- Email: [email protected]
Future of bone marrow transplantation in oncology
In! J Kad,o~,on Onndoy, &,,I Phvr Vol Pnnted I” the L S A All nghts reserved
X. pp
949
036&3016/82/050949~02503.00/0 CopyrIght 0 1982 Pergamon
950
Press Ltd.
??Editorial FUTURE OF BONE MARROW
TRANSPLANTATION
ALEXANDER Division
of Oncology
Total body irradiation,
RK-25,
BBIOI
FEFER,
M.D.
5 Health Sciences, University of Washington Research Center, Seattle, WA 98 I95
Bone marrow transplantation,
IN ONCOLOGY
and the Fred Hutchinson
Cancer
Leukemia.
reduced by performing the BMT in patients with acute nonlymphocytic leukemia (ANL) when they are in their first chemotherapy-induced complete remission (CR)8 and, to a lesser extent, in patients with acute lymphocytic leukemia in CR.” Indeed, results such as those presented by Thomas et al. in this issue’ strongly suggest that BMT for ANL in first CR will cure 50% of patients. The failures reflect mortality largely due to GVHD and IP. Nevertheless, leukemic relapse remains a major problem for patients transplanted for acute leukemia in relapse or when they are beyond their first CR. Its resolution may depend on the development of new antileukemic agents and/or radiotherapy regimens. The other major obstacles to long-term tumor-free survival remain IP and GVHD.” The IP is idiopathicprobably related to the chemoradiotherapy+r is associated with cytomegalovirus infection.’ Its pathogenesis, prevention and management is being intensely studied without significant progress to date. GVHD-which can be mild or fatal, acute and/or chronic-is now better understood but remains a formidable problem.6 Its resolution is complicated by the important finding that although GVHD is generally deleterious to the host, it may also exert an antileukemic efTect.‘3 Therefore, it may be critical not to prevent GVHD but to modulate its severity and duration. The persistence of the complex problems makes it necessary that BMT for neoplasia continue to be performed only in experienced specialized centers. This certainly applies to patients transplanted for end-stage refractory disease because they are most difficult to manage. However, BMT, even for ANL in first CR, is best performed at a center because although such patients are easier to manage, it it ethically essential to minimize the chance of nonleukemic transplant-related deaths in chance of these patients who do have about a 15-20s being alive 3 years later even without BMT. Therefore, allogeneic BMT will be better justified as a service outside the centers only after more progress has been
The availability of normal bone marrow for transplantation makes it possible to administer higher and potentially curative antileukemic doses of chemotherapy and/or total body irradiation. Although bone marrow transplantation (BMT) generally failed in the 1950’s, advances in histocompatibility typing and in the supportive care of pancytopenic patients e.g. platelet transfusions, antibiotics, etc., stimulated a resurgence of BMT trials in 1970. Early results were reviewed in 1975.12 More than 1000 transplants have been performed in BMT research centers, with dramatic successes as well as disappointing failures. The belief that BMT is already the treatment of choice for selected patients raises questions about its potential for wider application and its performance outside of specialized centers. This editorial presents a bird’s eye view of the current status of BMT for neoplasia and the problems that must be resolved to render the approach more widely applicable. The simplest clinical setting in which to evaluate the effect of a given supralethal chemoradiotherapy regimen on a tumor and on normal tissues is the transplantation of marrow from a normal genetically identical twin (syngeneic), so as to avoid the complications of transplantation immunology and the possibility of marrow contamination by tumor. Supralethal chemoradiotherapy and syngeneic BMT has been shown to be effective and often curative in patients with refractory hematologic malignancies.’ ’ The principal problem is a significant incidence of relapse of acute leukemia. Nevertheless, every twin with a hematologic malignancy should be considered for BMT. Similar chemoradiotherapy and transplantation of nonidentical (allogeneic) marrow from a sibling matched at the major histocompatibility complex (MHC) has also cured a small fraction of patients with refractory acute leukemia.’ However, the results have been limited not only by a high incidence of leukemic relapse, but also by graft-versus-host disease (GVHD) and interstitial pneumonitis (IP).’ Leukemic relapse has been dramatically Accepted for publication 4 December 198 1. 949
