RESUMO
Autoimmune or alloimmune cytopenia (AIC) is a known rare complication of hematopoietic stem cell transplantation (SCT). AIC after SCT is considered difficult to treat and is associated with high morbidity and mortality. In this retrospective study in pediatric patients we evaluated incidence, outcome, potential risk factors, and current treatment strategies. A nested matched case-control study was performed to search for biomarkers associated with AIC. Of 531 consecutive SCTs at our center between 2000 and 2016, 26 were complicated by the development of AIC (cumulative incidence, 5.0%) after a median of 5 months post-SCT. Autoimmune hemolytic anemia was the most common AIC with 12 patients (46%). We identified nonmalignant disease, alemtuzumab serotherapy pre-SCT, and cytomegalovirus (CMV) reactivation as independently associated risk factors. The cytokine profile of patients at the time of AIC diagnosis appeared to skew toward a more pronounced Th 2 response compared with control subjects at the corresponding time point post-SCT. Corticosteroids and intravenous immunoglobulin as first-line treatment or a wait-and-see approach led to resolution of AIC in 35% of cases. Addition of step-up therapies rituximab (n = 15), bortezomib (n = 7), or sirolimus (n = 3) was associated with AIC resolution in 40%, 57%, and 100% of cases, respectively. In summary, we identified CMV reactivation post-SCT as a new clinical risk factor for the development of AIC in children. The cytokine profile during AIC appears to favor a Th 2 response. Rituximab, bortezomib, and sirolimus are promising step-up treatment modalities.
Assuntos
Doenças Autoimunes , Transplante de Células-Tronco Hematopoéticas , Adolescente , Corticosteroides/administração & dosagem , Adulto , Alemtuzumab/administração & dosagem , Aloenxertos , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/mortalidade , Doenças Autoimunes/terapia , Bortezomib/administração & dosagem , Criança , Pré-Escolar , Citomegalovirus/imunologia , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/terapia , Feminino , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco , Rituximab/administração & dosagem , Células Th2/imunologiaRESUMO
BACKGROUND: The efficacy and safety of recombinant Escherichia coli-asparaginase (rASNase) was compared to native E.coli asparaginase (Asparaginase medac). METHODS: One hundred and ninety-nine children with newly diagnosed acute lymphoblastic leukemia were randomized to receive one of both agents at a dose of 5,000 U/m² during induction (eight doses) and 10,000 U/m² during the postinduction phase (only high-risk patients; standard- and medium-risk patients received pegaspargase). RESULTS: Median trough serum asparaginase activity levels were comparable between both groups; they ranged from 143 to 182 U/l during induction and were above the target value of 100 U/l. Complete asparagine depletion in serum was achieved in 97.9% of patients, with no significant differences between both groups. On day 33 (end of induction), only two (2%) evaluable patients in each group had measurable asparagine serum levels, and complete asparagine depletion in the cerebrospinal fluid was achieved in 98.8% and 93.6% of the patients with rASNase and Asparaginase medac, respectively. During induction, 2.1% and 5% of patients developed an allergic reaction to rASNase or Asparaginase medac, respectively. Approximately 41% of the patients in both groups had a clinical allergy or enzyme inactivation to the first dose of any asparaginase preparation in postinduction. A comparable proportion of patients in both groups developed anti-asparaginase antibodies (57%) during repeated administration of asparaginase. Minimal residual disease levels at the end of induction, 5-year event-free survival, and 5-year cumulative incidence of relapse did not differ between both groups. CONCLUSION: The efficacy, safety, and immunogenicity of both asparaginase preparations are comparable. This trial was registered at www.clinicaltrials.gov as #NCT00784017; EudraCT number 2006-003180-31.
