Publications by authors named "Eliane Gluckman"

236 Publications

Upfront Alternative Donor Transplant Versus Immunosuppressive Therapy in Patients with Severe Aplastic Anemia Who Lack Fully HLA Matched Related Donor: Systematic Review and Meta-Analysis of Retrospective Studies. on Behalf of the Severe Aplastic Anemia Working Party of European Group for Blood and Marrow Transplantation (SAAWP of EBMT).

Transplant Cell Ther 2021 Oct 11. Epub 2021 Oct 11.

King Fahad Medical City, Riyadh, Saudi Arabia. Electronic address:

Idiopathic aplastic anemia is a rare and life-threatening disorder with hematopoietic stem cell transplant (HSCT) from matched sibling donor (MSD) being the standard treatment strategy for young patients. The use of alternative donor transplant (ADT) from a matched unrelated donor (MUD) or HLA haploidentical donor (HID) is not commonly used in the frontline setting. The aim of this systematic review/meta-analysis is to compare ADT as an upfront, rather than delayed, treatment strategy in the absence of a MSD to immunosuppressive therapy (IST) in severe aplastic anemia (SAA). We searched PUBMED/MEDLINE and EMBASE (1998-2019) for studies that compared the outcomes of ADT with IST as upfront therapy in patients with SAA. We included studies with five patients or more in each arm. Studies that included patients with inherited forms of bone marrow failure syndromes were excluded. The primary outcome was the 5- year overall survival rate. Five studies met the inclusion criteria and were included in this meta-analysis. The pooled 5-year odd ratio (OR) for OS was statistically significant at 0.44 [95% CI 0.23-0.85] in favor of upfront ADT. Additionally, the survival was compared between upfront versus salvage ADT in six studies. The pooled 5-year OR for OS was statistically significant at 0.31 [95% CI 0.15-0.64] in favor of upfront ADT. Although this analysis has some limitations including the retrospective nature of the included studies, the lack of ethnic diversity, the predominantly pediatric population and the relatively suboptimal IST regimen used in some of the studies, it indicated that upfront ADT is a potential alternative treatment option in young and pediatric SAA patients who lack an HLA identical sibling donor, particularly when optimal IST is not available.
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http://dx.doi.org/10.1016/j.jtct.2021.10.006DOI Listing
October 2021

The impact of GVHD on outcomes after adult single cord blood transplantation in European and Japanese populations.

Bone Marrow Transplant 2021 Oct 11. Epub 2021 Oct 11.

Eurocord, Hospital Saint Louis, AP-HP, IUH University Paris VII, Paris, France.

The impact of GVHD and graft-versus-leukemia effect in unrelated cord blood transplantation (UCBT) is controversial. In the Eurocord/ALWP EBMT and JSTCT/JDCHCT collaborative study, we evaluated the impact of GVHD on UCBT outcomes in Japanese and European registries. A total of 3,690 adult patients with acute leukemia who received their first single UCBT were included. A multivariate analysis of overall survival (OS) revealed a positive impact of grade II acute GVHD compared with grade 0-I GVHD, in the Japanese cohort (hazard ratio (HR), 0.81; P = 0.001), and an adverse impact in the European cohort (HR, 1.37; P = 0.007). A negative impact of grade III-IV acute GVHD on OS was observed regardless of registries. In the analysis of relapse, a positive impact of grade II acutes GVHD compared with grade 0-I GVHD was observed only in the Japanese cohort, regardless of disease risk. The positive impact of limited chronic GVHD on OS was observed only in the Japanese cohort. In conclusion, a positive impact of mild GVHD after a single UCBT was observed only in the Japanese cohort. This could explain the ethnic difference in UCBT outcomes and might contribute to the preference usage of UCBT in Japan.
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http://dx.doi.org/10.1038/s41409-021-01479-4DOI Listing
October 2021

Impact of the human leucocyte antigen (HLA)-B leader peptide dimorphism and HLA-A expression on outcomes of stem cell transplantation for sickle cell disease.

Br J Haematol 2021 Oct 2;195(2):e128-e131. Epub 2021 Aug 2.

Eurocord, Research Institute Saint-Louis (IRSL) EA3518, Université de Paris, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris, Paris, France.

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http://dx.doi.org/10.1111/bjh.17665DOI Listing
October 2021

Umbilical cord blood transplants facilitated by the French cord blood banks network. On behalf of the Agency of Biomedicine, Eurocord and the French society of bone marrow transplant and cell therapy (SFGM-TC).

Bone Marrow Transplant 2021 10 14;56(10):2497-2509. Epub 2021 May 14.

Eurocord, Hopital Saint-Louis, AP-HP, Institut de Recherche de Saint-Louis (IRSL) EA3518, Université de Paris, Paris, France.

The public French Cord Blood Banks Network was established in 1999 with the objective of standardizing the practices governing umbilical cord blood (UCB) banking in France. The Network adopted a strategy to optimize its inventory and improve the quality of its banked units based on a quality improvement process using outcome data regularly provided by Eurocord. This study aimed to describe the results, over 10 years, of UCBT facilitated by a national network that used the same criteria of UCB collection and banking and to assess how modifications of banking criteria and unit selection might influence transplant outcomes. Nine hundred and ninety-nine units (593 single-unit and 203 double-unit grafts) were released by the Network to transplant 796 patients with malignant (83%) and non-malignant (17%) diseases. Median cell dose exceeded 3.5 × 10 TNC/kg in 86%. There was a trend to select units more recently collected and with higher cell dose. Neutrophil engraftment was 88.2% (85.7-90.7) and 79.3% (72.6-86.5) respectively for malignant and non-malignant diseases with a trend to faster recovery with higher cell doses. The respective 3-year transplant-related mortality were 31.1% (27.5-35.1) and 34.3% (27.0-43.5). OS was 49% ± 4 in malignant and 62% ± 4 in non-malignant disorders. In multivariate analysis, cell dose was the only unit-related factor associated with outcomes. Our results reflect the benefit on clinical outcomes of the strategy adopted by the Network to bank units with higher cell counts.
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http://dx.doi.org/10.1038/s41409-021-01313-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120495PMC
October 2021

[Hematopoietic stem cell transplant yesterday and today].

