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RELATED DONOR BONE MARROW TRANSPLANTATION FOR CHRONIC MYELOGENOUS LEUKEMIA
BIOLOGY AND THERAPY OF CHRONIC MYELOGENOUS LEUKEMIA
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RELATED DONOR BONE MARROW TRANSPLANTATION FOR CHRONIC MYELOGENOUS LEUKEMIA Jakob R. Passweg, MD, MS, Philip A. Rowlings, MD, MS, and Mary M. Horowitz, MD, MS
HISTORY AND CURRENT USE OF BONE MARROW TRANSPLANTATION FOR CHRONIC MYELOGENOUS LEUKEMIA
Allogeneic bone marrow transplantation was first introduced to treat congenital immune deficiencies and other nonmalignant hematologic disorders in the late 1960s.3, 19, 25 In the 1970s, Thomas and colleagues68,69 showed convincingly that some patients with refractory acute leukemia had long-term leukemia-free survival after high-dose therapy and HLA-identical sibling transplantation. Cytogenetic remissions and long-term leukemia-free survival after identical twin and allogeneic bone marrow transplants for chronic myelogenous leukemia 15,22, 46, 47, (CML) were demonstrated in the late 1970s and early 1980~.'~, Since then, transplantation from an HLA-identical sibling donor has become an accepted therapy for CML, accounting for about 25% of the 4000 to 5000 allogeneic transplants done yearly in North America.51 Although the first transplants for leukemia were done in persons with end-stage disease refractory to conventional treatment, success in this setting soon led to trials in patients with less advanced disease. Both From the Department of Innere Medizin, Kantonsspital, Basel, Switzerland (JRF'); International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, Wisconsin (PAR, MMH); and the Department of Medicine, Division of Hematology/ Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (PAR, MMH)
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relapse and transplant-related mortality were lower when transplants were done in first chronic phase of CML.70In an early report of 117 transplants for CML done between 1978 and 1982, only 39 (33%) were done in first chronic phase and 22 (19%) were done in blast phase.61In contrast, among 1105 transplants for CML done in 1995 and reported to the International Bone Marrow Transplant Registry (IBMTR), 851 (71%) were done in first chronic phase and only 59 (5%)in blast phase (unpublished data provided by the IBMTR Statistical Center). A study of 10 countries in Europe, North America, Australia, and New Zealand suggests that about 35% of persons with CML under the age of 55 years receive allogeneic bone marrow transplant^.^^
ANTILEUKEMIA EFFECT OF ALLOGENEIC TRANSPLANTS IN CML
Allogeneic transplantation is the only known cure for CML.67The initial rationale for its use was to allow delivery of high doses of radiation or chemotherapy (or both), known to cause irreversible bone marrow failure, to increase leukemia cell kill. It is likely that myeloablative therapy cures some persons with CML, accounting for long-term leukemia-free survival in persons receiving identical twin transplants; however, considerable data point to the importance of graft-mediated antileukemia effects in allogeneic transplantation for CML, termed graftversus-leukemia (GVL). One observation supporting a GVL effect in clinical transplantation is the lower risk of post-transplant leukemia recurrence in patients developing graft-versus-host disease (GVHD) after HLA-identical sibling transplants, an immune reaction of donor lymphocytes against host cells, presumably triggered by differences in minor histocompatibility antigens.28,35, 6s* 71 Recipients of identical twin transplants for CML who do not develop GVHD also have significantly higher risks of post-transplant relapse than do recipients of allogeneic transplant^.^^, 35 Development of clinically evident GVHD is apparently not necessary for a GVL effect in CML because patients who receive allogeneic grafts and do not develop acute or chronic GVHD have lower relapse rates than do those who receive identical twin transplant^.^^ The GVL effects of allografts in CML are largely abrogated by removing T lymphocytes from the donor bone marrow, an effective strategy for reducing GVHD that was introduced in the 1980s.’.27, 28, 45 Relapse rates after T-cell-depleted allogeneic transplants are similar to rates after identical twin transplants, even among T-cell-depleted transplant recipients who develop GVHD.= An effective GVL response can be established in many patients who relapse after HLA-identical sibling transplants for CML by infusing donor lymphocytes. The subsequent hematologic, cytogenetic, and molecular remissions appear durable,21,40, 41, 49 as discussed in the article by Porter and Antin on p. 123 of this issue.
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OUTCOME OF HLA-IDENTICAL SIBLING TRANSPLANTS FOR CML
The most important development leading to successful bone marrow transplantation in humans was the understanding of the importance of donor-recipient compatibility for major histocompatibility antigens. Selection of related donors genotypically identical for HLA led to acceptable levels of engraftment, GVHD, and survival. Bone marrow transplants for CML and other diseases are restricted largely to patients having a genotypically HLA-identical donor; about 70% of allogeneic transplants reported to the IBMTR in 1995 were from HLA-identical siblings (unpublished data from the IBMTR Statistical Center). However, only 25% to 30% of patients with CML have an HLA-identical sibling, severely limiting the application of this therapy. Consequently, there is considerable interest in using alternative donors for transplantation, especially HLA-matched unrelated donors; these are discussed in the article by McGlave on p. 93 of this issue. The strongest determinant of outcome after HLA-identical sibling transplants for CML is the phase of the disease at time of tran~p1ant.I~. 27, 70 Among 3409 recipients of HLA-identical sibling transplants done between 1989 and 1995 and reported to the IBMTR, 3-year actuarial probabilities of relapse (95% confidence interval) are 16% (14%-18%) for 2753 patients transplanted in first chronic phase, 36% (30%42%)for 490 in accelerated phase, and 61% (50%-72%) for 166 in blast phase (Fig. 1). Three-year probabilities of leukemia-free survival (LFS) are 59% (57%-61%), 37% (35'/0-39%), and 17% (10%-24%), respectively (Fig. 2)?l Patients relapsing after an HLA-identical sibling transplant for CML often survive for long periods with conventional treatment. Many
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Figure 1. Probability of relapse after HLA-identical sibling bone marrow transplants for CML, 1989-1 995, as reported to the International Bone Marrow Transplant Registry.
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achieve durable remissions with infusion of donor lymphocytes (see previous comments and discussion in the article by Porter and Antin on p. 123 of this issue). Some have successful second bone marrow transplants. Consequently, 3-year survival rates after transplants are somewhat higher than LFS rates: 66% (64%-68%)in chronic phase, 44% (39%-@%) in accelerated phase, and 19% (l2%-26%) in blast phase (Fig. Several disease-related features at diagnosis, such as white blood cell count, percent circulating blasts, hemoglobin, and spleen size, are known to predict survival duration in patients presenting with chronic phase CML and receiving nontransplant therapy.59,6o These factors are associated with the rate of transformation to acute or blast phase, which is the cause of death in most patients receiving nontransplant treatment. In contrast, relatively few deaths after HLA-identical sibling transplants for chronic phase CML result from leukemia, particularly if the transplants are not T cell-depleted. Most deaths are from transplant-related complications such as regimen-related toxicity, GVHD, and infection (Fig. 4). Consequently, prognostic factors for survival after HLA-identical sibling transplants for chronic phase CML are those that influence the risk of transplant-related complications, such as older age, donor parity, and prior treatment?, 14, 28, 29* 32 There has been some concern about high tumor burden in patients with CML and large spleens, but splenomegaly is not associated with more relapses, although it may lead to delayed eng~aftment.~~ Studies of pretransplant splenic irradiation or splenectomy do not show a survival benefit after HLA-identical sibling transplants for CML.31,37, 38 An IBMTR study of HLA-identical sibling
100 80
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60 40
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YEARS Figure 2. Probability of leukemia-free survival after HLA-identical sibling bone marrow transplants for CML, 1989-1995, as reported to the International Bone Marrow Transplant Registty.
