RESUMO
Allogeneic stem cell transplantation has been increasingly performed for a variety of hematologic diseases. Clinically significant acute graft-versus-host disease (GVHD) occurs in 9 to 50 percent of patients who receive allogeneic grafts, resulting in high morbidity and mortality. There is no standard therapy for patients with acute GVHD who do not respond to steroids. Studies have shown a possible benefit of anti-TNF-a (infliximab)for the treatment of acute GVHD. We report here on the outcomes of 10 recipients of related or unrelated stem cell transplants who received 10 mg/kg infliximab, iv, once weekly for a median of 3.5 doses (range: 1-6) for the treatment of severe acute GVHD and who were not responsive to standard therapy. All patients had acute GVHD grades II to IV (II = 2, III = 3, IV = 5). Overall, 9 patients responded and 1 patient had progressive disease. Among the responders, 3 had complete responses and 6 partial responses. All patients with cutaneous or gastrointestinal involvement responded, while only 2 of 6 patients with liver disease showed any response. None of the 10 patients had any kind of immediate toxicity. Four patients died, all of them with sepsis. Six patients are still alive after a median follow-up time of 544 days (92-600) after transplantation. Considering the severity of the cases and the bad prognosis associated with advanced acute GVHD, we find our results encouraging. Anti-TNF-a seems to be a useful agent for the treatment of acute GVHD.
Assuntos
Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Anticorpos Monoclonais/uso terapêutico , Glucocorticoides/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Metilprednisolona/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Doença Aguda , Quimioterapia Combinada , Seguimentos , Leucemia/mortalidade , Leucemia/cirurgia , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Allogeneic stem cell transplantation has been increasingly performed for a variety of hematologic diseases. Clinically significant acute graft-versus-host disease (GVHD) occurs in 9 to 50% of patients who receive allogeneic grafts, resulting in high morbidity and mortality. There is no standard therapy for patients with acute GVHD who do not respond to steroids. Studies have shown a possible benefit of anti-TNF-a (infliximab)for the treatment of acute GVHD. We report here on the outcomes of 10 recipients of related or unrelated stem cell transplants who received 10 mg/kg infliximab, iv, once weekly for a median of 3.5 doses (range: 1-6) for the treatment of severe acute GVHD and who were not responsive to standard therapy. All patients had acute GVHD grades II to IV (II = 2, III = 3, IV = 5). Overall, 9 patients responded and 1 patient had progressive disease. Among the responders, 3 had complete responses and 6 partial responses. All patients with cutaneous or gastrointestinal involvement responded, while only 2 of 6 patients with liver disease showed any response. None of the 10 patients had any kind of immediate toxicity. Four patients died, all of them with sepsis. Six patients are still alive after a median follow-up time of 544 days (92-600) after transplantation. Considering the severity of the cases and the bad prognosis associated with advanced acute GVHD, we find our results encouraging. Anti-TNF-a seems to be a useful agent for the treatment of acute GVHD.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Glucocorticoides/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Metilprednisolona/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Doença Aguda , Adolescente , Adulto , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Infliximab , Leucemia/mortalidade , Leucemia/cirurgia , Masculino , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Striking progress has been observed in the number of volunteer donors for hematopoietic stem cell transplantation in the last years in Brazil. By the end of 1998, the number of donors barely reached 4200 but it has grown progressively. It was close to 48,000 by the end of May 1993. It is possible to notice a steady increase from the first (1993 to 2000) to the last years (2001 to 2003). The regulation of each procedure by the Brazilian Health System, with the collaboration of the Hematology Societies, was essential for the success of Redome and for the stem cell transplantation program in Brazil. However, when analyzing these results some problems were detected: 95% of Redome donors come from the south and southeastern regions of the country, while few donors are from the north, northeast, and central parts of Brazil. The different miscegenation of races in different regions and states of Brazil makes this an important issue: to represent the whole Brazilian population, Redome must improve the donor search in such places. It also became clear that several other centers involved in unrelated hematopoietic transplantation must be accredited to avoid a long line of patients with compatible donors a waiting transplantation.
