RESUMEN
BACKGROUND: Minimal residual disease (MRD) measured on end-of-induction bone marrow (BM) is the most important biomarker for guiding therapy in pediatric acute lymphoblastic leukemia (ALL). Due to limited sensitivity of current approaches, peripheral blood (PB) is not a reliable source for identifying patients needing treatment changes. We sought to determine if high-throughput sequencing (HTS) (next-generation sequencing) of rearranged immunoglobulin and T-cell receptor genes can overcome this and be used to measure MRD in PB. PROCEDURE: We employed a quantitative HTS approach to accurately measure MRD from one million cell equivalents of DNA from 17 PB samples collected at day 29 after induction therapy in patients with precursor B-cell ALL. We compared these results to the gold-standard real-time PCR result obtained from their paired BM samples, median follow-up 49 months. RESULTS: With the increased sensitivity, detecting up to one abnormal cell in a million normal cells, we were able to detect MRD in the PB by HTS in all those patients requiring treatment intensification (MRD ≥ 0.005% in BM). CONCLUSION: This is proof of principle that using the increased sensitivity of HTS, PB can be used to measure MRD and stratify children with ALL. The method is cost effective, rapid, accurate, and reproducible, with inherent advantages in children. Importantly, increasing the frequency testing by PB as opposed to intermittent BM sampling may allow extension of the dynamic range of MRD, giving a more complete picture of the kinetics of disease remission while improving relapse prediction and speed of detection.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Estudios de Factibilidad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Células Precursoras de Linfocitos B , Estudios ProspectivosRESUMEN
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).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Neoplasia Residual , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas c-abl/genéticaRESUMEN
Despite the substantial outcome improvements achieved in paediatric acute lymphoblastic leukaemia (ALL), survival in teenage and young adult (TYA) patients has remained inferior. We report the treatment outcomes and toxicity profiles observed in TYA patients treated on the UK paediatric ALL trial, UKALL2003. UKALL2003 was a multi-centre, prospective, randomized phase III trial, investigating treatment intensification or de-escalation according to minimal residual disease (MRD) kinetics at the end of induction. Of 3126 patients recruited to UKALL2003, 229 (7·3%) were aged 16-24 years. These patients were significantly more likely to have high risk MRD compared to 10-15 year olds (47·9% vs. 36·6%, P = 0·004). Nonetheless, 5-year event-free survival for the TYA cohort (aged 16-24 years) was 72·3% [95% confidence interval (CI): 66·2-78·4] overall and 92·6% (95% CI: 85·5-99·7) for MRD low risk patients. The risk of serious adverse events was higher in patients aged ≥10 years compared to those aged 9 or younger (P < 0·0001) and novel age-specific patterns of treatment-related toxicity were observed. TYA patients obtain excellent outcomes with a risk- and response-adapted paediatric chemotherapy protocol. Whilst those aged 10 years and older have excess toxicity compared with younger patients, the age association is specific to individual toxicities.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Factores de Edad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Asparaginasa/administración & dosificación , Asparaginasa/efectos adversos , Niño , Preescolar , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Femenino , Humanos , Masculino , Mercaptopurina/administración & dosificación , Mercaptopurina/efectos adversos , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Neoplasia Residual , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Medición de Riesgo/métodos , Análisis de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversos , Adulto JovenRESUMEN
Although infection is the major cause of treatment-related mortality (TRM) in childhood acute lymphoblastic leukemia, factors associated with infection-related mortality (IRM) are poorly understood. To address this, we report an analysis of all 75 cases of IRM in the United Kingdom Childhood Acute Lymphoblastic Leukaemia Randomised Trial 2003 (UKALL 2003). The 5-year cumulative incidence of IRM was 2.4% (95% confidence interval [CI], 1.9%-3.0%), accounting for 75 (30%) of 249 trial deaths and 75 (64%) of 117 TRM deaths. Risk for IRM as a proportion of TRM was greater in induction than other phases (77% vs 56%; P = .02). Sixty-eight percent of cases were associated with bacterial infection (64% Gram-negative) and 20% with fungal infection. Down syndrome was the most significant risk factor for IRM (odds ratio [OR], 12.08; 95% CI, 6.54-22.32; P < .0001). In addition, there was a trend toward increased IRM in girls (OR, 1.63; 95% CI, 1.02-2.61; P = .04), as well as increasing treatment intensity (regimen B vs A: OR, 2.11 [95% CI, 1.24-3.60]; regimen C vs A: OR, 1.41 [95% CI, 0.76-2.62]; P = .02). Importantly, patients with Down syndrome were at significantly higher risk for IRM during maintenance (P = .048). Our results confirm Down syndrome as a major risk factor for IRM. Enhanced supportive care and prophylactic antibiotics should be considered in high-risk patient groups and during periods of increased risk. This study was registered at http://www.controlled-trials.com/ as #ISRCTN07355119.
