RESUMO
The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.
Assuntos
Infecções por Vírus Epstein-Barr , Linfoma não Hodgkin , Linfoma , Segunda Neoplasia Primária , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Herpesvirus Humano 4 , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Linfoma/complicações , Linfoma não Hodgkin/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaçõesRESUMO
The prognostic impact of PICALM::MLLT10 status in childhood leukaemia is not well described. Ten International Berlin Frankfurt Münster-affiliated study groups and the Children's Oncology Group collaborated in this multicentre retrospective study. The presence of the PICALM::MLLT10 fusion gene was confirmed by fluorescence in situ hybridization and/or RNA sequencing at participating sites. Ninety-eight children met the study criteria. T-cell acute lymphoblastic leukaemia (T-ALL) and acute myeloid leukaemia (AML) predominated 55 (56%) and 39 (40%) patients, respectively. Most patients received a chemotherapy regimen per their disease phenotype: 58% received an ALL regimen, 40% an AML regimen and 1% a hybrid regimen. Outcomes for children with PICALM::MLLT10 ALL were reasonable: 5-year event-free survival (EFS) 67% and 5-year overall survival (OS) 76%, but children with PICALM::MLLT10 AML had poor outcomes: 5-year EFS 22% and 5-year OS 26%. Haematopoietic stem cell transplant (HSCT) did not result in a significant improvement in outcomes for PICALM::MLLT10 AML: 5-year EFS 20% for those who received HSCT versus 23% for those who did not (p = 0.6) and 5-year OS 37% versus 36% (p = 0.7). In summary, this study confirms that PICALM::MLLT10 AML is associated with a dismal prognosis and patients cannot be salvaged with HSCT; exploration of novel therapeutic options is warranted.
Assuntos
Leucemia Mieloide Aguda , Proteínas Monoméricas de Montagem de Clatrina , Criança , Humanos , Hibridização in Situ Fluorescente , Estudos Retrospectivos , Proteínas de Fusão Oncogênica/genética , Resultado do Tratamento , Leucemia Mieloide Aguda/genética , Fatores de Transcrição/genética , Doença Aguda , Prognóstico , Proteínas Monoméricas de Montagem de Clatrina/genéticaRESUMO
Survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for severe idiopathic aplastic anemia (SAA) has improved in recent years, approaching 75% at 5 years. However, an SAA-adapted composite endpoint, graft-versus-host disease (GvHD) and relapse/rejection-free survival (GRFS), may more accurately assess patient outcomes beyond survival. We analyzed GRFS to identify risk factors and specific causes of GRFS failure. Our retrospective analysis from the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation included 479 patients with idiopathic SAA who underwent allo-HSCT in two conventional situations: i) upfront allo-HSCT from a matched related donor (MRD) (upfront cohort), and ii) allo-HSCT for relapsed or refractory SAA (rel/ref cohort). Relevant events for GRFS calculation included graft failure, grade 3-4 acute GvHD, extensive chronic GvHD, and death. In the upfront cohort (n=209), 5-year GRFS was 77%. Late allo-HSCT (i.e., >6 months after SAA diagnosis) was the main poor prognostic factor, specifically increasing the risk of death as the cause of GRFS failure (hazard ratio [HR]=4.08; 95% confidence interval [CI]: 1.41-11.83; P=0.010). In the rel/ref cohort (n=270), 5-year GRFS was 61%. Age was the main factor significantly increasing the risk of death (HR=1.04; 95% CI: 1.02-1.06; P<0.001), acute GvHD (HR=1.03; 95% CI: 1.00-1.07; P=0.041), and chronic GvHD (HR=1.04; 95% CI: 1.01-1.08; P=0.032) as the cause of GRFS failure. GRFS after upfront MRD allo-HSCT was very good, notably with early allo-HSCT, confirming that younger patients with an MRD should be transplanted immediately. GRFS was worse in cases of salvage allo-HSCT, most notably in older patients, questioning the utility of allo-HSCT earlier in the disease course.
Assuntos
Anemia Aplástica , Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Idoso , Anemia Aplástica/complicações , Estudos Retrospectivos , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante Homólogo/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged <18 years) and 77 adults. Median follow-up was 45 months. Median age at transplantation was 7 years (range, 0.1-48.6). Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS) at 3 years were 85.7% and 75.8%, respectively. In multivariate analysis, older age was associated with reduced survival and increased chronic graft-versus-host disease. Nevertheless, OS and EFS at 3 years for patients ≥18 years were 76% and 69%, respectively. Use of 1-antigen-mismatched donors was associated with reduced OS and EFS . No significant difference was found in OS, but a significantly reduced EFS was noted in the small group of patients who received a transplant from a donor with a >1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.
