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2.
Am J Hematol ; 94(8): 880-890, 2019 08.
Article in English | MEDLINE | ID: mdl-31095771

ABSTRACT

Severe infections (SI) significantly impact on non-relapse mortality after hematopoietic stem cell transplantation (HSCT). We assessed 432 children and adolescents with acute lymphoblastic leukemia (ALL) after total body irradiation based myeloablative HSCT within the multicenter ALL-BFM-SCT 2003 trial for SI grade 3 or higher according to common terminology criteria for adverse events. A total 172 patients experienced at least one SI. Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period (hazard ratio [HR]: 2.57; P < .001), and with any SI between day +30 and + 100 (HR: 2.91; P = .011). Bacterial (HR: 2.24; P = .041) and fungal infections (HR: 4.06; P = .057) occurred more often in the pre-engraftment phase and viral infections more often before day +30 (HR: 2.66; P = .007) or between day +30 and + 100 (HR: 3.89; P = .002) after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100 (HR: 2.57; P < .002). We conclude that allogeneic HSCT from MUD in children and adolescents with pediatric ALL is associated with higher infection rates, which seems attributable to an intensified GvHD prophylaxis including serotherapy and methotrexate.


Subject(s)
Bacterial Infections/epidemiology , Hematopoietic Stem Cell Transplantation/methods , Mycoses/epidemiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Unrelated Donors , Virus Diseases/epidemiology , Adolescent , Bacterial Infections/etiology , Bacterial Infections/prevention & control , Child , Child, Preschool , Female , Humans , Incidence , Male , Multivariate Analysis , Mycoses/etiology , Mycoses/prevention & control , Prospective Studies , Severity of Illness Index , Transplantation, Homologous , Unrelated Donors/statistics & numerical data , Virus Diseases/etiology , Virus Diseases/prevention & control , Whole-Body Irradiation
4.
Am J Transplant ; 19(6): 1798-1805, 2019 06.
Article in English | MEDLINE | ID: mdl-30586230

ABSTRACT

We report data obtained from a retrospective multicenter pediatric survey on behalf of the European Society for Blood and Marrow Transplantation (EBMT). Information on solid organ transplantation (SOT) performed in pediatric recipients of either autologous or allogeneic hematopoietic stem cell transplantation (HSCT) between 1984 and 2016 was collected in 20 pediatric EBMT Centers (25.6%). Overall, we evaluated data on 44 SOTs following HSCT including 20 liver (LTx), 12 lung (LuTx), 6 heart (HTx), and 6 kidney (KTx) transplantations. The indication for SOT was organ failure related to intractable graft-vs-host disease in 16 children (36.3%), acute or chronic HSCT-related toxicity in 18 (40.9%), and organ dysfunction related to the underlying disease in 10 (22.8%). The median follow-up was 10.9 years (95% confidence interval: 1.7-29.5). The overall survival rate at 1 and 5 years after SOT was 85.7% and 80.4%, respectively: it was 74% and 63.2% after LTx, 83.2% after HTx, and 100% equally after LuTx and KTx. This multicenter survey confirms that SOT represents a promising option in children with severe organ failure occurring after HSCT. Additional studies are needed to further establish the effectiveness of SOT after HSCT and to better understand the mechanism underlying this encouraging success.


Subject(s)
Graft vs Host Disease/etiology , Graft vs Host Disease/surgery , Hematopoietic Stem Cell Transplantation/adverse effects , Organ Transplantation , Adolescent , Allografts , Autografts , Child , Child, Preschool , Cohort Studies , Europe/epidemiology , Female , Heart Transplantation , Humans , Infant , Kidney Transplantation , Liver Transplantation , Lung Transplantation , Male , Organ Transplantation/adverse effects , Organ Transplantation/mortality , Proportional Hazards Models , Retrospective Studies , Surveys and Questionnaires , Survival Rate , Treatment Outcome
6.
Biol Blood Marrow Transplant ; 23(7): 1128-1133, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28359910

