Publications by authors named "Frans Smiers"

33 Publications

Stem Cell Transplantation for Diamond-Blackfan Anemia. A Retrospective Study on Behalf of the Severe Aplastic Anemia Working Party of the European Blood and Marrow Transplantation Group (EBMT).

Transplant Cell Ther 2021 Mar 25;27(3):274.e1-274.e5. Epub 2020 Dec 25.

Haematology Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy.

Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients.
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http://dx.doi.org/10.1016/j.jtct.2020.12.024DOI Listing
March 2021

Usefulness of NGS for Diagnosis of Dominant Beta-Thalassemia and Unstable Hemoglobinopathies in Five Clinical Cases.

Front Physiol 2021 5;12:628236. Epub 2021 Feb 5.

Translational Research in Child and Adolescent Cancer - Rare Anemia Disorders Research Laboratory, Vall d'Hebron Research Institute, ERN-EuroBloodNet Member, Barcelona, Spain.

Unstable hemoglobinopathies (UHs) are rare anemia disorders (RADs) characterized by abnormal hemoglobin (Hb) variants with decreased stability. UHs are therefore easily precipitating, causing hemolysis and, in some cases, leading to dominant beta-thalassemia (dBTHAL). The clinical picture of UHs is highly heterogeneous, inheritance pattern is dominant, instead of recessive as in more prevalent major Hb syndromes, and may occur . Most cases of UHs are not detected by conventional testing, therefore diagnosis requires a high index of suspicion of the treating physician. Here, we highlight the importance of next generation sequencing (NGS) methodologies for the diagnosis of patients with dBTHAL and other less severe UH variants. We present five unrelated clinical cases referred with chronic hemolytic anemia, three of them with severe blood transfusion dependent anemia. Targeted NGS analysis was performed in three cases while whole exome sequencing (WES) analysis was performed in two cases. Five different UH variants were identified correlating with patients' clinical manifestations. Four variants were related to the beta-globin gene (Hb Bristol-Alesha, Hb Debrousse, Hb Zunyi, and the novel Hb Mokum) meanwhile one case was caused by a mutation in the alpha-globin gene leading to Hb Evans. Inclusion of alpha and beta-globin genes in routine NGS approaches for RADs has to be considered to improve diagnosis' efficiency of RAD due to UHs. Reducing misdiagnoses and underdiagnoses of UH variants, especially of the severe forms leading to dBTHAL would also facilitate the early start of intensive or curative treatments for these patients.
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http://dx.doi.org/10.3389/fphys.2021.628236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893112PMC
February 2021

Haplo-identical or mismatched unrelated donor hematopoietic cell transplantation for Fanconi anemia: Results from the Severe Aplastic Anemia Working Party of the EBMT.

Am J Hematol 2021 Feb 19. Epub 2021 Feb 19.

French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Saint Louis Hospital and University Paris Diderot, Paris, France.

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 = .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 = .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 = .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.
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http://dx.doi.org/10.1002/ajh.26135DOI Listing
February 2021

Hematopoietic Stem Cell Transplantation for Hepatitis-associated Aplastic Anemia Following Liver Transplantation for Nonviral Hepatitis: A Retrospective Analysis and a Review of the Literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT).

J Pediatr Hematol Oncol 2020 Dec 2. Epub 2020 Dec 2.

Hopital St. Louis, Paris.

Hepatitis-associated aplastic anemia (HAAA) has been reported in 23% to 33% of patients who received orthotopic liver transplantation (LT) for acute liver disease of unknown origin (nonviral hepatitis). In this situation, hematopoietic stem cell transplantation (HSCT) might be a curative option. Here the authors report on 6 patients who received HSCT after LT for nonviral HAAA hepatitis. The outcomes were interpreted in the context of recently reported immune suppressive therapy (IST) outcomes in 8 patients with HAAA and to HSCT outcomes in patients with HAAA who recovered from hepatitis without undergoing LT. All patients transplanted by using HLA-identical sibling donors (3 out of 6) were alive and had normal liver function and hematopoiesis without graft versus host disease. Both patients receiving bone marrow from a matched unrelated donor (MUD) experienced extensive graft versus host disease that was fatal for one patient. Thereby, the authors conclude that HSCT can be considered as a first-choice treatment for this category of patients when HLA-identical donors are available. When no HLA-identical donor is available, IST should be applied as HSCT with other donor sources might be reserved for IST nonresponders or poor responders.
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http://dx.doi.org/10.1097/MPH.0000000000001991DOI Listing
December 2020

Long-term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT).