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Accelerated Phase (N = 490) -
-
Blast Phase (N = 166)
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YEARS Figure 3. Probability of survival after HLA-identical sibling bone marrow transplants for CML, 1989-1 995, as reported to the International Bone Marrow Transplant Registry.
transplants for CML in first chronic phase done between 1985 and 1990 identified prior treatment with hydroxyurea rather than busulfan and a short interval between diagnosis and transplant (less than 1 versus at least 1 year) as favorable prognostic factors.29Three-year probabilities of survival were 67% for patients treated with hydroxyurea and receiving
infe
Figure 4. Causes of death after HLA-identical sibling transplants for CML in first chronic phase, reported to the International Bone Marrow Transplant Registry. VOD = venoocclusive disease of the liver; GVHD = grait-versus-host disease.
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transplant within 1 year of diagnosis, 59% for those treated with hydroxyurea and receiving transplant later, 54% for patients treated with busulfan and receiving transplant less than 1 year after diagnosis, and 45% in those treated with busulfan and receiving transplant later. Similar 70 Whether prior treatment with findings are reported in other st~dies.'~, interferon changes transplant outcome is not clear. Conflicting results are reported.6,26 Preliminary data from the IBMTR suggest little effect of prior interferon treatment on outcome of HLA-identical sibling transplant~.~~ Transplant-related mortality after HLA-identical sibling transplantation has decreased since the 1970s. An IBMTR study of 7788 patients receiving transplants between 1980 and 1989 showed decreases from 38% to 31% in early leukemia (first remission of acute leukemia or first chronic phase of CML), from 47% to 41% in intermediate stage leukemia (subsequent remission of acute leukemia or accelerated phase CML), and from 68% to 46% in advanced leukemia (acute leukemia not in remission or blast-phase CML).'" Possible reasons include altered radiation schedules, blood product screening for cytomegalovirus, improved antiviral and antibiotic therapy, and better GVHD prophylaxis. Relapse probabilities changed little during this time. TRANSPLANT REGIMENS
In the early 1980s, most recipients of HLA-identical sibling transplants for CML received high-dose cyclophosphamide and single-dose total body irradiation for pretransplant conditioning. In the mid-1980s many centers switched to fractionated total body irradiation schedules and added lung shielding to minimize radiation-induced organ toxicity. Several studies, both randomized and nonrandomized, suggested that a regimen of high-dose cyclophosphamide and busulfan is as effective as radiation-containing regimens in transplants for CML.17,*O, 52 Among HLA-identical sibling transplants done in 1995 and reported to the IBMTR, about 60% used the combination of busulfan and cyclophosphamide for pretransplant conditioning (unpublished data from the IBMTR Statistical Center). Other studies reported results with alternative pretransplant conditioning regimens, including various schedules of total body irradiation and addition of other drugs to intensify therapy.16,44, 58 LFS was similar with all reported regimens; wherever dose-intensification resulted in lower relapse risks, the survival advantage was offset by increased regimen-related toxicity. Because GVHD is the major cause of transplant-related mortality after HLA-identical sibling transplants: decreasing the risk of severe GVHD has been the focus of many studies over the years. The first, commonly used GVHD prophylaxis was post-transplant immune suppression with methotrexate. In the 1980s, T-cell depletion of donor marrow, with or without post-transplant immunosuppressive drugs, was used in many centers. Although highly effective in decreasing
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GVHD, T-cell-depleted transplants had high rates of graft failure and relapse, leading to either similar or lower LFS than with non-T-celldepleted tran~plants.4~ Cyclosporine replaced methotrexate for posttransplant immunosuppression in the 1980s in most centers. More recent studies indicate that the combination of methotrexate and cyclosporine results in lower rates of acute GVHD than does either drug alone.50, 6 3 , 6 4 An IBMTR study indicates not only lower GVHD risk but also higher LFS with combined methotrexate and cyclosporine as compared with therapy with either drug alone.50There is recently renewed interest in using T-cell depletion to prevent GVHD, using newer methods of selective T-cell depletion, intensification of pre- and post-transplant immunosuppression to facilitate engraftment, and donor lymphocyte infusions to re-induce remissions in patients who relapse.", 13, 21* 40, 41, 49 TIMING OF HLA-IDENTICAL SIBLING TRANSPLANTS Because most patients with CML survive 3 or more years with conventional therapy, and some much longer, the decision to do a transplant early, with its attendant risk of early transplant-related mor56 Delaying transplant, however, decreases the likelitality, is diffi~ult.5~. 29, 70 There are few data to guide these hood of a successful decisions. In a study by the Italian Cooperative Group on CML, 50 of 258 patients diagnosed with CML between 1984 and 1986 received an HLA-identical sibling transplant, whereas 208 were treated with hydroxyurea, busulfan, and/or other Eight-year survival was 43% in the transplant cohort and 25% in the nontransplant cohort. The survival advantage was statistically significant only in patients younger than 30 years at diagnosis. An IBMTR study compared 548 recipients of HLA-identical sibling transplants with 196 patients receiving hydroxyurea or interferon in a randomized trial of the German CML Study Group. Patients were diagnosed with chronic phase CML between 1983 and 1991. Seven-year survival probabilities were 58% (50%-66%) with transplant and 32% (22%41%) with hydroxyurea or interferon. There was a significant survival advantage for hydroxyurea or interferon in the first 4 years after diagnosis, and for transplants starting 5.5 years after diagnosis. For transplants done within 1 year of diagnosis, the survival advantage for transplantation began earlier. Survival advantage for transplants was greater and occurred earlier in patients with intermediate- and high-risk prognostic features than in those with low-risk feat~res.2~ These data confirm the long-term survival advantage of HLAidentical sibling transplantation and quantify the trade-off with early transplant-related mortality. TRANSPLANTS USING OTHER RELATED DONORS Extended family typing identifies a phenotypically HLA-identical nonsibling relative or a 1-HLA-antigen mismatched related donor in
