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Matched related versus unrelated versus haploidentical donors for allogeneic transplantation in AML patients achieving first complete remission after two induction courses: a study from the ALWP/EBMT
Nagler, A., Labopin, M., Mielke, S., Passweg, J., Blaise, D., Gedde-Dahl, T., Cornelissen, J. J., Salmenniemi, U., Yakoub-Agha, I., Reményi, P., et al
Bone marrow transplantation. 2023;58(7):791-800
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Editor's Choice
Abstract
We compared transplants (HSCT) from matched related siblings (MSD) with those from matched 10/10 and mismatched 9/10 unrelated (UD) and T-replete haploidentical (Haplo) donors in acute myeloid leukemia (AML) in first complete remission (CR1) achieved after two inductions, a known poor prognostic factor. One thousand two hundred and ninety-five patients were included: MSD (n = 428), UD 10/10 (n = 554), UD 9/10 (n = 135), and Haplo (n = 178). Acute GVHD II-IV was higher in all groups compared to MSD. Extensive chronic (c) GVHD was significantly higher in UD 9/10 (HR = 2.52; 95% CI 1.55-4.11, p = 0.0002) and UD 10/10 (HR = 1.48; 95% CI 1.03-2.13, p = 0.036) and cGVHD all grades were higher in UD 9/10 vs MSD (HR = 1.77; 95% CI 1.26-2.49, p = 0.0009). Non-relapse mortality was higher in all groups compared to MSD. Relapse incidence, leukemia-free, and overall survival did not differ significantly between donor types. Finally, GVHD-free relapse-free survival was lower in HSCT from UD 9/10 (HR = 1.56, 95% CI 1.20-2.03, p = 0.0009) but not in those from UD 10/10 (HR = 1.13, p = 0.22) and Haplo donors (HR = 1.12, p = 0.43) compared to MSD. In conclusion, in AML patients undergoing HSCT in CR1 achieved after two induction courses 10/10 UD and Haplo but not 9/10 UD donors are comparable alternatives to MSD.
PICO Summary
Population
Adults with acute myeloid leukemia (AML) in first complete remission (CR1) achieved after two inductions (n=1295)
Intervention
Allo-HSCT from matched related sibling donor (MSD, n=428)
Comparison
Matched 10/10 unrelated donor (UD 10/10 n=554), Mismatched 9/10 unrelated (UD 9/10, n=135) or T-replete haploidentical (Haplo, n=178)
Outcome
Acute GVHD II-IV was higher in all groups compared to MSD. Extensive chronic (c) GVHD was significantly higher in UD 9/10 (HR = 2.52; 95% CI 1.55-4.11) and UD 10/10 (HR = 1.48; 95% CI 1.03-2.13) and cGVHD all grades were higher in UD 9/10 vs MSD (HR = 1.77; 95% CI 1.26-2.49). Non-relapse mortality was higher in all groups compared to MSD. Relapse incidence, leukemia-free, and overall survival did not differ significantly between donor types. Finally, GVHD-free relapse-free survival was lower in HSCT from UD 9/10 (HR = 1.56, 95% CI 1.20-2.03) but not in those from UD 10/10 (HR = 1.13) and Haplo donors (HR = 1.12) compared to MSD
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Comparison of long-term outcome for AML patients alive free of disease 2 years after allogeneic hematopoietic cell transplantation with umbilical cord blood versus unrelated donor: a study from the ALWP of the EBMT
Baron, F., Ngoya, M., Labopin, M., Cornelissen, J. J., Ganser, A., Forcade, E., Sengeloev, H., Socié, G., Blaise, D., Bornhäuser, M., et al
Bone marrow transplantation. 2021
Abstract
Since cord blood transplantation (CBT) has been associated with high graft-versus-leukemia effects and a low incidence of chronic graft-versus-host disease (GVHD), we hypothesized that long-term outcomes might be better in CBT patients than in those given grafts from unrelated donors (UD). Therefore, we performed a landmark study comparing long-term outcomes in acute myeloid leukemia (AML) patients alive and disease-free 2 years after transplantation who received grafts from either CBT or UD. A total of 364 CBT recipients, 2648 UD 10/10 patients and 681 patients given grafts from UD 9/10 were included. Median follow-up was 6.0 years. Five-year leukemia-free survival (LFS) from transplantation was 86% in CBT patients, 84% in UD 10/10 patients (P?=?0.36) and 84% in UD 9/10 patients (P?=?0.86). On multivariate analysis, donor type had no impact on LFS. Similarly, no impact of donor type was observed on relapse incidence or non-relapse mortality. Factors associated with poorer LFS on multivariate analysis included higher age at transplantation (P?0.001), male gender (P?0.001), second complete remission (CR2) versus CR1 (P?=?0.05), secondary AML (P?=?0.01), antecedent of chronic GVHD (P?0.001) and poor-risk cytogenetics (P?=?0.01). In conclusion, our study shows that long-term outcome for AML patients in CR two years after transplantation is not impacted by donor type.
