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1.
Bone Marrow Transplant ; 54(Suppl 2): 743-748, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31431703

RESUMO

We review current approaches in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for pediatric patients with hemoglobinopathies with a focus on recent developments using TCRα/ß+/CD19+ depleted grafts in patients with ß-thalassemia major (TM) or sickle cell disease (SCD) in two European transplant units. Eleven TM and three SCD patients (Roma cohort) received a preparative regimen consisting of busulfan/thiotepa/cyclophosphamide/ATG preceded by fludarabine/hydroxyurea/azathioprine. The preparative regimen for 5 SCD patients included treosulfan/thiotepa/fludarabine/ATG (Berlin pilot cohort). All grafts were PBSC engineered by TCR-α/ß+/CD19+ depletion. In both cohorts, rates for graft failure, treatment related mortality (TRM) and GvHD were encouraging. Overall survival (OS) and disease-free survival (DFS) in the Roma cohort were 84 and 69%, respectively, while OS and DFS are 100% in the Berlin cohort. Immune reconstitution was satisfactory. Although asymptomatic viral reactivation was common, no severe viral infection occured. These data confirm that TCR-α/ß+/CD19+ depletion is a well-suited haplo-HSCT strategy for children with hemoglobinopathies. We discuss the results in the context of additional optimization strategies and introduce our concepts for multicenter trial protocols in Germany.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31082473

RESUMO

Gonadal impairment is an important late effect with a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after busulfan (Bu) or treosulfan (Treo) conditioning regimens in pre- and postpubertal children. This retrospective, multicenter study included children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemoradiotherapy before the transplant. We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range, 5 to 18); 89 patients were boys and 48 girls. Eighty-nine patients were prepubertal at transplant and 48 postpubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of girls treated with Treo in the prepubertal stage reached spontaneous puberty compared with those treated with Bu (P = .02). Spontaneous menarche was more frequent after Treo than after Bu (P < .001). Postpubertal boys and girls treated with Treo had significantly lower luteinizing hormone levels (P = .03 and P = .04, respectively) compared with the Bu group. Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31089288

RESUMO

Despite significant improvements in the supportive care, sickle cell disease (SCD) leads to significant morbidity and mortality. Allogeneic hematopoietic stem cell transplantation (HSCT), the only curative option, is limited due to matched donor availability. This could be met with T-cell-depleted haploidentical HSCT. Twenty advanced-stage SCD patients, median age 15 years, and 9 patients, median age 14 years, were transplanted with CD3/CD19- or TCRαß/CD19-depleted grafts and from matched sibling donors (MSDs). The conditioning consisted of ATG, thiotepa, fludarabine, and treosulfan. The median follow-up in the T-haplo-HSCT and the MSD patients was 21 (9-62) and 25 (7-60) months, respectively. The OS in the T-haplo-HSCT and MSD was 90% and 100%, respectively. In the T-haplo-HSCT group, two patient succumbed to a CMV pneumonitis and a macrophage activation syndrome (MAS). One patient in the T-haplo-HSCT group requires renal replacement therapy because of BK virus nephritis. None developed grade III-IV acute GvHD. In the T-haplo-HSCT and in the MSD, 20% and 22%, respectively, developed a mild or moderate chronic GvHD. These results demonstrate the feasibility, safety, and efficacy of T-haplo-HSCT also for adult advanced stage SCD patients.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30932018

RESUMO

The original version of this article included some minor typesetting errors in Table 1-a corrected version of which is provided in this correction article and has been corrected in the original article-and one error in text, which has been corrected in the original article. Furthermore, the article was erroneously published with the copyright holders as 'Springer Nature Limited', however, since the article is Open Access, the copyright holders should in fact be 'The Author(s)'. This has also been corrected in the original article.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30953028

