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Conditioning intensity in allogeneic HSCT
mentioned randomized trials have been published but are limited by the heterogeneous characteristics across the trials.28,29 In conclusion, for AML and MDS, the overall quality of evidence for the optimal conditioning intensity is low. For higher-risk patients, MAC appeared to provide some benefit.29 However, in the current setting, only data synthesis on the level of individual patient data may be of additional value.
Retrospective studies in acute myeloid leukemia/myelodysplastic syndromes
The wide basis for current clinical consensus statements with regards to conditioning intensity in AML/MDS draws on data from retrospective comparisons (Table 2). The first study to compare outcomes of conventional MAC versus RIC was from an EMBT registry study that looked at 722 patients with AML >50 years.30 Four hundred seven patients received MAC consisting of TBI doses >10 Gy or busulfan doses >8 mg/kg plus other drugs, and 315 patients underwent RIC including fludarabine in combination with low-dose TBI (<2 Gy) or busulfan doses <8 mg/kg. The results showed that NRM was higher after MAC, while RIC transplants were associated with a higher relapse risk, even after adjustment for various factors. There was, how- ever, no difference in 2-year relapse-free and overall sur- vival. The incidences of grades 2-4 acute GvHD and chronic GvHD were also lower after RIC. (Table 2).
Another retrospective EBMT registry study by Martino et al. in MDS patients compared RIC (mainly consisting of flu- darabine-busulfan regimens) with standard MAC (mainly TBI-cyclophosphamide or busulfan-cyclophosphamide).31 In multivariate analysis, the 3-year incidence of relapse was significantly higher in the RIC group, with a risk increased by 64%. In contrast, the risk of NRM was significantly decreased by 39% compared with that in the MAC arm. Acute GvHD was seen more frequently in MAC, while rates of chronic GvHD were comparable. The 3-year esti- mated progression-free and overall survival rates were sim- ilar in both groups. Of note, these findings were also con- firmed after long-term follow-up.32
Similar conclusions were reached from comparative analyses of unrelated donor transplants.33 More stratified comparisons of NMA, RIC, conventional, and so-called hyper-intensive MAC in patients with AML/MDS with <10% blasts13 showed significant and interesting differ- ences in NRM over time: while the NRM at day 100 was highest for hyper-intensive MAC (22%) followed by MAC (11%) and RIC (4%) and NMA (0%), the landmark NRM
after day 100 showed the highest NRM rate for NMA (32%) followed by RIC (17%), MAC (14%) and hyper- intensive conditioning (11%).
Another large Center for International Blood & Marrow Transplant Research (CIBMTR) analysis considered 3,731 MAC and 1,448 RIC/NMA procedures performed between 1997 and 2004. The relapse rates were significantly higher in the RIC and NMA groups than in the MAC group, but there was no difference in NRM rates. Adjusted overall sur- vival rates at 5 years were 34%, 33% and 26% for MAC, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior disease-free survival and overall survival, but there was no difference in these survival outcomes between RIC and MAC regimens (Table 2).34
In summary, retrospective studies in AML/MDS depict a homogeneous landscape of evidence, suggesting increased risk of relapse after RIC and a higher NRM after MAC, while overall survival appeared to be similar comparing bothintensities.
Retrospective studies in other diseases
Other myeloid malignancies
In chronic phase chronic myeloid leukemia, using CIBMTR information 1,395 allogeneic HSCT recipients aged 18-60 years were evaluated in the era of tyrosine kinase inhibition (2007-2014).35 No significant differences between conditioning intensities were detected in multi- variable analysis with respect to leukemia-free survival and NRM. Regarding relapse, the RIC group showed a higher risk of early relapse, and the incidence of chronic GvHD was lower with RIC than with MAC.
In myelofibrosis, an EBMT analysis using data from 2000-2014 showed comparable incidences of NRM between the intensity groups and slightly increased relapse incidence for RIC, with rates at 1 and 5 years of, respective- ly, 14% and 23% for RIC, and 11% and 20% for MAC.36 No significant difference in 5-year overall survival was seen between the two arms.
Lymphoid malignancies
In acute lymphoblastic leukemia, an analysis evaluated the outcomes of 576 adult patients ≥45 years, undergoing HSCT from an HLA-identical sibling in complete remis- sion.37 With a median follow-up of 16 months, the 2-year NRM rate was higher in the MAC group and relapse was increased following RIC. In multivariate analysis, the type of conditioning regimen was not significantly associated with survival.
Table 2. Selected retrospective registry comparisons of conditioning intensity in acute myeloid leukemia/myelodysplastic syndromes.
Trial
Aoudjhane et al.30 Martino et al.13 Luger et al.34
Registry Population N
EBMT AML 722 Age >50 y
EBMT AML/MDS 878
Blasts <10%
CIBMTR AML/MDS 5179
Age 18-69 y
LFS/RFS Relapse NRM %, RIC vs. MAC (P)
OS
44 vs. 46 (ns)
53 vs. 56 (ns)
33 vs 34 (ns)
40 vs. 47 41 vs. 24 (ns) (<0.01)
48 vs. 54 34 vs. 24 (ns) (0.01)
30 vs 33 40 vs 32* (ns) (<0.01)
18 vs. 32 (<0.01)
18 vs. 22 (ns)
29 vs 29 (ns)
RIC: reduced intensity conditioning; EBMT: European Society for Blood and Marrow Transplantation; CIBMTR: Center for International Blood & Marrow Transplant Research; MAC: myeloablative conditioning; AML: acute myeloid leukemia; CML: chronic myeloid leukemia; DLBCL: diffuse large B-cell lymphoma; ALL: acute lymphoblastic leukemia; MM: multiple myeloma; MDS: myelodysplastic syndromes; N: number; LFS: leukemia-free survival; RFS: relapse-free survival; NRM: non-relapse mortality; OS: overall survival; ns: not sig- nificant; y: years. *in the RIC arm of the CIBMTR study non-myeloablative conditioning regimens are also included.
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