Editorial Allogeneic Bone Marrow Transplantation: Problems and Prospects Bone marrow transplantation refers to the intravenous infusion of hematopoietic progenitor cells to reestablish hematopoiesis after an otherwise fatal bone marrow insult. The patient's own bone marrow is destroyed by high doses of chemotherapy with or without total-body irradiation that is given to eradicate a malignant lesion (the most common situation), to provide immunosuppression so normal bone marrow can grow in a patient with aplastic anemia, or to destroy a dysfunctional bone marrow (such as in thalassemia) before "transplanting" a normal hematopoietic system. In the treatment of a malignant tumor, the hematopoietic progenitor cells are given to alleviate an unwanted side effect of therapy. The patient's own hematopoietic progenitor cells can be used for this purpose (that is, an autologous bone marrow transplant) if they can be obtained free from contamination by malignant cells. For patients with aplastic anemia, immune deficiency states, or inherited dysfunction of myeloid cells, however, the hematopoietic progenitor cells used for transplantation must be donated by another person (that is, an allogeneic transplant). Most frequently, the donor is someone fully compatible for the major histocompatibility antigens. Although donors are usually siblings, the National Marrow Donor Program is making use of unrelated but matched donors. Thus, allogeneic bone marrow transplantation may become available to increasing numbers of patients. In the rare situation in which a monozygotic twin donor is available, many of the immunologic complications of allogeneic transplantation such as graftversus-host disease can be avoided. The potential for bone marrow transplantation to have wide clinical applicability was recognized many years ago. The first report in the medical literature of an allogeneic bone marrow transplantation of which I am aware was published in 1939. 1 Unfortunately, the procedure was unsuccessful. Nevertheless, the identification of the existence of "transplantation antigens" and the development of the ability to match patients for the major histocompatibility complex in the 1960s made allogeneic bone marrow transplantation practical. The first successful allogeneic bone marrow transplantations were performed in the late 1960s, and during the Address reprint requests to Dr. J. O. Armitage, Department of Internal Medicine, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-3332. Mayo Clin Proc 67:195-197,1992

decade of the 1970s, many of the technical problems related to the procedure were addressed. All the clinical problems related to bone marrow transplantation, however, have not been resolved. In this issue of the Mayo Clinic Proceedings, four articles from the Mayo Clinic bone marrow transplant team deal with several of the major unresolved issues in allogeneic bone marrow transplantation. Timing of Transplantation.-Letendre and associatesdescribe the results of allogeneic and syngeneic bone marrow transplantation at the Mayo Clinic between 1982 and 1990. The most obvious conclusion to be drawn from these data is that patients who undergo transplantation for malignant lesions early in the course of their illness have dramatically better results than do patients with end-stage refractory disease. Although not a new observation, this represents the central dilemma to the wider application of allogeneic bone marrow transplantation. In patients in whom cure is possible with standard therapy, accepting a 20 to 30% treatmentrelated mortality is often difficult, even if the ultimate cure rate is higher with bone marrow transplantation. Unfortunately, when patients undergo bone marrow transplantation after becoming refractory to standard therapies, the treatment-related mortality is often higher and the possibility of cure is minimal. In actual practice, the decision of whether to use bone marrow transplantation early in the treatment of a patient with leukemia is usually made after the chances for benefit with standard treatment and the risks of transplantation in that patient have been considered. In patients with chronic granulocytic leukemia, in whom standard therapies seldom yield a cure, bone marrow transplantation is widely used soon after diagnosis. In fact, this condition has become the most common indication for allogeneic bone marrow transplantation. In contrast, in adult patients with acute myeloid leukemia, the cure rate with use of bone marrow transplantation as part of the primary therapy is no higher than what can be achieved with use of standard therapy initially and bone marrow transplantation at first relapse.. Respiratory Complications.-Afessa and colleagues' report the results of transferring patients who have undergone bone marrow transplantation at the Mayo Clinic to the intensive-care unit for the care of organ failure-usually respiratory failure. Patients with respiratory failure related to an infectious cause had a 95% mortality rate, and no patients survived when multiple organs failed. These results are similar to what other investigators have observed and illustrate the lethality of severe pulmonary complications in these patients after bone marrow transplantation. At least three types of respiratory complications can occur. One syndrome, sometimes termed "diffuse alveolar hemor195

