Myeloablative conditioning regimens for allogeneic stem cell transplantation

Myeloablative conditioning regimens for allogeneic stem cell transplantation

CHAPTER 27

James A Russell

Agents used in myeloablative combinations Most of the more widely employed agents have in common the feature that hematologic toxicity is dose limiting when they are given without stem cell support. In addition, cytotoxic activity is dose dependent, thus achieving more tumor cell killing with increasing doses. The most commonly used have hitherto been TBI, cyclophosphamide, busulfan, and VP16 (etoposide). These agents share acute toxicities, in part related to their inherent cytotoxic activity. Short-term complications include nausea and vomiting, mucositis (particularly stomatitis and enteritis), hair loss and the sequelae of bone marrow suppression. Other side-effects are more agent specific (Table 27.1).

Total-body irradiation (TBI) Total-body irradiation is a powerful immunosuppressant and cytotoxic agent and has been a component of some of the most widely used regimens since the early days of transplantation. The potential to penetrate sanctuary sites such as the central nervous system (CNS) may give TBI an advantage over some drugs. Radiation is delivered from a linear accelerator or a cobalt source used for routine cancer treatments. These machines need to be adapted to deliver TBI; such adaptation requires the patient to be sufficiently far from the source to allow the whole body to be included in a single field. The effect of TBI depends largely on the dose rate, the total dose delivered and the number of fractions into which the total dose is divided.2–6 Some earlier protocols involved delivering about 1000 cGy in a single fraction at a low dose rate. This required several hours to

3 PREPARATION FOR TRANSPLANT

Selection of the conditioning or preparative treatment given before allogeneic stem cell transplantation depends on a number of factors including the disease being treated, the donor and the stem cell product to be given. Historically, it was believed that the regimen needed to be sufficiently immunosuppressive to prevent graft rejection and that it needed, in some circumstances, to provide ‘space’ in the recipient bone marrow. Finally, in the case of malignant disease, it should exert a profound cytotoxic effect on the cancer cells. In a condition such as severe aplastic anemia (SAA) immunosuppression is paramount. In other non-malignant diseases this would need to be accompanied by the ability to provide space in bone marrows with normal or increased cellularity. A transplant for malignancy could be seen essentially as a ‘rescue’ procedure allowing dose escalation of cytotoxic agents whose primary dose-limiting toxicity is on the bone marrow. In general, agents given in such doses would also achieve the immunosuppression required for engraftment, particularly in patients who had previously been exposed to cytotoxic therapy. We now know that agents selected primarily for their immunosuppressive qualities, particularly if given with the high doses of progenitor cells which can be collected from peripheral blood, are capable of producing durable engraftment without myeloablation. For practical purposes, a myeloablative regimen could be seen as one which, when used for malignant disease, is given with the intent of achieving maximal tumor cell kill by the cytotoxic agents. For non-malignant disease, where regimens with myeloablative potential have traditionally been used, our understanding of the relative contributions of immunosuppression and creation of space in the recipient marrow is evolving and it could be that newer agents such as fludarabine may contribute to durable engraftment without myeloablation. However, non-malignant diseases for which regimens thought to be myeloablative have traditionally been used will be considered briefly in this chapter. When given with stem cell rescue, the ability to escalate doses of agents used in myeloablative regimens is limited by their toxicity to organs and tissues other than the bone marrow. With unmanipulated (not T-depleted or CD34+ cell selected) transplants a major, if not the predominant, contribution to morbidity and mortality is that from graft-versus-host disease (GvHD). There is increasing evidence that dose escalation of cytotoxic agents may, in fact, increase mortality by a synergistic effect with acute GvHD, in particular perhaps by increasing cytokine release from tissue damage.1 Improved GvHD prophylaxis may therefore be necessary for the high transplant-related mortality (TRM) historically associated with myeloablative regimens to be significantly reduced. The aim of the myeloablative regimen in

malignancy is to achieve the maximum possible antitumor effect while limiting toxicity (either ‘regimen related’ or from GvHD). In practice, the relative contributions of graft-versus-malignancy (GvM) and dose escalation may be difficult to determine in view of the complex interaction described above between GvHD, regimen-related toxicity, GvM, the direct tumor kill of cytotoxic agents and the diseases being treated. Particularly in view of the increase in popularity of non-myeloablative regimens, it is important to emphasize that there is substantial evidence for the value of dose intensity at least in some malignancies. The first, of course, is the success of autologous transplants which depend solely on the principle of dose escalation. Secondly, there is evidence that relapse after allotransplant may be reduced by higher doses of cytotoxic agents such as total-body irradiation (TBI) for some diseases.2 In this case, however, it is difficult to be absolutely sure how much this effect is due to a direct cytotoxic effect and how much to an impact on GvHD as described above.

