Conditioning regimens for allogeneic bone marrow transplantation

E.A.

Copelan -

SUMMA R Y. Conditioning regimens for transplantation are important in determining transplant outcome. This review focuses on transplantation in aplastic anemia and leukemia using marrow from HLA-identical siblings. Results of conditioning with newer regimens such as busulfan plus cyclophosphamide and etoposide plus total body irradiation are reviewed and compared to results achieved with cyclophosphamide and total body irradiation. The potential for improved results using recent innovations such as dose adjustment of busulfan, agents which may decrease transplant-related toxicity, and directed radiation are discussed.

Conditioning regimens for allogeneic bone marrow transplantation must adequately immunosuppress the recipient to prevent rejection of donor marrow cells, must destroy malignant or otherwise defective hematopoietic progenitor cells along with normal hematopoietic progenitors, and should cause minimal toxicity. This review summarizes the extent to which commonly utilized conditioning regimens fulfill these aims and addresses potential directions for future clinical studies.

Total Body Irradiation (TBI) Based on extensive experience in animal models,‘-3 total body irradiation (TBI) alone was initially utilized by the Seattle group to condition patients with aplastic anemia and endstage leukemia for allogeneic bone marrow transplantation. TBI is the most effective single agent for conditioning patients with leukemia for allogeneic marrow grafts. Animal studies have demonstrated engraftment of infused marrow Department of Internal Medicine and the Arthur G. James Cancer Hospital and Research Institute of The Ohio State University, Columbus, Ohio, USA. Correspondence address: Edward A. Copelan, MD, The Ohio State University Hospitals, 410 W. 10th Avenue, Room 303 East Doan Hall, Columbus, OH 43210, USA. Blood Review (1992) 6. 234-242 0 1992 Longman Croup UK Lid

in irradiated but not shielded body parts indicating that irradiation eradicates normal recipient stem cells which can compromise or prevent engraftment4 TBI is sufficiently immunosuppressive to permit engraftment of histocompatible allogeneic donors, is an effective anti-leukemic agent, and reaches sites such as the central nervous system where drugs may not achieve high concentrations. Thomas and colleagues used opposing 6oC0 sources in order to achieve relatively homogenous TBI. Consistent engraftment required a single exposure of 10 GY.~ A single exposure followed shortly thereafter by the marrow graft minimizes the duration of neutropenia and thrombocytopenia, an important strategy in patients whose clinical condition is compromised by advanced leukemia. TBI alone, however, did not exert sufficient anti-leukemic effect to eradicate leukemia in patients with advanced disease.

Cyclophosphamide

(Cy) Plus TBI

Thomas and colleagues combined 1000 rads TBI and 120 mg/kg Cy, sometimes with other agents, and demonstrated sustained leukemia-free survival in 13 of 100 patients6 with endstage leukemia. The Seattle group later showed, utilizing Cy and TBI as conditioning, that the cure rate in acute myelogenous

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leukemia (AML) could be increased to approximately 50% by performing transplantation in first remission.7 Because patients in first remission were in better condition than were patients with advanced disease, fractionation of irradiation over several days was explored in a randomized study. Patients who received 2 Gy per day for 6 consecutive days had a better outcome than patients who received 10 Gy in a single exposure. * Memorial Sloan Kettering Cancer Center has reported a lower incidence of interstitial pneumonia and of relapsed acute leukemia using a hyperfractionated regimen of small fractions of irradiation three times a day over a 4-day period compared to a single dose regimen utilized previously.’ While TBI has remained the mainstay of conditioning for leukemia at most institutions a variety of different radiation regimens have been given, often dependent on the availability of radiation facilities. No radiation regimen has been clearly demonstrated to be superior, however, comparison of different approaches has been difficult because of the multitude of confounding variables. Results using Cy/TBI have been widely reported for patients with leukemia. Using Cy plus TBI in patients younger than 40 years old in first complete remission from AML who receive HLA-identical marrow grafts from siblings, the actuarial diseasefree survival exceeds 50% and has been reported to be as high as 70%. lo-l3 Patients treated in second remission or untreated first relapse experience approximately a 30% leukemia-free survival at 5 years. Patients beyond second remission or with refractory disease have a low rate of disease-free survival. In patients conditioned with Cy/TBI, the relapse rate for patients undergoing transplantation in first remission is approximately 20% and is substantially higher in patients with more advanced disease, exceeding 60% in those transplanted in second or subsequent relapse. In patients in chronic phase of chronic myelogenous leukemia (CML) undergoing allogeneic BMT following Cy/TBI. 50-60% of patients achieve sustained leukemia-free survival.“*‘4~‘5 The proportion of disease-free survivors is increased to roughly 70% if transplantation is performed within I year of diagnosis. l6 Relapse occ urs in 15-25%. Roughly 35% and 10% of patients in accelerated or blastic phases respectively, are disease-free survivors following allogeneic marrow transplantation using Cy and TBI. For patients with acute lymphoblastic leukemia (ALL) transplanted in second and subsequent remission using Cy/TBI conditioning, roughly 20- 25% survive free of leukemia at 5 years.” Their relapse rate approaches 50%. Patients transplanted in first CR experience a 40-45% leukemia free survival,‘7~‘8 however, age and risk factors for relapse are crucial in determining the proportion of patients achieving sustained disease-free survival. Cy/TBI has also been utilized as conditioning for allogeneic trans-