Bone Marrow Transplant 2020 09 19;55(9):1796-1809. Epub 2020 Mar 19.

G. Gaslini Research Institute (IRRCS), Genova, Italy.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative procedure in patients with Shwachman-Diamond syndrome (SDS) with bone marrow abnormalities. The results of 74 patients with SDS (6 acute myeloid leukemia, 7 myelodysplastic syndrome, and 61 bone marrow failure) treated with HSCT between 1988 and 2016 are reported. The donor source was: 24% sibling, 8% parent, and 68% unrelated donor. The stem cell source was: 70% bone marrow, 19% peripheral blood stem cells, and 11% cord blood. The conditioning regimen was myeloablative in 54% and reduced intensity in 46%. Neutrophil engraftment was achieved in 84% of patients after a median time of 17.5 days. Graft failure occurred in 15% of HSCTs. Grades I-IV acute and chronic GVHD were observed in 55% and 20% of patients, respectively. After a median follow-up of 7.3 years (95% CI 4.8-10.2), 28 patients died for progression/relapse (7) or toxicity (21). The 5-year overall survival and nonrelapse mortality were 63.3% (95% CI 50.8-73.4) and 19.8% (95% CI 10.8-30.8), respectively. In conclusion, this is the largest series so far reported and confirms that HSCT is a suitable option for patients with SDS. Further efforts are needed to lower transplant-related toxicity and reduce graft failure.
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http://dx.doi.org/10.1038/s41409-020-0863-zDOI Listing
September 2020

Proceeding of the European Group for Blood and Marrow Transplantation (EBMT) congress on sickle cell disease, 16-17 may 2019, Regensburg, Germany: What is the impact of antithymocyte globulin pharmacokinetics on haploidentical hematopoietic stem cell transplantation?

Hematol Oncol Stem Cell Ther 2020 Jun 12;13(2):61-65. Epub 2020 Mar 12.

Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands.

Antithymocyte globulin (ATG) is a widely accepted part of the conditioning regimen applied in the setting of hematopoietic stem cell transplantation (HSCT) to prevent graft rejection and graft-versus-host disease. Although weight-based dosing of ATG has been introduced to optimize ATG dosing, substantial variance in clearance of active ATG, the actual lymphocyte binding component, remains a challenge. Therefore, further research regarding ATG pharmacokinetics and pharmacodynamics in different HSCT settings and in patients with different types of underlying diseases is required.
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http://dx.doi.org/10.1016/j.hemonc.2019.12.003DOI Listing
June 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

Parental experiences in end-of-life decision-making in allogeneic pediatric stem cell transplantation: "Have I been a good parent?"

Pediatr Blood Cancer 2020 05 5;67(5):e28229. Epub 2020 Mar 5.

Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: In pediatric hematopoietic stem cell transplantation (HSCT), the end-of-life (EOL) phase and the loss of the child is often characterized by a sudden deterioration of the child following a period of intensive curative treatment. This demands a fast transition for parents. Therefore, an understanding of the parents' perspective on decision-making in such a complex situation is needed. This study aims to gain insight in parental experiences in EOL decision-making in allogeneic pediatric HSCT.

Methods: A qualitative descriptive study was performed among parents of eight families. Data were thematically analyzed.

Results: All parents were aware of their child's deterioration. Six families were confronted with a rapid deterioration, while two families experienced a gradual realization that their child would not survive. Parental EOL decision-making in pediatric HSCT shows a reflective perspective on the meaning of parenthood in EOL decision-making. Two central themes were identified: "survival-oriented decision-making" and "struggling with doubts in hindsight." Six subthemes within the first theme described the parents' goal of doing everything to achieve survival.

Discussion: Parents experienced EOL decision-making mainly as a process guided by health care professionals (HCPs) based on the child's condition and treatment possibilities. The decision-making is characterized by following opportunities and focusing on hope for cure. In hindsight parents experienced doubts about treatment steps and their child's suffering. HCPs can strengthen the parental role by an early integration of palliative care, providing timely support to parents in the process of imminent loss. Advance care planning can be used to support communication processes, defining preferences for future care.
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http://dx.doi.org/10.1002/pbc.28229DOI Listing
May 2020

Plasmapheresis to eliminate immunosuppressive alemtuzumab levels in a child with disseminated adenovirus infection after allogeneic stem cell transplantation.