PART

Introduction

Table 27.1 Cytotoxic agents in myeloablative conditioning protocols

280

Agent

PART

Approximate upper limit of total dose#

Common scheduling

Total-body irradiation

1400–1500 cGy

Cyclophosphamide

200 mg/kg

Busulfan po

16 mg/kg

Organ-specific toxicity* Short term (<3 mo)

Long term (>3 mo)

6–12 fractions over 3–4 days

Parotitis Skin erythema Xerostomia Interstitial pneumonitis

Cataracts Xerostomia Hypothyroidism Growth arrest Gonadal failure Delayed puberty Dental decay Second malignancies

5 92 93 93 94,96 95 90 8,97

Over 2–4 days

Cardiac failure Hemorrhagic cystitis

Cardiac failure

98,99

4 days

Veno-occlusive disease Hemorrhagic cystitis Convulsions Skin erythema and pigmentation

Alopecia

3

30,100 26

Busulfan iv

12.8 mg/kg or 520 mg/m

Once to 4 times daily over 4 days

VP-16

60 mg/kg

Single dose

Hypotension Hepatotoxicity Hand-foot syndrome

101

Fludarabine

240–250 mg/m2

iv over 4–6 days

Neurotoxicity

102

2

Melphalan

200–220 mg/m

Single dose

Ara-C

36 g/m2

Up to q12h over 6 days

Cerebellar toxicity Skin rash Renal Hepatic

2

Thiotepa

600 mg/m

Single dose

Treosulfan

47 mg/m2

Single dose

103 Cerebellar toxicity

102 104

105

# Upper limit will vary according to other components of regimen. * Some effects are common to more than one agent.

administer and was inconvenient because of the time involved and the fact that patients would often vomit and be otherwise uncomfortable during the procedure. Subsequent refinements resulted in TBI being given at a somewhat higher dose rate, in multiple fractions, which appears to improve tolerability while maintaining the antitumor effect. Thus, some long-term effects such as cataracts and thyroid dysfunction seem to be less after fractionated schedules.7,8 Dose escalation above about 1500 cGy has increased TRM with or without a compensatory effect on relapse.9,10 Single doses as low as 500 cGy delivered at a high dose rate have been remarkably effective but no direct comparisons with fractionated schedules have been performed.11 While dose and dose rate are closely monitored, the details of delivery vary in different institutions. Moreover, there may be changes over time in TBI dose rates when delivered from a cobalt source.

Cyclophosphamide Cyclophosphamide is an alkylating agent which was originally used alone as conditioning for SAA in view of its powerful immunosuppressant effects. Cyclophosphamide is not strictly speaking a myeloablative agent, as primitive stem cells appear to lack the enzyme pathway necessary for activation. Cardiotoxicity is the main adverse effect limiting dose escalation. Cyclophosphamide metabolism is very variable, and high concentrations of metabolites are related to liver injury including veno-occlusive disease (VOD) or sinusoidal obstruction syndrome.12 High doses should be administered with hydration and/or Mesna in order to minimize hemorrhagic cystitis.

Busulfan Busulfan is an alkylating agent originally given qid by mouth, generally with cyclophosphamide in the so-called BuCy regimens.13–15 Pharmacokinetic studies revealed very wide variations in exposure because

Therapeutic window Graft failure

GvHD

Disease progression

Organ toxicity

% patients

PREPARATION FOR TRANSPLANT

2

References to toxicity

Increasing drug exposure Figure 27.1 Relationship of exposure to clinical effects for a chemotherapeutic agent such as busulfan.

