Нарушение минерализации костей после аллогенной трансплантации гемопоэтических стволовых клеток у детей: одноцентровое когортное исследование

Bone mineral metabolism disorders are one of the most frequent late complications after allogeneic hematopoietic stem cell transplantation (HSCT) in children.The aim of the study was to detect the incidence and risk factors for bone mineral metabolism disorders in children who underwent allogeneic HSCT.Methods. We analyzed the data of medical charts of 294 children aged 0–17 y.o. who were hospitalized in 1994–2011, received  allogeneic HSCT, and survived for at least a year after intervention.  We determined the cumulative incidence and revealed risk factors for the development of osteopenia/osteoporosis and avascular necrosis.  Osteopenia/ osteoporosis was diagnosed after X-ray examination and annual computer X-ray osteodensitometry of the lumbar spine (during a 5-year period since 2003). The criteria for osteopenia is  bone density z-score 2.0, for osteoporosis — z-score 2.0 and  suffered fractures of the bones of the legs, compression fractures of  the spine and / or 2 fractures of the tubular bones of the hands (for both diagnoses). Avascular necrosis was diagnosed  radiographically and basing on magnetic resonance imaging results  (if there were complaints of pain or limb dysfunctions).Results. After the allogeneic HSCT during the median follow-up of 7.5 years bone mineral metabolism disorders developed in 48  patient (16%). Osteopenia / osteoporosis development was  associated with the following factors: the age 10 years (frequency  23.2% vs. 12% in children under 10 years, p = 0.014), acute graft- versus-host disease (GVHD) grade II–IV (24.2 vs 8.7% at GVHD  grade 0–I; p = 0.001), chronic GVHD (36.0% in extensive form vs.  14.5% in restricted form and 8.4% in the absence of chronic GVHD; p<0.001), immunosuppressive therapy >12 months (31.9 vs. 6.9% for therapy <3 months; p<0.001), glucocorticosteroid intake >3  months (93.8 vs 8.1% with GCs administration 3 months and 3.2% without GCs administration; p<0.001).Conclusion. Bone mineral metabolism disorders are revealed in 16% of cases in children who underwent HSCT. Determination of risk factors provides the possibility for timely diagnostics and improvement of therapy results.Нарушения костного минерального обмена являются поздними осложнениями аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) у детей.Цель исследования — определить частоту и факторы риска нарушений костного минерального обмена у детей после аллогенной ТГСК.Методы. Использовали данные, извлеченные из медицинской документации (истории  болезни, амбулаторные карты) детей (0–17 лет), госпитализированных в 1994–2011 гг. и  проживших минимум 1 год после аллогенной ТГСК. Определяли кумулятивную (до мая 2017  г.) частоту и факторы риска развития остеопении, остеопороза и аваскулярных некрозов.  Остеопению/остеопороз устанавливали рентгенологически (1994–2002 гг.) и по результатам ежегодной (на протяжении 5 лет начиная с 2003 г.) компьютерной рентгеновской  остеоденситометрии поясничного отдела позвоночника. Критерии остеопении — z-score  плотности костной ткани 2,0, остеопороза — z-score 2,0 и перенесенные переломы  костей ног, компрессионные переломы позвоночника и/или 2 переломов трубчатых костей  рук. Аваскулярные некрозы устанавливали (при наличии жалоб на боли или нарушения  функций конечностей) рентгенологически и по данным магнитно-резонансной томографии.Результаты. Нарушения костного минерального обмена в течение (медиана) 7,5 (6; 9) лет  развились у 48 (16%) из 294 детей, перенесших аллогенную ТГСК. С развитием остеопении/ остеопороза были ассоциированы возраст 10 лет (частота 23,2% против 12% у детей  младше 10 лет; р=0,014), острая реакция «трансплантат против хозяина» (РТПХ) II–IV  стадии (24,2 против 8,7% при РТПХ 0–I стадии; р=0,001), хроническая РТПХ (36,0% при  экстенсивной форме против 14,5% при ограниченной форме и 8,4% при отсутствии  хронической РТПХ; р<0,001), иммуносупрессивная терапия >12 мес (31,9 против 6,9% при  длительности <3 мес; р<0,001), прием глюкокортикостероидов >3 мес (93,8 против 8,1% при приеме 3 мес и 3,2% без терапии; р<0,001).Заключение. Нарушения костного минерального обмена встречаются в 16% случаев после  аллогенной ТГСК у детей, определение факторов риска их развития позволяет проводить своевременную диагностику и улучшать результаты терапии

Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study.

peer reviewedAllogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT

Hematopoietic stem cell transplantation in a patient with type 1 mosaic variegated aneuploidy syndrome