Assuntos
Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Doença Granulomatosa Crônica/patologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Condicionamento Pré-Transplante , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND: In addition to treatment response, cytogenetic and molecular aberrations are the most important prognostic factors in children with de novo acute myeloid leukemia (AML). However, little is known about cytogenetics at the time of relapse. METHODS: This international study analyzed the prognostic value of cytogenetic profiles and karyotypic changes in pediatric relapsed AML in relation to the probability of event-free (pEFS) and overall survival (pOS). For this purpose, cytogenetic reports from all patients registered on the Relapsed AML 2001/01 Study were reviewed and classified. RESULTS: Cytogenetic information at relapse was available for 403 (71%) of 569 registered patients. Frequently detected aberrations at relapse were t(8;21)(q22;q22) (n = 60) and inv(16)(p13.1q22)/t(16;16)(p13.1;q22) (n = 24), both associated with relatively good outcome (4-year pOS 59% and 71%, respectively). Monosomy 7/7q-, t(9;11)(p22;q23), t(10;11)(p12;q23), and complex karyotypes were associated with poor outcomes (4-year pOS 17%, 19%, 22%, and 22%, respectively). Of 261 (65%) patients for whom cytogenetic data were reliable at both diagnosis and relapse, pEFS was inferior for patients with karyotypic instability (n = 128, 49%), but pOS was similar. Unstable karyotypes with both gain and loss of aberrations were associated with inferior outcome. Early treatment response, time to relapse, and cytogenetic profile at time of relapse were the most important prognostic factors, both outweighing karytoypic instability per se. CONCLUSION: The cytogenetic subgroup at relapse is an independent risk factor for (event-free) survival. Cytogenetic assessment at the time of relapse is of high importance and may contribute to improved risk-adapted treatment for children with relapsed AML.
Assuntos
Aberrações Cromossômicas , Leucemia Mieloide Aguda , Criança , Estudos de Coortes , Humanos , Leucemia Mieloide Aguda/genética , Prognóstico , Recidiva , Estudos RetrospectivosRESUMO
Patients with an ABL-class fusion have a high risk of relapse on standard chemotherapy but are sensitive to tyrosine kinase inhibitors (TKI). In UKALL2011, we screened patients with post-induction MRD ≥1% and positive patients (12%) received adjuvant TKI. As the intervention started during UKALL2011, not all eligible patients were screened prospectively. Retrospective screening of eligible patients allowed the outcome of equivalent ABL-class patients who did and did not receive a TKI in first remission to be compared. ABL-class patients who received a TKI in first remission had a reduced risk of relapse/refractory disease: 0% vs. 63% at four years (P = 0·009).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neoplasia Residual , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-abl/genéticaRESUMO
There are few biomarkers to predict efficacy of glucocorticoid treatment in childhood acute lymphoblastic leukemia (ALL) at diagnosis. Here, we demonstrate reciprocal regulation of 11beta-hydroxysteroid dehydrogenase (11ß-HSD), may predict the apoptotic response of ALL to glucocorticoid treatment. Our data may be useful to refine glucocorticoid treatment, to retain benefit while minimizing side effects.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/fisiologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/fisiologia , Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prednisolona/uso terapêutico , Adolescente , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Resultado do TratamentoRESUMO
Pediatric acute promyelocytic leukemia (APL) can be cured with all-trans retinoic acid (ATRA) and anthracycline. However, most published trials have employed high cumulative doses of anthracyclines. Here, we report the outcome of newly diagnosed APL patients enrolled in the International Consortium for Childhood APL (ICC-APL-01) trial, which reduced anthracycline exposure but extended that of ATRA. The study recruited 258 children/adolescents with molecularly/cytogenetically proven APL. Patients were stratified into standard-risk (SR) and high-risk (HR) groups according to baseline white blood cell counts (<10 × 109/L or ≥10 × 109/L); both groups received identical induction treatment