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1.
Ann Hematol ; 85(5): 308-14, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16525786

RESUMO

Between June 2003 and November 2004, we collected mobilized peripheral blood units from 29 patients with non-Hodgkin's lymphoma and multiple myeloma for autologous peripheral blood stem cell transplantation. They received granulocyte colony-stimulating factor (G-CSF) (16 micro g/kg/day) for a total of 5 days. Immediately before and 3 h after the fourth and fifth dose of G-CSF, we performed flow cytometry analysis to quantify: T cells (CD3+CD4+, CD3+CD8+), B cells (CD19+), NK cells (CD3-CD16+CD56+), NKT cells (CD3+CD16+CD56+), type 1 dendritic cells (DC1) (lin-HLA-DR+CD11c+), type 2 dendritic cells (DC2) (lin-HLA-DR+CD123+), regulatory T cells (Tregs) (CD4+CD25+), and activated T cells (CD3+HLA-DR+). All cell subsets were mobilized after G-CSF treatment with the exception of B, NK, and NKT lymphocytes. The median number of Treg cells before and after G-CSF was statistically different (29+/-14.9x10(6)/l vs 70.1+/-46.1x10(6)/l, P<0.02). DCs were mobilized significantly with a 5.9-fold increase in DC2 (15.1+/-30.3x10(6)/l vs 89.8+/-81.0x10(6)/l, P<0.02) and a 2.6-fold increase for DC1 (41+/-42.5x10(6)/l vs 109.5+/-58.0x10(6)/l, P<0.04). Patients received a mean of 3.1+/-1.2x10(7)/kg NK cells, 1.3+/-0.9x10(7)/kg NKT cells, 0.41+/-0.29x10(7)/kg DC1, 0.2+/-0.22x10(7)/kg DC2, and 1.8+/-1.9x10(7)/kg Tregs. In conclusion, intermediate doses of G-CSF induce mobilization of different lymphocyte subsets, with the exception of B, NK, and NKT cells. The mobilization of certain suppressive populations (DC2 and Treg) could be in theory deleterious, at least in patients with cancer.


Assuntos
Células Dendríticas , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Linfócitos , Linfoma não Hodgkin , Mieloma Múltiplo , Adulto , Idoso , Antígenos de Diferenciação/metabolismo , Fracionamento Celular/métodos , Células Dendríticas/patologia , Feminino , Filgrastim , Humanos , Linfócitos/patologia , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Proteínas Recombinantes , Transplante Autólogo
2.
Ann Hematol ; 85(2): 113-20, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16311734

RESUMO

To analyze the relationship between the cellular composition of peripheral blood allografts and clinical outcome, we performed a prospective study in 45 adult patients who underwent allogeneic peripheral blood hematopoietic stem cell transplantation (HSCT) from a histocompatibility leukocyte antigen identical sibling donor for different hematological malignancies. The dose of CD34+, CD3+, CD4+, CD8+, and CD19+ lymphocytes, natural killer (NK) cells, natural killer T (NKT) cells, type 1 and type 2 dendritic cells (DC1 and DC2), as well as regulatory T (Treg) lymphocytes was analyzed. All patients were conditioned with busulphan and cyclophosphamide (BuCy2) +/- VP-16 and received a short course of methotrexate and cyclosporin-A as graft-versus-host disease (GVHD) prophylaxis. Acute GVHD (aGVHD) was present in 9 of 43 (21%) patients, and chronic GVHD (cGVHD) developed in 18 of 39 (46%) patients. There was a significantly higher incidence of aGVHD in patients receiving more than 6x10(6)/kg CD34+ cells. In univariate analysis, variables associated with better survival were as follows: a dose of less than 1.5x10(7)/kg NKT cells and less than 1.7x10(6)/kg DC2 for disease-free survival (DFS), and a dose of less than 3x10(7)/kg NK cells, less than 1.5x10(7)/kg NKT cells, less than 3x10(6)/kg DC1, and less than 1.7x10(6)/kg DC2 for overall survival (OS). In the Cox regression analysis, the dose of NKT cells was the only variable associated with better DFS, while the doses of NK, NKT, and CD34+ cells (less than 8x10(6)/kg) were associated with better OS. In conclusion, different circulating cell populations, other than CD34+ cells, are also of relevance in predicting the clinical outcome after allogeneic peripheral blood HSCT.


