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Graft-versus-host disease and relapse/rejection-free survival after allogeneic transplantation for idiopathic severe aplastic anemia: a comprehensive analysis from the SAAWP of the EBMT
Devillier, R., Eikema, D. J., Dufour, C., Aljurf, M., Wu, D., Maschan, A., Kulagin, A., Halkes, C. J. M., Collin, M., Snowden, J., et al
Haematologica. 2023
Abstract
Survival after Allo-HSCT for severe idiopathic aplastic anemia (SAA) has improved in recent years, approaching 75% at 5 years. However, an SAA-adapted composite endpoint, GVHD and relapse/rejection-free survival (GRFS), may more accurately assess patient outcomes beyond survival. We analyzed GRFS to identify risk factors and specific causes of GRFS failure. Our retrospective analysis from the SAAWP of the EBMT included 479 patients with idiopathic SAA who underwent Allo-HSCT in 2 conventional situations: i) upfront Allo-HSCT from a matched related donor (MRD) (upfront cohort), and ii) Allo-HSCT for relapsed or refractory SAA (rel/ref cohort). Relevant events for GRFS calculation included graft failure, grade 3-4 acute GVHD, extensive chronic GVHD, and death. In the upfront cohort (n=209), 5-year GRFS was 77%. Late Allo-HSCT (i.e., >6 months after SAA diagnosis) was the main poor prognostic factor, specifically increasing the risk of death as the cause of GRFS failure (HR: 4.08, 95% CI [1.41-11.83], p=0.010). In the rel/ref cohort (n=270), 5-year GRFS was 61%. Age was the main factor significantly increasing the risk of death (HR: 1.04, 95% CI [1.02-1.06], p.
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New Perspectives on Primary Prophylaxis of Invasive Fungal Infection in Children Undergoing Hematopoietic Stem Cell Transplantation: A 10-Year Retrospective Cohort Study
Ricard, N., Zebali, L., Renard, C., Goutagny, M. P., Benezech, S., Bertrand, Y., Philippe, M., Domenech, C.
Cancers. 2023;15(7)
Abstract
BACKGROUND Allogenic hematopoietic stem cell transplantation (a-HCT) remains a therapeutic treatment for many pediatric hematological diseases. The occurrence of invasive fungal infections (IFIs) is a complication for which ECIL-8 recommends primary antifungal prophylaxis. In this study, we evaluated the impact of our local strategy of not systematically administering primary antifungal prophylaxis in children undergoing a-HCT on the occurrence and mortality of IFIs. METHODS We performed a retrospective monocentric study from 2010 to 2020. We retained all proven and probable IFIs diagnosed during the first year post a-HCT. RESULTS 308 patients were included. Eighteen patients developed twenty IFIs (thirteen proven, seven probable) (6.5%) among which aspergillosis (n = 10, 50%) and candidosis (n = 7, 35%) were the most frequently diagnosed infections. Only 2% of children died because of an IFI, which represents 14% of all deaths. Multivariate analysis found that age > 10 years (OR: 0.29), the use of a therapeutic antiviral treatment (OR: 2.71) and a low neutrophil count reconstitution (OR: 0.93) were significantly associated with the risk of IFI occurrence. There was also a trend of malignant underlying disease and status ≥ CR2 but it was not retained in multivariate analysis. CONCLUSIONS IFI occurrence was not higher in our cohort than what is reported in the literature with the use of systematic antifungal prophylaxis, with a good survival rate nonetheless. Thus, a prophylaxis could be considered for children with a high risk of IFI such as those aged over 10 years.
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Interest of the preventive and curative use of defibrotide on the occurrence and severity of sinusoidal obstruction syndrome after hematopoietic stem cell transplant in children
Rudebeck, C. J., Renard, C., Halfon-Domenech, C., Ouachée-Chardin, M., Philippe, M., Valla, F. V., Bertrand, Y., Penel-Page, M.
EJHaem. 2022;3(3):885-893
Abstract
Defibrotide (DF) is indicated for the treatment of severe sinusoidal obstruction syndrome (SOS) following hematopoietic stem cell transplantation (HSCT), but its prophylactic use against SOS is not recommended yet. This study describes the impact of the preventive and curative use of DF on reducing the incidence and severity of SOS in children. Patients aged 0-19 years, who received allogenic HSCT after myeloablative conditioning regimen with busulfan or total body irradiation in our comprehensive cancer center, between 2013 and 2017, were included. The Baltimore or modified Seattle criteria were used for SOS diagnosis. SOS was graded using the 2017 European Society for Blood and Marrow Transplantation classification defining severity criteria of SOS in children. SOS occurrence tended to decrease with prophylactic DF, but no significant difference was observed in terms of severity. When not treated with preventive DF, 50% (19/38) of the patients with SOS were graded severe to very severe, but only 37% (7/19) had organ dysfunction. Curative DF was administered at a median of 2 days post-HSCT, for a median of 6.5 days. The absence of fatal SOS supports the use of early curative DF with acceptable toxicities and questions the optimal duration of DF treatment.
