Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favourable efficacy and toxicity profile.... Show moreTreosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favourable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationship between systemic treosulfan exposure, early and long term clinical outcome in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for non-malignant diseases is unresolved. In this thesis we aimed to answer these questions. We found a relationship between the level of exposure to treosulfan and acute toxicity, but we found no relationship with the risk of rejection, survival and long-term endocrine complications. A personalized dose of treosulfan can therefore be useful to reduce toxicity in children, but because the toxicity profile of treosulfan is generally relatively mild, it will not be necessary in most cases. This is beneficial, because measuring blood levels is not always available in every hospital. Future research should focus on specific disease categories or patient groups that may benefit from treosulfan monitoring. More research is also needed on the late complications of treosulfan, such as dental, neurocognitive, hair, eye and lung problems, as this aspect becomes increasingly important as more (very young) patients undergo stem cell transplantation. Show less
This thesis examines the clinical and immunological outcome after paediatric stem cell transplantation in inborn errors of immunity (IEI). First part reviews the general principles of... Show moreThis thesis examines the clinical and immunological outcome after paediatric stem cell transplantation in inborn errors of immunity (IEI). First part reviews the general principles of haematopoietic cell transplantation (HCT) in IEI. The second part of this thesis focuses on practice pattern changes over the past three decades in the field of transplant for non-SCID IEI. The third part of this thesis analyses the outcome after HCT in IEI using ex-vivo T cell depleted mismatched grafts and compares the HCT outcomes between T deplete HLA-mismatched grafts and T-replete HLA-matched family/unrelated grafts. Part 4 focuses on late effects of HCT, particularly post-transplant autoimmunity and malignancy post-HCT in IEI. The final part explores the potential future directions of research into the diversity in the use of HCT in IEI. Show less
Elssen, C. van; Gorkom, G. van; Voorter, C.; Borne, P. von dem; Meijer, E.; Wieten, L.; Bos, G. 2020
Disease relapse is an important problem after allogeneic stem cell transplantations in multiple myeloma (MM). To test the hypothesis that natural killer (NK) cell alloreactivity in the setting of a... Show moreDisease relapse is an important problem after allogeneic stem cell transplantations in multiple myeloma (MM). To test the hypothesis that natural killer (NK) cell alloreactivity in the setting of a haploidentical stem cell transplantation (haploSCT) can reduce the risk of myeloma relapse, we performed a small prospective phase 2 study in which we transplanted poor-risk MM patients using a killer cell immunoglobulin-like receptor (KIR)-ligand mismatched haploidentical donor. Patients received bone marrow grafts after reduced-intensity conditioning, with post-transplantation cyclophosphamide (PTCY) graft-versus-host-disease (GVHD) prophylaxis. The primary endpoint was 1.5-year progression-free survival (PFS); stopping rules were installed in case interim results made a benefit of 50% PFS at 1.5 years unlikely. After inclusion of 12 patients, of which 9 were evaluable for the primary endpoint, all patients relapsed within a median time of 90 days. All except 1 patient showed engraftment, with a median time to neutrophil recovery of 18 (12-30) days. The study was prematurely terminated based on the predefined stopping rules after the inclusion of 12 patients. With this small study, we show that in chemo-resistant myeloma patients, NK cell KIR-mismatch is not superior to conventional alloSCT. This strategy, however, can serve as a platform for new treatment concepts. Clinical Trial Registry: NCT02519114 Show less
Heiden, P.L.J. van der; Egmond, H.M. van; Veld, S.A.J.; Meent, M. van de; Eefting, M.; Wreede, L.C. de; ... ; Jedema, I. 2018
Anti-thymocyte globulin (ATG) and alemtuzumab are both used in hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure. Main toxicities include... Show moreAnti-thymocyte globulin (ATG) and alemtuzumab are both used in hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure. Main toxicities include absent or slow immune reconstitution. This thesis aims to develop evidence based dosing regimens for both agents. We found that current weight-based dosing of ATG and alemtuzumab lead to highly biased exposures across the different age groups in the pediatric population. Furthermore, ATG clearance was not found to increase with increasing body weight in patients over 50 kg (i.e. adolescents and adults). Timely CD4+ T-cell immune reconstitution after HCT is essential for reducing viral reactivations and relapse following HCT, and thereby improves survival chances. High exposure to ATG after infusion of the graft diminishes chances for CD4+ T-cell reconstitution. Therefore, exposure to ATG has a major impact on the clinical outcomes including survival following HCT in children and adults. We conclude that individualizing dosing and timing of ATG potentially makes HCT a safer and more effective treatment option, and will lead to improved survival chances. Individualized dosing regimens for ATG in children have been designed based on the results in this thesis, and are currently being evaluated in prospective clinical trials for efficacy and safety. Show less
Potter, V.T.; Iacobelli, S.; Biezen, A. van; Maertens, J.; Bourhis, J.H.; Passweg, J.R.; ... ; Kroger, N. 2016