ABSTRACT

Veno-occlusive disease (VOD) remains a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prophylactic use of defibrotide (DF) might further reduce VOD rates but has no impact on the incidence of severe VOD or VOD-associated mortality. We investigated the cost-effectiveness of prophylactic DF according to the British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation guidelines in 348 children who underwent transplantation between 2001 and 2014 in our hospital, 138 of whom were at risk for VOD. The VOD incidence was 7.4% for the total cohort. Patients at risk had a higher incidence of VOD compared with patients without risk factors (15.2% versus 2.4%, P < .0001). VOD occurred more often in patients after busulfan-based myeloablative conditioning than in patients after total body irradiation (11.2% versus 3.5%, P = .001). Donor types or the transplantation-related mortality (TRM) risk score did not correlate with VOD incidence. In 81% of patients who responded to therapeutic DF, VOD resolved completely. Overall VOD-associated mortality was .3% for the complete cohort, 3.7% for patients diagnosed with VOD, and 20% for patients with severe VOD. Neither the cumulative incidence of TRM (19% ± 8% versus 17% ± 2%, P = .706) nor the median length of hospitalization differed between patients with VOD and patients without. The median costs per HSCT in patients with VOD were about one-third higher than the overall median costs per transplantation at our institution. The calculated total costs of prophylactic DF treatment for 138 patients at risk was almost 6 times as high as the incremental costs for patients with VOD. We conclude that prophylactic DF for children at risk for VOD is not cost-effective with respect to TRM and length of hospital stay.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Hepatic Veno-Occlusive Disease/drug therapy , Platelet Aggregation Inhibitors/economics , Polydeoxyribonucleotides/economics , Transplantation Conditioning/methods , Transplantation, Homologous/methods , Adolescent , Adult , Child , Child, Preschool , Cost-Benefit Analysis , Female , Hepatic Veno-Occlusive Disease/pathology , Humans , Infant , Infant, Newborn , Male , Platelet Aggregation Inhibitors/therapeutic use , Polydeoxyribonucleotides/therapeutic use , Young Adult
7.
Blood ; 129(11): 1548-1556, 2017 03 16.
Article in English | MEDLINE | ID: mdl-27965196

ABSTRACT

Despite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n = 873; 87%); the remainder received reduced-intensity conditioning regimens (n = 125; 13%). Bone marrow was the predominant stem cell source (n = 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Event-free survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after 2006 (HR, 0.95; P = .013). Twenty-three patients experienced graft failure, and 70 patients (7%) died, with the most common cause of death being infection. The excellent outcome of a cohort transplanted over the course of 3 decades confirms the role of HLA-identical sibling transplantation for children and adults with SCD.


Subject(s)
Anemia, Sickle Cell/therapy , Hematopoietic Stem Cell Transplantation/methods , Adolescent , Anemia, Sickle Cell/epidemiology , Anemia, Sickle Cell/mortality , Child , Child, Preschool , Disease-Free Survival , Female , Graft Survival , HLA Antigens , Hematopoietic Stem Cell Transplantation/mortality , Histocompatibility , Humans , Infant , Male , Siblings , Surveys and Questionnaires , Survival Rate , Transplantation Conditioning/methods , Treatment Outcome
9.
J Adolesc Health ; 60(1): 33-37, 2017 01.
Article in English | MEDLINE | ID: mdl-27836532

ABSTRACT

PURPOSE: Adolescents with anorexia nervosa (AN) face an increased lifetime risk of bone fragility. This randomized controlled study examined the efficacy and safety of a high-impact activity program on markers of bone turnover and stabilization of vital signs (VSS). METHODS: Forty-one hospitalized adolescents with AN were randomly assigned to routine care or routine care plus 20 jumps twice daily. Bone markers were measured at baseline days 1-3 (T1), days 4-6 (T2), and days 7-9 (T3). The primary outcome was change in bone-specific alkaline phosphatase (BSAP) at T3 adjusted for BSAP and % median body mass index at T1. Secondary outcomes were serum N-telopeptide (NTX) and osteocalcin at T3. Safety was determined by comparing weight gain, time to VSS and length of stay for each group. RESULTS: BSAP, NTX, or osteocalcin did not differ between groups at baseline or at T3. BSAP and NTX at T3 were not associated with group of enrollment or % median body mass index. VSS was significantly reduced in the intervention group compared with the control group (11.6 ± 5.7 days vs. 17 ± 10.5 days, p = .049). There was no significant difference in weight gain or length of stay between groups. CONCLUSIONS: Twice-daily jumping activity failed to influence markers of bone turnover in adolescents with AN but was well tolerated, shortened time to vital-sign stabilization and did not slow weight gain.