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Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study
Mohty, M., Blaise, D., Peffault de Latour, R., Labopin, M., Bourhis, J. H., Bruno, B., Ceballos, P., Detrait, M., Gandemer, V., Huynh, A., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin <2 mg/dL, multiorgan failure resolution) at Day 100 post-HCT among patients with severe/very severe VOD/SOS. A secondary endpoint was evaluation of treatment-emergent serious adverse events (TESAEs) of interest. Of 798 patients analysed, 251 and 81 received defibrotide treatment for severe/very severe VOD/SOS and mild/moderate VOD/SOS post-HCT, respectively; 381 received defibrotide for VOD/SOS prophylaxis. In patients with severe/very severe VOD/SOS post-HCT, Kaplan-Meier-estimated CR at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan-Meier-estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%. DEFIFrance represents the largest collection of real-world data on post-registration defibrotide use, supporting the real-world utility of defibrotide for patients with severe/very severe VOD/SOS post-HCT.
PICO Summary
Population
Adults and children receiving defibrotide for treatment or prophylaxis of veno-occlusive disease / sinusoidal obstruction syndrome (VOD/SOS) between July 2014 to March 2020 at 53 French HCT centres (n=798)
Intervention
Defibrotide for severe/very severe VOD/SOS (n=251); Defibrotide for mild/moderate VOD/SOS (n=81)
Comparison
Defibrotide for VOD/SOS prophylaxis (n=381)
Outcome
In patients with severe/very severe VOD/SOS post-HCT, Kaplan-Meier-estimated complete remission (CR) at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan-Meier-estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%.
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Improved outcome in children compared to adolescents and young adults after allogeneic hematopoietic stem cell transplant for acute myeloid leukemia: a retrospective study from the Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC)
Pochon, C., Detrait, M., Dalle, J. H., Michel, G., Dhédin, N., Chalandon, Y., Brissot, E., Forcade, E., Sirvent, A., Izzadifar-Legrand, F., et al
Journal of cancer research and clinical oncology. 2021
Abstract
BACKGROUND There are currently few data on the outcome of acute myeloid leukemia (AML) in adolescents after allogeneic HSCT. The aim of this study is to describe the outcome and its specific risk factors for children, adolescents and young adults after a first allogeneic HSCT for AML. METHODS In this retrospective study, we compared the outcome of AML patients receiving a first allogeneic HSCT between 2005 and 2017 according to their age at transplantation's time: children (15 years, n?=?564), adolescent and post-adolescent (APA) patients (15-25 years, n?=?647) and young adults (26-40 years; n?=?1434). RESULTS With a median follow-up of 4.37 years (min-max 0.18-14.73 years), the probability of 2-year overall survival (OS) was 71.4% in children, 61.1% in APA patients and 62.9% in young adults (p?=?0.0009 for intergroup difference). Both relapse and non-relapse mortality (NRM) Cumulative Incidence (CI) estimated at 2 years were different between the age groups (30.8% for children, 35.2% for APA patients and 29.4% for young adults-p?=?0.0254, and 7.0% for children, 10.6% for APA patients and 14.2% for young adults, p?0.0001; respectively). Whilst there was no difference between the three groups for grade I to IV acute GVHD CI at 3 months, the chronic GVHD CI at 2 years was higher in APA patients and young adults (31.4% and 36.4%, respectively) in comparison to the children (17.5%) (p?0.0001). In multivariable analysis, factors associated with death were AML cytogenetics (HR1.73 [1.29-2.32] for intermediate risk 1, HR 1.50 [1.13-2.01] for intermediate risk 2, HR 2.22 [1.70-2.89] for high cytogenetics risk compared to low risk), use of TBI?=?8 Grays (HR 1.33 [1.09-1.61]), disease status at transplant (HR 1.40 [1.10-1.78] for second Complete Remission (CR), HR 2.26 [1.02-4.98] for third CR and HR 3.07 [2.44-3.85] for active disease, compared to first CR), graft source (HR 1.26 [1.05-1.50] for Peripheral Blood Stem Cells compared to Bone Marrow) and donor age (HR 1.01 (1-1.02] by increase of 1 year). CONCLUSION Age is an independent risk factor for NRM and extensive chronic GVHD. This study suggests that APA patients with AML could be beneficially treated with a chemotherapy-based MAC regimen and bone marrow as a stem cells source.