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about 5% to 10% of patients without an HLA-identical sibling donor. Some studies suggest that survival after transplants from such donors is similar to that after HLA-identical sibling transplants? whereas others indicate lower survival owing to higher risks of graft failure and acute GVHD.2,66 In a recent study by the IBMTR, outcome of transplants using 1-antigen mismatched related donors was similar to that using matched unrelated donors, whereas outcome with 2-antigen mismatched related donors was similar to outcome with 1-antigen mismatched unrelated donors. Outcomes with all types of alternative donors were worse than with HLA-identical sibling donors.66This and most studies of alternative related donor and unrelated donor transplants have used serologic typing to define class I and/or class I1 HLA compatibility. Use of DNAbased techniques to select more closely matched donors may lead to better results and survivals similar to those with HLA-identical sibling transplants. These issues are discussed in the article by Petersdorf et a1 on p. 107 of this issue. Some studies suggest that 2- and 3-antigen disparate related donor transplants can be successful with intensive preand post-transplant immunosuppression and T-cell depletion of donor 48 marrow, although numbers of patients studied are FUTURE DEVELOPMENTS
HLA-identical sibling transplantation is clearly an effective treatment for CML. Success is limited primarily by transplant-related complications. Relapse risks are low when transplants are done in early first chronic phase. The key to better transplant outcomes is further reduction in transplantation mortality without compromising antileukemia efficacy. Use of less intensive conditioning regimens with lower regimenrelated toxicity but sufficient immunosuppression to allow donor cell engraftment is being studied as a way of allowing transplants to be done in older patient^.^^,^^ Use of blood instead of bone marrow as a source of allogeneic stem cells may allow new approaches to cell manipulation because of the large numbers of cells that can be collected 8, 42* 43*53 This and the effectiveness of donor lymphocytes by aphere~is.~, in inducing remission has increased interest in protocols using selective T-cell depletion or stem cell selection or both, and in prophylactic T-cell infusions at various dose levels and time intervals after T-cell-depleted transplantation, with the goals of minimizing GVHD, reducing trans57 The issue of pretransplant plant mortality, and preventing re1ap~e.l~. treatment with interferon and use of interferon-response to make decisions about timing of transplantation also must be addressed. ACKNOWLEDGMENTS This work was supported by Public Health Service Grant Pol-CA-40053 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute, and Contract CP-21161 from the National Cancer Institute of the US Department of Health and Human Services; and grants from
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Activated Cell Therapy, Inc; Alpha Therapeutic Corporation; American Oncology Resources; Amgen, Inc; Anonymous; Astra Pharmaceutical; Baxter Healthcare Corporation; Bayer Corporation; Biogen; Blue Cross and Blue Shield Association; Lynde and Harry Bradley Foundation; Bristol-Myers Squibb Company; Frank G. Brotz Family Foundation; CellPro, Inc; Cell Therapeutics, Inc; Centeon; Center for Advanced Studies in Leukemia; Chimeric Therapies; Chiron Therapeutics; Cigna Healthcare; COBE BCT, Inc; Coram Healthcare; Coulter Corporation; Charles E. Culpeper Foundation; Eleanor Naylor Dana Charitable Trust; Deborah J. Dearholt Memorial Fund; Eppley Foundation for Research; Fujisawa USA; Genentech, Inc; Glaxo Wellcome Company; Hewlett-Packard Company; Hoechst Marion Roussel, Inc; ICN Pharmaceuticals; Immunex Corporation; Janssen Pharmaceutica; Kettering Family Foundation; Kirin Brewery Company; Robert J. Kleberg, Jr and Helen C. Kleberg Foundation; Herbert H. Kohl Chanties; Life Technologies, Inc; Eli Lilly Company Foundation; The Liposome Company; Nada and Herbert P. Mahler Charities; MDS Nordian; Medical SafeTEC; MGI Pharma, Inc; Milliman & Robertson, Inc; Milstein Family Foundation; Milwaukee Foundation/Elsa Schoeneich Research Fund; NCSG and Associates; NeXstar Pharmaceuticals, Inc; Samuel Roberts Noble Foundation; Northwestern Mutual Life Insurance Foundation; Novartis Pharmaceuticals; Ortho Biotech Corporation; John Oster Family Foundation; Elsa U. Pardee Foundation; Jane and Lloyd Pettit Foundation; Alirio Pfiffer Bone Marrow Transplant Support Association; Pfizer, Inc; Pharmacia and Upjohn; Principal Mutual Life Insurance Company; Quantum Health Resources; QLT PhotoTherapeutics; RGK Foundation; Roche Laboratories; Rockwell Automation Allen Bradley Company; RPR GenCell; SangStat Medical Corporation; Schering-Plough International; Walter Schroeder Foundation; Searle; SEQUUS Pharmaceuticals, Inc; Stackner Family Foundation; Starr Foundation; Joan and Jack Stein Charities; StemCell Technologies, Inc; SyStemix; Therakos; TS Scientific and Planer Products; Wyeth-Ayerst Laboratories; and Xoma Corporation.
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chronic myelogenous leukemia given T-cell depleted marrow compared to methotrexate combined with cyclosporin or monotherapy for the prevention of graft-versus-host disease. Eur J Haematol 50:269, 1993 2. Ash RC, Horowitz MM, Gale RF, et al: Bone marrow transplantation from related donors other than HLA-identical siblings: Effect of T-cell depletion. Bone Marrow Transplant 7443,1991 3. Bach FH, Albertini RJ, Joo P, et al: Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome. Lancet 2:1364,1968 4. Bacigalupo A, Gualandi F, Van Lint MT, et al: Multivariate analysis of risk factors for survival and relapse in chronic granulocytic leukemia following allogeneic marrow transplantation: Impact of disease related variables (Sokal score). Bone Marrow Transplant 12:443, 1993 5. Beatty PG, Clift RA, Mickelson EM, et al: Marrow transplantation from related donors other than HLA-identical siblings. N Engl J Med 313:765, 1985 6. Beelen DW, Graeven U, Elmaagacli AH, et al: Prolonged administration of interferonalpha in patients with chronic-phase Philadelphia chromosomepositive chronic myelogenous leukemia before allogeneic bone marrow transplantation may adversely affect transplant outcome. Blood 852981, 1995 7. Bensinger WI, Weaver CH, Appelbaum FR, et al: Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor. Blood 85:1655, 1995 8. Bensinger WI, Buckner CD, Shannon-Dorcy K, et al: Transplantation of allogeneic CD34+ peripheral blood stem cells in patients with advanced hematologic malignancy. Blood 884132,1996 9. Bortin MM, Ringden 0, Horowitz MM, et al: Temporal relationships between the major complications of bone marrow transplantation for leukemia. Bone Marrow Transplant 4:339, 1989