Assuntos
Antineoplásicos/uso terapêutico , Asparaginase/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Escherichia coli , Feminino , Humanos , Lactente , Masculino , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoRESUMO
Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L). The aim of this study was to describe the population pharmacokinetics of intravenous Erwinia asparaginase to quantify and gather insight into inter-individual and inter-occasion variability. The starting dose was evaluated on the basis of the derived population pharmacokinetic parameters. In a multicenter prospective observational study, a total of 714 blood samples were collected from 51 children (age 1-17 years) with acute lymphoblastic leukemia. The starting dose was 20,000 IU/m2 three times a week and adjusted according to trough levels from week three onwards. A population pharmacokinetic model was developed using NONMEM® A 2-compartment linear model with allometric scaling best described the data. Inter-individual and inter-occasion variability of clearance were 33% and 13%, respectively. Clearance in the first month of treatment was 14% higher (P<0.01). Monte Carlo simulations with our pharmacokinetic model demonstrated that patients with a low weight might require higher doses to achieve similar concentrations compared to patients with high weight. The current starting dose of 20,000 IU/m2 might result in inadequate concentrations, especially for smaller, lower weight patients, hence dose adjustments based on individual clearance are recommended. The protocols were approved by the institutional review boards. (Registered at NTR 3379 Dutch Trial Register; www.trialregister.nl).
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Asparaginase/administração & dosagem , Asparaginase/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Administração Intravenosa , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Modelos Estatísticos , Vigilância da População , Reprodutibilidade dos TestesRESUMO
Pediatric acute myeloid leukemia (AML) is a heterogeneous disease, characterized by different collaborating karyotypic and molecular abnormalities, which are used in risk group stratification. In â¼20% of the pediatric AML cases a specific genetic aberration is still unknown. Minimally differentiated myeloid leukemia or FAB-type M0 is a rare morphological subtype of AML. The translocation t(10;17)(p15;q21) is described to be recurrent in minimally differentiated AML, but the involved genes and location of the breakpoints have so far not been identified. In this study, we show that this translocation results in an in-frame translocation fusing exon 12 of the tumor suppressor gene ZMYND11 to exon 3 of the chromatin protein MBTD1, encoding a protein of 1,054 amino acids, while the reciprocal fusion product is predicted to lack a productive start codon. Gene expression profiling of the leukemic cells showed high HOXA expression. ZMYND11, also known as BS69, is a tumor suppressor that specifically recognizes H3K36me3, which is linked to aberrant HOXA expression in leukemogenesis. Aberrant expression of the genes involved in this fusion may thus contribute to the HOXA-phenotype observed with gene expression profiling.
Assuntos
Proteínas de Transporte/genética , Proteínas Cromossômicas não Histona/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Ciclo Celular , Diferenciação Celular , Criança , Cromossomos Humanos Par 11 , Proteínas Correpressoras , Proteínas de Ligação a DNA , Humanos , Masculino , Dados de Sequência Molecular , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismoRESUMO
OBJECTIVE: To determine the genotype-phenotype association in patients with adenosine deaminase-2 (ADA2) deficiency due to identical homozygous R169Q mutations inCECR1 METHODS: We present a case series of nine ADA2-deficient patients with an identical homozygous R169Q mutation. Clinical and diagnostic data were collected and available MRI studies were reviewed. We performed genealogy and haplotype analyses and measured serum ADA2 activity. ADA2 activity values were correlated to clinical symptoms. RESULTS: Age of presentation differed widely between the nine presented patients (range: 0 months to 8 years). The main clinical manifestations were (hepato)splenomegaly (8/9), skin involvement (8/9) and neurological involvement (8/9, of whom 6 encountered stroke). Considerable variation was seen in type, frequency and intensity of other symptoms, which included aplastic anaemia, acute myeloid leukaemia and cutaneous ulcers. Common laboratory abnormalities included cytopenias and hypogammaglobulinaemia. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. Genealogical studies did not identify a common ancestor; however, based on allele frequency, a North-West European founder effect can be noted. Three patients underwent haematopoietic cell transplantation, after which ADA2 activity was restored and clinical symptoms resolved. CONCLUSION: This case series revealed large phenotypic variability in patients with ADA2 deficiency though they were homozygous for the same R169Q mutation inCECR1 Disease modifiers, including epigenetic and environmental factors, thus seem important in determining the phenotype. Furthermore, haematopoietic cell transplantation appears promising for those patients with a severe clinical phenotype.
Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Mutação , Imunodeficiência Combinada Severa/genética , Adenosina Desaminase/sangue , Adenosina Desaminase/genética , Agamaglobulinemia/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Efeito Fundador , Haplótipos , Homozigoto , Humanos , Imunossupressores/uso terapêutico , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Linhagem , Fenótipo , Imunodeficiência Combinada Severa/tratamento farmacológicoRESUMO
This study prospectively analyzed the efficacy of very prolonged courses of pegylated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2500 IU/m(2) every 2 weeks) in intensification after receiving native E coli asparaginase in induction. In case of allergy to or silent inactivation of PEGasparaginase, Erwinia asparaginase (20 000 IU/m(2) 2-3 times weekly) was given. Eighty-nine patients were enrolled in the PEGasparaginase study. Twenty (22%) of the PEGasparaginase-treated patients developed an allergy; 7 (8%) showed silent inactivation. The PEGasparaginase level was 0 in all allergic patients (grade 1-4). Patients without hypersensitivity to PEGasparaginase had serum mean trough levels of 899 U/L. Fifty-nine patients were included in the Erwinia asparaginase study; 2 (3%) developed an allergy and none silent inactivation. Ninety-six percent had at least 1 trough level ≥100 U/L. The serum asparagine level was not always completely depleted with Erwinia asparaginase in contrast to PEGasparaginase. The presence of asparaginase antibodies was related to allergies and silent inactivation, but with low specificity (64%). Use of native E coli asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Therefore, PEGasparaginase should be used upfront in induction, and we suggest that the dose could be lowered. Switching to Erwinia asparaginase leads to effective asparaginase levels in most patients. Therapeutic drug monitoring has been added to our ALL-11 protocol to individualize asparaginase therapy.
Assuntos
Antineoplásicos/uso terapêutico , Asparaginase/administração & dosagem , Asparaginase/imunologia , Monitoramento de Medicamentos , Erwinia/enzimologia , Polietilenoglicóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Anticorpos/sangue , Criança , Pré-Escolar , Proteínas de Escherichia coli/uso terapêutico , Feminino , Humanos , Lactente , Masculino , Fatores de Tempo , Resultado do TratamentoRESUMO
Cidofovir is frequently used to treat life-threatening human adenovirus (HAdV) infections in immunocompromised children after hematopoietic stem cell transplantation (HSCT). However, the antiviral effect irrespective of T cell reconstitution remains unresolved. Plasma HAdV DNA levels were monitored by real-time quantitative PCR during 42 cidofovir treatment episodes for HAdV viremia in 36 pediatric allogeneic HSCT recipients. HAdV load dynamics were related to T and natural killer (NK) cell reconstitution measured by flow cytometry. To evaluate the in vivo antiadenoviral effect of cidofovir, we focused on 20 cidofovir treatment episodes lacking concurrent T cell reconstitution. During 2 to 10 weeks of follow-up in the absence of T cells, HAdV load reduction (n = 7) or stabilization (n = 8) was observed in 15 of 20 treatments. Although HAdV load reduction was always accompanied by NK cell expansion, HAdV load stabilization was measured in 2 children lacking both T and NK cell reconstitution. In cases with T cell reconstitution, rapid HAdV load reduction (n = 14) or stabilization (n = 6) was observed in 20 of 22 treatments. In the absence of T cells, cidofovir treatment was associated with HAdV viremia control in the majority of cases. Although the contribution of NK cells cannot be excluded, cidofovir has the potential to mediate HAdV load stabilization in the time pending T cell reconstitution.