Soins 2021 Apr;66(854):26-31

Hôpital Saint-Louis, AP-HP, Eurocord, 1 avenue Claude-Vellefaux, 75010 Paris, France.

Bone marrow transplant, more recently called hematopoietic stem cell transplant (HSC), is a complex medical procedure in which a patient with or without malignant hematologic disease receives a combination of chemoradiation followed by an injection of HSC, either from the same patient (autologous transplant) or from a healthy donor (allogeneic transplant).
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http://dx.doi.org/10.1016/S0038-0814(21)00096-7DOI Listing
April 2021

Systematic Review/Meta-Analysis on Efficacy of Allogeneic Hematopoietic Cell Transplantation in Sickle Cell Disease: An International Effort on Behalf of the Pediatric Diseases Working Party of European Society for Blood and Marrow Transplantation and the Sickle Cell Transplantation International Consortium.

Transplant Cell Ther 2021 02 10;27(2):167.e1-167.e12. Epub 2020 Dec 10.

Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, Florida. Electronic address:

Sickle cell disease (SCD) affects more than 300,000 children annually worldwide. Despite improved supportive care, long-term prognosis remains poor. Allogeneic hematopoietic cell transplantation (allo-HCT) is the sole validated curative option, resulting in sustained resolution of the clinical phenotype. The medical literature on allo-HCT for SCD is largely limited to children. Recent studies have evaluated allo-HCT efficacy in adults. Here, we conducted a systematic review/meta-analysis to assess the totality of evidence on the efficacy, or lack thereof, of allo-HCT in treating SCD. We performed a comprehensive literature search using PubMed/Medline, Embase, and Cochrane library databases on November 13, 2019. Four authors independently extracted data on clinical outcomes related to benefits (overall survival [OS] and disease-free survival [DFS]) and harms (acute graft-versus-host disease [aGVHD], chronic graft-versus-host disease [cGVHD], nonrelapse mortality [NRM], and graft failure [GF]). Our search identified a total of 1906 references. Only 33 studies (n= 2853 patients) met our inclusion criteria. We also performed a subset analysis by age. Analyses of all-age groups showed pooled rates of 96% for OS, 90% for DFS, 20% for aGVHD, 10% for cGVHD, 4% for NRM, and 5% for GF. In the pediatric population, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 97%, 91%, 26%, 11%, 5%, and 3%, respectively. In adults, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 98%, 90%, 7%, 1%, 0%, and 14%, respectively. Our data show that allo-HCT is safe and effective, yielding pooled OS rates exceeding 90%. The high GF rate of 14% in adults is concerning and emphasizes the need to evaluate new strategies.
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http://dx.doi.org/10.1016/j.jtct.2020.10.007DOI Listing
February 2021

Worldwide Network for Blood and Marrow Transplantation (WBMT) Recommendations Regarding Essential Medications Required To Establish An Early Stage Hematopoietic Cell Transplantation Program.

Transplant Cell Ther 2021 03 16;27(3):267.e1-267.e5. Epub 2020 Dec 16.

Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

Establishing a hematopoietic cell transplantation (HCT) program is complex. Planning is essential while establishing such a program to overcome the expected challenges. Authorities involved in HCT program establishment will need to coordinate the efforts between the different departments required to start up the program. One essential department is pharmacy and the medications required. To help facilitate this, the Worldwide Network for Blood and Marrow Transplantation organized a structured survey to address the essential medications required to start up an HCT program. A group of senior physicians and pharmacists prepared a list of the medications used at the different phases of transplantation. These drugs were then rated by a questionnaire using a scale of necessity based on the stage of development of the transplant program. The questionnaire was sent to 30 physicians, in different parts of the world, who have between 5 and 40 years of experience in autologous and/or allogeneic transplantation. This group of experts scored each medication on a 7-point scale, ranging from an absolute requirement (score of 1) to not required (score of 7). The results are presented here to help guide the prioritization of required medications.
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http://dx.doi.org/10.1016/j.jtct.2020.12.015DOI Listing
March 2021

Optimizing selection of double cord blood units for transplantation of adult patients with malignant diseases.

Blood Adv 2020 12;4(24):6327-6335

Eurocord, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Institut de Recherche Saint Louis (IRSL) EA3518, Université de Paris, Paris, France.

Double-unit unrelated cord blood transplantation (DUCBT) is an option in patients for whom a single unit is not sufficient to provide an adequate number of cells. As current guidelines on UCB unit selection are mainly based on single-unit UCB data, we performed a retrospective analysis of 1375 adult recipients of DUCBT for hematologic malignancies to determine optimal criteria for graft selection. Cryopreserved total nucleated cells (TNCs; ≤3.5 vs >3.5 × 107/kg: hazard ratio [HR], 1.53; 30% vs 45%; P = .01), number of HLA mismatches (≥2 vs 0-1: HR, 1.28; 42% vs 48%; P = .01), and ABO compatibility (minor/major ABO incompatibility vs compatibility: HR, 1.28; P = .04) were independent risk factors for OS. Cryopreserved CD34+ cell dose ≥0.7 × 105/kg in the winning UCB was associated with improved OS (HR, 1.34; P = .03). Low TNC (≤3.5 × 107/kg) and CD34+ (≤1.4 × 105/kg) cell doses were related to decreased neutrophil recovery (HR, 0.65 [P = .01] and HR, 0.81 [P = .01], respectively). DUCBT recipients with ≥2 HLA mismatches had a higher incidence of grade II-IV and III-IV acute graft-versus-host disease (HR, 1.26 [P = .03] and 1.59 [P = .02], respectively). Low TNC dose (HR, 1.57; P = .02) and receiving UCB with ≥2 HLA mismatches (HR, 1.35; P = .03) were associated with increased transplant-related mortality. Our data support selecting adequately HLA-matched UCB units with a double-unit cryopreserved TNC dose >3.5 × 107/kg and CD34+ cell dose of ≥0.7 × 105/kg per unit in DUCBT candidates.
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http://dx.doi.org/10.1182/bloodadvances.2020002258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756987PMC
December 2020

The role of haematopoietic stem cell transplantation for sickle cell disease in the era of targeted disease-modifying therapies and gene editing.

