RESUMO
Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Humanos , Cadeias Leves de Imunoglobulina , Espectrometria de Massas , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Intervalo Livre de Progressão , Transplante Autólogo , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND AND OBJECTIVE: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy. METHODS: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. RESULTS: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent. CONCLUSIONS: These data support the hypothesis that the common polymorphism at position -93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antineoplásicos Alquilantes/efeitos adversos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/genética , Segunda Neoplasia Primária/etiologia , Proteínas Nucleares/genética , Polimorfismo Genético , Adolescente , Adulto , Idoso , Alelos , Sequência de Bases , Estudos de Casos e Controles , Metilação de DNA , Primers do DNA/genética , Reparo do DNA/genética , Feminino , Humanos , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/genética , Regiões Promotoras Genéticas , Fatores de RiscoRESUMO
Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10-7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10-14) and 1.68 (P=2.18 × 10-14), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10-27) for all patients and 3.19 (P=1.23 × 10-18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10-15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.
Assuntos
Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Deleção Cromossômica , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Modelos de Riscos Proporcionais , Translocação Genética/genética , Transplante Autólogo/métodosRESUMO
Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly defined high-risk patients who continue to do badly. Novel therapeutic approaches are, therefore, required. A growing number of epigenetic inhibitors are now available including EZH2 inhibitors that are in early-stage clinical trials for treatment of haematological and other cancers with EZH2 mutations or in which overexpression has been correlated with poor outcomes. For the first time, we have identified and validated a robust and independent deleterious effect of high EZH2 expression on outcomes in myeloma patients. Using two chemically distinct small-molecule inhibitors, we demonstrate a reduction in myeloma cell proliferation with EZH2 inhibition, which leads to cell cycle arrest followed by apoptosis. This is mediated via upregulation of cyclin-dependent kinase inhibitors associated with removal of the inhibitory H3K27me3 mark at their gene loci. Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies.
Assuntos
Pontos de Checagem do Ciclo Celular/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Expressão Gênica , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Apoptose/genética , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/genética , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Epigênese Genética , Perfilação da Expressão Gênica , Histonas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Células-Tronco Mesenquimais/metabolismo , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Fenótipo , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/genéticaAssuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos , Agentes de Imunomodulação/uso terapêutico , Mieloma Múltiplo/patologia , Mutação , Ubiquitina-Proteína Ligases/genética , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genéticaRESUMO
We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Segunda Neoplasia Primária/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Ácidos Hidroxâmicos , Estimativa de Kaplan-Meier , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/patologia , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/patologia , Oligopeptídeos/administração & dosagem , Fatores de Risco , Talidomida/administração & dosagem , VorinostatRESUMO
A major complication of multiple myeloma (MM) is the development of osteolytic lesions, fractures and bone pain. To identify genetic variants influencing the development of MM bone disease (MBD), we analyzed MM patients of European ancestry (totaling 3774), which had been radiologically surveyed for MBD. Each patient had been genotyped for ~6 00 000 single-nucleotide polymorphisms with genotypes for six million common variants imputed using 1000 Genomes Project and UK10K as reference. We identified a locus at 8q24.12 for MBD (rs4407910, OPG/TNFRSF11B, odds ratio=1.38, P=4.09 × 10(-9)) and a promising association at 19q13.43 (rs74676832, odds ratio=1.97, P=9.33 × 10(-7)). Our findings demonstrate that germline variation influences MBD and highlights the importance of RANK/RANKL/OPG pathway in MBD development. These findings will contribute to the development of future strategies for prevention of MBD in the early precancerous phases of MM.
Assuntos
Biomarcadores Tumorais/genética , Doenças Ósseas/etiologia , Mieloma Múltiplo/genética , Osteoprotegerina/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Doenças Ósseas/patologia , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Estadiamento de Neoplasias , Prognóstico , Fatores de RiscoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doença de Hodgkin/tratamento farmacológico , Lomustina/administração & dosagem , Satisfação do Paciente , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Clorambucila/administração & dosagem , Clorambucila/efeitos adversos , Progressão da Doença , Relação Dose-Resposta a Droga , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Lomustina/efeitos adversos , Cuidados Paliativos , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Análise de Sobrevida , Sobreviventes , Fatores de TempoRESUMO
It is apparent that treatment of Hodgkin's disease can be complicated by the development of secondary leukaemia. Most such leukaemias are of the non-lymphocytic type. We describe here a patient treated for Hodgkin's disease with chemo- and radiotherapy who developed secondary acute lymphoblastic leukaemia with a non-random chromosomal abnormality t(4;11). The frequency of such cases is assessed by a literature review and evidence for their pluripotent cell origin is discussed.
Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 4 , Doença de Hodgkin/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Translocação Genética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Feminino , Humanos , Leucemia Induzida por Radiação/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMO
Between May 1984 and October 1995 we performed 114 autologous stem cell transplants for lymphoma in our centre; 77/114 (68%) were transplanted after primary therapy. The conditioning regimen varied according to diagnosis; 26 patients were conditioned with melphalan and total body irradiation, 66 received melphalan and etoposide and the remainder (50) were conditioned with melphalan alone. The median follow-up is 62 months. Only two new haematological malignancies have occurred, both in patients with Hodgkin's disease. One patient developed Ph+ chronic myeloid leukaemia 18 months post-transplant. In this case, because of the timing of the haematological disorder, we considered the malignancy to be concurrent with or to have preceded the transplant. A second patient developed acute myeloid leukaemia 20 months post-transplant. She had been treated for Hodgkin's disease for 10 years and was transplanted in third complete remission. Cytogenetic analysis in this case showed trisomy 11. We believe this to have been an unequivocal second malignancy. Our finding of a 1.1% incidence of secondary haematological malignancy (95% CI 0.02-4.96) from a census population adds weight to the hypothesis that haematological problems post-transplant reflects prior chemotherapy rather than toxicity from the transplant procedure itself.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Síndromes Mielodisplásicas/epidemiologia , Adolescente , Adulto , Criopreservação , Feminino , Seguimentos , Doença de Hodgkin/terapia , Humanos , Incidência , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/etiologiaRESUMO
Acute myeloid leukaemia (AML) is predominantly a disease of the elderly but such patients are not always appropriate candidates for intensive intravenous (i.v.) based treatment regimens. The development of the anthracycline idarubicin which is highly effective in the treatment of AML and is active when given orally has made it possible to design anti-leukaemic regimens which may be given orally and be particularly useful in those elderly patients with AML considered unsuitable for standard intensive aggressive treatments. We have assessed an oral regimen combining idarubicin 30 mg/m2 and etoposide 80 mg/m2 for 3 consecutive days as initial treatment in 28 elderly patients with AML (median age 69 years, range 56-81) who were not considered suitable for more intensive i.v. chemotherapy schedules. Following informed consent, two patients died before treatment began and one patient withdrew prior to treatment. Twenty-five patients underwent one to four courses of treatment. The schedule was well tolerated with minor nonhaematological toxicity. The first course was given in hospital, eight of 21 subsequent courses of treatment were given entirely as an out-patient. Eleven patients responded to treatment with nine (36%) achieving complete remission (CR). The median survival for all patients was 3 months, but for the nine who achieved a CR it is 9 months with six patients still alive, five in first CR and one in second CR. We conclude that a combination of idarubicin and etoposide given orally as first-line treatment in elderly patients with AML is safe and effective. In some patients this means treatment and follow-up can be given entirely on an out-patient basis.
Assuntos
Etoposídeo/administração & dosagem , Idarubicina/administração & dosagem , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Administração Oral , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Intervalo Livre de Doença , Humanos , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
DNA from 76 cases of acute lymphoblastic leukemia (ALL) was tested with a cDNA probe encoding the alpha 2B interferon (IFN) gene transcript. Deletions were found in three of ten pre-B, three of 21 T-cell, four of 22 common and one of 23 null ALL cases. Amongst those with null ALL were 20 infants, most with characteristic translocations, none of whom had deletion of alpha IFN genes. The results confirm that alpha IFN gene deletions may occur without visible abnormalities of chromosome 9p and show that they occur across a wide range of ALL phenotypes. The results suggest that alpha IFN gene deletions may be rare events in null ALL of infants but their incidence and cellular consequences remain unknown.