950
Radiation Oncology 0 Biology 0 Physics
made in the management of GVHD and IP and after the centers have developed less toxic curative BMT regimens. Resolution of the above problems will also improve the therapeutic results and thereby increase the usefulness of BMT. In addition, the role of BMT in oncology is likely to expand because of the following potential developments: I) If a comparative study now in progress confirms the superiority of matched sibling BMT over chemotherapy for ANL in first CR, BMT will become the treatment of choice, especially for the younger patient. 2) If studies in progress document that a complete match at the MHC is not absolutely essential, more patients will become candidates for BMT. Indeed, marrow from an unrelated donor has been transplanted4 and techniques are now available for identifying unrelated donors for the majority of patients. 3) If studies in progress show that the patient’s own (autologous) marrow, cryopreserved when it has no detectable tumor and reinfused after supralethal chemoradiotherapy, is associated with long-term tumor-free survival, this approach would have wide applicability. Effective chemoradiotherapy regimens might be identified from studies of twin BMT, and the potential problem of tumor contamination of infused autologous marrow might be resolved by using monoclonal antibodies directed to tumor cells. 4) If the problems of syngeneic,
May 1982, Volume 8, Number 5
allogeneic or autologous BMT mentioned above are resolved, and BMT is also shown to be effective for nonhematologic malignancies-which may be sensitive to the unusually high doses of chemoradiotherapy made possible by BMT-many more patients would become candidates for BMT. In conclusion, BMT, which used to be reserved for patients in exfremis, has been shown to be curative in a significant number of patients with neoplasia but remains a relatively new form of treatment frought with complex problems. At this time BMT should continue to be performed in specialized centers because a) evaluation of every change in the therapeutic regimens requires the entry of a large number of patients-as exemplified by the first reported prospectively-randomized controlled study by Thomas et al.” comparing two radiation therapy regimens in a homogeneous patient population; and b) the complex acute and chronic problems of transplantation immunology are best managed and investigated in such centers. Resolution of the problems will greatly widen the applicability of syngeneic, allogeneic and autologous marrow transplantation. The role of BMT in oncology will, therefore, greatly increase in the future and will eventually be performed as a service to patients outside of specialized centers.
REFERENCES Appelbaum, F.R., Fefer, A., Cheever, M.A.. Buckner, C.D., Greenberg, P.D., Kaplan, H.G., Storb, R., Thomas, E.D.: Treatment of non-Hodgkin’s lymphoma with marrow transplantation in identical twins. Blood 58: 5099513. 1981. Fefer. A., Cheever, M.A., Greenberg, P.D., Appelbaum, F.R., Boyd. C.N., Buckner, C.D., Kaplan, H.G., Ramberg. B.S., Sanders, J.E., Storb, R., Thomas, E.D.: Treatment of chronic granulocytic leukemia with chemoradiotherapy and transplantation of marrow from identical twins. N. Engl. J. of Med. 306: 63-68, 1982. Fefer, A., Cheever, M.A., Thomas, E.D., Appelbaum, F.R., Buckner, C.D., Clift, R.A., Clucksberg, H., Greenberg, P.D., Johnson, F.L., Kaplan, H.G., Sanders, J.E., Storb, R., Weiden, P.L.: Bone marrow transplantation for refractory acute leukemia in 34 patients with identical twins. Blood 57: 421-430, 1981. Hansen, J.A., Clift, R.A., Thomas, E.D., Buckner, C.D., Storb, R., Giblett, E.R.: Transplantation of marrow from an unrelated donor to a patient with acute leukemia. N. Engl. J. Med. 303: 565-567, 1980. Myers, J.D.. Flournoy. N., Thomas, E.D.: Non-bacterial pneumonia from allogeneic marrow transplantationReview of IO years experience. Rev. Infect. Dis. (In press). Sullivan, K.M., Shulman, H.M., Storb, R., Weiden, P.L., Witherspoon, R.P., McDonald, G.B., Schubert, M.M., Atkinson. K., Thomas, E.D.: Chronic graft-versus-host disease in fifty-two patients: Adverse natural course and successful treatment with combination immunosuppression. Blood 57: 267-276, I98 I. Thomas, E.D., Buckner, C.D., Banaji, M., Clift, R.A., Fefer, A., Flournoy, N., Goodell, B.W., Hickman, R.O., Lerner, K.G., Neiman, P.E., Sale, G.E., Sanders, J.E.,
