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1.
Cytotherapy ; 8(4): 375-80, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16923613

RESUMO

BACKGROUND: Poor graft function without rejection may occur after stem cell transplantation (SCT). CD34(+) stem cell boost (SCB) can restore marrow function but may induce or exacerbate GvHD. We therefore investigated the feasibility and efficacy of CD34(+)-selected SCB in some patients with poor graft function. We present the results for eight patients (median age 46 years) transplanted initially for myelofibrosis, acute leukemia, myeloma and NHL. Six patients had received HLA-matched and two mismatched grafts (PB, BM; n=5, 3). After a median of 128 days post-transplant, the median leukocyte and platelet counts were, respectively, 2.05/nL and 18/nL. None had achieved platelet counts >50/nL even though donor chimerism was >95% in seven recipients. METHODS: Positive selection of CD34(+) stem cells was performed on a CliniMACS device, observing GMP and achieving a median of 98.5% purity. The patients received a median of 1.7 x 10(6)/kg CD34(+) cells and 2.5 x 10(3)/kg CD3(+) T lymphocytes. RESULTS: Hemograms at days +30, +60 and +90, respectively, showed steadily increasing median leukocyte (2.55, 3.15 and 4.20/nL) and platelet (29, 39 and 95/nL) counts. After a median follow-up of 144 days, five patients remained alive. No patient had developed acute or chronic GvHD. One patient died of leukemic relapse and two others of systemic mycosis. DISCUSSION: These preliminary results point to the possibility of safely improving graft function using CD34(+) positively selected stem cells without necessarily increasing the incidence of GvHD in patients with poor graft function post-SCT. Experience with more patients and longer follow-up should clarify the optimal role for this procedure.


Assuntos
Antígenos CD34/metabolismo , Transplante de Células-Tronco , Células-Tronco/imunologia , Células-Tronco/fisiologia , Adolescente , Adulto , Feminino , Doença Enxerto-Hospedeiro , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco/citologia , Transplante Homólogo
2.
Bone Marrow Transplant ; 37(4): 339-44, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16415898

RESUMO

We investigated a dose-reduced conditioning regimen consisting of treosulfan and fludarabine followed by allogeneic stem cell transplantation (SCT) in 26 patients with secondary AML or MDS. Twenty patients were transplanted from matched or mismatched unrelated donors and six from HLA-identical sibling donors. The median age of the patients was 60 years (range, 44-70). None of the patients was eligible for a standard myeloablative preparative regimen. No graft-failure was observed, and leukocyte and platelet engraftment were observed after a median of 16 and 17 days, respectively. Acute graft-versus-host disease (GvHD) grade II-IV was seen in 23% and severe grade III GvHD in 12% of the patients. No patients experienced grade IV acute GvHD. Chronic GvHD was noted in 36% of the patients, which was extensive disease in 18%. The 2-year cumulative incidence of relapse was 21%. The relapse rate was higher in patients beyond CR1 or with intermediate two or high risk MDS (P = 0.02). The treatment-related mortality at day 100 was 28%. The 2-year estimated overall and disease-free survival was 36-34%, respectively. No difference in survival was seen between unrelated and related SCT.


Assuntos
Soro Antilinfocitário/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide/terapia , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Doença Aguda , Adulto , Idoso , Soro Antilinfocitário/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA/análise , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Irmãos , Taxa de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos
3.
Bone Marrow Transplant ; 37(1): 45-50, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16258531

RESUMO

We examined retrospectively 44 patients with refractory acute leukemia (acute myeloid leukemia (AML)/acute lymphoblastic leukemia=25/19) who underwent allogeneic transplantation at our center between 11/1990 and 04/2004. The median leukemic blasts was 25% and age 28 years (range, 3-56). Twenty-one patients had untreated relapse, 13 failed reinduction, eight in partial remission and two aplastic. Conditioning was myeloablative using cyclophosphamide, busulfan, total-body irradiation and etoposide (Bu/Cy/VP, n=22; TBI/Cy/VP, n=17; others, n=5) followed by marrow or peripheral blood transplant (n=23/21) from unrelated or related donors (n=28/16). All patients had graft-versus-host disease (GVHD) prophylaxis with cyclosporin and methotrexate. One patient experienced late graft failure. Severe acute-GVHD and chronic-GVHD appeared in eight and 14 patients, respectively. Thirteen patients (30%) remain alive after a median of 25.3 months (range, 2.4-134.1); with 31 deaths, mostly from relapse (n=15) and infections (n=12). Overall survival (OS) and progression-free survival (PFS) at 5 years was 28 and 26%, respectively. OS and PFS were significantly better with blasts < or =20% and time to transplant < or =1 year while transplant-related mortality was less with the use of TBI. We conclude that patients with refractory leukemia can benefit from allogeneic BMT, especially with < or =20% marrow blast.