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10. Bortin MM, Horowitz MM, Gale RE', et a1 Changing trends in bone marrow transplantation for leukemia in the 1980s. JAMA 268607, 1992 11. Champlin R Separation of graft-vs.-host disease and graft-vs.-leukemia effect against chronic myelogenous leukemia [editorial; comment]. Exp Hematol 23:1148, 1995 12. Champlin R, Ho W, Arenson E, et al: Allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic or accelerated phase. Blood 60:1038, 1982 13. Champlin RC, Jansen J, Ho W, et a1 Retention of graft-versus-host disease following bone marrow transplantation for chronic myelogenous leukemia. Transplant Proc 23:1695, 1991 14. Clift RA, Storb R Marrow transplantation for CML The Seattle experience. Bone Marrow Transplant 1751, 1996 15. Clift RA, Buckner CD, Thomas ED, et al: Treatment of chronic granulocytic leukemia in chronic phase by allogeneic marrow transplantation. Lancet 2621, 1982 16. Clift RA, Buckner CD, Appelbaum FR, et al: Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: A randomized trial of two irradiation regimens. Blood 771660, 1991 17. Clift RA, Buckner CD, Thomas ED, et al: Marrow transplantation for chronic myeloid leukemia: A randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood 842036, 1994 18. Collins RH Jr, Shpilberg 0, Drobyski WR, et al: Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation [see comments]. J Clin Oncol 15:433, 1997 19. De Konig J, Dooren LJ, Van Bekkum DW, et al: Transplantation of bone-marrow cells and fetal thymus in an infant with lymphopenic immunological deficiency. Lancet 1:1223, 1969 20. Devereie " A,. Blaise D. Attal M. et al: Alloeeneic bone marrow transulantation for chronic myeloid leukemia in first chronic Fhase: A randomized triai of busulfancytoxan versus cytoxan-total body irradiation as preparative regimen: A report from the French Society of Bone Marrow Graft (SEGM). Blood 85:2263, 1995 21. Drobyski WR, Keever CA, Roth MS, et a1 Salvage immunotherapy using donor leukocyte infusions as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation: Efficacy and toxicity of a defined T-cell dose. Blood 82:2310, 1993 22. Fefer A, Cheever MA, Greenberg PD, et al: Treatment of chronic granulocytic leukemia with chemoradiotherapy and transplantation of marrow from identical twins. N Engl J Med 306:63, 1982 23. Gale RP, Horowitz MM, Ash RC, et al: Identical-twin bone marrow transplants for leukemia. AM Intern Med 120646,1994 24. Gale RP, Hehlmann R, Zhang MJ, et al: Survival with bone marrow transplantation versus hydroxyurea or interferon for chronic myelogenous leukemia. Blood, in press 25. Gatti RA, Meuwissen HJ, Allen HD, et a1 Immunological reconstitution of sex-linked immunological deficiency. Lancet 2:1366, 1968 26. Giralt SA, Kantarjian HM, Talpaz M, et al: RE. Effect of prior interferon alfa therapy on the outcome of allogeneic bone marrow transplantation for chronic myelogenous leukemia. J Clin Oncol 11:1055, 1993 27. Goldman JM, Apperley JF, Jones L, et al: Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med 314:202, 1986 28. Goldman JM, Gale RP, Horowitz MM, et al: Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: Increased risk of relapse associated with Tcell depletion. AM Intern Med 108:806, 1988 29. Goldman JM, Szydlo R, Horowitz MM, et al: Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase. Blood 82:2235, 1993 30. Gratwohl A, Hermans J, von Biezen A, et al: No advantage for patients who receive splenic irradiation before bone marrow transplantation for chronic myeloid leukaemia: Results of a prospective randomized study. Bone Marrow Transplant 10:147, 1992 31. Gratwohl A, Hermans J, Biezen AV, et al: Splenic irradiation before bone marrow transplantation for chronic myeloid leukemia: Update of a prospective randomized study. Leuk Lymphoma ll(supp1 1):227, 1993 32. Gratwohl A, Hermans J, Apperley J, et al: Acute graft-versus-host disease: Grade and
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outcome in patients with chronic myelogenous leukemia. Working Party on Chronic Leukemia of the European Group for Blood and Marrow Transplantation. Blood 865313, 1995 33. Helenglass G, Treleaven J, Parikh P, et al: Delayed engraftment associated with splenomegaly in patients undergoing bone marrow transplantation for chronic myeloid leukaemia. Bone Marrow Transplant 5247, 1990 34. Henslee-Downey PJ, Parrish RS, MacDonald JS, et al: Combined in vitro and in vivo T lymphocyte depletion for the control of graft-versus-host disease following haploidentical marrow transplant. Transplantation 61:738, 1996 35. Horowitz MM, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75:555, 1990 36. Horowitz MM, Giralt S, Szydlo R, et al: Effect of prior interferon therapy on outcome of HLA-identical sibling bone marrow transplants for chronic myelogenous leukemia (CML) in first chronic phase. Blood 88:682a, 1996 37. Italian Cooperative Study Group on Chronic Myeloid Leukaemia: Evaluating survival after allogeneic bone marrow transplant for chronic myeloid leukemia in chronic phase: A comparison of transplant versus no-transplant in a cohort of 258 patients first seen in Italy between 1984 and 1986. Br J Haematol 85292, 1993 38. Kahls P, Schwarzinger I, Anderson G, et al: A retrospective analysis of the long-term effect of splenectomy on late infections, graft-versus-host disease, relapse, and survival after allogeneic bone marrow transplantation for chronic myelogenous leukemia. Blood 862028, 1995 39. Khouri I, Keating MJ, Przepiorka D, et al: Engraftment and induction of GVL with fludarabine-based non-ablative preparative regimen in patients with CLL and lymphoma. Blood 88(suppl 1):301a, 1996 40. Kolb HJ, Mittermueller J, Clemm C, et al: Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 762462, 1990 41. Kolb HJ, Schattenberg A, Goldman JM, et a1 Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 862041,1995 42. Korbling M, Przepiorka D, Huh YO, et al: Allogeneic blood stem cell transplantation for refractory leukemia and lymphoma: Potential advantage of blood over marrow allografts. Blood 85:1659, 1995 43. Link H, Arseniev L, Bahre 0, et al: Transplantation of allogeneic CD34 + blood cells. Blood 874903, 1996 44. Marks DI, Goldman JM: HLA-identical sibling bone marrow transplantation for chronic myeloid leukemia. i n Atkmson K (ed): Clinical Bone Marrow Transplantation: A Reference Textbook. Cambridge, Cambridge University Press, 1994, p 197 45. Marmont AM, Horowitz MM, Gale RP, et a 1 T-cell depletion of HLA-identical transplants in leukemia. Blood 78:2120, 1991 46. McGlave PB, Miller WJ, Hurd DD, et al: Cytogenetic conversion following allogeneic bone marrow transplantation for advanced chronic myelogenous leukemia. Blood ~58:1050, 1981 47. McGlave PB. Arthur DC. Kim TH. et al: Successful alloeeneic bone marrow transplatation for patients in the accelerated phase of chrznic granulocytic leukemia. Lancet 2625, 1982 48. Ottinger H, Beelen D, Sayer H, et al: Bone marrow transplantation from partially HLA-matched related donors in adults with leukaemia: The experience at the University Hospital of Essen, Germany. Br J Haematol92:913, 1996 49. Porter DL, Roth MS, McGarigle C, et al: Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med 33:100, 1994 50. Ringden 0, Horowitz MM, Sondel P, et al: Methotrexate, cyclosporine, or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia? Blood 81:109, 1993 51. Rowlings PA: Current use and outcome of blood and marrow transplantation. ABMTR Newsletter 3:6, 1996 52. Santos GW: Busulfan and cyclophosphamide versus cyclophosphamide and total body irradiation for marrow transplantation in chronic myelogenous leukemia-a review. Leuk Lymphoma ll(supp1 1):201,1993
