Max
08-18-2002, 07:32 PM
http://bmj.com/cgi/content/full/325/7360/348
Bone marrow transplants
New indications exploit the immune effects of the transplanted cells
Bone marrow, or haematopoietic stem cell, transplants were originally developed to allow the use of very high dose treatments for malignancies such as leukaemia. Their use was based on the idea that the high dose treatment might overcome inherent resistance of the malignancy to chemotherapy or radiotherapy. Transplants of stem cells from either the same person (autologous) or another person (allogeneic) are used to repopulate and regenerate the bone marrow, "rescuing" the patient from aplasia. Recently, attention has shifted from the straightforward pursuit of higher doses of cytotoxic drugs to the exploitation of immune effects exerted by allogeneic donor cells. Initial work in autologous transplantation concentrated on showing the safety of the process. Many early studies consisted only of case series, but in the past few years several important randomised trials have been reported, allowing closer definition of the conditions for which bone marrow transplants are useful. These include multiple myeloma, recurrent Hodgkin's disease, and aggressive lymphoma in second remission, for which high dose treatment is routinely given following evidence from randomised trials. 1 2
As the indications for stem cell transplants have been better defined overall activity has fallen. The number of high dose procedures reported to the European Blood and Marrow Transplant Registry fell from 19 346 in 1999 to 17 636 in 2000. This was due to a marked decrease in transplants for solid tumours, especially breast cancer. High dose chemotherapy for adjuvant treatment of breast cancer was tested in several trials worldwide and used as a routine component of treatment in some centres. This has now almost vanished in the wake of evidence from several randomised studies with a negative outcome and the exposure of one of the few trials with a positive outcome as seriously flawed.3
The role of autologous transplantation for acute myeloid leukaemia is still unclear, with some large trials showing improvements in survival whereas others show no benefit over conventional chemotherapy.4 Similar effects are seen in aggressive lymphoma where studies incorporating high dose treatment into initial therapy have generally had negative outcomes although the use of single drugs at high dose sequentially may hold some promise.5 This approach is being studied in a randomised trial in Europe.
In low grade lymphoma, few controlled trials have been conducted and efforts remain focused upon refinement of the transplant technique. Whether failure to obtain a stem cell harvest free from lymphoma or the resistance of the disease is the main reason of recurrence is not clear. A new approach has been to use anti-B cell monoclonal antibodies (such as rituximab) before collecting the stem cells, in the hope of eliminating residual lymphoma from the marrow and peripheral blood.6 The preliminary results in low grade lymphoma seem promising, and this too is now the subject of a trial.
Allogeneic transplantation adds a further dimensionthe potential for immune effector cells from the donor to recognise and eliminate residual tumour in the recipient.7 Ironically, it was because of a complication of this type of transplant that the immunological effect became apparent. Graft versus host disease is caused by the activation of lymphocytes derived from the donor, leading to immune damage to the skin, gut, and liver in the recipient. Patients who experience graft versus host disease, however, have a lower risk of developing recurrent leukaemia. This suggests an important antimalignancy effect due to the lymphocytes.
A more striking example of the importance of immune cells is the effect of donor lymphocyte infusions in patients with disease that recurs after a transplant. Lymphocytes are collected from the peripheral blood of the donor and given to the patient, and this can result in the eradication of recurrent malignancy. This may be due either to specific targeting of tumour antigens or simply the result of graft versus host disease affecting malignant cells preferentially.
Different illnesses vary in their responsiveness to donor lymphocyte infusionchronic myeloid leukaemia is the most responsive, myeloma and low grade lymphoma less so, and the acute leukaemias much less so.8 This reflects mainly the time needed for effective antimalignant immune responses to develop. Tumour regression after allotransplantation and treatment with donor lymphocytes has also been reported in patients with solid tumoursfor example, renal, breast, and bowel carcinomas9and we are just beginning to understand the targets that may be recognised by the donor cells.
An extension of the idea of exploiting donor immune responses is to carry out transplants where the chemotherapy is aimed at creating space for the donor immune system to develop rather than directly treating the malignancy.10 By giving chemotherapy that is strongly immunosuppressive but not myeloablative, a state of recipient-donor mixture, or chimerism, can be achieved. Because the chemotherapy is of low intensity the acute side effects are few. The risk of graft versus host disease, however, remains and makes intensive follow up with monitoring for opportunistic infection necessary. Although the chimeric state may be effective against single gene disorders such as sickle cell disease or thalassaemia, for malignancies the lower dose of chemotherapy used means that it may not be able to control the tumour. A second phase of treatment with donor lymphocytes is often needed. This approach has allowed the application of allotransplantation to patients who would otherwise have been excluded from treatment because of age or coexisting medical conditions. Prospective trials are needed to determine its usefulness.
A new area of transplant biology now exists, exploiting immune effects of donor lymphocytes to eradicate malignancy; transfusion of specific antivirus lymphocytes against infections such as cytomegalovirus; expansion in vitro of lymphocytes that recognise tumour cells, and specific depletion of lymphocytes that recognise normal recipient tissues.