RESUMO

This is the seventh special EBMT report on the indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders. Our aim is to provide general guidance on transplant indications according to prevailing clinical practice in EBMT countries and centres. In order to inform patient decisions, these recommendations must be considered together with the risk of the disease, the risk of the transplant procedure and the results of non-transplant strategies. In over two decades since the first report, the EBMT indications manuscripts have incorporated changes in transplant practice coming from scientific and technical developments in the field. In this same period, the establishment of JACIE accreditation has promoted high quality and led to improved outcomes of patient and donor care and laboratory performance in transplantation and cellular therapy. An updated report with operating definitions, revised indications and an additional set of data with overall survival at 1 year and non-relapse mortality at day 100 after transplant in the commonest standard-of-care indications is presented. Additional efforts are currently underway to enable EBMT member centres to benchmark their risk-adapted outcomes as part of the Registry upgrade Project 2020 against national and/or international outcome data.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30804485

RESUMO

Veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT) conditioning or high-dose nontransplant chemotherapy. VOD/SOS with multi-organ dysfunction (MOD) is associated with a mortality rate of > 80%. Defibrotide (25 mg/kg/day) is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post HSCT in the United States and to treat severe hepatic VOD/SOS in patients > 1 month of age in the European Union. A random effects model was used for pooling data from 17 systematically chosen defibrotide studies. For patients in these reports (n = 2598), and those in the subset of 10 reports of patients treated with ~ 25 mg/kg/day (n = 1691), estimated Day + 100 survival rates were 54% and 56%, respectively. Among those patients treated with ~ 25 mg/kg/day, estimated Day + 100 survival was 44% among patients with MOD and 71% in patients without MOD; survival was 41% and 70%, respectively, for the population of patients receiving any dose of defibrotide. Safety results were not pooled owing to differences in reporting methodology but were generally consistent with the known tolerability profile of defibrotide. This analysis provides the largest assessment of survival in patients treated with defibrotide for VOD/SOS with or without MOD.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30728439

RESUMO

Hematopoietic cell transplantation (HCT) is widely used for acquired and congenital disorders of the hematopoietic system. Number of transplants done in Europe and associated countries continues to rise with 45,418 HCT in 41,100 patients [(17,155 allogeneic (42%) and 23,945 autologous (58%)] reported by 683 centers in 50 countries in 2017. Main indications were myeloid malignancies 10,147 (25%; 96% allogeneic), lymphoid malignancies 26,488 (64%; 19% allogeneic), solid tumors 1,607 (3.9%; 2% allogeneic), and nonmalignant disorders 2,667 (7%; 81% allogeneic). Trends in donor choice seen before continue, with growing numbers of haploidentical HCT and decreasing use of cord blood. Of interest is that after many years of continued growth, the number of patients receiving an allogeneic HCT for marrow failure is decreasing slightly (p < 0.001). Such a change may be explained by the use of thrombopoietin analogs in aplastic anemia patients. Other nonmalignant indications, however continue to grow, most importantly HCT for hemoglobinopathies by 36%, equally for thalassemias and sickle cell disease. Non-HCT cell therapies have increased by 28% since 2015 and genetically modified T cells is type of cell therapy with the fastest growth. These annual reports reflect current activity and trends and are useful for health-care planning.

9.
Biol Blood Marrow Transplant ; 25(7): 1271-1280, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30797942

RESUMO

Veno-occlusive disease, also known as sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of allogeneic or autologous hematopoietic stem cell transplantation (HSCT) most commonly associated with high-intensity chemotherapies. The development of VOD/SOS may be rapid and unpredictable, and the importance of identifying risk factors to facilitate prompt diagnosis and timely treatment has become increasingly recognized. The reporting of new retrospective study data for adults and children and the emergence of novel anticancer therapies that may increase the risk of VOD/SOD also necessitate updates on risk factors, as provided in this review. The latest studies reporting VOD/SOS risk factors support previously published data, although the importance of patient-related factors, such as acute kidney injury, increased international normalized ratio, female sex (in children), and platelet refractoriness, is given greater emphasis in the recent data. Non-transplantation-related chemotherapies associated with increased risk for VOD/SOS include oxaliplatin and 5-fluorouracil chemotherapies. The novel antibody drug conjugates gemtuzumab ozogamicin and inotuzumab ozogamicin are now reported in product labeling to pose risks for VOD/SOS based on clinical trial data; an expert consensus panel has issued recommendations for risk reduction measures with inotuzumab ozogamicin treatment, including VOD/SOS prophylaxis and limitation to ≤2 inotuzumab ozogamicin treatment cycles. A wide range of biomarkers, including genetic, hematologic, hepatic, and inflammatory factors, as well as novel diagnostic techniques such as thromboelastography and measures of liver stiffness, may further enhance future risk calculation for VOD/SOS, although none has been widely adopted. Continual monitoring for and recognition of VOD/SOS risk factors are essential for optimal management of this complication.