many patients vomited the drug, replacement was haphazard and intestinal absorption was very variable. In some diseases low drug exposures predisposed to failed engraftment and relapse whereas toxic effects, including VOD, were more common at high levels (Fig. 27.1).16–20 Optimal therapeutic ranges have been established for oral busulfan.20,21 Exposures within the desired range appeared to produce better outcomes in myeloid malignancy, leading to a recommendation of therapeutic drug monitoring (TDM) for oral busulfan. An iv form is now available which, when given qid, gives more patients exposures in ranges considered optimal for oral busulfan and better outcomes within these ranges.22,23 Intravenous busulfan given 12 hourly or once daily in myeloablative doses appears effective and well tolerated although no direct

provide a regimen with relatively low TRM.24,26 The combination appears to be effective at least in AML and myelodysplasia (MDS).24 Concerns that combining two potentially neurotoxic agents at high doses could result in unacceptable neurologic sequelae have not been substantiated. Combinations of three or more of the above agents have been devised in order to provide more broadly based regimens combining cytotoxicity with the sparing of overlapping non-hematologic toxicity.18,38,39 Additional drugs have been combined with each other and/or one or more of the above in myeloablative regimens. These include thiotepa,40–43 treosulfan,44 melphalan,45–49 BCNU50 and Ara-C.51–53 However, in general the superiority of other combinations has been difficult to demonstrate; indeed, some studies have indicated worse results largely due to increased toxicity.53–55

VP16 (etoposide) VP16 (etoposide) is widely used in autotransplant regimens and may be more effective therapy for some leukemias than cyclophosphamide. Formerly given as a prolonged infusion at low concentration, it is now usually given in concentrated form as a short iv infusion.

Fludarabine This purine analog is increasingly used because it is a powerful immunosuppressant, is effective in leukemias and is less toxic than cyclophosphamide. Total doses in current regimens have not exceeded 240–250 mg/m2 because of concern regarding neurotoxicity at higher exposures.

Common myeloablative conditioning regimens The above agents have been combined in a variety of myeloablative regimens. In some cases dose-finding studies have determined the upper limit of one or more or of the constituents. As with combination chemotherapy in general, the intent is to maximize the dose of the individual constituents while trying to avoid overlapping nonhematologic toxicity. The cyclophosphamide and TBI (CyTBI) combination has the longest track record of any regimen for hematologic malignancy and perhaps remains the ‘gold standard’ against which others must be judged. Busulfan was substituted for TBI in myeloablative regimens in order to avoid some of the toxicities of TBI and to develop drug-based protocols which could be used by centers without TBI facilities. Busulfan was originally given po at 1 mg/kg qid for 4 days, with cyclophosphamide at 200 mg/kg over 4 days (BuCy4). While effective, this regimen was quite toxic and reducing the cyclophosphamide dose to 120 mg/kg over 2 days (BuCy2) improved the tolerability of the combination.14,15 The major concern was a relatively high incidence of VOD which reached 50% in some centers.28,29 Larger multicenter studies indicate a figure more in the order of 10%.30 However, VOD is often fatal and attempts to prevent it have not been uniformly successful. The clearance of cyclophosphamide is decreased if given shortly after the last dose of busulfan so attention should be paid to the details of scheduling.31 In the BuCy2 combination iv busulfan is associated with less toxicity and early TRM than the oral form.22, 32,33 The combination of VP16 and TBI (VPTBI) has been explored particularly by the Stanford group and showed activity in leukemia at least comparable to other regimens.34–37 Recent studies have demonstrated that myeloablative doses of iv busulfan in conjunction with relatively high doses of fludarabine

Comparison of commonly used myeloablative regimens The use of a particular myeloablative regimen in a transplant center depends on a number of factors including, for example, a particular research interest, involvement in multicenter studies requiring ‘standard’ regimens and other constraints such as the availability of TBI. The evolution of commonly used protocols has been somewhat haphazard and direct comparisons are relatively few. Comparative data are derived from a few randomized studies and information from large registries such as the CIBMTR and EBMT. Although there are limitations of registry-based comparisons, they may reflect outcomes in the ‘real world’ in comparison with those derived from randomized studies, where patient selection is quite rigorous, or from single center experiences. Registry data have been compared with results obtained in one or a few centers, but once again these need to be interpreted with some caution. If an optimal myeloablative regimen were to be developed, it would somehow have to balance the beneficial effects of antitumor activity with the higher toxicity to be expected from dose escalation. While a GvM effect may be important in some diseases, this may often be at the expense of GvHD, still a major cause of morbidity and mortality. Moreover, survival as an endpoint needs to be viewed in the light of quality of life, often impaired by delayed effects of conditioning therapy and chronic GvHD. The ideal regimen might also involve the ability to monitor the delivery of agents to account for differences in pharmacokinetics.

