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Comparable Long-Term Outcome after Allogeneic Stem-Cell Transplantation from Sibling and Matched Unrelated Donors in AML Patients Older than 50 years. A Report on Behalf of the ALWP of EBMT
Shimoni, A., Labopin, M., Savani, B., Byrne, M., Volin, L., Finke, J., Niederwieser, D., Ehninger, G., Blaise, D., Beelen, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Allogeneic stem-cell transplantation (SCT) is potentially curative therapy in acute myeloid leukemia (AML). Marked improvement has been achieved with SCT from matched unrelated-donors (MUD) in recent years. However, there is limited data comparing the long-term outcomes (beyond 10 years) after SCT from sibling donors and MUDs in older AML patients. We analyzed these outcomes in a large cohort of AML patients (n=1134), age ≥50 years, who were alive and leukemia-free 2 years after SCT from matched siblings (n=848) or MUD (n=286), with a median follow up 8.9 years. The median age was 56 and 58 years, after SCT from sibling and MUDs, respectively (P=0.005). 77%, 12% and 11% in the sibling group were in CR1, CR2 and active leukemia at SCT compared to 50%, 25% and 25% in the MUD group, respectively (P<0.001). 61% of sibling, and 62% of MUDs had reduced-intensity conditioning (P=0.78). The 10-year leukemia-free survival (LFS) of patients surviving leukemia-free 2 years after SCT was 72% and 62%, respectively (P=0.30). Multivariate-analysis identified active leukemia at SCT (HR 1.86, P=0.0001) or CR2 (HR 1.51, P=0.02) compared to CR1, female recipient (HR 0.71, P=0.006), adverse cytogenetics (HR 2.52, P=0.01) and prior GVHD (HR 1.31, P=0.04) as independent factors predicting LFS. Donor and conditioning type were not significant. The cumulative incidence of late relapse was 15% and 17% (P=0.97) and of late non-relapse mortality, 13% and 21%, respectively (P=0.15). Long-term LFS is similar and patients who are leukemia-free 2 years after SCT can expect favorable outcomes with both donor types.
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2.
Hematopoietic stem cell transplantation for adult patients with isolated NPM1 mutated acute myeloid leukemia in first remission
Poire, X., Labopin, M., Polge, E., Blaise, D., Chevallier, P., Maertens, J., Deconinck, E., Forcade, E., Rambaldi, A., Baerlocher, G. M., et al
American journal of hematology. 2018
Abstract
Acute myeloid leukemia (AML) in first remission (CR1) with isolated NPM1 mutation (iNPM1m) is considered a good prognosis genotype, although up to one third relapse. To evaluate the best transplant strategy, we retrospectively compared autologous stem cell transplantation (auto-SCT), related (MSD) and fully matched unrelated (MUD) allogeneic stem cell transplantation (allo-SCT). We identified 256 adult patients including 125 auto-SCT, 72 MSD and 59 MUD. The 2-year leukemia-free survival (LFS) was 62% in auto-SCT, 69% in MUD and 81% in MSD (p=0.02 for MSD versus others). The 2-year overall survival (OS) was not different among auto-SCT, MUD and MSD, reaching 83% (p=0.88). The 2-year non-relapse mortality (NRM) was 2.5% in auto-SCT and 7.5% in allo-SCT (p=0.04). The 2-year cumulative incidence of relapse (RI) was higher after auto-SCT (30%) than after MUD (22%) and MSD (12%, p=0.01). In multivariate analysis, MSD versus auto-SCT but not MUD versus auto-SCT was associated with lower RI (p<0.01 and p=0.13, respectively) and better LFS (p=0.01 and p=0.31, respectively). Age correlated with higher NRM (p<0.01). Allo-SCT using MSD appears as a reasonable transplant option for young patients with iNPM1m AML in CR1. Auto-SCT was followed by worse RI and LFS, but similar OS to both allo-SCT modalities. This article is protected by copyright. All rights reserved.
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3.