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Haplo-identical or mismatched unrelated donor hematopoietic cell transplantation for Fanconi anemia: results from the Severe Aplastic Anemia Working Party of the EBMT
Zubicaray, J., Pagliara, D., Sevilla, J., Eikema, D. J., Bosman, P., Ayas, M., Zecca, M., Yesilipek, A., Kansoy, S., Renard, C., et al
American journal of hematology. 2021
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n=123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n=33) or T cells depleted in-vivo with some type of graft manipulation ex-vivo (n=59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53-71%) for MMUD, versus 80% (66-95%) for HDs with only in vivo T cell depletion and 60% (47-73%) for HDs with in vivo and ex vivo T cell depletion (p 0.22). Event free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73-99%) than for those transplanted from a MMUD 58% (48-68%) or those with graft manipulation 56% (42-69%) (p=?0.046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p=0.005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts. This article is protected by copyright. All rights reserved.
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A multicentre, multinational, prospective, observational registry study of defibrotide in patients diagnosed with veno-occlusive disease/sinusoidal obstruction syndrome after haematopoietic cell transplantation: an EBMT study
Mohty, M., Battista, M. L., Blaise, D., Calore, E., Cesaro, S., Maximova, N., Perruccio, K., Renard, C., Wynn, R., Zecca, M., et al
Bone marrow transplantation. 2021
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Editor's Choice
Abstract
Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT). This multinational, prospective, observational study (NCT03032016), performed by the EBMT, enrolled patients treated with defibrotide from April 2015 to July 2018. This analysis focused on defibrotide-treated patients with VOD/SOS post-HCT. The primary endpoint was incidence of serious adverse events (SAEs) of interest up to 12 months post-HCT in patients with severe VOD/SOS. Overall, 104 defibrotide-treated patients with VOD/SOS post-HCT were enrolled: 62 had severe VOD/SOS and comprised the primary study population, including 36 with multi-organ dysfunction/failure (MOD/MOF). SAEs of interest occurred in 20 of 62 (32%) severe VOD/SOS patients; the most common by category were infection (24%) and bleeding (13%). In patients with severe VOD/SOS, the Kaplan-Meier-estimated Day 100 survival rate was 73% (95% CI: 60%, 82%) with VOD/SOS resolution by Day 100 in 45 of 62 (73%) patients. MOD/MOF resolved in 19 of 36 (53%) patients with MOD/MOF at VOD/SOS diagnosis. Results from this multicentre registry study build on prior defibrotide studies supporting the utility of defibrotide for the treatment of VOD/SOS post-HCT. These results provide additional real-world evidence of the effectiveness and safety of defibrotide in patients with VOD/SOS post-HCT.
PICO Summary
Population
Patients with veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) treated with defibrotide (n=104)
Intervention
Patients with severe VOD/SOS (n=62)
Comparison
None
Outcome
SAEs of interest occurred in 20 of 62 (32%) severe VOD/SOS patients; the most common by category were infection (24%) and bleeding (13%). In patients with severe VOD/SOS, the Kaplan-Meier-estimated Day 100 survival rate was 73% with VOD/SOS resolution by Day 100 in 45 of 62 (73%) patients. Multi-organ dysfunction/failure (MOD/MOF) resolved in 19 of 36 (53%) patients with MOD/MOF at VOD/SOS diagnosis.
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Teenagers and young adults with a past of allogenic hematopoietic stem cell transplantation are at significant risk of chronic kidney disease
da Silva Selistre, L., Renard, C., Bacchetta, J., Goutagny, M. P., Hu, J., Carla de Souza, V., Bertrand, Y., Dubourg, L., Domenech, C.
