtained appears to be directly related to gestational age and the best techniques for obtaining the cells are being developed. 15 Since women appear to be willing to allow this practice, some are concerned that women would be encouraged to abort for economic gain.13 Currently, testing exists to determine early in pregnancy if the fetus is genetically normal and human lymphocyte antigen identical to a sibling affected with genetic disease. A number of genetic diseases such as thalassemia, sickle cell, Fanconi's anemia, and adenonsine deaminase deficiency are potentially treatable by UCB transplants. 16 This leads to issues of having children for the sole purpose of saving the life of a sibling. One report describes 32 pregnancies for this purpose. Six cases allowed UCB collection at delivery, 24 cases were carried to full-term even though the siblings were not HLA matches, and 2 pregnancies were terminated because of a mismatch. 16Issues of moral and financial responsibility of the parents arise. Finally, there is potential use of UBC stem cells as vectors for gene transfer.17 Infusion of fetal UCB cells for in utero transplant has been performed unsuccessfully to treat congenital disease (thalassemia and sickle cell anemia). These two cases indicated UCB transplant is not effective after 12-weeks gestation. However, the investigators speculated that earlier or increased numbers of cells would promote engraftment. 18 Another example is the treatment of human immunodeficiency virus (HIV) infections with allogeneic CD34+ cells that have been transduced by vectors carrying the ribozyme gene, which has been shown to provide resistance against HIV- 1 infection. 19 New relationships must form as these options become more common. The traditional transplant team will be collaborating with the obstetric health care providers who are counseling patients with familial disorders. 2° As cells are collected, processed, and later infused, the teams must work together to provide continuity of care, ensure viability of the cells, and work through the numerous ethical issues that will be encountered, a3
REFERENCES
1. Beatty PG: Clinical and societal issues in blood and marrow transplantation for hematologicaldiseases. Biol Blood MarrowTransplant 1:94-114, 1994 2. International Bone Marrow Transplant Registry/Autolo-
gous Blood and Marrow Transplant Registry Statistical Center, MedicalCollegeof Wisconsin, Milwaukee,WI, 1996 3. Russell JA, Brown C, Bowen T, et al: Allogeneic blood cell transplants for haematological malignancy: Preliminary
218
comparison of outcomes with bone marrow transplantation. Bone Marrow Transplant 17:703-708, 1996 4. Rosenfeld C, Collins R, Pineiro L, et al: Allogeneic blood cell transplantation without posttransplant colony-stimulating factors in patients with hematopoietic neoplasm: A phase II study. J Clin Oncol 14:1314-1319, 1996 5. Stockschlader M, Loliger C, Kruger W, et al: Transplantation of allogeneic rhG-CSF mobilized peripheral CD34+ cells from an HLA-identical unrelated donor. Bone Marrow Transplant 16:719-722, 1995 • 6. Wagner JE: Umbilical cord and placental blood transplantation: Analysis of the clinical results. J Hematother 2:265-268, 1993 7. Wagner JE: Umbilical cord blood transplantation: Overview of the clinical experience. Blood Ceils 20:227-233, 1994 8. Harris DT: Analysis of the alloreactive capacity of human umbilical cord blood: Implications for graft-versus-hostdisease. Bone Marrow Transplant 14:545-553, 1994 9. Kogler G, Callejas J, Hakenberg P, et al: Hematopoietic transplant potential of unrelated cord blood: Critical issues. J Hematother 5:105-116, 1996 10. Gluckman E, Thierry D, Traineau R: Blood banking for hematopoietic stem cell transplantation. J Hematother 2:269270, 1993 11. Apperly JF: Umbilical cord blood progenitor cell transplantation. The International Conference Workshop on Cord Blood Transplantation, Indianapolis, November 1993. Bone Marrow Transplant 14:187-196, 1993 12. Wagner JE, Kernan NA, Steinbuch M, et al: Allogeneic
DEBRA WUJCIK
sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease. Lancet 346:214-219, 1995 13. Varadi G, Elchalal U, Shushan JG, et al: Umbilical cord blood for use in transplantation. Obstet Gynecol Surv 50:611617, 1995 14. VanZant G, Rummel SA, Killer MR, et al: Expansion in bioreactors of human progenitor populations from cord blood and mobilized peripheral blood. Blood Cells 20:482-490, 1994 15. Westgren M, Ek S, Bui TH, et al: Establishment of a tissue bank for fetal stem cell transplantation. Acta Obstet Gynecol Scand 73:385-388, 1994 16. Auerbach AD: Umbilical cord blood transplants for genetic disease: Diagnostic and ethical issues in fetal studies. Blood Cells 20:303-309, 1994 17. Hanley ME, Nolta Ja, Parkman R, et al: Umbilical cord blood cell transduction by retroviral vectors: Studies to optimize gene transfer. Blood Cells 20:539-543, 1994 18. Westgren M, Ringden O, Eik-Nes S, et al: Lack of evidence of permanent engraftment after in utero fetal stem cell transplantation in congenital hemoglobinopathies. Transplantation 61:1176-1179, 1996 19. Ho AD, Li X, Yu M, et al: Stem cells as vehicles for gene therapy: Novel strategies for HIV infection. Stem Cells 13:100-105, 1995 (suppl 3) 20. Cetmlo CL, Sbarra A J, Cetmlo CL Jr: Collection and cryopreservation of cord blood for the treatment of hematopoietic disorders: The obstetrician's overview. J Hematother 5:149-151, 1996