Reinventing Bone Marrow Transplantation
Reinventing Bone Marrow Transplantation
In his 1975 New England Journal of Medicine review article on bone marrow transplantation, Nobel laureate E. Donnall Thomas listed the major obstacles to successful transplantation as donor availability, graft-vs-host disease (GVHD), treatment-related complications, and relapse of disease. Nearly 25 years later, these obstacles still persist.
Nevertheless, there have been relatively impressive advances in each of these areas. Donor availability has increased through the use of alternative stem-cell sources, such as bone marrow from unrelated donors and placental blood. New immunosuppressive agents, such as tacrolimus (Prograf) and mycophenolate mofetil (CellCept), and new methods of T-cell depletion have been introduced for the prevention and treatment of GVHD. Infections, an important cause of treatment-related mortality, have been significantly reduced by means of new methods of detection and new antimicrobials (eg, ganciclovir [Cytovene]). Perhaps the most important advance has been the introduction of donor leukocyte infusions for the treatment of relapse following allogeneic stem-cell transplantation.
Overcoming the Obstacles to Allogeneic Stem-Cell Transplantation
The first part of the article by Dr. Champlin and colleagues provides an excellent overview of the intention and limitations of allogeneic stem-cell transplantation. The approaches being used to overcome the obstacles to allogeneic transplantation are not so much a reinvention of this therapeutic modality as an evolution.
Specifically, the authors extensively review the concept of the graft-vs-malignancy (GVM) effect that is associated with allogeneic stem-cell transplantation. The observation that T-cell depletion of allografts leads not only to a reduction in the incidence and severity of GVHD but also to an increase in relapse rates poses the very difficult question of whether GVHD and the GVM effect can be separated. It is encouraging that an apparent GVM effect can be observed without evidence of clinical GVHD. Unfortunately, this observation is made in only a minority of patients, as relapses are more frequent in individuals who do not develop GVHD either after allogeneic stem-cell transplantation or donor leukocyte infusions.
In addition, the authors point out that the GVM effect varies relative to the specific malignancy being treated. This effect appears to be greater in chronic myelogeneous leukemia (CML) and, possibly, chronic lymphocytic leukemia (CLL) than in the acute leukemias. This is especially true for donor leukocyte infusions, which have been found to be most effective in CML and in states of minimal residual disease. These observations would seem to suggest that minor histocompatibility antigens play an important role and that the separation of GVHD and the GVM effect remains extremely difficult.
Techniques to Achieve a Balance Between GVHD and the GVM Effect
The article extensively reviews techniques developed to achieve a balance between GVHD and the GVM effect. These include the development of tumor-specific clones, specifying either the number and/or types of T-cells to be infused, and the introduction of genes to control GVHD.
The ability to develop and use tumor-specific T-cells is limited by practical technology and the lack of tumor- specific antigens. Specifying T-cell dose is an encouraging approach, but it may also be limited to specific disease types and minimal disease states. The technology to bring T-cells transduced with suicide genes to the clinic appears to be improving at a rapid rate. Taken together, there is increasing evidence that our ability to treat a number of transplant-related complications will improve over the coming years.
Role of Nonmyeloablative Regimens
The latter portion of this article addresses the role of nonmyeloablative regimens. This approach can be considered a reinvention, at least conceptually, of allogeneic stem-cell transplantation.
As Champlin et al mention at the beginning of their article, allogeneic stem-cell transplantation was initially developed to deliver lethal doses of chemotherapy and radiation to patients with hematologic malignancies. However, chemotherapy and radiation doses also had to be adequately immuno- suppressive to permit the engraftment of allogeneic stem cells. This latter requirement has recently been called into question by the successful infusion of a larger number of stem and progenitor cells obtained from blood following mobilization with hematopoietic growth factors.
Also, new regimens that employ immunosuppressive agents, such as fludarabine (Fludara) and cytarabine (cytosine arabinoside), or reduced doses of irradiation that would not be considered myeloablative have been developed.[4,5] Use of regimens that are not necessarily myeloablative and yet are sufficiently immunosuppressive, along with larger progenitor and stem-cell numbers, can result in the sustained engraftment of allogeneic stem cells.[5,6]
The use of these nonmyeloablative regimens is based on the hypothesis that if a graft can be established, the positive effects of allogeneic stem-cell transplantation are retained (ie, GVM) while the morbidity and potential mortality associated with myeloablative regimens are reduced. This could potentially permit wider application of allogeneic transplantation to such populations as the elderly and patients with borderline performance status or borderline functioning of major organs.
Preliminary Results From M. D. Anderson
The preliminary results from the M. D. Anderson Cancer Center transplantation group are encouraging; however, these initial observations raise some concerns and cautions.[5,6] For example, patients with active bulky lymphomas, acute leukemias that are not in remission, or CML have greater difficulty in achieving significant responses. This is not surprising, as similar results have been observed with donor leukocyte infusions. Patients with more than minimal disease may require either optimal cytoreduction prior to transplantation or a conventional preparative regimen.
A second potential problem is whether nonmyeloablative regimens are adequately immunosuppressive to overcome the immunologic barriers associated with such diseases as severe aplastic anemia.
A third potential obstacle is that even though these regimens may potentially avoid the acute toxicities associated with myeloablative regimens, they may not prevent the more severe problems associated with allogeneic transplantation, especially chronic GVHD.
These caveats notwithstanding, the initial results reported by the M. D. Anderson group are clinically relevant, and the potential obstacles do not seem insurmountable. If the acute toxicities can be reduced, even broader applications can be foreseen for such regimens. These would include consolidation of initial responses to conventional chemotherapy in patients with malignant lymphomas, acute leukemias, CLL, and, possibly, even solid malignancies.
Nonmyeloablative regimens may also have potential application in patients with autoimmune diseases and would appear to lend themselves well to use in individuals with severe combined immune deficiencies and enzymatic defects. The use of nonmyeloablative regimens could potentially address many of the problems raised by Dr. Thomas and may turn out to be a true reinvention of allogeneic stem-cell transplantation.
1. Thomas ED, Storb R, Clift RA, et al: Bone-marrow transplantation. N Engl J Med 292:832-843, 895-902, 1975.
2. Collins RH Jr, Shpilberg O, Drobyski WR, et al: Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 15:433-444, 1997.
3. Horowitz MM, Gale RP, Sondel PM, et al: Graft-vs-leukemia reactions after bone marrow transplantation. Blood 75:555-562, 1990.
4. Storb R, Yu C, Wagner JL, et al: Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before pharmacological immunosuppression and after marrow transplantation. Blood 89:3048-3054, 1997.
5. Giralt S, Estey E, Albitar M, et al: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: Harnessing graft-vs-leukemia without myeloablative therapy. Blood 89:4531-4536, 1997.
6. Khouri IF, Keating M, Korbling M, et al: Transplant lite: Induction of graft-vs-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment of lymphoid malignancies. J Clin Oncol 16:2817-2824, 1998.