Assuntos
Células Dendríticas/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismo , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Células Matadoras Naturais/citologia , Adolescente , Adulto , Antígenos CD19/biossíntese , Antígenos CD34/biossíntese , Complexo CD3/biossíntese , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Criança , Feminino , Doença Enxerto-Hospedeiro/terapia , Humanos , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Linfócitos T Reguladores/metabolismo , Condicionamento Pré-Transplante/métodos , Transplante Homólogo
3.
Stem Cells Dev ; 14(3): 310-6, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15969626

RESUMO

We prospectively conducted a quantitative and phenotypic analysis of T, B, natural killer (NK), NKT, type 1 and 2 dendritic cells (DC), and regulatory T cells, before and after mobilization with intermediate doses of granulocyte colony-stimulating factor (G-CSF) (16 microg/kg per day). Between November, 2003, and December, 2004, we collected stem cells from 25 HLA identical sibling donors for allogeneic hematopoietic stem cell transplantation. Before mobilization and 3 h after the fourth and fifth doses of G-CSF, blood samples were taken for blood counts and flow cytometry. The median number of regulatory T cells before and after G-CSF was statistically different (69 +/- 41 x 10(6)/L versus 161 +/- 159 x 10(6)/L, p < 0.01). We observed a 1.7-fold increase in NK and NKT cells (p < 0.009 and p < 0.02, respectively). DC were mobilized with a 11.5-fold increase in type 2 (p < 0.004) and a 8.5-fold increase in type 1 DC (p < 0.003). The patients received a mean of: 2.2 x 10(7)/kg +/- 1.4 x 10(7)/kg of NK cells, 0.95 x 10(7)/kg +/- 0.81 x 107/kg of NKT cells, 0.43 x 107/kg +/- 0.53 x 10(7)/kg of type 1 DC, 0.3 v 10(7)/kg +/- 0.45 x 10(7)/kg of type 2 DC and 1.4 x 10(7)/kg +/- 1.2 x 10(7)/kg of regulatory T cells. Using intermediate doses of G-CSF, we have demonstrated the mobilization of different lymphocyte subsets, in particular regulatory T cells and DC, which can be expanded later and used in the treatment of cancer and autoimmune diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Transplante de Células/métodos , Células Dendríticas/imunologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Ativação Linfocitária , Linfócitos/imunologia , Receptores de Interleucina-2/análise , Células-Tronco/citologia , Adulto , Antígenos CD/análise , Remoção de Componentes Sanguíneos/métodos , Feminino , Mobilização de Células-Tronco Hematopoéticas/métodos , Humanos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Irmãos
4.
Stem Cells Dev ; 13(5): 571-9, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15588514

RESUMO

Reduced intensity conditioning (RIC) have allowed the application of transplantation to older patients and to patients with underlying medical problems. Between October, 1999, and June, 2003, 61 patients with acute leukemia or chronic myeloid leukemia received allogeneic peripheral blood hematopoietic stem cell transplantation (HSCT) from HLA-identical siblings. Thirty-four were conditioned with myeloablative protocols and twenty-seven with RIC regimens. The patients in the myeloablative group were younger (29 vs. 37 years; p < 0.0003), most of them were transplanted in complete remission (74% vs. 59%; p < 0.03), had a shorter interval between diagnosis and HSCT (12 vs. 21 months; p < 0.02) and a greater proportion belonged to standard-risk prognosis (68% vs. 48%; p < 0.1). The median times to neutrophil, platelet and red blood cell engraftment for the myeloablative and RIC groups were 14 versus 11 days (p < 0.009), 17 versus 9 days (p < 0.0001), and 19 versus 12 days (p < 0.007), respectively. Transfusion requirements were lower in the RIC group. Severe mucositis was present in 32% and 7%, respectively (p < 0.01). The proportion of patients having acute graft versus-disease (GVHD), chronic GVHD, and infections was the same, as well as early and late mortality, disease-free survival, and overall survival. Analyzing all the patients together, three factors significantly influenced overall survival: standard risk patients, complete remission at transplant, and the absence of severe acute GVHD. In conclusion, our data suggest that even in high-risk patients, RIC transplantation seems to be as useful as ablative HSCT.