Lancet Haematol 2020 Dec;7(12):e902-e911

Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Regensburg, Regensburg, Germany. Electronic address:

Sickle cell disease is one of the most common, life-threatening, non-communicable diseases in the world and a major public health problem. Following the implementation of simple preventive and therapeutic modalities, infant mortality has almost been abolished in high-income countries, but only a small amount of progress has been made in improving survival in adulthood. Progressive end-organ damage, partly related to a systemic vasculopathy, is increasingly recognised. With the availability of a variety of novel disease-modifying drugs, gene addition and gene editing strategies, matched sibling donor haematopoietic stem cell transplantation (HSCT) in children (offering an overall survival rate of 95% and an event-free survival rate of 92%), and encouraging outcomes after alternative donor HSCT, the new challenge is to risk stratify patients, revise transplantation indications, and define the best therapeutic approach for each patient. The ultimate challenge will be to enable these advances in low-income and middle-income countries, where disease prevalence is highest and where innovative strategies are most needed.
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http://dx.doi.org/10.1016/S2352-3026(20)30283-0DOI Listing
December 2020

Use of the HLA-B leader to optimize cord-blood transplantation.

Haematologica 2020 10 29;Online ahead of print. Epub 2020 Oct 29.

Eurocord, Hôpital Saint Louis APHP, Institut de Recherche de Saint-Louis (IRSL) EA3518, Université de Paris, Paris, France; Monacord, International Observatory on Sickle Cell Disease, Centre Scientifique de Monaco.

Cord-blood transplantation (CBT) can cure life-threatening blood disorders. The HLA-B leader affects the success of unrelated donor transplantation but its role in CBT is unknown. We tested the hypothesis that the HLA-B leader influences CBT outcomes in unrelated single-unit cord-blood transplants performed by Eurocord/European Blood and Marrow Transplant (EBMT) centers between 1990 and 2018 with data reported to Eurocord. Among 4822 transplants, 2178 had one HLA-B mismatch of which 1013 were HLA-A and HLA-DRB1-matched. The leader (M or T) was determined for each HLA-B allele in patients and units to define the genotype. Among single HLA-B-mismatched transplants, the patient/unit mismatched alleles were defined as leader-matched if they encoded the same leader, or leader-mismatched if they encoded different leaders; the leader encoded by the matched (shared) allele was determined. The risks of GVHD, relapse, non-relapse mortality and overall mortality were estimated for various leaderdefined groups using multivariable regression models. Among the 1013 HLA-A, -DRB1- matched transplants with one HLA-B mismatch, increasing numbers of cord-blood unit M-leader alleles was associated with increased risk of relapse (hazard ratio [HR] for each increase in one M-leader allele 1.30, 95% confidence interval [CI] 1.05 to 1.60, P 0.02). Furthermore, leader mismatching together with an M-leader of the shared HLA-B allele lowered non-relapse mortality (HR 0.44, 95% CI 0.23 to 0.81; P 0.009) relative to leader-matching and a shared T-leader allele. The HLA-B leader may inform relapse and non-relapse mortality risk after CBT. Future patients might benefit from the appropriate selection of units that consider the leader.
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http://dx.doi.org/10.3324/haematol.2020.264424DOI Listing
October 2020

Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease.

Front Immunol 2020 4;11:2041. Epub 2020 Sep 4.

INSERM U955, CHU Henri Mondor, Créteil, France.

Sickle cell disease (SCD), the most common monogenic disease worldwide, is marked by a phenotypic variability that is, to date, only partially understood. Because inflammation plays a major role in SCD pathophysiology, we hypothesized that single nucleotide polymorphisms (SNP) in genes encoding functionally important inflammatory proteins might modulate the occurrence of SCD complications. We assessed the association between 20 SNPs in genes encoding Toll-like receptors (TLR), NK cell receptors (NKG), histocompatibility leukocyte antigens (HLA), major histocompatibility complex class I polypeptide-related sequence A (MICA) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and the occurrence of six SCD clinical complications (stroke, acute chest syndrome (ACS), leg ulcers, cholelithiasis, osteonecrosis, or retinopathy). This study was performed in a cohort of 500 patients. We found that the 4696480 3804099 , and HLA-G, 9380142 genotypes were more frequent in patients who had fewer complications. Also, in logistic regression, the HLA-G 9380142 allele increased the risk of cholelithiasis ( vs. , OR 1.57, 95%CI 1.16-2.15; vs. , OR 2.47, 95%CI 1.34-4.64; = 0.02). For SNPs located in the loci, in logistic regression, the A allele in three SNPs was associated with a lower frequency of retinopathy, namely, 2246809 ( vs. : OR 0.22, 95%CI 0.09-0.50; vs. : OR 0.47, 95%CI 0.31-0.71; = 0.004, for patients of same origin), 2617160 ( vs. : OR 0.67, 95%CI 0.48-0.92; vs. : OR 0.45, 95%CI 0.23-0.84; = 0.04), and 2617169 ( vs. : OR 0.33, 95%CI 0.13-0.82; vs. : OR 0.58, 95%CI 0.36-0.91, = 0.049, in patients of same SCD genotype). These results, by uncovering susceptibility to, or protection against SCD complications, might contribute to a better understanding of the inflammatory pathways involved in SCD manifestations and to pave the way for the discovery of biomarkers that predict disease severity, which would improve SCD management.
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http://dx.doi.org/10.3389/fimmu.2020.02041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510050PMC
April 2021

Reduced-Intensity versus Myeloablative Conditioning in Cord Blood Transplantation for Acute Myeloid Leukemia (40-60 years) across Highly Mismatched HLA Barriers-On Behalf of Eurocord and the Cellular Therapy & Immunobiology Working Party (CTIWP) of EBMT.

