RESUMO
Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomized 852 older adults (median age, 68-years) with AML/high-risk myelodysplasia to GO on day 1 (GO1) or on days 1 and 4 (GO2) of course 1 induction. The median follow-up period was 50.2 months. Although complete remission (CR) rates after course 1 did not significantly differ between arms (GO2, 63%; GO1, 57%; odds ratio [OR], 0.78; P = .08), there were significantly more patients who achieved CR with a measurable residual disease (MRD)<0.1% (50% vs 41%; OR, 0.72; P = .027). This differential MRD reduction with GO2 varied across molecular subtypes, being greatest for IDH mutations. The 5-year overall survival (OS) was 29% for patients in the GO2 arm and 24% for those in the GO1 arm (hazard ratio [HR], 0.89; P = .14). In a sensitivity analysis excluding patients found to have adverse cytogenetics or TP53 mutations, the 5-year OS was 33% for GO2 and 26% for GO1 (HR, 0.83; P = .045). In total, 228 (27%) patients received an allogeneic transplantation in first remission. Posttransplant OS was superior in the GO2 arm (HR, 0.67; P = .033); furthermore, the survival advantage from GO2 in the sensitivity analysis was lost when data of patients were censored at transplantation. In conclusion, GO2 was associated with a greater reduction in MRD and improved survival in older adults with nonadverse risk genetics. This benefit from GO2 was dependent on allogeneic transplantation to translate the better leukemia clearance into improved survival. This trial was registered at www.isrctn.com as #ISRCTN 31682779.
Assuntos
Daunorrubicina , Leucemia Mieloide Aguda , Humanos , Idoso , Gemtuzumab/uso terapêutico , Anticorpos Monoclonais Humanizados , Citarabina , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Reino Unido , Aminoglicosídeos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Improving outcomes for older patients with acute myeloid leukaemia remains an unmet need. As part of the LI-1 trial, we evaluated lenalidomide (LEN) in combination with low-dose cytosine arabinoside (LDAC) in patients aged >60 years unfit for intensive therapy and compared this to LDAC alone. Two hundred and two patients, randomised 1:1, were evaluable. Overall response rate (CR + CRi) was higher for LDAC + LEN versus LDAC (26% and 13.7% respectively p = 0.031). However, there was no difference in overall survival between the arms (14% and 11.5% at 2 years for LDAC + LEN and LDAC respectively). The addition of LEN was associated with increased toxicity and supportive care requirements.
Assuntos
Citarabina , Leucemia Mieloide Aguda , Humanos , Idoso , Lenalidomida/uso terapêutico , Indução de Remissão , Leucemia Mieloide Aguda/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Prolonged cytopenia after CAR-T cell therapy is an acknowledged problem. At present, the causes and implications of prolonged cytopenia are unclear. The paper by Kitamura et al identified that prolonged cytopenia is associated with alterations in the bone marrow niche identified before CAR-T therapy, indicating a potential predictor of this serious side-effect of treatment. Commentary on: Kitamura et al. Bone marrow microenvironment disruption and sustained inflammation with prolonged haematologic toxicity after CAR T-cell therapy? Br J Haematol 2023;202:294-307.
Assuntos
Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , InflamaçãoRESUMO
The paper by Noor et al. in this issue provides important and interesting data on the incidence and outcomes of patients with acute myeloid leukaemia in Afghanistan. The age of patients is much lower than we are used to seeing in the West, reflecting in part the particular demographics of the country; these data provide an important first step to identifying areas for improvement. Commentary on: Noor et al. Demographic and clinical characteristics of acute myeloid leukaemia diagnosed and treated at tertiary level in Afghanistan. Br J Haematol 2023;203:404-410.
RESUMO
Secondary acute myeloid leukaemia (AML) has a poor outcome following "3 + 7-like" chemotherapy. While CPX-351 has been approved for patients aged 60-75, the optimal treatment, or comparator, in younger patients is less clear. The MRC AML15 trial randomised younger patients between daunorubicin and ara-C (DA) and DA plus etoposide (ADE) and ADE and fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor (FLAG-Ida) induction. Overall results failed to show an overall survival benefit for FLAG-Ida despite a reduction in relapse, the outcome of patients <60 years with secondary AML compared to DA/ADE was not reported. In this group (n = 115) response to induction was not different [complete remission/complete remission with incomplete haematological response 81% vs. 79%), however, 5-year overall survival and relapse free survival was superior for FLAG-Ida [37% vs. 27%, stratified hazard ratio (HR) 0·45 (0·33-0·90) P = 0·02 and 41% vs. 22%; stratified HR 0·54 (0·31-0·96) P = 0·04] respectively, suggesting that younger patients with secondary AML may benefit from treatment intensification and that "3 + 7" may not be the optimal comparator in trials for this group of patients.