Regimens for hematologic malignancies Credible information comparing myeloablative regimens for hematologic malignancy is really limited to the leukemias. Unfortunately, some of these studies do not report outcomes for the different leukemias separately. Randomized studies comparing CyTBI with BuCy2 for leukemia in general have indicated remarkable effectiveness of oral busulfan despite its very erratic pharmacokinetics. In general, BuCy2 has resulted in more VOD.56 While registry data have indicated that CyTBI causes more interstitial pneumonitis,57 a meta-analysis of randomized trials did not find this significant.56 Perhaps variability in TBI techniques may account for these differences. The latter analysis also indicated that while CyTBI is not demonstrably superior overall, it is unlikely to be inferior to BuCy2. A randomized study of VP16TBI against BuCy2 indicated very similar outcomes in patients beyond first chronic phase of CML or first complete response (CR1) of acute leukemia.58

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Chapter 27 Myeloablative conditioning regimens for allogeneic stem cell transplantation

comparisons have been done.24–26 Daily total exposures are similar to those achieved with qid dosing and the tolerable limit of daily exposure may also be much the same as for qid po busulfan even when combined with fludarabine instead of cyclophosphamide.27 Because 10–15% of patients given iv busulfan based on weight may experience unacceptably high exposures, TDM is probably justifiable. The availability of an assay may mean that the delivery can be more rationally based than with other agents used in myeloablative regimens. Although oral busulfan with TDM and dose adjustment could be as effective as the intravenous drug it may be more cumbersome, requiring more dose adjustments which are not always achieving the target and possibly expose more patients to the hazards of VOD. It is therefore becoming more difficult to justify the use of oral busulfan.

282

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3

Chronic myelogenous leukemia (CML)

PREPARATION FOR TRANSPLANT

Randomized trials showed BuCy2 to be as well or better tolerated than CyTBI with equivalent final outcomes.10, 59–61 Retrospective studies have also indicated that BuCy2 may be comparable to CyTBI.62 Some reports observed a trend to less relapse after BuCy2.60,62 Our increased understanding of the importance of graft-versus-leukemia effects (GvL) in CML has led to speculation that the dose intensity of the regimen may be of secondary importance. However, some studies with BuCy2 where the busulfan is given orally or iv have indicated that busulfan exposure seems to be important.23 The fact that BuCy2 is convenient and at least as effective as TBI-based regimens in CML has led it to be standard regimen for this disease in many centers. The use of imatinib as first-line therapy for most patients in chronic phase has altered the population of CML patients coming to allotransplant. Conceivably, these patients may need more intense cytoreduction but it will be some time before this can be established. Conversely, given the response of persistent or relapsed CML after transplant to donor lymphocytes or tyrosine kinase inhibitors, it will be critically important to minimize TRM.

Acute myelogenous leukemia (AML) The results of randomized comparisons of BuCy2 and CyTBI have not been entirely consistent. A combined analysis of trials8,63,64 devoted to or including AML patients demonstrated a non-significant trend to better projected survival and leukemia-free survival at 10 years with CyTBI.61 Registry data indicate again that ultimate outcomes are very similar.7,8,57,65 More relapse after BuCy2 compared with BuCy4 and CyTBI was seen in a pediatric series.7 A similar effect, compensated for by a slight reduction in TRM, was observed in a CIBMTR report.65 The VP16TBI combination seems active in AML and a randomized comparison with BuCy2 in advanced disease showed equivalent outcomes.36,58 Recent reports of fludarabine and daily iv busulfan combinations with or without TBI have indicated good survival with low TRM for AML and MDS.24,66 However, these regimens have not been directly compared to the alternatives and CyTBI should perhaps continue to be the reference for comparison. Another promising avenue is the addition of radiolabeled antibodies to provide enhanced radiation doses targeted to the bone marrow while sparing other tissues.67

Acute lymphoblastic leukemia (ALL) There is a preference for TBI-containing regimens before transplants for ALL.68,69 Most children with leukemia will therefore be exposed to TBI with the consequent late effects of growth retardation in particular. Survival is better after CyTBI than after BuCy2.70–72 A recent analysis comparing outcomes in adults with ALL given VP16TBI with those for patients in the CIBMTR database treated with CyTBI acknowledges the problem of comparing individual center results with registry data.35 Outcomes were similar in CR1 but for patients in CR2 it may be better to increase the dose of TBI from 1200 to 1320 cGy with Cy or to substitute VP16 for Cy. The VP16TBI combination is now being used as standard conditioning in multigroup studies of ALL.