10.
Brain Pathol ; 2018 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-30246434

RESUMO

Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo-rosettes, small to medium-sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot-like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1-MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1-11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow-up, 4.84 years). In this to date, largest series of ependymomas with YAP1-MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings.

11.
Leukemia ; 32(8): 1762-1767, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29749397

RESUMO

Dyskeratosis congenita (DKC) is a paradigmatic telomere disorder characterized by substantial and premature telomere shortening, bone marrow failure, and a dramatically increased risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). DKC can occur as a late-onset, so-called cryptic form, with first manifestation in adults. Somatic MDS-related mutations are found in up to 35% of patients with acquired aplastic anemia (AA), especially in patients with short telomeres. The aim of our study was to investigate whether cryptic DKC is associated with an increased incidence of MDS-related somatic mutations, thereby linking the accelerated telomere shortening with the increased risk of MDS/AML. Samples from 15 adult patients (median age: 42 years, range: 23-60 years) with molecularly confirmed cryptic DKC were screened using next-generation gene panel sequencing to detect MDS-related somatic variants. Only one of the 15 patients (7%) demonstrated a clinically relevant MDS-related somatic variant. This incidence was dramatically lower than formerly described in acquired AA. Based on our data, we conclude that clonal evolution of subclones carrying MDS-related mutations is not the predominant mechanism for MDS/AML initiation in adult cryptic DKC patients.

12.
Biol Blood Marrow Transplant ; 24(8): 1629-1642, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29548831

RESUMO

Outcome data were collected from the European Society for Blood and Marrow Transplantation registry on 373 children from 120 centers with relapsed leukemia (214 with acute lymphoblastic leukemia [ALL] and 159 with acute myelogenous leukemia [AML]) who underwent second allogeneic hematopoietic stem cell transplantation (HSCT) between 2004 and 2013. Overall survival (OS) was 38% at 2 years and 29% at 5 years, and leukemia-free survival (LFS) was 30% at 2 years and 25% at 5 years. Median follow-up after second HSCT was 36.4 months in the ALL group and 50.2 months in the AML group. In the ALL group, OS was 43% at 2 years and 33% at 5 years, and LFS was 34% at 2 years and 31% at 5 years. In the AML group, OS was 32% at 2 years and 24% at 5 years, and LFS was 24% at 2 years and 17% at 5 years. The 2-year nonrelapse mortality (NRM) rate was 22% in the ALL group and 18% in the AML group. Favorable prognostic factors (P < .05) for OS and LFS included >12 months between transplantations and chronic graft-versus-host disease after the first HSCT (in both groups), complete response before the second HSCT (ALL group only), and age >12 years (AML group only). Findings were more consistent over time in the ALL group, with no significant differences between 2-year and 5-year rates of relapse, NRM, and LFS. Children with relapsed acute leukemias have a substantial likelihood of long-term survival following second HSCT. Given the many novel targeted and immunomodulation therapies currently under development, it is important to identify specific patient subpopulations that may benefit from a second HSCT compared with those better suited to new approaches.

