Browsing by Subject "VERSUS-HOST-DISEASE"

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  • Canaani, Jonathan; Savani, Bipin N.; Labopin, Myriam; Michallet, Mauricette; Craddock, Charles; Socie, Gerard; Volin, Liisa; Maertens, Johan A.; Crawley, Charles; Blaise, Didier; Ljungman, Per T.; Cornelissen, Jan; Russell, Nigel; Baron, Frederic; Gorin, Norbert; Esteve, Jordi; Ciceri, Fabio; Schmid, Christoph; Giebel, Sebastian; Mohty, Mohamad; Nagler, Arnon (2017)
    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.
  • Bonifazi, Francesca; Solano, Carlos; Wolschke, Christine; Sessa, Mariarosaria; Patriarca, Francesca; Zallio, Francesco; Nagler, Arnon; Selleri, Carmine; Risitano, Antonio Maria; Messina, Giuseppe; Bethge, Wolfgang; Herrera, Pilar; Sureda, Anna; Carella, Angelo Michele; Cimminiello, Michele; Guidi, Stefano; Finke, Juergen; Sorasio, Roberto; Ferra, Christelle; Sierra, Jorge; Russo, Domenico; Benedetti, Edoardo; Milone, Giuseppe; Benedetti, Fabio; Heinzelmann, Marion; Pastore, Domenico; Jurado, Manuel; Terruzzi, Elisabetta; Narni, Franco; Voelp, Andreas; Ayuk, Francis; Ruutu, Tapani; Kroeger, Nicolaus (2019)
    Background We previously showed that human anti-T-lymphocyte globulin (ATLG) plus ciclosporin and methotrexate given to patients with acute leukaemia in remission, having allogeneic haemopoietic stem-cell transplantation with peripheral blood stem cells from an HLA-identical sibling donor after myeloablative conditioning, significantly reduced 2-year chronic graft-versus-host disease (cGVHD) incidence and severity, without increasing disease relapse and infections, and improves cGVHD-free and relapse-free survival (cGRFS). The aim of an extended follow-up study was the assessment of long-term outcomes, which are, in this context, scarcely reported in the literature. We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension. Methods In the original open-label study, patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, having sibling HLA-identical allogeneic peripheral blood stem-cell transplantation, were randomly assigned (1:1) to receive ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG group) or standard GVHD prophylaxis without ATLG (non-ATLG group). Conditioning regimens were cyclophosphamide 120 mg/kg with either total body irradiation (12 Gy) or busulfan (12 . 8 mg/kg intravenously or 16 mg/kg orally), with or without etoposide (30-60 mg/kg). Randomisation was stratified according to centre and disease risk. The primary endpoint was cumulative incidence of cGVHD at 2 years. The primary and secondary endpoints, excluding QoL, have been published. QoL, assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-HDC29 questionnaires, was an unpublished secondary endpoint, which we now report here. A follow-up extension was then done, with the primary endpoint cumulative incidence of cGVHD. Enrolment has been completed for both studies. Findings In the original study, from Dec 14, 2006, to Feb 2, 2012, 161 patients were enrolled and 155 were randomly assigned to either the ATLG group (n=83) or to the non-ATLG group (n=72). In the follow-up study, which started on Feb 7, 2017, and was completed on June 30, 2017, 61 patients were included in the ATLG group and 53 were included in the non-ATLG group. Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group (p=0 . 02; treatment by visit interaction). ATLG was descriptively superior to non-ATLG at 24 months for physical function (points estimate -14.8 [95% CI -26.4 to-3.1]; p= 0.014) and social function (-19.1 [-38.0 to -0.2]; p=0.047), gastrointestinal side-effects (8 . 8 [2.5-15.1]; p=0 . 008) and effect on family (13.5 [1.2-25.8]; p=0.032). Extended follow-up (median 5 . 9 years [IQR 1.7-7.9]) confirmed a lower 5-year cGVHD incidence (30.0% [95% CI 21.4-41.9] vs 69.1% [59.1-80.1]; analysis for entire follow-up, p Interpretation The addition of ATLG to standard GVHD prophylaxis improves the probability of surviving without disease relapse and cGVHD after myeloablative peripheral blood stem-cell transplantation from an HLA-identical sibling donor for patients with acute leukaemia in remission. Further additional benefits are better QoL and shorter immunosuppressive treatment compared with standard GVHD prophylaxis without ATLG. Therefore, in this setting, ATLG plus standard GVHD prophylaxis should be preferred over the standard GVHD prophylaxis alone. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