Assuntos
Crise Blástica/terapia , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Adolescente , Adulto , Crise Blástica/complicações , Crise Blástica/mortalidade , Crise Blástica/patologia , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Estudos Retrospectivos , Transplante Homólogo , Irradiação Corporal Total/métodos
4.
Bone Marrow Transplant ; 37(2): 155-63, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16284608

RESUMO

We report the results of 84 patients with ALL after related (n = 46) or unrelated (n = 38) allogeneic SCT. Mean recipient age was 23 years (range: 1-60) and median follow-up was 18 months (range: 1-133). Forty-three patients were transplanted in CR1; 25 in CR2 or CR3; four were primary refractory; four in PR; eight in relapse. The conditioning regimen consisted of TBI/VP16/CY (n = 76), TBI/VP16 (n = 2), TBI/CY (n = 2), Bu/VP16/CY (n = 4). The OS at 3 years was 45% (44% unrelated, 46% related). Univariate analysis showed a significantly better OS for patients <18 years (P=0.03), mismatched sex-combination (P = 0.03), both with a stronger effect on increasing OS after unrelated SCT. Factors decreasing TRM were patient age <18 years (P = 0.004), patient CMV-seronegativity (P = 0.014), female recipient (P = 0.04). There was no significant difference in TRM and the relapse rate was similar in both donor type groups. Multivariate analysis showed that factors for increased OS which remained significant were mismatched sex-combination (RR: 0.70,95% CI: 0.51-0.93, P = 0.015), patient age < 18 years (RR: 0.66, 95% CI: 0.47-0.93, P = 0.016). A decreased TRM was found for female patients (RR: 0.56, 95% CI: 0.33-0.98, P=0.042), negative CMV status of the patient (RR: 0.57, 95% CI: 0.36-0.90, P = 0.015). Unrelated stem cell transplantation for high-risk ALL patients with no HLA-compatible family donor is justifiable.


Assuntos
Seleção do Doador , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/mortalidade , Intervalo Livre de Doença , Seleção do Doador/métodos , Feminino , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/métodos , Taxa de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo
5.
Ann Hematol ; 81(11): 627-31, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12454700

RESUMO

We investigated the efficacy of an antithymocyte globulin/cyclophosphamide preparative regimen prior to allogeneic stem cell transplantation from HLA-identical siblings in patients with severe aplastic anemia. Since 1990, 21 patients, 6 males and 15 females, with a median age of 25 years (range: 7-43) have been enrolled in the protocol consisting of 200 mg/kg cyclophosphamide and 90-120 mg/kg antithymocyte globulin (ATG, rabbit, Fresenius, Bad Homburg, Germany). For further graft-versus-host disease (GVHD) prophylaxis all patients received cyclosporin A and a short course of methotrexate (MTX). Only one patient had a primary graft failure (5%). All other patients engrafted with a leukocyte count >1.0 x 10(9)/l and a platelet count >20 x 10(9)/l after a median of 19 (range: 11-28) and 26 days (range: 13-67), respectively. No late graft failure or relapse was observed. Two patients experienced mild acute GVHD grade I (10%), and one patient developed grade II GVHD (5%). No severe grade III/IV GVHD was observed; 17% of the patients developed limited chronic GVHD. The treatment-related mortality was 14% and mainly due to fungal infection. After a median follow-up of 70 months (range: 2-139), the estimated overall and event-free survival at 10 years for all patients is 86% (95% confidence interval: 70-100%). We conclude that ATG plus cyclophosphamide is an effective conditioning regimen in patients with aplastic anemia undergoing stem cell transplantation with a low treatment-related mortality, resulting in an excellent outcome.


Assuntos
Anemia Aplástica/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Anemia Aplástica/complicações , Anemia Aplástica/mortalidade , Soro Antilinfocitário/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Transplante de Medula Óssea/métodos , Transplante de Medula Óssea/mortalidade , Criança , Ciclofosfamida/administração & dosagem , Ciclosporina/administração & dosagem , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Estudos Longitudinais , Masculino , Metotrexato/administração & dosagem , Micoses/induzido quimicamente , Análise de Sobrevida , Condicionamento Pré-Transplante/mortalidade , Transplante Homólogo/métodos , Transplante Homólogo/mortalidade
6.
Bone Marrow Transplant ; 29(8): 683-9, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12180114

