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The European LeukemiaNet (ELN) genetic risk classifications were developed based on data from younger adults receiving intensive chemotherapy. Emerging analyses from patients receiving less-intensive therapies prompted a proposal for an ELN genetic risk classification specifically for this patient population.
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INTRODUCTION: For the majority of patients with acute myeloid leukemia (AML) an allogeneic stem cell transplant (SCT) in first complete remission (CR) is preferred. However, whether the number of courses required to achieve CR has a prognostic impact is unclear. It is unknown which factors remain important in patients requiring more than one course of induction to attain remission. METHODS: This Acute Leukaemia Working Party study from the European Society for Blood and Marrow Transplantation identified adults who received an allograft in first CR from either a fully matched sibling or 10/10 or 9/10 human leucocyte antigen (HLA)-matched unrelated donor (HLA-A, HLA-B, HLA-C, HLA-DR, or HLA-DQ). Univariate and multivariate analyses were undertaken to identify the prognostic impact of one or two courses of induction to attain CR. RESULTS: A total of 4995 patients were included with 3839 (77%) patients attaining a CR following one course of induction chemotherapy (IND1), and 1116 patients requiring two courses (IND2) to attain CR. IND2 as compared to IND1 was a poor prognostic factor in a univariate analysis and remained so in a multivariate Cox model, resulting in an increased hazard ratio of relapse (1.38; 95% confidence interval [CI], 1.16-1.64; p = .0003) and of death (1.27; 95% CI, 1.09-1.47; p = .002). Adverse prognostic factors in a multivariate analysis of the outcomes of patients requiring IND2 included age, FLT3-ITD, adverse cytogenetics, and performance status. Pretransplant measurable residual disease retained a prognostic impact regardless of IND1 or IND2. CONCLUSION: Initial response to chemotherapy as determined by number of courses to attain CR, retained prognostic relevance even following SCT in CR.
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Antígenos HLA , Leucemia Mieloide Aguda , Inducción de Remisión , Hermanos , Donante no Emparentado , Humanos , Masculino , Persona de Mediana Edad , Adulto , Femenino , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidad , Pronóstico , Antígenos HLA/inmunología , Adolescente , Adulto Joven , Anciano , Trasplante de Células Madre Hematopoyéticas/métodos , Quimioterapia de Inducción/métodos , Trasplante HomólogoRESUMEN
Allogeneic stem cell transplantation is a centrally important curative strategy in adults with acute myeloid leukaemia; however, relapse occurs in a significant proportion of patients and remains the leading cause of treatment failure. The prognosis for patients who relapse post-transplant remains poor, and the development of new strategies with the ability to reduce disease recurrence without increasing transplant toxicity remains a priority. In this review, within the context of our understanding of disease biology and the graft-versus-leukaemia (GVL) effect, we will discuss established, evolving and novel approaches for increasing remission rates, decreasing measurable residual disease pretransplant, future methods to augment the GVL effect and the opportunities for post-transplant maintenance. Future progress depends upon the development of innovative trials and networks, which will ensure the rapid assessment of emerging therapies in prospective clinical trials.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Trasplante Homólogo , Humanos , Leucemia Mieloide Aguda/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Recurrencia , Efecto Injerto vs Leucemia , Neoplasia ResidualRESUMEN
The 2010 and 2017 editions of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults are widely recognized among physicians and investigators. There have been major advances in our understanding of AML, including new knowledge about the molecular pathogenesis of AML, leading to an update of the disease classification, technological progress in genomic diagnostics and assessment of measurable residual disease, and the successful development of new therapeutic agents, such as FLT3, IDH1, IDH2, and BCL2 inhibitors. These advances have prompted this update that includes a revised ELN genetic risk classification, revised response criteria, and treatment recommendations.