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plantation with non-Hodgkin lymphoma, Hodgkin disease and multiple myeloma. Cy/TBI is exceptionally immunosuppressive and has been extensively utilized in mismatched and matched unrelated transplants where, compared to HLA-identical sibling additional immunosuppression is transplants, required.

Toxicit?, Allogeneic bone marrow transplantation is associated with a multitude of complications including many which may be life-threatening. Infection, bleeding and GVHD occur commonly and their incidence and severity are effected by the preparative regimen utilized.‘s*19 Other complications following transplantation are clearly regimen-related and include cardiac, bladder, renal, pulmonary, hepatic, central nervous system and gastrointestinal toxicities.” A review of 547 patients transplanted for aplastic anemia detected a 17% incidence of interstitial pneumonia, 37% associated with cytomegalovirus infection. The case of TBI in the fatality rate was 64%. ‘i Inclusion pretransplant regimen was a significant risk factor for the development of interstitial pneumonia. Hepatic veno-occlusive disease occurs commonly following Cy/TBI and is the cause of death in about 3% of patients.22 Higher doses of irradiation are associated with lower relapse rates but greater toxicity. For example, the Seattle group conducted randomized studies in AML in first remission23 and CML in chronic phase15 in which patients were randomized to receive Cy 120 mg/kg in combination with either 2 Gy per day on each of 6 consecutive days or 2.25 Gy per day for 7 days, i.e. total doses of 12 Gy versus 15.75 Gy. In each trial, patients who received higher irradiation doses had a substantially lower incidence of recurrent leukemia but a higher incidence of death from transplant-related complications. Patients who received 15.75 Gy TBI had higher incidences of interstitial pneumonia, hepatic VOD, renal failure, and mucositis than did patients receiving 12 Gy TBI.15.20*23

DeIayed Complications No clear relationship exists between the preparative regimen and the development of chronic GVHD. The preparative regimen, however, does contribute to the development of a variety of other delayed problems including chronic pulmonary disease, neuroendocrine problems, impaired growth and development, infertility, cataracts, and secondary malignancies.24 Chronic lung disease occurs in more than 10% of patients following preparation with Cy plus TBI. A progressive fall in diffusing capacity occurs commonly.25 Endocrine function is severely effected by TBI. Fractionated TBI results in hypothyroidism in 15525% of patients and single dose TBI in up to 50% of patients. 26,27 Roughly one-half of children

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given TBI demonstrate deficient production of growth hormone; nearly all children who also received prior cranial radiation are deficient.28 Deficiency of growth hormone combined with a direct effect of radiation on bones impairs growth. TBI leads to delayed menarche in girls and failure to produce sperm in boys.24*27 Primary gonadal failure nearly always results from TBI; only rarely do women recover ovarian function and most men never recover sperm production following transplantation. Cataracts occur in about 80% of patients given single dose TBI but in less than 50% given fractionated TBI.2g Lastly, patients prepared with TBI develop second malignancies at roughly six times the rate as a control population.24~30 Thus delayed complications following conditioning with Cy/TBI are substantial and appear to be primarily related to TBI. High Dose Cytosine Arabinoside

and TBI

Because Cy is not generally felt to be an effective antileukemic agent and because TBI is a potent immunosuppressive agent, drugs with greater antileukemic activity have been substituted for Cy. Mixed results have been achieved using high dose cytosine arabinoside in combination with TBI. High dose cytarabine together with fractionated TBI was reported to achieve excellent results in children with ALL,31 however, other studies have reported results similar to those achieved with CY/TBI.~~~~~ Due primarily to increased toxicity, the combination of cytarabine and TBI has not improved results in AML.34 Melphalan