Assuntos
Transfusão de Sangue/métodos , Leucemia/terapia , Transplante de Células-Tronco/métodos , Transplante Homólogo , Adolescente , Adulto , Transplante de Células , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Imunossupressores/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mucosa/metabolismo , Mucosa/patologia , Prognóstico , Recidiva , Indução de Remissão , Risco , Fatores de Tempo , Condicionamento Pré-Transplante , Resultado do Tratamento
5.
Ann Hematol ; 83(5): 295-301, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15060749

RESUMO

Between December 1993 and November 2001, 30 patients with chronic myeloid leukemia who relapsed after stem cell transplantation were studied. Seventeen patients were not treated before donor lymphocyte infusion (DLI), eight patients received interferon-alpha (IFN-alpha), and five underwent chemotherapy. The method of DLI was the bulk dose regimen. The median time between DLIs was 6 weeks. The median number of infusions was three; the median time from transplant to relapse was 17 months and from relapse to DLI 2 months. Eleven patients (37%) were in molecular/cytogenetic relapse, 14 (47%) in chronic phase, and five (16%) in accelerated or blastic phase. Seventeen patients (57%) developed acute graft-versus-host disease (GVHD). Chronic GVHD was observed in 15 of 24 (62%) patients. Four (13%) patients developed cytopenia after a median of 30 days. Nineteen (63%) patients achieved response, 15 of them developed GVHD. The response rate according to the disease phase was molecular or cytogenetic relapse: 91%, chronic phase: 57%, and accelerated or blastic phase: 20%. The median time to response was 6 months. Patients treated with IFN-alpha or no treatment as well as those who were in molecular/cytogenetic relapse and those who received a CD3(+) cell dose <1 x 10(8)/kg and CD4(+) <8 x 10(7)/kg had better survival. We conclude that patients who receive lower doses of lymphocytes have better survival. In some patients IFN-alpha seems to be a good choice to potentiate the graft-versus-leukemia (GVL) effect.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Transfusão de Linfócitos , Recidiva Local de Neoplasia/terapia , Transplante de Células-Tronco , Doadores de Tecidos , Adolescente , Adulto , Antineoplásicos/uso terapêutico , Complexo CD3/análise , Antígenos CD4/análise , Terapia Combinada , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Incidência , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/cirurgia , Transfusão de Linfócitos/efeitos adversos , Linfócitos/imunologia , Masculino , Análise Multivariada , Prognóstico , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento
6.
Ann Hematol ; 81(7): 362-7, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12185504

RESUMO

Primary plasma cell leukemia (PPCL) is a rare form of disease accounting for 1-2 percent of myelomas. Between September 1990 and November 2000, among 540 patients with myeloma studied, 24 fulfilled the criteria of PPCL (4.4 percent). We found high frequencies of female patients (62 percent), Bence Jones proteinuria (79 percent), anemia (88 percent), bleeding (54 percent), confusional syndrome (42 percent), weight loss (71 percent), hepatomegaly (25 percent), splenomegaly (21 percent), leukocytosis (62 percent), and thrombocytopenia (71 percent). High serum levels of creatinine, calcium, lactate dehydrogenase (LDH), and beta(2)-microglobulin were detected in 50 percent, 37 percent, 58 percent, and 71 percent, respectively. Four patients were treated with vincristine, melphalan, cyclophosphamide, prednisone, and adriamycin (VMCPA), 12 with vincristine, adriamycin, and dexamethasone (VAD), and 8 with M-80 (oral melphalan 80 mg/m(2) plus dexamethasone 40 mg/m(2)). There was a trend toward lower values of Karnofsky score (P=0.07) and higher values of LDH (P=0.2) in the VAD group. Other clinical characteristics were comparable among the three groups. Complete plus partial responses were achieved in one and six patients treated with VMCPA and M-80, respectively. All patients treated with VAD failed to respond to treatment. Patients receiving the M-80 regimen experienced higher platelet toxicity (P=0.05), vomiting (P<0.0003), and mucositis. Also, the need for red blood cell transfusions was higher in the M-80 group. Median overall survival was 60 days. Overall survival was better in patients achieving complete or partial response. In conclusion, our study illustrates that intermediate doses of melphalan plus dexamethasone are an effective chemotherapy regimen for this aggressive disease. Response to treatment is the only prognostic factor for survival in these patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Plasmocitária/tratamento farmacológico , Melfalan/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fotoquimioterapia , Análise de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem
7.
Arch Med Res ; 31(2): 206-9, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10880729