Biol Blood Marrow Transplant 2020 11 26;26(11):2098-2104. Epub 2020 Jul 26.

Eurocord, Hopital Saint Louis-EA3518, Paris, France; Haematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address:

The use of myeloablative conditioning (MAC) in umbilical cord blood transplantation (UCBT) has been associated with high nonrelapse mortality (NRM) in patients aged >40 years, especially those having a high HLA disparity, thus limiting wider applications. We hypothesized that the NRM advantage of reduced-intensity conditioning (RIC) and higher graft-versus-leukemia effect associated with greater HLA disparities would expand its use for patients (aged 40 to 60 years) without compromising efficacy and compared outcomes between RIC and MAC regimens. In total, 288 patients aged 40 to 60 years, with de novo acute myeloid leukemia, receiving UCBT with at least 2 HLA mismatches with RIC (n = 166) or MAC (n = 122) regimens were included. As compared to RIC, the MAC cohort included relatively younger patients, having received more single UCBT, with lower total nucleated cell counts and more in vivo T cell depletion. Median time to neutrophil engraftment, infections (bacterial, viral, and fungal), and grade II to IV acute and chronic graft-versus-host disease were similar in both groups. In the multivariate analysis, overall survival (hazard ratio [HR], 0.98; P = .9), NRM (HR, 0.68; P = .2), and relapse (HR, 1.24; P = .5) were not different between RIC and MAC. Refractory disease was associated with worse survival. Outcomes of UBCT for patients aged 40 to 60 years having ≥2 HLA mismatches are comparable after the RIC or MAC regimen.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.025DOI Listing
November 2020

HLA-Matched Unrelated Donors for Patients with Sickle Cell Disease: Results of International Donor Searches.

Biol Blood Marrow Transplant 2020 11 23;26(11):2034-2039. Epub 2020 Jul 23.

Monacord, Centre Scientifique de Monaco, Principauté de Monaco, Monaco; Eurocord, Hôpital Saint Louis, Institut de recherche Saint Louis, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy. Hematopoietic stem cell transplantation (HCT) is the sole curative therapy for SCD, but few patients will have a matched sibling donor. Patients with SCD are mostly of African origin and thus are less likely to find a matched unrelated donor in international registries. Using HaploStats, we estimated HLA haplotypes for 185 patients with SCD (116 from a Brazilian center and 69 from European Society for Blood and Marrow Transplantation [EBMT] centers) and classified the ethnic origin of haplotypes. Then we assessed the probability of finding an HLA-matched unrelated adult donor (MUD), considering loci A, B, and DRB1 (6/6), in international registries. Most haplotypes were African, but Brazilians showed a greater ethnic admixture than EBMT patients. Nevertheless, the chance of finding at least one 6/6 potential allelic donor was 47% for both groups. Most potential allelic donors were from the US National Marrow Donor Program registry and from the Brazilian REDOME donor registry. Although the probability of finding a donor is higher than previously reported, strategies are needed to improve ethnic diversity in registries. Moreover, predicting the likelihood of having an MUD might influence SCD management.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.015DOI Listing
November 2020

An Evaluation of Three Ways of Communicating Carrier Status Results to the Parents of Children in a Neonatal Sickle Cell Screening Programme.

Front Pediatr 2020 19;8:300. Epub 2020 Jun 19.

Centre d'Investigation Clinique de Biothérapie, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.

Sickle cell disease (SCD) is the most frequent monogenic disease worldwide; ~5-7% of the world population carry a hemoglobin disorder trait. In the US, one in every 1,941 newborns has SCD, whereas one in every 3,000 newborns in France is affected - resulting in 385 new cases and 5,883 newly identified carriers per year. The objective of the present study was to evaluate three different ways of providing information to parents at risk of having a child with SCD, with a view to increasing the parental screening rate and decreasing the number of new cases per year in France. In a randomized study, we contacted 300 couples of parents after their child had been identified as a SCD carrier in the French national newborn screening programme: 100 couples received an information letter (the standard procedure in France: arm A), 100 couples received a letter and then a follow-up phone call (arm B), and 100 received a letter and then three follow-up text messages at 5-day intervals (arm C). The primary endpoint was the number of parents in each arm screened in the 120 days after the letter had been sent. In a modified intention-to-treat analysis, the screening rate was 17% in arm A, 35% in arm B, and 30% in arm C. Telephone and text message follow-ups were associated with higher screening rates, compared with no follow-up. After being informed of their child's carrier status, some parents had consulted a healthcare professional but had not been referred for screening (16% in arm A, 19% in arm B, and 13% in arm C). A letter followed by a phone call or three text messages is more effective than a letter alone for informing parents at risk of having a child with SCD. The effective implementation of this follow-up programme probably requires better training of all the healthcare professionals involved.
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http://dx.doi.org/10.3389/fped.2020.00300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318296PMC
June 2020

Risk score to predict event-free survival after hematopoietic cell transplant for sickle cell disease.

Blood 2020 07;136(5):623-626

Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.

We developed a risk score to predict event-free survival (EFS) after allogeneic hematopoietic cell transplantation for sickle cell disease. The study population (n = 1425) was randomly split into training (n = 1070) and validation (n = 355) cohorts. Risk factors were identified and validated via Cox regression models. Two risk factors of 9 evaluated were predictive for EFS: age at transplantation and donor type. On the basis of the training cohort, patients age 12 years or younger with an HLA-matched sibling donor were at the lowest risk with a 3-year EFS of 92% (score, 0). Patients age 13 years or older with an HLA-matched sibling donor or age 12 years or younger with an HLA-matched unrelated donor were at intermediate risk (3-year EFS, 87%; score, 1). All other groups, including patients of any age with a haploidentical relative or HLA-mismatched unrelated donor and patients age 13 years or older with an HLA-matched unrelated donor were high risk (3-year EFS, 57%; score, 2 or 3). These findings were confirmed in the validation cohort. This simple risk score may guide patients with sickle cell disease and hematologists who are considering allogeneic transplantation as a curative treatment relative to other available contemporary treatments.
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http://dx.doi.org/10.1182/blood.2020005687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393258PMC
July 2020

Impact of detectable measurable residual disease on umbilical cord blood transplantation.