13.
Pediatr Blood Cancer ; 65(7): e27011, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29480574

RESUMO

BACKGROUND: The Cooperative Ewing Sarcoma Study and the Late Effects Surveillance System of the Society for Paediatric Oncology and Haematology recommend a structured follow-up imaging protocol (FUIP) for patients with Ewing sarcoma (EwS) with decreasing frequency of imaging over the first 5 years. The present study aims to assess the effectiveness of the FUIP for EwS patients regarding survival after relapse. PATIENTS AND METHODS: A retrospective multicenter analysis on 160 eligible patients with EwS recurrence was performed. Potential survival differences following recurrence diagnosis between patients with protocol-detected and symptomatic relapse were investigated using the Kaplan-Meier method. Additional subgroup analyses were performed on the relapse type. Overall survival (OS) was calculated from diagnosis of relapse to last follow-up or death. RESULTS: In the multicenter analysis, recurrence was detected by FUIP in 77 of 160 patients (48%) and due to symptoms in 83 patients (52%). Regarding the entire study population, OS was significantly superior in patients with protocol-detected relapse compared to patients with symptomatic relapse (median, 2.4 vs. 1.2 years; P < 0.001). In the subgroup analyses, patients whose lung recurrences were detected by the FUIP experienced longer survival after recurrence than those whose recurrences were detected symptomatically (P = 0.023). In the 83 symptomatic patients, pain was the most prevalent symptom of relapse (72%). CONCLUSION: FUIP may benefit survival in EwS relapse, especially in lung recurrence. Pain was the leading symptom of relapse.

14.
Klin Padiatr ; 229(6): 322-328, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29017184

RESUMO

Background Malignant melanoma (MM) is a common malignancy in adults while it is rare in children. Thus, information on clinical behavior of pediatric MM is incomplete. Patients The German Pediatric Rare Tumor Registry (STEP) presents a prospective analysis of 60 childhood MM cases diagnosed between June 2006 and December 2014. Method Patients' ages ranged between 0 and 17 years at initial diagnosis (median age 9.6 years). Information on patient's and tumor characteristics was obtained by standardized documentation. Three-year overall survival (OS) and event-free survival (EFS) were estimated by the Kaplan-Meier test. Results Follow-up ranged from 0 to 116 months with a median of 36.5 months, however, univariate analysis was performed for 46 cases with a follow-up > 3 months, only. Cases with spitzoid histotype (40%) did not show a significantly different outcome compared to cases with non-spitzoid MM. Breslow thickness ≤ 2.00 mm was identified in 30% of the cases and 18% were Clark level I to III. Adjuvant therapy was used in 45% of cases. OS at 3 years was 100%, EFS 95.2%. Conclusion We present a series of cases with a high number of spitzoid malignant melanoma and advanced pediatric melanoma, but surprisingly good overall survival rates. Spitzoid and non-spitzoid MM do not differ in clinical behavior and survival.

15.
Expert Rev Gastroenterol Hepatol ; 11(10): 885-898, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28825848

RESUMO

INTRODUCTION: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a complication that is typically associated with conditioning for hematopoietic stem cell transplantation (HSCT). In patients with concomitant multi-organ dysfunction, mortality may be >80%. Recently, the European Society for Blood and Marrow Transplantation established separate criteria for diagnosis and severity of VOD/SOS for adults and children, to better reflect current understanding of the disease. Areas covered: This review provides an overview of post-HSCT hepatic VOD/SOS and defibrotide, including its pharmacological, clinical, and regulatory profile. In children and adults following HSCT, defibrotide is approved for the treatment of hepatic VOD/SOS with concomitant renal or pulmonary dysfunction in the United States and for the treatment of severe hepatic VOD/SOS in the European Union. Day +100 survival rates with defibrotide are superior to those of historical controls receiving best supportive care only, and safety profiles are similar. Expert commentary: Defibrotide appears to act through multiple mechanisms to restore thrombo-fibrinolytic balance and protect endothelial cells, and there are promising data on the use of defibrotide for VOD/SOS prophylaxis in high-risk children undergoing HSCT. An ongoing randomized controlled trial in children and adults will better assess the clinical value of defibrotide as a preventive medication.