Subject(s)
Bone Remodeling/physiology , Exercise/physiology , Feeding and Eating Disorders/physiopathology , Vital Signs/physiology , Adolescent , Adult , Bone Density/physiology , Child , Female , Humans , Male , Pilot Projects , Young Adult
10.
Br J Haematol ; 173(6): 905-17, 2016 06.
Article in English | MEDLINE | ID: mdl-26996395

ABSTRACT

The impact of persistent mixed chimerism (MC) after haematopoietic stem cell transplantation (HSCT) remains unclarified. We investigated the incidence of MC in peripheral blood beyond day +50 after HSCT and its impact on rejection, chronic graft-versus-host disease (c-GvHD) and relapse in 161 children receiving allogeneic HSCT for haematological malignancies. The 1-year incidence of late MC was 26%. Spontaneous conversion to complete donor chimerism (CC) occurred in 43% of patients as compared to 62% after donor lymphocyte infusions. No graft rejection occurred. The 1-year incidence of c-GvHD was 20 ± 7% for MC, and 18 ± 4% for CC patients (P = 0·734). The 3-year cumulative incidence of relapse (CIR) according to chimerism status at days +50 and +100 was 22 ± 4% for CC patients vs. 22 ± 8% for MC patients (day +50; P = 0·935) and 21 ± 4% vs. 20 ± 7% (day +100; P = 0·907). Three-year CIRs in patients with persistent MC and patients with CC/limited MC were comparable (8 ± 7% vs. 19 ± 4%; P = 0·960). HSCT for acute leukaemia or myelodysplastic syndrome as secondary malignancies (hazard ratio (HR) 4·7; P = 0·008), for AML (HR 3·0; P = 0·02) and from mismatched donors (HR 3·1; P = 0·03) were independent factors associated with relapse. Our data suggest that late MC neither protects from c-GvHD nor does it reliably predict impending disease relapse.


Subject(s)
Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Transplantation Chimera/blood , Adolescent , Adult , Allografts , Child , Child, Preschool , Female , Graft Rejection , Graft vs Host Disease , Hematologic Neoplasms/complications , Humans , Infant , Lymphocyte Subsets , Male , Neoplasms, Second Primary , Recurrence , Time Factors , Transplantation Conditioning/methods , Young Adult
11.
Pediatr Transplant ; 20(1): 158-61, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26566972

ABSTRACT

POI is a relevant late complication after HSCT and occurring more frequently after MAC than after RIC regimens. Reports on the frequency of POI after RIC in a large pediatric and adolescent population are lacking. In this study, we describe a girl affected by CML diagnosed at the age of 15 yr and treated with oncarbide and interferon followed by imatinib and dasatinib. She had two pregnancies shortly after RIC performed according to the CML-SCT I-BFM protocol including TT, FLU, and MEL. Hypergonadotropic hypogonadism occurred four months after HSCT; menstruations resumed regularly six months after HSCT. Eight and 20 months after HSCT, the patient became pregnant and then delivered, respectively, two babies at term by cesarean section. Both newborns had no neonatal complications. Donor chimerism at time of two pregnancies and five yr after transplantation demonstrated complete donor engraftment. These findings suggest that I-BFM CML-SCT protocol could be a promising treatment option for adolescents or young adults with CML eligible for HSCT.


Subject(s)
Drug Administration Schedule , Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Transplantation Conditioning/methods , Adolescent , Antineoplastic Agents/administration & dosage , Dasatinib/administration & dosage , Disease-Free Survival , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Hydroxyurea/administration & dosage , Imatinib Mesylate/administration & dosage , Interferons/administration & dosage , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Pregnancy , Primary Ovarian Insufficiency/prevention & control , Transplantation Conditioning/adverse effects , Treatment Outcome , Young Adult
12.
Blood ; 127(11): 1387-97; quiz 1518, 2016 Mar 17.
Article in English | MEDLINE | ID: mdl-26702063

ABSTRACT

Germline GATA2 mutations cause cellular deficiencies with high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in 2 consecutive prospective studies of the European Working Group of MDS in Childhood (EWOG-MDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease compared with wild-type cases. For stratified analysis according to karyotype, 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2 mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72% of adolescents with monosomy 7). Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematologic phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced disease must guide decision-making toward timely HSCT.