Bone Marrow Transplant 2020 08 18;55(8):1671-1673. Epub 2020 Feb 18.

Department of Pediatric Stem Cell Transplantation, Willem Alexander Children's Hospital, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

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http://dx.doi.org/10.1038/s41409-020-0837-1DOI Listing
August 2020

Haploidentical transplantation and posttransplant cyclophosphamide for treating aplastic anemia patients: a report from the EBMT Severe Aplastic Anemia Working Party.

Bone Marrow Transplant 2020 06 16;55(6):1050-1058. Epub 2019 Dec 16.

Hematology-Transplantation Department, Saint-Louis Hospital, Paris, France.

In the absence of an HLA-matched donor, the best treatment for acquired aplastic anemia patients refractory to immunosuppression is unclear. We collected and analyzed data from all acquired aplastic anemia patients who underwent a haploidentical transplantation with posttransplant cyclophosphamide in Europe from 2011 to 2017 (n = 33). The cumulative incidence of neutrophil engraftment was 67% (CI: 51-83%) at D +28 and was unaffected by age group, stem cell source, ATG use, or Baltimore conditioning regimen. The cumulative incidence of grades II-III acute GvHD was 23% at D +100, and limited chronic GvHD was 10% (0-20) at 2 years, without cases of grade IV acute or extensive chronic GvHD. Two-year overall survival was 78% (64-93), and 2-year graft-versus-host disease-free survival was 63% (46-81). In univariate analysis, the 2-year OS was higher among patients who received the Baltimore conditioning regimen (93% (81-100) versus 64% (41-87), p = 0.03), whereas age group, stem cell source, and ATG use had no effect. Our results using unmanipulated haploidentical transplantation and posttransplant cyclophosphamide for treating refractory AA patients are encouraging, but warrant confirmation in a prospective study with a larger number of patients and longer follow-up.
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http://dx.doi.org/10.1038/s41409-019-0773-0DOI Listing
June 2020

Intravenous immunoglobulin vs observation in childhood immune thrombocytopenia: a randomized controlled trial.

Blood 2018 08 26;132(9):883-891. Epub 2018 Jun 26.

Department of Pediatric Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.

Management of children with newly diagnosed immune thrombocytopenia (ITP) consists of careful observation or immunomodulatory treatment. Observational studies suggest a lower risk for chronic ITP in children after intravenous immunoglobulin (IVIg) treatment. In this multicenter randomized trial, children aged 3 months to 16 years with newly diagnosed ITP, platelet counts 20 × 10/L or less, and mild to moderate bleeding were randomly assigned to receive either a single infusion of 0.8 g/kg IVIg or careful observation. Primary outcome was development of chronic ITP, which at the time of study initiation was defined as a platelet count lower than 150 × 10/L after 6 months. Two hundred six children were allocated to receive IVIg (n = 102) or careful observation (n = 104). Chronic ITP occurred in 18.6% of the patients in the IVIg group and 28.9% in the observation group (relative risk [RR], 0.64; 95% confidence interval [CI], 0.38-1.08). Platelet counts lower than 100 × 10/L at 12 months (current definition of chronic ITP) were observed in 10% of children in the IVIg group and 12% in the observation group (RR, 0.83; 95% CI, 0.38-1.84). Complete response rates in the first 3 months were significantly higher in the IVIg group. Immunoglobulin G Fc receptor IIb genetic variations were associated with early complete response in both groups. Grade 4 to 5 bleeding occurred in 9% of the patients in the observation group vs 1% in the IVIg group. This trial was registered at www.trialregister.nl as NTR 1563.
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http://dx.doi.org/10.1182/blood-2018-02-830844DOI Listing
August 2018

Risk Factors, Treatment, and Immune Dysregulation in Autoimmune Cytopenia after Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients.

Biol Blood Marrow Transplant 2018 04 19;24(4):772-778. Epub 2017 Dec 19.