  • Baron, Frederic; Galimard, Jacques-Emmanue; Labopin, Myriam; Yakoub-Agha, Ibrahim; Niittyvuopio, Riitta; Kroeger, Nicolaus; Griskevicius, Laimonas; Wu, Depei; Forcade, Edouard; Richard, Carlos; Aljurf, Mahmoud; Helbig, Grzegorz; Labussiere-Wallet, Helene; Mohty, Mohamad; Nagler, Arnon (2020)
    We compared severe graft-versus-host-disease GyHD) free and relapse-free survival and other transplantation outcomes of acute myeloid leukemia (AML) patients given bone marrow (BM) without and-thymocyte globulin (ATG) versus peripheral blood stem cells (PBSC) with ATG after myeloablative conditioning. In the cohort of patients receiving grafts from a human leukocyte antigen (HLA)-matched sibling donor, patients given PBSC with ATG (n=1,021) and those given BM without ATG (n=1,633) presented comparable severe GvHD-free relapse-free survival (GRSF)(hazard ratio [HR]=0.9, 95% confidence interval [CI]: 0.8-1.1, P=0.5) and overall survival (HR=1.0, 95% CI: 0.8-1.2, P=0.8). They had however, a lower incidence of chronic GvHD (cGvHD) (HR=0.7, 95% CI: 0.6-0.9, P=0.01). In the cohort of patients receiving grafts from HLA-matched unrelated donor , patients given PBSC with ATG (n=2,318) had better severe GvHD-free and relapse-free survival (GRFS) than those given BM without ATG (n=303) (HR=0.8, 95% CI: 0.6-0.9, P=0.001). They also had a lower incidence of cGvHD (HR=0.6, 95% CI: 0.5-0.8, P=0.0006) and better overall survival (HR=0.8, 95% CI: 0.6-1.0, P=0.04). In summary, these data suggest that PBSC with ATG results in comparable (in the case of sibling donor) or significantly better (in the case of unrelated donor) severe GRFS than BM without ATG in patients with AML in complete remission receiving grafts after myeloablative conditioning.
  • Halaburda, Kazimierz; Labopin, Myriam; Houhou, Mohamed; Niederwieser, Dietger; Finke, Juergen; Volin, Liisa; Maertens, Johan; Cornelissen, Jan J.; Milpied, Noel; Stuhler, Gernot; Kroeger, Nicolaus; Esteve, Jordi; Mohty, Mohamad; Nagler, Arnon (2018)
    Acute myeloid leukemia with inv(3)(q21;q26.2)/t(3;3)(q21;q26.2) (3q26 AML) is a rare disease with poor prognosis and median survival of
  • Robin, Marie; Chevret, Sylvie; Koster, Linda; Wolschke, Christine; Yakoub-Agha, Ibrahim; Bourhis, Jean Henri; Chevallier, Patrice; Cornelissen, Jan J.; Remenyi, Peter; Maertens, Johan; Poire, Xavier; Craddock, Charles; Socie, Gerard; Itälä-Remes, Maija; Schouten, Harry C.; Marchand, Tony; Passweg, Jakob; Blaise, Didier; Damaj, Gandhi; Ozkurt, Zubeyde Nur; Zuckerman, Tsila; Cluzeau, Thomas; Labussiere-Wallet, Helene; Cammenga, Jörg; McLornan, Donal; Chalandon, Yves; Kroger, Nicolaus (2019)
    The use of antihuman T-lymphocyte immunoglobulin in the setting of transplantation from an HLA-matched related donor is still much debated. Acute and chronic graft-versus-host disease are the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis (n= 287). The cumulative incidences of grade II-IV acute graft-versus-host disease among patients who were or were not given antihuman T-lymphocyte immunoglobulin were 26% and 41%, respectively. The corresponding incidences of chronic graft-versus-host disease were 52% and 55%, respectively. Non-adjusted overall survival, disease-free survival and non-relapse mortality rates were 55% versus 53%, 49% versus 45%, and 32% versus 31%, respectively, among the patients who were or were not given antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that the risk of acute graft-versus-host disease was lower following antihuman T-lymphocyte immunoglobulin (hazard ratio, 0.54; P= 0.010) while it did not decrease the risk of chronic graft-versus-host disease. The hazard ratios for overall survival and non-relapse mortality were 0.66 and 0.64, with P-values of 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease, relapse-free survival or relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases the risk of acute graft-versushost disease without increasing the risk of relapse.
