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X. Poiré et al.
model. We performed a first multivariate analysis including the following individual cytogenetics: abn(11q23), abn(17p) and -7/7q-. Then, MK and CK were added to the same model and thereafter we performed a stepwise selection for the cytogenetics variables (P in/out =0.10). Abn 17p, MK and CK remained in the Cox model for OS. Abn 17p and MK also remained in the Cox model for relapse, LFS and GRFS. The final Cox model contained all variables that were selected for at least one end point. Proportional hazards assumptions were checked systematically using the Grambsch-Therneau residual-based test. All interactions between cytogenetics groups and other co-variates were tested. Results were expressed as hazard ratio (HR) with 95% confidence interval (CI). Statistical analyses were performed with SPSS 24.0 (SPSS Inc., Chicago, IL, USA) and R 3.4.1 [R Core Team (2017). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL: https://www.R-project.org/.]
Results
Patients’ characteristics
Patients’ characteristics are summarized in Table 1. Five hundred and one patients met the study inclusion criteria. Median follow up was 57 months [Interquartile Range (IQR): 27-116 months] and median age was 55-years old (range: 18-75 years). The main MAC regimen was the combination of cyclophosphamide with TBI followed by cyclophosphamide and busulfan, or fludarabine and busulfan. The main RIC regimen was the association of fludarabine and busulfan, followed by fludarabine and low-dose TBI, or fludarabine and melphalan. The most frequent GvHD prophylaxis was the association of cyclosporine and methotrexate (44%) followed by cyclosporine and mycophenolate mofetil (29%). Additional cytogenetic abnormalities besides -5/5q are illustrated in Figure 1. The vast majority of the patients showed a CK (87%) and/or MK (67%) in combination with -5/5q-. Patients also showed frequent association with abn(17p) (39%) and -7/7q- (37%), although the vast majority of these additional cytogenetic features were observed in the context of a complex or monosomal kary- otype. Very few patients presented with abn(3q26) (n=22) or abn(11q23) (n=42). Most of those adverse cytogenetic features were not present as a single additional abnormal- ity but rather existed in combination.
Transplantation outcomes: relapse incidence, non-relapse mortality, leukemia-free survival, overall survival and graft-versus-host disease in the entire cohort
The 2-year cumulative incidence of relapse in the overall series was 59.9% (95%CI: 55.3-64.2) (Online Supplementary Figure S1A), and the median time to relapse was four months (IQR 0.2-130). In univariate analysis, a matched sibling donor (MSD), and the presence of addi- tional cytogenetic abnormalities defined as CK, MK and abn(17p) were all associated with an increased RI (Table 2). The 2-year probability of NRM was 19.9% (95%CI: 16.4-23.7) (Online Supplementary Table S1B). NRM was strongly associated with donor type and disease status in univariate analysis. None of the additional cytogenetic events impacted NRM (Table 2).
The 2-year probability of LFS in this entire cohort was 20.2% (95% CI: 16.4-23.9) (Online Supplementary Figure
S1C). In univariate analysis, we found that younger age (< 55-year old), being in first complete remission (CR1), better KPS (>80%) and administration of MAC were all significantly associated with better LFS. CK, MK, abn(17p) and -7/7q- also impacted on LFS (Table 2). The 2-year OS was 27% (95%CI: 22.8-31.2) (Online Supplementary Figure S1D). Similarly to LFS, younger age (< 55-year old), being in CR1, better KPS (>80%) and administration of MAC led to better OS in univariate analysis. Notably, CK, MK, abn(17p) and -7/7q- impacted prognosis (Table 2).
The cumulative incidence of grade II-IV acute GvHD was 29.3% (95%CI: 25.2-33.4) and the 2-year cumulative incidence of chronic GvHD was 27.3% (95%CI: 23.2- 31.5), leading to a 2-year probability of GRFS of 13.1% (95%CI: 10-16.3). In univariate analysis, the use of MUD and not being in remission at SCT were associated with a higher incidence of grade II-IV acute GvHD. In contrast, advanced disease status was associated with a lower risk of chronic GvHD, a fact probably due to the high risk of early relapse among patients not transplanted in remis- sion. A female donor to a male recipient led to higher inci- dence of chronic GvHD in univariate analysis. The pres- ence of additional cytogenetic abnormalities was not asso-
Table 1. Patients’ characteristics from the entire cohort (n=501).
Median follow-up (range)
Median age (range)
Time from diagnosis to SCT (range) Median year of SCT (range)
Disease status at SCT, N (%) CR1
CR2/CR3 Active disease
Secondary AML, N (%)
Donor type, N (%) MSD/MUD
Patients’ gender, N (%)
M/F
Female donor to male recipient, N (%) KPS ≥ 80%, N (%)
Patient CMV positive, N (%)
Donor CMV positive, N (%)
Conditioning intensity, N (%) MAC/RIC
Missing
Conditioning regimen, N (%) Busulfan-based
TBI-based Fludarabine-Busulfan Fludarabine Melphalan
Stem cell source, N (%) BM/PB
In vivo TCD, N (%) ATG
Alemtuzumab
Missing
21 months (2-173)
55 years (18-75) 5 months (0.1-24) 2010 (2000-2015)
338 (68%) 21 (4%) 142 (28%)
104 (21%) 224/277 (45%/55%)
271/230 (54%/46%)
92 (19%) 447 (94%) 314 (64%) 254 (52%)
223/278 (45%/55%) 2
225 (45%) 139 (28%) 143 (29%) 40 (8%)
82/419 (16%/84%)
282 (57%) 246 (49%) 36 (7%) 7
SCT: allogeneic stem cell transplantation; N: number; CR1: first remission; CR2: second remission; CR3: third remission; AML: acute myeloid leukemia; MSD: matched sibling donor; MUD: matched unrelated donor; M: male; F: female; KPS: Karnofsky’s perform- ance status; CMV: cytomegalovirus; MAC: myeloablative conditioning regimen; RIC: reduced-intensity conditioning regimen;BM:bone marrow;PB:peripheral blood;TCD: T-cell depletion; ATG: anti-thymocyte globulin.
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