Am J Hematol 2020 09 30;95(9):1057-1065. Epub 2020 Jun 30.

EBMT Paris Study Office/CEREST-TC, Paris, France.

The impact of measurable residual disease (MRD) on cord blood transplantation (CBT) outcomes has remained debated. To address this issue, we assessed the impact of measurable MRD at CBT on outcomes in large cohort of patients with acute leukemia. Inclusion criteria included adult patients with acute myeloid (AML) or acute lymphoblastic leukemia (ALL), CBT as first allo-HCT in first or second complete remission (CR) at transplantation, and known MRD status at the time of CBT. Data from 506 patients were included in the analysis. Among them, 317 patients had AML and 189 had ALL. Positive MRD was reported in 169 (33%) patients while the remaining 337 patients were MRD negative at CBT. At 2 years, relapse incidence was 18% in patients with MRD negativity vs 33% in those with MRD positivity at transplantation (P < .001). Two-year leukemia-free survival (LFS) and overall survival (OS) were 57% and 60%, respectively, in MRD negative patients, vs 38% (P < .001) and 48% (P = .004), respectively, in those with MRD positivity. There was no interaction between the impact of MRD on OS and LFS and diagnosis (ie, ALL vs AML), single or double CBT, and reduced-intensity or myeloablative conditioning. On multivariate analysis, MRD positivity was associated with a higher risk of relapse (HR = 1.8, P = .003), comparable non-relapse mortality (P = .44), worse LFS (HR = 1.4, P = .008) and a trend towards worse OS (HR = 1.3, P = .065). In conclusion, these data suggest that novel strategies that are aiming to achieve MRD negativity at CBT are needed for leukemic patients with positive MRD pre-CBT.
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http://dx.doi.org/10.1002/ajh.25879DOI Listing
September 2020

Haploidentical hematopoietic stem cell transplantation in aplastic anemia: a systematic review and meta-analysis of clinical outcome on behalf of the severe aplastic anemia working party of the European group for blood and marrow transplantation (SAAWP of EBMT).

Bone Marrow Transplant 2020 10 28;55(10):1906-1917. Epub 2020 Apr 28.

King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Aplastic anemia (AA) is a serious hematological disorder, which is solely cured by hematopoietic stem cell transplantation (HSCT). Haploidentical HSCT is an emerging modality with encouraging outcomes in several blood conditions. The present study aims to comprehensively assess the feasibility and safety of haploidentical HSCT in patients with severe and very severe AA. It is a systematic review and meta-analysis of studies related to haploidentical stem cell transplantation in idiopathic AA investigating rates of successful engraftment, acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), transplant-related mortality (TRM), and posttransplantation viral infections (including cytomegalovirus [CMV]) in patients with AA. The effects of reduced-intensity conditioning (RIC) and nonmyeloablative conditioning (NMA), as well as various GvHD prophylaxis regimens on these outcomes were evaluated. In total 15 studies were identified, (577 patients, 58.9% males), successful engraftment was observed in 97.3% of patients (95% CI, 95.9-98.7) while grades II-IV aGvHD and cGvHD were reported in 26.6% and 25.0%, respectively. The pooled incidence of TRM was 6.7% per year (95% CI, 4.0-9.4). RIC regimens were associated with higher proportions of successful engraftment (97.7% vs 91.7%, P = 0.03) and aGvHD (29.5% vs 18.7%, P = 0.008) when compared with NMA regimens with no differences in cGvHD or mortality incidence. When compared with methotrexate-containing regimens and other regimens, posttransplant cyclophosphamide-containing regimens reduced the rates of aGvHD (28.6%, 27.8%, and 12.8%, respectively, P = 0.02), CMV viremia (55.7%, 38.6%, and 10.4%, respectively, P < 0.001), and CMV disease in initially viremic patients (2.1%, 33.0%, and 0%, respectively, P < 0.001). We have concluded that Haploidentical HSCT was associated with promising outcomes in terms of successful engraftment and reduced complications. Future prospective trials are needed to identify the preferred conditioning regimen, GvHD prophylaxis, and graft source in the setting of haploidentical transplant for AA.
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http://dx.doi.org/10.1038/s41409-020-0897-2DOI Listing
October 2020

Alternative donor hematopoietic stem cell transplantation for sickle cell disease in Europe.

Hematol Oncol Stem Cell Ther 2020 Dec 16;13(4):181-188. Epub 2020 Mar 16.

Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Regensburg, Regensburg, Germany.

Allogeneic hematopoietic stem cell transplantation (HSCT) is, to date, the only curative treatment for sickle cell disease (SCD). Because an human leukocyte antigen (HLA)-matched sibling donor is not always available, alternative stem cell sources such as unrelated or haploidentical related donors have been explored. To date, few series of SCD patients transplanted with an unrelated donor, cord blood, and haploidentical related donor have been reported, but the high rates of rejection and chronic graft versus host disease have limited their widespread application. We describe the outcomes of a retrospective, registry-based, survey on 144 alternative donor HSCT performed for SCD in 30 European Society for Blood and Marrow Transplantation centers between 1999 and 2017. Data on 70 unrelated adult donors (49%), six cord blood (4%), and 68 haploidentical donors (47%; including post-HSCT Cy, ex vivo T-cell depleted, and other haplo-HSCTs) were reported and missing information was updated by the centers. Overall, 16% patients experienced graft failure, Grade II-IV acute GVHD at 100 days was 24%, whereas Grade III-IV was 10%. Chronic GVHD was observed in 24% (limited for 13 patients and extensive for 18 patients). Overall, the 3-year overall survival (OS) was 86% ± 3% and 3-year event-free survival (EFS; considering death and graft failure as events) was 72% ± 4%. We therefore conclude that alternative donor HSCT for SCD can be feasible but efforts in decreasing relapse and GVHD should be promoted to increase its safe and successful utilization. Moreover, a better knowledge of HLA matching and the tailoring of conditioning could help improve EFS and OS.
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http://dx.doi.org/10.1016/j.hemonc.2019.12.011DOI Listing
December 2020

The role of HLA matching in unrelated donor hematopoietic stem cell transplantation for sickle cell disease in Europe.

