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N. Gagelmann and N. Kröger
Regarding diffuse large B-cell lymphoma, the CIBMTR analyzed 396 patients, of whom 165 received MAC, 143 RIC, and 88 NMA.38 NRM was higher after MAC, while relapse incidence was higher after RIC. Survival and GvHD rates did not differ between groups. In patients with relapsed/refractory Hodgkin lymphoma,39 NRM rates were similar and relapse risk was slightly reduced for MAC com- pared with RIC. Subsequently, survival appeared to be bet- ter for recipients of MAC.
In multiple myeloma patients, an analysis from the EBMT (1991-2012) evaluated patients 40-60 years old at the time of HSCT.40 At a median follow-up of 54 months, MAC was associated with a higher risk of death than RIC.41 Notably, results after 2002 were comparable. The main results of the retrospective analyses for hematologic malignancies other than AML/MDS comparing RIC versus MAC are summarized in Table 3.
Factors which may be helpful in the decision process: balance between the risk of relapse and non-relapse mortality
Since, in general, compared to a lower intensity condi- tioning regimen, a higher intensity one is associated with more NRM but less relapse, selecting the optimal intensi- ty of the conditioning regimen requires an appropriate
balance between the risk of relapse and NRM (Figure 1). Thus, other disease-, patient-, and transplant-specific risk factors that affect the risk of relapse and NRM should be taken into account. Next we summarize specific factors that may complicate clinical decision-making (Table 4).
Measurable disease status
Multiple studies, mainly in acute lymphoblastic leukemia and more recently in AML, have investigated the association between the presence of measurable residual disease (MRD) prior to allogeneic HSCT,42 show- ing an increased risk of relapse and death among MRD- positive patients. However, significant between-study heterogeneity was found, underscoring site-specific methodological differences. A recent European LeukemiaNet consensus document identified key clinical and scientific issues in the measurement and application of MRD in AML, providing guidelines for the current and future use of MRD in clinical practice.43
With regards to the conditioning intensity, Walter et al.44 showed that MRD status had strong predictive value both in the MAC and NMA settings, with MRD-defined depth of response prior to HSCT being the most impor- tant predictor of outcome. Conversion from MRD-posi- tivity before HSCT to MRD-negativity after MAC was shown to not substantially improve the incidence of relapse or survival rate.45
Table 3. Selected retrospective registry comparisons of conditioning intensity in other hematologic malignancies.
Trial Registry
Population N
MF 2224 Age 18-74 y
CML 1395
Age18-60 y
DLBCL 396 Age 18-69 y
rrHL 312
LFS/RFS
26 vs. 32 (0.001)*
43 vs. 44 (ns)
15 vs. 18 (ns)
Relapse NRM OS %, RIC vs MAC (P)
McLornan et al.36 Chhabra et al.35
Bacher et al.38 Genadieva-Stravrik et al.39
Mohtyetal.37 Crawleyetal.41
EBMT
CIBMTR
CIBMTR
EBMT
36 vs. 48 (0.07)
20 vs. 23 (0.08)
25 vs. 26 (ns)
38 vs. 26 (0.03)
60 vs. 50 (ns)
47vs.31 (<0.01)
34 vs. 34 (ns)
29 vs. 32 (ns)
47 vs. 56 (0.01)
12 vs. 13 (ns)
21vs.29 (0.03)
24vs.37
(<0.01)
51 vs. 53 (ns)
53 vs. 53 (ns)
20 vs. 18 (ns)
62 vs. 73 (ns)
48vs.45 (ns)
39vs.51 (ns)
Age 25-40 y
EBMT ALL 576 32vs.38
Age ≥45 y (0.07) EBMT MM 516 19vs.34
54vs.27 Age 29-66 y (<0.01) (<0.01)
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. *Unadjusted graft-versus-host disease/relapse-free survival at 5 years.
Figure 1. The balance between risk for non-relapse mortality and risk for relapse when choosing conditioning intensity.
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