  • Penack, Olaf; Peczynski, Christophe; van der Werf, Steffie; Finke, Juergen; Ganser, Arnold; Schoemans, Helene; Pavlu, Jiri; Niittyvuopio, Riitta; Schroyens, Wilfried; Kaynar, Leylagul; Blau, Igor W.; van der Velden, Walter; Sierra, Jorge; Cortelezzi, Agostino; Wulf, Gerald; Turlure, Pascal; Rovira, Montserat; Ozkurt, Zubeydenur; Pascual-Cascon, Maria J.; Moreira, Maria C.; Clausen, Johannes; Greinix, Hildegard; Duarte, Rafael F.; Basak, Grzegorz W. (2020)
    Uric acid is a danger signal contributing to inflammation. Its relevance to allogeneic stem cell transplantation (alloSCT) derives from preclinical models where the depletion of uric acid led to improved survival and reduced graft-versus-host disease (GvHD). In a clinical pilot trial, peri-transplant uric acid depletion reduced acute GvHD incidence. This prospective international multicenter study aimed to investigate the association of uric acid serum levels before start of conditioning with alloSCT outcome. We included patients with acute leukemia, lymphoma or myelodysplastic syndrome receiving a first matched sibling alloSCT from peripheral blood, regardless of conditioning. We compared outcomes between patients with high and low uric acid levels with univariate- and multivariate analysis using a cause-specific Cox model. Twenty centers from 10 countries reported data on 366 alloSCT recipients. There were no significant differences in terms of baseline co-morbidity and disease stage between the high- and low uric acid group. Patients with uric acid levels above median measured before start of conditioning did not significantly differ from the remaining in terms of acute GvHD grades II-IV incidence (Hazard ratio [HR] 1.5, 95% Confidence interval [CI]: 1.0-2.4, P=0.08). However, they had significantly shorter overall survival (HR 2.8, 95% CI: 1.7-4.7, P
  • Przybyla, Beata; Pinomäki, Anne; Petäjä, Jari; Joutsi-Korhonen, Lotta; Strandberg, Karin; Hillarp, Andreas; Öhlin, Ann-Kristin; Ruutu, Tapani; Volin, Liisa; Lassila, Riitta (2017)
    Background Allogeneic stem cell transplantation (SCT) enhances coagulation via endothelial perturbation and inflammation. Role of natural anticoagulants in interactions between coagulation and inflammation as well as in acute graft-versus-host disease (GVHD) are not well known. The purpose of this study was to define changes in natural anticoagulants over time in association with GVHD. Patients and methods This prospective study included 30 patients who received grafts from siblings (n = 19) or unrelated donors (n = 11). Eight patients developed GVHD. Standard clinical assays were applied to measure natural anticoagulants, represented by protein C (PC), antithrombin (AT), protein S (PS), complex of activated PC with its inhibitor (APC-PCI) and by markers of endothelial activation: Factor VIII coagulant activity (FVIII: C) and soluble thrombomodulin (s-TM) at 6-8 time points over three months. Results Overall, PC, AT and FVIII: C increased in parallel after engraftment. Significant correlations between PC and FVIII: C (r = 0.64-0.82, p Conclusion The coordinated activation of natural anticoagulants in our longitudinal study indicates the sustained ability of adaptation to endothelial and inflammatory activation during allogenic SCT treatment. The suboptimal control of coagulation by natural anticoagulants at early stage of SCT may contribute to onset of GVHD.