Assuntos
Interferon Tipo I/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Southern Blotting , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 9 , Genes , Humanos , LactenteRESUMO
There has been a great deal of interest in the use of high dose chemotherapy and/or radiotherapy, with autologous bone marrow/peripheral blood stem cell rescue, in the treatment of haematological malignancies including acute lymphoblastic leukaemia (ALL). In this review we assess the role of autologous bone marrow transplantation (ABMT) in ALL. The heterogeneity of this disease makes the analysis of treatment results in ALL difficult to interpret. There is some evidence that ABMT may be useful in second complete remission (CR) and increasing interest in ABMT as a therapeutic option in first CR in adults. At the moment there is little evidence that such an approach will have an impact in childhood ALL. ABMT is considerably less toxic than allogeneic bone marrow transplantation and the major cause of 'treatment failure' is disease relapse. There has been considerable effort put into purging autologous bone marrow of malignant stem cells but whether purging is effective remains controversial and not proven. Newer studies involving cytokines post-ABMT to stimulate an artificial 'graft versus leukaemia' effect may prove of value.
Assuntos
Transplante de Medula Óssea , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Purging da Medula Óssea , Transplante de Medula Óssea/efeitos adversos , Criança , Ensaios Clínicos como Assunto , Humanos , Imunofenotipagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Prognóstico , Indução de Remissão , Terapia de Salvação , Transplante Autólogo , Resultado do Tratamento , Irradiação Corporal TotalRESUMO
The aim of the study was to identify all patients with poor risk Hodgkin's disease (HD) using a numerical prognostic index in a defined population and to recruit them into a trial of intensive chemotherapy prednisolone, vinblastine, doxorubicin, chlorambucil, etoposide, bleomycin, vincristine, procarbazine (PVACE-BOP)x3+autotransplant (Arm A) versus PVACE-BOPx5 (Arm B) in first remission. In 10 years, the Scotland and Newcastle Lymphoma Group (SNLG) registered 930 patients with HD of whom 178 (19%) were identified as 'poor risk' by the SNLG index and were aged 16-59 years. 126/178 (71%) entered the study. Of the 120 confirmed poor risk HD cases, all completed PVACE-BOPx3 with a 93% Complete Response/unconfirmed Complete Response (CR/CRu) rate. Only 65/107 in CR accepted the randomisation. With a median follow-up of 6 years, both arms of the trial have a similar time to treatment failure (TTF) (Arm A 79%+/-11 versus 85%+/-7 Arm B, P=0.35). Advanced stage 'good risk' patients not included in the trial receiving standard therapy with CLVPP or ABVD had a 75% 5-year survival. The study demonstrates that PVACE-BOP therapy in the poorest risk group (58% had an IPI>/=3) produces excellent CR rates (93%) and overall survival with minimal toxicity, and that the substitution of autotransplant in first CR does not improve outcome. The use of the objective SNLG index accurately helped in the selection of the poorest risk group in this population study. The placing of a randomised control trial within the context of a population-based study of HD enhances the validity of the outcome.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea/métodos , Doença de Hodgkin/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada/métodos , Feminino , Seguimentos , Doenças Hematológicas/induzido quimicamente , Doença de Hodgkin/patologia , Doença de Hodgkin/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Análise de Sobrevida , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND: Graft-versus-host disease (GVHD) is a major and sometimes fatal complication of allogeneic bone marrow transplantation (BMT). The prediction of GVHD remains an important issue in preventing morbidity and mortality after allogeneic BMT. In the past 10 years, there has been great interest in using the frequency analysis of alloreactive helper and cytotoxic T lymphocyte precursors (HTLp and CTLp) to detect recipient-specific alloreactivity and thus predict GVHD in HLA-matched related and unrelated BMT. However, the results remain controversial. The intention of the present study was to investigate whether alloreactive HTLp and CTLp frequencies measured in donor peripheral blood before BMT would be a useful predictor for the occurrence of acute GVHD after HLA-matched sibling BMT. METHOD: A combined limiting dilution assay was used to determine alloreactive HTLp and CTLp frequencies for 42 HLA-matched sibling