The optimal conditioning for patients with higher risk MDS receiving potentially curative allogeneic haematopoietic stem cell transplant(allo-HCT) remains to be defined. This is particularly the... Show moreThe optimal conditioning for patients with higher risk MDS receiving potentially curative allogeneic haematopoietic stem cell transplant(allo-HCT) remains to be defined. This is particularly the case for patients with excess of blasts at time of allo-HCT. Sequential (Seq) conditioning, whereby chemotherapy is followed rapidly by transplant conditioning, offers an opportunity to decrease disease burden, potentially improving outcomes allo-HCT outcomes. Herein we present the only analysis comparing Seq to myeloablative (MAC) and reduced intensity conditioning (RIC) specifically focussed on MDS patients with excess of blasts at allo-HCT. 303 patients were identified in the EBMT registry, receiving RIC (n = 158), Seq (n = 105), and MAC (n = 40). Median follow-up was 67.2 months and median age at allo-HCT was 59.5 years (IQR 53.5-65.6). For the entire cohort, 3 y overall survival (OS) was 50% (95% CI 45-56%) and relapse free survival (RFS) 45% (95% CI 40-51%). No significant differences in OS (log-rank p = 0.13) and RFS (log-rank p = 0.18) were observed between conditioning protocols. On multivariable analysis, lower performance status, worse IPSS-R cytogenetics, sibling donor (compared to 8/8 MUD) and >= 20% blasts at allo-HCT were associated with worse outcomes. In conclusion, the Seq protocol did little to influence the outcome in this high-risk group of patients, with outcomes mostly determined by baseline disease risk and patient characteristics such as performance status. Show less
Myelodysplastic syndromes (MDS) are the second common indication for an Allo-HCT. We compared the outcomes of 1414 matched sibling (MSD) with 415 haplo-identical donors (HD) transplanted with post... Show moreMyelodysplastic syndromes (MDS) are the second common indication for an Allo-HCT. We compared the outcomes of 1414 matched sibling (MSD) with 415 haplo-identical donors (HD) transplanted with post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis between 2014 and 2017. The median age at transplant with MSD was 58 and 61 years for HD. The median time to neutrophil engraftment was longer for HD being 20 vs 16 days for MSD (p < 0.001). Two-year overall survival (OS) and PFS (progression free survival) with MSD were significantly better at 58% compared with 50%, p <= 0.001, and 51% vs 47%, p = 0.029, with a HD. Relapse at 2 years was lower with a HD 23% than with MSD 29% (p = 0.016). Non relapse mortality (NRM) was higher with HD in the first 6 months post-transplant [HR 2.59 (1.5-4.48) p < 0.001] and was also higher at 2 years being 30% for HD and 20% for MSD, p <= 0.001. The incidence of acute GVHD grade II-IV and III-IV at 100 days was comparable for MSD and HD, however, chronic GVHD at 2 years was significantly higher with MSD being 44% vs 32% for HD (p < 0.001). After multivariable analysis, OS and primary graft failure were significantly worse for HD particularly before 6 months [HR 1.93(1.24-3.0)], and HR [3.5(1.5-8.1)]. The median age of HD 37 (IQR 30-47) years was significantly lower than sibling donors 56 (IQR 49-62 years) p < 0.001. However, there was no effect on NRM, relapse or PFS. This data set suggests that a MSD donor remains the preferred choice in MDS over a haplo donor. Transplants with haploidentical donors result in satisfactory long-term outcome, justifying it's use when no better donor is available. Show less
Robin, M.; Wreede, L.C. de; Padron, E.; Bakunina, K.; Fenaux, P.; Koster, L.; ... ; Itzykson, R. 2022
To determine the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in chronic myelomonocytic leukemias (CMML), we assembled a retrospective cohort of CMML patients 18-70... Show moreTo determine the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in chronic myelomonocytic leukemias (CMML), we assembled a retrospective cohort of CMML patients 18-70 years old diagnosed between 2000 and 2014 from an international CMML dataset (n 5 730) and the EBMT registry (n 5 384). The prognostic impact of allo-HCT was analyzed through univariable and multivariable time-dependent models and with a multistate model, accounting for age, sex, CMML prognostic scoring system (low or intermediate-1 grouped as lower-risk, intermediate-2 or high as higher-risk) at diagnosis, and AML transformation. In univariable analysis, lower-risk CMMLs had a 5-year overall survival (OS) of 20% with allo-HCT vs 42% without allo-HCT (P <.001). In higher-risk patients, 5-year OS was 27% with