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53. Schmitz N, Dreger P, Suttorp M, et al: Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by filgrastim (granulocyte colony-stimulating factor). Blood 85:1666, 1995 54. Segel GB, Simon W, Lichtman MA: Variables influencing the timing of marrow transplantation in patients with chronic myelogenous leukemia. Blood 68:1055, 1986 55. Silberman G, Crosse MG, Peterson EA, et al: Availability and appropriateness of allogeneic bone marrow transplantation for chronic myeloid leukemia in 10 countries. N Engl J Med 331:1063, 1994 56. Simon W, Segel GB, Lichtman M A Upper and lower time limits in the decision to recommend marrow transplantation for patients with chronic myelogenous leukaemia. Br J Haematol 7031, 1988 57. Slavin S, Or R, Nagler A, et al: Allogeneic cell therapy for prevention of relapse in high-risk acute leukemia following allogeneic bone marrow transplantation: Control of GVHD by graded increments of donor lymphocyte infusion. Blood 88(suppl 1):418a, 1996 58. Socie G, Devergie A, Girinsky T, et al: Influence of the fractionation of total body irradiation on complications and relapse rate for chronic myelogenous leukemia. The Groupe d’Etude des Greffes de Moelle Osseuse (GEGMO). Int J Radiat Oncol Biol Phys 20:397, 1991 59. Sokal JE: Prognosis in chronic myeloid leukaemia: Biology of the disease versus treatment. Baillieres Clinical Haematol 1:907, 1987 60. Sokal JE, Baccarani M, Tura S, et al: Prognostic discrimination among younger patients with chronic granulocytic leukemia: Relevance to bone marrow transplantation. Blood 66:1352, 1985 61. Speck B, Bortin MM, Champlin R, et al: Allogeneic bone marrow transplantation for chronic myelogenous leukemia. Lancet 1:665, 1984 62. Storb R, Deeg HJ, Farewell V, et al: Marrow transplantation for severe aplastic anemia: Methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood 68119, 1986 63. Storb R, Deeg HJ, Whitehead J, et al: Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft-versus-host disease after marrow transplantation for leukemia. N Engl J Med 314729, 1986 64. Storb R, Deeg HJ, Pepe M, et al: Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: Long-term follow-up of a controlled trial. Blood 731729, 1989 65. Sullivan KM, Weiden PL, Storb R, et a1 Influence of acute and chronic graft-versushost disease on relapse and survival after bone marrow transplantation from HLAidentical siblings as treatment of acute and chronic leukemia. Blood 731720, 1989 66. Szydlo R, Goldman JM, Klein JP, et al: Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings. J Clin Oncol15:1767,1997 67. Thomas ED, Clift RA: Indications for marrow transplantation in chronic myelogenous leukemia. Blood 73361, 1989 68. Thomas ED, Buckner CD, Banaji M, et a1 One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 49:511, 1977 69. Thomas ED, Buckner CD, Clift RA, et al: Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N Engl J Med 301:597, 1979 70. Thomas ED, Clift RA, Fefer A, et al: Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med 104.155, 1986 71. Weiden PL, Sullivan KM, Fluomoy N, et al: Anti-leukemia effect of chronic graftversus-host disease. N Engl J Med 304:1529, 1981
Address reprint requests to Mary M. Horowitz, MD, MS IBMTR/ ABMTR Medical College of Wisconsin 8701 Watertown Plank Road P.O. Box 26509 Milwaukee, WI 53226
0889-8588/98 $8.00
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.OO
RELATED DONOR BONE MARROW TRANSPLANTATION FOR CHRONIC MYELOGENOUS LEUKEMIA Jakob R. Passweg, MD, MS, Philip A. Rowlings, MD, MS, and Mary M. Horowitz, MD, MS
HISTORY AND CURRENT USE OF BONE MARROW TRANSPLANTATION FOR CHRONIC MYELOGENOUS LEUKEMIA
Allogeneic bone marrow transplantation was first introduced to treat congenital immune deficiencies and other nonmalignant hematologic disorders in the late 1960s.3, 19, 25 In the 1970s, Thomas and colleagues68,69 showed convincingly that some patients with refractory acute leukemia had long-term leukemia-free survival after high-dose therapy and HLA-identical sibling transplantation. Cytogenetic remissions and long-term leukemia-free survival after identical twin and allogeneic bone marrow transplants for chronic myelogenous leukemia 15,22, 46, 47, (CML) were demonstrated in the late 1970s and early 1980~.'~, Since then, transplantation from an HLA-identical sibling donor has become an accepted therapy for CML, accounting for about 25% of the 4000 to 5000 allogeneic transplants done yearly in North America.51 Although the first transplants for leukemia were done in persons with end-stage disease refractory to conventional treatment, success in this setting soon led to trials in patients with less advanced disease. Both From the Department of Innere Medizin, Kantonsspital, Basel, Switzerland (JRF'); International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, Wisconsin (PAR, MMH); and the Department of Medicine, Division of Hematology/ Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (PAR, MMH)
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relapse and transplant-related mortality were lower when transplants were done in first chronic phase of CML.70In an early report of 117 transplants for CML done between 1978 and 1982, only 39 (33%) were done in first chronic phase and 22 (19%) were done in blast phase.61In contrast, among 1105 transplants for CML done in 1995 and reported to the International Bone Marrow Transplant Registry (IBMTR), 851 (71%) were done in first chronic phase and only 59 (5%)in blast phase (unpublished data provided by the IBMTR Statistical Center). A study of 10 countries in Europe, North America, Australia, and New Zealand suggests that about 35% of persons with CML under the age of 55 years receive allogeneic bone marrow transplant^.^^
ANTILEUKEMIA EFFECT OF ALLOGENEIC TRANSPLANTS IN CML
Allogeneic transplantation is the only known cure for CML.67The initial rationale for its use was to allow delivery of high doses of radiation or chemotherapy (or both), known to cause irreversible bone marrow failure, to increase leukemia cell kill. It is likely that myeloablative therapy cures some persons with CML, accounting for long-term leukemia-free survival in persons receiving identical twin transplants; however, considerable data point to the importance of graft-mediated antileukemia effects in allogeneic transplantation for CML, termed graftversus-leukemia (GVL). One observation supporting a GVL effect in clinical transplantation is the lower risk of post-transplant leukemia recurrence in patients developing graft-versus-host disease (GVHD) after HLA-identical sibling transplants, an immune reaction of donor lymphocytes against host cells, presumably triggered by differences in minor histocompatibility antigens.28,35, 6s* 71 Recipients of identical twin transplants for CML who do not develop GVHD also have significantly higher risks of post-transplant relapse than do recipients of allogeneic transplant^.^^, 35 Development of clinically evident GVHD is apparently not necessary for a GVL effect in CML because patients who receive allogeneic grafts and do not develop acute or chronic GVHD have lower relapse rates than do those who receive identical twin transplant^.^^ The GVL effects of allografts in CML are largely abrogated by removing T lymphocytes from the donor bone marrow, an effective strategy for reducing GVHD that was introduced in the 1980s.’.27, 28, 45 Relapse rates after T-cell-depleted allogeneic transplants are similar to rates after identical twin transplants, even among T-cell-depleted transplant recipients who develop GVHD.= An effective GVL response can be established in many patients who relapse after HLA-identical sibling transplants for CML by infusing donor lymphocytes. The subsequent hematologic, cytogenetic, and molecular remissions appear durable,21,40, 41, 49 as discussed in the article by Porter and Antin on p. 123 of this issue.