Assuntos
Fibrinolíticos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Polidesoxirribonucleotídeos/uso terapêutico , Adulto , Criança , Ensaios Clínicos como Assunto , Hepatopatia Veno-Oclusiva/etiologia , Humanos
16.
Eur J Cancer ; 81: 1-8, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28586748

RESUMO

BACKGROUND: Temozolomide (TMZ) is widely used in high-grade glioma (HGG). There is a major concern of treatment-induced secondary haematological malignancies (SHMs). Due to the poor overall survival of HGG patients, the true incidence is yet elusive. Thus, the aim of this study was to determine the risk of SHMs following TMZ in paediatric HGG. METHODS: We analysed 487 patients from the HIT-HGG database of the German-speaking Society of Pediatric Oncology and Hematology with follow up beyond 1 year. RESULTS: The incidence of SHM was 7.7 ± 3.2% at 10 years. No SHM occurred in 194 patients after first-line TMZ therapy, but four out of 131 patients treated with TMZ for relapse following first-line multiagent chemotherapy experienced SHM (20% at 10 years; p = 0.041). SHMs occurred in two out of 162 patients who underwent multiagent chemotherapy without TMZ (4.1% at 10 years). Gender, patient age and acute haematological toxicity during treatment did not affect the incidence of SHMs. CONCLUSION: Data of our cohort do not indicate an increased risk of SHM following TMZ treatment when compared to previous chemotherapy regimen. However, if TMZ is administered as a second-line treatment following conventional chemotherapy regimen, the risk might be disproportionately increasing.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Neoplasias Hematológicas/induzido quimicamente , Adolescente , Áustria/epidemiologia , Criança , Pré-Escolar , Dacarbazina/efeitos adversos , Feminino , Seguimentos , Alemanha/epidemiologia , Neoplasias Hematológicas/epidemiologia , Humanos , Incidência , Lactente , Estimativa de Kaplan-Meier , Masculino , Suíça/epidemiologia , Temozolomida
17.
Eur J Haematol ; 98(4): 322-329, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27992075

RESUMO

Although it is considered a relatively rare disorder, veno-occlusive disease (VOD) is one of the main causes of overall, non-relapse mortality associated with haematopoietic stem cell transplantation (HSCT). This article, based on the consensus opinion of haemato-oncology nurses, haemato-oncologists and pharmacists from both adult and paediatric services at the VOD International Multi-Disciplinary Advisory Board at the European Society for Blood and Marrow Transplantation (EBMT) meeting, Istanbul, 2015, aims to explore the multidisciplinary approach to care for the management of VOD, with an emphasis on current challenges in this area. The careful monitoring of HSCT patients allows early detection of the symptoms associated with VOD and timely treatment, ultimately improving patient outcomes. As part of a multidisciplinary team, nurses have an essential role to play, from pretransplant assessment to medical management and overall care of the patient. Physicians and pharmacists have a responsibility to facilitate education and training so that nurses can work effectively within that team.


Assuntos
Consenso , Educação em Enfermagem , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Enfermagem/métodos , Cuidados Pré-Operatórios , Doenças Vasculares , Adulto , Congressos como Assunto , Humanos , Monitorização Fisiológica/métodos , Cuidados Pré-Operatórios/educação , Cuidados Pré-Operatórios/métodos , Turquia , Doenças Vasculares/etiologia , Doenças Vasculares/mortalidade , Doenças Vasculares/prevenção & controle
18.
Int J Hematol Oncol ; 6(3): 75-93, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30302228

RESUMO

Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening and unpredictable complication of hematopoietic stem cell transplantation (HSCT). Characterized by a prothrombotic-hypofibrinolytic state, VOD/SOS typically presents with hyperbilirubinemia, ascites, weight gain and painful hepatomegaly; VOD/SOS with multiorgan failure may be associated with >80% mortality. Treatment has been mainly supportive. However, defibrotide is now approved in the USA for treatment of hepatic VOD/SOS with renal or pulmonary dysfunction following HSCT and in the European Union for treatment of severe hepatic VOD/SOS post-HSCT. In vitro evidence suggests defibrotide may restore thrombotic-fibrinolytic balance at the endothelial level and protect endothelial cells. Defibrotide has demonstrated significant reduction in VOD/SOS-related mortality and resolved VOD/SOS-related symptoms, with a manageable safety profile.