Bone Marrow Transplant 2020 10 10;55(10):1946-1954. Epub 2020 Mar 10.

Department of Pediatric Hematology Oncology and Stem Cell Transplantation, University of Regensburg, Regensburg, Germany.

We report the results of an analysis of unrelated allogeneic hematopoietic stem cell transplantations (HSCT) in 71 patients with sickle cell disease (SCD) transplanted in EBMT centers between 2005 and 2017. Median age was 9.3 years; graft type was bone marrow in 79% and peripheral blood in 21%. Recipient-donor HLA match at high resolution typing was 10/10 in 31, 9/10 in 20, and 8/10 in 4 patients; the other patients had intermediate resolution typing. The most frequent conditioning regimens were fludarabine-thiotepa-treosulfan (64%) or busulfan-cyclophosphamide (12%). Cumulative incidence of neutrophil engraftment was 92%; platelet engraftment was 90%. Eleven patients (15%) experienced graft failure. Grade II-IV acute graft-vs.-host disease (GvHD) was 23%; 3-year chronic GvHD was 23%. Three-year overall survival (OS) was 88 ± 4%. GRFS was 62 ± 6%. HLA matching was the most significant risk factor for OS: 3-year OS was 96 ± 4% in 10/10 group vs. 75 ± 10% in 9-8/10 (p = 0.042); GRFS was 69 ± 9% vs. 50 ± 12% (p = 0.114), respectively. In conclusion, unrelated donor HSCT is a valid option for SCD patients who lack an HLA-identical sibling donor, preferably in the context of clinical trials. Using a 10/10 HLA-matched unrelated donor yields better survival indicating that HLA matching is an important donor selection factor in this nonmalignant disease.
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http://dx.doi.org/10.1038/s41409-020-0847-zDOI Listing
October 2020

Nonmyeloablative Alternative Donor Transplantation for Hodgkin and Non-Hodgkin Lymphoma: From the LWP-EBMT, Eurocord, and CIBMTR.

J Clin Oncol 2020 05 7;38(14):1518-1526. Epub 2020 Feb 7.

Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.

Purpose: To compare the outcomes of patients with Hodgkin or non-Hodgkin lymphoma undergoing nonmyeloablative haploidentical or unrelated cord blood (UCB) hematopoietic cell transplantation.

Patients And Methods: We retrospectively studied 740 patients with Hodgkin lymphoma (n = 283, 38%) and non-Hodgkin lymphoma (n = 457, 62%) age 18-75 years who received transplantations from 2009 to 2016. Data were reported to the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation, Eurocord, or Center for International Blood and Marrow Transplant Research. Of the 526 patients who received haploidentical transplantation, 68% received bone marrow and 32% received peripheral blood. All patients received a uniform transplantation conditioning regimen (2 Gy of total-body irradiation, cyclophosphamide, and fludarabine) and graft-versus-host disease prophylaxis (calcineurin inhibitor and mycophenolate). In addition, patients who received a haploidentical transplantation received posttransplantation cyclophosphamide.

Results: Compared with haploidentical bone marrow and peripheral-blood transplantations and adjusted for age, lymphoma subtype, and disease status, survival was lower after UCB transplantation (hazard ratio [HR], 1.55; = .001; and HR, 1.59; = .005, respectively). Similarly, progression-free survival was lower after UCB transplantations compared with haploidentical bone marrow and peripheral-blood transplantations (HR, 1.44; = .002; and HR, 1.86; < .0001), respectively. The 4-year overall and progression-free survival rates after UCB transplantation were 49% and 36%, respectively, compared with 58% and 46% after haploidentical bone marrow transplantation and 59% and 52% after peripheral-blood transplantation, respectively. Lower survival was attributed to higher transplantation-related mortality after UCB transplantation compared with haploidentical bone marrow and peripheral-blood transplantation (HR, 1.91; = .0001; and HR, 2.27; = .0002, respectively).

Conclusion: When considering HLA-mismatched transplantation for Hodgkin or non-Hodgkin lymphoma, the data support haploidentical related donor transplantation over UCB transplantation.
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http://dx.doi.org/10.1200/JCO.19.02408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213591PMC
May 2020

Role of HLA Matching in Single Umbilical Cord Blood Transplantation Outcomes.

Authors:
Eliane Gluckman

Biol Blood Marrow Transplant 2020 03 15;26(3):e53-e54. Epub 2019 Dec 15.

Department of Hematology, Eurocord, Hôpital Saint Louis, Université de Paris, IRSL, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.bbmt.2019.12.014DOI Listing
March 2020

Extensive multilineage analysis in patients with mixed chimerism after allogeneic transplantation for sickle cell disease: insight into hematopoiesis and engraftment thresholds for gene therapy.

Haematologica 2020 05 19;105(5):1240-1247. Epub 2019 Sep 19.