Assuntos
Infecções por Adenovirus Humanos/tratamento farmacológico , Antivirais/uso terapêutico , Citosina/análogos & derivados , DNA Viral/antagonistas & inibidores , Transplante de Células-Tronco Hematopoéticas , Hospedeiro Imunocomprometido , Organofosfonatos/uso terapêutico , Viremia/tratamento farmacológico , Infecções por Adenovirus Humanos/imunologia , Infecções por Adenovirus Humanos/patologia , Infecções por Adenovirus Humanos/virologia , Adenovírus Humanos/efeitos dos fármacos , Adenovírus Humanos/imunologia , Adolescente , Criança , Pré-Escolar , Cidofovir , Estudos de Coortes , Citosina/uso terapêutico , DNA Viral/sangue , Feminino , Humanos , Lactente , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Contagem de Linfócitos , Depleção Linfocítica , Masculino , Linfócitos T/citologia , Linfócitos T/imunologia , Transplante Homólogo , Carga Viral/efeitos dos fármacos , Viremia/imunologia , Viremia/patologia , Viremia/virologiaRESUMO
BACKGROUND: Ovarian insufficiency (OI) and infertility are common and devastating late effects of cancer treatment and hematopoietic stem cell transplantation (HSCT). In children, gonadal insufficiency may subsequently lead to abnormal pubertal development. The aim of this study was to assess the cumulative incidence of OI and the need for hormonal induction of pubertal development after HSCT in childhood. We additionally assessed HSCT-related risk factors for OI. PROCEDURES: A single center cohort study was undertaken of female patients transplanted during childhood, surviving at least 2 years post-HSCT and who were at least 10 years old at initiation of the study. Of 141 eligible patients, 109 were included and hormone levels and clinical data of these patients during follow-up were collected. Risk factors for OI were analyzed by multivariate Cox regression analysis. RESULTS: Cumulative incidence of OI was 56% at a median follow-up of 7.2 years. Eight patients, initially diagnosed with OI, showed recovery of ovarian function over time. Hormonal induction of puberty was necessary in 44% of females who were pre-pubertal or pubertal at HSCT. In multivariate analysis, more advanced pubertal stage at HSCT was associated with OI. We found a trend for an association of busulfan with OI in patients conditioned with chemotherapy only. CONCLUSIONS: The incidence of OI after HSCT was high and associated with more advanced pubertal stage at HSCT. Almost half of the females who were pre-pubertal or pubertal at HSCT required hormonal induction of pubertal development.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Insuficiência Ovariana Primária/etiologia , Puberdade/fisiologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Insuficiência Ovariana Primária/epidemiologia , Modelos de Riscos Proporcionais , Fatores de Risco , Condicionamento Pré-TransplanteRESUMO
The aim of treating childhood cancer remains to cure all. As survival rates improve, long-term health outcomes increasingly define quality of care. The International Childhood Cancer Outcome Project developed a set of core outcomes for most types of childhood cancers involving relevant international stakeholders (survivors; pediatric oncologists; other medical, nursing or paramedical care providers; and psychosocial or neurocognitive care providers) to allow outcome-based evaluation of childhood cancer care. A survey among healthcare providers (n = 87) and online focus groups of survivors (n = 22) resulted in unique candidate outcome lists for 17 types of childhood cancer (five hematological malignancies, four central nervous system tumors and eight solid tumors). In a two-round Delphi survey, 435 healthcare providers from 68 institutions internationally (response rates for round 1, 70-97%; round 2, 65-92%) contributed to the selection of four to eight physical core outcomes (for example, heart failure, subfertility and subsequent neoplasms) and three aspects of quality of life (physical, psychosocial and neurocognitive) per pediatric cancer subtype. Measurement instruments for the core outcomes consist of medical record abstraction, questionnaires and linkage with existing registries. This International Childhood Cancer Core Outcome Set represents outcomes of value to patients, survivors and healthcare providers and can be used to measure institutional progress and benchmark against peers.