  • Mauramo, Matti; Rohde, Luzius; Ramseier, Adrian M.; Rovo, Alicia; Waltimo, Tuomas (2017)
    The aetiology of hyposalivation in haematopoietic stem cell transplantation (HSCT) recipients is not fully understood. This study examined the effects of treatment-related aetiological factors, particularly medications, on stimulated salivary flow in HSCT recipients. Adult HSCT recipients (N = 118, 66 males, 27 autologous and 91 allogeneic transplants) were examined. Stimulated whole salivary flow rates (SWSFR) were measured before HSCT and at 6 and 12 months post-HSCT. Linear regression models were used to analyse the associations of medications and transplant-related factors with salivary flow rates, which were compared to salivary flow rates of generally healthy controls (N = 247). The SWSFR of recipients were lower pre-HSCT (mean +/- standard deviation, 0.88 +/- 0.56 ml/min; P <0.001), 6 months post-HSCT (0.84 +/- 0.61; P <0.001) and 12 months post-HSCT (1.08 +/- 0.67; P = 0.005) than the SWSFR of controls (1.31 +/- 0.65). In addition, hyposalivation (<0.7 ml/min) was more frequent among HSCT recipients pre-HSCT (P <0.001), 6 months post-HSCT (P <0.001) and 12 months post-HSCT (P = 0.01) than among controls. The SWSFR was observed to improve over time being significantly higher 12 months post-HSCT compared to pre-HSCT (P <0.001). The observed decrease of salivary flow could not be explained by the examined transplant-related factors and medications. Decreased stimulated salivary flow rates could not be explained by the examined factors alone; these findings indicate that hyposalivation in HSCT recipients exhibits a multifactorial aetiology. All HSCT recipients should be considered to be at high risk of hyposalivation and consequent oral diseases, and they should be treated accordingly.
  • Bekker, Vincent; Zwittink, Romy D.; Knetsch, Cornelis W.; Sanders, Ingrid M. J. G.; Berghuis, Dagmar; Heidt, Peter J.; Vossen, Jaak M. J. J.; de Vos, Willem M.; Belzer, Clara; Bredius, Robbert G. M.; van't Hof, Peter J.; Lankester, Arjan C.; Kuijper, Ed J. (2019)
    Bloodstream infections and graft-versus-host disease are common complications after hematopoietic stem cell transplantation (HSCT) procedures, associated with the gut microbiota that acts as a reservoir for opportunistic pathogens. Selective gut decontamination (SGD) and total gut decontamination (TGD) during HSCT have been associated with a decreased risk of developing these complications after transplantation. However, because studies have shown conflicting results, the use of these treatments remains subject of debate. In addition, their impact on the gut microbiota is not well studied. The aim of this study was to elucidate the dynamics of the microbiota during and after TGD and to compare these with the dynamics of SGD. In this prospective, observational, single center study fecal samples were longitudinally collected from 19 children eligible for allogenic HSCT (TGD, n=12; SGD, n=7), weekly during hospital admission and monthly after discharge. In addition, fecal samples were collected from 3 family stem cell donors. Fecal microbiota structure of patients and donors was determined by 16S rRNA gene amplicon sequencing. Microbiota richness and diversity markedly decreased during SGD and TGD and gradually increased after cessation of decontamination treatment. During SGD, gut microbiota composition was relatively stable and dominated by Bacteroides, whereas it showed high inter- and intraindividual variation and low Bacteroides abundance during TGD. In some children TGD allowed the genera Enterococcus and Streptococcus to thrive during treatment. A gut microbiota dominated by Bacteroides was associated with increased predicted activity of several metabolic processes. Comparing the microbiota of recipients and their donors indicated that receiving an SCT did not alter the patient's microbiota to become more similar to that of its donor. Overall, our findings indicate that SGD and TGD affect gut microbiota structure in a treatment-specific manner. Whether these treatments affect clinical outcomes via interference with the gut microbiota needs to be further elucidated. (C) 2019 American Society for Blood and Marrow Transplantation.