As the use of straightforward chemotherapy at intensive doses with autologous rescue becomes more circumscribed, so the application of allotransplantation has expanded. The hope for the future is that by better understandingparticularly of alloimmunity we will be able to move towards use of transplant procedures that are safer but effective in quite different ways.
Peter W M Johnson, professor of medical oncology.
(johnsonp@soton.ac.uk)
Kim Orchard, director of transplantation.
Cancer Research UK Oncology Unit, Southampton University School of Medicine, Southampton SO16 6YD
Acknowledgments
We thank Keiren Towlson and Professor Nigel Russell for providing registry data.
--------------------------------------------------------------------------------
1. Johnson PWM, Simnett SJ, Sweetenham JW, Morgan GJ, Stewart LA. Bone marrow and peripheral blood stem cell transplantation for malignancy. Health Techn Assess 1998; 2: 1-187.
2. Fassas A, Tricot G. Results of high-dose treatment with autologous stem cell support in patients with multiple myeloma. Semin Hematol 2001; 38: 231-242[Medline].
3. Antman KH. Overview of the six available randomized trials of high-dose chemotherapy with blood or marrow transplant in breast cancer. J Natl Cancer Inst Monogr 2001; 30: 114-116[Medline].
4. Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK, Gray RG, et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children's Leukaemia Working Parties. Lancet 1998; 351: 700-708[Medline].
5. Gianni AM, Bregni M, Siena S, Brambilla C, Di Nicola M, Lombardi F, et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 336: 1290-1297[Abstract/Full Text].
6. Magni M, Di Nicola M, Devizzi L, Matteucci P, Lombardi F, Gandola L, et al. Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion. Blood 2000; 96: 864-869[Abstract/Full Text].
7. Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature 2001; 411: 385-389[Medline].
8. MacKinnon S. Who may benefit from donor leucocyte infusions after allogeneic stem cell transplantation? Br J Haematol 2000; 110: 12-17[Medline].
9. Childs R, Barrett J. Nonmyeloablative stem cell transplantation for solid tumors: Expanding the application of allogeneic immunotherapy. Semin Hematol 2002; 39: 63-71[Medline].
10. Hennessy BJ, Orchard KH, Potter MN. Novel approaches to transplant conditioning. Hematol Oncol 2001; 19: 43-57[Medline].
--------------------------------------------------------------------------------
==============================
"With every scientific advance, we grow closer to unlocking the mysteries of life and creation. But what have we gained if in the process, we lose our humanity. The most powerful thing we pass along to our children may not reside in the genes, but in the soul."
The Outer Limits(Criminal Nature)
[This message was edited by Wise Young on Aug 22, 2002 at 08:34 AM.]
Bone marrow transplants
New indications exploit the immune effects of the transplanted cells
Bone marrow, or haematopoietic stem cell, transplants were originally developed to allow the use of very high dose treatments for malignancies such as leukaemia. Their use was based on the idea that the high dose treatment might overcome inherent resistance of the malignancy to chemotherapy or radiotherapy. Transplants of stem cells from either the same person (autologous) or another person (allogeneic) are used to repopulate and regenerate the bone marrow, "rescuing" the patient from aplasia. Recently, attention has shifted from the straightforward pursuit of higher doses of cytotoxic drugs to the exploitation of immune effects exerted by allogeneic donor cells. Initial work in autologous transplantation concentrated on showing the safety of the process. Many early studies consisted only of case series, but in the past few years several important randomised trials have been reported, allowing closer definition of the conditions for which bone marrow transplants are useful. These include multiple myeloma, recurrent Hodgkin's disease, and aggressive lymphoma in second remission, for which high dose treatment is routinely given following evidence from randomised trials. 1 2
As the indications for stem cell transplants have been better defined overall activity has fallen. The number of high dose procedures reported to the European Blood and Marrow Transplant Registry fell from 19 346 in 1999 to 17 636 in 2000. This was due to a marked decrease in transplants for solid tumours, especially breast cancer. High dose chemotherapy for adjuvant treatment of breast cancer was tested in several trials worldwide and used as a routine component of treatment in some centres. This has now almost vanished in the wake of evidence from several randomised studies with a negative outcome and the exposure of one of the few trials with a positive outcome as seriously flawed.3
The role of autologous transplantation for acute myeloid leukaemia is still unclear, with some large trials showing improvements in survival whereas others show no benefit over conventional chemotherapy.4 Similar effects are seen in aggressive lymphoma where studies incorporating high dose treatment into initial therapy have generally had negative outcomes although the use of single drugs at high dose sequentially may hold some promise.5 This approach is being studied in a randomised trial in Europe.
In low grade lymphoma, few controlled trials have been conducted and efforts remain focused upon refinement of the transplant technique. Whether failure to obtain a stem cell harvest free from lymphoma or the resistance of the disease is the main reason of recurrence is not clear. A new approach has been to use anti-B cell monoclonal antibodies (such as rituximab) before collecting the stem cells, in the hope of eliminating residual lymphoma from the marrow and peripheral blood.6 The preliminary results in low grade lymphoma seem promising, and this too is now the subject of a trial.