patient/donor pairs. The pretransplantation host-reactive HTLp and CTLp frequencies were then correlated with post-transplantation clinical outcomes of acute GVHD. The association between HTLp/CTLp frequencies and the incidence of acute GVHD was determined using the Fisher's exact test. RESULTS: The mean values of HTLp and CTLp frequencies for this cohort of HLA-matched sibling patient/donor pairs were 1:321,322 (range 1:71,000 to 1:1000,000) and 1:195,260 (range 1:3,717 to 1:1000,000), respectively. Acute GVHD (> or =II) was observed in one of four patients with high (>1:100,000) HTLp frequencies and 20 of 36 patients with low (<1:100,000) HTLp frequencies. Similarly, 6 of 10 patients with high (>1: 100,000) CTLp frequencies and 14 of 29 patients with low (<1:100,000) CTLp frequencies developed acute GVHD (> or =II). The overall correlation between hostreactive HTLp/CTLp frequencies and the incidence of acute GVHD in this cohort of patients was 42.5% and 53.9%, respectively. There was no significant difference in the incidence of acute GVHD between the patients with either high or low host-reactive HTLp/ CTLp frequencies (P=0.331 and 0.716, respectively). The data were also analyzed separately for the adult patient group based on GVHD prophylaxis with either cyclosporine alone or the combination of cyclosporine and methotrexate. Within these two prophylaxis groups, neither HTLp nor CTLp frequencies correlated with acute GVHD. CONCLUSION: Host-reactive HTLp and CTLp frequency analysis did not provide informative prediction for the occurrence of acute GVHD after HLA-matched sibling BMT.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/imunologia , Doença Enxerto-Hospedeiro/etiologia , Linfócitos T/imunologia , Doença Aguda , Adolescente , Adulto , Criança , Pré-Escolar , Testes Imunológicos de Citotoxicidade , Doença Enxerto-Hospedeiro/imunologia , Antígenos HLA , Teste de Histocompatibilidade , Humanos , Técnicas In Vitro , Lactente , Pessoa de Meia-Idade , Núcleo Familiar , Fatores de Risco , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transplante HomólogoRESUMO
We describe two cases of severe constrictive pericarditis arising after allogeneic BMT conditioning involving total body irradiation and melphalan to treat Philadelphia-chromosome positive ALL. Both patients required pericardectomy, resulting in marked improvement in ventricular filling. However, a degree of right-sided cardiac failure persisted in both patients secondary to restrictive cardiomyopathy. Constrictive pericarditis has not been previously described after BMT, but has been observed following thoracic radiotherapy for malignancy, usually involving a substantially higher radiation dose. Pericardial constriction and restrictive cardiomyopathy should be considered as causes of breathlessness and/or oedema occurring late after BMT. Bone Marrow Transplantation (2000) 25, 571-573.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Pericardite Constritiva/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante/efeitos adversos , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/toxicidade , Terapia Combinada , Edema/etiologia , Infecções por Escherichia coli/etiologia , Evolução Fatal , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/toxicidade , Pericardiectomia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Transplante Homólogo , Irradiação Corporal Total/efeitos adversosRESUMO
We investigated the role of polymorphism of the vitamin D receptor (VDR) gene in HLA-matched sibling BMT for polymorphisms previously associated with human disease pathology. In intron 8 of the VDR gene, the B and A alleles of the BsmI and ApaI RFLPs were found to associate with reduced aGVHD when present in the patient's genotype. Logistic regression analysis demonstrated that patient VDR genotype, along with previously identified IL-10(-1064) and IFN-gamma genotype to be risk factors for severe acute GVHD. The A allele also associates with increased likelihood of death when present in the donor genotype (AA vs Aa or aa, hazard ratio 2.03, P = 0.0232). In patients who received increased prophylaxis with multi-agent therapy, patients whose graft was from a donor with an AA genotype had a substantially worse survival than patients whose graft was from a donor with a non-AA genotype (hazard ratio 12.93, P < 0.0001). Analysis of VDR genotype in prospective BMT recipients could indicate patients at risk of severe aGVHD. Analysis of VDR genotype in prospective BMT donors may identify individuals who have greater transplant-related mortality, and also allow appropriately restricted use of increased immunosuppressive prophylaxis.