Assuntos
Neoplasias , Humanos , Criança , Neoplasias/terapia , Qualidade de Vida , Técnica Delphi , Avaliação de Resultados em Cuidados de Saúde , Pessoal de SaúdeRESUMO
We prospectively studied clofarabine-fludarabine-busulfan (CloFluBu)-conditioning in allogeneic hematopoietic cell therapy (HCT) for lymphoid and myeloid malignancies and hypothesized that CloFluBu provides a less toxic alternative to conventional conditioning regimens, with adequate antileukemic activity. All patients receiving their first HCT, from 2011-2019, were included and received CloFluBu. The primary endpoint was event-free survival (EFS). Secondary endpoints were overall survival (OS), graft-versus-host disease (GvHD)-relapse-free survival (GRFS), treatment-related mortality (TRM), cumulative incidence of relapse (CIR), acute and chronic GvHD (aGvHD and cGvHD), and veno-occlusive disease (VOD). Cox proportional hazard and Fine and Gray competing-risk models were used for data analysis. One hundred fifty-five children were included: 60 acute lymphoid leukemia (ALL), 69 acute myeloid leukemia (AML), and 26 other malignancies (mostly MDS-EB). The median age was 9.7 (0.5 to 18.6) years. Estimated 2-year EFS was 72.0% ± 6.0 in ALL patients, and 62.4% ± 6.0 in AML patients. TRM in the whole cohort was 11.0% ± 2.6, incidence of aGvHD 3 to 4 at 6 months was 12.3% ± 2.7, extensive cGvHD at 2 years was 6.4% ± 2.1. Minimal residual disease-positivity prior to HCT was associated with higher CIR, both in ALL and AML. CloFluBu showed limited toxicity and encouraging EFS. CloFluBu is a potentially less toxic alternative to conventional conditioning regimens. Randomized prospective studies are needed.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Bussulfano/efeitos adversos , Criança , Clofarabina , Doença Enxerto-Hospedeiro/patologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva , Vidarabina/análogos & derivadosRESUMO
Adoptive transfer of virus-specific T cells can treat infections complicating allogeneic hematopoietic cell transplants. However, autologous APCs are often limited in supply. In this study, we describe a panel of artificial APCs (AAPCs) consisting of murine 3T3 cells transduced to express human B7.1, ICAM-1, and LFA-3 that each stably express one of a series of six common HLA class I alleles. In comparative analyses, T cells sensitized with AAPCs expressing a shared HLA allele or autologous APCs loaded with a pool of 15-mer spanning the sequence of CMVpp65 produced similar yields of HLA-restricted CMVpp65-specific T cells; significantly higher yields could be achieved by sensitization with AAPCs transduced to express the CMVpp65 protein. T cells generated were CD8(+), IFN-gamma(+), and exhibited HLA-restricted CMVpp65-specific cytotoxicity. T cells sensitized with either peptide-loaded or transduced AAPCs recognized epitopes presented by each HLA allele known to be immunogenic in humans. Sensitization with AAPCs also permitted expansion of IFN-gamma(+) cytotoxic effector cells against subdominant epitopes that were either absent or in low frequencies in T cells sensitized with autologous APCs. This replenishable panel of AAPCs can be used for immediate sensitization and expansion of virus-specific T cells of desired HLA restriction for adoptive immunotherapy. It may be of particular value for recipients of transplants from HLA-disparate donors.