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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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Impact of donor type in patients with AML given allogeneic hematopoietic cell transplantation after low-dose TBI based regimen
Baron, F., Labopin, M., Ruggeri, A., Cornelissen, J. J., Meijer, E., Sengeloev, H., Niederwieser, D., de Groot, M. R., Schouten, H. C., Milpied, N. J., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2018
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Editor's Choice
Abstract
PURPOSE We assessed the impact of donor type in acute myeloid leukemia (AML) patients transplanted with 2 Gy total body irradiation (TBI)-based nonmyeloablative conditioning regimen. Experimental Design: Data from 1715 adult patients, with AML in CR1 or CR2 were included in this retrospective survey. RESULTS Donors consisted either of HLA-matched sibling donors (MSD, n=701), 10/10 HLA-matched unrelated donors (MUD, n=611), HLA-haplo-identical donors (haplo, n=112) or single or double umbilical cord bloods (CBT, n=291). Chronic graft-versus-host disease (GVHD) was less frequent in CBT (28%) and in haplo (30%) patients than in MSD (50%) and MUD (51%) recipients (P<0.001). Two-year incidence of relapse was 32%, 30%, 34% and 34% in MSD, MUD, CBT and haplo patients, respectively (P=0.7). Two-year overall (OS) and GVHD-free relapse free survival (GRFS) were 59% and 29% in MSD patients, 56% and 39% in CBT recipients, 53% and 23% in MUD recipients, and 43% and 37% in haplo patients, respectively. In multivariate analyses, MUD patients had lower GRFS than MSD patients beyond day 100 (HR 1.3, P=0.001) while CBT was associated with a better GRFS than MSD beyond day 100 (HR 0.6, P=0.002). Conclusions: In this large cohort of AML patients transplanted following low-dose TBI-based conditioning the relapse incidence was not affected by donor type suggesting that the intensity of GVL effects might be comparable with these four transplant approaches. Further, CBT was associated with better GRFS beyond day 100 than MSD while the opposite was observed for MUD.
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HLA mismatched donors in patients with myelodysplastic syndrome: an EBMT registry analysis
Robin, M., Porcher, R., Ruggeri, A., Blaise, D., Wolschke, C., Koster, L., Angelucci, E., Stolzel, F., Potter, V., Yakoub-Agha, I., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
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Editor's Choice
Abstract
Recently, haplo-identical transplantation (haplo) using post-transplant cyclophosphamide (PTCy) has been reported to give very encouraging results in patients with hematological malignancies. Patients who have no HLA-matched donor currently have the choice between a mismatched unrelated donor, an unrelated cord blood donor and a haplo-identical related donor. The aim of our study is to compare the outcome of patients with myelodysplastic syndrome (MDS) who have been transplanted from a haplo-identical donor using PTCy, a HLA mismatched unrelated donor (marrow or peripheral blood stem cells) or an unrelated mismatched cord blood donor (CB). 833 MDS patients from the EBMT registry, transplanted between 2011 and 2016, were identified. The potential benefit of haplo was compared to mismatched unrelated and CB in an adjusted and weighted model taking into account potential confounders and other prognostic variables. Haplo was at lower risk of acute GVHD than mismatched unrelated donor (p=0.010) but at similar risk than CB. Progression-free survival was better after haplo (vs. mismatched unrelated, p=0.056, vs. CB, p=0.003) and overall survival tended to be superior after haplo (vs. mismatched unrelated, p=0.082, vs. CB, p=0.002). Non-relapse mortality was not significantly different between haplo and mismatched unrelated donor. Relapse risk was not influenced by the type of donor. In conclusion, patients with MDS from the EBMT registry receiving HSCT from a haplo donor have significant better outcome than CB and at least similar or better outcome than mismatched unrelated donor. Prospective studies comparing the type of donors will be needed to confirm this assumption.
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The increase of the global donor inventory is of limited benefit to patients of non-Northwestern European descent
van Walraven, S. M., Brand, A., Bakker, J. N., Heemskerk, M. B., Nillesen, S., Bierings, M. B., Bungener, L. B., Hepkema, B. G., Lankester, A., van der Meer, A., et al
Haematologica. 2017;102(1):176-183
Abstract
Between 2001 and 2012, the number of unrelated donors registered worldwide increased from 7 to 21 million, and the number of public cord blood units increased to over 500,000. We addressed the question of whether this expansion resulted in higher percentages of patients reaching transplantation. Unrelated donor searches were evaluated for 3,124 eligible patients in the Netherlands in two cohorts (2001-2006, n=995; 2007-2012, n=2129), comparing results for patients of Northwestern European and non-Northwestern European origin. Endpoints were 'donor found' and 'transplantation reached'. The substantial growth of the donor inventory over the period studied did not increase the median number of potential unrelated donors (n=7) for non-Northwestern European patients, but almost doubled the number for Northwestern European patients from 42 to 71. Before and after 2007, an unrelated donor or cord blood was identified for 91% and 95%, respectively, of Northwestern European patients and for 65% and 82% of non-Northwestern European patients (P<0.0001). Non-Northwestern European patients more often needed a cord blood transplant. The degree of HLA matching was significantly lower for non-Northwestern European patients (P<0.0006). The time needed to identify a donor decreased for both populations. The percentage of Northwestern European patients reaching transplantation increased from 77% to 83% and for non-Northwestern European patients from 57% to 72% (P=0.0003). The increase of the global inventory resulted in more transplants for patients lacking a family donor, although the quality and quantity of (potential) haematopoietic cell grafts for patients of a non-Northwestern European descent remained inferior, indicating the need for adaptation of recruitment.
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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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Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD
Carapito, R., Jung, N., Kwemou, M., Untrau, M., Michel, S., Pichot, A., Giacometti, G., Macquin, C., Ilias, W., Morlon, A., et al
Blood. 2016;128(15):1979-1986
Abstract
Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice. Copyright © 2016 by The American Society of Hematology.