Department of Pediatrics, Section Immunology, Hematology and Stem Cell Transplantation, Leiden University Medical Center, Leiden, The Netherlands. Electronic address:

Autoimmune or alloimmune cytopenia (AIC) is a known rare complication of hematopoietic stem cell transplantation (SCT). AIC after SCT is considered difficult to treat and is associated with high morbidity and mortality. In this retrospective study in pediatric patients we evaluated incidence, outcome, potential risk factors, and current treatment strategies. A nested matched case-control study was performed to search for biomarkers associated with AIC. Of 531 consecutive SCTs at our center between 2000 and 2016, 26 were complicated by the development of AIC (cumulative incidence, 5.0%) after a median of 5 months post-SCT. Autoimmune hemolytic anemia was the most common AIC with 12 patients (46%). We identified nonmalignant disease, alemtuzumab serotherapy pre-SCT, and cytomegalovirus (CMV) reactivation as independently associated risk factors. The cytokine profile of patients at the time of AIC diagnosis appeared to skew toward a more pronounced Th 2 response compared with control subjects at the corresponding time point post-SCT. Corticosteroids and intravenous immunoglobulin as first-line treatment or a wait-and-see approach led to resolution of AIC in 35% of cases. Addition of step-up therapies rituximab (n = 15), bortezomib (n = 7), or sirolimus (n = 3) was associated with AIC resolution in 40%, 57%, and 100% of cases, respectively. In summary, we identified CMV reactivation post-SCT as a new clinical risk factor for the development of AIC in children. The cytokine profile during AIC appears to favor a Th 2 response. Rituximab, bortezomib, and sirolimus are promising step-up treatment modalities.
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http://dx.doi.org/10.1016/j.bbmt.2017.12.782DOI Listing
April 2018

Pediatric Diamond-Blackfan anemia in the Netherlands: An overview of clinical characteristics and underlying molecular defects.

Eur J Haematol 2018 Feb 1;100(2):163-170. Epub 2017 Dec 1.

Department of Pediatric Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.

Introduction: Diamond-Blackfan anemia (DBA) is characterized by hypoplastic anemia, congenital anomalies, and a predisposition for malignancies. Most of our understanding of this disorder stems from molecular studies combined with extensive data input from international patient registries.

Objectives: To create an overview of the pediatric DBA population in the Netherlands.

Methods: Forty-three patients diagnosed with DBA from all Dutch university pediatric hospitals were included in this study, and their clinical and genetic characteristics were collected from patient records.

Results: Congenital malformations were present in 24 of 43 patients (55.8%). An underlying genetic defect was identified in 26 of 43 patients (60.5%), the majority of which were found in the RPS19 gene (12 of 43, 27.9%) with 1 patient carrying a mutation in a novel DBA candidate gene, RPL9. In 31 of 35 (88.6%) patients, an initial response to glucocorticoid treatment was observed. Six patients (14.0%) underwent hematopoietic stem cell transplantation, and eleven patients (11 of 43, 25.6%) became treatment-independent spontaneously.

Conclusion: In agreement with previous reports, the Dutch pediatric DBA population is both clinically and genetically heterogeneous. National and international registries, together with more extensive genetic testing, are crucial to increase our understanding of genotype and phenotype correlations of this intriguing disorder.
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http://dx.doi.org/10.1111/ejh.12995DOI Listing
February 2018

High interpatient variability of treosulfan exposure is associated with early toxicity in paediatric HSCT: a prospective multicentre study.

Br J Haematol 2017 12 19;179(5):772-780. Epub 2017 Oct 19.

Department of Paediatrics, Leiden University Medical Centre, Leiden, the Netherlands.

Treosulfan-based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen-related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30 g/m , administered over 3 consecutive days in infants <1 year old (n = 12) and 42 g/m in children ≥1 year old (n = 65). Mean day 1 treosulfan exposure was 1744 ± 795 mg*h/l (10 g/m ) and 1561 ± 511 mg*h/l (14 g/m ), with an inter-individual variability of 56 and 33% in the respective groups. High treosulfan exposure (>1650 mg*h/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19-16·28, P = 0·026] and skin toxicity (OR 4·51; 95% CI 1·07-18·93, P = 0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft-versus-host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long-term disease-specific outcome and late treatment-related toxicity.
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http://dx.doi.org/10.1111/bjh.14960DOI Listing
December 2017

The use of intravenous pentamidine for the prophylaxis of Pneumocystis pneumonia in pediatric patients.