allo-HCT vs 15% without allo-HCT (P 5.13). With multistate models, performing allo-HCT before AML transformation reduced OS in patients with lower-risk CMML, and a survival benefit was predicted for men with higher-risk CMML. In a multivariable analysis of lower-risk patients, performing allo-HCT before transformation to AML significantly increased the risk of death within 2 years of transplantation (hazard ratio [HR], 3.19; P <.001), with no significant change in long-term survival beyond this time point (HR, 0.98; P 5.92). In higherrisk patients, allo-HCT significantly increased the risk of death in the first 2 years after transplant (HR 1.46; P 5.01) but not beyond (HR, 0.60; P 5.09). Performing allo-HCT before AML transformation decreases life expectancy in lower-risk patients but may be considered in higher-risk patients. Show less
Acute graft-versus-host disease (aGvHD) remains a major threat to successful outcome following allogeneic hematopoietic cell transplantation though advances in prophylaxis and supportive care have... Show moreAcute graft-versus-host disease (aGvHD) remains a major threat to successful outcome following allogeneic hematopoietic cell transplantation though advances in prophylaxis and supportive care have been made. The aim of this study is to test whether the incidence and mortality of aGvHD have decreased over time. 102,557 patients with a median age of 47.6 years and with malignancies after first allogeneic sibling or unrelated donor (URD) transplant were studied in the following periods: 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015. Findings: 100-day incidences of aGvHD grades II-IV decreased from 40% to 38%, 32%, 29% and 28%, respectively, over calendar time (P<0.001). In multivariate analysis URD, not in complete remission (CR) at transplant or untreated, and female donor for male recipient were factors associated with increased risk whereas the use of ATG/alemtuzumab decreased aGvHD incidence. Median follow-up was 214, 169, 127, 81 and 30 months, respectively, for the periods analyzed. Three-year-survival after aGvHD grades II-IV increased significantly from 38% to 40%, 43%, 44%, and 45%, respectively. In multivariate analysis URD, not in CR at transplant, peripheral blood as stem cell source, female donor for male recipient, and the use of ATG/alemtuzumab were associated with increased mortality whereas reduced-intensity conditioning was linked to lower mortality. Mortality increased with increasing patient age but decreased in the recent cohorts. Our analysis demonstrates that aGvHD has decreased over recent decades and also that the survival rates of patients affected with aGvHD has improved. Show less
Nabergoj, M.; Mauff, K.; Beelen, D.; Ganser, A.; Kroger, N.; Stolzel, F.; ... ; Yakoub-Agha, I. 2022
We performed a registry study on therapy-related myeloid neoplasm (t-MN), both therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) following treatment for breast... Show moreWe performed a registry study on therapy-related myeloid neoplasm (t-MN), both therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) following treatment for breast cancer who underwent a first allogeneic hematopoietic cell transplant (allo-HCT). Of 252 identified female patients (median age 57 years), 77% were transplanted for t-AML and 23% for t-MDS, with a median time from breast cancer diagnosis to the diagnosis of tMN and subsequent allo-HCT of 3.7 and 4.6 years, respectively. At transplant, 191 patients were in remission for breast cancer, while 4 were not (57 missing). T-MN was in a complete remission at the time of transplant in 67% of patients. 2-year overall survival, relapse free-survival, relapse incidence and non-relapse mortality were 50%, 45%, 33%, and 22%, respectively. Multivariable analysis revealed that if the t-MN was not in CR pre-transplant, this was associated with lower OS, RFS, and a higher relapse incidence. Seventeen cases of breast cancer recurrence were recorded after a median of 2.4 years post-transplant, and relapse of primary breast cancer accounted for 7% of deaths. This study indicates that allo-HCT for t-MN following treatment for breast cancer shows encouraging transplant outcomes. The incidence of breast cancer relapse post-transplant remains a cause for concern. Show less