Asunto(s)
Antiinfecciosos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Micosis/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Adolescente , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/mortalidad , Niño , Preescolar , Síndrome de Down/genética , Femenino , Humanos , Lactante , Masculino , Análisis Multivariante , Micosis/complicaciones , Micosis/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: No randomised study has shown whether stratification of treatment by minimal residual disease (MRD) response improves outcome in children and young people with acute lymphoblastic leukaemia (ALL). We assessed whether children and young people with clinical standard and intermediate-risk ALL who have persistent MRD at the end of induction therapy benefit from augmented post-remission therapy. METHODS: Between Oct 1, 2003, and June 30, 2011, we enrolled eligible patients aged 1-24 years and initially categorised them into clinical standard-risk, intermediate-risk, and high-risk groups on the basis of a combination of National Cancer Institute criteria, cytogenetics, and early morphological response to induction therapy. Clinical standard-risk and intermediate-risk patients with MRD of 0·01% or higher at day 29 of induction (MRD high risk) were randomly assigned (1:1) to standard therapy (treatment regimens A and B) or augmented post-remission therapy (regimen C). Compared with standard therapy, the augmented treatment regimen (regimen C) included an additional eight doses of pegylated asparaginase, 18 doses of vincristine, and escalated-dose intravenous methotrexate without folinic acid rescue during interim maintenance courses. Computer randomisation was used for treatment allocation and was balanced for sex, age (<10 years vs ≥10 years), and white blood cell count at diagnosis (<50â×â10(9)/L vs ≥50â×â10(9)/L) by minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcomes were event-free survival and overall survival. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07355119. FINDINGS: 533 MRD high-risk patients were randomly assigned to receive standard (n=266) or augmented (n=267) post-remission therapy. After a median follow-up of 70 months (IQR 52-91), 5-year event-free survival was better in the augmented treatment group (89·6% [95% CI 85·9-93·3]) than in the standard group (82·8% [78·1-87·5]; odds ratio [OR] 0·61 [95% CI 0·39-0·98], p=0·04). Overall survival at 5 years was numerically, but not significantly, higher in the augmented treatment group (92·9% [95% CI 89·8-96·0]) than in the standard therapy group (88·9% [85·0-92·8]; OR 0·67 [95% CI 0·38-1·17], p=0·16). More adverse events occurred in the augmented treatment group than in the standard group (asparaginase-related hypersensitivity in 18 [6·7%] in the augmented group vs two [0·8%] in the standard group and asparaginase-related pancreatitis in eight [3·0%] vs one [0·4%]; intravenous methotrexate-related mucositis in 11 [4·1%] vs three [1·1%] and methotrexate-related stomatitis in 48 [18·0%] vs 12 [4·5%]). INTERPRETATION: Our findings suggest that children and young people with acute lymphoblastic leukaemia and 0·01% or more MRD at the end of remission induction therapy could benefit from augmented post-remission therapy. However, the asparaginase and intravenous methotrexate used in the augmented treatment regimen is associated with more adverse events than is the standard post-remission treatment regimen. FUNDING: Medical Research Council and Leukaemia and Lymphoma Research.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Consolidación/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Asparaginasa/administración & dosificación , Asparaginasa/efectos adversos , Niño , Preescolar , Quimioterapia de Consolidación/efectos adversos , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Hipersensibilidad a las Drogas/etiología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Mercaptopurina/administración & dosificación , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Mucositis/inducido químicamente , Neoplasia Residual , Pancreatitis/inducido químicamente , Polietilenglicoles/administración & dosificación , Inducción de Remisión , Medición de Riesgo , Estomatitis/inducido químicamente , Tasa de Supervivencia , Vincristina/administración & dosificaciónRESUMEN