Department of Biotherapy, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Although studies of mixed chimerism following hematopoietic stem cell transplantation in patients with sickle cell disease (SCD) may provide insights into the engraftment needed to correct the disease and into immunological reconstitution, an extensive multilineage analysis is lacking. We analyzed chimerism simultaneously in peripheral erythroid and granulomonocytic precursors/progenitors, highly purified B and T lymphocytes, monocytes, granulocytes and red blood cells (RBC). Thirty-four patients with mixed chimerism and ≥12 months of follow-up were included. A selective advantage of donor RBC and their progenitors/precursors led to full chimerism in mature RBC (despite partial engraftment of other lineages), and resulted in the clinical control of the disease. Six patients with donor chimerism <50% had hemolysis (reticulocytosis) and higher HbS than their donor. Four of them had donor chimerism <30%, including a patient with AA donor (hemoglobin >10 g/dL) and three with AS donors (hemoglobin <10 g/dL). However, only one vaso-occlusive crisis occurred with 68.7% HbS. Except in the patients with the lowest chimerism, the donor engraftment was lower for T cells than for the other lineages. In a context of mixed chimerism after hematopoietic stem cell transplantation for SCD, myeloid (rather than T cell) engraftment was the key efficacy criterion. Results show that myeloid chimerism as low as 30% was sufficient to prevent a vaso-occlusive crisis in transplants from an AA donor but not constantly from an AS donor. However, the correction of hemolysis requires higher donor chimerism levels ( ≥50%) in both AA and AS recipients. In the future, this group of patients may need a different therapeutic approach.
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http://dx.doi.org/10.3324/haematol.2019.227561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193509PMC
May 2020

Effect of donor type and conditioning regimen intensity on allogeneic transplantation outcomes in patients with sickle cell disease: a retrospective multicentre, cohort study.

Lancet Haematol 2019 Nov 5;6(11):e585-e596. Epub 2019 Sep 5.

Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Donors other than matched siblings and low-intensity conditioning regimens are increasingly used in haematopoietic stem cell transplantation. We aimed to compare the relative risk of donor type and conditioning regimen intensity on the transplantation outcomes of in patients with sickle cell disease.

Methods: For this retrospective cohort study, we collected data from 90 US centres reported to the Center for International Blood and Marrow Transplant Research. Eligible patients were younger than 50 years, had genetically confirmed sickle cell disease (Hb SS) or sickle beta thalassemia (Hb Sβ), and underwent allogeneic haematopoietic cell transplantation between Jan 15, 2008, and Dec 28, 2017. We considered transplants from donor-recipient pairs matched at the allele-level (HLA-A, HLA-B, HLA-C, and HLA-DRB1), including HLA-matched sibling donors, haploidentical related donors, matched unrelated donors, or mismatched unrelated donors. The main outcome was event-free survival. The effect of donor type, conditioning regimen intensity (myeloablative, non-myeloablative, and reduced-intensity regimens), age (≤12 or 13-49 years), sex, performance score, comorbidity index, recipient cytomegalovirus serostatus, graft type (bone marrow, peripheral blood, or umbilical cord blood), and transplantation period (2008-12 and 2013-17) on outcomes was studied using Cox regression models.

Findings: Of 996 patients with sickle cell disease and who underwent transplantation in 2008-17, 910 (91%) were included (558 [61%] patients had HLA-matched sibling donors, 137 [15%] haploidentical related donors, 111 [12%] matched unrelated donors, and 104 [11%] mismatched unrelated donors). The median follow-up was 36 months (IQR 18-60) after transplantation from HLA-matched siblings, 25 months (12-48) after transplantation from haploidentical related donors, 37 months (23-60) after transplantation from HLA-matched unrelated donors, and 47 months (24-72) after transplantation from mismatched unrelated donors. Event-free survival was worse in recipients aged 13 years or older than in those younger than 13 years (hazard ratio 1·74, 95% CI 1·24-2·45; p=0·0014) and in those who received a transplant from haploidentical related donors (5·30, 3·17-8·86; p<0·0001), matched unrelated donors (3·71, 2·39-5·75; p<0·0001), and mismatched unrelated donors (4·34, 2·58-7·32; p<0·0001) than in patients who received a transplant from matched siblings. There was no significant difference in event-free survival between recipients of transplants from non-sibling donors: haploidentical related donors (1·43, 0·81-2·50; p=0·21) or mismatched unrelated donors (1·17, 0·67-2·05; p=0·58) versus HLA-matched unrelated donors, or mismatched unrelated donors versus haploidentical related donors (1·22, 0·65-2·27; p=0·98). Event-free survival was also worse in patients conditioned with reduced-intensity regimens (1·97, 1·15-3·36; p=0·013) than in those conditioned with non-myeloablative regimens, but did not differ between those who received myeloablative compared with non-myeloablative regimens (1·57, 0·95-2·61; p=0·079). Interpretation Our data suggest that event-free survival is improved in patients with sickle cell disease who receive an allogenic transplantation at age 12 years or younger and those with an HLA-matched sibling donor. For patients without a matched sibling available for transplantation, our data do not favour one alternative donor type over another in this setting.

Funding: National Institutes of Health and US Health Services Research Administration, Department of Health and Human Services.
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http://dx.doi.org/10.1016/S2352-3026(19)30154-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813907PMC
November 2019

Worldwide Network for Blood and Marrow Transplantation (WBMT) recommendations for establishing a hematopoietic cell transplantation program (Part I): Minimum requirements and beyond.

Hematol Oncol Stem Cell Ther 2020 Sep 20;13(3):131-142. Epub 2019 Aug 20.

Haematology Department, Imperial College, Hammersmith Hospital, London, UK.