The EBMT Chronic Malignancies Working Party performed a retrospective analysis of 215 patients who underwent a second allo-HCT for myeloma between 1994 and 2017, 159 for relapse and 56 for graft... Show moreThe EBMT Chronic Malignancies Working Party performed a retrospective analysis of 215 patients who underwent a second allo-HCT for myeloma between 1994 and 2017, 159 for relapse and 56 for graft failure. In the relapse group, overall survival (OS) was 38% (30-46%) at 2 years and 25% (17-32%) at 5 years. Patients who had a HLA-identical sibling (HLAid-Sib) donor for their first and second transplants had superior OS (5 year OS: HLAid-Sib/HLAid-Sib: 35% (24-46%); Others 9% (0-17%), p < 0.001). There was a significantly higher incidence of acute grade II-IV GvHD in those patients who had also developed GvHD following their initial HLA-identical sibling allo-HCT (HLAid-Sib/HLAid-Sib: 50% (33-67%); Other 22% (8-36%), p = 0.03). More as opposed to fewer than 2 years between transplants was associated with superior 5-yr OS (31% (21-40%) vs. 10% (1-20%), P = 0.005). On multivariate analysis, consecutive HLA-identical sibling donor transplants conferred a significant OS advantage (0.4 (0.24-0.67), p < 0.001). In the graft failure group, OS was 41% at 2 years. In summary, a second allo-HCT using a HLA-identical sibling donor, if available, provides the best transplant outcomes for relapsed myeloma in this setting. Show less
We performed a retrospective assessment of patient- and transplant-specific characteristics and outcomes for 4142 patients undergoing allogeneic haematopoietic cell transplant for myelofibrosis... Show moreWe performed a retrospective assessment of patient- and transplant-specific characteristics and outcomes for 4142 patients undergoing allogeneic haematopoietic cell transplant for myelofibrosis between 1995 and 2018 across 278 centres. Activity increased steadily across the four analysed eras (<2006, 2006-2010, 2011-2014 and 2015-2018). Median recipient age increased over time between the earliest and most recent cohort (49.4 years (range, 20.1-68) versus 59.3 years (range, 18.1-78.1). Increasing number of patients with a Karnofsky performance status <90 underwent transplant over time. Increased utilisation of matched unrelated donors was apparent (<2006, 22.5% versus 2015-18, 45.2%; p < 0.001). Decreased use of myeloablative conditioning, increased use of busulphan-based platforms and anti-thymocyte globulin was evident. Of note, rates of acute (a)GVHD grade II-IV by day +100 decreased over time (p = 0.027) as did rates of chronic (c) GVHD, predominantly extensive cGVHD (<2006, 36% (31-41%) versus 2015-18, 23% (21-25%); p = 0.001). Overall, significant factors associated with worse overall survival and non-relapse mortality (NRM) remained older age, use of donors other than matched sibling, recipient CMV seropositivity and a lower Karnofsky performance status (<90). Multivariable analysis demonstrated improvements in overall survival and reductions in relapse risk over time with stable NRM rates despite increasing numbers of older, less fit patients and use of unrelated donors. Show less
Nabergoj, M.; Mauff, K.; Robin, M.; Kroger, N.; Angelucci, E.; Poire, X.; ... ; Yakoub-Agha, I. 2021
Therapeutic management of patients with primary or secondary myelofibrosis (MF) who experience relapse or graft failure following allogeneic haematopoietic cell transplantation (allo-HCT) remains... Show moreTherapeutic management of patients with primary or secondary myelofibrosis (MF) who experience relapse or graft failure following allogeneic haematopoietic cell transplantation (allo-HCT) remains heterogeneous. We retrospectively analyzed 216 patients undergoing a second allo-HCT for either relapse (56%) or graft failure (31%) between 2010 and 2017. Median age was 57.3 years (range 51-63). The same donor as for the first allo-HCT was chosen in 66 patients (31%) of whom 19 received an HLA-identical sibling donor, whereas a different donor was chosen for 116 patients (54%). Median follow-up was 40 months. Three-year overall survival (OS) and relapse-free survival (RFS) were 42% and 39%, respectively. Three-year non-relapse mortality (NRM) and relapse rates were 36% and 25%, respectively. Grade II-IV and III-IV acute GVHD occurred in 25% and 11% of patients, respectively, and the 3-year incidence of chronic GVHD was 33% including 14% for extensive grade. Graft-failure incidence at 1 year was 14%. In conclusion, our data suggest that a second allo-HCT is a potential option for patients failing first allo-HCT for MF albeit careful patient assessment is fundamental to identify individual patients who could benefit from this approach. Show less