Assuntos
Idarubicina , Leucemia Mieloide Aguda , Segunda Neoplasia Primária , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina , Seguimentos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Idarubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Segunda Neoplasia Primária/tratamento farmacológico , Indução de Remissão , VidarabinaRESUMO
Although we earlier reported a very poor outcome for younger adult patients with isocitrate dehydrogenase 2 (IDH2)R172 -mutated acute myeloid leukaemia (AML) entered into UK trials compared to IDH2WT and IDH2R140 -mutated patients, this was not corroborated by a study from the German-Austrian AML Study Group. We have therefore investigated a later cohort of IDH2-mutated patients to identify any changes in outcome and whether this could inform the optimal treatment for IDH2R172 AML. We found an improved outcome for IDH2R172 -mutated AML in the later trials and the data suggests that this may be due to the increased use of allogeneic transplantation to consolidate first remission.
Assuntos
Isocitrato Desidrogenase , Leucemia Mieloide Aguda , Adulto , Estudos de Coortes , Humanos , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , PrognósticoRESUMO
The prognosis for younger patients with relapsed acute myeloid leukaemia (AML) is generally dismal. Allogeneic stem cell transplantation is the preferred therapy for these patients. As part of the UK NCRI AML17 trial, daunorubicin/clofarabine (DClo) was compared with fludarabine, cytarabine, granulocyte colony-stimulating factor with idarubicin (FLAG-Ida) in 311 patients designated high-risk following course one of induction therapy, which has previously been reported. We now report the results of the same randomisation in patients who were refractory to two induction courses or subsequently relapsed. A total of 94 relapsed or refractory AML patients, usually less than 60 years of age and with mainly favourable or intermediate-risk cytogenetics, were randomised to receive up to three courses of DClo or FLAG-Ida, with the aim of proceeding to transplant. Complete remission was achieved in 74% of patients with no difference between the arms. Overall, 57% of patients received a transplant with no difference between the arms, likewise overall survival at five years showed no significant difference (21% for DClo vs. 22% for FLAG-Ida). No patient who did not receive a transplant survived beyond 21months. A stratified analysis including the 311 post course 1 high-risk patients who underwent the same randomisation showed a consistent treatment benefit for FLAG-Ida.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Clofarabina , Idarubicina , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença Crônica , Clofarabina/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Idarubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Reino Unido , Vidarabina/efeitos adversosRESUMO
Relapse remains the most common cause of treatment failure for patients with acute myeloid leukemia (AML) who undergo allogeneic stem cell transplantation (alloSCT), and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry before alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays, which have far greater sensitivity. We analyzed pretransplant blood and bone marrow samples by reverse-transcription polymerase chain reaction in 107 patients with NPM1-mutant AML enrolled in the UK National Cancer Research Institute AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies per 105ABL in the peripheral blood and <1000 copies in the bone marrow aspirate), and high levels of MRD had an estimated 2-year overall survival (2y-OS) of 83%, 63%, and 13%, respectively (P < .0001). Focusing on patients with low-level MRD before alloSCT, those with FLT3 internal tandem duplications(ITDs) had significantly poorer outcome (hazard ratio [HR], 6.14; P = .01). Combining these variables was highly prognostic, dividing patients into 2 groups with 2y-OS of 17% and 82% (HR, 13.2; P < .0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y-OS, 56% vs 96%; HR, 3.24; P = .0005) and in MRD-positive patients (2y-OS, 34% vs 100%; HR, 3.78; P = .003), but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).
Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Neoplasia Residual , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Nucleofosmina , Recidiva , Adulto JovemRESUMO
Reduced intensity conditioning (RIC) transplantation is increasingly offered to older patients with acute myeloblastic leukemia. We have previously shown that a RIC allograft, particularly from a sibling donor, is beneficial in intermediate-risk patients aged 35-65 years. We here present analyses from the NCRI AML16 trial extending this experience to older patients aged 60-70 inclusive lacking favorable-risk cytogenetics. Nine hundred thirty-two patients were studied, with RIC transplant in first remission given to 144 (sibling n=52, matched unrelated donor n=92) with a median follow-up for survival from complete remission of 60 months. Comparisons of outcomes of patients transplanted versus those not were carried out using Mantel-Byar analysis. Among the 144 allografted patients, 93 had intermediate-risk cytogenetics, 18 had adverse risk and cytogenetic risk group was unknown for 33. In transplanted patients survival was 37% at 5 years, and while the survival for recipients of grafts from siblings (44%) was better than that for recipients of grafts from matched unrelated donors (34%), this difference was not statistically significant (P=0.2). When comparing RIC versus chemotherapy, survival of patients treated with the former was significantly improved (37% versus 20%, hazard ratio = 0.67 [0.53-0.84]; P<0.001). When stratified by Wheatley risk group into good, standard and poor risk there was consistent benefit for RIC across risk groups. When stratified by minimal residual disease status after course 1, there was consistent benefit for allografting. The benefit for RIC was seen in patients with a FLT3 ITD or NPM1 mutation with no evidence of a differential effect by genotype. We conclude that RIC transplantation is an attractive option for older patients with acute myeloblastic leukemia lacking favorable-risk cytogenetics and, in this study, we could not find a group that did not benefit.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Condicionamento Pré-Transplante/métodosRESUMO
Older patients with acute myeloid leukaemia (AML) account for nearly half of those with the disease. Because they are perceived to be unfit for, unwilling to receive, or unlikely to benefit from conventional chemotherapy they represent an important unmet need. Tosedostat is a selective oral aminopeptidase inhibitor, which in phase I/II trials showed acceptable toxicity and encouraging efficacy. We report the only randomised study of low-dose cytosine arabinoside (LDAC) combined with tosedostat (LDAC-T) versus LDAC in untreated older patients not suitable for intensive treatment. A total of 243 patients were randomised 1:1 as part of the 'Pick-a-Winner' LI-1 trial. There was a statistically non-significant increase in the complete remission (CR) rate with the addition of tosedostat, LDAC-T 19% versus LDAC 12% [odds ratio (OR) 0·61, 95% confidence interval (CI) 0·30-1·23; P = 0·17]. For overall response (CR+CR with incomplete recovery of counts), there was little evidence of a benefit to the addition of tosedostat (25% vs. 18%; OR 0·68, 95% CI 0·37-1·27; P = 0·22). However, overall survival (OS) showed no difference (2-year OS 16% vs. 12%, hazard ratio 0·97, 95% CI 0·73-1·28; P = 0·8). Exploratory analyses failed to identify any subgroup benefitting from tosedostat. Despite promising pre-clinical, early non-randomised clinical data with acceptable toxicity and an improvement in response, we did not find evidence that the addition of tosedostat to LDAC produced a survival benefit in this group of patients with AML. International Standard Randomised Controlled Trial Number: ISRCTN40571019.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Glicina/análogos & derivados , Ácidos Hidroxâmicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/uso terapêutico , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
In acute myeloid leukaemia (AML) t(8;16)(p11;p13)/MYST3-CREBBP is a very rare abnormality. Previous small series suggested poor outcome. We report on 59 patients with t(8;16) within an international, collaborative study. Median age was 52 (range: 16-75) years. AML was de novo in 58%, therapy-related (t-AML) in 37% and secondary after myelodysplastic syndrome (s-AML) in 5%. Cytogenetics revealed a complex karyotype in 43%. Besides MYST3-CREBBP, whole-genome sequencing on a subset of 10 patients revealed recurrent mutations in ASXL1, BRD3, FLT3, MLH1, POLG, TP53, SAMD4B (n = 3, each), EYS, KRTAP9-1 SPTBN5 (n = 4, each), RUNX1 and TET2 (n = 2, each). Complete remission after intensive chemotherapy was achieved in 84%. Median follow-up was 5·48 years; five-year survival rate was 17%. Patients with s-/t-AML (P = 0·01) and those with complex karyotype (P = 0·04) had an inferior prognosis. Allogeneic haematopoietic cell transplantation (allo-HCT) was performed in 21 (36%) patients, including 15 in first complete remission (CR1). Allo-HCT in CR1 significantly improved survival (P = 0·04); multivariable analysis revealed that allo-HCT in CR1 was effective in de novo AML but not in patients with s-AML/t-AML and less in patients exhibiting a complex karyotype. In summary, outcomes of patients with t(8;16) are dismal with chemotherapy, and may be substantially improved with allo-HCT performed in CR1.