Assuntos
Alelos , Citomegalovirus/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Epitopos Imunodominantes/imunologia , Imunoterapia Adotiva , Ativação Linfocitária/imunologia , Fosfoproteínas/imunologia , Linfócitos T Citotóxicos/transplante , Proteínas da Matriz Viral/imunologia , Animais , Células Cultivadas , Epitopos de Linfócito T/imunologia , Antígenos HLA-A/genética , Antígeno HLA-A2 , Antígeno HLA-A24 , Antígeno HLA-A3 , Antígenos HLA-B/genética , Antígeno HLA-B7 , Antígeno HLA-B8 , Antígenos de Histocompatibilidade Classe I/biossíntese , Humanos , Epitopos Imunodominantes/administração & dosagem , Camundongos , Células NIH 3T3 , Fosfoproteínas/administração & dosagem , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/transplante , Subpopulações de Linfócitos T/virologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/virologia , Proteínas da Matriz Viral/administração & dosagemRESUMO
Two adolescents, on immunosuppressive therapy for graft-versus-host disease, developed hemophagocytic lymphohistiocytosis (HLH) after varicella zoster virus (VZV) reactivation. In the absence of dermatome restricted characteristic skin lesions, VZV reactivation was not immediately recognized and treatment with acyclovir was delayed. The first patient developed optical neuritis and died 2 months after the VZV episode due to massive intracranial hemorrhage. The second patient presented with severe abdominal pain and pancreatitis, followed by atypical skin eruptions, which prompted a faster diagnosis. Both patients recovered from their HLH, the first patient being successfully treated with immunosuppressive agents and the second with VZV treatment only. These two cases demonstrate the difficulties in recognizing VZV reactivation, and in order to start adequate and timely treatment, the need to consider VZV as a possible cause of HLH in severely immunocompromised patients.
Assuntos
Herpes Zoster/complicações , Hospedeiro Imunocomprometido , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/virologia , Aciclovir/uso terapêutico , Adolescente , Antivirais/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Herpes Zoster/tratamento farmacológico , Humanos , Leucemia Mieloide Aguda/terapia , Linfo-Histiocitose Hemofagocítica/fisiopatologia , MasculinoAssuntos
Biomarcadores Tumorais/genética , Síndrome de Down/complicações , Detecção Precoce de Câncer/métodos , Fator de Transcrição GATA1/genética , Leucemia Mieloide/diagnóstico , Mutação , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Recém-Nascido , Leucemia Mieloide/etiologia , Leucemia Mieloide/patologia , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
PURPOSE: To elucidate incidence and risk factors of bone mineral density and fracture risk in children with Acute Lymphoblastic Leukemia (ALL). METHODS: Prospectively, cumulative fracture incidence, calculated from diagnosis until one year after cessation of treatment, was assessed in 672 patients. This fracture incidence was compared between subgroups of treatment stratification and age subgroups (Log-Rank test). Serial measurements of bone mineral density of the lumbar spine (BMDLS) were performed in 399 ALL patients using dual energy X-ray absorptiometry. We evaluated risk factors for a low BMD (multivariate regression analysis). Osteoporosis was defined as a BMDLS≤-2 SDS combined with clinical significant fractures. RESULTS: The 3-year cumulative fracture incidence was 17.8%. At diagnosis, mean BMDLS of ALL patients was lower than of healthy peers (mean BMDLS=-1.10 SDS, P<0.001), and remained lower during/after treatment (8months: BMDLS=-1.10 SDS, P<0.001; 24months: BMDLS=-1.27 SDS, P<0.001; 36months: BMDLS=-0.95 SDS, P<0.001). Younger age, lower weight and B-cell-immunophenotype were associated with a lower BMDLS at diagnosis. After correction for weight, height, gender and immunophenotype, stratification to the high risk (HR)-protocol arm and older age lead to a larger decline of BMDLS (HR group: ß=-0.52, P<0.01; age: ß=-0.16, P<0.001). Cumulative fracture incidences were not different between ALL risk groups and age groups. Patients with fractures had a lower BMDLS during treatment than those without fractures. Treatment-related bone loss was similar in patients with and without fractures (respectively: ΔBMDLS=-0.36 SDS and ΔBMDLS=-0.12 SDS; interaction group time, P=0.30). Twenty of the 399 patients (5%) met the criteria of osteoporosis. CONCLUSION: Low values of BMDLS at diagnosis and during treatment, rather than the treatment-related decline of BMDLS, determine the increased fracture risk of 17.8% in children with ALL.