Assuntos
Transplante de Medula Óssea/mortalidade , Doença Enxerto-Hospedeiro/genética , Polimorfismo Genético , Receptores de Calcitriol/genética , Adulto , Feminino , Frequência do Gene , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Histocompatibilidade , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Irmãos , Análise de Sobrevida , Taxa de Sobrevida , Doadores de Tecidos , Transplante Homólogo/mortalidade , Transplante Isogênico/mortalidade , Resultado do TratamentoRESUMO
This study evaluates the relationship between bone marrow growth in a long-term bone marrow culture (LTBMC) system and speed of engraftment of the same marrow following autologous bone marrow transplantation (ABMT). Bone marrow from 21 patients transplanted with unmanipulated, non-cryopreserved autologous marrow was cultured. Samples from 21 normal donors were cultured to establish the normal supernatant cell count range. Supernatant counts from LTBMCs established from marrow taken from patients at the time of bone marrow harvest were compared with the time to neutrophil and platelet engraftment. Supernatant counts, particularly after 1 week in culture, showed close correlation with time to neutrophil and platelet engraftment following ABMT (r = 0.733, p less than 0.01; r = 0.735, p less than 0.01 respectively). Where supernatant cell counts were within the normal range rapid engraftment was predicted (neutrophils greater than 0.5 x 10(9)/l within 21 days, platelets greater than 50 x 10(9)/l within 28 days) and if supernatant counts were below this range, engraftment was predicted to be delayed. After 1 week in culture, the speed of neutrophil and platelet engraftment were correctly predicted in 19 and 18 cases respectively. Preliminary data suggest that LTBMC of marrow obtained 2-6 weeks before harvesting provides similar data, thus allowing the opportunity to intervene, for example with growth factors, in selected patients.
Assuntos
Células da Medula Óssea , Transplante de Medula Óssea/fisiologia , Adolescente , Adulto , Plaquetas/citologia , Plaquetas/fisiologia , Medula Óssea/fisiologia , Contagem de Células , Divisão Celular/fisiologia , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Neutrófilos/fisiologia , Fatores de Tempo , Transplante AutólogoRESUMO
Oestrogen receptors mediate the cellular response to oestrogens and related compounds and promote a wide range of effects on haemopoiesis. Polymorphisms of the oestrogen receptor genes have previously been associated with variation in bone mineral density, likelihood of fractures, risk of developing Alzheimer's disease, endometrial cancer and response to hormone replacement therapy. We examined the polymorphisms in both ERalpha and ERbeta genes in 108 patients receiving a bone marrow transplant from an HLA-matched sibling donor, and compared ER genotype with outcomes of occurrence of graft-versus-host disease (GVHD) and survival using logistic regression analysis. Polymorphism of ERalpha (presence of the PX haplotype (PvuII-XbaI RFLP) of intron 1), but not ERbeta, in the patient genotype associates with occurrence of acute GVHD and with lower overall survival, following correction for known clinical and genotypic risk features. Analysis of ER genotype prior to transplant might therefore inform on a patient's likelihood of developing post-transplant complications. Variation in transplant performance because of ER genotype suggests an underlying role for oestrogens in the pathophysiology of transplant-related complications, and suggests that oestrogen-related therapy may offer a new modality of post-transplant support.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/genética , Polimorfismo Genético , Receptores de Estrogênio/genética , Adulto , Transplante de Medula Óssea/mortalidade , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Feminino , Predisposição Genética para Doença , Genótipo , Doença Enxerto-Hospedeiro/patologia , Teste de Histocompatibilidade , Humanos , Masculino , Irmãos , Análise de Sobrevida , Taxa de Sobrevida , Transplante HomólogoRESUMO
AIM: Acute lymphoblastic leukaemia (ALL) with an L3 morphological FAB type is regarded by some as being synonymous with B cell ALL or ALL with a Burkitt-type chromosomal translocation-t(8;14), t(2;8), t(8;22). This paper describes a series from a population based study of 24 patients with L3 ALL presenting over 17 years. METHODS: Clinical data were collected prospectively from all adult patients presenting with acute leukaemia in the Northern region since 1982. Data from all patients diagnosed with FAB type L3 ALL were analysed. RESULTS: Overall, L3 ALL accounts for 8.6% of all adult ALL and it is more common in the elderly than has hitherto been recognised. In addition to classic Burkitt-type translocations (11 of 24 cases), the t(14;18) translocation, which is characteristically found in lower grade lymphomas such as follicular lymphoma, is frequently present (five of 24 cases). CONCLUSION: The presence of L3 ALL is often associated with non-Burkitt-type translocations and the presence of a t(14;18) translocation may indicate that in some cases a clinically non-apparent lymphoproliferative disorder, such as a low grade follicular lymphoma, has transformed to a more aggressive form and, thus, presents as a de novo acute leukaemia.