RESUMO

BACKGROUND: Bone marrow transplantation (BMT) is the therapy of choice for patients with chronic myeloid leukemia (CML) who have a human leukocyte antigen (HLA)-identical donor and are under 50 years of age. METHODS: Here, 45 patients with CML were treated with busulfan (Bu) 16 mg/kg and cyclophosphamide (Cy) 120 mg/kg before allogeneic BMT from an HLA-identical sibling 27 (60%) or a 1-antigen mismatch donor 18 (40%). Eighteen patients (40%) were in the early chronic phase (CP) and 27 (60%) in late CP. We used cyclosporin-A (CsA) in 20 patients and cyclosporin-A-methotrexate (CsA-MTX) in 25 for graft-vs.-host disease (GVHD) prophylaxis. RESULTS: We observed a high incidence of acute and chronic GVHD (69% and 67%, respectively). A multivariate analysis identified differences in the sex of the donor and the recipient (p = 0.03) and grade III-IV acute GVHD (p = 0.0001) as significant adverse influences on disease-free survival. Age, sex, chronic GVHD, disease phase, one antigen-mismatch and use of CsA or CsA-MTX had no statistical significance. The 3-year probabilities of relapse, disease-free survival, and overall survival were 11%, 55%, and 60%, respectively. Transplant-related mortality occurred in 31% of the cases. The high frequency of GVHD is explained by HLA determination by serological typing, differences in sex between the donor and recipient, and a high proportion (40%) of 1 antigen-mismatch donors. CONCLUSIONS: BMT is a procedure feasible for patients with CML in early and late chronic phase and even in those with an HLA non-identical donor. Strategies directed to decrease acute GVHD could improve the outcome of these patients.


Assuntos
Transplante de Medula Óssea , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Transplante Homólogo , Adolescente , Adulto , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/estatística & dados numéricos , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Histocompatibilidade , Humanos , Infecções/etiologia , Infecções/mortalidade , Inflamação/etiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Tábuas de Vida , Masculino , México , Pessoa de Meia-Idade , Cromossomo Filadélfia , Pré-Medicação , Modelos de Riscos Proporcionais , Recidiva , Análise de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/estatística & dados numéricos , Resultado do Tratamento
8.
Bone Marrow Transplant ; 25(11): 1141-6, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10849526

