RESUMO
BACKGROUND: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. METHODS: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 µg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. FINDINGS: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. INTERPRETATION: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.
Assuntos
Doença de Crohn , Transplante de Células-Tronco Hematopoéticas , Insuficiência Renal , Adulto , Humanos , Doença de Crohn/tratamento farmacológico , Padrão de Cuidado , Medicina Estatal , Úlcera/etiologia , Resultado do Tratamento , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Ciclofosfamida/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêuticoRESUMO
Allogeneic stem-cell transplant allows for the delivery of curative graft-versus-leukemia (GVL) in patients with acute myeloid leukemia/myelodysplasia (AML/MDS). Surveillance of T-cell chimerism, measurable residual disease (MRD) and blast HLA-DR expression may inform whether GVL effectiveness is reduced. We report here the prognostic impact of these biomarkers in patients allografted for AML/MDS. One hundred eighty-seven patients from FIGARO, a randomized trial of reduced-intensity conditioning regimens in AML/MDS, were alive and relapse-free at the first MRD time-point and provided monitoring samples for flow cytometric MRD and T-cell chimerism, requested to month+12. Twenty-nine (15.5%) patients had at least 1 MRD-positive result posttransplant. MRD-positivity was associated with reduced overall survival (OS) (hazard ratio [HR], 2.18; P = .0028) as a time-varying Cox variable and remained significant irrespective of pretransplant MRD status in multivariate analyses (P < .001). Ninety-four patients had sequential MRD with T-cell chimerism results at months+3/+6. Patients with full donor T-cell chimerism (FDTC) had an improved OS as compared with patients with mixed donor T-cell chimerism (MDTC) (adjusted HR=0.4; P = .0019). In patients with MDTC (month+3 or +6), MRD-positivity was associated with a decreased 2-year OS (34.3%) vs MRD-negativity (71.4%) (P = .001). In contrast, in the group with FDTC, MRD was infrequent and did not affect the outcome. Among patients with posttransplant MRD-positivity, decreased HLA-DR expression on blasts significantly reduced OS, supporting this as a mechanism for GVL escape. In conclusion, posttransplant MRD is an important predictor of the outcome in patients allografted for AML/MDS and is most informative when combined with T-cell chimerism results, underlining the importance of a GVL effect in AML/MDS.
Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Quimerismo , Linfócitos T , Leucemia Mieloide Aguda/terapia , AloenxertosRESUMO
OBJECTIVES: The aim of this study was to assess the reduction in red cell transfusions following a change in the red cell transfusion threshold for haematology inpatients from 80 to 70 g/L. BACKGROUND: Haematology patients are among the high users of red blood cells. We reduced the threshold for transfusion of haematology inpatients to 70 g/L. This was based on evidence provided by randomised controlled trial published in 2020 that showed restrictive transfusion is non-inferior to liberal transfusion. METHOD: We assessed red cell transfusions for haematology inpatients at Oxford University Hospitals NHS Foundation Trust for 9 months before and 9 months after a change in red cell transfusion threshold from 80 to 70 g/L. RESULTS: After the change in threshold to 70 g/L or less from 80 g/L, the median number of red cell transfusions per month reduced to 88 from 111. This was a 23% reduction in the total number of red cells administered per month. CONCLUSION: These results show the real-world reductions in transfusion that can be made by putting local transfusion guidelines in line with the international recommendations. This is of particular importance at a time of national blood shortage.