Pediatr Blood Cancer 2017 Aug 11;64(8). Epub 2017 Jan 11.

Department of Pediatric Immunology-Infections and Stem Cell Transplantation, Leiden University Medical Center, Leiden, The Netherlands.

Pneumocystis jiroveci pneumonia was common in the immunocompromised host before the widespread use of prophylaxis. When trimethoprim-sulfamethoxazole is not tolerated, prophylaxis with intravenous pentamidine (IVP) may be initiated. We performed a retrospective analysis of all pediatric patients who received IVP regarding efficacy, safety, and reason for initiation. Of 106 patients included in our analysis, one patient tested positive for Pneumocystis DNA. Adverse events were reported in 18% of IVP courses, and main reason for initiation was cytopenia (59%). We found IVP to be effective and safe, and recommend the use of IVP in pediatric patients in whom first-line prophylaxis is contraindicated.
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http://dx.doi.org/10.1002/pbc.26453DOI Listing
August 2017

Four decades of stem cell transplantation for Fanconi anaemia in the Netherlands.

Br J Haematol 2016 09 29;174(6):952-61. Epub 2016 Jul 29.

Department of Paediatric Haematology and Stem Cell Transplantation, University Medical Centre Utrecht, Utrecht, The Netherlands.

This article presents the haematopoietic stem cell transplantation (SCT) results of the complete Dutch Fanconi anaemia (FA) patient cohort. Sixty-eight Dutch FA patients have been transplanted since 1972. In total, 63 (93%) patients engrafted, 54 after first SCT and 9 after second SCT. Fludarabine (FLU)-based conditioning was associated with decreased graft failure (odds ratio 0·21, P = 0·01), decreased early mortality (hazard ratio 0·25, P = 0·01) and improved 5-year overall survival (FLU 87·8% [standard error (SE) 5·1%] versus non-FLU 59·3% [SE 9·5%], P = 0·01). Late mortality was mainly caused by squamous cell carcinoma. Twenty-two patients were treated with the current Dutch FA conditioning regimen (FLU 150 mg/m(2) and cyclophosphamide 30 mg/kg ± anti-thymocyte globulin - no irradiation). Stem cell donors were matched related (n = 8) or alternative donors (n = 14). Stable engraftment after first SCT was achieved in 19 (86%) patients. At a median follow-up of 3·9 years 20 (91%) patients are alive. Our study provides a unique overview of a nation-wide SCT cohort illustrating the major improvements in treatment regimen and patient outcome in recent years. It shows that a non-irradiation and busulfan-free conditioning regimen can be used successfully, also in alternative donor SCT. Furthermore, it underlines the importance of late cancer screening and comprehensive care for this complex disorder.
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http://dx.doi.org/10.1111/bjh.14165DOI Listing
September 2016

Higher Tinzaparin Dosing Is Needed to Achieve Target Anti-Xa Levels in Pediatric Cardiac Intensive Care Patients.

Pediatr Crit Care Med 2016 Mar;17(3):203-9

1Department of Pediatric Intensive Care, Leiden University Medical Center, Leiden, the Netherlands. 2Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands. 3Department of Pediatric Hematology, Leiden University Medical Center, Leiden, the Netherlands.

Objectives: This study was conducted to evaluate tinzaparin dosing and therapeutic drug monitoring.

Design: Retrospective study.

Setting: Single tertiary-level PICU.

Patients: Tinzaparin doses and anti-Xa levels from all children admitted to a PICU (from October 1, 2010, to December 31, 2013) were retrospectively analyzed. Thirty-nine children, median age of 13 months (interquartile range, 73 mo), with 46 episodes of newly started therapeutic tinzaparin were identified.

Interventions: None.

Measurements And Main Results: Local hospital policy is to determine the first anti-Xa level after 3-4 doses, 4 hours post dose, targeting 0.5-1.0 IU/mL for therapeutic dosing. First anti-Xa levels were determined after 3.8 (± 2.4; range, 1-14) doses and were below the target range in 37 of 46 episodes (76%) of tinzaparin use: mean, 0.30 (± 0.11) IU/mL. Tinzaparin was then increased by 23% (± 19) in 23 of 37 episodes (62%), and further anti-Xa levels were determined. In 14 episodes, further levels were not available because of cessation of tinzaparin therapy. Target anti-Xa levels, 0.69 (± 0.24) IU/mL, were eventually reached in the PICU in 22 patients after a mean of 8.8 (± 7.3) doses. In the entire cohort, the dose required to achieve target anti-Xa levels was significantly higher (+51 [± 62] U/kg; p = 0.003) than the recommended starting dose.