Assuntos
Medula Óssea , Experimentação Humana/estatística & dados numéricos , Sistema de Registros , Doadores de Tecidos/estatística & dados numéricos , Brasil , HumanosRESUMO
BACKGROUND: PBSC transplant provides 10 times more T cells than BMT However, the incidence and severity of acute GvHD is similar among recipients of both types of transplants. Studies in mouse models suggest that the similar clinical outcome in BMT and PBSCT is due to differences in the lymphokine profiles. METHODS: PBMC, PBMC from G-CSF mobilized donors (G-PBMC)and BM mononuclear cells (BM-MC) were analyzed by flow cytometry and ELISA to detect gamma-IFN and IL-4 production. Hematoxylin and eosin staining was used to identify morphology and annexin/propidium-iodide was used for apoptosis assays. RESULTS: We show decreased production of gamma-interferon (85%) and IL-4 (60%) in G-PBMC when compared with either PBMC or BM-MCT cells on ex vivo assays. Surprisingly, 85% of fresh G-PBMC is composed of low-density granulocytes (LDG), which undergo apoptosis after 48 h in culture. At this same time, gamma-IFN production from G-PBMC T cell was reverted. In vitro, G-CSF converts granulocytes into LDGs, able to inhibit T-cell function by H2O2 production, and not through immune-deviation towards a Th2-type phenotype. DISCUSSION: We show that the estimated numbers of Th1 and Th2 cells infused in BMT and PBSCT do not differ significantly. These findings are discussed with reference to the relatively low incidence of acute GvHD in PBSCT shown in the literature. We suggest that these results might depend on the high number of granulocytes and progenitors infused. The potential use of granulocytes as immunosupressive short-term therapy is now being investigated by our group using a mouse experimental model.
Assuntos
Granulócitos/fisiologia , Transplante de Células-Tronco de Sangue Periférico , Linfócitos T/fisiologia , Acetato de Tetradecanoilforbol/análogos & derivados , Anexina A5/análise , Antígenos CD/análise , Apoptose/fisiologia , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/fisiologia , Transplante de Medula Óssea , Complexo CD3/análise , Catalase/farmacologia , Contagem de Células , Citometria de Fluxo , Fator Estimulador de Colônias de Granulócitos/farmacologia , Granulócitos/citologia , Granulócitos/efeitos dos fármacos , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Humanos , Peróxido de Hidrogênio/metabolismo , Interferon gama/análise , Interleucina-4/análise , Ionomicina/farmacologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/fisiologia , Leucossialina , Teste de Cultura Mista de Linfócitos , Ativação de Neutrófilo/efeitos dos fármacos , Ativação de Neutrófilo/fisiologia , Sialoglicoproteínas/análise , Linfócitos T/química , Linfócitos T/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia , Fatores de TempoRESUMO
In order to assess the effect of delaying G-CSF administration after autologous peripheral blood progenitor cell (PBPC) transplantation on the duration of neutropenia, 87 patients were randomized to receive G-CSF 5 microg/kg/day starting on day +1 (n = 45) or +5 (n = 42) following PBPC transplantation, until recovery of the neutrophils. The duration of neutropenia (<0.5 x 10(9)/l) was shorter in the day +1 group (7 vs 8 days; P = 0.02), especially in patients receiving melphalan 200 mg/m(2) and CD34(+) cell doses >3.0 x 10(6)/kg. These patients had a later onset of neutropenia after transplant. There were no differences in time to neutrophil and platelet engraftment, or in the incidence of fever and documentation of infection. Although the duration of antibiotic therapy (7 vs 10.5 days; P = 0.01) and time to hospital discharge (13 vs 15 days; P = 0.02) were shorter in the day +1 group, these differences could not be predicted by the day of G-CSF initiation in multivariate analysis. Starting G-CSF on day +1 does not result in faster neutrophil engraftment but in later onset and consequently, slightly shorter duration of neutropenia in patients who receive melphalan 200 mg/m(2) and CD34(+) cell doses >3.0 x 10(6)/kg.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco de Sangue Periférico/métodos , Adolescente , Adulto , Idoso , Esquema de Medicação , Feminino , Febre/etiologia , Febre/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Hematopoese/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/prevenção & controle , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Estudos Prospectivos , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodos , Resultado do TratamentoRESUMO