Subject(s)
GATA2 Transcription Factor/deficiency , Myelodysplastic Syndromes/genetics , Adolescent , Age of Onset , Child , Child, Preschool , Chromosome Aberrations , Chromosomes, Human, Pair 1/genetics , Chromosomes, Human, Pair 7/genetics , Chromosomes, Human, Pair 8/genetics , Clinical Trials, Phase III as Topic , DNA Mutational Analysis , Deafness/genetics , Female , GATA2 Transcription Factor/genetics , Genetic Predisposition to Disease , Germ-Line Mutation , Humans , Immunologic Deficiency Syndromes/genetics , Kaplan-Meier Estimate , Male , Myelodysplastic Syndromes/epidemiology , Myelodysplastic Syndromes/etiology , Myelodysplastic Syndromes/pathology , Phenotype , Prevalence , Prognosis , Prospective Studies , Selection Bias , Young Adult
13.
Blood ; 126(16): 1885-92; quiz 1970, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26185129

ABSTRACT

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment of severe congenital neutropenia (SCN), but data on outcome are scarce. We report on the outcome of 136 SCN patients who underwent HSCT between 1990 and 2012 in European and Middle East centers. The 3-year overall survival (OS) was 82%, and transplant-related mortality (TRM) was 17%. In multivariate analysis, transplants performed under the age of 10 years, in recent years, and from HLA-matched related or unrelated donors were associated with a significantly better OS. Frequency of graft failure was 10%. Cumulative incidence (day +90) of acute graft-versus-host disease (GVHD) grade 2-4 was 21%. In multivariate analysis, HLA-matched related donor and prophylaxis with cyclosporine A and methotrexate were associated with lower occurrence of acute GVHD. Cumulative incidence (1 year) of chronic GVHD was 20%. No secondary malignancies occurred after a median follow-up of 4.6 years. These data show that the outcome of HSCT for SCN from HLA-matched donors, performed in recent years, in patients younger than 10 years is acceptable. Nevertheless, given the TRM, a careful selection of HSCT candidates should be undertaken.


Subject(s)
Cyclosporine/administration & dosage , Graft Rejection , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Methotrexate/administration & dosage , Neutropenia , Unrelated Donors , Acute Disease , Adolescent , Adult , Allografts , Child , Child, Preschool , Europe/epidemiology , Female , Graft Rejection/epidemiology , Graft Rejection/prevention & control , Graft vs Host Disease/epidemiology , Graft vs Host Disease/prevention & control , Histocompatibility Testing , Humans , Incidence , Male , Middle East , Neutropenia/congenital , Neutropenia/epidemiology , Neutropenia/therapy , Retrospective Studies , Societies, Medical
14.
Haematologica ; 100(7): 978-88, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26022711

ABSTRACT

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/µL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as "lympho"-histiocytosis in these patients; and (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogeneses. This is important because of implications for therapy, in particular for protocols targeting T cells.


Subject(s)
Immunologic Deficiency Syndromes/diagnosis , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphoproliferative Disorders/diagnosis , Registries , Adolescent , Adult , Bacterial Infections/complications , Bacterial Infections/drug therapy , Bacterial Infections/immunology , Child , Child, Preschool , Diagnosis, Differential , Europe , Female , Humans , Immunoglobulins, Intravenous/therapeutic use , Immunologic Deficiency Syndromes/complications , Immunologic Deficiency Syndromes/drug therapy , Immunologic Deficiency Syndromes/immunology , Immunologic Factors/therapeutic use , Infant , Infant, Newborn , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Leishmaniasis/complications , Leishmaniasis/drug therapy , Leishmaniasis/immunology , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphohistiocytosis, Hemophagocytic/pathology , Lymphoproliferative Disorders/complications , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/immunology , Male , Mycoses/complications , Mycoses/drug therapy , Mycoses/immunology , Opportunistic Infections/complications , Opportunistic Infections/drug therapy , Opportunistic Infections/immunology , Steroids/therapeutic use , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Terminology as Topic , Virus Diseases/complications , Virus Diseases/drug therapy , Virus Diseases/immunology
15.
J Clin Oncol ; 33(11): 1265-74, 2015 Apr 10.
Article in English | MEDLINE | ID: mdl-25753432

