Search strategy and selection criteria

Studies for this review were identified by searches of PubMed/Medline, EMBASE databases and appropriate references from the relevant articles. Only papers in English were reviewed and only studies reporting on the allograft conditioning regimens in AML with at least 20 patients in a disease specific setting (eg CR1 or advanced disease) were included.

Evolution of myeloablative conditioning regimens in acute leukemia

Cyclophosphamide and total body irradiation (CyTBI) has long been used as a myeloablative conditioning or preparatory regimen after the initial reports of encouraging results of alloBMT in acute leukemia.^1,2,15 Based on studies in rats^16,17,18 and initial allotransplant trials in patients with relapsed acute leukemia,^19,20 a myeloablative dose of busulfan (16 mg/kg p.o. over 4 days) was established. The total daily dose of busulfan is usually given in four divided doses, mainly for ease of administration of the large total dose. The busulfan/cyclophosphamide (BuCy) regimen was considered an effective alternative to radiation-based regimens for AML.²¹ While initial studies with BuCy used Cy at a dose of 200 mg/kg (50 mg/kg daily 4 days, also known as BuCy 4),^21,22 further attempts were made to refine this regimen by decreasing the dose of Cy to 120 mg/kg (60 mg/kg daily 2 days, also known as BuCy 2), which appeared to be equally effective and less toxic.^23,24,25 It is noteworthy that there has been no randomized comparison of BuCy 4 with BuCy 2. The CyTBI and BuCy regimens have become the two most commonly used standard myeloablative regimens in AML (IBMTR database, personal communication, Horowitz, MM).

Comparison of BuCy vs CyTBI in AML

The regimens will be compared for survival outcomes, treatment-related complications and relapse rate, according to the remission status, a powerful factor affecting treatment outcome.^21,26

AML CR1

These two conditioning regimens in AML in CR1 were compared in two randomized^27,28 and two registry-based studies^29,30 in adults and one registry-based study³¹ in children. The main limitation of the randomized studies from the French²⁷ and Nordic group²⁸ and the registry-based pediatric study is the small number of subjects. In contrast, the observational database studies from the EBMT²⁹ and IBMTR³⁰ groups have large numbers of patients but selection bias remains an issue despite careful matching for patient and disease characteristics. The biases relate to unknown factors that influence the choice of one particular regimen over the other by the treating physician or center and are not possible to exclude from these studies. Other center-specific effects that may affect outcome³² are also difficult to eliminate from these studies. Problems in the interpretation of data from the literature on conditioning regimens in AML are highlighted in Table 2. Results from the five studies comparing BuCy with CyTBI are summarized in Table 3.

Table 2 - Limitations of studies on conditioning regimens in AML.

Full table

Table 3 - Comparison of BuCy and CyTBI in AML CR1.

Full table

Survival outcomes

The multicenter randomized French study is the only study in adults that showed the superiority of CyTBI (n=50) over BuCy (n=51) in disease-free survival (DFS) (72 vs 47%, P<0.01) and overall survival (OS) (75 vs 51%, P<0.02). The superior survival was attributed to a lower relapse rate (14 vs 34%, P<0.04) and low TRM (8 vs 27%, P<0.06) in favor of the CyTBI arm.²⁷ In contrast, the randomized study on a cohort of patients with AML and other leukemias (AML CR1 patients, BuCy (n=25), CyTBI (n=26)) from the Nordic group did not show a significant difference in the outcome of patients with 'early-disease' treated with these two regimens.²⁸ The results for AML in CR1 are difficult to interpret in this study because several parameters were reported on a mixed cohort of patients with AML, CML and ALL with different remission status. Subsequent comparative studies from the EBMT²⁹ and IBMTR³⁰ groups did not show any significant difference in survival with these two treatment regimens.

Treatment-related complications

No difference in the incidence of GVHD, either acute or chronic, was observed with these two regimens in the registry database studies.^29,30 The randomized comparative studies showed more deaths from GVHD in the BuCy Group²⁷ and a higher number of cases with grades III–V aGVHD or cGVHD.²⁸ It is also noteworthy that the diagnosis of GVHD was mainly clinical in these studies. In the absence of a pathologic diagnosis, it may be difficult to differentiate between VOD (consistently higher in the BuCy group) and GVHD. Moreover, how VOD modifies the course and severity of GVHD is not known.