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Antineoplásicos , Leucemia Mieloide Aguda , Adulto , Antineoplásicos/uso terapéutico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutación , Neoplasia Residual/diagnóstico , Neoplasia Residual/tratamiento farmacológico , Nucleofosmina , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/genéticaRESUMEN
Limited data exist on COVID-19 vaccination efficacy in patients with acute myeloid leukemia and myelodysplasia with excess blasts (AML/MDS-EB2). We report results from a prospective study, PACE (Patients with AML and COVID-19 Epidemiology). 93 patients provided samples post-vaccine 2 or 3 (PV2, PV3). Antibodies against SARS-COV-2 spike antigen were detectable in all samples. Neutralization of the omicron variant was poorer than ancestral variants but improved PV3. In contrast, adequate T-cell reactivity to SARS-COV-2 spike protein was seen in only 16/47 (34%) patients PV2 and 23/52 (44%) PV3. Using regression models, disease response (not in CR/Cri), and increasing age predicted poor T cell response.
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COVID-19 , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Vacunas contra la COVID-19 , Estudios Prospectivos , Linfocitos T , COVID-19/prevención & control , SARS-CoV-2 , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Vacunación , Anticuerpos AntiviralesRESUMEN
Acute myeloid leukaemia (AML) creates an immunosuppressive environment to conventional T cells through Arginase 2 (ARG2)-induced arginine depletion. We identify that AML blasts release the acute phase protein serum amyloid A (SAA), which acts in an autocrine manner to upregulate ARG2 expression and activity, and promote AML blast viability. Following in vitro cross-talk invariant natural killer T (iNKT) cells become activated, upregulate mitochondrial capacity, and release IFN-γ. iNKT retain their ability to proliferate and be activated despite the low arginine AML environment, due to the upregulation of Large Neutral Amino Acid Transporter-1 (LAT-1) and Argininosuccinate Synthetase 1 (ASS)-dependent amino acid pathways, resulting in AML cell death. T cell proliferation is restored in vitro and in vivo. The capacity of iNKT cells to restore antigen-specific T cell immunity was similarly demonstrated against myeloid-derived suppressor cells (MDSCs) in wild-type and Jα18-/- syngeneic lymphoma-bearing models in vivo. Thus, stimulation of iNKT cell activity has the potential as an immunotherapy against AML or as an adjunct to boost antigen-specific T cell immunotherapies in haematological or solid cancers.
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Leucemia Mieloide Aguda , Células Supresoras de Origen Mieloide , Células T Asesinas Naturales , Humanos , Proliferación Celular , ArgininaRESUMEN
BACKGROUND: The presence of TP53 mutations is associated with an unfavorable outcome in patients allografted for acute myeloid leukemia (AML), leading some to question the benefit of an allogeneic stem cell transplantation (allo-SCT) for this patient group, although this has not been studied in a large cohort. METHODS: A total of 780 patients with AML in first complete remission, with either intermediate- or adverse-risk cytogenetics, whose TP53 mutation status was reported, were included in this study from the European Society for Blood and Marrow Transplantation. RESULTS: Two-year overall survival (OS) was impaired in patients (n = 179) with evidence of a TP53 mutation at diagnosis (35.1%; 95% confidence interval [CI], 26.7-43.7) as compared to the cohort without (n = 601) (64%; 95% CI, 59.1-68.4; P = .001). In patients with mutant TP53 AML with no evidence of either chromosome 17p loss (17p-) and/or complex karyotype (CK) (n = 53, 29.6%), 2-year OS was 65.2% (95% CI, 48.4-77.6). This was not significantly different to patients without TP53 mutations. In patients with mutant TP53 AML with either 17p- and/or CK (n = 126, 70.4%), the OS was lower (24.6%; 95% CI, 16.2-34; P = .001). CONCLUSIONS: In summary, the adverse prognostic effect of TP53 mutations in AML following an allo-SCT is not evident in patients with neither co-occurring 17p- and/or CK, and these data inform decisions regarding allo-SCT in patients with TP53 mutant AML.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Deleción Cromosómica , Análisis Citogenético , Citogenética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Pronóstico , Estudios Retrospectivos , Trasplante Homólogo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Azacitidine (AZA) is important in the management of patients with acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. Romidepsin (ROM) is a histone deacetylase inhibitor which synergises with AZA in vitro. The ROMAZA trial established the maximum tolerated dose (MTD) of combined ROM/AZA therapy in patients with AML, as ROM 12 mg/m2 on Days 8 and 15, with AZA 75 mg/m2 administered for 7/28 day cycle. Nine of the 38 (23·7%) patients treated at the MTD were classified as responders by Cycle 6 (best response: complete remission [CR]/incomplete CR n = 7, partial response n = 2). Correlative next-generation sequencing studies demonstrated important insights into therapy resistance.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Toma de Decisiones Clínicas , Análisis Citogenético , Depsipéptidos/administración & dosificación , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Leucemia Mieloide Aguda/etiología , Masculino , Terapia Molecular Dirigida , Pronóstico , Resultado del Tratamiento , Adulto JovenRESUMEN
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).