Singer, J., Stevens, M., Storb, R., Weiden, R.L.: One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 49: 5 I l-533, 1977. 8 Thomas, E.D., Buckner, C.D., Clift, R.A., Fefer, A., Johnson, F.L., Neiman, P.E., Sale, G.E., Sanders, J.E., Singer, J.W., Shulman, H., Storb, R., Weiden, P.L.: Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N. Engl. J. Med. 301: 597-599, 1979. 9 Thomas, E.D., Clift, R.A., Hersman, J., Sanders, J.E., Stewart, P., Buckner, C.D., Fefer, A., McGuffin, R., Smith, J.W., Storb, R.: Marrow transplantation for acute nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation. fnt. J. Radial. Oncol. Biol. Phys. 8: 8 17-822, 1982. IO Thomas, E.D., Fefer, A.: Marrow transplantation in the treatment of leukemia. In Leukemia, Gunz, F. and Henderson, E.S. (Eds.). New York, Grune and Stratton (In press). II Thomas, E.D., Sanders, J.E., Flournoy, N., Johnson, F.L., Buckner, C.D., Clift, R.A., Fefer, A., Goodell, B.W., Storb, R. Weiden, P.L.: Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood 54: 468476, 1979. I2 Thomas, E.D., Storb, R., Clift, R.A., Fefer, A., Johnson, F.L., Neiman, P.E., Lerner, K.G., Glucksberg, H., Buckner, C.D.: Bone-marrow transplantation. N. Engl. J. Med. 292: 832-843,895-902, 1975. I3 Weiden, P.L., Flournoy, N., Thomas, E.D., Prentice, R., Fefer, A., Buckner, C.D., Storb, R.: Antileukemic effect of graft-versus-host disease in human recipients of allogeneic marrow grafts. N. Engl. J. Med. 300: 106881073, 1979.
X. pp
949
036&3016/82/050949~02503.00/0 CopyrIght 0 1982 Pergamon
950
Press Ltd.
??Editorial FUTURE OF BONE MARROW
TRANSPLANTATION
ALEXANDER Division
of Oncology
Total body irradiation,
RK-25,
BBIOI
FEFER,
M.D.
5 Health Sciences, University of Washington Research Center, Seattle, WA 98 I95
Bone marrow transplantation,
IN ONCOLOGY
and the Fred Hutchinson
Cancer
Leukemia.
reduced by performing the BMT in patients with acute nonlymphocytic leukemia (ANL) when they are in their first chemotherapy-induced complete remission (CR)8 and, to a lesser extent, in patients with acute lymphocytic leukemia in CR.” Indeed, results such as those presented by Thomas et al. in this issue’ strongly suggest that BMT for ANL in first CR will cure 50% of patients. The failures reflect mortality largely due to GVHD and IP. Nevertheless, leukemic relapse remains a major problem for patients transplanted for acute leukemia in relapse or when they are beyond their first CR. Its resolution may depend on the development of new antileukemic agents and/or radiotherapy regimens. The other major obstacles to long-term tumor-free survival remain IP and GVHD.” The IP is idiopathicprobably related to the chemoradiotherapy+r is associated with cytomegalovirus infection.’ Its pathogenesis, prevention and management is being intensely studied without significant progress to date. GVHD-which can be mild or fatal, acute and/or chronic-is now better understood but remains a formidable problem.6 Its resolution is complicated by the important finding that although GVHD is generally deleterious to the host, it may also exert an antileukemic efTect.‘3 Therefore, it may be critical not to prevent GVHD but to modulate its severity and duration. The persistence of the complex problems makes it necessary that BMT for neoplasia continue to be performed only in experienced specialized centers. This certainly applies to patients transplanted for end-stage refractory disease because they are most difficult to manage. However, BMT, even for ANL in first CR, is best performed at a center because although such patients are easier to manage, it it ethically essential to minimize the chance of nonleukemic transplant-related deaths in chance of these patients who do have about a 15-20s being alive 3 years later even without BMT. Therefore, allogeneic BMT will be better justified as a service outside the centers only after more progress has been