RESUMO

One-hundred and two patients with good risk myeloid leukemia (CML first chronic phase or AML first CR) were transplanted from HLA-related donors after conditioning with (n = 45) or without anti-thymocyte globulin (ATG) (n = 57). One graft failure was observed in the non-ATG and none in the ATG group. The median time to leukocyte engraftment (> 1 x 10(9)/l) was 16 (range 12-33) in the ATG group and 17 days (range 11-29) in the non-ATG group (NS) and for platelet engraftment (> 20 x 10(9)/l) 24 and 19 days (P = 0.002), respectively. Acute GVHD grade II-IV was observed in 47% of the non-ATG and in 20% of the ATG group (P = 0.004). Grade III/IV GVHD occurred in 7% of the ATG and in 32% of the non-ATG group (P = 0.002). Chronic GVHD was seen in 36% and 67% (P = 0.005), respectively. After a median follow-up of 48 months (range 2-128), the 5-year estimated OS is 66% (95% KI: 51-81%) for the ATG group and 59% (95% KI: 46-72%) for the non-ATG group (NS). The 5-year estimated DFS is 64% (95% KI: 50-78%) for ATG and 55% (95% KI: 43-67%) for the non-ATG regimen (NS). The 5-year probability of relapse was 5% in the ATG and 15% in the non-ATG group (NS). ATG as part of the conditioning regimen leads to a significant reduction in GVHD without increase of relapse in patients with myeloid leukemia after stem cell transplantation from HLA-related donors.


Assuntos
Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide de Fase Crônica/terapia , Depleção Linfocítica/métodos , Linfócitos T/imunologia , Adolescente , Adulto , Criança , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide de Fase Crônica/imunologia , Masculino , Pessoa de Meia-Idade , Doadores de Tecidos , Transplante Homólogo
7.
Bone Marrow Transplant ; 29(9): 727-30, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12040468

RESUMO

We compared two doses of recombinant human granulocyte-stimulating factor (G-CSF) for stem cell mobilisation in 90 healthy donors for allogeneic stem cell transplantation in a retrospective analysis. Group I (n = 46) received 10 microg/kg G-CSF (filgrastim) given as 5 microg/kg twice daily, and group II (n = 44) received 16 microg/kg, given as 8 microg/kg twice daily with a 12-h interval. The groups were well-balanced for age and body-weight. G-CSF application was performed on an out-patient basis, and leukapheresis was started in all donors on day 5. The most frequent side-effects of G-CSF were grade I/II, bone pain, headache and fatigue in both groups, whereas grade III of bone pain, headache and fatigue occurred in the 2 x 8 microg/kg group only. One serious non-fatal event with non-traumatic spleen rupture occurred in the 2 x 5 microg/kg group. The CD34(+)cell count in the first apheresis of all donors was 5.1 x 10(6)/kg donor weight (range, 1.5-19.3). The CD34(+) cell harvest was higher in the 2 x 8 microg/kg group than in the 2 x 5 microg/kg group (7.1 x 10(6)/kg vs 4.9 x 10(6)/kg; P = 0.09). The target of collecting >5.0 x 10(6) CD34(+) cells/kg donor weight with one apheresis procedure was achieved in 45% of group I and in 61% of group II, respectively. Administering G-CSF at a dosage of 8 microg/kg twice daily leads to a higher CD34(+) cell yield than a dosage of 2 x 5 microg/kg, but is associated with increased toxicity and higher cost.


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco de Sangue Periférico/métodos , Adulto , Antígenos CD34/análise , Remoção de Componentes Sanguíneos , Doadores de Sangue , Relação Dose-Resposta a Droga , Feminino , Fator Estimulador de Colônias de Granulócitos/toxicidade , Mobilização de Células-Tronco Hematopoéticas/normas , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo/métodos
8.
Bone Marrow Transplant ; 28(7): 643-7, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11704786