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OUTCOME OF HLA-IDENTICAL SIBLING TRANSPLANTS FOR CML
The most important development leading to successful bone marrow transplantation in humans was the understanding of the importance of donor-recipient compatibility for major histocompatibility antigens. Selection of related donors genotypically identical for HLA led to acceptable levels of engraftment, GVHD, and survival. Bone marrow transplants for CML and other diseases are restricted largely to patients having a genotypically HLA-identical donor; about 70% of allogeneic transplants reported to the IBMTR in 1995 were from HLA-identical siblings (unpublished data from the IBMTR Statistical Center). However, only 25% to 30% of patients with CML have an HLA-identical sibling, severely limiting the application of this therapy. Consequently, there is considerable interest in using alternative donors for transplantation, especially HLA-matched unrelated donors; these are discussed in the article by McGlave on p. 93 of this issue. The strongest determinant of outcome after HLA-identical sibling transplants for CML is the phase of the disease at time of tran~p1ant.I~. 27, 70 Among 3409 recipients of HLA-identical sibling transplants done between 1989 and 1995 and reported to the IBMTR, 3-year actuarial probabilities of relapse (95% confidence interval) are 16% (14%-18%) for 2753 patients transplanted in first chronic phase, 36% (30%42%)for 490 in accelerated phase, and 61% (50%-72%) for 166 in blast phase (Fig. 1). Three-year probabilities of leukemia-free survival (LFS) are 59% (57%-61%), 37% (35'/0-39%), and 17% (10%-24%), respectively (Fig. 2)?l Patients relapsing after an HLA-identical sibling transplant for CML often survive for long periods with conventional treatment. Many
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achieve durable remissions with infusion of donor lymphocytes (see previous comments and discussion in the article by Porter and Antin on p. 123 of this issue). Some have successful second bone marrow transplants. Consequently, 3-year survival rates after transplants are somewhat higher than LFS rates: 66% (64%-68%)in chronic phase, 44% (39%-@%) in accelerated phase, and 19% (l2%-26%) in blast phase (Fig. Several disease-related features at diagnosis, such as white blood cell count, percent circulating blasts, hemoglobin, and spleen size, are known to predict survival duration in patients presenting with chronic phase CML and receiving nontransplant therapy.59,6o These factors are associated with the rate of transformation to acute or blast phase, which is the cause of death in most patients receiving nontransplant treatment. In contrast, relatively few deaths after HLA-identical sibling transplants for chronic phase CML result from leukemia, particularly if the transplants are not T cell-depleted. Most deaths are from transplant-related complications such as regimen-related toxicity, GVHD, and infection (Fig. 4). Consequently, prognostic factors for survival after HLA-identical sibling transplants for chronic phase CML are those that influence the risk of transplant-related complications, such as older age, donor parity, and prior treatment?, 14, 28, 29* 32 There has been some concern about high tumor burden in patients with CML and large spleens, but splenomegaly is not associated with more relapses, although it may lead to delayed eng~aftment.~~ Studies of pretransplant splenic irradiation or splenectomy do not show a survival benefit after HLA-identical sibling transplants for CML.31,37, 38 An IBMTR study of HLA-identical sibling
100 80
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60 40
a
0 20
z 1
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YEARS Figure 2. Probability of leukemia-free survival after HLA-identical sibling bone marrow transplants for CML, 1989-1995, as reported to the International Bone Marrow Transplant Registty.
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Accelerated Phase (N = 490) -
-
Blast Phase (N = 166)
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0
I
I
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I
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YEARS Figure 3. Probability of survival after HLA-identical sibling bone marrow transplants for CML, 1989-1 995, as reported to the International Bone Marrow Transplant Registry.
transplants for CML in first chronic phase done between 1985 and 1990 identified prior treatment with hydroxyurea rather than busulfan and a short interval between diagnosis and transplant (less than 1 versus at least 1 year) as favorable prognostic factors.29Three-year probabilities of survival were 67% for patients treated with hydroxyurea and receiving
infe
Figure 4. Causes of death after HLA-identical sibling transplants for CML in first chronic phase, reported to the International Bone Marrow Transplant Registry. VOD = venoocclusive disease of the liver; GVHD = grait-versus-host disease.