Conclusions: Target anti-Xa levels were reached with tinzaparin dosing in PICU patients after more than 8 doses, warranting further dose-effect research. Especially in the younger age group, substantially higher dose requirements than proposed in the internationally used guidelines are required. With the results of our study, we suggest a different therapeutic drug monitoring approach than that currently used.
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http://dx.doi.org/10.1097/PCC.0000000000000640DOI Listing
March 2016

Bleeding spectrum in children with moderate or severe von Willebrand disease: Relevance of pediatric-specific bleeding.

Am J Hematol 2015 Dec 17;90(12):1142-8. Epub 2015 Nov 17.

Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.

The bleeding phenotype of children with von Willebrand disease (VWD) needs to be characterized in detail to facilitate diagnosis during childhood and aid in the planning and assessment of treatment strategies. The objective was to evaluate the occurrence, type, and severity of bleeding in a large cohort of children with moderate and severe VWD. We included 113 children (aged 0-16 years) with Type 1 (n = 60), 2 (n = 44), and 3 (n = 9) VWD with von Willebrand factor (VWF) antigen and/or VWF ristocetin cofactor levels ≤ 30 U/dL from a nation-wide cross-sectional study ("Willebrand in the Netherlands" study). Bleeding severity and frequency were determined using the International Society on Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) with supplementary pediatric-specific bleeding symptoms (umbilical stump bleeding, cephalohematoma, cheek hematoma, conjunctival bleeding, postcircumcision and postvenipuncture bleeding). We found that all 26 postmenarche girls experienced menorrhagia. Other common bleedings were cutaneous (81%), oropharyngeal (64%), prolonged bleeding from minor wounds (58%), and epistaxis (56%). Pediatric-specific bleeding symptoms were present in 44% of patients. ISTH-BAT bleeding score was higher in index cases than in affected family members (median, 12.0 vs. 6.5, P < 0.001), higher in Type 3 VWD than in Type 2 or 1 (17.0 vs. 10.5 or 6.5, P < 0.001) and higher in children with severe (<10 U/dL) than moderate VWD (10-30 U/dL) (11.0 vs. 7.0, P < 0.001). Frequency of any bleeding, epistaxis, and oral cavity was higher in types 2 and 3 than in Type 1 VWD and was associated with VWF levels. We conclude that pediatric-specific bleeding symptoms occurred in a large proportion of children with moderate or severe VWD and should be included when evaluating children for VWD.
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http://dx.doi.org/10.1002/ajh.24195DOI Listing
December 2015

Inhibitors in nonsevere haemophilia A: outcome and eradication strategies.

Thromb Haemost 2015 Jul 16;114(1):46-55. Epub 2015 Apr 16.

K. Fijnvandraat, MD PhD, Emma Children's Hospital, Academic Medical Center, Room number H7-228, PO Box 22660, 1100 DD Amsterdam, The Netherlands, Tel.: +31 20 566 2727, Fax: +31 20 566 9683, E-mail:

In nonsevere haemophilia A (HA) patients the presence of an inhibitor may exacerbate the bleeding phenotype dramatically. There are very limited data on the optimal therapeutic approach to eradicate inhibitors in these patients. We aimed to describe inhibitor eradication treatment in a large cohort of unselected nonsevere HA patients with inhibitors. We included 101 inhibitor patients from a source population of 2,709 nonsevere HA patients (factor VIII 2-40 IU/dl), treated in Europe and Australia (median age 37 years, interquartile range (IQR) 15-60; median peak titre 7 BU/ml, IQR 2-30). In the majority of the patients (71 %; 72/101) the inhibitor disappeared; either spontaneously (70 %, 51/73) or after eradication treatment (75 %, 21/28). Eradication treatment strategies varied widely, including both immune tolerance induction and immunosuppression. Sustained success (no inhibitor after rechallenge with factor VIII concentrate after inhibitor disappearance) was achieved in 64 % (30/47) of those patients rechallenged with FVIII concentrate. In high-titre inhibitor patients sustained success was associated with eradication treatment (unadjusted relative risk 2.3, 95 % confidence interval 1.3-4.3), compared to no eradication treatment. In conclusion, in nonsevere HA patients most inhibitors disappear spontaneously. However, in 35 % (25/72) of these patients an anamnestic response still can occur when rechallenged, thus disappearance in these patients does not always equal sustained response. Treatment for those requiring eradication has to be decided case by case, as one single approach is unlikely to be appropriate for all.
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http://dx.doi.org/10.1160/TH14-11-0940DOI Listing
July 2015