It is noteworthy that TRM in the CyTBI arm (8%) was significantly lower in the French study, but this has not been matched in other studies (Table 3). The cause of this discrepancy is not clear. The fractionation of TBI and lung shielding reduce the incidence of interstitial pneumonitis in TBI-based regimens.^33,34 Lung shielding was used in all cases in the TBI group in the French study²⁷ compared with 60% of evaluable cases in the IBMTR registry study.³⁰ The lungs receive 10–20% higher dose of radiation than the prescribed dose, because they are air-containing organs. The practice of lung shielding to eliminate this 'overdose effect' is not universal and varies at different centers. It seems unlikely that this factor alone led to lower TRM in the TBI group in the French study and may be a chance association due to the small number of patients studied. While the EBMT study described a significantly higher proportion of cases of interstitial pneumonitis in the CyTBI arm,²⁹ this was not observed in the IBMTR study.³⁰

Other complications appear to be more frequent in patients receiving BuCy. A consistent finding in all these studies was the significantly higher incidence of VOD of the liver with BuCy compared to CyTBI.^27,28,29,30 Also, a significantly higher incidence of hemorrhagic cystitis was observed with the BuCy regimen.^28,29 In addition, seizures occur in a significantly higher proportion of patients receiving busulfan.²⁸

Engraftment

There were no differences in the engraftment rate between the two groups in the EBMT study,²⁹ although the IBMTR study showed a significant difference in earlier neutrophil recovery in the BuCy cohort.³⁰

Relapse rate

The French randomized trial and the IBMTR registry study, but not the EBMT registry study showed significantly lower relapse rates in the CyTBI arm. A different pattern of relapse, especially increased relapses at extramedullary (EM) sites, particularly the central nervous system (CNS), was observed in patients receiving BuCy compared to CyTBI.³⁰ A high incidence of EM relapses was also observed in patients with AML treated with BuCy conditioning at a single center.³⁵ These observations suggest that TBI-based regimens are more effective in treating occult CNS disease.

It is noteworthy that in the French study, the dose of Cy was 120 mg/kg (BuCy2). It is unlikely however, that this led to the increased relapses in the BuCy arm as previous studies suggested that the efficacy of BuCy2 may be similar to BuCy4.^23,24,25 Furthermore, both registry studies found no difference in the outcome of patients treated with the lower dose of Cy.^29,30 Nevertheless, the pediatric registry study, based on a small number of patients, demonstrated the superiority of BuCy4 to BuCy2 in a comparison of BuCy2, BuCy4 and TBI-based conditioning regimens for patients with AML in CR1.³¹ This study showed a significantly higher risk of relapse with BuCy2, but no difference between BuCy4 and CyTBI. Plasma busulfan levels, however, were not monitored in any of these studies. Inter- and intrapatient variability in the kinetics of busulfan may explain the different results among the various studies.

Long-term complications

Concerns have been raised at the increased risk of secondary malignancies in patients treated with TBI-based regimens.^36,37 There are few data on the comparative risk of secondary malignancies with these two regimens. Long-term follow-up of patients treated with these two regimens in the French study did not show significant difference in the number of cases of second malignancy.³⁸ In the absence of clear evidence that one regimen causes more cases of cancer, it is important to keep patients treated with either regimen under long-term surveillance for secondary malignancies.

While long-term follow-up in the Nordic study found significantly more cases of obstructive bronchiolitis in the BuCy group and cataracts in TBI cohort,³⁹ no such long-term differences were observed in AML patients treated with these two conditioning regimens in the French study.³⁸

Quality of life and costs

The quality of life (QOL) and health care utilization costs have not been studied prospectively in any of these studies. In a combined long-term analysis of the French and Nordic studies, equal proportions of AML patients treated with CyTBI or BuCy returned to work/school (85 vs 88%).⁴⁰

Beyond CR1

Very scanty data are available to determine whether patients with advanced AML (second or later remissions, early relapse) benefit preferentially from TBI- or chemotherapy-based regimens. In the EBMT comparative study, no difference in TRM, relapse or LFS was observed in patients receiving CyTBI (n=46) compared with BuCy (n=46).²⁹ In the Nordic study, the TBI-based regimen was superior for patients with advanced disease in a mixed cohort (beyond CR1 or CML patients beyond first chronic phase), however, the number of AML patients with advanced disease in this study was too small to reach any meaningful conclusions (BuCy, n=12; CyTBI, n=6).²⁸

Other comparative studies of myeloablative conditioning regimens in AML

AML CR1

The question of the optimum dose and schedule of TBI was addressed by two randomized studies from the Seattle group. In the first randomized study, AML patients in CR1 were randomized between cyclophosphamide and single exposure 10 Gy TBI (n=27) vs 12 Gy TBI in six fractions in combination with cyclophosphamide (n=26).⁴¹ This study showed a significant survival advantage for patients treated with the fractionated TBI regimen.

In an effort to increase the antileukemic efficacy of TBI, AML patients in CR1 were randomized to receive 12 Gy TBI in six fractions (n=34) vs 15.75 Gy TBI in seven fractions (n=37).⁸ Indeed, the relapses in the cohort receiving higher dose of TBI was significantly lower, however, this did not translate into a survival benefit because nonrelapse mortality from aGVHD was higher. Updated results of this study reported the same trend.⁴²

In another prospective study, the CyTBI regimen (n=36) was compared with melphalan and TBI (n=27) in AML CR1.⁴³ Neither the actuarial probability of remaining in remission (66 vs 94%, P>0.1), nor the OS was significantly different between the two groups (53 vs 55%).