We investigated the outcome for children and young people with Early T-precursor acute lymphoblastic leukaemia (ETP-ALL), a recently described poor prognosis sub-group of T-ALL, treated on a contemporary protocol, UKALL 2003. After a median follow-up of 4 years and 10 months, the ETP sub-group, representing 16% of T-ALL patients, had non-significantly inferior 5-year event-free survival (76·7% vs. 84·6%, P = 0·2) and overall survival (82·4% vs. 90·9%, P = 0·1), and a higher relapse rate (18·6% vs. 9·6%, P = 0·1) compared to typical T-ALL. ETP-ALL has an intermediate risk outcome, which does not warrant experimental treatment or first remission allogeneic transplant for the group universally.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estadificación de Neoplasias , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification. METHODS: Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1-25 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119. FINDINGS: Of 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42-72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5%, 92·8-98·2; unadjusted odds ratio 1·00, 95% CI 0·43-2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI -5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3-8·9) given one delayed intensification and six (2·4%, 0·2-4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0-2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one (<1%) treatment-related death, and 74 episodes of grade 3 or 4 toxic effects in 45 patients (17%). INTERPRETATION: Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy. FUNDING: Medical Research Council and Leukaemia and Lymphoma Research.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Resultado del Tratamiento , Adolescente , Adulto , Asparaginasa/administración & dosificación , Niño , Preescolar , Ciclofosfamida , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Irlanda , Masculino , Metotrexato/administración & dosificación , Neoplasia Residual/complicaciones , Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Recurrencia , Factores de Riesgo , Reino Unido , Vincristina/administración & dosificaciónRESUMEN
Children with primary immunodeficiency diseases, particularly those less than 1 year of age, experience significant toxicity after hematopoietic stem cell transplantation, with busulfan- or melphalan-based conditioning. Treosulfan causes less veno-occlusive disease than busulfan and does not require pharmacokinetic monitoring. We report its use in 70 children. Children received 42 g/m(2) or 36 g/m(2) with cyclophosphamide 200 mg/kg (n = 30) or fludarabine 150 mg/m(2) (n = 40), with alemtuzumab in most. Median age at transplantation was 8.5 months (range, 1.2-175 months); 46 (66%) patients were 12 months of age or younger. Donors were as follows: matched sibling donor, 8; matched family donor, 13; haploidentical, 4; and unrelated, 45. Median follow-up was 19 months (range, 1-47 months). Overall survival was 81%, equivalent in those age less or greater than 1 year. Skin toxicity was common. Veno-occlusive disease occurred twice with cyclophosphamide. Eighteen patients (26%) had graft-versus-host disease, and only 7 (10%) greater than grade 2. Two patients rejected; 24 of 42 more than 1 year after transplantation had 100% donor chimerism. The remainder had stable mixed chimerism. T-cell chimerism was significantly better with fludarabine. Long-term follow-up is required, but in combination with fludarabine, treosulfan is a good choice of conditioning for hematopoietic stem cell transplantation in primary immunodeficiency disease.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Busulfano/análogos & derivados , Trasplante de Células Madre Hematopoyéticas , Síndromes de Inmunodeficiencia/cirugía , Inmunosupresores/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Adolescente , Antineoplásicos Alquilantes/efectos adversos , Busulfano/efectos adversos , Busulfano/uso terapéutico , Niño , Preescolar , Quimerismo , Estudios de Cohortes , Enfermedad Injerto contra Huésped/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Análisis de Supervivencia , Reino UnidoAsunto(s)
Médula Ósea/patología , Sistema Nervioso Central/patología , Células Clonales/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Preescolar , Humanos , Lactante , Invasividad Neoplásica , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , RecurrenciaRESUMEN
Umbilical cord blood transplant (UCBT) is associated with impaired early immune reconstitution. This might be explained by a lower T-cell dose infused, the naivety of cord blood T-cells and the use of in vivo T-cell depletion. We studied the pattern of early immune reconstitution and the clinical outcome of children undergoing unrelated UCBT when in vivo T-cell depletion was omitted. Thirty children affected by malignancies (46%) or immunodeficiencies (54%) underwent an unrelated UCBT. Prospective assessment of immune reconstitution and clinical outcome was performed. We observed an unprecedented CD4(+) T-cell reconstitution, with a median cell count at 30 and 60 d post UCBT of 0.3 × 10(9) /l and 0.56 × 10(9) /l, respectively. Early T-cell expansion was thymic-independent, with a rapid shift from naïve to central memory phenotype and early regulatory T-cell recovery. Viral infections were frequent (63%) but resolved rapidly in most cases and virus-specific T-lymphocytes were detected within 2 months post-UCBT. Acute graft-versus-host disease (GvHD) was frequent (grade II = 34%, grade III-IV = 16%) but steroid responsive, and the incidence of chronic GvHD was low (14%). The omission of in vivo T-cell depletion promotes a unique thymic-independent CD4(+) T-cell reconstitution after unrelated UCBT in children. We postulate that this relates to the specific immunological and ontological qualities of fetal-derived lymphocytes.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Inmunidad Adaptativa , Linfocitos B/inmunología , Recuento de Linfocito CD4 , Niño , Preescolar , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Memoria Inmunológica , Inmunofenotipificación , Lactante , Células Asesinas Naturales/inmunología , Recuento de Linfocitos , Depleción Linfocítica , Masculino , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/prevención & control , Linfocitos T Reguladores/inmunología , Resultado del TratamientoRESUMEN
We retrospectively analysed the outcome of consecutive children with idiopathic severe aplastic anaemia in the United Kingdom who received immunosuppressive therapy (IST) or matched unrelated donor (MUD) haematopoietic stem cell transplantation (HSCT). The 6-month cumulative response rate following rabbit antithymocyte globulin (ATG)/ciclosporin (IST) was 32·5% (95% CI 19·3-46·6) (n = 43). The 5-year estimated failure-free survival (FFS) following IST was 13·3% (95% confidence interval [CI] 4·0-27·8). In contrast, in 44 successive children who received a 10-antigen (HLA-A, -B, -C, -DRB1, -DQB1) MUD HSCT there was an excellent estimated 5-year FFS of 95·01% (95% CI 81·38-98·74). Forty of these children had failed IST previously. HSCT conditioning was a fludarabine, cyclophosphamide and alemtuzumab (FCC) regimen and did not include radiotherapy. There were no cases of graft failure. Median donor chimerism was 100% (range 88-100%). A conditioning regimen, such as FCC that avoids total body irradiation is ideally suited in children. Our data suggest that MUD HSCT following IST failure offers an excellent outcome and furthermore, if a suitable MUD can be found quickly, MUD HSCT may be a reasonable alternative to IST.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Donante no Emparentado , Adolescente , Suero Antilinfocítico/uso terapéutico , Niño , Preescolar , Ciclosporina/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/etiología , Humanos , Inmunosupresores/uso terapéutico , Lactante , Estimación de Kaplan-Meier , Masculino , Infecciones Oportunistas/etiología , Recurrencia , Estudios Retrospectivos , Quimera por Trasplante , Acondicionamiento Pretrasplante/métodos , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
We report the incidence and outcome of venous thrombosis (VT) in the UK acute lymphoblastic leukaemia (ALL) 2003 trial. VT occurred in 59/1824 (3.2%) patients recruited over 5 years with 90% occurring during a period of Asparagine depletion. Pegylated Escherichia Coli Asparaginase (Peg-ASP) 1000 units/m(2) was used throughout. Thirty-four children received further Peg-ASP, most with concurrent heparin prophylaxis. There were no episodes of bleeding or recurrent thrombosis. Optimal Asparagine depletion is central to success of modern regimes for treatment of ALL. This report confirms a significant risk of thrombosis with such therapy, but demonstrates that re-exposure to Asparaginase is feasible and safe.