Plus TBI

In a randomized study, patients with AML in first remission receiving melphalan 110 mg/m* in combination with TBI experienced lower relapse rates than patients receiving Cy 120 mg/m2 plus TBI. Transplant-related deaths, however, were more frequent in the melphalan group and actuarial leukemia-free survival rates were similar.35 Etoposide Plus TBI

Blume reported the results of a phase I/II study in which TBI was administered in 11 fractions of 120 cGy over 4 days (total dose 1320 cGy) followed by infusion of etoposide. Engraftment occurred consistently in HLA-identical sibling transplants. Mucositis and hepatic dysfunction were dose limiting. The maximum tolerated dose of etoposide was 60 mg/kg and 43% (95% confidence interval ) 18%) of patients with advanced acute leukemia achieved sustained disease-free survival. The relapse rate was 32% (95% confidence interval k20%).36 A Phase II trial of 69 patients with hematologic malignancy treated with 60 mg/kg etoposide plus TBI demonstrates a 65%

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disease-free survival at 3 years. Three of 28 patients with AML in first remission relapsed and no patients with ALL in first remission relapsed.37 Additional studies in patients with hematologic malignancies also indicate that the combination of TBI and etoposide is an effective preparative regimen and suggest a greater antitumor effect than with Cy/TBI in standard doses.38 The vast majority of patients conditioned with etoposide and TBI received CsA and steroids for GVHD prevention. Long-term data with CsA and steroids following other conditioning regimens suggest that it is no better and perhaps worse than CsA and methotrexate in terms of long-term diseasefree survival, largely related to increased fungal infections3g*40 and that it may be associated with an increased incidence of chronic GVHD.41 The addition of Cy to etoposide and TB14* may increase toxicities without substantially improving anti-leukemic effectiveness. Etoposide, like cytarabine and melphelan, has been shown to exert less immunosuppressive potency than Cy43 and its substitution for Cy appears to increase the risk of graft rejection in HLA-mismatched and/or T-cell depleted marrow transplantation.38 Toxicity Although data is limited, following etoposide 60 mg/kg and TBI there appears to be more severe mucositis and less hemorrhagic cystitis than with Cy/ TBI. Interstitial pneumonia was relatively frequent in the phase I/II study; 13 patients died of respiratory failure due to interstitial pneumonia. Follow-up is insufficient to analyze delayed effects. Cyclophosphamide

Santos and colleagues at Johns Hopkins initially conditioned patients with advanced leukemia undergoing allogeneic marrow transplantation with Cy 60 mg/kg on each of 4 consecutive days.44 This dose was lowered to 50 mg/kg/day in an attempt to decrease the incidence of fatal cardiac toxicity which proved dose-limiting in animals and in humans.45 Although this regimen was sufficiently immunosuppressive to consistently permit engraftment of HLA-identical donors, its anti-leukemic effect proved inadequate. In contrast to patients with leukemia where eradication of malignant and normal hematopoietic cells is important, in patients with aplastic anemia the chief role of the conditioning regimen is to provide sufficient immunosuppression to prevent graft rejection. Histocompatibility differences between the donor and recipient, sensitization of the recipient by prior transfusions of blood products, and the dose of donor cells in part determine the degree of immunosuppression required.46 Storb et al utilized Cy 200 mg/kg for the treatment of patients with aplastic anemia. Actuarial survival was approximately

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55% for a group of patients with aplastic anemia conditioned with Cy which was superior to that of another group of patients prepared with 1000 rads immunoof TBI.47 C y 200 mg/kg is adequately suppressive to permit engraftment in 90% of untransfused patients with aplastic anemia receiving HLAidentical sibling marrow. Sustained survival in these untransfused patients exceeds 80°h.46.48 In patients who have received transfusions, sensitization of the recipient increases the likelihood of graft failure. In previously transfused patients prepared for marrow transplantation with Cy 200 mg/kg, 35% reject their grafts and less than 50% of patients survive 3 years. The addition of thoracoabdominal radiation4’ or total lymphoid irradiation50 to Cy reduces graft failure in these patients to less than 5%, however, transplant related complications, including graftversus-host disease (GVHD) and interstitial pneumonia, occur at an increased rate. Survival exceeds 60%.

Hepatic VOD, interstitial pneumonia and most other complications of transplantation occur less frequently when Cy alone is used for conditioning than when it is combined with irradiation.