  • Malard, Florent; Labopin, Myriam; Cho, Christina; Blaise, Didier; Papadopoulos, Esperanza B.; Passweg, Jakob; O'Reilly, Richard; Forcade, Edouard; Maloy, Molly; Volin, Liisa; Castro-Malaspina, Hugo; Hicheri, Yosr; Jakubowski, Ann A.; Orvain, Corentin; Giralt, Sergio; Mohty, Mohamad; Nagler, Arnon; Perales, Miguel-Angel (2018)
    BackgroundGraft-versus-host disease (GVHD) is one of the leading causes of non-relapse mortality and morbidity after allogeneic hematopoietic stem cell transplantation (allo-HCT).MethodsWe evaluated the outcomes of two well-established strategies used for GVHD prevention: in vivo T cell depletion using antithymocyte globulin (ATG) and ex vivo T cell depletion using a CD34-selected (CD34+) graft. A total of 525 adult patients (363 ATG, 162 CD34+) with intermediate or high-risk cytogenetics acute myeloid leukemia (AML) in first complete remission (CR1) were included. Patients underwent myeloablative allo-HCT using matched related or unrelated donors.ResultsTwo-year overall survival estimate was 69.9% (95% CI, 58.5-69.4) in the ATG group and 67.6% (95% CI, 60.3-74.9) in the CD34+ group (p=0.31). The cumulative incidence of grade II-IV acute GVHD and chronic GVHD was higher in the ATG cohort [HR 2.0 (95% CI 1.1-3.7), p=0.02; HR 15.1 (95% CI 5.3-42.2), p
  • Knobler, R.; Berlin, G.; Calzavara-Pinton, P.; Greinix, H.; Jaksch, P.; Laroche, L.; Ludvigsson, J.; Quaglino, P.; Reinisch, W.; Scarisbrick, J.; Schwarz, T.; Wolf, P.; Arenberger, P.; Assaf, C.; Bagot, M.; Barr, M.; Bohbot, A.; Bruckner-Tuderman, L.; Dreno, B.; Enk, A.; French, L.; Gniadecki, R.; Gollnick, H.; Hertl, M.; Jantschitsch, C.; Jung, A.; Just, U.; Klemke, C. -D.; Lippert, U.; Luger, T.; Papadavid, E.; Pehamberger, H.; Ranki, A.; Stadler, R.; Sterry, W.; Wolf, I. H.; Worm, M.; Zic, J.; Zouboulis, C. C.; Hillen, U. (2014)
  • Koskela, Satu; Ritari, Jarmo; Hyvärinen, Kati; Kwan, Tony; Niittyvuopio, Riitta; Itälä-Remes, Maija; Pastinen, Tomi; Partanen, Jukka (2018)
    Matching classical HLA alleles between donor and recipient is an important factor in avoiding adverse immunological effects in HSCT. Siblings with no differences in HLA alleles, either due to identical-by-state or identical-by-descent status, are considered to be optimal donors. We carried out a retrospective genomic sequence and SNP analysis of 336 fully HLA-A, -B, -DRB1 matched and 14 partially HLA-matched sibling HSCT pairs to determine the level of undetected mismatching within the MHC segment as well as to map their recombination sites. The genomic sequence of 34 genes locating in the MHC region revealed allelic mismatching at 1 to 8 additional genes in partially HLA-matched pairs. Also, fully matched pairs were found to have mismatching either at HLA-DPB1 or at non-HLA region within the MHC segment. Altogether, 3.9% of fully HLA-matched HSCT pairs had large genomic mismatching in the MHC segment. Recombination sites mapped to certain restricted locations. The number of mismatched nucleotides correlated with the risk of GvHD supporting the central role of full HLA matching in HSCT. High-density genome analysis revealed that fully HLA-matched siblings may not have identical MHC segments and even single allelic mismatching at any classical HLA gene often implies larger genomic differences along MHC.