Assuntos
Cromossomos Humanos Par 16/ultraestrutura , Cromossomos Humanos Par 8/ultraestrutura , Leucemia Mieloide Aguda/genética , Translocação Genética , Cariótipo Anormal , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Quimioterapia de Consolidação , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Cooperação Internacional , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/epidemiologia , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/epidemiologia , Proteínas de Fusão Oncogênica/genética , Indução de Remissão , Análise de Sobrevida , Sequenciamento Completo do GenomaRESUMO
Cohesin complex disruption alters gene expression, and cohesin mutations are common in myeloid neoplasia, suggesting a critical role in hematopoiesis. Here, we explore cohesin dynamics and regulation of hematopoietic stem cell homeostasis and differentiation. Cohesin binding increases at active regulatory elements only during erythroid differentiation. Prior binding of the repressive Ets transcription factor Etv6 predicts cohesin binding at these elements and Etv6 interacts with cohesin at chromatin. Depletion of cohesin severely impairs erythroid differentiation, particularly at Etv6-prebound loci, but augments self-renewal programs. Together with corroborative findings in acute myeloid leukemia and myelodysplastic syndrome patient samples, these data suggest cohesin-mediated alleviation of Etv6 repression is required for dynamic expression at critical erythroid genes during differentiation and how this may be perturbed in myeloid malignancies.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Regulação Leucêmica da Expressão Gênica , Mutação , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Biomarcadores Tumorais , Linhagem Celular Tumoral , Feminino , Dosagem de Genes , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Histonas/metabolismo , Humanos , Masculino , Transtornos Mieloproliferativos/diagnóstico , Gradação de Tumores , Ligação Proteica , Proteínas Proto-Oncogênicas c-ets/metabolismo , Sequências Reguladoras de Ácido Nucleico , Proteínas Repressoras/metabolismo , Coesinas , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Acute myeloid leukemia with t(8;21)(q22;q22) is characterized by considerable clinical and biological heterogeneity leading to relapse in up to 40% of patients. We sequenced coding regions or hotspot areas of 66 recurrently mutated genes in a cohort of 331 t(8;21) patients. At least 1 mutation, in addition to t(8;21), was identified in 95%, with a mean of 2.2 driver mutations per patient. Recurrent mutations occurred in genes related to RAS/RTK signaling (63.4%), epigenetic regulators (45%), cohesin complex (13.6%), MYC signaling (10.3%), and the spliceosome (7.9%). Our study identified mutations in previously unappreciated genes: GIGYF2, DHX15, and G2E3 Based on high mutant levels, pairwise precedence, and stability at relapse, epigenetic regulator mutations were likely to occur before signaling mutations. In 34% of RAS/RTKmutated patients, we identified multiple mutations in the same pathway. Deep sequencing (â¼42 000×) of 126 mutations in 62 complete remission samples from 56 patients identified 16 persisting mutations in 12 patients, of whom 5 lacked RUNX1-RUNX1T1 in quantitative polymerase chain reaction analysis. KIT high mutations defined by a mutant level ≥25% were associated with inferior relapse-free survival (hazard ratio, 1.96; 95% confidence interval, 1.22-3.15; P = .005). Together with age and white blood cell counts, JAK2, FLT3-internal tandem duplicationhigh, and KIT high mutations were identified as significant prognostic factors for overall survival in multivariate analysis. Whole-exome sequencing was performed on 19 paired diagnosis, remission, and relapse trios. Exome-wide analysis showed an average of 16 mutations with signs of substantial clonal evolution. Based on the resemblance of diagnosis and relapse pairs, genetically stable (n = 13) and unstable (n = 6) subgroups could be identified.