In contrast to patients conditioned with TBI, no fall in diffusing capacity follows transplantation using Cy alone as conditioning. 25 Thyroid function, longitudinal growth and sexual development are generally normal following conditioning with Cy alone. Many women recover ovarian function and bear normal children; male fertility is generally normal. Cataracts occur in approximately 20% of patients conditioned with Cy. Second malignancies develop substantially less frequently than in patients receiving TBI.24*30

CY Plus ATG In 18 patients with graft failure following transplantation with Cy alone, the Seattle group was able to achieve sustained engraftment in 15 and sustained survival in 11 following conditioning with Cy plus antithymocyte globulin. 51 Engraftment has occurred in 19 consecutive patients undergoing initial bone marrow transplantation using this regimen. Improved supportive care, e.g., the use of methotrexate and cyclosporine in combination for the prevention of acute GVHD has also contributed to improved results in aplastic anemia. Acute GVHD is a significant adverse occurrence in aplastic anemia. More than 85% of patients who do not develop grade >2 or greater acute GVHD will be long-term survivors compared with less than 45% who develop GVHD 2 grade 2.51 Transplants from donors other than HLA-matched

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siblings are associated with a higher risk of graft failure and GVHD and consequently with poorer survival. These patients require more intense immunosuppression, Most commonly Cy plus TBI is utilized, however. the optimal preparative regimen has not been determined.

BuCy Recent investigations at many institutions have explored the use of non-radiation containing regimens in hematologic malignancies. Since Cy is in itself an effective immunosuppressive agent, the immunosuppressive effect of TBI in conjunction with Cy is not required. Although TBI is an effective antileukemic agent, it is clear from several studies that when the TBI dose is raised to levels which result in very low relapse rates, a trade off in toxicity occurs. At less toxic levels of TBI, relapse incidence is higher. Based on animal studies,52.53 Santos added busulfan to 200 mg/kg of Cy in the hope that leukemic recurrence would be diminished and the rate and quality of engraftment improved. Studies in mice, rats and non-human primates had demonstrated that busulfan and dimethylbusulfan were effective in the eradication of recipient stem cells.52~54 Dose finding studies of busulfan in combination with 200 mg/kg of Cy identified mucositis and hepatic toxicity as dose limiting.4’ Subsequently 16 mg/kg busulfan was used in combination with 200 mg/kg of Cy over 4 days (‘Big BuCy’). 55 Coupled with improvements in supportive care including the use of CsA for GVHD prophylaxis, this regimen has resulted in leukemiafree survival of more than 60% of patients in first remission of AML.56 A lower Cy dose of 120 mg/kg given over 2 days in combination with 16 mg/kg busulfan (‘little BuCy’) also led to consistent engraftment 57 in HLA-identical sibling transplants; only 3 of 281 patients (1%) with AML, ALL or CML failed to engraft.41.58,59 Studies of marrow and peripheral blood cytogenetics and DNA RFLP demonstrate that the incidence of mixed chimerism with little BuCy is similar to that experienced with Cy/ TBI.s7.60 In patients with AML in first remission, disease-free survival of roughly 60% has been achieved with relapse frequency < 20°~.58~“’ Diseasefree survival and relapse rates in early and advanced AML have been roughly similar in most studies of little or big BuCy to that reported with Cy/TBI. However, in the only randomized study of little BuCy versus Cy/TBI in patients with AML in first remission 15 French transplant centers reported that patients receiving BuCy had a significantly higher incidence of relapse and a lower survival.r3 Little BuCy has been extensively utilized in CML. A multi-institutional study of 115 patients demonstrated a 58 + 12% leukemia-free survival for chronic phase CML patients, 41+22% for accelerated phase patients and 25_+ 19% for patients in blastic transformation with relapse rates of 3 ) I%, 12 f 6% and