The availability of normal bone marrow for transplantation makes it possible to administer higher and potentially curative antileukemic doses of chemotherapy and/or total body irradiation. Although bone marrow transplantation (BMT) generally failed in the 1950’s, advances in histocompatibility typing and in the supportive care of pancytopenic patients e.g. platelet transfusions, antibiotics, etc., stimulated a resurgence of BMT trials in 1970. Early results were reviewed in 1975.12 More than 1000 transplants have been performed in BMT research centers, with dramatic successes as well as disappointing failures. The belief that BMT is already the treatment of choice for selected patients raises questions about its potential for wider application and its performance outside of specialized centers. This editorial presents a bird’s eye view of the current status of BMT for neoplasia and the problems that must be resolved to render the approach more widely applicable. The simplest clinical setting in which to evaluate the effect of a given supralethal chemoradiotherapy regimen on a tumor and on normal tissues is the transplantation of marrow from a normal genetically identical twin (syngeneic), so as to avoid the complications of transplantation immunology and the possibility of marrow contamination by tumor. Supralethal chemoradiotherapy and syngeneic BMT has been shown to be effective and often curative in patients with refractory hematologic malignancies.’ ’ The principal problem is a significant incidence of relapse of acute leukemia. Nevertheless, every twin with a hematologic malignancy should be considered for BMT. Similar chemoradiotherapy and transplantation of nonidentical (allogeneic) marrow from a sibling matched at the major histocompatibility complex (MHC) has also cured a small fraction of patients with refractory acute leukemia.’ However, the results have been limited not only by a high incidence of leukemic relapse, but also by graft-versus-host disease (GVHD) and interstitial pneumonitis (IP).’ Leukemic relapse has been dramatically Accepted for publication 4 December 198 1. 949
950
Radiation Oncology 0 Biology 0 Physics
made in the management of GVHD and IP and after the centers have developed less toxic curative BMT regimens. Resolution of the above problems will also improve the therapeutic results and thereby increase the usefulness of BMT. In addition, the role of BMT in oncology is likely to expand because of the following potential developments: I) If a comparative study now in progress confirms the superiority of matched sibling BMT over chemotherapy for ANL in first CR, BMT will become the treatment of choice, especially for the younger patient. 2) If studies in progress document that a complete match at the MHC is not absolutely essential, more patients will become candidates for BMT. Indeed, marrow from an unrelated donor has been transplanted4 and techniques are now available for identifying unrelated donors for the majority of patients. 3) If studies in progress show that the patient’s own (autologous) marrow, cryopreserved when it has no detectable tumor and reinfused after supralethal chemoradiotherapy, is associated with long-term tumor-free survival, this approach would have wide applicability. Effective chemoradiotherapy regimens might be identified from studies of twin BMT, and the potential problem of tumor contamination of infused autologous marrow might be resolved by using monoclonal antibodies directed to tumor cells. 4) If the problems of syngeneic,
May 1982, Volume 8, Number 5
allogeneic or autologous BMT mentioned above are resolved, and BMT is also shown to be effective for nonhematologic malignancies-which may be sensitive to the unusually high doses of chemoradiotherapy made possible by BMT-many more patients would become candidates for BMT. In conclusion, BMT, which used to be reserved for patients in exfremis, has been shown to be curative in a significant number of patients with neoplasia but remains a relatively new form of treatment frought with complex problems. At this time BMT should continue to be performed in specialized centers because a) evaluation of every change in the therapeutic regimens requires the entry of a large number of patients-as exemplified by the first reported prospectively-randomized controlled study by Thomas et al.” comparing two radiation therapy regimens in a homogeneous patient population; and b) the complex acute and chronic problems of transplantation immunology are best managed and investigated in such centers. Resolution of the problems will greatly widen the applicability of syngeneic, allogeneic and autologous marrow transplantation. The role of BMT in oncology will, therefore, greatly increase in the future and will eventually be performed as a service to patients outside of specialized centers.