Asunto(s)
Antineoplásicos/efectos adversos , Asparaginasa/efectos adversos , Trombosis de la Vena/inducido químicamente , Adolescente , Anticoagulantes/uso terapéutico , Antineoplásicos/uso terapéutico , Asparaginasa/uso terapéutico , Niño , Preescolar , Estudios de Factibilidad , Femenino , Heparina de Bajo-Peso-Molecular/uso terapéutico , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Estudios Prospectivos , Trombosis de la Vena/prevención & controlRESUMEN
Minimal residual disease detection, used for clinical management of children with acute lymphoblastic leukemia, can be performed by molecular analysis of antigen-receptor gene rearrangements or by flow cytometric analysis of aberrant immunophenotypes. For flow minimal residual disease to be incorporated into larger national and international trials, a quality assured, standardized method is needed which can be performed in a multi-center setting. We report a four color, flow cytometric protocol established and validated by the UK acute lymphoblastic leukemia Flow minimal residual disease group. Quality assurance testing gave high inter-laboratory agreement with no values differing from a median consensus value by more than one point on a logarithmic scale. Prospective screening of B-ALL patients (n=206) showed the method was applicable to 88.3% of patients. The minimal residual disease in bone marrow aspirates was quantified and compared to molecular data. The combined risk category concordance (minimal residual disease levels above or below 0.01%) was 86% (n=134). Thus, this standardized protocol is highly reproducible between laboratories, sensitive, applicable, and shows good concordance with molecular-based analysis.
Asunto(s)
Citometría de Flujo/métodos , Leucemia de Células B/diagnóstico , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Antígenos CD19/análisis , Antígenos CD34/análisis , Niño , Citometría de Flujo/normas , Reordenamiento Génico , Humanos , Leucemia de Células B/genética , Leucemia de Células B/metabolismo , Neoplasia Residual/genética , Neoplasia Residual/metabolismo , Neprilisina/análisis , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Pronóstico , Estudios Prospectivos , Receptores de Antígenos de Linfocitos T/genética , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: The use of dexamethasone in acute lymphoblastic leukaemia therapy contributes to short- and long-term toxicities. The UKALL 2011 randomised trial investigated whether a more intense dexamethasone dose (10 mg/m2/d x 14d, short vs 6 mg/m2/d x 28d, standard) would lead to a more rapid cytoreduction and reduced adverse effects associated with longer durations of steroids in induction. The impact of dose and duration on dexamethasone pharmacokinetics was investigated. METHODS: Blood samples were obtained on one of the first three and last three days of induction dexamethasone dosing at time points up to 8 h after oral administration. Plasma dexamethasone levels were quantified in 1084 plasma samples obtained from 174 children and a population pharmacokinetic model developed. RESULTS: Drug exposure varied significantly between patients, with a >12-fold variation in AUC0-12h values and a marked overlap in dexamethasone exposures between dose levels. Intuitively, AUC0-12h was significantly higher with short dosing (10 mg/m2/d), but cumulative exposure was significantly higher with standard dosing over 28 days, after a higher cumulative dose. Concomitant rasburicase administration was associated with a 60% higher dexamethasone clearance. Day 8 bone marrow response was comparable between dosing arms, but those with <5% blast count exhibited a greater mean dexamethasone exposure than those with >5%. No statistical differences were observed between arms in terms of steroid-related toxicity or minimal residual disease at the end of induction. CONCLUSION: The potential significance of dexamethasone AUC0-12h on early response and higher cumulative exposure on the standard arm suggest that duration of therapy and exposure may be more important factors than absolute dose from a clinical pharmacology perspective.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Adulto , Asparaginasa/administración & dosificación , Niño , Preescolar , Dexametasona/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Metotrexato/administración & dosificación , Pronóstico , Factores de Tiempo , Distribución Tisular , Vincristina/administración & dosificación , Adulto JovenRESUMEN