Other hematologic malignancies Allogeneic transplantation is increasingly being applied to other hematologic malignancies including chronic lymphocytic leukemia, lymphomas and multiple myeloma. The advantages of using myeloablative regimens over less intense protocols are not well established. Many patients are relatively old and/or have been heavily pretreated

with chemotherapy, irradiation and often autologous transplants. Historically, TRM has tended to be high with myeloablative regimens but possibly this may improve with better patient selection and GvHD prophylaxis. However, it is difficult to make a solid recommendation for one regimen over another.

Non-malignant disease Non-malignant diseases provide particular challenges for selection of conditioning regimens. Hematologic disorders such as SAA and thalassemia occur in the context of largely intact cell-mediated immunity and resistance to engraftment may be enhanced by previous transfusion. Myeloablative conditioning is aimed simply at providing sufficient immunosuppression for engraftment while attempting to avoid long-term complications of agents such as TBI. Additionally, there is no benefit from GvHD.

Severe aplastic anemia (SAA) Aplastic anemia was the first disease to be successfully transplanted in significant numbers. Initially, high doses of cyclophosphamide were used alone for conditioning. It became clear that presensitization by multiple transfusions, particularly from family members, increased the risk of rejection.73 This is now less of an issue with sibling transplants which can be done soon after diagnosis but may influence outcomes of alternative donor transplants. Immunosuppressants such as antithymocyte globulins (ATG) may facilitate engraftment in addition to reducing GvHD.74 Further addition of a single fraction of 200 cGy TBI has proved sufficient to allow engraftment of stem cells from most unrelated donors.75 An alternative approach is to avoid irradiation and substitute some of the cyclophosphamide with fludarabine.76,77

β-Thalassemia The transplant program in Pesaro has pioneered the development of effective drug-based regimens for thalassemia.78 Graft failure has been somewhat more common than in hematologic malignancy, perhaps related in part to multiple transfusions.79 A regimen of 14 mg/kg busulfan with 200 mg/kg cyclophosphamide has been suitable for the majority of patients in Class 1 and 2. Cyclophosphamide doses may need to be reduced for Class 3 disease although rejection may be more frequent. Even with intensive regimens there is a significant incidence of autologous reconstitution. Complete engraftment may depend as much on immunosuppression and the immunologic effect of the graft as on the ability of conditioning to eradicate recipient hemopoiesis. Whether agents such as fludarabine can replace some of the other drugs to improve tolerability and maintain engraftment remains to be seen but early case reports are encouraging.80–82

Metabolic disorders Once again, these conditions have proven somewhat more refractory to engraftment than the hematologic malignancies. There is a preference for chemotherapy regimens because of the significant long-term effects of TBI in children. There may be promise in non-myeloablative transplants particularly as full donor engraftment may not be necessary for amelioration of some of these disorders.83

Modification of conditioning according to stem cell product and donor In both malignant and non-malignant disorders, engraftment may be influenced by the degree of matching and relatedness of the donor and