Allogeneic transplantation adds a further dimensionthe potential for immune effector cells from the donor to recognise and eliminate residual tumour in the recipient.7 Ironically, it was because of a complication of this type of transplant that the immunological effect became apparent. Graft versus host disease is caused by the activation of lymphocytes derived from the donor, leading to immune damage to the skin, gut, and liver in the recipient. Patients who experience graft versus host disease, however, have a lower risk of developing recurrent leukaemia. This suggests an important antimalignancy effect due to the lymphocytes.
A more striking example of the importance of immune cells is the effect of donor lymphocyte infusions in patients with disease that recurs after a transplant. Lymphocytes are collected from the peripheral blood of the donor and given to the patient, and this can result in the eradication of recurrent malignancy. This may be due either to specific targeting of tumour antigens or simply the result of graft versus host disease affecting malignant cells preferentially.
Different illnesses vary in their responsiveness to donor lymphocyte infusionchronic myeloid leukaemia is the most responsive, myeloma and low grade lymphoma less so, and the acute leukaemias much less so.8 This reflects mainly the time needed for effective antimalignant immune responses to develop. Tumour regression after allotransplantation and treatment with donor lymphocytes has also been reported in patients with solid tumoursfor example, renal, breast, and bowel carcinomas9and we are just beginning to understand the targets that may be recognised by the donor cells.
An extension of the idea of exploiting donor immune responses is to carry out transplants where the chemotherapy is aimed at creating space for the donor immune system to develop rather than directly treating the malignancy.10 By giving chemotherapy that is strongly immunosuppressive but not myeloablative, a state of recipient-donor mixture, or chimerism, can be achieved. Because the chemotherapy is of low intensity the acute side effects are few. The risk of graft versus host disease, however, remains and makes intensive follow up with monitoring for opportunistic infection necessary. Although the chimeric state may be effective against single gene disorders such as sickle cell disease or thalassaemia, for malignancies the lower dose of chemotherapy used means that it may not be able to control the tumour. A second phase of treatment with donor lymphocytes is often needed. This approach has allowed the application of allotransplantation to patients who would otherwise have been excluded from treatment because of age or coexisting medical conditions. Prospective trials are needed to determine its usefulness.
A new area of transplant biology now exists, exploiting immune effects of donor lymphocytes to eradicate malignancy; transfusion of specific antivirus lymphocytes against infections such as cytomegalovirus; expansion in vitro of lymphocytes that recognise tumour cells, and specific depletion of lymphocytes that recognise normal recipient tissues.
As the use of straightforward chemotherapy at intensive doses with autologous rescue becomes more circumscribed, so the application of allotransplantation has expanded. The hope for the future is that by better understandingparticularly of alloimmunity we will be able to move towards use of transplant procedures that are safer but effective in quite different ways.
Peter W M Johnson, professor of medical oncology.
(johnsonp@soton.ac.uk)
Kim Orchard, director of transplantation.
Cancer Research UK Oncology Unit, Southampton University School of Medicine, Southampton SO16 6YD
Acknowledgments
We thank Keiren Towlson and Professor Nigel Russell for providing registry data.
--------------------------------------------------------------------------------
1. Johnson PWM, Simnett SJ, Sweetenham JW, Morgan GJ, Stewart LA. Bone marrow and peripheral blood stem cell transplantation for malignancy. Health Techn Assess 1998; 2: 1-187.
2. Fassas A, Tricot G. Results of high-dose treatment with autologous stem cell support in patients with multiple myeloma. Semin Hematol 2001; 38: 231-242[Medline].
3. Antman KH. Overview of the six available randomized trials of high-dose chemotherapy with blood or marrow transplant in breast cancer. J Natl Cancer Inst Monogr 2001; 30: 114-116[Medline].
4. Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK, Gray RG, et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children's Leukaemia Working Parties. Lancet 1998; 351: 700-708[Medline].
5. Gianni AM, Bregni M, Siena S, Brambilla C, Di Nicola M, Lombardi F, et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 336: 1290-1297[Abstract/Full Text].
6. Magni M, Di Nicola M, Devizzi L, Matteucci P, Lombardi F, Gandola L, et al. Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion. Blood 2000; 96: 864-869[Abstract/Full Text].
7. Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature 2001; 411: 385-389[Medline].
8. MacKinnon S. Who may benefit from donor leucocyte infusions after allogeneic stem cell transplantation? Br J Haematol 2000; 110: 12-17[Medline].
9. Childs R, Barrett J. Nonmyeloablative stem cell transplantation for solid tumors: Expanding the application of allogeneic immunotherapy. Semin Hematol 2002; 39: 63-71[Medline].
10. Hennessy BJ, Orchard KH, Potter MN. Novel approaches to transplant conditioning. Hematol Oncol 2001; 19: 43-57[Medline].
--------------------------------------------------------------------------------
==============================
"With every scientific advance, we grow closer to unlocking the mysteries of life and creation. But what have we gained if in the process, we lose our humanity. The most powerful thing we pass along to our children may not reside in the genes, but in the soul."
The Outer Limits(Criminal Nature)
[This message was edited by Wise Young on Aug 22, 2002 at 08:34 AM.]