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Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Neoplasia Residual , Proteínas Nucleares/genética , Adolescente , Adulto , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Nucleofosmina , Recurrencia , Adulto JovenRESUMEN
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.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Adulto , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodosRESUMEN
BACKGROUND: For patients with acute myeloid leukaemia (AML), the only potentially curative treatment is intensive chemotherapy (IC). This is highly toxic, particularly for patients > 60 years, potentially leading to prolonged hospitalisations requiring intensive supportive care, and sometimes treatment-related death. This also results in extensive healthcare costs and negatively impacts quality of life (QoL). Venetoclax with low-dose cytarabine (VEN + LDAC) is a novel, low-intensity treatment for AML patients who cannot receive IC. VEN + LDAC is given as an outpatient and toxicity appears significantly lower than with IC. Analysis of clinical trials performed to date are promising for patients with the genotype NPM1mutFLT3 ITDneg, where remission and survival rates appear comparable to those achieved with IC. METHODS: VICTOR is an international, two-arm, open-label, multi-centre, non-inferiority, randomised-controlled phase II trial to assess VEN + LDAC compared to standard of care (IC) as first-line treatment in older patients (initially aged ≥ 60 years) with newly diagnosed AML. The trial will recruit patients with a NPM1mutFLT3 ITDneg genotype; those with a favourable risk in relation to the experimental treatment. University of Birmingham is the UK co-ordinating centre, with national hubs in Aarhus University Hospital, Denmark, and Auckland District Health Board, New Zealand. The primary outcome is molecular event-free survival time where an event is defined as failure to achieve morphological complete response (CR) or CR with incomplete blood count recovery after two cycles of therapy; molecular persistence, progression or relapse requiring treatment change; morphological relapse, or; death. Secondary outcomes include cumulative resource use at 12- and 24-months, and QoL as assessed by EORTCQLQ-C30 and EQ-5D-3L at 3-, 6-, 12-, 18- and 24-months. The trial employs an innovative Bayesian design with target sample size of 156 patients aged > 60 years. DISCUSSION: The principle underpinning the VICTOR trial is that the chance of cure for patients in the experimental arm should not be compromised, therefore, an adaptive design with regular checks on accumulating data has been employed, which will allow for a staged expansion of the trial population to include younger patients if, and when, there is sufficient evidence of non-inferiority in older patients. TRIAL REGISTRATION: EudraCT: 2020-000,273-24; 21-Aug-2020. ISRCTN: 15,567,173; 08-Dec-2020.