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Hematologia , Pacientes Internados , Humanos , Transfusão de Eritrócitos/métodos , EritrócitosRESUMO
Allogeneic haematopoietic stem cell transplant (HSCT) recipients remain at high risk of adverse outcomes from coronavirus disease 2019 (COVID-19) and emerging variants. The optimal prophylactic vaccine strategy for this cohort is not defined. T cell-mediated immunity is a critical component of graft-versus-tumour effect and in determining vaccine immunogenicity. Using validated anti-spike (S) immunoglobulin G (IgG) and S-specific interferon-gamma enzyme-linked immunospot (IFNγ-ELIspot) assays we analysed response to a two-dose vaccination schedule (either BNT162b2 or ChAdOx1) in 33 HSCT recipients at ≤2 years from transplant, alongside vaccine-matched healthy controls (HCs). After two vaccines, infection-naïve HSCT recipients had a significantly lower rate of seroconversion compared to infection-naïve HCs (25/32 HSCT vs. 39/39 HCs no responders) and had lower S-specific T-cell responses. The HSCT recipients who received BNT162b2 had a higher rate of seroconversion compared to ChAdOx1 (89% vs. 74%) and significantly higher anti-S IgG titres (p = 0.022). S-specific T-cell responses were seen after one vaccine in HCs and HSCT recipients. However, two vaccines enhanced S-specific T-cell responses in HCs but not in the majority of HSCT recipients. These data demonstrate limited immunogenicity of two-dose vaccination strategies in HSCT recipients, bolstering evidence of the need for additional boosters and/or alternative prophylactic measures in this group.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Transplante de Células-Tronco Hematopoéticas , Fatores Etários , Anticorpos Antivirais/imunologia , Vacina BNT162/imunologia , Vacina BNT162/uso terapêutico , Transplante de Medula Óssea/efeitos adversos , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/farmacologia , Vacinas contra COVID-19/uso terapêutico , ChAdOx1 nCoV-19/imunologia , ChAdOx1 nCoV-19/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Imunidade Humoral/efeitos dos fármacos , Imunidade Humoral/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Soroconversão , Transplante Homólogo/efeitos adversos , Vacinação/efeitos adversosRESUMO
A woman who had undergone haematopoietic stem cell transplantation presented with cutaneous features suggestive of graft-versus-host disease. Histopathological examination revealed a diffuse dermal infiltration of atypical monomorphic cells with a high proliferative index. Immunohistochemistry revealed positivity for monocytic markers, but negativity for T-cell markers.
Assuntos
Exantema , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Prurigo , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , PruridoAssuntos
COVID-19/epidemiologia , Mieloma Múltiplo/epidemiologia , Idoso , Idoso de 80 Anos ou mais , COVID-19/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Pandemias , SARS-CoV-2/isolamento & purificação , Resultado do Tratamento , Reino Unido/epidemiologiaRESUMO
PURPOSE: Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS: Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS: There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION: The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.
Assuntos
Amsacrina/administração & dosagem , Bussulfano/administração & dosagem , Citarabina/administração & dosagem , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/administração & dosagem , Síndromes Mielodisplásicas/terapia , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adulto , Idoso , Amsacrina/efeitos adversos , Bussulfano/efeitos adversos , Citarabina/efeitos adversos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/efeitos adversos , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Intervalo Livre de Progressão , Recidiva , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/mortalidade , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/mortalidade , Transplante Homólogo , Reino Unido , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Adulto JovemAssuntos
Betacoronavirus , Infecções por Coronavirus , Doenças Hematológicas/complicações , Doenças Hematológicas/terapia , Pandemias , Pneumonia Viral , Guias de Prática Clínica como Assunto , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , COVID-19 , Comorbidade , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Epidemias , Humanos , Pessoa de Meia-Idade , Pandemias/prevenção & controle , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , SARS-CoV-2RESUMO
Our understanding of the perturbation of normal cellular differentiation hierarchies to create tumor-propagating stem cell populations is incomplete. In human acute myeloid leukemia (AML), current models suggest transformation creates leukemic stem cell (LSC) populations arrested at a progenitor-like stage expressing cell surface CD34. We show that in â¼25% of AML, with a distinct genetic mutation pattern where >98% of cells are CD34(-), there are multiple, nonhierarchically arranged CD34(+) and CD34(-) LSC populations. Within CD34(-) and CD34(+) LSC-containing populations, LSC frequencies are similar; there are shared clonal structures and near-identical transcriptional signatures. CD34(-) LSCs have disordered global transcription profiles, but these profiles are enriched for transcriptional signatures of normal CD34(-) mature granulocyte-macrophage precursors, downstream of progenitors. But unlike mature precursors, LSCs express multiple normal stem cell transcriptional regulators previously implicated in LSC function. This suggests a new refined model of the relationship between LSCs and normal hemopoiesis in which the nature of genetic/epigenetic changes determines the disordered transcriptional program, resulting in LSC differentiation arrest at stages that are most like either progenitor or precursor stages of hemopoiesis.