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transplant within 1 year of diagnosis, 59% for those treated with hydroxyurea and receiving transplant later, 54% for patients treated with busulfan and receiving transplant less than 1 year after diagnosis, and 45% in those treated with busulfan and receiving transplant later. Similar 70 Whether prior treatment with findings are reported in other st~dies.'~, interferon changes transplant outcome is not clear. Conflicting results are reported.6,26 Preliminary data from the IBMTR suggest little effect of prior interferon treatment on outcome of HLA-identical sibling transplant~.~~ Transplant-related mortality after HLA-identical sibling transplantation has decreased since the 1970s. An IBMTR study of 7788 patients receiving transplants between 1980 and 1989 showed decreases from 38% to 31% in early leukemia (first remission of acute leukemia or first chronic phase of CML), from 47% to 41% in intermediate stage leukemia (subsequent remission of acute leukemia or accelerated phase CML), and from 68% to 46% in advanced leukemia (acute leukemia not in remission or blast-phase CML).'" Possible reasons include altered radiation schedules, blood product screening for cytomegalovirus, improved antiviral and antibiotic therapy, and better GVHD prophylaxis. Relapse probabilities changed little during this time. TRANSPLANT REGIMENS
In the early 1980s, most recipients of HLA-identical sibling transplants for CML received high-dose cyclophosphamide and single-dose total body irradiation for pretransplant conditioning. In the mid-1980s many centers switched to fractionated total body irradiation schedules and added lung shielding to minimize radiation-induced organ toxicity. Several studies, both randomized and nonrandomized, suggested that a regimen of high-dose cyclophosphamide and busulfan is as effective as radiation-containing regimens in transplants for CML.17,*O, 52 Among HLA-identical sibling transplants done in 1995 and reported to the IBMTR, about 60% used the combination of busulfan and cyclophosphamide for pretransplant conditioning (unpublished data from the IBMTR Statistical Center). Other studies reported results with alternative pretransplant conditioning regimens, including various schedules of total body irradiation and addition of other drugs to intensify therapy.16,44, 58 LFS was similar with all reported regimens; wherever dose-intensification resulted in lower relapse risks, the survival advantage was offset by increased regimen-related toxicity. Because GVHD is the major cause of transplant-related mortality after HLA-identical sibling transplants: decreasing the risk of severe GVHD has been the focus of many studies over the years. The first, commonly used GVHD prophylaxis was post-transplant immune suppression with methotrexate. In the 1980s, T-cell depletion of donor marrow, with or without post-transplant immunosuppressive drugs, was used in many centers. Although highly effective in decreasing
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GVHD, T-cell-depleted transplants had high rates of graft failure and relapse, leading to either similar or lower LFS than with non-T-celldepleted tran~plants.4~ Cyclosporine replaced methotrexate for posttransplant immunosuppression in the 1980s in most centers. More recent studies indicate that the combination of methotrexate and cyclosporine results in lower rates of acute GVHD than does either drug alone.50, 6 3 , 6 4 An IBMTR study indicates not only lower GVHD risk but also higher LFS with combined methotrexate and cyclosporine as compared with therapy with either drug alone.50There is recently renewed interest in using T-cell depletion to prevent GVHD, using newer methods of selective T-cell depletion, intensification of pre- and post-transplant immunosuppression to facilitate engraftment, and donor lymphocyte infusions to re-induce remissions in patients who relapse.", 13, 21* 40, 41, 49 TIMING OF HLA-IDENTICAL SIBLING TRANSPLANTS Because most patients with CML survive 3 or more years with conventional therapy, and some much longer, the decision to do a transplant early, with its attendant risk of early transplant-related mor56 Delaying transplant, however, decreases the likelitality, is diffi~ult.5~. 29, 70 There are few data to guide these hood of a successful decisions. In a study by the Italian Cooperative Group on CML, 50 of 258 patients diagnosed with CML between 1984 and 1986 received an HLA-identical sibling transplant, whereas 208 were treated with hydroxyurea, busulfan, and/or other Eight-year survival was 43% in the transplant cohort and 25% in the nontransplant cohort. The survival advantage was statistically significant only in patients younger than 30 years at diagnosis. An IBMTR study compared 548 recipients of HLA-identical sibling transplants with 196 patients receiving hydroxyurea or interferon in a randomized trial of the German CML Study Group. Patients were diagnosed with chronic phase CML between 1983 and 1991. Seven-year survival probabilities were 58% (50%-66%) with transplant and 32% (22%41%) with hydroxyurea or interferon. There was a significant survival advantage for hydroxyurea or interferon in the first 4 years after diagnosis, and for transplants starting 5.5 years after diagnosis. For transplants done within 1 year of diagnosis, the survival advantage for transplantation began earlier. Survival advantage for transplants was greater and occurred earlier in patients with intermediate- and high-risk prognostic features than in those with low-risk feat~res.2~ These data confirm the long-term survival advantage of HLAidentical sibling transplantation and quantify the trade-off with early transplant-related mortality. TRANSPLANTS USING OTHER RELATED DONORS Extended family typing identifies a phenotypically HLA-identical nonsibling relative or a 1-HLA-antigen mismatched related donor in
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about 5% to 10% of patients without an HLA-identical sibling donor. Some studies suggest that survival after transplants from such donors is similar to that after HLA-identical sibling transplants? whereas others indicate lower survival owing to higher risks of graft failure and acute GVHD.2,66 In a recent study by the IBMTR, outcome of transplants using 1-antigen mismatched related donors was similar to that using matched unrelated donors, whereas outcome with 2-antigen mismatched related donors was similar to outcome with 1-antigen mismatched unrelated donors. Outcomes with all types of alternative donors were worse than with HLA-identical sibling donors.66This and most studies of alternative related donor and unrelated donor transplants have used serologic typing to define class I and/or class I1 HLA compatibility. Use of DNAbased techniques to select more closely matched donors may lead to better results and survivals similar to those with HLA-identical sibling transplants. These issues are discussed in the article by Petersdorf et a1 on p. 107 of this issue. Some studies suggest that 2- and 3-antigen disparate related donor transplants can be successful with intensive preand post-transplant immunosuppression and T-cell depletion of donor 48 marrow, although numbers of patients studied are FUTURE DEVELOPMENTS
HLA-identical sibling transplantation is clearly an effective treatment for CML. Success is limited primarily by transplant-related complications. Relapse risks are low when transplants are done in early first chronic phase. The key to better transplant outcomes is further reduction in transplantation mortality without compromising antileukemia efficacy. Use of less intensive conditioning regimens with lower regimenrelated toxicity but sufficient immunosuppression to allow donor cell engraftment is being studied as a way of allowing transplants to be done in older patient^.^^,^^ Use of blood instead of bone marrow as a source of allogeneic stem cells may allow new approaches to cell manipulation because of the large numbers of cells that can be collected 8, 42* 43*53 This and the effectiveness of donor lymphocytes by aphere~is.~, in inducing remission has increased interest in protocols using selective T-cell depletion or stem cell selection or both, and in prophylactic T-cell infusions at various dose levels and time intervals after T-cell-depleted transplantation, with the goals of minimizing GVHD, reducing trans57 The issue of pretransplant plant mortality, and preventing re1ap~e.l~. treatment with interferon and use of interferon-response to make decisions about timing of transplantation also must be addressed. ACKNOWLEDGMENTS This work was supported by Public Health Service Grant Pol-CA-40053 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute, and Contract CP-21161 from the National Cancer Institute of the US Department of Health and Human Services; and grants from
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Activated Cell Therapy, Inc; Alpha Therapeutic Corporation; American Oncology Resources; Amgen, Inc; Anonymous; Astra Pharmaceutical; Baxter Healthcare Corporation; Bayer Corporation; Biogen; Blue Cross and Blue Shield Association; Lynde and Harry Bradley Foundation; Bristol-Myers Squibb Company; Frank G. Brotz Family Foundation; CellPro, Inc; Cell Therapeutics, Inc; Centeon; Center for Advanced Studies in Leukemia; Chimeric Therapies; Chiron Therapeutics; Cigna Healthcare; COBE BCT, Inc; Coram Healthcare; Coulter Corporation; Charles E. Culpeper Foundation; Eleanor Naylor Dana Charitable Trust; Deborah J. Dearholt Memorial Fund; Eppley Foundation for Research; Fujisawa USA; Genentech, Inc; Glaxo Wellcome Company; Hewlett-Packard Company; Hoechst Marion Roussel, Inc; ICN Pharmaceuticals; Immunex Corporation; Janssen Pharmaceutica; Kettering Family Foundation; Kirin Brewery Company; Robert J. Kleberg, Jr and Helen C. Kleberg Foundation; Herbert H. Kohl Chanties; Life Technologies, Inc; Eli Lilly Company Foundation; The Liposome Company; Nada and Herbert P. Mahler Charities; MDS Nordian; Medical SafeTEC; MGI Pharma, Inc; Milliman & Robertson, Inc; Milstein Family Foundation; Milwaukee Foundation/Elsa Schoeneich Research Fund; NCSG and Associates; NeXstar Pharmaceuticals, Inc; Samuel Roberts Noble Foundation; Northwestern Mutual Life Insurance Foundation; Novartis Pharmaceuticals; Ortho Biotech Corporation; John Oster Family Foundation; Elsa U. Pardee Foundation; Jane and Lloyd Pettit Foundation; Alirio Pfiffer Bone Marrow Transplant Support Association; Pfizer, Inc; Pharmacia and Upjohn; Principal Mutual Life Insurance Company; Quantum Health Resources; QLT PhotoTherapeutics; RGK Foundation; Roche Laboratories; Rockwell Automation Allen Bradley Company; RPR GenCell; SangStat Medical Corporation; Schering-Plough International; Walter Schroeder Foundation; Searle; SEQUUS Pharmaceuticals, Inc; Stackner Family Foundation; Starr Foundation; Joan and Jack Stein Charities; StemCell Technologies, Inc; SyStemix; Therakos; TS Scientific and Planer Products; Wyeth-Ayerst Laboratories; and Xoma Corporation.