RESUMO

We investigated the feasibility and efficacy of a fludarabine-based dose-reduced conditioning regimen followed by stem cell transplantation from related (n = 5) or unrelated HLA-matched donors (n = 7) in 12 patients with high risk MDS, who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days and anti-thymocyte globulin (ATG, rabbit) 10 mg/kg daily for 4 days in 11 patients, while one patient received fludarabine, ATG, cyclophosphamide and thiotepa. Graft-versus-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. The median age of the patients was 53 years (range 37-59). The median percentage of blasts in bone marrow aspirate at transplantation was 15% (range <5% to 35%). Diagnosis at transplant was RA (n = 1), RAEB (n = 5), RAEB-T (n = 5) and sAML (n = 1). A complex karyotype including monosomy 7 was noted in five patients. The reasons for using a dose-reduced conditioning regimen were prior autologous/syngeneic BMT (n = 4), active fungal infection (n = 2) or age/reduced performance status (n = 6). Engraftment was observed in all patients with complete donor chimerism. The incidence of acute GVHD (grade II-IV) was 33%. Eight patients died during follow-up due to relapse (n = 4), liver toxicity (n = 2), aspergillus (n = 1) or aGVHD grade IV (n = 1). After a median follow-up of 19 months, the 2-year estimated disease-free survival is 12% (95% CI: 2-23%) and the overall survival is 26% (95% CI: 4-52%). Fludarabine dose-reduced conditioning prior to allogeneic stem cell transplantation in high risk MDS patients, who were not eligible for standard transplantation, resulted in stable engraftment with complete chimerism, but the toxicity and relapse rate were considerable.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Adulto , Anemia Refratária com Excesso de Blastos/genética , Anemia Refratária com Excesso de Blastos/mortalidade , Anemia Refratária com Excesso de Blastos/patologia , Anemia Refratária com Excesso de Blastos/terapia , Soro Antilinfocitário/administração & dosagem , Soro Antilinfocitário/efeitos adversos , Medula Óssea/patologia , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Contagem de Células , Cromossomos Humanos Par 7/genética , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Estudos de Viabilidade , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/mortalidade , Histocompatibilidade , Humanos , Infecções/etiologia , Infecções/mortalidade , Cariotipagem , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Monossomia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Recidiva , Taxa de Sobrevida , Linfócitos T , Doadores de Tecidos , Condicionamento Pré-Transplante/efeitos adversos , Resultado do Tratamento , Vidarabina/efeitos adversos
9.
J Hematother Stem Cell Res ; 10(5): 681-9, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11672515

RESUMO

Women with breast cancer in a distinct stage of disease can benefit from high-dose therapy (HDT) with autologous stem cell support; however, a significant number of these patients relapse despite this intensive treatment. This study investigates the persistence of malignancy on the single-cell level. A total of 194 data sets consisting of bone marrow and blood samples obtained prior to and after HDT and of aliquots of apheresis products were searched with immunocytochemistry and reverse transcriptase polymerase chain reaction (RT-PCR) for disseminated cancer cells. Presence of cancer cells in the marrow is frequent prior to and after HDT, but HDT reduces the amount of malignant cells in marrow significantly. In contrast, there was no effect on the number of circulating cancer cells. Reinfusion of contaminated apheresis products was surprisingly associated with a low number of malignant cells in bone marrow after HDT and vice versa. The impact of disseminated tumor cells in bone marrow, apheresis, and peripheral blood on disease-free survival after HDT could be investigated in a total of 165 samples. Surprisingly, neither the presence of tumor cells in marrow or blood nor in apheresis was associated with a bad prognosis in Kaplan-Meyer survival analysis. These results suggest that apheresis products and bone marrow should be regarded as different biological compartments for epithelial cancer cells. It can be concluded that complete elimination of disseminated cancer cells by HDT is not always possible. The theory of reinduction of metastatic breast cancer by accidentally reinfused contaminants is not supported by this study so far. However, further research is necessary to identify distinct cell populations with the potentially capacity to metastasize.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/terapia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Terapia Combinada , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Imuno-Histoquímica , Queratinas/análise , Queratinas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
10.
Br J Haematol ; 113(4): 1060-71, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11442503

RESUMO

We evaluated the cytomegalovirus (CMV) serostatus as a risk factor for survival and treatment-related mortality (TRM) in 125 patients allografted from an unrelated donor between 1994 and 1999. All patients received pretransplant in vivo T-cell depletion using rabbit anti-thymocyte globulin (ATG). Only one patient had primary graft failure and severe grade III/IV graft-versus-host disease occurred in 14% of the patients. The overall survival (OS) at 3 years was 70% for CMV-negative patients (n = 76) and 29% in the seropositive cohort (n = 49) (P > 0.001). In multivariate analyses, CMV seropositivity remained an independent negative prognostic factor for OS (RR: 2.1; CI: 1.2-3.8; P = 0.014), apart from age > 20 years (RR: 2.74; CI: 1.2-3.8; P = 0.004) and late leucocyte engraftment (RR: 2.4; CI: 1.2-4.9; P = 0.015). The TRM for all patients was 27%. Despite monitoring for CMV antigenaemia and preemptive therapy with ganciclovir when reactivation occurred, seropositive patients had a three times higher risk of fatal treatment-related complications than seronegative patients. In multivariate analyses, CMV seropositivity remained the strongest independent negative factor for TRM (RR: 5.3; CI: 1.9-14.6; P = 0.002), followed by age > 20 years (RR: 4.8; CI: 1.3-18.1; P = 0.02) and delayed leucocyte engraftment (RR: 3.6; CI: 1.2-11; P = 0.02). The TRM was identical in seropositive patients with (n = 27) or without (n = 22) CMV reactivation (44% versus 50%). We conclude that CMV seropositivity, despite preemptive ganciclovir therapy and even without reactivation, is a major negative prognostic factor for survival as well as for TRM in unrelated stem cell transplantation using pretransplant in vivo T-cell depletion with ATG.