Assuntos
Antígenos CD34/genética , Células Progenitoras de Granulócitos e Macrófagos/metabolismo , Leucemia Mieloide Aguda , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Animais , Antígenos CD34/metabolismo , Células Progenitoras de Granulócitos e Macrófagos/patologia , Xenoenxertos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologiaRESUMO
Disease relapse is the major cause of treatment failure after allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML). To identify AML-associated genes prognostic of AML relapse post-allo-SCT, we resequenced 35 genes in 113 adults at diagnosis, 49 of whom relapsed. Two hundred sixty-two mutations were detected in 102/113 (90%) patients. An increased risk of relapse was observed in patients with mutations in WT1 (P = .018), DNMT3A (P = .045), FLT3 ITD (P = .071), and TP53 (P = .06), whereas mutations in IDH1 were associated with a reduced risk of disease relapse (P = .018). In 29 patients, we additionally compared mutational profiles in bone marrow at diagnosis and relapse to study changes in clonal structure at relapse. In 13/29 patients, mutational profiles altered at relapse. In 9 patients, mutations present at relapse were not detected at diagnosis. In 15 patients, additional available pre-allo-SCT samples demonstrated that mutations identified posttransplant but not at diagnosis were detectable immediately prior to transplant in 2 of 15 patients. Taken together, these observations, if confirmed in larger studies, have the potential to inform the design of novel strategies to reduce posttransplant relapse highlighting the potential importance of post-allo-SCT interventions with a broad antitumor specificity in contrast to targeted therapies based on mutational profile at diagnosis.
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Treatment options are limited in myeloma relapsed or refractory to both bortezomib and lenalidomide (double-relapsed/refractory multiple myeloma; DRMM). Bendamustine is an antitumour agent that has efficacy in relapsed myeloma. We retrospectively analysed data from 30 DRMM patients who received a combination of bendamustine, thalidomide and dexamethasone (BTD) in 28-day treatment cycles. Bendamustine was administered with a cumulative dose of up to 200 mg/m(2). Thalidomide (50-150 mg) was given daily as tolerated, and dexamethasone was given at an equivalent dose of up to 160 mg per cycle. A median of 5 (2-9) treatment cycles were administered per patient. Twenty-six patients (87 %) achieved stable disease or better. At a median follow-up time of 12.1 (2.3-21.5) months, median (95 % CI) progression-free survival and overall survival were 4.0 (2.6-5.3) months and 7.2 (5.2-9.2) months, respectively. The most common grade 3-4 adverse events were haematological: anaemia (n = 8, 34.8 %), neutropenia (n = 16, 69.6 %) and thrombocytopenia (n = 10, 43.5 %). Non-haematological toxicities included pain (n = 3, 13.0 %), infection (n = 7, 30.4 %) and sensory neuropathy (n = 1, 4.3 %). We propose that BTD is a viable salvage treatment option for DRMM patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/uso terapêutico , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Compostos de Mostarda Nitrogenada/administração & dosagem , Pirazinas/uso terapêutico , Terapia de Salvação/métodos , Talidomida/análogos & derivados , Talidomida/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Cloridrato de Bendamustina , Bortezomib , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Talidomida/uso terapêutico , Falha de TratamentoRESUMO
BACKGROUND: Rarely, healthy donors fail adequate peripheral blood stem cell (PBSC) mobilization. If the recipient has already received conditioning chemotherapy, this can result in the donor undergoing urgent marrow harvest under general anesthesia. Plerixafor is a novel CXCR4 antagonist, licensed for autologous PBSC harvest (PBSCH) in patients who failed mobilization with granulocyte-colony-stimulating factor (G-CSF) alone. Experience using plerixafor in healthy allogeneic donors failing G-CSF mobilization is scarce. CASE REPORT: A 65-year-old patient was referred for a reduced-intensity conditioning sibling allograft for relapsed follicular lymphoma. She received fludarabine, melphalan, and alemtuzumab conditioning. Her 68-year-old brother was fully HLA matched. PBSCH was planned on Day -1 after 4 days of 10 µg/kg G-CSF. Day 1 PBSCH collected an inadequate number of CD34+ 0.35 × 10(6) /kg cells. Despite increasing G-CSF (16 µg/kg), Day 2 yielded 0.33 × 10(6) /kg CD34+ cells, giving a suboptimal total dose. He proceeded to a third PBSCH day after plerixafor (0.24 mg/kg) and G-CSF (16 µg/kg) were given the evening before. A total of 1.79 × 10(6) /kg CD34+ cells were harvested, giving a total dose of 2.46 × 10(6) /kg CD34+ cells. After initial neutrophil engraftment on Day +13, the patient's neutrophils gradually decreased to 0.02 × 10(9) /L by Day +74. A marrow aspirate on Day +81 was markedly hypocellular. Total white blood cell chimerism was near 100% donor on Days +32, +74, and +102. Despite chimeric-only engraftment, the patient remains platelet and red blood cell transfusion dependent. CONCLUSION: Rescue plerixafor to assist PBSCH in healthy allogeneic donors has been effective in terms of CD34+ cell number mobilized. It is unclear whether the partial engraftment seen was coincidental or related to a difference in PBSC quality.