References 1. Aschan J, Ringden 0, Sundberg 8, et al: Increased risk of relapse in patients with
chronic myelogenous leukemia given T-cell depleted marrow compared to methotrexate combined with cyclosporin or monotherapy for the prevention of graft-versus-host disease. Eur J Haematol 50:269, 1993 2. Ash RC, Horowitz MM, Gale RF, et al: Bone marrow transplantation from related donors other than HLA-identical siblings: Effect of T-cell depletion. Bone Marrow Transplant 7443,1991 3. Bach FH, Albertini RJ, Joo P, et al: Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome. Lancet 2:1364,1968 4. Bacigalupo A, Gualandi F, Van Lint MT, et al: Multivariate analysis of risk factors for survival and relapse in chronic granulocytic leukemia following allogeneic marrow transplantation: Impact of disease related variables (Sokal score). Bone Marrow Transplant 12:443, 1993 5. Beatty PG, Clift RA, Mickelson EM, et al: Marrow transplantation from related donors other than HLA-identical siblings. N Engl J Med 313:765, 1985 6. Beelen DW, Graeven U, Elmaagacli AH, et al: Prolonged administration of interferonalpha in patients with chronic-phase Philadelphia chromosomepositive chronic myelogenous leukemia before allogeneic bone marrow transplantation may adversely affect transplant outcome. Blood 852981, 1995 7. Bensinger WI, Weaver CH, Appelbaum FR, et al: Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor. Blood 85:1655, 1995 8. Bensinger WI, Buckner CD, Shannon-Dorcy K, et al: Transplantation of allogeneic CD34+ peripheral blood stem cells in patients with advanced hematologic malignancy. Blood 884132,1996 9. Bortin MM, Ringden 0, Horowitz MM, et al: Temporal relationships between the major complications of bone marrow transplantation for leukemia. Bone Marrow Transplant 4:339, 1989
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10. Bortin MM, Horowitz MM, Gale RE', et a1 Changing trends in bone marrow transplantation for leukemia in the 1980s. JAMA 268607, 1992 11. Champlin R Separation of graft-vs.-host disease and graft-vs.-leukemia effect against chronic myelogenous leukemia [editorial; comment]. Exp Hematol 23:1148, 1995 12. Champlin R, Ho W, Arenson E, et al: Allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic or accelerated phase. Blood 60:1038, 1982 13. Champlin RC, Jansen J, Ho W, et a1 Retention of graft-versus-host disease following bone marrow transplantation for chronic myelogenous leukemia. Transplant Proc 23:1695, 1991 14. Clift RA, Storb R Marrow transplantation for CML The Seattle experience. Bone Marrow Transplant 1751, 1996 15. Clift RA, Buckner CD, Thomas ED, et al: Treatment of chronic granulocytic leukemia in chronic phase by allogeneic marrow transplantation. Lancet 2621, 1982 16. Clift RA, Buckner CD, Appelbaum FR, et al: Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: A randomized trial of two irradiation regimens. Blood 771660, 1991 17. Clift RA, Buckner CD, Thomas ED, et al: Marrow transplantation for chronic myeloid leukemia: A randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood 842036, 1994 18. Collins RH Jr, Shpilberg 0, Drobyski WR, et al: Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation [see comments]. J Clin Oncol 15:433, 1997 19. De Konig J, Dooren LJ, Van Bekkum DW, et al: Transplantation of bone-marrow cells and fetal thymus in an infant with lymphopenic immunological deficiency. Lancet 1:1223, 1969 20. Devereie " A,. Blaise D. Attal M. et al: Alloeeneic bone marrow transulantation for chronic myeloid leukemia in first chronic Fhase: A randomized triai of busulfancytoxan versus cytoxan-total body irradiation as preparative regimen: A report from the French Society of Bone Marrow Graft (SEGM). Blood 85:2263, 1995 21. Drobyski WR, Keever CA, Roth MS, et a1 Salvage immunotherapy using donor leukocyte infusions as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation: Efficacy and toxicity of a defined T-cell dose. Blood 82:2310, 1993 22. Fefer A, Cheever MA, Greenberg PD, et al: Treatment of chronic granulocytic leukemia with chemoradiotherapy and transplantation of marrow from identical twins. N Engl J Med 306:63, 1982 23. Gale RP, Horowitz MM, Ash RC, et al: Identical-twin bone marrow transplants for leukemia. AM Intern Med 120646,1994 24. Gale RP, Hehlmann R, Zhang MJ, et al: Survival with bone marrow transplantation versus hydroxyurea or interferon for chronic myelogenous leukemia. Blood, in press 25. Gatti RA, Meuwissen HJ, Allen HD, et a1 Immunological reconstitution of sex-linked immunological deficiency. Lancet 2:1366, 1968 26. Giralt SA, Kantarjian HM, Talpaz M, et al: RE. Effect of prior interferon alfa therapy on the outcome of allogeneic bone marrow transplantation for chronic myelogenous leukemia. J Clin Oncol 11:1055, 1993 27. Goldman JM, Apperley JF, Jones L, et al: Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med 314:202, 1986 28. Goldman JM, Gale RP, Horowitz MM, et al: Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: Increased risk of relapse associated with Tcell depletion. AM Intern Med 108:806, 1988 29. Goldman JM, Szydlo R, Horowitz MM, et al: Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase. Blood 82:2235, 1993 30. Gratwohl A, Hermans J, von Biezen A, et al: No advantage for patients who receive splenic irradiation before bone marrow transplantation for chronic myeloid leukaemia: Results of a prospective randomized study. Bone Marrow Transplant 10:147, 1992 31. Gratwohl A, Hermans J, Biezen AV, et al: Splenic irradiation before bone marrow transplantation for chronic myeloid leukemia: Update of a prospective randomized study. Leuk Lymphoma ll(supp1 1):227, 1993 32. Gratwohl A, Hermans J, Apperley J, et al: Acute graft-versus-host disease: Grade and
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