  • Giebel, Sebastian; Labopin, Myriam; Czerw, Tomasz; Socie, Gerard; Blaise, Didier; Ghavamzadeh, Ardeshir; Passweg, Jacob; Ljungman, Per; Poire, Xavier; Chevallier, Patrice; Remenyi, Peter; Rambaldi, Alessandro; Anafasyev, Boris; Fegueux, Nathalie; Rovira, Montserrat; Itälä-Remes, Maija; Bornhaeuser, Martin; Mohty, Mohamad; Nagler, Arnon (2019)
    Background: Anti-thymocyte globulin (ATG) is widely used to prevent graft-versus-host disease (GVHD) after allogeneic peripheral blood stem cell transplantation (alloPBSCT). The goal of this study was to retrospectively assess the effect of ATG on outcomes in the setting of Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL). Methods: In the analysis, 1170 adult patients undergoing alloPBSCT from human leucocyte antigen-matched sibling or unrelated donors in the first complete remission between 2007 and 2016 were included. ATG was used in 429/575 (75%) and 121/595 (20%) patients transplanted from unrelated or sibling donors, respectively. Results: The incidence of chronic GVHD was 35% for patients treated with ATG compared with 52% in those not receiving ATG (p <0.001), while the rate of extensive chronic GVHD was 16% and 36%, respectively (p <0.001). The probability of survival free from GVHD and relapse (GRFS) was 42% and 32%, respectively (p = 0.002). In a multivariate model, the use of ATG was associated with reduced risk of overall chronic GVHD (hazard ratio [HR] = 0.52, p <0.001) and extensive chronic GVHD (HR = 0.46, p <0.001). It was also associated with better GRFS (HR = 0.77, p = 0.007), despite increased risk of relapse (HR = 1.41, p = 0.02). No significant effect was found with regard to the risk of non-relapse mortality and overall mortality. Conclusions: The use of ATG for patients with Ph+ ALL undergoing alloPBSCT is associated with reduced risk of chronic GVHD without impact on survival and therefore, could be considered. However, increased risk of relapse suggests the need for strict monitoring of minimal residual diseases and appropriate interventions after transplantation. (C) 2018 Elsevier Ltd. All rights reserved.
  • Nagler, Arnon; Labopin, Myriam; Dholaria, Bhagirathbhai; Niittyvuopio, Riitta; Maertens, Johan; Poire, Xavier; Cornelissen, Jan; Remenyi, Peter; Bourhis, Jean Henri; Beguin, Yves; Malladi, Ram; Kerre, Tessa; Schroyens, Wilfried; Savani, Bipin N.; Mohty, Mohamad (2019)
    The impact of the use of antithymocyte globulin (ATG) following a total body irradiation (TBI)-based myeloablative conditioning regimen has been poorly explored. We retrospectively analyzed 724 patients who underwent a first allogeneic hematopoietic cell transplantation (allo-HCT) following a TBI-based conditioning regimen for acute myeloid leukemia (AML) and compared the outcomes of 251 (35%) patients who received ATG (ATG group) with 473 (65%) patients who did not (non-ATG group). Median follow-up of surviving patients was 59 months (interquartile range, 28-83). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) for non-ATG and ATG groups in the first 100 days was 33% vs 24%, respectively (P = .0098). The 2-year cumulative incidence of chronic graft-versus-host disease (cGVHD) was reduced significantly in the ATG group in comparison with the non-ATG group (46% vs 34%, P = .003). Using multivariate analysis, in vivo T-cell depletion (ATG group) was independently associated with a decreased incidence of grade II-IV aGVHD (hazard ratio [HR], 0.28; P <.001), grade III-IV aGVHD (HR, 0.21; P <.001), cGVHD (HR, 0.63; P = .02), and nonrelapse mortality (NRM) (HR, 0.54; P = .02). Relapse risk, overall survival, and leukemia-free survival were similar between the 2 groups. Our results suggest that the addition of ATG to TBI-based myeloablative conditioning for allo-HCT in AML patients results in a significant reduction in aGVHD and cGVHD, translating into a significant reduction in NRM without increasing the relapse rate.
