Survival rates in pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases have improved due to advances in conditioning regimens, donor selection, and prophylaxis and... Show moreSurvival rates in pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases have improved due to advances in conditioning regimens, donor selection, and prophylaxis and treatment of infections and graft-versus-host disease. Insight into the long-term patient-reported outcomes (PROs) after pediatric HSCT for nonmalignant disease is lacking but essential for optimal shared decision making, counseling, and quality of care. The purpose of this research was to determine long-term patient-reported outcomes in allogeneic pediatric HSCT for nonmalignant diseases and to compare these results with Dutch reference data. This single-center cohort study evaluated PROs (PedsQL 4.0, PROMIS item banks), self- or proxy-reported, among patients at >= 2 years after pediatric allogeneic HSCT for nonmalignant disease. Mean scores were compared with those of the Dutch general population. Of 171 eligible patients, 119 participated, for a 70% response rate. The median patient age was 15.8 years (range, 2 to 49 years), and the median duration of follow-up was 8.7 years (range, 2 to 34 years). Indications for HSCT included inborn errors of immunity (n = 41), hemoglobinopathies (n = 37), and bone marrow failure (n = 41). Compared with reference data, significantly lower scores were found in adolescents (age 13 to 17 years) on the Total, Physical Health, and School Functioning PedsQL subscales. Significantly more Sleep Disturbance was reported in children (age 8 to 18 years). On the other hand, significantly better scores were seen on PROMIS Fatigue (age 5 to 7 years) and Pain Interference (age 8 to 18 years) and, in adults (age 19 to 30 years), on Depressive Symptoms and Sleep Disturbance. This study showed better or comparable very long-term PROs in patients after pediatric HSCT for nonmalignant diseases compared with the reference population. Children and adolescents seem to be the most affected, indicating the need for supportive care to prevent impaired quality of life and, more importantly, to amplify their long-term well-being. (c) 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Show less
Andersen, N.S.; Bornhauser, M.; Gramatzki, M.; Dreger, P.; Vitek, A.; Karas, M.; ... ; CLL subcomm Chronic 2019
Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potentially curative treatment for various hematological malignancies. The beneficial Graft-versus-Leukemia (GvL) effect of alloSCT... Show moreAllogeneic hematopoietic stem cell transplantation (alloSCT) is a potentially curative treatment for various hematological malignancies. The beneficial Graft-versus-Leukemia (GvL) effect of alloSCT is mediated by donor-derived allo-reactive T cells targeting the malignant cells of the patient. Unfortunately, detrimental Graft-versus-Host-Disease (GvHD) often co-develops due to recognition of allo-antigens by donor-derived T cells on non-hematopoietic tissues. To prevent the development of GvHD, donor T cells can be depleted from the alloSCT graft. Although the risk and severity of GvHD are effectively reduced by T cell depleted (TCD) alloSCT, the absence of donor T cells in the stem cell graft also leads to an increased risk of relapses of malignancies. Early intervention with unmanipulated donor lymphocyte infusion (DLI) may effectively prevent or treat post-transplant relapses, but is frequently associated with re-introduction of GvHD. Although post-transplant relapses of chronic myeloid leukemia (CML) in chronic phase can be effectively treated with DLI, patients with relapsed acute leukemia often fail to respond to DLI and their prognosis remains poor. This disease-specific difference in efficacy of DLI may be explained by the poor capacity of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and CML in blast crisis (CML-BC) to function as professional antigen presenting cells (APC) and induce primary T cell responses. In addition, acute leukemias are generally rapidly proliferating aggressive malignancies that may outpace the donor T cell responses as induced after DLI. Therefore, novel T cell based immunotherapeutic strategies with potent efficacy, but limited treatment-related toxicity are highly relevant to improve the clinical outcome for patients with aggressive acute malignancies. In contrast to constitutive expression of HLA-class I molecules on all nucleated cells, HLAclass II molecules are only constitutively expressed on normal hematopoietic cells as well as most B-lineage and myeloid malignancies, while most non-hematopoietic cells only express HLA-class II under inflammatory conditions. Therefore, CD4+ T cells recognizing allo-antigens in the context of HLA-class II molecules under non-inflammatory circumstances are likely to mediate selective GvL reactivity without GvHD. Clinical application of HLA-identical DLI depleted of CD8+ T cells has demonstrated to induce conversion to donor hematopoiesis and disease remissions in patients with relapsed malignancies, in the absence of induction of severe GvHD. In addition, it has been demonstrated that allo-HLA-DPB1 specific CD4+ T cells can mediate profound GvL reactivity in the absence of clinically significant GvHD after DLI following HLA-DPB1 mismatched TCD alloSCT, indicating that allo-HLA-class II molecules can also serve as malignancy-specific targets. Therefore, a possible strategy to induce profound and selective GvL immunity against acute leukemia without causing GvHD may be achieved by targeting (disparate) HLA-class II molecules by CD4+ T cell based immunotherapy following TCD alloSCT. This thesis explored the benefits and threats of this approach in a preclinical mouse model and in patients. Show less