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Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Adulto , Anciano , Citarabina , Calidad de Vida , Teorema de Bayes , Nivel de Atención , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Antineoplásicos/uso terapéutico , Proteínas Nucleares , Ensayos Clínicos Fase II como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutational status is a pivotal prognosticator in acute myeloid leukemia (AML) patients and significantly increases the risk of disease relapse. However, it remains unclear whether in FLT3-ITD patients referred for allogeneic stem cell transplantation (allo-SCT), baseline cytogenetics significantly impacts clinical outcome. Using the European Society of Blood and Marrow Transplantation registry, we performed a retrospective analysis of 1631 FLT3-ITD AML patients who underwent allo-SCT with the aim of determining the influence of cytogenetic risk category on patient outcomes. Median patient age was 49 years and median follow-up duration was 36 months. Two-year leukemia-free survival (LFS) and incidence of relapse were 54% and 31.6%, respectively. Non-relapse mortality was experienced by 14.4% with a 2-year overall survival (OS) of 60.1%. On multivariate analysis, LFS was significantly lower in patients with intermediate and adverse risk cytogenetics compared with those with favorable risk cytogenetics, (hazard ratio [HR] = 1.48, 95% confidence interval [CI], 1.06-2.06; p = .02), and (HR = 01.65, 95% CI, 1.13-2.40; p = .009), respectively. OS was significantly lower in patients with adverse risk cytogenetics compared with patients with favorable risk cytogenetics (HR = 1.74, 95% CI, 1.16-2.61; p = .008) with a trend toward lower OS in patients with intermediate risk cytogenetics compared to those with favorable risk cytogenetics (HR = 1.43, 95% CI, 1.00-2.05; p = .052). In addition, adverse risk patients and intermediate risk patients experienced higher relapse rates compared with favorable risk patients (HR = 1.83, 95% CI, 1.13-2.94; p = .013 and HR = 1.82, 95% CI, 1.19-2.77; p = .005). Overall, cytogenetic studies aid in refinement of risk stratification in transplanted FLT3-ITD AML patients.
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Análisis Citogenético , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Mutación , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Tasa de SupervivenciaRESUMEN
Outcomes in acute myeloid leukaemia have improved steadily over the last six decades thanks to advances in disease classification, risk stratification and the advent of new drug and transplant therapies. Over this period the UK has made a major contribution to this international effort, both through its delivery of large prospective randomised trials with integrated genomic and measurable residual disease assessments and its pioneering role in the development of allogeneic stem cell transplantation as a potent anti-leukaemic therapy.
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Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/terapia , Ensayos Clínicos como Asunto , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Manejo de la Enfermedad , Humanos , Evaluación de Resultado en la Atención de Salud , Reino Unido/epidemiologíaRESUMEN
Bone marrow transplantation (BMT) has evolved over the last 60 years from a pioneering treatment fraught with unknown factors and complications to a widely practiced standard of care that has saved the lives of countless individuals with malignant and non-malignant conditions. Over this period, transplanters in the UK have made a significant international contribution to the field through cutting edge clinical and laboratory research. Today, stem cell transplantation in the UK continues to advance through rigorous and innovative clinical trials which focus on improving outcome by reducing transplant toxicity and the risk of disease relapse. In this review, we start with a personal view of the early years of BMT in the UK, document the many seminal accomplishments in the field of BMT which took place in the UK, and end with a look towards the future of BMT, in the UK and worldwide.
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Trasplante de Médula Ósea , Trasplante de Células Madre Hematopoyéticas , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/historia , Trasplante de Médula Ósea/métodos , Ensayos Clínicos como Asunto , Trasplante de Células Madre Hematopoyéticas/historia , Trasplante de Células Madre Hematopoyéticas/métodos , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Evaluación de Resultado en la Atención de Salud , Trasplante Autólogo , Trasplante Homólogo , Reino UnidoRESUMEN
Acute myeloid leukaemia (AML) is the commonest indication for allogeneic stem cell transplantation (allo-SCT) worldwide. The accumulated experience of allografting in AML over the last four decades has provided critical insights into both the contribution of the conditioning regimen and the graft-versus-leukaemia effect to the curative potential of the most common form of immunotherapy utilised in standard clinical practice. Coupled with advances in donor availability and transplant technologies, this has resulted in allo-SCT becoming an important treatment modality for the majority of adults with high-risk AML. At the same time, advances in genomic classification, coupled with progress in the accurate quantification of measurable residual disease, have increased the precision with which allo-mandatory patients can be identified, whilst simultaneously permitting accurate identification of those patients who can be spared the toxicity of an allograft. Despite this progress, disease recurrence still remains a major cause of transplant failure and AML has served as a paradigm for the development of strategies to reduce the risk of relapse - notably the novel concept of post-transplant maintenance, utilising pharmacological or cellular therapies.