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27 + 17% for the three groups respectively.5g Only one hematologic relapse occurred in the chronic phase patients. Similar to results obtained with Cy/TBI, chronic phase patients transplanted within 1 year of diagnosis had a probability of leukemia-free survival of 70%. These results have also been supported by studies at other institutions‘j’ Ongoing randomized studies at Seattle and at 19 French transplant centers suggest similar leukemia-free survivals in both Cy/ TBI and little BuCy groups.63 The French study demonstrated 6 patients in the BuCy group who failed to engraft, a substantially higher incidence than in other studies. This group used real body weight for dosing. Dosing of busulfan as well as Cy has varied from institution to institution. Dosing has been based on ideal body weight derived from a variety of techniques, real body weight, or body surface area. At different institutions, a 60 kg man whose ideal body weight is 75 kg might receive ‘little BuCy’ at substantially different doses. Whether differences in dosing account for the high relapse rate in AML and high rejection rate in CML seen by the French group is not clear. Big BuCy and little BuCy have also been used in children64 and adults41 with ALL, and in multiple myeloma65, Hodgki@j and non-Hodgkin lymphoma67 with roughly similar results to those obtained with Cy/TBI. Toxicity Compared to patients conditioned with Cy/TBI, the incidence of hepatic VOD or other hepatic dysfunction appears to be higher in patients receiving BuCY,~‘,~’ especially in those receiving methotrexate for prevention of GVHD.3g The incidence of interstitial pneumonia appears to be 1ower,68*6gparticularly in patients who have previously received mediastinal irradiation. 7o Severe stomatitis is less frequent. Hemorrhagic cystitis occurs roughly twice as frequently. In addition, seizures occur in roughly 10% of patients given busulfan, although this incidence can be markedly reduced by adequate phenytoin prophylaxis. 71 Most institutions using BuCy have noted similar transplant-related mortality to that seen with Cy/TBI. New approaches may improve the safety of busulfan. The establishment of sensitive assays for busulfan led to the demonstration that patients with an area under the curve exceeding 1 standard deviation above the mean develop hepatic VOD at a significantly increased frequency. 72 Dose adjustment based on plasma levels following the first dose may lessen toxicity. In addition the application of drugs, e.g. corticosteroids and ciprofloxacin, pentoxyfylline, which reduce the peritransplant production of tumor necrosis factor alpha, may decrease the severity of hepatic and other complications following transplantation.73*74 While this approach appears effective in radiation containing or radiation-free regimens, the high incidence of hepatic problems following busulfan

may make this approach especially useful in conjunction with BuCy. Delayed Complications The generic grouping of radiation-free conditioning regimens has led to the unsubstantiated generalization that patients who do not receive radiation experience a marked decrease in frequency and severity of delayed complications. While this is true for patients conditioned with Cy alone, it is not yet clear whether BuCy is associated with a substantial improvement in delayed complications. Chronic obstructive and restrictive pulmonary disease occurs following BuCy as well as TBI containing regimens. The fall in diffusing capacity following transplantation may be less in patients receiving BuCy than in those receiving TBI.25 Growth impairment in children given BuCy appears similar to that following Cy/TBI. 75 Aspermia occurs in most men following BuCy, although recovery appears to occur sooner (sometimes within 2 years) and more frequently than following TBI.76 Busulfan causes cataracts as does TBI. The frequency of cataracts appears roughly similar to that following fractionated TBI. Animal studies suggest that busulfan does not increase the likelihood of developing a second malignancy to the same extent as TBI. 24 Thus current data suggests that some delayed complications may be less frequent or less severe with busulfan compared to TBI, however, additional follow-up of patients conditioned with busulfan is needed. BuCy Plus Etoposide To increase effectiveness, etoposide has been added to little BuCy at several centers. Spitzer et al reported in combination with 16 mg/kg busulfan and 120 mg/kg Cy a maximum tolerated dose of 30 mg/kg etoposide, half the maximum tolerated dose that could be utilized in combination with TBI and CY.~’ Vaughan reported 24 patients with advanced AML, ALL, CML or lymphoma who underwent marrow transplantation following little BuCy plus 60 mg/kg etoposide.78 These patients received GVHD prophylaxis with CsA alone or CsA and prednisone. While 11 patients (46%) died of transplant-related complication, the estimated incidence of relapse was only 20% and of disease-free survival was 40% at 60 weeks, which appeared to be better than that in similar patients prepared with TBI containing regimens during that time period. BuCy Plus ARA-C Ratanatharathorn et al utilized 16 mg/kg busulfan followed by 4 doses of cytarabine 2 g/m’ every 12 h then Cy 60 mg/kg twice daily in 21 patients with advanced AML, CML, or myelodysplastic syndrome.7g 10 patients died of transplant-related causes

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including 2 from hepatic VOD and 4 from respiratory failure. Mucositis, diarrhea and hepatic dysfunction were common reversible toxicities. The projected relapse rate was 5% and estimated disease-free survival was 52% with a median follow-up of 18 months. Geller et al conducted a phase II trial of busulfan/ Cy followed by continuous infusion of cytarabine. Adult respiratory distress syndrome was dose-limiting in a phase I trial.80

BuCy Plus TBI A phase I trial designed to determine the maximum tolerated doses of busulfan and Cy following 200 cGy TBI for 6 consecutive days, concluded that a regimen of 7 mg/kg/day busulfan and 50 mg/kg Cy could be safely combined with radiation. Hepatic VOD and interstitial pneumonia were dose limiting toxicities81 Results did not appear to be improved over Cy/TBI.