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rhage," manifests as fever, tachypnea, hypoxia, and pulmonary infiltrates early after transplantation-usually during the first 30 days.' This syndrome is probably related to pulmonary injury from the high-dose therapy, is most frequently seen in patients who receive an autologous transplant, and seems to be responsive to corticosteroids.' A second syndrome usually occurs during the second or third month after allogeneic bone marrow transplantation and is often associated with graft-versus-host disease. This process, frequently termed "post-bone marrow transplant interstitial pneumonia," also can manifest as fever, tachypnea, hypoxia, and pulmonary infiltrates. It is often, but not always, associated with infection attributable to cytomegalovirus and can sometimes be treated, and regularly be prevented, by the administration of ganciclovir," Finally, during the third month or later after bone marrow transplantation, some patients have the syndrome of progressive pulmonary fibrosis. This syndrome can be related to high-dose therapy with carmustine or can be a complication of chronic graftversus-host disease.' Treatment of this syndrome has generally been disappointing. Hemorrhagic Cystitis.-Letendre and co-workers" discuss the frequent clinical problem of hemorrhagic cystitis after use of high doses of cyclophosphamide in bone marrow transplantation. Their conclusion is that bladder irrigation through an indwelling catheter is an effective approach to preventing the occurrence of this phenomenon. Other investigators have demonstrated that use of the uroprotective agent mesna also effectively prevents the development of hemorrhagic cystitis after administration of high doses of cyclophosphamide. At least two large comparative trials have found no difference in the efficacy of these two approaches.v'" A study performed at our institution showed a higher frequency of complications with bladder irritation and a preference for the use of mesna in male patients.'? For these reasons, I believe that mesna should be the standard therapy at the present time. Cytogenetic or Molecular Relo:pse.-Graham and assoelates!' review the Mayo Clinic experience with use of cytogenetic and molecular techniques to identify residualleukemia cells in patients who have undergone allogeneic bone marrow transplantation for chronic granulocytic leukemia. A substantial number of patients clearly harbor identifiable leukemia cells for some time after allogeneic bone marrow transplantation for chronic granulocytic leukemia. 12 These cells seem to persist longer and have more ominous implications in patients in whom T lymphocytes have been removed from the marrow graft in an attempt to prevent graft-versushost disease. These findings raise the issue of how bone marrow transplantation cures patients with a malignant disease. If the intensive chemotherapy and radiotherapy are curative, allogeneic bone marrow transplantation should be

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equally effective whether or not the bone marrow graft has been depleted of T lymphocytes. The fact that this outcome does not prevail suggests that allogeneic bone marrow transplantation may be effective partly because it is immunotherapy.13,14 Both the higher relapse rate associated with autologous rather than allogeneic bone marrow transplantation in diseases in which either procedure can be used and the remissions of leukemia noted in patients who have flares of graft-versus-host disease support this viewpoint. At a minimum, these observations prompt the question of how chemotherapy and radiotherapy cure cancer and suggest the possibility that simply killing every cancer cell with cytotoxic therapy might not be the entire story. Evolution of Bone Marrow Transplo:ntation.-As the reports from the Mayo Clinic bone marrow transplant team presented in this issue of the Mayo Clinic Proceedings illustrate, allogeneic bone marrow transplantation continues to be an evolving therapy. Allogeneic bone marrow transplantation is limited by the age of the patient and the availability of appropriate donors. The use of hematopoietic growth factors to ameliorate toxicity after transplantation, more effective treatments for infection and graft-versus-host disease, and the existence of the National Marrow Donor Program are all likely to increase the number of patients who will be able to undergo this procedure. Allogeneic bone marrow transplantation will almost certainly continue to be an important therapy for certain patients with hematologic disorders. James O. Armitage, M.D. Department of Internal Medicine University of Nebraska Medical Center Omaha, Nebraska