Pediatric nephrology (Berlin, Germany). 2021
Abstract
BACKGROUND Allogenic hematopoietic stem cell transplantation (aHSCT) remains the treatment of choice for some malignant hemopathies in children, albeit with the risk of long-term consequences, including chronic kidney disease (CKD). METHODS In our single tertiary referral center, we retrospectively assessed the long-term renal outcome in a cohort of children and adolescents who had undergone aHSCT for malignant hemopathies between 2003 and 2017. We distinguished glomerular and tubular dysfunctions and assessed the accuracy of the most common formula(s) to estimate glomerular filtration rate (GFR) during standard clinical follow-up. RESULTS Among the 166 patients who had received aHSCT, 61 underwent kidney functional assessment 1 to 10 years post-transplantation. Twenty-seven patients (44.3%) had a CKD with glomerular impairment, including 20 patients with a GFR?90 mL/min/1.73 m(2), and among these, 5 patients?60 mL/min/1.73 m(2). Patients with tubular signs had a significantly higher baseline GFR: 112 mL/min/1.73 m(2) [100; 120] versus 102 [99.0; 112.5] for patients without kidney involvement, and 76 [61; 86] for patients with CKD (p?0.01). Schwartz, CKiDU25, and EKFC formulas significantly overestimated mGFR, with a P30%?=?30%, which could lead to overlooking CKD diagnosis in this population. No patient reached kidney failure. CONCLUSIONS In conclusion, our study shows that CKD represents an important long-term sequela for children and adolescents who undergo aHSCT for malignant hemopathies, either with glomerular dysfunction or with the more insidious tubular dysfunction which could potentially impact growth. These patients could benefit from specialized long-term nephrology follow-up. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Medication adherence after pediatric allogeneic stem cell transplantation: Barriers and facilitators
Hoegy, D., Bleyzac, N., Rochet, C., De Freminville, H., Renard, C., Kebaili, K., Bertrand, Y., Dussart, C., Janoly-Dumenil, A.
European journal of oncology nursing : the official journal of European Oncology Nursing Society. 2019;38:1-7
Abstract
PURPOSE Immunosuppressive therapy following pediatric hematopoietic stem cell transplantation is essential for the patient's prognosis, as the antibioprophylaxis and the isolation measures. But medication adherence is suboptimal for children and adolescents, from 52 to 73% in literature. The aim of this study is to provide an understanding of medication adherence after pediatric allogeneic stem cell transplantation (SCT), by identifying facilitators and barriers. METHOD Semi-structured interviews were conducted by a pharmacist with caregivers and healthcare providers in a pediatric centre. Four topics were discussed: transplantation, post-transplantation therapies, caregivers' experience and the healthcare system. Interviews were audiotaped, transcribed and analysed by inductive approach. FINDINGS Semi-structured interviews with 15 caregivers and 21 healthcare providers identified factors of medication adherence and hygiene measures. The long-term nature of therapy and difficult transitions of care were identified as major barriers. Recognizing the benefits of medication and parental involvement are facilitators. Furthermore, caregivers expressed the need to take into consideration the family entity. They would like also to receive earlier information from healthcare providers before hospital discharge. Those needs were not always identified by healthcare providers. CONCLUSION This analysis revealed barriers and facilitators to the medication adherence and to the care. It demonstrated similarities and differences between caregivers and healthcare providers' perceptions and has thereby initiated an improvement process of the healthcare system. As part of this process, medical and paramedical healthcare providers at this French pediatric centre are currently working on a support program for post-alloSCT hospital-home transition.
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Better outcome with haploidentical over HLA-matched related donors in patients with Hodgkin's lymphoma undergoing allogeneic haematopoietic cell transplantation-a study by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy
Gauthier, J., Poiré, X., Gac, A. C., Leclerc, M., Guillaume, T., Chalandon, Y., Nguyen, S., Forcade, E., Régny, C., Bay, J. O., et al
Bone marrow transplantation. 2018;53(4):400-409
Abstract
The question of the best donor type between haploidentical (HAPLO) and matched-related donors (MRD) for patients with advanced HL receiving an allogeneic hematopoietic cell transplantation (allo-HCT) is still debated. Given the lack of data comparing these two types of donor in the setting of non-myeloablative (NMA) or reduced-intensity (RIC) allo-HCT, we performed a multicentre retrospective study using graft-vs.-host disease-free relapse-free survival (GRFS) as our primary endpoint. We analysed the data of 151 consecutive HL patients who underwent NMA or RIC allo-HCT from a HAPLO (N = 61) or MRD (N = 90) between January 2011 and January 2016. GRFS was defined as the probability of being alive without evidence of relapse, grade 3-4 acute GVHD or chronic GVHD. In multivariable analysis, MRD donors were independently associated with lower GRFS compared to HAPLO donors (HR = 2.95, P < 0.001). Disease status at transplant other than CR was also associated with lower GRFS in multivariable analysis (HR = 1.74, P = 0.01). In addition, the administration of ATG was independently linked to higher GRFS (HR = 0.52, P = 0.009). In summary, we observed significantly higher GRFS in HL patients receiving an allo-HCT using the HAPLO PT-Cy platform compared to MRD.