Assuntos
Soro Antilinfocitário/administração & dosagem , Infecções por Citomegalovirus/complicações , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia/virologia , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucemia/terapia , Leucemia Mieloide/terapia , Leucemia Mieloide/virologia , Leucemia Mieloide de Fase Acelerada/terapia , Leucemia Mieloide de Fase Acelerada/virologia , Leucemia Mieloide de Fase Crônica/terapia , Leucemia Mieloide de Fase Crônica/virologia , Leucemia Mielomonocítica Aguda/terapia , Leucemia Mielomonocítica Aguda/virologia , Linfoma/terapia , Linfoma/virologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Mieloma Múltiplo/virologia , Análise Multivariada , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/virologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Fatores de Risco , Taxa de Sobrevida , Transplante Homólogo
11.
J Hematother Stem Cell Res ; 10(3): 419-25, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11454317

RESUMO

Y chromosome-specific sequences can be used to detect remaining male cells after sex-mismatched allogeneic blood stem cell transplantation (HSCT) involving a male patient and female donor, which represents approximately 25% of all cases. We developed a quantitative Y chromosome-specific PCR assay (QYCS-PCR) based on the DFFRY gene for the determination of hematopoietic donor chimerism. We analyzed blood and marrow samples from more than 40 patients at various time points after both standard and nonmyeloablative allogeneic HSCT. We found that real-time PCR combines extreme sensitivity, with a detection level of less than 1 male in 100,000 female cells (<0.001%), with very good reproducibility, especially in the important range of minor host chimerism. QYCS-PCR results were in close agreement with data from other techniques as bcr/abl-PCR and/or fluorescent in situ hybridization (FISH) analysis. In two relapsed patients, increasing numbers of Y-positive hematopoietic cells indicated recurrence of malignant disease prior to clinical confirmation. In conclusion, quantitative Y chromosome-specific PCR is a promising approach for monitoring the extent of chimerism in blood and other tissues after sex-mismatched hematopoietic stem cell transplantation (HSCT) or organ transplantation.


Assuntos
Quimera/genética , Endopeptidases/genética , Neoplasias Hematológicas/patologia , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Menor/genética , Reação em Cadeia da Polimerase/métodos , Transplante Homólogo , Cromossomo Y/genética , Adolescente , Adulto , Biomarcadores , Biomarcadores Tumorais/análise , Células Sanguíneas/ultraestrutura , Células da Medula Óssea/ultraestrutura , Exame de Medula Óssea/métodos , Sobrevivência Celular , Criança , Pré-Escolar , Sistemas Computacionais , Feminino , Proteínas de Fusão bcr-abl/análise , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Reprodutibilidade dos Testes , Doadores de Tecidos
12.
Ann Hematol ; 80(4): 209-15, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11401086

RESUMO

To reduce the incidence of GvHD and the rate of graft failure in unrelated stem cell transplantation, we incorporate anti-thymocyte globulin in the preparative regimen in 98 patients with hematological or inherited storage disease. The median age was 32 years (range: 1-56) and 84 patients underwent transplantation from HLA-A,-B and DR identical donor, while in 14 patients the donor were mismatched either in HLA- A, -B or -DR locus. Only one patient with chronic myelocytic leukemia (CML) and blast crisis had a primary graft failure (1%). Grade II-IV acute GvHD occurred in 37 patients (37%), grade III/IV GvHD developed in 15 patients (15%). Chronic GvHD was observed in 29%, and only 12 patients had extensive GvHD (17%). After a median follow-up of 34 months (range, 9-90), the estimated overall survival at 3 years for all patients is 58% (CI 95%: 48%-68%), and the estimated disease-free survival at 3 years is 49% (CI 95%: 38%-60%). For patients with CML transplanted in first chronic phase or accelerated phase (n=40), the estimated overall survival at 3 years is 70% (CI 95%: 56%-84%), and the estimated disease-free survival at 3 years is 58% (CI 95%: 17%-85%). ATG in unrelated stem cell transplantation reduces the risk of severe acute and chronic GvHD and of graft failure without an obvious increase of severe infection. Further follow-up is mandatory to determine the incidence of late relapse.