Abstract Background Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal instability disorder that leads to aneuploidies of different chromosomes in various tissues. Type 1 MVA (MVA1) is caused by mutations in the budding uninhibited by benzimidazoles 1 homolog beta (BUB1B) gene. The main clinical features of MVA1 syndrome are growth and mental retardation, central nervous system anomalies, microcephaly, and predisposition to cancers. There have been no reports of hematopoietic stem cell transplantation (HSCT) in MVA patients. Results We report an 11-year old boy diagnosed with MVA1 syndrome. The BUB1B gene mutations c.498_505delAAACTTTA and c.1288 + 5G > A were detected using the next generation sequencing (NGS) method. The patient presented with cytopenia soon after birth, but remained stable until 9 years of age, when he developed myelodysplastic syndrome associated with monosomy of chromosome 7. Due to severe dependence on blood transfusions, a TCRαβ+/CD19+ depleted HSCT was performed from a matched unrelated donor (MUD) using a treosulfan-based reduced intensity conditioning (RIC) regimen. The engraftment occurred, and no severe toxicity was observed soon after the HSCT, but on day + 47, graft rejection was detected. It was followed by prolonged pancytopenia and sepsis with multi-organ Enterococcus faecium infection, which led to the patient’s death on day + 156 after HSCT. Conclusions In conclusion, we demonstrate that RIC HSCT with TCRαβ+/CD19+ depletion was well tolerated and resulted in complete hematologic recovery in our MVA1 patient, but, unfortunately, it was followed by rapid graft rejection. This fact needs to be taken into consideration for HSCT in other MVA patients

Bone Mineral Turnover after Allogeneic Hematopoietic Stem Cell Transplantation in Children: A Single Center Cohort Study

Bone mineral metabolism disorders are one of the most frequent late complications after allogeneic hematopoietic stem cell transplantation (HSCT) in children.The aim of the study was to detect the incidence and risk factors for bone mineral metabolism disorders in children who underwent allogeneic HSCT.Methods. We analyzed the data of medical charts of 294 children aged 0–17 y.o. who were hospitalized in 1994–2011, received  allogeneic HSCT, and survived for at least a year after intervention.  We determined the cumulative incidence and revealed risk factors for the development of osteopenia/osteoporosis and avascular necrosis.  Osteopenia/ osteoporosis was diagnosed after X-ray examination and annual computer X-ray osteodensitometry of the lumbar spine (during a 5-year period since 2003). The criteria for osteopenia is  bone density z-score 2.0, for osteoporosis — z-score 2.0 and  suffered fractures of the bones of the legs, compression fractures of  the spine and / or 2 fractures of the tubular bones of the hands (for both diagnoses). Avascular necrosis was diagnosed  radiographically and basing on magnetic resonance imaging results  (if there were complaints of pain or limb dysfunctions).Results. After the allogeneic HSCT during the median follow-up of 7.5 years bone mineral metabolism disorders developed in 48  patient (16%). Osteopenia / osteoporosis development was  associated with the following factors: the age 10 years (frequency  23.2% vs. 12% in children under 10 years, p = 0.014), acute graft- versus-host disease (GVHD) grade II–IV (24.2 vs 8.7% at GVHD  grade 0–I; p = 0.001), chronic GVHD (36.0% in extensive form vs.  14.5% in restricted form and 8.4% in the absence of chronic GVHD; p<0.001), immunosuppressive therapy >12 months (31.9 vs. 6.9% for therapy <3 months; p<0.001), glucocorticosteroid intake >3  months (93.8 vs 8.1% with GCs administration 3 months and 3.2% without GCs administration; p<0.001).Conclusion. Bone mineral metabolism disorders are revealed in 16% of cases in children who underwent HSCT. Determination of risk factors provides the possibility for timely diagnostics and improvement of therapy results

Second allogeneic stem cell transplant for aplastic anaemia: a retrospective study by the severe aplastic anaemia working party of the European society for blood and marrow transplantation

We analysed the outcome of a second allogeneic haematopoietic stem cell transplant (alloHSCT) in 162 patients reported to the European Society for Blood and Marrow Transplantation between 1998 and 2009. Donor origin was a sibling in 110 and an unrelated donor in 52 transplants, respectively. The stem cell source was bone marrow in 31% and peripheral blood in 69% of transplants. The same donor as for the first alloHSCT was used in 81% of transplants whereas a change in the choice of stem cell source was reported in 56% of patients, mainly from bone marrow to peripheral blood. Neutrophil and platelet engraftment occurred in 85% and 72% of patients, after a median time of 15 and 17 days, respectively. Grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 21% and 37% of patients, respectively. Graft failure (GF) occurred in 42 patients (26%). After a median follow-up of 3·5 years, the 5-year overall survival (OS) was 60·7%. In multivariate analysis, the only factor significantly associated with a better outcome was a Karnofsky/Lansky score ≥80 (higher OS). We conclude that a second alloHSCT is feasible rescue option for GF in SAA, with a successful outcome in 60% of cases.status: publishe

Second allogeneic stem cell transplant for aplastic anaemia: a retrospective study by the Severe Aplastic Anaemia Working Party of the European Society for Blood and Marrow Transplantation

