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Current developments in haematopoietic progenitor cell transplantation
Transfus. Sci. Vol.16, No.3, pp. 261-263, 1995
Pergamon
0955-3886(95}00032-1
Copyright © 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0955-3886/95 $9.50 + 0.00
What's Happening?: Stem Cells Current Developments in
Haematopoietic Progenitor Cell Transplantation "
M.J. Seghatchian, PhD* D o r o t h y F. M c D o n a l d , P h D t M a t t h e w A. L u m l e y , MB, ChB, M R C P ¢
It is becoming increasingly difficult for those interested in the evolving field of haematopoietic progenitor cells to keep up to date with the ever extending volume of information, either reported at various symposiums or published on this topic in various primary journals and which may not be available to everyone. With this in mind we have decided to produce a summary of current opinion on the haematopoietic progenitor cells to help readers with the new developments on this topic. This short report will be followed by a symposium summary on haematopoietic stem cells which will take place at the National Blood Service (West Midlands Centre), Birmingham, U.K., under the auspices of the BBTS -- Components SIG and BSH. We are grateful to Gail Rock for giving us the opportunity for developing this new form of information transfer in transfusion science. Peripheral blood progenitor cell transplantation (PBPCT) to restore haemopoiesis in patients suffering from haematological and non-haematological malignancies following myeloablative chemotherapy has become a well-established practice. In many situations PBPCT is replacing autologous bone marrow transplantation. Mobilizing and harvesting PBPCs is a relatively simple complication-free procedure and following infusion of PBPCs, bone marrow function recovers more rapidly than after marrow infusion and transplant related morbidity and mortality is reduced. Peripheral blood progenitor cell transplants have also been shown to provide long-term marrow reconstitution. The clinical application of PBPCs is expanding as scientific knowledge regarding the biology of haemopoietic stem and progenitor cells increases. Expertise in detecting minimal residual disease in peripheral blood harvests is developing and recent investigations have shown that there can be residual tumour cell contamination in many peripheral blood harvests. The concern that this is likely to be a contributory factor in relapse following PBPCT has prompted increasing endeavour in the laboratory manipulation of peripheral blood harvests to provide a tumour-free product. Strategies have been developed for the positive selection of CD34+ cells, the heterogeneous population in which stem and progenitor cells reside, and two clinical-scale devices are currently available. Both employ monoclonal antibodies, but while one relies on an immunoaffinity technique for cell separation the other makes use of an immunomagnetic system. Evidence exists to suggest that, unfortunately, certain tumour cells may also carry the CD34+ marker. Alternative strategies may be needed, therefore,
* North London Blood Transfusion Centre, Colindale Avenue, London NW9 5BG, U.K. t National Blood Service (West Midlands Centre], Birmingham, West Midlands, U.K. ~: Heartlands Hospital, Birmingham, West Midlands, U.K. 261
262 Transfus. Sci. Vol. 16, No. 3 to eliminate residual tumour cells and a recent report describes the immunomagnetic purging of B cells in B-cell non-Hodgkin's lymphoma. ~ The potential for ex v i v o expansion of stem and progenitor cell populations in culture is generating increasing interest and many encouraging results have been reported by groups employing enriched CD34+ populations stimulated with cytokines. 2 If it proves that these populations can be sufficiently expanded ex vivo, a reduction in the number of leucapheresis procedures necessary to provide sufficient numbers of cells for a graft should be possible. Expanded and activated stem cell populations are also a prerequisite for gene transfer and therapy. Gene therapy offers the possibility of the correction of genetic defects and other exciting prospects, but this aspect of stem cell research is still very m u c h in its infancy. 3 Haemopoietic stem cell rescue has permitted cytotoxic dose intensification in the treatment of solid tumours, in particular breast cancer. 4 Recently, a multicyclic approach to treatment intensification in cancer has been investigated, supported by repeated infusions of mobilized peripheral blood, s If such an approach proves to be effective, cryopreservation of PBPCs may no longer be necessary in this setting. Certainly, it has been shown in assay that the cells responsible for long-term marrow engraftment remain viable for 5 days at 4°C. Such a therapeutic procedure should make it possible to treat patients on an out-patient basis, thus reducing costs and at the same time extending the therapy to patients at cancer centres lacking cryopreservation facilities. The possibility of using allogeneic PBPCs for transplantation from both related and unrelated donors is being explored in a number of centres. Original concerns regarding growth factor priming of normal individuals and durability of engraftment appear unfounded, and the high numbers of T cells in peripheral blood harvests relative to bone marrow harvests have apparently not given rise to more severe acute Graft versus Host Disease (GVHD). In some instances T-cell depletion of PBPCs has been carried out to reduce the risk of GVHD, but in a number of cases allogeneic transplants have been managed successfully with conventional treatment using cyclosporin and methotrexate. The use of allogeneic PBPCT is potentially an excellent alternative to allogeneic bone marrow where the fitness of the donor for general anaesthesia and bone marrow harvesting is in doubt. 6 Donors would prefer to avoid general anaesthesia and as PBPC mobilization with growth factors is reported to be well tolerated with minor bone pain and headache as the only side effects, the feasibility of more general use of harvested PBPCs from unrelated donors for transplantation is being considered. H u m a n umbilical cord blood (HUC) has been recognized as being a rich source of haematopoietic progenitor cells for some time but this hitherto untapped source of cells is only slowly being utilized for allogeneic transplantation. Banks of HUC are being set up internationally and a number of sibling and unrelated transplants have been carried out. The adequacy of the numbers of cells harvested for adult transplantation is in doubt though, in this context, HUC harvests may be prime candidates for e x v i v o expansion. Data obtained from the initial transplants, however, support the contention that HUC is an acceptable source of transplantable stem cells with low GVHD potential. 7 Laboratory and clinical research involving haemopoietic stem and progenitor cells is moving quickly. It is likely that PBPCT will be indicated for an ever widening range of diseases and that prospects for m a n y patients will be greatly improved. These developments will be welcomed with considerable enthusiasm. REFERENCES
1. Straka C, Drexler E, Mitterer M, Langenmayer I, Pfefferkorn L, Stade B, Koll R, Emerich B: Autotransplantation of B-cell purged peripheral blood progenitor cells in B-cell lymphoma.