ABSTRACT

PURPOSE: Although hematopoietic stem-cell transplantation is widely performed in children with high-risk acute lymphoblastic leukemia (ALL), the influence of donor types is poorly understood. Thus, transplantation outcomes were compared in the prospective multinational Berlin-Frankfurt-Muenster (BFM) study group trial: ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia). PATIENTS AND METHODS: After conditioning with total-body irradiation and etoposide, 411 children with high-risk ALL received highly standardized stem-cell transplantations during the first or later remissions. Depending on donor availability, grafts originated from HLA-genoidentical siblings or from HLA-matched unrelated donors who were identified and matched by high-resolution allelic typing and were compatible in at least 9 of 10 HLA loci. RESULTS: Four-year event-free survival (± standard deviation [SD]) did not differ between patients with transplantations from unrelated or sibling donors (0.67 ± 0.03 v 0.71 ± 0.05; P = .405), with cumulative incidences of nonrelapse mortality (± SD) of 0.10 ± 0.02 and 0.03 ± 0.02 (P = .017) and relapse rates (± SD) of 0.22 ± 0.02 and 0.24 ± 0.04 (P = .732), respectively. Among recipients of transplantations from unrelated donors, no significant differences in event-free survival, overall survival, or nonrelapse mortality were observed between 9/10 and 10/10 matched grafts or between peripheral blood stem cells and bone marrow. The absence of chronic graft-versus-host disease had no effect on event-free survival. Engraftment was faster after bone marrow transplantation from siblings and was associated with fewer severe infections and pulmonary complications. CONCLUSION: Outcome among high-risk pediatric patients with ALL after hematopoietic stem-cell transplantation was not affected by donor type. Standardized myeloablative conditioning produced a low incidence of treatment-related mortality and effective control of leukemia.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Living Donors , Precursor Cell Lymphoblastic Leukemia-Lymphoma/surgery , Siblings , Unrelated Donors , Adolescent , Child , Child, Preschool , Disease-Free Survival , Etoposide/administration & dosage , Europe , Female , HLA Antigens/genetics , HLA Antigens/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/mortality , Histocompatibility , Histocompatibility Testing , Humans , Infant , Infant, Newborn , Kaplan-Meier Estimate , Male , Myeloablative Agonists/administration & dosage , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Proportional Hazards Models , Prospective Studies , Recurrence , Risk Factors , Time Factors , Transplantation Conditioning/methods , Transplantation, Homologous , Treatment Outcome , Whole-Body Irradiation
16.
J Clin Immunol ; 35(2): 189-98, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25627830

ABSTRACT

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.


Subject(s)
Genetic Association Studies , Guanine Nucleotide Exchange Factors/deficiency , Guanine Nucleotide Exchange Factors/genetics , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Female , Follow-Up Studies , Humans , Immunoglobulin E/blood , Immunoglobulin E/immunology , Incidence , Infant , Infections/diagnosis , Infections/epidemiology , Infections/etiology , Job Syndrome/complications , Job Syndrome/diagnosis , Job Syndrome/genetics , Job Syndrome/immunology , Job Syndrome/mortality , Job Syndrome/therapy , Lymphocyte Count , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Male , Middle Aged , Mutation , Neoplasms/epidemiology , Neoplasms/etiology , Phenotype , Young Adult
17.
Blood ; 125(12): 1986-94, 2015 Mar 19.
Article in English | MEDLINE | ID: mdl-25617426