19.
Biol Blood Marrow Transplant ; 22(10): 1874-1882, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27397724

RESUMO

Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable and potentially fatal complication of hematopoietic cell transplantation (HCT) or nontransplantation-associated chemotherapy/radiotherapy. In cases of severe hepatic VOD/SOS, typically defined by associated multiorgan failure (MOF, also known as multiorgan dysfunction), mortality exceeds 80%. Preclinical and early clinical data have provided a rationale for defibrotide treatment in hepatic VOD/SOS. Based on this evidence and in recognition of the dismal prognosis for these patients, defibrotide was made available through an international multicenter compassionate-use program conducted from December 1998 to March 2009. Physicians participating in the program voluntarily provided demographic and outcome data for patients given defibrotide. Efficacy and safety analyses were performed using the data received for 710 treated patients. Defibrotide was given at 10, 25, 40, 60, or 80 mg/kg/day for a median of 15 days (range, 1 to 119 days). By Kaplan-Meier analysis, the estimated overall day +100 survival was 54% (58% in the 25 mg/kg/day dose group). Adverse events (AEs) were reported in 53% of patients. The most common AEs were MOF, progression of hepatic VOD/SOS, sepsis, and graft-versus-host disease, which were consistent with the AEs expected for this patient population. No clinically meaningful trends in AEs were identified by gender, age, or dose group. Safety and efficacy resultswere consistent with prior studies of defibrotide in hepatic VOD/SOS, and subgroup analyses lend support to the use of the 25 mg/kg/day dose.


Assuntos
Ensaios de Uso Compassivo , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Polidesoxirribonucleotídeos/administração & dosagem , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Progressão da Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/complicações , Hepatopatia Veno-Oclusiva/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/etiologia , Polidesoxirribonucleotídeos/efeitos adversos , Sepse/etiologia , Adulto Jovem
20.
Blood ; 127(25): 3281-90, 2016 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-27099148

RESUMO

Reduced-intensity conditioning has improved survival after hematopoietic stem cell transplantation (HSCT) for hemophagocytic lymphohistiocytosis (HLH) at the cost of more frequent mixed chimerism. The minimum level of donor chimerism (DC) required to prevent HLH reactivation in humans remains to be determined. In a multicenter retrospective study, 103 patients transplanted for hereditary HLH (2000-2013) and DC permanently or transiently <75% (overall, CD3(+), CD56(+)) were analyzed regarding DC, specific immunologic function, occurrence of systemic reactivations (≥5/8 HLH criteria), partial systemic flares (<5 criteria and HLH-directed treatment), isolated central nervous system reactivations, and management. Recurrence was reported in 18 patients (systemic reactivation n = 11, partial flare n = 3, isolated central nervous system reactivation n = 4). Ten events occurred during profound immune suppression before day 180 (median DC, 10%; range, 1-100%; CD3(+) if available, otherwise overall DC), which renders a differentiation between secondary post-HSCT HLH and HLH related to the genetic defect difficult. Eight events occurred between 0.5 and 6.7 years post-HSCT (median DC, 13%; range, 0-30%). In 5 patients, overall and lineage-specific DC were ≤10% for >6 months (median, 5.1; range, 1.1-10 years) without reactivation. A second HSCT was performed in 18 patients (median, DC 4%; range, 0-19%). Death from reactivation occurred in 4 patients (22% of recurrences). Six patients died of transplant complications following a second HSCT (33% of second HSCT). We conclude that a DC >20%-30% is protective against late reactivation. Lower levels do not, however, inescapably result in recurrences. The decision for or against second HSCT must be based on a thorough risk assessment.


Assuntos
Quimerismo , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/terapia , Doadores de Tecidos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Recém-Nascido , Masculino , Recidiva , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Imunologia de Transplantes , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Adulto Jovem
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