Single-step Multiplex RT-PCR was used as a rapid and highly sensitive method for screening patients with myeloproliferative conditions and ALL for the presence of underlying BCR-ABL gene fusions. Positive and negative results obtained with the multiplex assay were subsequently confirmed by nested PCR. We studied 21 patients for detecting the presence of b3a2, b2a2 and e1a2 BCR-ABL transcripts at diagnosis and following treatment with different therapeutical procedures. These studies allowed the molecular characterisation of patients with different haematological disorders and for demonstrating BCR-ABL transcripts in Ph-CML. In a Ph+ CML patient, a switch of isoforms was detected after bone marrow transplantation and infusion with donor lymphocytes, implying substitution of e1a2 for b3a2 coexisting with a myeloid/lymphoid biphenotypic profile. In ALL, one Ph+ patient showed coexpression of e1a2 and b2a2 at diagnosis followed by persistence of e1a2 after bone marrow transplantation. Our results were compared to previous findings in the literature on molecular diagnosis of leukaemias.
Assuntos
Proteínas de Fusão bcr-abl/metabolismo , Neoplasias Hematológicas/metabolismo , DNA Complementar , Proteínas de Fusão bcr-abl/genética , Neoplasias Hematológicas/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , RNA/análiseRESUMO
Polymerase chain reaction (PCR) is a powerful and rapid method for specifically detecting BCR-ABL rearrangement by amplification of the complementary DNA (cDNA) produced by reverse transcription of BCR-ABL mRNA. We studied 29 patients for detecting the presence of BCR-ABL transcripts before and after bone marrow transplantation (BMT). Our sample was composed of two different groups of patients: one group (n = 18) was studied by serial follow-ups before and after BMT; a second group (n = 11) was studied several years after BMT. Detection of BCR-ABL was carried out with different primer sets at different periods of the clinical outcome of chronic myeloid leukaemia (CML). A comparison of PCR data and clinical-haematological conditions showed clear differences between patients. In the first group, eight patients showed a positive correlation between a favourable clinical outcome and molecular remission. Conversely, in the second group, six patients were BCR-ABL positive between 20 and 117 months after BMT, while only two of these patients showed signs of clinical relapse. Among all patients whose isoforms were known at some time during the course of CML, the more frequent isoform was b3a2. These results were compared to previous findings in the literature on diagnosis, outcome and prognosis of CML.
Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , Transplante de Medula Óssea , HumanosRESUMO
Clinical, karyotypic, immunophenotypic, and molecular profiles of three TALL cases carrying a t(11;14) are discussed and compared with data in the literature. As previously reported, t(11;14)(p13;q11) was associated in one patient with a TALL profile of intermediate stage of maturation (CD7+, CD4+, CD8+). However, the same translocation was found to be present in another patient with a more immature, pro-TALL profile (CD7+, CD4-, CD8-). Both patients showed molecular rearrangements of the TCR beta chain gene. A third patient, with a very immature pro-TALL profile (CD34+, CD7+, CD4-, CD8-), carrying a t(11;14)(p15;q11), showed molecular rearrangements of the TCR beta and gamma chain genes, while the IgH chain genes were in germline configuration. Our data indicate that t(11;14) can also be present in TALLs of more immature stages of intrathymic development; the significant factor determining the clinical behavior of TALLs is apparently related more to cell differentiation than to the presence of this chromosome rearrangement.
Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Leucemia-Linfoma de Células T do Adulto/genética , Translocação Genética , Adolescente , Antígenos CD/análise , Criança , Humanos , Leucemia-Linfoma de Células T do Adulto/imunologia , MasculinoRESUMO
The immunological reconstitution that follows bone marrow transplantation (BMT) was studied in 40 leukaemia patients: 19 with chronic myeloid leukaemia (CML), 12 with acute myeloid leukaemia (AML) and the remaining 9 with acute lymphoblastic leukaemia (ALL). The recovery of the CML group was slower than that of the ALL and AML groups. This difference was produced by the T cell compartment, as NK cell activity and B cell numbers did not differ significantly. Factors such as conditioning treatment and graft versus host disease (GVHD) prophylaxis were analysed. Our experience suggests that all leukaemia patients should not be considered as one group when analysing their immunological reconstitution, as factors related to the original disease may affect their outcome.
Assuntos
Transplante de Medula Óssea/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Linfócitos T/fisiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Células Matadoras Naturais/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
The enzyme myeloperoxidase (MPO) is the most specific marker of myeloid lineage. The recognition of acute myeloid leukaemia (AML) with minimally differentiation (AML-M0) is established with methods that include myeloid markers CD13/CD33 and detection of MPO in blast cells by immunological techniques or electron microscopy cytochemistry (EM). We have analysed the presence of MPO in leukaemic blast cells by conventional cytochemistry and immunological methods using a monoclonal antibody anti-MPO (CLB-MPO1) in 121 cases of acute leukaemia. The aim of the study was to investigate the sensitivity of this McAb to identify AML-M0, as CD13/CD33 can be expressed in some cases of acute lymphoblastic leukaemia (ALL) and EM cytochemistry is not always available in many laboratories. Anti-MPO was positive in all cases of AML (M1-M5) which were positive by Sudan Black B reaction in similar or higher percentage ratio for each case, although in some of them did not label with CD13/CD33 tested by IF and IPc techniques. Based on the anti-MPO positivity, 5 out of 10 cases called undifferentiated leukaemia (AUL) were reclassified as AML-M0, though 4 cases were CD13/CD33 negative. Furthermore, after analysing the anti-MPO expression among 32 cases of ALL, we had to reclassify four of them as acute biphenotypic leukaemia. We conclude that anti-MPO is a very sensitive and reliable tool in AML diagnosis and has an important role in distinguishing minimally differentiated AML and biphenotypic acute leukaemia from AUL and ALL.
Assuntos
Anticorpos Monoclonais , Biomarcadores Tumorais/análise , Leucemia Mieloide/diagnóstico , Peroxidase/análise , Doença Aguda , Adolescente , Adulto , Idoso , Antígenos CD/análise , Crise Blástica/diagnóstico , Crise Blástica/patologia , Diferenciação Celular , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Leucemia Mieloide/enzimologia , Leucemia Mieloide/patologia , Masculino , Pessoa de Meia-Idade , Peroxidase/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnósticoRESUMO
Administration of interleukin 1 (IL-1) or tumor necrosis factor-alpha (TNF alpha) protects bone marrow precursor cells (BMPC) from ionizing radiation and antineoplastic drugs. The time of injection is critical: the best protective results being obtained when cytokines are given around 24h prior to the induced injury. Multiple daily cytokine injections that precede irradiation or drug administration are more effective than single ones although single doses are quite effective at increasing survival in mice. Protection is positively correlated with both rapid granulocyte recovery and BMPC survival. Mechanisms involved in BMPC radioprotection include: (1) push to the S/G2 + M or arrest in the G0 phases of the cell cycle by IL-1 or TNF alpha, respectively, and (2) induction of mitochondrial manganous superoxide dismutase synthesis. For BMPC chemoprotection, proposed mechanisms are: (1) increase of aldehyde dehydrogenase synthesis, and (2) modulation of multiple-drug resistant gene expression. Stimulation of glutathione synthesis in BMPC could be operating in both radio- and chemoprotection. These findings point to the relevance of IL-1 or TNF alpha in cancer therapy as a means of reducing BMPC sensitivity to cytoreductive drugs or irradiation (including radioimmunotherapy) as well as in in vitro tumor cell purging with drugs in autologous BMT. Prior administration of these cytokines should be also considered for people in imminent danger of exposure to radiation.