Assuntos
Doadores de Sangue , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/farmacologia , Receptores CXCR4/antagonistas & inibidores , Idoso , Benzilaminas , Ciclamos , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Masculino , IrmãosAssuntos
Amplificação de Genes , Proteínas de Fusão Oncogênica/genética , Plasmídeos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Ensaios de Seleção de Medicamentos Antitumorais , Amplificação de Genes/fisiologia , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Adulto JovemRESUMO
Molecular detection of minimal residual disease (MRD) has become established to assess remission status and guide therapy in patients with ProMyelocytic Leukemia-RARA+ acute promyelocytic leukemia (APL). However, there are few data on tracking disease response in patients with rarer retinoid resistant subtypes of APL, characterized by PLZF-RARA and STAT5b-RARA. Despite their rarity (<1% of APL) we identified 6 cases (PLZF-RARA, n = 5; STAT5b-RARA, n = 1), established the respective breakpoint junction regions and designed reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) assays to detect leukemic transcripts. The relative level of fusion gene expression in diagnostic samples was comparable to that observed in t(15;17) - associated APL, affording assay sensitivities of â¼1 in 10(4)-10(5). Serial samples were available from two PLZF-RARA APL patients. One showed persistent polymerase chain reaction positivity, predicting subsequent relapse, and remains in CR2, â¼11 years post-autograft. The other, achieved molecular remission (CRm) with combination chemotherapy, remaining in CR1 at 6 years. The STAT5b-RARA patient failed to achieve CRm following frontline combination chemotherapy and ultimately proceeded to allogeneic transplant on the basis of a steadily rising fusion transcript level. These data highlight the potential of RT-qPCR detection of MRD to facilitate development of more individualized approaches to the management of rarer molecularly defined subsets of acute leukemia.
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BACKGROUND: Reduced intensity conditioning regimens permit the delivery of a potentially curative graft-versus-leukemia effect in older patients with acute myeloid leukemia. Although T-cell depletion is increasingly used to reduce the risk of graft-versus-host disease its impact on the graft-versus-leukemia effect and long-term outcome post-transplant is unknown. DESIGN AND METHODS: We have characterized pre- and post-transplant factors determining overall survival in 168 patients with acute myeloid leukemia transplanted using an alemtuzumab based reduced intensity conditioning regimen with a median duration of follow-up of 37 months. RESULTS: The 3-year overall survival for patients transplanted in CR1 or CR2/CR3 was 50% (95% CI, 38% to 62%) and 44% (95% CI, 31% to 56%), respectively compared to 15% (95% CI, 2% to 36%) for patients with relapsed/refractory disease. Multivariate analysis demonstrated that both survival and disease relapse were influenced by status at transplant (P=0.008) and presentation cytogenetics (P=0.01). Increased exposure to cyclosporine A (CsA) in the first 21 days post-transplant was associated with an increased relapse risk (P<0.0001) and decreased overall survival (P<0.0001). CONCLUSIONS: Disease stage, presentation karyotype and post-transplant CsA exposure are important predictors of outcome in patients undergoing a T-cell depleted reduced intensity conditioning allograft for acute myeloid leukemia. These data confirm the presence of a potent graft-versus-leukemia effect after a T-cell depleted reduced intensity conditioning allograft in acute myeloid leukemia and identify CsA exposure as a manipulable determinant of outcome in this setting.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/cirurgia , Linfócitos T , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Alemtuzumab , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Linfócitos T/imunologia , Fatores de Tempo , Condicionamento Pré-Transplante/mortalidade , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Therapy-related acute promyelocytic leukemia (t-APL) with t(15;17)(q22;q21) involving the PML and RARA genes is associated with exposure to agents targeting topoisomerase II (topoII), particularly mitoxantrone and epirubicin. We previously have shown that mitoxantrone preferentially induces topoII-mediated DNA damage in a "hotspot region" within PML intron 6. To investigate mechanisms underlying epirubicin-associated t-APL, t(15;17) genomic breakpoints were characterized in 6 cases with prior breast cancer. Significant breakpoint clustering was observed in PML and RARA loci (P = .009 and P = .017, respectively), with PML breakpoints lying outside the mitoxantrone-associated hotspot region. Recurrent breakpoints identified in the PML and RARA loci in epirubicin-related t-APL were shown to be preferential sites of topoII-induced DNA damage, enhanced by epirubicin. Although site preferences for DNA damage differed between mitoxantrone and epirubicin, the observation that particular regions of the PML and RARA loci are susceptible to these agents may underlie their respective propensities to induce t-APL.