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BuFlu (MAC)
8 GyTBIFlu (MAC)
TreoFlu (MAC)
BuFlu (RIC)
BuFlu (RIC) incl n=4 CML (NMA)
BuFlu; FluMel
(RIC) BuFlu (RIC)
FLAMSA-Bu
(seq RIC)
BuCy (MAC)
12 GyTBI/Cy (MAC)
BuFlu (RIC)
FluTBI (NMA)
BuCy(MAC)
BuFlu; BuCy;
TBICy (MAC) BuCy (MAC)
Bu/Flu or
Mel/Flu (RIC)
40 vs. 47 (ns)
58 vs. 56 (ns)
64 vs. 50 (0.001)
35 vs. 23 (ns)
NR
47 vs. 68 (<0.01)
62 vs. 58 (ns)
54 vs. 49 (ns)
24 vs. 21 (ns)
28 vs. 26 (ns)
25 vs. 23 (ns)
27 vs. 54 (<0.01)
12 vs. 35 (ns)
48 vs. 14 (<0.001)
17 vs. 15 (ns)
27 vs. 30 (ns)
8vs.18 (0.03)
13 vs. 18 (ns)
11 vs. 23 (0.05)
38 vs. 22 (0.03)
11 vs. 11 (ns)
4vs.16 (<0.01)
17 vs. 25 (ns)
21 vs. 17 (ns)
27 vs. 35 (ns)
61 vs. 58 (ns)
71 vs. 56 (0.01)
41 vs. 41 (ns)
76 vs. 62 (ns)
78 vs. 68 (0.07)
76 vs. 63 (0.08)
61 vs. 59 (ns)
Conditioning intensity in allogeneic HSCT
the inclusion of new regimens showing reduced non- hematologic toxicity and different safety profiles in gen- eral.10 Moreover, this classification ignores the additional intensity of purine analogs used for immune-ablation11 or of disease-specific drugs used to achieve reduction in relapse risk. Thus, in literature less well-defined terms, such as “reduced toxicity”,12 “hyper-intensive”13 or “aug- mented reduced intensity” are now more commonly used.14 To address this increasing variability, the EBMT has recently proposed an updated refined classification, assigning intensity weight scores for frequently used conditioning regimen components in relation to their prognostic value for non-relapse mortality (NRM); and using their sum to generate a transplant conditioning intensity score. This also categorized classification showed only slightly improved discrimination for the outcome of NRM, while discrimination and thus prog- nostic utility with respect to the outcome of relapse were comparable to the previous dichotomized RIC/MAC classification.15
Prospective randomized studies with different dose intensities
Prospective randomized studies comparing different condition regimen intensities exist only for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (including very few patients with chronic myeloid leukemia; see Table 1), while no prospective randomized studies exist for other hematologic malignancies includ-
ing non-Hodgkin lymphoma, Hodgkin lymphoma and multiple myeloma.
Toxicity-reduced myeloablative conditioning versus myeloablative conditioning
The first trial of toxicity-reduced MAC versus MAC was a randomized phase III trial by Bornhäuser et al. in 195 patients (median age 44 years) with intermediate- or high-risk AML in first complete remission.16 Treatment in the lower intensity arm consisted of a lower dose of TBI (800 cGy) plus fludarabine which was compared to a standard MAC approach of cyclophosphamide-TBI (1200 cGy). Although the study was concluded early because of slow accrual of patients, outcomes were not significantly different with regards to NRM, cumulative incidence of relapse, and survival, with these findings being confirmed in a long-term follow-up report.17 Interestingly, severe mucositis and in-hospital mortality were less frequent in the RIC group, leading to the conclusion that RIC regi- mens lessened the toxic effects of transplantation, and the short-term mortality at 1 year was lower in the RIC group. An age limit of 60 years may impede the interpre- tation of the findings. In contrast, these results suggest that perhaps RIC regimens should be used preferentially in patients <60 years old with AML in first complete remission. Aside from this, the RIC regimen of TBI 800 cGy is, according to the current definition, still a MAC regimen .
Another attempt to reduce intensity and toxicity with- out losing myeloablative intensity of the conditioning regimen was made by replacing cyclophosphamide with
Table 1. Characteristics and results of prospective randomized trials comparing different intensities and toxicity of conditioning regimens.
Trial Population
Toxicity reduced MAC vs. MAC or RIC
Regimen
RFS Relapse NRM OS %(P) %(P) %(P) %(P)
Rambaldi et al.20 Bornhäuser et al.16
Beelen et al.24
RIC vs. NMA Blaise et al.2
RIC vs. MAC Ringdén et al.90
Scott et al.26 Kröger et al.25
RIC vs. sequential RIC Craddock et al.14
AML
Age >40 y
AML CR1
Age 18-60 y
IR/HR cytogenetics
AML/MDS
Age ≥50 y and/or CI >2/KPS >60%
Hematologic malignancies
AML/CML Age ≤60 y
AML/MDS in CR
Age 18-65 y
MDS/sAML Age 18-60 y UD Age 18-65 RD
AML /MDS
Age 18-75 y
RIC: reduced intensity conditioning; MAC: myeloablative conditioning; NMA: nonmyeloablative; RFS: relapse-free survival; NRM: non-relapse mortality; OS: overall survival; (s)AML: (secondary) acute myeloid leukemia; CML: chronic myeloid leukemia; CR: complete remission; Cy: cyclophosphamide; Treo: treosulfan; Flu: fludarabine; TBI: total body irradia- tion; Bu: busulfan; IR: intermediate-risk; HR: high-risk; Mel: melphalan; MDS: myelodysplastic syndrome; UD: unrelated donor; RD: related donor; ns: not significant; y: years; CI: comorbidity index; KPS: Karnofsky performance status; NR: not reported; seq: sequential.
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