with ATRA and 3 doses of idarubicin. Two or 3 blocks of consolidation therapy were administered to SR and HR patients, respectively, while maintenance therapy with low-dose chemotherapy and ATRA cycles was given to all patients for 2 years. The cumulative dose of daunorubicin equivalent anthracyclines in SR and HR patients was lower than that of previous studies (355 mg/m2 and 405 mg/m2, respectively). Hematologic remission was obtained in 97% of patients; 8 children died of intracranial hemorrhage in the first 2 weeks following diagnosis. Five-year overall and event-free survival for the whole cohort were 94.6% and 79.9%, respectively; they were 98.4% and 89.4% in SR patients and 84.3% and 74.2% in HR patients (P = .002 and P = .043, respectively). These data demonstrate that extended use of ATRA coupled to a risk-adapted consolidation can achieve high cure rates in childhood APL and limit anthracycline exposure. The trial was registered at www.clinicaltrials.gov as EudractCT 2008-002311-40.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Adolescente , Adulto , Antraciclinas/administração & dosagem , Criança , Pré-Escolar , Daunorrubicina/administração & dosagem , Feminino , Humanos , Idarubicina/administração & dosagem , Lactente , Agências Internacionais , Leucemia Promielocítica Aguda/patologia , Masculino , Indução de Remissão , Fatores de Risco , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemRESUMO
Background PF-06650808 is a novel anti-Notch3 antibody-drug conjugate (ADC) able to deliver an auristatin-based cytotoxic payload to target cells. In this first-in-human, dose-finding, phase I study (NCT02129205), we investigated safety, pharmacokinetics, immunogenicity, and preliminary antitumor activity of single-agent PF-06650808 in 40 patients with advanced breast cancer (BC) and other solid tumors unselected for Notch3 expression. Primary endpoint was dose-limiting toxicity (DLT). PF-06650808 was administered intravenously every 3 weeks at a starting dose of 0.2 mg/kg, escalated up to 6.4 mg/kg following the modified continual reassessment method. An additional dose level, 2.0 mg/kg, was evaluated in patients with advanced, estrogen receptor-positive (ER+) BC. Results The majority of patients had advanced BC (60%) and almost all (90%) had received ≥3 prior lines of anticancer therapy. Treatment with PF-06650808 was generally well tolerated at dose levels ≤2.0 mg/kg with no DLTs. The maximum tolerated dose (MTD) was estimated to be 2.4 mg/kg. The most common treatment-related AEs in all patients were fatigue (40.0%), decreased appetite (37.5%), nausea (35.0%), alopecia (32.5%), abdominal pain (25.0%), pruritus (25.0%), and vomiting (25.0%). Five patients achieved a partial response (PR), including 2 unconfirmed PRs; 4 of the responders had ER+/PR+/HER2- BC. Sixteen (51.6%) patients achieved stable disease, including 8 (57.1%) of 14 patients with ER+ BC. Tumor samples from all responders tested positive for NOTCH3 expression in a retrospective, exploratory analysis. Conclusions The anti-Notch3 ADC PF-06650808 has demonstrated a manageable safety profile and early signs of antitumor activity in patients with advanced BC.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Imunoconjugados/química , Neoplasias/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Receptor Notch3/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Imunológicos/farmacocinética , Neoplasias da Mama/secundário , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Oligopeptídeos/farmacocinética , Prognóstico , Receptor Notch3/imunologia , Estudos Retrospectivos , Distribuição Tecidual , Adulto JovemRESUMO
Corticosteroids are incorporated into protocols for the treatment of acute lymphoblastic leukaemia, and hyperglycaemia is a recognised side effect. Corticosteroids exert their hyperglycaemic effect with a multifactorial mechanism. Complications of hyperglycaemia include an increased risk of infection - bacterial, viral and fungal. Approximately half of the children who develop corticosteroid-associated hyperglycaemia are predicted to require insulin treatment, with age and obesity having found to be predictive factors. Fasting and random glucose values can be used to define hyperglycaemia. This review focuses on the published evidence for significant predictive factors for the development of corticosteroid-induced hyperglycaemia and provides guidance on management.
