- Top of page
- Design and methods
- Conflict of interest statement
- Author contributions
The most common toxicity after HSCT is oral mucositis. We found that MAC patients had significantly more mucositis, median WHO grade 4, as opposed to median WHO grade 1 for the RIC group (P < 0.001). This is consistent with the findings of a previous retrospective study in which patients treated with MAC had more mucositis than those treated with RIC . As a result of this, patients in the MAC group required significantly more days with TPN than those in the RIC group (P < 0.001; Table 2). The fact that haemorrhagic cystitis was more common in MAC-treated patients than in those treated with RIC was not unexpected. In a previous study, we also found that MAC (compared with RIC) was a risk factor for haemorrhagic cystitis . Maximum serum creatinine, bilirubin, S-ALAT and S-ASAT did not differ significantly between the two groups. However, the possibility that with many more patients, there may have been a difference in kidney and liver toxicity cannot be excluded. Nevertheless, the findings of this study suggest that there is no major difference in renal, hepatic or cardiac toxicity between MAC and RIC.
There were several advantages of RIC treatment. First, platelet engraftment was faster with RIC than MAC, which has not been reported previously (Fig. 1b). In addition, fewer transfusions of platelets and erythrocytes were required in the RIC group (Table 2). We did not find an increase in the speed of engraftment of ANC, which may have been due to the small number of patients. Faster engraftment of ANC using RIC as compared to MAC was previously reported in a retrospective analysis of patients with AML . The time of discharge from hospital was similar between the two groups, which was probably due to the fact that there was no significant difference in the time to reach an ANC of >0.5 × 109 L−1.
Cytomegalovirus reactivation was more common in the MAC group, which may have been due to the fact that immune recovery is better with RIC. CMV infection has been reported to be associated with delayed immune reconstitution and an increased risk of bacterial and fungal infection . In the present study, there was no difference in the rate of bacteraemia between the two groups. The increased risk of CMV infection in the MAC group may also have contributed to the increased risk of haemorrhagic cystitis in these patients, as CMV infection was previously found to be a risk factor for haemorrhagic cystitis .
Using RIC rather than MAC, it is likely that DC would be delayed. No significant difference in DC was seen for CD19+ or CD33+ cells 1 month after HSCT. However, DC of CD3+ cells was delayed until 9 months after HSCT. It is possible that T cells in the circulation are less sensitive to chemotherapy than other cells. Most importantly, after 1 year, DC of all three lineages was similar in the two groups.
There was no significant difference in acute and chronic GVHD in the two groups of patients. Stronger chemotherapy may cause tissue damage, which may result in GVHD . Although we found no significant differences in acute or chronic GVHD, four patients in the MAC group developed severe acute GVHD and two patients died, compared with none in the RIC group. It was previously shown in two studies that GVHD is more common with MAC than with RIC, supporting the idea that MAC may cause tissue toxicity, leading to GVHD [3, 25].
There is selection bias in retrospective multicentre analyses [3-6], which is avoided in randomized studies. However, the advantage of large multicentre retrospective analyses is that a large number of patients can be included. The present analysis was not powered to detect differences in TRM, relapse, survival or LFS. However, our findings complement those of the large multicentre retrospective analyses, which have not addressed the issue of toxicity.
Transplant-related mortality was the same in the two groups, at around 11%. This shows that both regimens are well tolerated in patients <61 years of age. A retrospective study of transplants from MUDs showed that, in patients <50 years of age, TRM was the same irrespective of whether RIC or MAC was used . In patients over 50 years of age, TRM was reported to be increased in HLA-identical sibling transplants and MUDs using MAC compared with RIC [3, 6]. These findings are in contrast to those of the present study, probably because of the low overall TRM rate in both groups and because there were too few patients over 50 years of age to be able to conduct a separate analysis based on age.
There was no statistically significant difference in relapse probability between patients conditioned with MAC and those conditioned with RIC. There was a trend for fewer relapses in the RIC group (Fig. 2d, P = 0.17). However, this is most probably due to chance as there were too few patients in the study for a powerful statistical analysis. With more intensified chemoradiotherapy, relapse has been found to be reduced in patients with AML . In retrospective studies, an increased risk of relapse has also been reported in patients with AML treated with RIC compared with those treated with MAC [3, 6]. Of note, Martino et al.  reported an increased risk of relapse in patients with myelodysplastic syndrome or secondary AML who had received RIC instead of MAC for sibling transplant.
Overall survival and LFS were not significantly different in the RIC and MAC groups. The main predictor of survival in patients with AML was cytogenetics (Fig. 3b), in line with the well-established finding that cytogenetics is extremely important for outcome in these patients after HSCT . Similar overall survival and LFS has also been reported in retrospective analyses comparing RIC and MAC [3, 4, 6].
In conclusion, the findings of three large retrospective studies suggest that survival and LFS are not decreased by RIC compared with MAC in patients with AML [3, 4, 6]. Therefore, RIC may be favoured in standard-risk patients because of an association with less mucositis, less haemorrhagic cystitis, faster platelet engraftment, the need for fewer transfusions and less TPN, and fewer CMV infections, as demonstrated in the present study.