Hematopoietic cell transplantation (HCT) is a highly complex procedure that requires a dedicated multidisciplinary team to optimize its safety. In addition, institutions may have different needs regarding indications based on regional disease prevalence or may have an interest in developing specialized services. Yet, structured recommendations are not commonly available. Here, the Transplant Center and Recipient Issues Standing Committee for the Worldwide Network for Blood and Marrow Transplantation (WBMT) organized a structured review of all pertinent elements to establish a transplant program. First, we solicited components from committee members and grouped them in domains (infrastructure, staff, cell processing laboratory, blood banking, laboratory, radiology, pharmacy, HLA testing, ancillary services and quality). Subsequently, reviewers scored all elements on a 7-point scale, from an absolute requirement (score of 1) to not required (score of 7). An independent group of five experienced transplant physicians reviewed the rankings. Minimum requirements to establish any HCT program were identified among elements with mean score of ≤2.0, and specific elements for allogeneic and autologous HCT were identified. Mean scores >2.0-4.0 were classified as preferred recommendation, and mean scores of >4.0 to ≤7.0 were considered ideal recommendations for advanced and complex types of transplantation. This structured set of recommendations guides the prioritization of minimum requirements to establish a transplant program and to set the path for expansion and further development.
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http://dx.doi.org/10.1016/j.hemonc.2019.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125509PMC
September 2020

Prognostic factors for adult single cord blood transplantation among European and Japanese populations: the Eurocord/ALWP-EBMT and JSHCT/JDCHCT collaborative study.

Leukemia 2020 01 14;34(1):128-137. Epub 2019 Aug 14.

Eurocord, Hospital Saint Louis, AP-HP, IUH University Paris VII, Paris, France.

Large differences in patient and transplant backgrounds make it difficult to identify consistent prognostic factors of unrelated cord blood transplantation (UCBT) among different populations. Thus, we performed a collaborative study between Eurocord/ALWP-EBMT and JSHCT/JDCHCT. Adults with acute leukaemia who underwent a single UCBT were eligible. In total, 3764 and 1027 patients of the JSHCT/JDCHCT and Eurocord/ALWP-EBMT registries, respectively, were included. The median ages of the Japanese and European cohorts were 51 and 38 years, respectively. Three or more HLA mismatches were more frequently observed in the Japanese cohort. The median total nucleated cell (TNC) counts were 2.58 and 3.51 × 10/kg in the Japanese and European cohorts, respectively. Anti-thymocyte globulin was used in only 2% of the Japanese cohort compared with 65% of the European cohort. The 3-year overall survival (OS) was 41% in JSHCT/JDCHCT and 33% in Eurocord/ALWP-EBMT. In the multivariate analysis, TNC dose and HLA matching had no significant effect on OS in either cohort, whereas year of transplantation, age, and refined disease risk index affected OS in both cohorts. Despite considerable differences in characteristics between the Japanese and European cohorts, we observed similar prognostic factors affecting UCBT outcomes in adult patients with acute leukaemia in both registries.
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http://dx.doi.org/10.1038/s41375-019-0534-5DOI Listing
January 2020

Myeloablative Unrelated Cord Blood Transplantation in Adolescents and Young Adults with Acute Leukemia.

Biol Blood Marrow Transplant 2019 12 5;25(12):2438-2446. Epub 2019 Aug 5.

Eurocord, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France; Monacord, Centre Scientifique de Monaco, Principauté de Monaco, Monaco. Electronic address:

Outcomes for adolescents and young adults (AYAs) with leukemia differ from other age groups and are still under-represented in clinical research. The aim of this study was to analyze outcomes of umbilical cord blood transplant (UCBT) in AYAs with acute leukemia reported to Eurocord/European Society for Blood and Marrow Transplantation. Patients (N = 504) had acute lymphoblastic (59%) or myeloid leukemia (41%), were aged 15 to 25 years, and received UCBT after myeloablative conditioning regimens between 2004 and 2016. The primary endpoint was 3-year overall survival (OS). Median follow-up was 3.9 years. Transplant was single in 58% and double UCBT in 42%. Three-year OS was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIFs) of nonrelapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute graft-versus-host disease (GVHD) grades II to IV at day 100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT (hazard ratio [HR], 2.74; P < .001) and more recent UCBT (HR, 1.43; P = .01) were associated with increased OS, and a similar effect of these factors was observed on LFS. Contrastingly, the use of antithymocyte globulin had a negative effect in LFS. The risk of acute GVHD grades II to IV increased with the use of double UCBT (HR, 1.65; P  = .02) and decreased with more recent transplant period (HR, .65; P = .02) and antithymocyte globulin use (HR, .55; P  = .01). Outcomes of AYA UCBT improved in more recent years, becoming comparable with pediatric results. Demonstrating the feasibility of UCBT in AYAs facilitates stem cell source selection and provides the basis for future prospective studies.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.031DOI Listing
December 2019

Hematopoietic stem cell transplantation with unrelated cord blood or haploidentical donor grafts in adult patients with secondary acute myeloid leukemia, a comparative study from Eurocord and the ALWP EBMT.

Bone Marrow Transplant 2019 12 31;54(12):1987-1994. Epub 2019 May 31.

Hôpital Saint Antoine, Service d'Hématologie et Thérapie Cellulaire, AP-HP, Paris, France.

Survival of patients with secondary acute myeloid leukemia (sAML) is poor. Cord blood transplantation (UCBT) and non-T-cell-depleted stem cell transplantation from haploidentical donors (HAPLO) are both strategies that have shown encouraging results in patients who do not have an human leukocyte antigen (HLA)-matched sibling or unrelated donor. We retrospectively analyzed outcomes of 409 adults with sAML receiving either UCBT (n = 163) or HAPLO (n = 246) in EBMT centers. Myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPD) was the antecedent diagnosis in 79% of UCBT and 85% of HAPLO recipients. In multivariate analysis, UCBT was associated with higher risk of grade II-IV acute GVHD (HR 1.9, p = 0.009) and lower GHVD-free-relapse-free-survival (GRFS) (HR 1.57, p = 0.007) compared to HAPLO. Chronic-GVHD, RI, NRM, LFS, and OS were not statistically different between the two. Early disease stage at transplant was independently associated with lower RI and NRM and higher OS and LFS. These results indicate that HAPLO is associated with better GRFS and lower aGvHD compared to UCBT in patients with sAML and that UCBT can be a valid alternative for sAML patients who lack a matched sibling, a proper haploidentical or an unrelated donor.
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http://dx.doi.org/10.1038/s41409-019-0582-5DOI Listing
December 2019
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