ABSTRACT

Hematopoietic stem cell transplantation (HSCT) has improved over the last few decades. However, viral infections are often refractory to pharmacologic treatment and require alternative treatment strategies such as immunotherapy. Adenovirus (AdV) is th predominant disease-causing pathogen in pediatric HSCT. In a clinical trial, we analyzed safety and efficacy of ex vivo adoptive T-cell transfer (ACT) with hexon-specific T cells, predominantly of the T-helper cell 1 (Th1) phenotype, in 30 patients with AdV disease or viremia. ACT was feasible with no acute toxicities or significant onset of graft-versus-host disease. ACT led to in vivo antiviral immunity for up to 6 months with viral control, resulting in complete clearance of viremia in 86% of patients with antigen-specific T-cell responses. After ACT and a follow-up of 6 months, overall survival was markedly increased in responders (mean, 122 days; 15 survivors) compared with nonresponders who all died shortly after ACT (mean, 24 days; no survivors). AdV-related mortality was 100% in nonresponders compared with 9.5% in responders (≥1 log reduction of DNA copies per milliliter after ACT). In summary, ex vivo ACT of AdV-specific Th1 cells was well tolerated and led to successful and sustained restoration of T-cell immunity correlated with virologic response and protection from virus-related mortality. This cellular immunotherapy is a short-term available and broadly applicable treatment. The study is registered at European Union Clinical Trials Register as 2005-001092-35.


Subject(s)
Adenoviridae Infections/complications , Capsid Proteins/metabolism , Hematopoietic Stem Cell Transplantation/adverse effects , Immunotherapy, Adoptive/methods , T-Lymphocytes/cytology , Th1 Cells/cytology , Adenoviridae Infections/etiology , Adolescent , Adoptive Transfer , Adult , Child , Child, Preschool , Humans , Infant , Male , Middle Aged , Phenotype , Probability , T-Lymphocytes/immunology , Treatment Outcome , Young Adult
18.
J Allergy Clin Immunol ; 135(4): 988-997.e6, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25595268

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted. OBJECTIVE: We sought to define the outcomes of HSCT for patients with CVID. METHODS: Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012. RESULTS: Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved. CONCLUSION: This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome.


Subject(s)
Common Variable Immunodeficiency/therapy , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells , Adolescent , Adult , Cause of Death , Child , Common Variable Immunodeficiency/complications , Common Variable Immunodeficiency/mortality , Female , Follow-Up Studies , Graft Survival , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Male , Middle Aged , Retrospective Studies , Transplantation Conditioning , Treatment Outcome , Young Adult
19.
Haematologica ; 99(5): 811-20, 2014 May.
Article in English | MEDLINE | ID: mdl-24790059

ABSTRACT

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.


Subject(s)
Anemia, Sickle Cell/therapy , Hematopoietic Stem Cell Transplantation , beta-Thalassemia/therapy , Anemia, Sickle Cell/diagnosis , Child , Humans , beta-Thalassemia/diagnosis
20.
J Immunother ; 37(4): 245-9, 2014 May.
Article in English | MEDLINE | ID: mdl-24714358

ABSTRACT

Adoptive immunotherapy against viral infections is a promising treatment option for patients after hematopoietic stem cell transplantation. However, the generation of virus-specific T cells is either cost-intensive or time-consuming. We developed the first GMP-compliant protocol to generate donor-derived adenovirus (HAdV), cytomegalovirus, and Epstein-Barr virus-specific T-cell lines (TCLs) within 12 days by the use of overlapping polypeptides derived from different viruses in combination with IL-15. Two patients after undergoing haploidentical hematopoietic stem cell transplantation with HAdV viremia displaying rising viral loads despite treatment with cidofovir received 1×10 donor-derived short-term expanded HAdV-specific TCLs per kg body weight. In both patients, HAdV-specific T cells could be detected by IFN-γ-ELISpot 30 and 22 days postinfusion, and resulted in complete clearance or >1.5 log reduction of viral load within 15 and 18 days, respectively. This protocol facilitates rapid and cost-effective generation of virus-specific TCLs, which appear to provide an effective treatment option.


Subject(s)
Adenovirus Infections, Human/immunology , Adenovirus Infections, Human/therapy , Adenoviruses, Human/immunology , Immunotherapy, Adoptive , T-Cell Antigen Receptor Specificity/immunology , T-Lymphocytes/immunology , T-Lymphocytes/transplantation , Adenovirus Infections, Human/virology , Adenoviruses, Human/classification , Child, Preschool , Fatal Outcome , Female , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunotherapy, Adoptive/methods , Immunotherapy, Adoptive/standards , Infant , Male , Peptides/pharmacology , T-Lymphocytes/drug effects , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/transplantation , Transplantation, Homologous , Treatment Outcome , Viral Load
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