Assuntos
Soro Antilinfocitário/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Teste de Histocompatibilidade , Humanos , Lactente , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Reoperação , Transplante Homólogo , Resultado do Tratamento
13.
J Hematother Stem Cell Res ; 10(2): 303-7, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11359677

RESUMO

Tumor cell contamination of stem cell collections harvested from breast cancer patients is a common phenomenon described by several investigators but with findings that vary among reports. Although so-called co-mobilization of these cells has been hypothesized, the origin of tumor cell contamination in stem cells is still unknown. A total of 47 G-CSF mobilized stem cell grafts from patients with nodal-positive (n = 30), chemosensitive metastatic (n = 11), and 5 women with inflammatory breast cancer were evaluated for cancer cells by immunocytochemistry. Additionally, 40 bone marrow aspirations and 23 peripheral blood samples collected prior to apheresis and after one to two cycles of conventional chemotherapy were available for examination. Tumor cell contamination of leukapheresis correlated best with preharvest blood state. This was valid when the nominal (positive/negative) presence of tumor cells in blood was compared to the nominal presence of tumor cells in apheresis samples and when the it was correlated to the tumor cell load of apheresis samples (TCL = tumor cells per 10(6) nucleated cells investigated). The correlation between blood and stem cells was better (nominal and quantitative) than that between marrow and stem cells, despite the larger sample size of marrow aspirations. The presence or absence of cancer cells in apheresis samples could not be safely predicted by the presence or absence of tumor cells in marrow or blood alone. Diagnostic specificity seems to improve from a combination of results from marrow and blood analysis. No correlation was found in quantitative analysis of tumor cell contamination between marrow and blood. In conclusion, the results suggest that blood and bone marrow represent different compartments for epithelial cancer cells and that contaminating tumor cells in stem cell harvests may be derived from the blood and/or marrow compartment. The tumor cell contamination of a stem cell harvest cannot be safely predicted by a preceding blood or marrow analysis.


Assuntos
Medula Óssea/patologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/patologia , Neoplasias da Mama/sangue , Feminino , Humanos , Leucaférese , Metástase Neoplásica , Transplante Autólogo
14.
Bone Marrow Transplant ; 27(4): 349-54, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11313663

RESUMO

We compared fractionated total body irradiation (12 Gy)/cyclophosphamide (120 mg/kg) with busulfan (16 mg/kg)/cyclophosphamide (120 mg/kg) as preparative therapy in unrelated donor stem cell transplantation of CML patients. Fifty patients with CML (1.CP = 46; aP = 4) and a median age of 36 years (range 16-52) were enrolled in this sequential trial between 1994 and 1999. In both groups patients were well balanced with respect to age, disease status, stem cell source and CMV status. All patients received standard doses of cyclosporin A, methotrexate and anti-thymocyte globulin (ATG) as GVHD prophylaxis. No graft failures occurred in either group. The median day of leukocyte engraftment was earlier in the Bu/Cy than in the TBI/Cy group (day 15 vs 17; P = 0.006). The incidence of grade II-IV GVHD was 40% in the TBI/Cy and 36% in the Bu/Cy group, whereas severe grade III/IV GVHD was only observed in 12% of patients in both groups. The incidence of chronic GVHD (limited and extensive) at 1 year was higher in the Bu/Cy arm (65% vs 30%; P = 0.02). More toxicity grade I/II of the liver (88% vs 44%; P = 0.002) and more hemorrhagic cystitis (32% vs 8%; P = 0.02) were observed in the Bu/Cy regimen. Seven relapses in the TBI and no relapse in the Bu/Cy group were observed after a median follow-up of 44 and 15 months, respectively. The estimated 3 year OS and DFS was 72% (95% CI: 55-98%) and 58% (95% CI: 39-77%) in the TBI and 70% (95% CI: 51-89%) for DFS and OS in the Bu/Cy group. We conclude that the anti-leukemic effect of the Bu/Cy regimen seems to be at least as effective as the TBI/Cy combination in unrelated stem cell transplantation of CML patients, with no graft failures, but that it correlates with a higher incidence of liver toxicity, hemorrhagic cystitis and chronic GVHD. Longer follow-up is necessary to determine the late relapse rate and late toxicity.


Assuntos
Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/radioterapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Bussulfano/toxicidade , Ciclofosfamida/toxicidade , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Imunossupressores/uso terapêutico , Imunossupressores/toxicidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Masculino , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/normas , Transplante Homólogo/métodos , Transplante Homólogo/mortalidade , Transplante Homólogo/normas , Irradiação Corporal Total/efeitos adversos , Irradiação Corporal Total/normas
15.
J Hematother Stem Cell Res ; 10(1): 141-5, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11276367

