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N. Gagelmann and N. Kröger
a less toxic immunosuppressive agent, fludarabine.18,19 The important prospective randomized study by Rambaldi et al. comparing busulfan-fludarabine condi- tioning versus busulfan-cyclophosphamide in patients >40 years of age with AML showed significantly reduced 1- year transplant-related mortality (8% vs. 17%).20 Importantly, the comparison showed reduced NRM specifically for patients with a higher comorbidity index and busulfan-fludarabine conditioning, as well as in patients in first complete remission. Adverse event rates were similar in the two groups, except for organ-failure, which was more frequent in the group treated with cyclophosphamide.
Another option to maintain myeloablation, according to the given definition, and immunosuppression but also to reduce non-hematologic toxicity was investigated by replacing busulfan by the alkylator treosulfan,21 which exhibits low inter- and intra-patient variability without the need for dose adjustments.22,23 A recent prospective randomized trial by Beelen et al. in older (≥50 years) and/or comorbid AML/MDS patients randomly assigned patients to receive either intravenous 3x10 g/m2 treosul- fan or reduced intensity busulfan. The initial treosulfan dose of 14 g/m2 daily was changed due to safety con- cerns.24 Both groups received 30 mg/m2 intravenous flu- darabine. Overall, the 2-year event-free survival rate was 64% in the treosulfan group and 50% in the busulfan group, but differences were most pronounced in the sub- group of patients ≥50 years receiving matched unrelated HSCT, whereas there was not a significant difference among patients with a comorbidity index of ≥2. Notably, despite higher intensity, the survival benefit of treosulfan was caused by a higher NRM in the busulfan group which did, however, appear somewhat higher than previ- ously reported.25,26
Reduced intensity conditioning versus myeloablative conditioning
The BMT-CTN study reported by Scott et al.26 prospec- tively compared RIC versus MAC approaches in AML and MDS. In order to have more flexibility, transplant physi- cians had some choice of preparative approaches. The study design allowed higher-dose busulfan (12.8 mg/kg intravenously) with fludarabine or busulfan with cyclophosphamide along with cyclophosphamide-TBI in the MAC arm and lower-dose busulfan (8 mg/kg intra- venously) with fludarabine or fludarabine with melpha- lan in the RIC arm. Enrollment was more rapid and accured 272 patients with AML/MDS patients aged 18-65 years with a comorbidity index <5 and <5% marrow myeloblasts prior to matched-related or unrelated donor HSCT. The study was closed early because of the finding of superior relapse-free survival in the MAC arm. This study clearly demonstrated that myeloablative busulfan regimens resulted in a significantly improved relapse-free survival (despite a higher NRM rate) and in a significantly lower relapse incidence than the lower-dose busulfan/flu- darabine RIC arm. The main cause of death in the MAC arm was graft-versus-host disease (GvHD) (50%), as com- pared to relapse (86%) in the RIC arm. The ability to per- form subgroup analyses was limited by the early closure. Nevertheless, these analyses showed survival benefit for MAC for AML patients, high-risk patients and patients with a comorbidity index of 0.
issue in patients with MDS or secondary AML. The patients included in this trial had to be 18-60 years for those with unrelated donors and 18-65 years for those with related donors. Eighty-five percent of chemothera- pies before transplantation were administered in advanced MDS (chronic myelomonocytic leukemia, refractory anemia with excess of blasts, and secondary AML) to reduce the number of blasts. Regimens were busulfan (16 mg/kg orally or 12.8 mg/kg intravenously) and cyclophosphamide (120 mg/kg) for MAC and busul- fan (8 mg/kg orally or 6.4 mg/kg intravenously) and flu- darabine (150 mg/m2) for RIC. The trial also accrued slowly, assigning 129 patients, and was closed early after calculations suggested enough power to address the pri- mary aim of determining differences in NRM. The trial showed similar 2-year incidences of relapse, relapse-free survival, and overall survival. Short-term NRM, at 1 year, was also similar but was much lower than predicted. In the multivariable model of NRM, an interaction was found between conditioning intensity and cytogenetics, which led to a subgroup analysis stratified by cytogenetic risk group. In the low-risk cytogenetic group, lower per- formance status was associated with higher NRM, while the comparison of conditioning intensities showed lower NRM after RIC in this risk group. In the intermediate- and high-risk cytogenetic groups, RIC resulted in a higher NRM rate.
Reduced intensity conditioning versus sequential reduced intensity conditioning
More recently, Craddock et al. compared, in a prospec- tive, randomized fashion, a sequential transplant regimen with fludarabine-amsacrine-cytarabine followed by busulfan “augmented” RIC to a fludarabine-based RIC in high-risk AML and MDS and did not find any statistically significant difference in therapy-related mortality, relapse or overall survival between the two groups.14
Reduced intensity conditioning versus non-myeloablative conditioning
A further reduction of intensity and toxicity was intro- duced by a non-myeloablative regimen with only 2 Gy TBI and fludarabine. A prospective randomized study reported by Blaise et al. compared a 2 Gy TBI-based NMA regimen with a busulfan-fludarabine-based RIC regi- men.27 The incidence of grade 2-4 acute GvHD was 47% in the RIC group versus 27% in the group given NMA conditioning, with no difference in chronic GvHD. The RIC group showed a lower relapse rate (27% vs. 54%), while the NRM rate was higher (38% vs. 22%). At 5 years, the overall survival rates were identical (41%).
Evidence summary
In summary, prospective studies in AML/MDS show a challenging landscape of evidence. No superiority for any arm regarding relapse or NRM was found for AML patients with intermediate-/high-risk cytogenetics and ≤60 years or MDS/secondary AML patients,16,25 with a trend towards better overall survival after RIC in the trial by Kröger et al.25 In contrast, Scott et al.26 showed a clearly reduced risk of relapse and better overall survival for MAC, despite higher NRM in AML/MDS patients. Intensifying RIC by adminis- tering sequential RIC did not improve outcome compared to conventional RIC in high-risk AML/MDS.14
The EBMT RICMAC trial25 prospectively addressed this
Meta-analyses summarizing findings from the afore-
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haematologica | 2021; 106(7)