Assuntos
Medula Óssea/efeitos dos fármacos , Medula Óssea/efeitos da radiação , Interleucina-1/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/antagonistas & inibidores , Células da Medula Óssea , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Ensaio de Unidades Formadoras de Colônias , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos da radiação , Humanos , Técnicas In Vitro , Interleucina-1/administração & dosagem , Interleucina-1/efeitos adversos , Neoplasias/terapia , Lesões por Radiação/prevenção & controle , Protetores contra Radiação/farmacologia , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/efeitos adversosRESUMO
We describe a case of allograft rejection that occurred 23 months after successful bone marrow transplantation for severe aplastic anemia in a patient with paroxysmal nocturnal hemoglobinuria. The allograft rejection appears to have been induced by recombinant alpha-interferon (rINF-alpha) treatment for non-A, non-B hepatitis that developed 11 months after transplantation. During the 9 months of active hepatitis, the donor graft functioned normally; however, 3 months after rINF-alpha therapy was started, pancytopenia and a chimeric hematopoietic state developed. rINF-alpha was discontinued, cyclosporin A was reintroduced, and autologous bone marrow recovery followed. rINF-alpha treatment may be detrimental to some recipients of allogeneic bone marrow transplants.
Assuntos
Transplante de Medula Óssea , Rejeição de Enxerto , Hemoglobinúria Paroxística/terapia , Hepatite Crônica/terapia , Interferon-alfa/efeitos adversos , Adulto , Transplante de Medula Óssea/efeitos adversos , Ciclosporina/uso terapêutico , Feminino , Hepatite Crônica/etiologia , HumanosRESUMO
1. Acute leukemias have been defined as major types of lymphoblastic and myeloblastic leukemias according to morphological and cytochemical criteria. 2. The technical improvements and standardization of immunofluorescence and immunocytology staining methods have provided new insights for classifying these disorders on the basis of monoclonal antibodies. 3. The scheme used to describe normal lymphoid and myeloid differentiation, when also used to describe their malignant counterparts, provides a well-established model for the immunological classification of acute leukemias. 4. In this review article, we suggest some guidelines for performing a series of cytochemical reactions using immunological markers to ensure a reliable diagnosis of acute leukemia.
Assuntos
Anticorpos Monoclonais , Leucemia Mieloide Aguda/diagnóstico , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Antígenos de Diferenciação de Linfócitos T/análise , Diferenciação Celular , Imuno-Histoquímica , Fenótipo , Linfócitos T/patologiaRESUMO
1. Acute leukemias have been defined as major types as of lymphoblastic and myeloblastic leuckemias according to morphological and cytochemical criteria. 2. The thecnical improvements and standardization of immunofluorescence and immunocytology staining methods have provied new insights for classifying these disorders on the basis of monoclonal antibodies. 3. The scheme used to describe normal lymphoid and myeloid differentiation, when also used to describe their malignant counterparts, provides a well-established model for the immunological classification of acute leukemias. 4. In this review article, we suggest some guidelines for performing a series of cytochemical reactions using immunological markers to ensure a reliable diagnosis of acute leukemia
Assuntos
Anticorpos Monoclonais , Leucemia Linfoide/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Antígenos de Diferenciação de Linfócitos T , Diferenciação Celular , Imunofluorescência , Imuno-Histoquímica , Leucemia/classificação , Fenótipo , Linfócitos T/citologiaRESUMO
8 patients with bone marrow failure after a caesium-137 radiation accident were treated with recombinant human granulocyte-macrophage colony stimulating factor (rHuGM-CSF). The 7 who were evaluable had prompt increases in granulocytes and bone marrow cellularity. 2 patients died of radiation toxicity and haemorrhage and 2 of bacterial sepsis acquired before the start of rHuGM-CSF treatment. 4 patients survive, including 2 who were treated early and never became infected. This therapeutic approach to radiation-induced granulocytopenia may therefore be useful after radiation and nuclear accidents.