  • Pagliuca, Simona; de Latour, Regis Peffault; Volt, Fernanda; Locatelli, Franco; Zecca, Marco; Dalle, Jean-Hugues; Comoli, Patrizia; Vettenranta, Kim; Angel Diaz, Miguel; Reuven, Or; Bertrand, Yves; Diaz de Heredia, Cristina; Nagler, Arnon; Ghavamzadeh, Ardeshir; Sufliarska, Sabina; Lawson, Sarah; Kenzey, Chantal; Rocha, Vanderson; Dufour, Carlo; Gluckman, Eliane; Passweg, Jakob; Ruggeri, Annalisa (2017)
    Cord blood transplantation (CBT) from HLA-identical siblings is an attractive option for patients with bone marrow failure (BMF) syndrome because of the low risk of graft-versus-host disease (GVHD) and the absence of risk to the donor. We analyzed outcomes of 117 patients with inherited or acquired BMF syndrome who received CBT from a related HLA-identical donor in European Society for Blood and Marrow Transplantation centers between 1988 and 2014. Ninety-seven patients had inherited and 20 patients acquired BMF syndrome. Eighty-two patients received a single cord blood (CB) unit, whereas 35 patients received a combination of CB and bone marrow cells from the same donor. Median age at CBT was 6.7 years, and median follow-up was 86.7 months. The cumulative incidence function (CIF) of neutrophil recovery was 88.8% (95% CI, 83.1% to 94.9%), 100-day CIF of grades II to IV acute GVHD was 15.2%, and 7-year CIF of chronic GVHD was 14.5%. Overall survival at 7 years was 87.9% (95% CI, 80.8% to 92.6%), 89% for inherited and 81% for acquired BMF syndromes (P=.66). Results of this study are consistent with outcomes of bone marrow transplantation shown by previous series in the same setting and indicate that in pediatric patients with BMF syndrome, CBT from an HLA-identical sibling donor is associated with excellent long-term outcomes and that collection of CB unit at birth of a new sibling is strongly recommended. (C) 2017 American Society for Blood and Marrow Transplantation.
  • Greer, Mark; Berastegui, Cristina; Jaksch, Peter; Benden, Christian; Aubert, John; Roux, Antoine; Lhuillier, Elodie; Hirschi, Sandrine; Reynaud-Gaubert, Martine; Philit, Francois; Claustre, Johanna; LePalud, Pierre; Stern, Marc; Knoop, Christiane; Vos, Robin; Verschuuren, Erik; Fisher, Andrew; Riise, Gerdt; Hansson, Lennart; Iversen, Martin; Hämmäinen, Pekka; Wedel, Hans; Smits, Jacqueline; Gottlieb, Jens; Holm, Are M. (2018)
    Late-onset noninfectious pulmonary complications (LONIPCs) affect 6% of allogeneic stem cell transplantation (SCT) recipients within 5 years, conferring subsequent 5-year survival of 50%. Lung transplantation is rarely performed in this setting due to concomitant extrapulmonary morbidity, excessive immunosuppression and concerns about recurring malignancy being considered contraindications. This study assesses survival in highly selected patients undergoing lung transplantation for LONIPCs after SCT. SCT patients undergoing lung transplantation at 20 European centres between 1996 and 2014 were included. Clinical data pre- and post-lung transplantation were reviewed. Propensity score-matched controls were generated from the Eurotransplant and Scandiatransplant registries. Kaplan-Meier survival analysis and Cox proportional hazard regression models evaluating predictors of graft loss were performed. Graft survival at 1, 3 and 5 years of 84%, 72% and 67%, respectively, among the 105 SCT patients proved comparable to controls (p=0.75). Sepsis accounted for 15 out of 37 deaths (41%), with prior mechanical ventilation (HR 6.9, 95% CI 1.0-46.7; p Lung transplantation outcomes following SCT were comparable to other end-stage diseases. Lung transplantation should be considered feasible in selected candidates. No SCT-specific factors influencing outcome were identified within this carefully selected patient cohort.
  • Saraceni, Francesco; Labopin, Myriam; Gorin, Norbert-Claude; Blaise, Didier; Tabrizi, Reza; Volin, Liisa; Cornelissen, Jan; Cahn, Jean-Yves; Chevallier, Patrice; Craddock, Charles; Wu, Depei; Huynh, Anne; Arcese, William; Mohty, Mohamad; Nagler, Arnon (2016)
    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, rho = 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, rho = 0.2). Overall survival was similar across the groups (10/10 UD-HSCT vs auto-HSCT: HR 0.98, rho = 0.84; 9/10 UD-HSCT vs auto-HSCT: HR 1.1, rho = 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, rho = 0.049), while it did not differ between auto-HSCT and 10/10 UD-HSCT (HR 0.95, rho = 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.