Human leukocyte antigen (HLA) class-I mismatches that trigger donor-versus-recipient natural killer (NK)-cell alloreactivity reduce the incidence of leukemia relapse and improve survival of acute... Show moreHuman leukocyte antigen (HLA) class-I mismatches that trigger donor-versus-recipient natural killer (NK)-cell alloreactivity reduce the incidence of leukemia relapse and improve survival of acute myeloid leukemia patients after T-cell-depleted HLA-haplotype mismatched ("haploidentical") hematopoietic transplantation. In murine graft-versus-host disease (GvHD) models, alloreactive NK-cells also prevent GvHD. Here we report the results of a non-interventional, prospective study performed on behalf of the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation. The study was aimed at re-assessing the role of NK-cell alloreactivity in a cohort of haploidentical transplants performed in Europe between 2012 and 2015 and composed of unmanipulated, as well as T-cell-depleted transplants. One hundred thirty-eight patients with acute myeloid or lymphoid leukemias were analyzed. Eighty-six patients received ex-vivo T-cell-depleted transplants, 52 patients received unmanipulated transplants. Fifty patients were transplanted from NK alloreactive donors, 88 from non-NK alloreactive donors. NK cell alloreactivity did not impact on GvHD/relapse-free survival (GRFS) in unmanipulated transplants (HR: 1.66 (0.9-3.1), p = 0.1). In contrast, it did impact beneficially on GRFS in T-cell-depleted transplants (HR: 0.6, (0.3-1.2), p = 0.14, interaction p < 0.001). This effect was the consequence of reduced incidences of acute and chronic GvHD and non-relapse mortality. Show less
Schetelig, J.; Baldauf, H.; Koster, L.; Kuxhausen, M.; Heidenreich, F.; Wreede, L.C. de; ... ; Robin, M. 2021
Results from registry studies suggest that harnessing Natural Killer (NK) cell reactivity mediated through Killer cell Immunoglobulin-like Receptors (KIR) could reduce the risk of relapse after... Show moreResults from registry studies suggest that harnessing Natural Killer (NK) cell reactivity mediated through Killer cell Immunoglobulin-like Receptors (KIR) could reduce the risk of relapse after allogeneic Hematopoietic Cell Transplantation (HCT). Several competing models have been developed to classify donors as KIR-advantageous or disadvantageous. Basically, these models differ by grouping donors based on distinct KIR-KIR-ligand combinations or by haplotype motif assignment. This study aimed to validate different models for unrelated donor selection for patients with Myelodysplatic Syndromes (MDS) or secondary Acute Myeloid Leukemia (sAML). In a joint retrospective study of the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) registry data from 1704 patients with secondary AML or MDS were analysed. The cohort consisted mainly of older patients (median age 61 years) with high risk disease who had received chemotherapy-based reduced intensity conditioning and anti-thymocyte globulin prior to allogeneic HCT from well-matched unrelated stem cell donors. The impact of the predictors on Overall Survival (OS) and relapse incidence was tested in Cox regression models adjusted for patient age, a modified disease risk index, performance status, donor age, HLA-match, sex-match, CMV-match, conditioning intensity, type of T-cell depletion and graft type. KIR genes were typed using high-resolution amplicon-based next generation sequencing. In univariable and multivariable analyses none of the models predicted OS and the risk of relapse consistently. Our results do not support the hypothesis that optimizing NK-mediated alloreactivity is possible by KIR-genotype informed selection of HLA-matched unrelated donors. However, in the context of allogeneic transplantation, NK-cell biology is complex and only partly understood. KIR-genes are highly diverse and current assignment of haplotype motifs based on the presence or absence of selected KIR genes is over-simplistic. As a consequence, further research is highly warranted and should integrate cutting edge knowledge on KIR genetics, and NK-cell biology into future studies focused on homogeneous groups of patients and treatment modalities. Show less
We analyzed newly diagnosed multiple myeloma patients with del(17p) and/or t(4;14) undergoing either upfront single autologous (auto), tandem autologous (auto-auto) or tandem autologous/reduced... Show moreWe analyzed newly diagnosed multiple myeloma patients with del(17p) and/or t(4;14) undergoing either upfront single autologous (auto), tandem autologous (auto-auto) or tandem autologous/reduced-intensity allogeneic (auto-allo) stem cell transplantation. 623 patients underwent either auto (n = 446), auto-auto (n = 105), or auto-allo (n = 72) between 2000 and 2015. 