The effect of cidofovir on adenovirus plasma DNA levels in stem cell transplantation recipients without T cell reconstitution.

Biol Blood Marrow Transplant 2015 Feb 16;21(2):293-9. Epub 2014 Oct 16.

Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.

Cidofovir is frequently used to treat life-threatening human adenovirus (HAdV) infections in immunocompromised children after hematopoietic stem cell transplantation (HSCT). However, the antiviral effect irrespective of T cell reconstitution remains unresolved. Plasma HAdV DNA levels were monitored by real-time quantitative PCR during 42 cidofovir treatment episodes for HAdV viremia in 36 pediatric allogeneic HSCT recipients. HAdV load dynamics were related to T and natural killer (NK) cell reconstitution measured by flow cytometry. To evaluate the in vivo antiadenoviral effect of cidofovir, we focused on 20 cidofovir treatment episodes lacking concurrent T cell reconstitution. During 2 to 10 weeks of follow-up in the absence of T cells, HAdV load reduction (n = 7) or stabilization (n = 8) was observed in 15 of 20 treatments. Although HAdV load reduction was always accompanied by NK cell expansion, HAdV load stabilization was measured in 2 children lacking both T and NK cell reconstitution. In cases with T cell reconstitution, rapid HAdV load reduction (n = 14) or stabilization (n = 6) was observed in 20 of 22 treatments. In the absence of T cells, cidofovir treatment was associated with HAdV viremia control in the majority of cases. Although the contribution of NK cells cannot be excluded, cidofovir has the potential to mediate HAdV load stabilization in the time pending T cell reconstitution.
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http://dx.doi.org/10.1016/j.bbmt.2014.10.012DOI Listing
February 2015

Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel.

Haematologica 2014 May;99(5):811-20

Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management.
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http://dx.doi.org/10.3324/haematol.2013.099747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008115PMC
May 2014

Pharmacokinetics of treosulfan in pediatric patients undergoing hematopoietic stem cell transplantation.

Ther Drug Monit 2014 Aug;36(4):465-72

*Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center; †LAP&P Consultants; and ‡Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.

Background: High-dose treosulfan is used in conditioning regimens before hematopoietic stem cell transplantation in children. Pharmacokinetic data to optimize treosulfan dosing are scarce in this patient population. The aims of this study were the development and validation of an analytical method for treosulfan in human serum and the development of a pharmacokinetic model for treosulfan in pediatric patients. Furthermore, we aimed to develop a limited sampling strategy to estimate treosulfan systemic exposure with a minimum of inconvenience and risk for the patient.

Methods: A reversed phase high-performance liquid chromatography method using ultraviolet detection to determine treosulfan in human serum samples was developed and validated according to food and drug administration guidelines. Serum pharmacokinetics after the first treosulfan administration was investigated in 20 children using nonlinear mixed-effect modeling, and a limited sampling strategy was developed and validated.

Results: The assay was validated in a 10-500 mg/L concentration range with a lower limit of quantification of 10 mg/L. Accuracies were within the 90%-110% limit. The coefficients of variation of the within-day imprecision and between-days imprecision were less than 5%. Pharmacokinetics was adequately described with a 1-compartment model. The population estimates for clearance (CL) and volume of distribution were 6.85 L/h and 13.2 L for a typical patient of 20 kg, respectively. Treosulfan exposure could be adequately quantified with 2 samples, at 4 and 7 hours after the start of a 3-hour treosulfan infusion, with a mean deviation of 3% of individual CL and area under the curve based on limited sampling in comparison with the full data set in a total cohort.