Genomic prediction of relapse in recipients of allogeneic haematopoietic stem cell transplantation
Ritari, J., Hyvarinen, K., Koskela, S., Itala-Remes, M., Niittyvuopio, R., Nihtinen, A., Salmenniemi, U., Putkonen, M., Volin, L., Kwan, T., et al
Leukemia. 2018
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Editor's Choice
Abstract
Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the most informative variants while controlling against overfitting. Our results show that germline genetic polymorphisms in patients entail a significant contribution to relapse risk, as judged by the predictive performance of the model (AUC = 0.72 [95% CI: 0.63-0.81]). Furthermore, the top contributing variants were predictive in two independent replication cohorts (n = 258 and n = 125) from the same population. The results can help elucidate relapse mechanisms and suggest novel therapeutic targets. A computational genomic model could provide a step toward individualized prognostic risk assessment, particularly when accompanied by other data modalities.
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ABO incompatibility in mismatched unrelated donor allogeneic hematopoietic cell transplantation for acute myeloid leukemia: A report from the acute leukemia working party of the EBMT
Canaani, J., Savani, B. N., Labopin, M., Michallet, M., Craddock, C., Socie, G., Volin, L., Maertens, J. A., Crawley, C., Blaise, D., et al
American Journal of Hematology. 2017;92(8):789-796
Abstract
ABO incompatibility is commonly observed in stem cell transplantation and its impact in this setting has been extensively investigated. HLA-mismatched unrelated donors (MMURD) are often used as an alternative stem cell source but are associated with increased transplant related complications. Whether ABO incompatibility affects outcome in MMURD transplantation for acute myeloid leukemia (AML) patients is unknown. We evaluated 1,013 AML patients who underwent MMURD transplantation between 2005 and 2014. Engraftment rates were comparable between ABO matched and mismatched patients, as were relapse incidence [34%; 95% confidence interval (CI), 28-39; for ABO matched vs. 36%; 95% CI, 32-40; for ABO mismatched; P=.32], and nonrelapse mortality (28%; 95% CI, 23-33; for ABO matched vs. 25%; 95% CI, 21-29; for ABO mismatched; P=.2). Three year survival was 40% for ABO matched and 43% for ABO mismatched patients (P=.35), Leukemia free survival rates were also comparable between groups (37%; 95% CI, 32-43; for ABO matched vs. 38%; 95% CI, 33-42; for ABO mismatched; P=.87). Incidence of grade II-IV acute graft versus host disease was marginally lower in patients with major ABO mismatching (Hazard ratio of 0.7, 95% CI, 0.5-1; P=.049]. ABO incompatibility probably has no significant clinical implications in MMURD transplantation.
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Alternative donors for allogeneic hematopoietic stem cell transplantation in poor-risk AML in CR1
Versluis, J., Labopin, M., Ruggeri, A., Socie, G., Wu, D., Volin, L., Blaise, D., Milpied, N., Craddock, C., Yakoub-Agha, I., et al
Blood Advances. 2017;1(7):477-485
Abstract
Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the treatment of choice to consolidate remission in patients with poor-risk acute myeloid leukemia (AML). With increasing alternative donors available, the preferred donor or stem cell source is debated. We set out to study outcome in recipients of alloHSCT with poor-risk AML in first complete remission (CR1) by donor type. A total of 6545 adult patients with poor-risk AML in CR1 receiving an alloHSCT using matched related donor (MRD, n = 3511) or alternative donors, including 10/10 (n = 1959) or 9/10 matched unrelated donors (MUDs, n = 549), umbilical cord blood (UCB) grafts (n = 333), or haplo-identical (haplo) donors (n = 193) were compared. Overall survival (OS) at 2 years following MRD alloHSCT was an estimated 59 +/- 1%, which did not differ from 10/10 MUD (57 +/- 1%) and haplo alloHSCT (57 +/- 4%). OS, however, was significantly lower for 9/10 MUD alloHSCT (49 +/- 2%) and UCB grafts (44 +/- 3%), respectively (P < .001). Nonrelapse mortality (NRM) depended on donor type and was estimated at 26 +/- 3% and 29 +/- 3% after haplo alloHSCT and UCB grafts at 2 years vs 15 +/- 1% following MRD alloHSCT. Multivariable analysis confirmed the impact of donor type with OS following MRD, 10/10 MUD, and haplo alloHSCT not being statistically significantly different. NRM was significantly higher for alternative donors as compared with MRD alloHSCT. Collectively, these results suggest that alloHSCT with MRDs and 10/10 MUDs may still be preferred in patients with poor-risk AML in CR1. If an MRD or 10/10 MUD is not available, then the repertoire of alternative donors includes 9/10 MUD, UCB grafts, and haplo-identical donors. The latter type of donor is increasingly applied and now approximates results with matched donors. Presented by J.V. as an oral presentation at the 56th annual meeting of the American Society of Hematology, San Francisco, CA, 6-9 December 2014, and at the 42nd annual meeting of the European Society for Blood and Marrow Transplantation, Valencia, Spain, 3-6 April 2016.Conflict-of-interest disclosure: The authors declare no competing financial interests.