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Leucemia Mieloide Aguda/terapia , Trasplante de Células Madre , Adulto , Aloinjertos , Humanos , Leucemia Mieloide Aguda/mortalidad , Neoplasia ResidualRESUMEN
T-cell depletion with alemtuzumab represents an effective form of graft-versus-host disease (GVHD) prophylaxis after allogeneic haematopoietic stem cell transplantation (allo-HSCT); however, little is known regarding the impact of in vivo alemtuzumab on either the incidence or clinical characteristics of acute and chronic GVHD. We therefore studied 201 consecutive adult patients who received an alemtuzumab-based, reduced-intensity conditioned (RIC) allograft. With a median follow-up of 24 months, the cumulative incidence of classic acute and late acute (persistent, recurrent and late onset) GVHD grades II-IV (grades III-IV) was 34% (13%) and 20% (8%) respectively; the cumulative incidence of classic chronic GVHD and overlap syndrome were 4% and 7% respectively. A previous diagnosis of classic acute GVHD is a risk factor for chronic GVHD (hazard ratio 10·91, 95% confidence interval 2·35-50·63, P = 0·0023) while late onset acute GVHD is not a risk factor for later development of chronic GVHD. Unrelated donor transplant is a risk factor for the development of classic acute GVHD but not for late onset or chronic GVHD. In conclusion, this study describes a distinctive pattern of GVHD following alemtuzumab-RIC allografts, identifies the risk factors for GVHD development and provides prognostic information of patients with GVHD.
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Alemtuzumab/administración & dosificación , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Enfermedad Aguda , Adolescente , Adulto , Anciano , Aloinjertos , Enfermedad Crónica , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/terapia , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Especificidad de Órganos , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Donante no EmparentadoRESUMEN
Core binding factor acute myeloid leukemia (AML) comprises two subtypes with distinct cytogenetic abnormalities of either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22). Since long-term response to chemotherapy in these leukemias is relatively good, allogeneic hematopoietic stem cell transplantation is considered in patients who relapse and achieve second complete remission. To evaluate the outcomes of allogeneic transplantation in this indication, we studied 631 patients reported to the European Society for Blood and Marrow Transplantation Registry between the years 2000 and 2014. Leukemia-free survival probabilities at two and five years were 59.1% and 54.1%, while overall survival probabilities were 65% and 58.2%, respectively. The incidence of relapse and risk of non-relapse mortality at the same time points were 19.8% and 22.5% for relapse and 20.9% and 23.3% for non-relapse mortality, respectively. The most important adverse factors influencing leukemia-free and overall survival were: leukemia with t(8;21), presence of three or more additional chromosomal abnormalities, and Karnofsky performance score <80. Relapse risk was increased in t(8;21) leukemia and associated with additional cytogenetic abnormalities as well as reduced intensity conditioning. Measurable residual disease in molecular evaluation before transplantation was associated with increased risk of relapse and inferior leukemia-free survival.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Médula Ósea , Factores de Unión al Sitio Principal/genética , Enfermedad Injerto contra Huésped/etiología , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Inducción de Remisión , Estudios Retrospectivos , Acondicionamiento PretrasplanteRESUMEN
Monosomy 7 or deletion 7q (-7/7q-) is the most frequent adverse cytogenetic features reported in acute myeloid leukemia (AML), and is a common indication for allogeneic stem cell transplantation (SCT). Nevertheless, -7/7q- occurs frequently with other high-risk cytogenetic abnormalities such as complex karyotype (CK), monosomal karyotype (MK), monosomy 5 or deletion 5q (-5/5q-), 17p abnormalities (abn(17p)) or inversion of chromosome 3 (inv(3)), the presence of which may influence the outcomes after SCT. A total of 1109 patients were allocated to this study. Two-year probability of leukemia-free survival (LFS) and overall survival (OS) were 30% and 36%, respectively. Two-year probability of non-relapse mortality (NRM) was 20%. We defined five different cytogenetic subgroups: the "-7/7q- ± CK group- designated group1," the "MK group-designated group 2," the "-5/5q- group- designated group 3," the "abn(17p) group- designated group 4" and the "inv(3) group- designated group 5." The 2-year probability of LFS in first remission was 48% for group 1, 36.4% for group 2, 28.4% for group 3, 19.1% for group 4 and 17.3% for group 5, respectively (P < .001). Multivariate analysis confirmed those significant differences across groups. Note, SCT in -7/7q- AML provides durable responses in one third of the patients. The presence of -7/7q- with or without CK in the absence of MK, abn(17p) or inv(3) is associated with a better survival after SCT. On the contrary, addition of MK, -5/5q-, abn(17p) or inv(3) identifies a sub-group of patients with poor prognosis even after SCT.