References 1. Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood 1992;80(12):2964–2968 2. Clift RA, Buckner CD, Appelbaum FR et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission : a randomized trial of two irradiation regimens. Blood 1990;76(9):1867–1871 3. Brochstein JA, Kernan NA, Groshen S et al. Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med 1987;317(26):1618–1624 4. Deeg HJ, Sullivan KM, Buckner CD et al. Marrow transplantation for acute nonlymphoblastic leukemia in first remission : toxicity and long-term follow-up of patients conditioned with single dose or fractionated total body irradiation. Bone Marrow Transplant 1986; 1(2):151–157 5. Demirer T, Petersen FB, Appelbaum FR et al. Allogeneic marrow transplantation following cyclophosphamide and escalating doses of hyperfractionated total body irradiation in patients with advanced lymphoid malignancies: a Phase I/II trial. Int J Radiat Oncol Biol Phys 1995;4:1103–1109 6. Thomas ED, Clift RA, Hersman J et al. Marrow transplantation for acute nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation. Int J Radiat Oncol Biol Phys 1982;8(5):817–821 7. Michel G, Gluckman E, Esperou-Bourdeau H et al. Allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission : impact of conditioning regimen without total-body irradiation – a report from the Societe Francaise de Greffe de Moelle. J Clin Oncol1994;12(6):1217–1222 8. Ringden O, Remberger M, Ruutu T et al. Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group. Blood 1999;93(7):2196–2201 9. Alyea E, Neuberg D, Mauch P et al. Effect of total body irradiation dose escalation on outcome following T-cell-depleted allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 2002;8(3):139–144 10. Clift RA, Radich J, Appelbaum FR et al. Long-term follow-up of a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide for patients receiving allogeneic marrow transplants during chronic phase of chronic myeloid leukemia. Blood 1999;94(11):3960–3962 11. Fyles GM, Messner HA, Lockwood G et al. Long-term results of bone marrow transplantation for patients with AML, ALL and CML prepared with single dose total body irradiation of 500 cGy delivered with a high dose rate. Bone Marrow Transplant 1991;8(6):453–463 12. DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids : sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis 2002;22(1):27–42 13. Copelan EA, Deeg HJ. Conditioning for allogeneic marrow transplantation in patients with lymphohematopoietic malignancies without the use of total body irradiation. Blood 1992;80(7):1648–1658 14. Santos GW. Busulfan and cyclophosphamide versus cyclophosphamide and total body irradiation for marrow transplantation in chronic myelogenous leukemia – a review. Leuk Lymphoma 1993;11(suppl 1):201–204 15. Tutschka PJ, Copelan EA, Klein JP. Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood 1987;70(5):1382–1388 16. Copelan EA, Bechtel TP, Avalos BR et al. Busulfan levels are influenced by prior treatment and are associated with hepatic veno-occlusive disease and early mortality but not with delayed complications following marrow transplantation. Bone Marrow Transplant 2001;27(11):1121–1124 17. Grochow LB, Jones RJ, Brundrett R et al. Pharmacokinetics of busulfan : correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol 1989;25(1):55–61

18. Kroger N, Zabelina T, Sonnenberg S et al. Dose-dependent effect of etoposide in combination with busulfan plus cyclophosphamide as conditioning for stem cell transplantation in patients with acute myeloid leukemia. Bone MarrowTransplant 2000;26(7):711–716 19. Ljungman P, Hassan M, Bekassy AN et al. High busulfan concentrations are associated with increased transplant-related mortality in allogeneic bone marrow transplant patients. Bone Marrow Transplant 1997;20(11):909–913 20. Slattery JT, Clift RA, Buckner CD et al. Marrow transplantation for chronic myeloid leukemia : the influence of plasma busulfan levels on the outcome of transplantation. Blood 1997;89(8):3055–3060 21. Deeg HJ, Storer B, Slattery JT et al. Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood 2002;100(4):1201–1207 22. Andersson BS, Gajewski J, Donato M et al. Allogeneic stem cell transplantation (BMT) for AML and MDS following i.v. busulfan and cyclophosphamide (i.v. BuCy). Bone Marrow Transplant 2000;25(suppl 2):S35–38 23. Andersson BS, Thall PF, Madden T et al. Busulfan systemic exposure relative to regimenrelated toxicity and acute graft-versus-host disease : defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia. Biol Blood Marrow Transplant 2002; 8(9):477–485 24. de Lima M, Couriel D, Thall PF et al. Once-daily intravenous busulfan and fludarabine : clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood 2004; 104(3):857–864 25. Fernandez HF, Tran HT, Albrecht F et al. Evaluation of safety and pharmacokinetics of administering intravenous busulfan in a twice-daily or daily schedule to patients with advanced hematologic malignant disease undergoing stem cell transplantation. Biol Blood Marrow Transplant 2002;8(9):486–492 26. Russell JA, Tran HT, Quinlan D et al. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation : study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant 2002;8(9):468–476 27. Geddes M, Kangarloo SB, Naveed F et al. High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen. Biol Blood Marrow Transplant 2008;14(2):220–228 28. Jones RJ, Lee KS, Beschorner WE et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987;44(6):778–783 29. McDonald GB, Hinds MS, Fisher LD et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation : a cohort study of 355 patients. Ann Intern Med 1993;118(4):255–267 30. Carreras E, Bertz H, Arcese W et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation : a prospective cohort study of the European Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood 1998;92(10):3599–3604 31. Slattery JT, Kalhorn TF, McDonald GB et al. Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients. J Clin Oncol 1996;14(5):1484–1494 32. Kashyap A, Wingard J, Cagnoni P et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation : decreased incidence of hepatic venoocclusive disease (HVOD), HVODrelated mortality, and overall 100-day mortality. Biol Blood Marrow Transplant 2002; 8(9):493–500 33. Thall PF, Champlin RE, Andersson BS. Comparison of 100-day mortality rates associated with i.v. busulfan and cyclophosphamide vs other preparative regimens in allogeneic bone marrow transplantation for chronic myelogenous leukemia: Bayesian sensitivity analyses of confounded treatment and center effects. Bone Marrow Transplant 2004;33(12): 1191–1199 34. Jamieson CH, Amylon MD, Wong RM et al. Allogeneic hematopoietic cell transplantation for patients with high-risk acute lymphoblastic leukemia in first or second complete remission using fractionated total-body irradiation and high-dose etoposide : a 15-year experience. Exp Hematol 2003;31(10):981–986 35. Marks DI, Forman SJ, Blume KG et al. A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant 2006;12(4):438–453 36. Snyder DS, Chao NJ, Amylon MD et al. Fractionated total body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in first complete remission. Blood 1993;82(9):2920–2928 37. Snyder DS, Negrin RS, O’Donnell MR et al. Fractionated total-body irradiation and highdose etoposide as a preparatory regimen for bone marrow transplantation for 94 patients with chronic myelogenous leukemia in chronic phase. Blood 1994;84(5):1672–1679 38. Kroger N, Kruger W, Wacker-Backhaus G et al.Intensified conditioning regimen in bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Bone Marrow Transplant 1998;22(11):1029–1033 39. Zander AR, Berger C, Kroger N et al. High dose chemotherapy with busulfan, cyclophosphamide, and etoposide as conditioning regimen for allogeneic bone marrow transplantation for patients with acute myeloid leukemia in first complete remission. Clin Cancer Res 1997;3(12 Pt 2):2671–2675 40. Aversa F, Tabilio A, Velardi A et al.Treatment of high-risk acute leukemia with T-celldepleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 1998;339(17):1186–1193 41. Bibawi S, Abi-Said D, Fayad L et al. Thiotepa, busulfan, and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced myelodysplastic syndrome and acute myelogenous leukemia. Am J Hematol 2001;67(4):227–233 42. Cahn JY, Bordigoni P, Souillet G et al. The TAM regimen prior to allogeneic and autologous bone marrow transplantation for high-risk acute lymphoblastic leukemias : a cooperative study of 62 patients. Bone Marrow Transplant 1991;7(1):1–4 43. Zecca M, Pession A, Messina C et al. Total body irradiation, thiotepa, and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or