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Matched and mismatched unrelated donor compared to autologous stem cell transplantation for acute myeloid leukemia in first complete remission: a retrospective, propensity score-weighted analysis from the ALWP of the EBMT
Saraceni, F., Labopin, M., Gorin, N. C., Blaise, D., Tabrizi, R., Volin, L., Cornelissen, J., Cahn, J. Y., Chevallier, P., Craddock, C., et al
Journal of hematology & oncology. 2016;9(1):79
Abstract
BACKGROUND Optimal post-remission strategy for patients with acute myeloid leukemia (AML) is matter of intense debate. Recent reports have shown stronger anti-leukemic activity but similar survival for allogeneic stem cell transplantation (allo-HSCT) from matched sibling donor compared to autologous transplantation (auto-HSCT); however, there is scarcity of literature confronting auto-HSCT with allo-HSCT from unrelated donor (UD-HSCT), especially mismatched UD-HSCT. METHODS We retrospectively compared outcome of allogeneic transplantation from matched (10/10 UD-HSCT) or mismatched at a single HLA-locus unrelated donor (9/10 UD-HSCT) to autologous transplantation in patients with AML in first complete remission (CR1). A total of 2879 patients were included; 1202 patients received auto-HSCT, 1302 10/10 UD-HSCT, and 375 9/10 UD-HSCT. A propensity score-weighted analysis was conducted to control for disease risk imbalances between the groups. RESULTS Matched 10/10 UD-HSCT was associated with the best leukemia-free survival (10/10 UD-HSCT vs auto-HSCT: HR 0.7, p=0.0016). Leukemia-free survival was not statistically different between auto-HSCT and 9/10 UD-HSCT (9/10 UD-HSCT vs auto-HSCT: HR 0.8, p=0.2). Overall survival was similar across the groups (10/10 UD-HSCT vs auto-HSCT: HR 0.98, p=0.84; 9/10 UD-HSCT vs auto-HSCT: HR 1.1, p=0.49). Notably, in intermediate-risk patients, OS was significantly worse for 9/10 UD-HSCT (9/10 UD-HSCT vs auto-HSCT: HR 1.6, p=0.049), while it did not differ between auto-HSCT and 10/10 UD-HSCT (HR 0.95, p=0.88). In favorable risk patients, auto-HSCT resulted in 3-year LFS and OS rates of 59 and 78 %, respectively. CONCLUSIONS Our findings suggest that in AML patients in CR1 lacking an HLA-matched sibling donor, 10/10 UD-HSCT significantly improves LFS, but this advantage does not translate in better OS compared to auto-HSCT. In intermediate-risk patients lacking a fully HLA-matched donor, auto-HSCT should be considered as a valid option, as better survival appears to be provided by auto-HSCT compared to mismatched UD-HSCT. Finally, auto-HSCT provided an encouraging outcome in patients with favorable risk AML.