Conclusions: In this study, a bioanalytical method, PK model, and limited sampling model were developed and validated. Furthermore, PK parameters of 20 pediatric patients were analyzed, demonstrating an interpatient variability in area under the curve of 14.5%. This study demonstrates the essential developments in the optimization of treosulfan therapy based on PK data.
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http://dx.doi.org/10.1097/FTD.0000000000000047DOI Listing
August 2014

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.

Blood 2013 Sep 7;122(11):1954-62. Epub 2013 Aug 7.

Academic Medical Center, Amsterdam, The Netherlands;

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.
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http://dx.doi.org/10.1182/blood-2013-02-483263DOI Listing
September 2013

Hematopoietic stem cell transplantation for hemoglobinopathies: current practice and emerging trends.

Pediatr Clin North Am 2010 Feb;57(1):181-205

Leiden University Medical Center, Department of Pediatrics, Hematology Oncology and BMT unit, Postbus 9600, 2300 RC, Leiden, The Netherlands.

Despite improvements in the management of thalassemia major and sickle cell disease, treatment complications are frequent and life expectancy remains diminished for these patients. Hematopoietic stem cell transplantation (HSCT) is the only curative option currently available. Existing results for HSCT in patients with hemoglobinopathy are excellent and still improving. New conditioning regimens are being used to reduce treatment-related toxicity and new donor pools accessed to increase the number of patients who can undergo HSCT.
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http://dx.doi.org/10.1016/j.pcl.2010.01.003DOI Listing
February 2010

Delayed hemolytic transfusion reaction with hyperhemolysis after first red blood cell transfusion in child with beta-thalassemia: challenges in treatment.

Transfusion 2010 Feb 24;50(2):429-32. Epub 2009 Sep 24.

Juliana Children's Hospital, Haga Hospital, Den Haag, the Netherlands.

Background: Delayed hemolytic transfusion reaction (DHTR) can manifest with hyperhemolysis, a serious complication of red blood cell (RBC) transfusions. This has mostly been described in sickle cell anemia but occasionally in beta-thalassemia. Treatment is challenging; immunosuppressive medication has been reported to be useful by some but not others.

Case Report: A 1.5-year-old girl with homozygous beta-thalassemia was put on a regular RBC transfusion program because of anemia with stunted growth and abnormal bone development. After the first transfusion she developed DHTR with hyperhemolysis. Further RBC transfusions could not be avoided. Despite treatment with prednisone, immunoglobulins, rituximab, and azathioprine hemolysis continued. She received an allogeneic bone marrow transplantation after conditioning using cyclophosphamide, treosulfan, melfalan, and ATG. The transplantation was followed by treatment with cyclosporin A, methotrexate, and prednisone. Because of poor engraftment and later rejection, she received a retransplantation after conditioning using fludarabine instead of cyclophosphamide and was subsequently treated with prednisone, but hemolysis continued. Only after splenectomy did she no longer need RBC transfusions and the direct antiglobulin test turned negative.

Discussion And Conclusion: Treatment of DHTR remains challenging. The role of immunosuppressive medication such as azathioprine, cyclosporin A, and rituximab remains to be seen. Splenectomy may be helpful. Mainstay is to minimize RBC transfusions as much as possible.
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http://dx.doi.org/10.1111/j.1537-2995.2009.02399.xDOI Listing
February 2010

Delayed immune recovery following sequential orthotopic liver transplantation and haploidentical stem cell transplantation in erythropoietic protoporphyria.

Pediatr Transplant 2010 Jun 7;14(4):471-5. Epub 2009 Sep 7.

Division of Immunology, Hematology, Oncology, Bone marrow transplantation and Auto-immune disease, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.

A nine-yr-old boy with EPP suffered from severe skin burns and liver failure caused by progressive cholestasis and fibrosis. OLT was performed without major complications. Four months following liver transplantation he underwent parental haploidentical HSCT. The myeloablative conditioning regimen was relatively well tolerated and hematological engraftment was rapid (on day 10). Protoporphyrin concentrations returned to normal following HSCT. However, immune recovery was significantly delayed. Varicella zoster virus reactivation resulted in impaired vision, prolonged hospitalization and eventually in multiorgan failure and death. Sequential liver and haploidentical HSCT proved feasible though a high risk procedure in this EPP patient. The management of post-IST after these combined transplantations remains a challenge and needs to be further established.
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http://dx.doi.org/10.1111/j.1399-3046.2009.01233.xDOI Listing
June 2010