We analysed the outcome of a second allogeneic haematopoietic stem cell transplant (alloHSCT) in 162 patients reported to the European Society for Blood and Marrow Transplantation between 1998 and 2009. Donor origin was a sibling in 110 and an unrelated donor in 52 transplants, respectively. The stem cell source was bone marrow in 31% and peripheral blood in 69% of transplants. The same donor as for the first alloHSCT was used in 81% of transplants whereas a change in the choice of stem cell source was reported in 56% of patients, mainly from bone marrow to peripheral blood. Neutrophil and platelet engraftment occurred in 85% and 72% of patients, after a median time of 15 and 17\ua0days, respectively. Grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 21% and 37% of patients, respectively. Graft failure (GF) occurred in 42 patients (26%). After a median follow-up of 3\ub75\ua0years, the 5-year overall survival (OS) was 60\ub77%. In multivariate analysis, the only factor significantly associated with a better outcome was a Karnofsky/Lansky score 6580 (higher OS). We conclude that a second alloHSCT is feasible rescue option for GF in SAA, with a successful outcome in 60% of cases

Flow cytometry for pediatric platelets

The ability of platelets to carry out their hemostatic function can be impaired in a wide range of inherited and acquired conditions: trauma, surgery, inflammation, pre-term birth, sepsis, hematological malignancies, solid tumors, chemotherapy, autoimmune disorders, and many others. Evaluation of this impairment is vitally important for research and clinical purposes. This problem is particularly pronounced in pediatric patients, where these conditions occur frequently, while blood volume and the choice of blood collection methods could be limited. Here we describe a simple flow cytometry-based screening method of comprehensive whole blood platelet function testing that was validated for a range of pediatric and adult samples (n = 31) in the hematology hospital setting including but not limited to: classic inherited platelet function disorders (Glanzmann’s thrombasthenia; Bernard-Soulier, Wiscott-Aldrich, and Hermasky-Pudlak syndromes, MYH9-dependent thrombocytopenia), healthy and pre-term newborns, acute and chronic immune thrombocytopenia, chronic lympholeukemia, effects of therapy on platelet function, etc. The method output includes levels of forward and side scatter, levels of major adhesion and aggregation glycoproteins Ib and IIb-IIIa, active integrins’ level based on PAC-1 binding, major alpha-granule component P-selectin, dense granule function based on mepacrine uptake and release, and procoagulant activity quantified as a percentage of annexin V-positive platelets. This analysis is performed for both resting and dual-agonist-stimulated platelets. Preanalytical and analytical variables are provided and discussed. Parameter distribution within the healthy donor population for adults (n = 72) and children (n = 17) is analyzed

Syngeneic transplantation in aplastic anemia: pre-transplant conditioning and peripheral blood are associated with improved engraftment:an observational study on behalf of the Severe Aplastic Anemia and Pediatric Diseases Working Parties of the European Group for Blood and Marrow Transplantation

Aplastic anemia is usually treated with immunosuppression or allogeneic transplant, depending on patient and disease characteristics. Syngeneic transplant offers a rare treatment opportunity with minimal transplant-related mortality, and offers an insight into disease mechanisms. We present here a retrospective analysis of all syngeneic transplants for aplastic anemia reported to the European Group for Blood and Marrow Transplantation. Between 1976 and 2009, 88 patients received 113 transplants. Most transplants (n=85) were preceded by a conditioning regimen, 22 of these including anti-thymocyte globulin. About half of transplants with data available (39 of 86) were followed by posttransplant immunosuppression. Graft source was bone marrow in the majority of cases (n=77). Transplant practice changed over time with more transplants with conditioning and anti-thymocyte globulin as well as peripheral blood stem cells performed in later years. Ten year overall survival was 93% with 5 transplant-related deaths. Graft failure occurred in 32% of transplants. Risk of graft failure was significantly increased in transplants without conditioning, and with bone marrow as graft source. Lack of posttransplant immunosuppression also showed a trend towards increased risk of graft failure, while anti-thymocyte globulin did not have an influence. In summary, syngeneic transplant is associated with a significant risk of graft failure when no conditioning is given, but has an excellent long-term outcome. Furthermore, our comparatively large series enables us to recommend the use of pre-transplant conditioning rather than not and possibly to prefer peripheral blood as a stem cell source

Improved Outcome in Pediatric Relapsed Acute Myeloid Leukemia:Results of a Randomized Trial on Liposomal Daunorubicin by the International BFM Study Group

<p>Purpose</p><p>In pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Munster Study Group.</p><p>Patients and Methods</p><p>Patients with relapsed or primary refractory non-French-American-British type M3 AML who were younger than 21 years of age were eligible. Patients were randomly assigned to fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or to FLAG plus DNX in the first reinduction course. The primary end point was status of the bone marrow (BM) sampled shortly before the second course of chemotherapy (the day 28 BM). Data are presented according to intention-to-treat for all 394 randomly assigned patients (median follow-up, 4.0 years).</p><p>Results</p><p>The complete remission (CR) rate was 64%, and the 4-year probability of survival (pOS) was 38% (SE, 3%). The day 28 BM status (available in 359 patients) was good (</p><p>Conclusion</p><p>DNX added to FLAG improves early treatment response in pediatric relapsed AML. Overall long-term survival was similar, but CBF-AML showed an improved survival with FLAG/DNX. International collaboration proved feasible and resulted in the best outcome for pediatric relapsed AML reported thus far. J Clin Oncol 31:599-607. (C) 2013 by American Society of Clinical Oncology</p>