Assuntos
Evolução Clonal , Leucemia Mieloide Aguda/genética , Mutação , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Análise Mutacional de DNA , Feminino , GTP Fosfo-Hidrolases/genética , Genômica , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Indução de Remissão , Transdução de Sinais , Adulto JovemRESUMO
Despite recent advances in therapies including immunotherapy, patients with acute myeloid leukaemia (AML) still experience relatively poor survival rates. The Inhibition of Apoptosis (IAP) family member, survivin, also known by its gene and protein name, Baculoviral IAP Repeat Containing 5 (BIRC5), remains one of the most frequently expressed antigens across AML subtypes. To better understand its potential to act as a target for immunotherapy and a biomarker for AML survival, we examined the protein and pathways that BIRC5 interacts with using the Kyoto Encyclopedia of Genes and Genomes (KEGG), search tool for recurring instances of neighbouring genes (STRING), WEB-based Gene Set Analysis Toolkit, Bloodspot and performed a comprehensive literature review. We then analysed data from gene expression studies. These included 312 AML samples in the Microarray Innovations In Leukemia (MILE) dataset. We found a trend between above median levels of BIRC5 being associated with improved overall survival (OS) but this did not reach statistical significance (p = 0.077, Log-Rank). There was some evidence of a beneficial effect in adjusted analyses where above median levels of BIRC5 were shown to be associated with improved OS (p = 0.001) including in Core Binding Factor (CBF) patients (p = 0.03). Above median levels of BIRC5 transcript were associated with improved relapse free survival (p < 0.0001). Utilisation of a second large cDNA microarray dataset including 306 AML cases, again showed no correlation between BIRC5 levels and OS, but high expression levels of BIRC5 correlated with worse survival in inv(16) patients (p = 0.077) which was highly significant when datasets A and B were combined (p = 0.001). In addition, decreased BIRC5 expression was associated with better clinical outcome (p = 0.004) in AML patients exhibiting CBF mainly due to patients with inv(16) (p = 0.007). This study has shown that BIRC5 expression plays a role in the survival of AML patients, this association is not apparent when we examine CBF patients as a cohort, but when those with inv(16) independently indicating that those patients with inv(16) would provide interesting candidates for immunotherapies that target BIRC5.
Assuntos
Bases de Dados de Ácidos Nucleicos , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Proteínas de Neoplasias/biossíntese , Survivina/biossíntese , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Proteínas de Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos , Taxa de Sobrevida , Survivina/genéticaRESUMO
Since the launch of their first trial in Acute myeloid leukaemia (AML) in 1959, the Medical Research Council (and latterly National Cancer Research Institute) has conducted randomised trials in AML uninterrupted for six decades. These sixty years have seen a transformation in the way we diagnose, characterise and treat the disease, (and indeed a sea change in clinical trial regulations) and a continuing improvement in outcomes. The increasing refinement of diagnosis, leading to the advent of tailored therapies, and the use of disease monitoring both have the potential to improve outcomes further, but the associated complexities will require an evolution in our approach to trial design. This article looks at the extent to which the guiding principles of the first AML trials remain relevant today, and the challenges facing the next generation of trials methodologists.
Assuntos
Leucemia Mieloide Aguda/história , Leucemia Mieloide Aguda/terapia , Feminino , História do Século XX , História do Século XXI , Humanos , Masculino , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Reino UnidoRESUMO
Although an NPM1 mutation is generally considered to be a good prognostic marker in acute myeloid leukaemia, it has recently been suggested that a higher level of NPM1 mutant (NPM1MUT ) alleles relative to wild-type alleles is associated with poor clinical outcome. We therefore sought to confirm this finding in a larger study of 876 NPM1MUT cases entered into UK national trials. In univariate analysis, the higher NPM1MUT allele burden was associated with a lower complete remission (CR) rate, higher relapse rate and reduced overall survival, but this was largely attributable to the association of the higher NPM1MUT allele burden with other known poor risk factors, particularly the presence of a concomitant FLT3 internal tandem duplication. In multivariate analysis, there was no significant impact of the NPM1MUT allele burden on CR rates, and the impact on relapse and overall survival, whilst still significant, was greatly reduced. This impact was similar in patients who did or did not receive an allogeneic transplant in first CR. We conclude that the binary presence or absence of an NPM1 mutation, combined with minimal residual disease levels following induction therapy, should continue to be used in therapeutic management rather than stratification according to the NPM1MUT level.