Purpose Minimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy. The aim of our study was to exploit the full power of MRD by examining it as a continuous variable and to integrate it with genetics. Patients and Methods We used a population-based cohort of 3,113 patients who were treated in UKALL2003, with a median follow-up of 7 years. MRD was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements, and patients were assigned to a genetic subtype on the basis of immunophenotype, cytogenetics, and fluorescence in situ hybridization. To examine response kinetics at the end of induction, we log-transformed the absolute MRD value and examined its distribution across subgroups. Results MRD was log normally distributed at the end of induction. MRD distributions of patients with distinct genetic subtypes were different ( P < .001). Patients with good-risk cytogenetics demonstrated the fastest disease clearance, whereas patients with high-risk genetics and T-cell acute lymphoblastic leukemia responded more slowly. The risk of relapse was correlated with MRD kinetics, and each log reduction in disease level reduced the risk by 20% (hazard ratio, 0.80; 95% CI, 0.77 to 0.83; P < .001). Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype. Integration of genetic subtype-specific MRD values allowed more refined risk group stratification. Conclusion A single threshold for assigning patients to an MRD risk group does not reflect the response kinetics of the different genetic subtypes. Future risk algorithms should integrate genetics with MRD to accurately identify patients with the lowest and highest risk of relapse.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasia Residual/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Niño , Preescolar , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Genotipo , Humanos , Hibridación Fluorescente in Situ , Masculino , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Evaluación de Resultado en la Atención de Salud/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inducción de RemisiónAsunto(s)
Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/secundario , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adolescente , Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquídeo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Recurrencia , Adulto JovenRESUMEN
Purpose Our aim was to determine the role of end-of-induction (EOI) minimal residual disease (MRD) assessment in the identification and stratification of induction failure in patients with pediatric acute lymphoblastic leukemia (ALL) and to identify genetic abnormalities that drive disease in these patients. Patients and Methods Analysis included 3,113 patients who were treated in the Medical Research Council UKALL2003 multicenter randomized trial (NCT00222612) between 2003 and 2011. MRD was measured by using standardized real-time quantitative PCR. Median follow-up was 5 years 9 months. Results Fifty-nine patients (1.9%) had morphologic induction failure with 5-year event-free survival (EFS) of 50.7% (95% CI, 37.4 to 64.0) and 5-year overall survival of 57.7% (95% CI, 44.2 to 71.2). Of these, a small proportion of patients with M2 marrow (6 of 44) and a low EOI MRD level (< 0.01%) had 5-year EFS of 100%. Conversely, among patients with morphologic remission 2.3% (61 of 2,633) had high MRD (≥ 5%) and 5-year EFS of 47.0% (95% CI, 32.9 to 61.1), which was similar to those with morphologic induction failure. Redefining induction failure to include morphologic induction failure and/or MRD ≥ 5% identified 3.9% (120 of 3,133 patients) of the trial cohort with 5-year EFS of 48.0% (95% CI, 39.3 to 58.6). Induction failure (morphologic or MRD ≥ 5%) occurred most frequently in T-ALL (10.1%; 39 of 386 T-ALL cases) and B-other ALL, that is, lacking established chromosomal abnormalities (5.6%; 43 of 772 B-other cases). Genetic testing within the B-other group revealed the presence of PDGFRB gene fusions, particularly EBF1-PDGFRB, in almost one third of B-other ALL cases. Conclusion Integration of EOI MRD level with morphology identifies induction failure more precisely than morphology alone. Prevalence of EBF1-PDGFRB fusions in this group highlights the importance of genetic screening to identify abnormalities that may be targets for novel agents.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adolescente , Médula Ósea/patología , Niño , Femenino , Humanos , Masculino , Estudios Multicéntricos como Asunto , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Reacción en Cadena en Tiempo Real de la Polimerasa , Inducción de Remisión , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Minimal residual disease (MRD) is defined as the presence of sub-microscopic levels of leukaemia. Measurement of MRD from bone marrow at the end of induction chemotherapy (day 28) for childhood acute lymphoblastic leukaemia (ALL) can highlight a large group of patients (>40%) with an excellent (>90%) short-term event-free survival (EFS). However, follow-up in recent published trials is relatively short, raising concerns about using this result to infer the safety of further therapy reduction in the future. METHODS: We examined MRD data on 225 patients treated on one of three UKALL trials between 1997 and 2003 to assess the long-term (>10â years follow-up) outcome of those patients who had low-risk MRD (<0.01%) at day 28. RESULTS: Our pilot data define a cohort of 53% of children with MRD <0.01% at day 28 who have an EFS of 91% and long-term overall survival of 97%. Of 120 patients with day-28 MRD <0.01% and extended follow-up, there was one death due to treatment-related toxicity, one infectious death while in complete remission, and four relapse deaths. CONCLUSIONS: The excellent outcome for childhood ALL in patients with MRD <0.01% after induction chemotherapy is sustained for more than 10â years from diagnosis. This supports the potential exploration of further reduction of therapy in this group, in an attempt to reduce treatment-related mortality and late effects.