RESUMO

Between August 1994 and June 1999, 56 patients were prospectively randomized to receive ifosfamide 10 g/m2 + GM-CSF 5 microg/kg/day (IFO+GM-CSF n = 28) and cyclophosphamide 4 g/m2 + GM-CSF 5 microg/kg/day (CY+GM-CSF n = 28). Both groups were comparable for age, gender, diagnosis, disease stage and previous chemotherapy. The IFO+GM-CSF group demonstrated a shorter median interval between therapy and apheresis (10 days (8-14) vs 13 days (8-25) P = 0.002), median number of doses of GM-CSF (9 (7-13) vs 15 (9-31) P = 0.001), median of days with aplasia (0.5 (0-10) vs 6 (0-21) P = 0.001), median days with fever (0 (0-6) vs 3 (0-9) P = 0.006) and median of days using i.v. antibiotics (0 (0-11) vs 7.5 (0-19) P = 0.002). The median MNC yield was similar in both groups. The CD34+ cell yield was better in the CY+GM-CSF group (3.14 (0.9-11.8) vs 5.33 (0. 08-32)) but not at significant levels (P = 0.1). White blood cell hematopoietic recovery was more rapid in the CY+GM-CSF group (16 (10-22) vs 13 (10-24) P = 0.02). Platelet engraftment was similar in both groups. Costs of mobilization and transplantation were almost the same: $28 570 ($18 527-$47 028) and $30 020 ($17 281-$67 591), respectively (P = 0.9). There were no differences in disease-free survival and overall survival between both groups. Mild and transient non-hematological toxicity (hemorrhagic cystitis, decrease in serum creatinine clearance and CNS dysfunction) was seen most frequently in the IFO+GM-CSF group.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Ifosfamida/uso terapêutico , Linfoma não Hodgkin/terapia , Mieloma Múltiplo/terapia , Adolescente , Adulto , Carmustina/administração & dosagem , Criopreservação , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Células-Tronco Hematopoéticas/patologia , Doença de Hodgkin/mortalidade , Humanos , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Estudos Prospectivos , Proteínas Recombinantes , Análise de Regressão , Taxa de Sobrevida , Transplante Autólogo
9.
Bone Marrow Transplant ; 24(9): 1029-31, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10556964

RESUMO

A 24-year-old woman with CML underwent allogeneic BMT in August 1995 from a one-antigen HLA mismatched brother. Conditioning included BuCy2 and CsA and MTX were used to prevent GVHD. In July 1997 she developed right leg pain, lytic bone lesions of distal femur and a solid mass of soft tissue. Histological diagnosis of malignant fibrous histiocytoma was made. Despite treatment with surgery and chemotherapy (doxorubicin and ifosfamide), the patient died 1 year later with local recurrence of the tumor and liver, lung and brain metastases. The CML was in CR.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Histiocitoma Fibroso Benigno/etiologia , Leucemia Mieloide de Fase Crônica/terapia , Segunda Neoplasia Primária/etiologia , Adulto , Feminino , Neoplasias Femorais/diagnóstico , Neoplasias Femorais/etiologia , Histiocitoma Fibroso Benigno/diagnóstico , Humanos , Masculino , Segunda Neoplasia Primária/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/etiologia , Transplante Homólogo
10.
Bone Marrow Transplant ; 24(12): 1307-10, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10627639

RESUMO

In the present study, we assessed the clinical effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in the treatment of refractory, grade III-IV hemorrhagic cystitis (HC) in six patients who underwent bone marrow transplantation (BMT). These were four males and two females, aged 24-40 years (median age 30.5 years). All received allogeneic BMT from HLA-identical siblings after preparation with busulfan-cyclophosphamide. HC was evident 24. 5 days (range 15-33 days) after BMT. Median duration of HC before treatment was 5 days (range 4-9 days). Treatment consisted of intravesical instillation of rhGM-CSF (400 microg) for 3 consecutive days. A complete response was observed in three patients, the other three showed a partial response. Median time to achieve response was 36 h (range 0.2-72 h). Hematuria was controlled after the first (two patients), second (two patients) or third (two patients) dose of intravesical rhGM-CSF. Patients were discharged from the hospital 10. 5 days (range 3-41 days) after treatment. All patients have been followed for up to 10 months and none have required further treatment. No systemic or bladder side-effects have been observed. Although our results indicate that intravesical instillation of rhGM-CSF is effective in the treatment of HC, a phase II clinical trial, including a larger series of patients, is needed.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Cistite/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Adulto , Cistite/etiologia , Intervalo Livre de Doença , Transfusão de Eritrócitos , Feminino , Hematúria/complicações , Hemorragia , Humanos , Leucemia/complicações , Masculino , Proteínas Recombinantes/administração & dosagem , Transplante Homólogo , Resultado do Tratamento , Doenças da Bexiga Urinária/complicações
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