Haematopoietic Progenitor Cell Transplantation 263 Lancet 1995; 345:797. 2. Heimfeld S, Fei R, Xu Z, Fogarty B, Vanderbosch L, Jones H, Berenson R: Ex-vivo expansion of human CD34+ haematopoietic progenitor cells. Bone Marrow Transplant 1995; 2:$43. 3. Mehtali M: Basic aspects of gene therapy. Bone Marrow Transplant 1995; 15(2):$52. 4. Myers S, Mick R, Williams S: High-dose chemotherapy with autologous stem cell rescue in women with metastatic breast cancer with involved bone marrow, a role for peripheral blood progenitor transplant. Bone Marrow Transplant 1994; 13:449454. 5. Pettengell R: Filgrastim(r-met HuG-CSF)-mobilised autologous whole blood to support multicycle dose-intensive chemotherapy in the treatment of small cell lung cancer (SCLC). PBPC Update issue 2, 1994. 1st Cambridge Symposium on Peripheral Blood Progenitor Cells. 6. Russell N, Hunter A, Rogers S, Hanley J, Anderson D: Peripheral blood stem cells as an alternative to marrow for allogeneic transplantation. Lancet 1993; 341:1482. 7. Wagner J, Kernan N, Broxmeyer H, Gluckman E: Transplantation of umbilical cord blood in 50 patients. Analysis of the registry data. Blood 1994; 84(10, suppl 1.):395a.
TS 16:3-E
Pergamon
0955-3886(95}00032-1
Copyright © 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0955-3886/95 $9.50 + 0.00
What's Happening?: Stem Cells Current Developments in
Haematopoietic Progenitor Cell Transplantation "
M.J. Seghatchian, PhD* D o r o t h y F. M c D o n a l d , P h D t M a t t h e w A. L u m l e y , MB, ChB, M R C P ¢
It is becoming increasingly difficult for those interested in the evolving field of haematopoietic progenitor cells to keep up to date with the ever extending volume of information, either reported at various symposiums or published on this topic in various primary journals and which may not be available to everyone. With this in mind we have decided to produce a summary of current opinion on the haematopoietic progenitor cells to help readers with the new developments on this topic. This short report will be followed by a symposium summary on haematopoietic stem cells which will take place at the National Blood Service (West Midlands Centre), Birmingham, U.K., under the auspices of the BBTS -- Components SIG and BSH. We are grateful to Gail Rock for giving us the opportunity for developing this new form of information transfer in transfusion science. Peripheral blood progenitor cell transplantation (PBPCT) to restore haemopoiesis in patients suffering from haematological and non-haematological malignancies following myeloablative chemotherapy has become a well-established practice. In many situations PBPCT is replacing autologous bone marrow transplantation. Mobilizing and harvesting PBPCs is a relatively simple complication-free procedure and following infusion of PBPCs, bone marrow function recovers more rapidly than after marrow infusion and transplant related morbidity and mortality is reduced. Peripheral blood progenitor cell transplants have also been shown to provide long-term marrow reconstitution. The clinical application of PBPCs is expanding as scientific knowledge regarding the biology of haemopoietic stem and progenitor cells increases. Expertise in detecting minimal residual disease in peripheral blood harvests is developing and recent investigations have shown that there can be residual tumour cell contamination in many peripheral blood harvests. The concern that this is likely to be a contributory factor in relapse following PBPCT has prompted increasing endeavour in the laboratory manipulation of peripheral blood harvests to provide a tumour-free product. Strategies have been developed for the positive selection of CD34+ cells, the heterogeneous population in which stem and progenitor cells reside, and two clinical-scale devices are currently available. Both employ monoclonal antibodies, but while one relies on an immunoaffinity technique for cell separation the other makes use of an immunomagnetic system. Evidence exists to suggest that, unfortunately, certain tumour cells may also carry the CD34+ marker. Alternative strategies may be needed, therefore,
* North London Blood Transfusion Centre, Colindale Avenue, London NW9 5BG, U.K. t National Blood Service (West Midlands Centre], Birmingham, West Midlands, U.K. ~: Heartlands Hospital, Birmingham, West Midlands, U.K. 261