RESUMO

Disseminated tumor cells are detected frequently in bone marrow, peripheral blood, and cytokine-mobilized peripheral blood cell products of women undergoing high-dose therapy for breast cancer. Several attempts were made to purge autografts from contaminating cancer cells; however, the biological and clinical impact of these contaminations has not been clarified so far. Expression of distinct phenotypes is a surrogate marker for metastatic behavior of cancer cells. The expression of the urokinase-like plasminogen activator receptor seems to be a factor of high importance. It is not expressed by normal mammary tissue. Disseminated cancer cells from marrow, blood, and stem cell products have been investigated by double-stain technique for urokinase-like plasminogen activator receptor (uPA-R) expressing cytokeratin-positive cells. uPA-R(+)/CK(+) cells could be found in all qualities of samples; however, significantly less in G-CSF-mobilized peripheral blood stem cells compared to samples of other provenance (p = 0.02). It can be concluded that epithelial cells of malignant phenotype occur in blood, marrow, and autografts of breast cancer patients. Populations of disseminated tumor cells are phenotypically heterogeneous. Reduced uPA-R expression on cancer cells from leukapheresis samples might suggest a less aggressive nature of these cells compared to disseminated cells found in bone marrow. Furthermore, the data suggest that the phenotype of tumor cell contamination in leukapheresis products differs significantly from those of disseminated cancer cells in bone marrow or blood.


Assuntos
Neoplasias da Mama/patologia , Receptores de Superfície Celular/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Células Sanguíneas/patologia , Medula Óssea/patologia , Neoplasias da Mama/química , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Queratinas/metabolismo , Leucaférese , Proteínas de Neoplasias/metabolismo , Células Neoplásicas Circulantes , Células-Tronco/patologia
16.
Br J Haematol ; 112(2): 421-3, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11167841

RESUMO

Two patients with persistent disease after allografting for multiple myeloma received donor T-cell lymphocyte infusion (DLI) (1.5 x 10(8) and 7 x 10(7)) to induce a graft-vs.-myeloma effect for further tumour regression after withdrawal of immunosuppression. The interval between stem cell transplantation and DLI was 8 and 14 months respectively. Both patients converted from partial to complete remission, lasting 12+ and 28+ months. Immunofixation became negative after 3 and 4 months. The main toxicity was grade II and III acute graft-vs.-host disease (GvHD) and limited or extensive chronic GvHD in each patient. We conclude that DLI induced further tumour reduction in patients with persistent disease after allografting for multiple myeloma.


Assuntos
Efeito Enxerto vs Tumor , Imunoterapia Adotiva/métodos , Mieloma Múltiplo/terapia , Adulto , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/cirurgia , Indução de Remissão , Transplante Homólogo
17.
Med Oncol ; 18(1): 33-8, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11778968

RESUMO

Several reverse-transcriptase polymerase chain reaction (rtPCR) assays have been designed for the detection of disseminated cancer cells. The specificity of these discussed molecular approaches is controversial. Biological interference of the cytokeratin-20 and mammaglobin rtPCR assays has been investigated. Cell lines of different lineages and bone marrow and peripheral stem cells from patients without epithelial cancer have been examined for the transcription of the cytokeratin-20 (CK20) and mammaglobin messages prior to and after stimulation with different cytokines in a total of 370 liquid cultures. Amplification of both messages from clinical samples prior to stimulation does not support the high specificity for the detection of disseminated epithelial cancer cells as reported. Cytokeratin-20 was amplified from the chronic myeloic leukemia (CML)-derived line K562. Transcription was not influenced by cytokines, either in cell-line experiments or in clinical samples. The thesis of a low-level background transcription in granulocytes is supported. Mammaglobin was induced in cell lines significantly by GM-CSF and in clinical samples additionally by several more cytokines. These results indicate that under certain conditions involving cytokine production, the use of mammaglobin rtPCR for the detection of epithelial cancer cells could be limited. In conclusion, the mechanism of interference of both rtPCR assays are completely different and further research is necessary before the cytokeratin-20 or mammaglobin rtPCR could become standard methods for the detection of disseminated epithelial cancer cells. These factors leading to so-called false-positive results have to be considered in future applications of rtPCR for the detection of minimal residual disease.


Assuntos
Carcinoma/diagnóstico , Regulação Neoplásica da Expressão Gênica , Proteínas de Filamentos Intermediários/biossíntese , Metástase Neoplásica/diagnóstico , Proteínas de Neoplasias/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/normas , Uteroglobina/biossíntese , Carcinoma/genética , DNA de Neoplasias/análise , Reações Falso-Positivas , Humanos , Queratina-20 , Mamoglobina A , Metástase Neoplásica/genética , Sensibilidade e Especificidade , Transcrição Gênica , Células Tumorais Cultivadas
18.
Ann Hematol ; 79(10): 578-80, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11100750

RESUMO

We report about a 28-year-old woman with relapsed mantle cell lymphoma (MCL, centrocytic lymphoma according to the Kiel classification) refractory to salvage chemotherapy. The patient underwent allogeneic bone marrow transplantation from a HLA-identical brother after myeloablative chemotherapy consisting of busulfan, etoposide, and cyclophosphamide. The patient experienced hepatic toxicity (grade I), mucositis (grade II) according the Bearman scale, and graft versus host disease of the skin (grade II) and showed stable engraftment with complete chimerism on day 15 after bone marrow transplantation. Eight years after transplantation, the patient is still disease free and in good condition without any late side effects. This report suggests a curative potential of allogeneic stem cell transplantation in MCL.