Assuntos
Leucemia Mieloide Aguda/genética , Proteínas Nucleares/metabolismo , Adolescente , Adulto , Alelos , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Nucleofosmina , Prognóstico , Resultado do Tratamento , Adulto JovemRESUMO
Chronic lymphocytic leukaemia (CLL) patients often have abnormal expansions of CD4+ and CD8+ T cells and this can be associated with progressive disease. To characterise the key T-cell populations involved in this phenomenon, we used flow cytometry and 11 phenotypic markers to study 74 CLL patients and 14 controls. T cells of CLL patients were more phenotypically complex than those of healthy controls with significant increases in the frequencies of CD4 and CD8 memory T cells expressing exhaustion-, activation- and senescence-associated markers. Multivariate analysis of 111 different T-cell subsets showed that high frequencies of four subsets (three CD8 and one CD4) were associated with shorter progression-free survival. The most significant association was with CD4+ HLA-DR+ PD-1+ T cells, and patients could be stratified into high- and low-risk groups based on the frequency of these T cells. The expansion of this CD4+ subset could not be accounted for by age, cytomegalovirus infection or increases in Treg cells. Overall, these results highlight two relatively simple biomarkers, percentage CD8+ and percentage CD4+ PD-1+ HLA-DR+ T cells, which can be used to risk-stratify CLL patients, independent of other tumour-associated markers. They also provide further evidence for the pivotal role of T cells in modulating the pathology of CLL.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Antígenos HLA-DR/metabolismo , Leucemia Linfocítica Crônica de Células B/genética , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Minimal residual disease (MRD) in acute myeloid leukaemia (AML) poses a major challenge due to drug insensitivity and high risk of relapse. Intensification of chemotherapy and stem cell transplantation are often pivoted on MRD status. Relapse rates are high even with the integration of first-generation FMS-like tyrosine kinase 3 (FLT3) inhibitors in pre- and post-transplant regimes and as maintenance in FLT3-mutated AML. Pre-clinical progress is hampered by the lack of suitable modelling of residual disease and post-therapy relapse. In the present study, we investigated the nature of pro-survival signalling in primary residual tyrosine kinase inhibitor (TKI)-treated AML cells adherent to stroma and further determined their drug sensitivity in order to inform rational future therapy combinations. Using a primary human leukaemia-human stroma model to mimic the cell-cell interactions occurring in patients, the ability of several TKIs in clinical use, to abrogate stroma-driven leukaemic signalling was determined, and a synergistic combination with a mitogen-activated protein kinase (MEK) inhibitor identified for potential therapeutic application in the MRD setting. The findings reveal a common mechanism of stroma-mediated resistance that may be independent of mutational status but can be targeted through rational drug design, to eradicate MRD and reduce treatment-related toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Leucemia Mieloide Aguda , Modelos Biológicos , Tirosina Quinase 3 Semelhante a fms , Adolescente , Adulto , Idoso , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Adesão Celular/efeitos dos fármacos , Criança , Pré-Escolar , MAP Quinases Reguladas por Sinal Extracelular , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
A hallmark of acute promyelocytic leukemia (APL) is altered nuclear architecture, with disruption of promyelocytic leukemia (PML) nuclear bodies (NBs) mediated by the PML-retinoic acid receptor α (RARα) oncoprotein. To address whether this phenomenon plays a role in disease pathogenesis, we generated a knock-in mouse model with NB disruption mediated by 2 point mutations (C62A/C65A) in the Pml RING domain. Although no leukemias developed in PmlC62A/C65A mice, these transgenic mice also expressing RARα linked to a dimerization domain (p50-RARα model) exhibited a doubling in the rate of leukemia, with a reduced latency period. Additionally, we found that response to targeted therapy with all-trans retinoic acid in vivo was dependent on NB integrity. PML-RARα is recognized to be insufficient for development of APL, requiring acquisition of cooperating mutations. We therefore investigated whether NB disruption might be mutagenic. Compared with wild-type cells, primary PmlC62A/C65A cells exhibited increased sister-chromatid exchange and chromosome abnormalities. Moreover, functional assays showed impaired homologous recombination (HR) and nonhomologous end-joining (NHEJ) repair pathways, with defective localization of Brca1 and Rad51 to sites of DNA damage. These data directly demonstrate that Pml NBs are critical for DNA damage responses, and suggest that Pml NB disruption is a central contributor to APL pathogenesis.