Outline of the Thesis Part I Pneumocystis in kidney transplant recipients: transmission, risk factors , new diagnostic and chemo-prophylactic strategies. Chapter 2 describes the characteristics of... Show moreOutline of the Thesis Part I Pneumocystis in kidney transplant recipients: transmission, risk factors , new diagnostic and chemo-prophylactic strategies. Chapter 2 describes the characteristics of a large outbreak of Pneumocystis pneumonia among kidney transplant recipients. By performing a classical outbreak investigation and by application of new molecular genotyping techniques, the potential of the __interhuman transmission hypothesis__ is addressed and discussed. In Chapter 3 all currently available data on reported outbreaks of Pneumocystis pneumonia is systematically reviewed with the emphasis on mortality data, clinical risk factors and transmission analyses. In the case-control study described in Chapter 4, we performed a detailed risk factor analysis for development of PCP in kidney transplant recipients and used the multivariate output data to estimate the effects of several chemoprophylactic strategies by modeling the expected incidence and number-needed-to-treat to provide efficient PCP chemoprophylaxis over a 2-year period post transplantation. Chapter 5 reports the data of a prospective study on the serum markers S-adenosylmethionine and (1-->3)-_-D-glucan serum levels and correlation with clinical parameters in HIVnegative immunocompromised patients __ the majority kidney transplant recipients - with Pneumocystis pneumonia. Potential applicability for treatment monitoring and assessment of P. jirovecii pulmonary load is also discussed. Part II Genetic predisposition for development of invasive aspergillosis in stem cell transplant recipients Chapter 6 describes a multicenter study on the impact of the Y238X stop mutation in the human Dectin-1 receptor (which senses and attaches to glucan moieties of the fungal cell wall) on the risk of development of invasive aspergillosis in stem cell transplant recipients. In Chapter 7 a retrospective study of the influence of genetic variation in the macrophage activation route with respect to the relative additional risk for development of invasive aspergillosis is presented. Part III Experimental markers for detection of fungal infection: scintigraphic imaging. In Chapter 8 the clinical applicability of radiolabeled antimicrobial peptides and antifungal drugs for the diagnosis of invasive fungal infections is reviewed, together with a concise discussion about how promising agents should be further developed. The results of the thesis are summarized and discussed in Chapter 9. Show less
This thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis... Show moreThis thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis of potential improvements in risk stratification and possible treatment adaptation, in order to decrease relapse frequency and disease-related death. Firstly, to study the role of chemokine receptor/ligand interactions in the context of extramedullary leukaemia, we analyzed the homing receptor expression on leukemic blast cells in skin or intestine, peripheral blood and bone marrow of patients with T-ALL en AML, respectively. Secondly, the treatment results of 132 children, who received an allogeneic HLA-identical SCT for acute leukaemia was evaluated, showing the effect of biologically effective TBI dose on relapse risk. Thirdly, to optimize the use of Cyclosporin A(CsA) for adequate Graft-versus-host disease(GVHD) prophylaxis and to avoid drug toxicity, we investigated the pharmacokinetics of CsA in children after SCT, and showed that monitoring CsA exposure early after SCT may provide a tool to influence outcome. Finally, to gain a better understanding of the mechanism of chimerism induction of endothelial and epithelial cells following allogeneic SCT, the occurrence of chimerism in relation to the conditioning regimen, time interval after SCT and development of GVHD was studied. Show less
This thesis describes clinical and immunological aspects of immunoablative therapy followed by reinfusion of T-cell depleted autologous stem cells in patients with progressive refractory Juvenile... Show moreThis thesis describes clinical and immunological aspects of immunoablative therapy followed by reinfusion of T-cell depleted autologous stem cells in patients with progressive refractory Juvenile Idiopathic Arthritis (JIA). After an intensive immunoablative therapy in order to eradicate auto-agressive T cells, autologous hematopoietic stem cells of bone marrow, purged of potentially autoreactive mature T lymphocytes, were reinfused as rescue to reduce the aplastic phase after autologous stem cell transplantation (ASCT). Chapter 1 addresses the background and rationale leading to this study. Chapter 2 describes the safety, efficacy, complications and long term clinical outcome after ASCT in 22 patients with JIA, who were refractory to conventional medication. In chapter 3 the efficacy and safety of ASCT in 34 JIA patients transplanted in 9 different centers in Europe were evaluated. In chapter 4 the immunological effects of the conditioning on cellular infiltrates and expression of cytokines in the synovial tissue of two JIA patients were studied before and 6 months after ASCT. The subject of chapter 5 of this thesis is macrophage activation syndrome in systemic JIA patients. The actual effect of conditioning in vivo and graft manipulation ex vivo on the intended elimination of the adaptive (auto)immunological memory after ASCT was studied in 19 JIA/systemic lupus erythematodes (SLE) and 10 multiple sclerosis (MS) patients (chapter 7). In order to obtain reference values for anti-rabies specific humoral and cellular immune responses after a single and booster vaccination, we conducted a study in 18 healthy controls as described in chapter 6. Show less