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Chapter 27 Myeloablative conditioning regimens for allogeneic stem cell transplantation

also by the product infused, particularly the progenitor cell dose. Recovery may be compromised by in vitro T-cell depletion which involves some loss not only of stem cells but also of lymphocytes which may facilitate engraftment.84–86 Immunosuppression can be enhanced by increasing TBI dose or by adding total lymphoid irradiation87–89 or other agents. Engraftment from cord blood is significantly influenced by the progenitor cell doses infused and tends to result in slower recovery than other sources, particularly in adults. Most regimens are TBI or busulfan based and many include ATG.90 As matching techniques have become more sophisticated there is currently little evidence that cytotoxic conditioning appropriate for a matched sibling transplant should be modified for a limited degree of mismatching and/or for an unrelated donor. It may be rational, however, to add immune suppression such as ATG in order to modify GvHD as well as facilitating engraftment. Most haploidentical transplants from family members have been heavily T-cell depleted, both in vivo and in vitro. The resistance to engraftment is offset somewhat by high doses of infused donor cells and many regimens have used quite intense conditioning in addition to ATG in this setting.40 On the other hand, unmanipulated haploidentical transplants appear to engraft well with conventional conditioning and ATG..91

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46.

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47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

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102. Cheson BD, Vena DA, Foss FM et al. Neurotoxicity of purine analogs : a review. J Clin Oncol 1994;12(10):2216–2228 103. Samuels BL, Bitran JD. High-dose intravenous melphalan: a review. J Clin Oncol 1995;13(7): 1786–1799 104. Devetten MP, Qazilbash MH, Beall CL et al. Thiotepa and fractionated TBI conditioning prior to allogeneic stem cell transplantation for advanced hematologic malignancies : a phase II single institution trial. Bone Marrow Transplant 2004;34(7):577–580 105. Scheulen ME, Hilger RA, Oberhoff C et al. Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies. Clin Cancer Res 2000;6(11):4209–4216

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