CBV Cy 1.5 gm/m’ per day on days l-4, carmustine 300 mg/m’ on day 1 and etoposide 100 mg/m’ every 12 h for 6 doses have been used in patients with acute leukemia.82 Direct evidence of engraftment was present in all but 1 of 22 patients with a distinguishable marker. Higher doses of these drugs have been utilized in autologous and allogeneic transplantations of patients with advanced lymphoid malignancy, however, transplant related mortality has been substantial. The administration of pentoxyfylline appears to reduce the toxicity of this regimen and might improve results.83

Directed Irradiation Directed irradiation of malignant cells with limited exposure of extramedullary organs, e.g. liver and lung, could permit effective therapy with minimal extramedullary toxicity. Evidence is accumulating that radiolabeled antibodies84 or bone-seeking radioisotopes can be utilized effectively. Their use in combination with chemotherapy conditioning regimens is a logical and promising approach which is in a very early stage of investigation.

T-Cell Depleted Transplantation This review has focused primarily on transplantation in aplastic anemia and leukemia using nonmanipulated marrow from HLA-identical siblings. Compared to HLA-identical sibling transplants, transplantation from mismatched or matched unrelated donors or with T-cell depleted marrow is associated with a higher risk of graft failure. For example, it appears that standard Cy/TBI results in a lower rate of graft failure in matched unrelated transplants than little BuCy (J. Gajewski; personal communication).

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A major limitation of T-cell depleted transplants has been a high incidence of graft failure. Kernan et al have implicated host T-cells with donor specific cytotoxic or cytoinhibitory activity.85 Enhanced cytoreduction and immunosuppression are needed for durable hematopoietic reconstitution. Higher doses of radiation, i.e. 1500 rads of hyperfractionated TBI, in conjunction with 120 mg/kg Cy and thiotepa 10 mg/kg appears to lower the incidence of graft failure.86 Alternatively, a total of 1375 rads hyperfractionated radiation with etoposide 1 g/m’, Cy 120 mg/ mz and ATG in T-cell depleted transplants using matched unrelated donors results in a low incidence of graft failure. 87 Although only limited data has been accumulated, regimens, e.g. little BuCy or TBI/ etoposide, are probably not adequate for transplantation of T-cell depleted marrow.

Summary The preparative regimen plays an important role in eradicating disease and in determining the incidence and severity of acute and delayed complications of transplantation. In aplastic anemia where immunosuppression and not eradication of hematopoietic cells is crucial, the least toxic regimen which consistently results in engraftment, namely Cy plus ATG, appears optimal. In patients with mismatched or unrelated donors, additional immunosuppression with irradiation appears necessary. In patients with lymphohematopoietic malignancies undergoing allogeneic BMT, eradication of the malignant cells is the most difficult obstacle. Standard Cy/TBI is associated with high recurrence rates, particularly in patients with advanced disease. Raising the dose of TBI or the addition of other agents lowers relapse rates at the cost of increased toxicity. The combination of TBI and etoposide does appear to exert a more potent effect on leukemic cells than Cy/TBI. This regimen has generally been utilized with CsA/corticosteroids. If transplant-related toxicity could be lessened by agents, e.g., pentoxifylline, the use of CsA and methotrexate might improve results further. With the possible exception of patients with CML, substitution of busulfan for TBI does not appear to improve leukemia-free survival, although ease of administration and probable improvement of delayed complications are advantages of this approach. The addition of cytarabine or etoposide to BuCy, especially in concert with dose adjustment of busulfan based on plasma levels and perhaps with agents to decrease transplantrelated toxicity, may improve results. The trend for more intense regimens to be associated with better anti-leukemic effectiveness but greater toxicity would appear to limit the degree to which modification of present preparative regimens will improve antileukemic effectiveness. Conditioning with chemotherapy together with selective radiation exposure is a promising new strategy. Well-designed clinical studies are needed to define the appropriate conditioning

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regimen for specific patients and to investigate innovative approaches. 19.

Acknowledgement Supported of Health,

in part by grant DHHS.

20. CA 16058 from the National

Institutes

21.

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