  • Hyvärinen, Kati; Koskela, Satu; Niittyvuopio, Riitta; Nihtinen, Anne; Volin, Liisa; Salmenniemi, Urpu; Putkonen, Mervi; Buño, Ismael; Gallardo, David; Itälä-Remes, Maija; Partanen, Jukka; Ritari, Jarmo (2020)
    Graft-vs.-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation that causes mortality and severe morbidity. Genetic disparities in human leukocyte antigens between the recipient and donor are known contributors to the risk of the disease. However, the overall impact of genetic component is complex, and consistent findings across different populations and studies remain sparse. To gain a comprehensive understanding of the genes responsible for GvHD, we combined genome-wide association studies (GWAS) from two distinct populations with previously published gene expression studies on GvHD in a single gene-level meta-analysis. We hypothesized that genes driving GvHD should be associated in both data modalities and therefore could be detected more readily through their combined effects in the integrated analysis rather than in separate analyses. The meta-analysis yielded a total of 51 acute GvHD-associated genes (false detection rate [FDR]
  • Brissot, Eolia; Labopin, Myriam; Moiseev, Ian; Cornelissen, J. J.; Meijer, Ellen; Van Gorkom, Gwendolyn; Rovira, Montserrat; Ciceri, Fabio; Griskevicius, Laimonas; Blaise, Didier; Forcade, Edouard; Mistrik, Martin; Mielke, Stephan; Bulabois, Claude Eric; Niittyvuopio, Riitta; Deconinck, Eric; Ruggeri, Annalisa; Sanz, Jaime; Spyridonidis, Alexandros; Savani, Bipin; Giebel, Sebastian; Nagler, Arnon; Mohty, Mohamad (2020)
    Background Graft-versus-host disease (GVHD) remains a major contributor to mortality and morbidity after allogeneic stem-cell transplantation (allo-HSCT). The updated recommendations suggest that rabbit antithymocyte globulin or anti-T-lymphocyte globulin (ATG) should be used for GVHD prophylaxis in patients undergoing matched-unrelated donor (MUD) allo-HSCT. More recently, using post-transplant cyclophosphamide (PTCY) in the haploidentical setting has resulted in low incidences of both acute (aGVHD) and chronic GVHD (cGVHD). Therefore, the aim of our study was to compare GVHD prophylaxis using either PTCY or ATG in patients with acute myeloid leukemia (AML) who underwent allo-HSCT in first remission (CR1) from a 10/10 HLA-MUD. Methods Overall, 174 and 1452 patients from the EBMT registry receiving PTCY and ATG were included. Cumulative incidence of aGVHD and cGVHD, leukemia-free survival, overall survival, non-relapse mortality, cumulative incidence of relapse, and refined GVHD-free, relapse-free survival were compared between the 2 groups. Propensity score matching was also performed in order to confirm the results of the main analysis Results No statistical difference between the PTCY and ATG groups was observed for the incidence of grade II-IV aGVHD. The same held true for the incidence of cGVHD and for extensive cGVHD. In univariate and multivariate analyses, no statistical differences were observed for all other transplant outcomes. These results were also confirmed using matched-pair analysis. Conclusion These results highlight that, in the10/10 HLA-MUD setting, the use of PTCY for GVHD prophylaxis may provide similar outcomes to those obtained with ATG in patients with AML in CR1.
  • Mohty, M.; Malard, F.; Abecassis, M.; Aerts, E.; Alaskar, A. S.; Aljurf, M.; Arat, M.; Bader, P.; Baron, F.; Bazarbachi, A.; Blaise, D.; Ciceri, F.; Corbacioglu, S.; Dalle, J-H; Dignan, F.; Fukuda, T.; Huynh, A.; Masszi, T.; Michallet, M.; Nagler, A.; NiChonghaile, M.; Okamoto, S.; Pagliuca, A.; Peters, C.; Petersen, F. B.; Richardson, P. G.; Ruutu, T.; Savani, B. N.; Wallhult, E.; Yakoub-Agha, I.; Duarte, R. F.; Carreras, E. (2016)
    Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although SOS/VOD progressively resolves within a few weeks in most patients, the most severe forms result in multi-organ dysfunction and are associated with a high mortality rate (480%). Therefore, careful attention must be paid to allow an early detection of SOS/VOD, particularly as drugs have now proven to be effective and licensed for its treatment. Unfortunately, current criteria lack sensitivity and specificity, making early identification and severity assessment of SOS/VOD difficult. The aim of this work is to propose a new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, on behalf of the European Society for Blood and Marrow Transplantation.