Assuntos
Corticosteroides/efeitos adversos , Hiperglicemia/induzido quimicamente , Hiperglicemia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Criança , Gerenciamento Clínico , Humanos , Hiperglicemia/patologia , Fatores de RiscoRESUMO
Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable nonmalignant diseases and the lower incidence of graft-versus-host disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with ≥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: Single-agent cyclosporine A (CsA) was used for matched sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in nonmalignant diseases. Most centers used additional anti-thymocyte globulin for matched unrelated and mismatched donor HCT, but not for matched siblings. Regarding prophylaxis in nonmyeloablative conditioning (mainly for nonmalignant diseases), responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches toward aGVHD prophylaxis/treatment differentiated for malignant and nonmalignant underlying diseases.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doença Aguda , Adulto , Soro Antilinfocitário , Criança , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Inquéritos e Questionários , Condicionamento Pré-TransplanteRESUMO
Chromosomal rearrangements of the mixed lineage leukaemia (MLL, also known as KMT2A) gene on chromosome 11q23 are amongst the most common genetic abnormalities observed in human acute leukaemias. MLL rearrangements (MLLr) are the most common cytogenetic abnormalities in infant and childhood acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL) and do not normally acquire secondary mutations compared to other leukaemias. To model these leukaemias, we have used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to induce MLL-AF9 (MA9) chromosomal rearrangements in murine hematopoietic stem and progenitor cell lines and primary cells. By utilizing a dual-single guide RNA (sgRNA) approach targeting the breakpoint cluster region of murine Mll and Af9 equivalent to that in human MA9 rearrangements, we show efficient de novo generation of MA9 fusion product at the DNA and RNA levels in the bulk population. The leukaemic features of MA9-induced disease were observed including increased clonogenicity, enrichment of c-Kit-positive leukaemic stem cells and increased MA9 target gene expression. This approach provided a rapid and reliable means of de novo generation of Mll-Af9 genetic rearrangements in murine haematopoietic stem and progenitor cells (HSPCs), using CRISPR/Cas9 technology to produce a cellular model of MA9 leukaemias which faithfully reproduces many features of the human disease in vitro.
Assuntos
Edição de Genes/métodos , Células-Tronco Hematopoéticas/citologia , Histona-Lisina N-Metiltransferase/genética , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-kit/genética , Animais , Sistemas CRISPR-Cas , Células Cultivadas , Pontos de Quebra do Cromossomo , Modelos Animais de Doenças , Células HEK293 , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Modelos Biológicos , Células NIH 3T3RESUMO
Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR αß/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan-containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility.
Assuntos
Bussulfano/análogos & derivados , Doença Granulomatosa Crônica , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adolescente , Adulto , Aloenxertos , Plaquetas/metabolismo , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Sobrevivência de Enxerto/efeitos dos fármacos , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/mortalidade , Doença Granulomatosa Crônica/sangue , Doença Granulomatosa Crônica/mortalidade , Doença Granulomatosa Crônica/terapia , Humanos , Lactente , Masculino , Neutrófilos/metabolismo , Taxa de SobrevidaRESUMO
Hematopoietic stem cell transplantation (HSCT) represents the cornerstone of treatment in pediatric high-risk and relapsed acute myeloid leukemia (AML). The aim of the present study was to compare outcomes of pediatric patients with AML undergoing HSCT using 3 different conditioning regimens: total body irradiation (TBI) and cyclophosphamide (Cy); busulfan (Bu) and Cy; or Bu, Cy, and melphalan (Mel). In this retrospective study, registry data for patients > 2 and <18 years age undergoing matched allogeneic HSCT for AML in first complete remission (CR1) in 204 European Group for Blood and Marrow Transplantation centers between 2000 and 2010 were analyzed. Data were available for 631 patients; 458 patients received stem cells from a matched sibling donor and 173 from a matched unrelated donor. For 440 patients, bone marrow was used as stem cell source, and 191 patients received peripheral blood stem cells. One hundred nine patients received TBICy, 389 received BuCy, and 133 received BuCyMel as their preparatory regimen. Median follow-up was 55 months. Patients receiving BuCyMel showed a lower incidence of relapse at 5 years (14.7% versus 31.5% in BuCy versus 30% in TBICy, P < .01) and higher overall survival (OS) (76.6% versus 64% versus 64.5%, P = .04) and leukemia-free survival (LFS) (74.5% versus 58% versus 61.9%, P < .01), with a comparable nonrelapse mortality (NRM) (10.8% versus 10.5% versus 8.1%, P = .79). Acute graft-versus-host disease (GVHD) grades III and IV but not chronic GVHD, was higher in patients receiving BuCyMel. Older age at HSCT had an adverse impact on NRM and the use of peripheral blood as stem cell source was associated with increased chronic GVHD and NRM as well as lower LFS and OS. Among pediatric patients receiving HSCT for AML in CR1, the use of BuCyMel conditioning proved superior to TBICy and BuCy in reducing relapse and improving LFS.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Europa (Continente) , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Melfalan/administração & dosagem , Recidiva , Sistema de Registros , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Condicionamento Pré-Transplante/mortalidade , Transplante Homólogo , Resultado do Tratamento , Irradiação Corporal TotalRESUMO