Beyond CR1

A randomized study from the Southwest Oncology Group (SWOG) of 114 leukemia patients (including AML, ALL and CML) not in first remission, compared fTBI (1320 cGy of TBI in 11 fractions) and VP-16 (60 mg/kg) for one dose vs BuCy2.⁴⁴ The investigators stratified the patients to 'good-risk' (CR2 or accelerated phase) and 'poor-risk' (CR3, induction failure, in relapse, blast phase) categories and showed equivalent survival outcomes with the fTBI and BuCy regimens (55 vs 34%, P=0.30). There were a total of 40 AML patients (good-risk (n=11), poor-risk (n=29)) in this trial. Owing to the limited number of patients, the results were not analyzed according to the type of leukemia.

Modifications of standard myeloablative regimens in AML

In an effort to improve the efficacy of the regimens, several investigators have modified standard protocols by

1. Replacing cyclophosphamide with agents such as VP-16.
2. Intensifying the regimens with
   1. Additional chemotherapy.
   2. Radioimmunotherapy.
3. Using newer strategies with busulfan.
4. T-cell depletion.

Replacing cyclophosphamide with VP-16

The fTBI/VP-16 regimen was studied in 99 patients with acute leukemia in CR1 (AML, n=61).⁴⁵ The regimen was well tolerated and for AML patients, cumulative probabilities for DFS and relapse rates at 3 years were 61 and 12% (Table 4). This regimen has not been tested in AML CR1 patients in comparative studies. Another pilot study reported encouraging results (3 years DFS 56% and relapse rate 25%) by using VP-16 with busulfan for AML autografts.⁴⁶ However, this regimen has not been tested for AML allografts.

Table 4 - Studies using chemotherapy modifications of standard myeloablative regimens in AML CR1.

Full table

Intensification of standard myeloablative regimens with

(a) Additional chemotherapy

Attempts were subsequently made to improve the efficacy of standard regimens by the addition of other agents such as VP16 (etoposide),^47,48,49,50 Thiotepa,⁵¹ and cytarabine.⁵² These regimens were well tolerated and results from these studies are summarized in Tables 4 and 5, according to remission status. The German group have reported impressive results using a combination of VP-16 with BuCy2 in AML CR1 in a mixed group of patients (adults and children).^48,49 Of particular note, none of the patients relapsed in these two studies. The data suggest that VP-16 30 mg/kg for one dose with BuCy2 is well tolerated. Another study reported severe pulmonary toxicity of this regimen in patients with a prior history of chest irradiation undergoing ABMT and alloBMT.⁵³ The dose of VP-16 in this study was 40 mg/kg for one dose along with BuCy2.

Table 5 - Studies using chemotherapy modifications of standard myeloablative regimens in AML beyond CR1.

Full table

(b) Radioimmunotherapy

Targeted radioimmunotherapy, either in combination with radiation-based or chemotherapy-based regimens is another means of increasing the radiation dose without increasing toxicity.⁵⁴ Clinical trials using ¹³¹I-labeled anti-CD33 antibody M195,^{55 131}I-labeled anti-CD45 antibody^56,57 and ¹⁸⁸Rhenium-labeled anti-CD66 antibody⁵⁸ in combination with the CyTBI and BuCy regimens demonstrate the feasibility of this approach. These approaches mainly use -emitting isotopes conjugated to monoclonal antibodies. More recently, an -particle emitter, ²¹³Bi in conjugation with Hum195, was shown to be active in a phase I study in advanced myeloid leukemias.⁵⁹ Unlike -particle emitting isotopes, emitters can selectively kill individual cancer cells. The use of -particle-based targeted radiation with conditioning regimens has not yet been studied. These strategies appear promising and may further improve the efficacy of the conditioning regimens, but are restricted to larger centers because of the requirement for special facilities.

Newer strategies with busulfan

A major limitation of p.o. busulfan is wide interpatient variability of pharmacokinetics due to unpredictable intestinal absorption, dosing uncertainties due to emesis, erratic bioavailability and a narrow therapeutic window. A suboptimal dose of busulfan expressed as a low area under the curve (AUC) resulted in a higher frequency of graft rejection and relapses⁶⁰ and a higher AUC correlated with increased toxicity, mainly VOD and seizures.^61,62,63 The pharmacokinetics of busulfan are also age-dependent and children tend to clear busulfan faster.⁶¹ Some of these issues may be addressed by monitoring blood busulfan levels using limited sampling models followed by dose adjustment to achieve a 'targeted' steady-state concentration.^64,65 Cyclophosphamide levels however, are not routinely monitored after conditioning therapy. It was recently shown in patients treated with CyTBI protocols that increased exposure to toxic metabolites of cyclophosphamide resulted in increased liver toxicity and nonrelapse mortality.⁶⁶ Whether a 'targeting strategy' with cyclophosphamide similar to the approach used with busulfan will result in better survival is currently not known.