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Leucemia Mieloide Aguda , Trasplante de Células Madre , Adolescente , Adulto , Anciano , Aloinjertos , Deleción Cromosómica , Cromosomas Humanos Par 7/genética , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Prueba de Histocompatibilidad , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Sistema de Registros , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
PURPOSE OF REVIEW: Disease relapse remains the major cause of treatment failure in adults with acute myeloid leukemia (AML) in first complete remission (CR1) treated with intensive chemotherapy alone. Allogeneic stem cell transplantation (allo-SCT) reduces the risk of disease recurrence, and thus the advent of reduced intensity-conditioning regimens coupled with increased donor availability has increased the deliverability of potentially curative transplant therapy in AML. However, allo-SCT remains associated with significant additional morbidity and mortality, and it is therefore important to identify patients whose outcome if treated with chemotherapy alone is good enough to spare them the risks associated with allo-SCT. RECENT FINDINGS: Characterization of cytogenetic and molecular abnormalities present at diagnosis coupled with dynamic assessments of measurable residual disease now permit greater accuracy in defining the relapse risk in patients treated with chemotherapy alone. At the same time, the risk of transplant-related mortality can be predicted by a number of scoring systems which assess patient comorbidity. Taken together, such assessments permit a dynamic assessment of the risks and benefits of transplantation aiding the identification of patients who are unlikely to benefit from transplantation in CR1. SUMMARY: Increasingly accurate risk stratification in adults with AML CR1 aids the rational utilization of allo-SCT. Future research integrating the results of serial MRD analysis in molecularly defined subtypes of AML will further improve rational selection of patients for transplant.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Receptores de Complemento 3b/metabolismo , Acondicionamiento Pretrasplante , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológicoRESUMEN
Therapeutic approaches which aim to target Acute Myeloid Leukaemia through enhancement of patients' immune responses have demonstrated limited efficacy to date, despite encouraging preclinical data. Examination of AML patients treated with azacitidine (AZA) and vorinostat (VOR) in a Phase II trial, demonstrated an increase in the expression of Cancer-Testis Antigens (MAGE, RAGE, LAGE, SSX2 and TRAG3) on blasts and that these can be recognised by circulating antigen-specific T cells. Although the T cells have the potential to be activated by these unmasked antigens, the low arginine microenvironment created by AML blast Arginase II activity acts a metabolic brake leading to T cell exhaustion. T cells exhibit impaired proliferation, reduced IFN-γ release and PD-1 up-regulation in response to antigen stimulation under low arginine conditions. Inhibition of arginine metabolism enhanced the proliferation and cytotoxicity of anti-NY-ESO T cells against AZA/VOR treated AML blasts, and can boost anti-CD33 Chimeric Antigen Receptor-T cell cytotoxicity. Therefore, measurement of plasma arginine concentrations in combination with therapeutic targeting of arginase activity in AML blasts could be a key adjunct to immunotherapy.