Survivors of hematopoietic cell transplantation (HCT) are at risk of subsequent solid tumors, including central nervous system (CNS) tumors. The risk of CNS tumors after HCT in pediatric HCT recipients is not known. We evaluated the incidence and risk factors for CNS tumors in pediatric recipients of allogeneic HCT reported to the Center for International Blood and Marrow Transplant Research between 1976 and 2008. A case control design was used. There were no CNS tumors in the nonmalignant cohort (n = 4543) or in those undergoing HCT for solid tumors (n = 26). There were 59 CNS tumors in 8720 patients transplanted for hematologic malignancies. In comparison with the general population, pediatric HCT recipients with hematologic malignancies had a 33 times higher than expected rate of CNS tumors (95% confidence interval, 22.98 to 45.77; P < .0001). The cumulative incidence of subsequent CNS tumors was 1.29% (95% confidence interval .87 to 1.87) at 20 years after HCT. Significant risk factors in the entire cohort were having an unrelated donor (HR, 3.35; P = .0002) and CNS disease before HCT for both acute lymphoblastic leukemia (HR, 8.21; P = .0003) and acute myeloid leukemia (HR, 6.21; P = .0174). Analysis of the matched cohort showed having an unrelated donor transplant (HR, 4.79; P = .0037), CNS disease before HCT (HR, 7.67; P = .0064), and radiotherapy exposure before conditioning (HR, 3.7; P = .0234) to be significant risk factors. Chronic graft-versus-host disease was associated with a lower risk (HR, .29; P = .0143). Survivors of HCT for nonmalignant diseases did not show an increased incidence of CNS tumors, whereas survivors of hematologic malignancies have a markedly increased incidence of CNS tumors that warrants lifelong surveillance.
Assuntos
Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Segunda Neoplasia Primária/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doadores não Relacionados , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Feminino , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Incidência , Lactente , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaAssuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaAssuntos
Transplante de Medula Óssea , COVID-19/epidemiologia , SARS-CoV-2 , Transplantados/estatística & dados numéricos , Adolescente , COVID-19/imunologia , Criança , Feminino , Doenças Hematológicas/complicações , Doenças Hematológicas/terapia , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Leucemia/complicações , Leucemia/terapia , Linfoma/complicações , Linfoma/terapia , Masculino , Pancitopenia/etiologia , Transplante de Células-Tronco de Sangue Periférico , Estudos Prospectivos , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo , Reino UnidoAssuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Criança , Feminino , Humanos , Imunoterapia , Irlanda/epidemiologia , Masculino , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiologia , Análise de Sobrevida , Reino Unido/epidemiologia , Adulto JovemRESUMO
Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next-generation-sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical-grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically-reliable diagnostic test and minimize false-negative results we developed an open-source tool (CoverMi) to accurately determine base-coverage and the 'discoverability' of known mutations for every sample. We validated our 33-gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS-based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family.
Assuntos
Anemia/diagnóstico , Anemia/genética , Predisposição Genética para Doença , Testes Genéticos , Biologia Computacional/métodos , Gerenciamento Clínico , Estudos de Associação Genética , Testes Genéticos/métodos , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Doenças Raras , Reprodutibilidade dos Testes , Fluxo de TrabalhoRESUMO
Genome-wide association studies have consistently implicated the interleukin-15 (IL-15) gene in acute lymphoblastic leukemia (ALL) biology, including associations with disease susceptibility, and increased risk of central nervous system (CNS) involvement. However, whether pre-B ALL blasts directly respond to IL-15 is unknown. Here, we show that most pre-B ALL primary samples and cell lines express IL-15 and components of its receptor and that primary pre-B ALL cells show increased growth in culture in response to IL-15. Investigation of mechanisms of action using IL-15-responsive SD-1 cells shows this growth advantage is maximal under low-serum conditions, mimicking those found in cerebrospinal fluid. IL-15 also upregulates PSGL-1 and CXCR3, molecules associated with CNS trafficking. Investigation of downstream signaling pathways indicates that IL-15 induces signal transducer and activator of transcription 5 (STAT5), extracellular signal-regulated kinase (ERK) 1/2, and to a lesser extent phosphatidylinositol 3-kinase (PI3K) and nuclear factor κB (NF-κB) phosphorylation. The IL-15-mediated growth advantage is abolished by mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK), PI3K, and NF-κB inhibitors but preserved in the presence of STAT5 inhibition. Together, these observations provide a mechanistic link between increased levels of IL-15 expression and leukemogenesis, high-risk disease, and CNS relapse and suggest potential therapeutic targets.