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Osgood EE, Riddle MC, Mathews TJ: Aplastic anemia treated with daily transfusions and intravenous marrow: case report. Ann Intern Med 13:357-367, 1939 Letendre L, Hoagland HC, Moore SB, Chen MG, Gastineau DA, Gertz MA, Habermann TM, Litzow MR, Noel P, Solberg LA Jr, Tefferi A: Mayo Clinic experience with allogeneic and syngeneic bone marrow transplantation, 1982 through 1990. Mayo Clin Proc 67:109-116, 1992 Afessa B, Tefferi A, Hoagland HC, Letendre L, Peters SG: Outcome of recipients of bone marrow transplants who require intensive-care unit support. Mayo Clin Proc 67: 117122, 1992 Robbins RA, Linder J, Stahl MG, Thompson AB m, Haire W, Kessinger A, Armitage JO, Arneson M, Woods G, Vaughan WP, Rennard 51: Diffuse alveolar hemorrhage in autologous bone marrow transplant recipients. Am J Med 87:511-518,1989 Chao NJ, Duncan SR, Long GD, Horning SJ, Blume KG: Corticosteroid therapy for diffuse alveolar hemorrhage in

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autologous bone marrow transplant recipients. Ann Intern Med 114:145-146,1991 6. Goodrich JM, Mori M, Gleaves CA, Du Mond C, Cays M, Ebeling DF, Buhles WC, DeArmond B, Meyers JD: Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. N Engl J Med 325:1601-1607,1991 7. Raschko JW, CottIer-Fox M, Abbondanzo SL, Torrisi JR, Spitzer TR, Deeg HJ: Pulmonary fibrosis after bone marrow transplantation responsive to treatment with prednisone and cyclosporine. Bone Marrow Transplant 4:201-205, 1989 8. Letendre L, Hoagland HC, Gertz MA: Hemorrhagic cystitis complicating bone marrow transplantation. Mayo Clin Proc 67:128-130,1992 9. Shepherd JD, Pringle LE, Bamett MJ, Klingemann H-G, Reece DE, Phillips GL: Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation. J Clin Oncol 9:20162020, 1991 10. Vose lM, Pipert G, Reed EC, Anderson JR, Bierman PJ, Kessinger A, Armitage JO: Randomized trial comparing

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mesna to bladder irrigation for prevention of hemorrhagic cystitis following high-dose cyclophosphamide and bone marrow transplantation (abstract). Blood 78 (Suppll):247a, 1991 II. Graham DL, Tefferi A, Letendre L, Gastineau DA, Hoagland HC, Noel P: Cytogenetic and molecular detection of residual leukemic cells after allogeneic bone marrow transplantation in chronic granulocytic leukemia. Mayo Clin Proc 67:123127, 1992 iz. Arthur CK, Apperley JF, Rassool GF, Gao LM, Goldman lM: Cytogenetic events after bone marrow transplantation for chronic myeloid leukemia in chronic phase. Blood 71:11791186,1988 13. Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW, Champlin RE, Dicke KA, Goldman JM, Good RA, Herzig RH, Hong R, Masaoka T, Rimm AA, Ringden 0, Speck B, Weiner RS, Bortin MM: T-cell depletion of HLA-identical transplants in leukemia. Blood 78:2120-2130, 1991 14. Butturini A, Bortin MM, Gale RP: Graft-versus-leukemia following bone marrow transplantation. Bone Marrow Transplant 2:233-242, 1987

Allogeneic bone marrow transplantation: problems and prospects.

Editorial Allogeneic Bone Marrow Transplantation: Problems and Prospects Bone marrow transplantation refers to the intravenous infusion of hematopoiet...
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