262 Transfus. Sci. Vol. 16, No. 3 to eliminate residual tumour cells and a recent report describes the immunomagnetic purging of B cells in B-cell non-Hodgkin's lymphoma. ~ The potential for ex v i v o expansion of stem and progenitor cell populations in culture is generating increasing interest and many encouraging results have been reported by groups employing enriched CD34+ populations stimulated with cytokines. 2 If it proves that these populations can be sufficiently expanded ex vivo, a reduction in the number of leucapheresis procedures necessary to provide sufficient numbers of cells for a graft should be possible. Expanded and activated stem cell populations are also a prerequisite for gene transfer and therapy. Gene therapy offers the possibility of the correction of genetic defects and other exciting prospects, but this aspect of stem cell research is still very m u c h in its infancy. 3 Haemopoietic stem cell rescue has permitted cytotoxic dose intensification in the treatment of solid tumours, in particular breast cancer. 4 Recently, a multicyclic approach to treatment intensification in cancer has been investigated, supported by repeated infusions of mobilized peripheral blood, s If such an approach proves to be effective, cryopreservation of PBPCs may no longer be necessary in this setting. Certainly, it has been shown in assay that the cells responsible for long-term marrow engraftment remain viable for 5 days at 4°C. Such a therapeutic procedure should make it possible to treat patients on an out-patient basis, thus reducing costs and at the same time extending the therapy to patients at cancer centres lacking cryopreservation facilities. The possibility of using allogeneic PBPCs for transplantation from both related and unrelated donors is being explored in a number of centres. Original concerns regarding growth factor priming of normal individuals and durability of engraftment appear unfounded, and the high numbers of T cells in peripheral blood harvests relative to bone marrow harvests have apparently not given rise to more severe acute Graft versus Host Disease (GVHD). In some instances T-cell depletion of PBPCs has been carried out to reduce the risk of GVHD, but in a number of cases allogeneic transplants have been managed successfully with conventional treatment using cyclosporin and methotrexate. The use of allogeneic PBPCT is potentially an excellent alternative to allogeneic bone marrow where the fitness of the donor for general anaesthesia and bone marrow harvesting is in doubt. 6 Donors would prefer to avoid general anaesthesia and as PBPC mobilization with growth factors is reported to be well tolerated with minor bone pain and headache as the only side effects, the feasibility of more general use of harvested PBPCs from unrelated donors for transplantation is being considered. H u m a n umbilical cord blood (HUC) has been recognized as being a rich source of haematopoietic progenitor cells for some time but this hitherto untapped source of cells is only slowly being utilized for allogeneic transplantation. Banks of HUC are being set up internationally and a number of sibling and unrelated transplants have been carried out. The adequacy of the numbers of cells harvested for adult transplantation is in doubt though, in this context, HUC harvests may be prime candidates for e x v i v o expansion. Data obtained from the initial transplants, however, support the contention that HUC is an acceptable source of transplantable stem cells with low GVHD potential. 7 Laboratory and clinical research involving haemopoietic stem and progenitor cells is moving quickly. It is likely that PBPCT will be indicated for an ever widening range of diseases and that prospects for m a n y patients will be greatly improved. These developments will be welcomed with considerable enthusiasm. REFERENCES
1. Straka C, Drexler E, Mitterer M, Langenmayer I, Pfefferkorn L, Stade B, Koll R, Emerich B: Autotransplantation of B-cell purged peripheral blood progenitor cells in B-cell lymphoma.
Haematopoietic Progenitor Cell Transplantation 263 Lancet 1995; 345:797. 2. Heimfeld S, Fei R, Xu Z, Fogarty B, Vanderbosch L, Jones H, Berenson R: Ex-vivo expansion of human CD34+ haematopoietic progenitor cells. Bone Marrow Transplant 1995; 2:$43. 3. Mehtali M: Basic aspects of gene therapy. Bone Marrow Transplant 1995; 15(2):$52. 4. Myers S, Mick R, Williams S: High-dose chemotherapy with autologous stem cell rescue in women with metastatic breast cancer with involved bone marrow, a role for peripheral blood progenitor transplant. Bone Marrow Transplant 1994; 13:449454. 5. Pettengell R: Filgrastim(r-met HuG-CSF)-mobilised autologous whole blood to support multicycle dose-intensive chemotherapy in the treatment of small cell lung cancer (SCLC). PBPC Update issue 2, 1994. 1st Cambridge Symposium on Peripheral Blood Progenitor Cells. 6. Russell N, Hunter A, Rogers S, Hanley J, Anderson D: Peripheral blood stem cells as an alternative to marrow for allogeneic transplantation. Lancet 1993; 341:1482. 7. Wagner J, Kernan N, Broxmeyer H, Gluckman E: Transplantation of umbilical cord blood in 50 patients. Analysis of the registry data. Blood 1994; 84(10, suppl 1.):395a.
TS 16:3-E