REFERENCES Appelbaum, F.R., Fefer, A., Cheever, M.A.. Buckner, C.D., Greenberg, P.D., Kaplan, H.G., Storb, R., Thomas, E.D.: Treatment of non-Hodgkin’s lymphoma with marrow transplantation in identical twins. Blood 58: 5099513. 1981. Fefer. A., Cheever, M.A., Greenberg, P.D., Appelbaum, F.R., Boyd. C.N., Buckner, C.D., Kaplan, H.G., Ramberg. B.S., Sanders, J.E., Storb, R., Thomas, E.D.: Treatment of chronic granulocytic leukemia with chemoradiotherapy and transplantation of marrow from identical twins. N. Engl. J. of Med. 306: 63-68, 1982. Fefer, A., Cheever, M.A., Thomas, E.D., Appelbaum, F.R., Buckner, C.D., Clift, R.A., Clucksberg, H., Greenberg, P.D., Johnson, F.L., Kaplan, H.G., Sanders, J.E., Storb, R., Weiden, P.L.: Bone marrow transplantation for refractory acute leukemia in 34 patients with identical twins. Blood 57: 421-430, 1981. Hansen, J.A., Clift, R.A., Thomas, E.D., Buckner, C.D., Storb, R., Giblett, E.R.: Transplantation of marrow from an unrelated donor to a patient with acute leukemia. N. Engl. J. Med. 303: 565-567, 1980. Myers, J.D.. Flournoy. N., Thomas, E.D.: Non-bacterial pneumonia from allogeneic marrow transplantationReview of IO years experience. Rev. Infect. Dis. (In press). Sullivan, K.M., Shulman, H.M., Storb, R., Weiden, P.L., Witherspoon, R.P., McDonald, G.B., Schubert, M.M., Atkinson. K., Thomas, E.D.: Chronic graft-versus-host disease in fifty-two patients: Adverse natural course and successful treatment with combination immunosuppression. Blood 57: 267-276, I98 I. Thomas, E.D., Buckner, C.D., Banaji, M., Clift, R.A., Fefer, A., Flournoy, N., Goodell, B.W., Hickman, R.O., Lerner, K.G., Neiman, P.E., Sale, G.E., Sanders, J.E.,
Singer, J., Stevens, M., Storb, R., Weiden, R.L.: One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 49: 5 I l-533, 1977. 8 Thomas, E.D., Buckner, C.D., Clift, R.A., Fefer, A., Johnson, F.L., Neiman, P.E., Sale, G.E., Sanders, J.E., Singer, J.W., Shulman, H., Storb, R., Weiden, P.L.: Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N. Engl. J. Med. 301: 597-599, 1979. 9 Thomas, E.D., Clift, R.A., Hersman, J., Sanders, J.E., Stewart, P., Buckner, C.D., Fefer, A., McGuffin, R., Smith, J.W., Storb, R.: Marrow transplantation for acute nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation. fnt. J. Radial. Oncol. Biol. Phys. 8: 8 17-822, 1982. IO Thomas, E.D., Fefer, A.: Marrow transplantation in the treatment of leukemia. In Leukemia, Gunz, F. and Henderson, E.S. (Eds.). New York, Grune and Stratton (In press). II Thomas, E.D., Sanders, J.E., Flournoy, N., Johnson, F.L., Buckner, C.D., Clift, R.A., Fefer, A., Goodell, B.W., Storb, R. Weiden, P.L.: Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood 54: 468476, 1979. I2 Thomas, E.D., Storb, R., Clift, R.A., Fefer, A., Johnson, F.L., Neiman, P.E., Lerner, K.G., Glucksberg, H., Buckner, C.D.: Bone-marrow transplantation. N. Engl. J. Med. 292: 832-843,895-902, 1975. I3 Weiden, P.L., Flournoy, N., Thomas, E.D., Prentice, R., Fefer, A., Buckner, C.D., Storb, R.: Antileukemic effect of graft-versus-host disease in human recipients of allogeneic marrow grafts. N. Engl. J. Med. 300: 106881073, 1979.