46% of patients had t(4;14), 45% had del(17p) while 9% were reported having both abnormalities. Five-year overall survival (OS) was 51% (95% confidence interval [CI], 45-58%) for single auto, 60% (95% CI, 49-72%) for auto-auto, and 67% (95% CI, 53-80%) for auto-allo (p = 0.187). Five-year progression-free survival (PFS) was 17% (95% CI, 12-22%), 33% (95% CI, 22-43%), and 34% (95% CI, 21-38%;p = 0.048). Five-year relapse rate was 82, 63, and 56%, while non-relapse mortality was 1, 4, and 10%. In multivariable analysis, in t(4;14) with single auto as reference, auto-auto (hazard ratio [HR], 0.44;p = 0.007) and auto-allo (HR, 0.45;p = 0.018) were associated with better PFS. In terms of t(4;14) and OS, auto-auto appeared to improve outcome compared with single auto (HR, 0.49;p = 0.096). In del(17p), outcome in PFS was similar between single auto and auto-auto, while auto-allo appeared to improve PFS (HR, 0.65;p = 0.097). No significant difference in OS was identified between the groups in patients with del(17p). Show less
Background and purpose - The uncemented Symax hip stem has shown early proximal ingrowth as result of the BONIT-hydroxyapatite (HA) coating and the distal DOTIZE surface treatment. We evaluated 2... Show moreBackground and purpose - The uncemented Symax hip stem has shown early proximal ingrowth as result of the BONIT-hydroxyapatite (HA) coating and the distal DOTIZE surface treatment. We evaluated 2-year postoperative radiostereometric analysis (RSA) migration of the Symax hip stem in THA patients. We also investigated the correlation between migration at 4 weeks and clinical outcomes after 2 years. Patients and methods - Patients in a 2-year clinical follow-up single-centre RSA randomized controlled trial were randomized to 2 different cup designs. All 45 patients received a Symax hip stem. RSA migration patterns of the Symax hip stem is presented here as a single cohort. RSA examinations were performed postoperatively, but before weight-bearing, and subsequently after 1, 3, 6, 12, and 24 months. Clinical outcomes and radiographic evaluations were assessed 3, 6, 12, and 24 months postoperatively. Results - During the first 4 weeks, the Symax hip stem subsided, rotated into retroversion, and translated posteriorly, after which the migration ceased and the prosthesis stabilized. All clinical outcomes improved from preoperatively to 2 years. There was no clinically or statistically significant correlation between subsidence and retroversion at 4 weeks and clinical outcomes after 2 years. Interpretation - RSA evaluation of the uncemented Symax hip stem confirms that the design principles and coating properties lead to early stabilization of the stem, as early as 4 weeks postoperatively. There was no correlation between subsidence and retroversion at 4 weeks and clinical outcomes after 2 years. Based on the predictive potential of the RSA technique, we anticipate excellent long-term survival of this hip stem. Show less
Styczynski, J.; Tridello, G.; Koster, L.; Iacobelli, S.; Biezen, A. van; Werf, S. van der; ... ; Infect Dis Working Party EBMT 2020
Information on incidence, and factors associated with mortality is a prerequisite to improve outcome after hematopoietic stem cell transplantation (HSCT). Therefore, 55 ' 668 deaths in 114 ' 491... Show moreInformation on incidence, and factors associated with mortality is a prerequisite to improve outcome after hematopoietic stem cell transplantation (HSCT). Therefore, 55 ' 668 deaths in 114 ' 491 patients with HSCT (83.7% allogeneic) for leukemia were investigated in a landmark analysis for causes of death at day 30 (very early), day 100 (early), at 1 year (intermediate) and at 5 years (late). Mortality from all causes decreased from cohort 1 (1980-2001) to cohort 2 (2002-2015) in all post-transplant phases after autologous HSCT. After allogeneic HSCT, mortality from infections, GVHD, and toxicity decreased up to 1 year, increased at 5 years; deaths from relapse increased in all post-transplant phases. Infections of unknown origin were the main cause of infectious deaths. Lethal bacterial and fungal infections decreased from cohort 1 to cohort 2, not unknown or mixed infections. Infectious deaths were associated with patient-, disease-, donor type, stem cell source, center, and country- related factors. Their impact varied over the post-transplant phases. Transplant centres have successfully managed to reduce death after HSCT in the early and intermediate post-transplant phases, and have identified risk factors. Late post-transplant care could be improved by focus on groups at risk and better identification of infections of "unknown origin". Show less
Cremers, E.M.P.; Witte, T. de; Wreede, L. de; Eikema, D.J.; Koster, L.; Biezen, A. van; ... ; Kroger, N. 2019