More recently, intravenous (i.v.) preparations of busulfan have become available. Four different formulations of busulfan have been tested in phase I/II studies.^67,68,69,70 The safety profile of i.v. preparations of busulfan is favorable with fewer acute side effects and better engraftment. A comparative retrospective analysis of i.v. busulfan vs p.o. busulfan in the BuCy2 regimen showed a significantly lower VOD (8 vs 33%, P=0.002) and significantly superior 100-day survival in favor of i.v. preparation.⁷¹ It is important to note that busulfan levels were not reported in this study. The superiority of i.v. busulfan over p.o. busulfan with 'targeted levels' is not known at present and this remains a key study question for future clinical trials in this area.

Initial studies with i.v. busulfan used the four times daily dosing schedule as with p.o. busulfan. A recent study reported once daily i.v. busulfan (3.2 mg/kg i.v. 4 days) with fludarabine as a myeloablative conditioning regimen for hematologic malignancies.⁷² Pharmacokinetic studies on a subset of patients showed linear kinetics with this approach with cumulative AUC comparable to that established for p.o. busulfan. The once daily regimen may help to further simplify the treatment regimen.

T-cell depletion

As GVHD is one of the main factors that influences TRM, approaches to decrease the incidence and severity of GVHD by decreasing the number of T cells in the donor marrow have caught investigative attention. Several methods of T-cell depletion such as negative selection by physical separation or antibody-based purging have been tried.⁷³ The results of clinical trials using this approach in AML patients in CR1 are summarized in Table 6^74,75,76 . No additional GVHD prophylaxis to CR1 patients was given in these trials. The main problem with this approach remains the higher risk of relapse, graft failure and immune reconstitution.⁷⁷ Graft rejection with T-cell depletion allografts may be overcome by increasing pretransplant immunosuppression and myeloablation with ATG and thiotepa.^76,78 All AML patients in these two studies achieved primary and sustained engraftment with full donor chimerism. Moreover, GVHD was either significantly reduced (grade I aGVHD <5%, no cases of grades II–IV aGVHD, cGVHD 3%)⁷⁶ or not seen at all.⁷⁸

Table 6 - Studies evaluating myeloablative conditioning regimens with T-cell depletion in AML CR1.

Full table

Despite the increased scientific knowledge gained over the last two decades in this area, the exact role of T-cell depletion in allotransplants for AML remains unclear.

Novel strategies for conditioning regimens

More recently, several groups have focused on nonmyeloablative or reduced intensity conditioning regimens. The main aim is to exploit the beneficial graft-versus-leukemia (GVL) effect and reduce regimen-related complications such as GVHD. These approaches offer patients who are not candidates for myeloablative transplants due to age or concomitant medical problems, the opportunity to benefit from a GVL effect.^79,80 Experience with AML however is limited.^81,82,83,84 A high relapse rate continues to be a major issue with nonmyeloablative protocols.^84,85 Although the comparison of nonmyeloablative and myeloablative protocols for the incidence of GVHD is difficult because of different patient eligibility criteria, a recent study showed that the cumulative incidence of grades II–IV aGVHD was significantly in favor of nonmyeloablative transplants (64 vs 85%, P=0.001).⁸⁶ Nonetheless, there was no difference in cGVHD requiring treatment (73 vs 71%). More disease-specific and long-term data are needed to fully evaluate the efficacy of these approaches.

At present, myeloablative conditioning regimens, clinically tested for over 30 years, remain the gold standard of treatment and allotransplants with novel strategies for patients at high risk of TRM should only be offered as a part of a clinical trial.

Conclusion

Based on an assessment of the literature, survival with the two most commonly used myeloablative conditioning regimens, BuCy and CyTBI, are similar. Local availability and expertise may determine the preference of one over the other. Neither regimen is suitable for all the situations and a particular regimen should be avoided in selected clinical situations; for example, BuCy should be avoided in a patient with abnormal liver function and CyTBI, in patients with a prior history of radiation to the lung. Modification of these regimens by intensification with additional chemotherapy or radioimmunotherapy, newer preparations of busulfan and T-cell depletion may enhance efficacy and tolerability. Whether these modifications will result in better survival in AML patients remain to be established in randomized studies.

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Acknowledgements

We thank Dr JM Rowe for a careful review of the manuscript and helpful comments. AK holds the Gloria and Seymour Epstein Chair in Cell Therapy and Transplantation at University Health Network and University of Toronto.