Assuntos
Transplante de Medula Óssea , Linfoma de Célula do Manto/terapia , Adulto , Feminino , Humanos , Recidiva
19.
Br J Haematol ; 111(3): 761-5, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11122135

RESUMO

To evaluate the schedule dependency of granulocyte colony-stimulating factor (G-CSF) (filgrastim) for stem cell mobilization, we conducted a randomized comparison in 50 healthy donors, with one subcutaneous daily injection of 10 microg/kg G-CSF (n = 25) compared with twice injections daily of 5 microg/kg G-CSF (n = 25). The two groups were well balanced for age, body weight and sex. G-CSF application was performed on an out-patient basis and leukapheresis was started in all donors on day 5. The most frequent side-effects of G-CSF were mild to moderate bone pain (88%), mild headache (72%), mild fatigue (48-60%) and nausea (8%) without differences between the two groups. The CD34(+) cell count in the first apheresis was 5.4 x 10(6)/kg donor weight (range 2.8-13.3) in the 2 x 5 microg/kg group compared with 4.0 x 10(6)/kg (range 0.4-8.8) in the 1 x 10 microg/kg group (P = 0.007). The target of collecting > 3.0 x 10(6) CD34(+) cells/kg donor weight with one apheresis procedure was achieved in 24/25 (96%) donors in the 2 x 5 microg/kg group and in 17/25 (68%) donors in the 1 x 10 microg/kg group. The target of collecting > 5.0 x 10(6) CD34(+) cells/kg in the first apheresis was achieved in 64% in the 2 x 5 microg/kg group, but in only 36% in the 1 x 10 microg/kg group. The progenitor cell assay for granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) was higher in the 2 x 5 microg/kg group than in the 1 x 10 microg/kg group (7.0 vs. 3.5 x 10(5)/kg, P = 0.01; 6.6 vs. 5.0 x 10(5)/kg; P = 0.1). Administering G-CSF (filgrastim) at a dosage of 5 microg/kg twice daily rather than 10 microg/kg once daily is recommended; this leads to a higher CD34(+) cell yield and requires fewer apheresis procedures without increasing toxicity or cost.


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Doadores de Tecidos , Adulto , Antígenos CD34 , Esquema de Medicação , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Injeções Subcutâneas , Leucaférese , Contagem de Linfócitos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes
20.
Bone Marrow Transplant ; 26(7): 711-6, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11042650

RESUMO

To evaluate the efficacy and toxicity of two different etoposide (VP-16) dosages (30 or 45 mg/kg) in combination with busulfan/cyclophosphamide as conditioning therapy followed by stem cell transplantation in acute myeloid leukemia (AML), 90 patients with AML received either 30 mg/kg (n = 60) or 45 mg/kg (n = 30) etoposide in combination with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). The stem cell source was allogeneic related bone marrow (BM) (n = 53), allogeneic unrelated BM (n = 5), allogeneic unrelated peripheral blood (PBSC) (n = 2), syngeneic BM (n = 2), autologous BM purged (n = 9) or unpurged (n = 9), autologous PBSC (n = 10). Fifty-six patients (62%) were in first CR, 26 (29%) were > first CR, and eight (9%) were transplanted in relapse. Principal toxicities in both groups were mucositis and hepatotoxicity. Forty-five mg/kg etoposide resulted in greater hepatic toxicity (P = 0.03), and a higher incidence of VOD (23 vs 12%, P = 0.04) and acute GVHD grade III/IV (13 vs 5%, NS). The treatment-related mortality was 17% in the 30 mg/kg group and 33% in the 45 mg/kg group, mainly due to infections, intestinal pneumonia and GVHD. Hematological recovery of leukocytes 1/nl was comparable in both groups (17 vs 16 days). After a median follow-up of 16 months 19% in the 30 mg/kg group and 23% in the 45 mg/kg group relapsed. In patients who had undergone allogeneic related bone marrow transplantation in first CR no relapses occurred after a median follow-up of 3 years. For all patients the 3-year estimated disease-free survival was 62% in the 30 mg/kg group and 40% in the 45 mg/kg group (P = 0.03). For patients in first CR who underwent allogeneic related stem cell transplantation the 3 year disease-free survivals were 80% and 66%, respectively (P = 0.4). We conclude that etoposide 30 mg/kg or 45 mg/kg in combination with busulfan/cyclophosphamide is a highly active regimen for bone marrow transplantation of patients with AML with a low relapse rate. However, conditioning with 30 mg/kg rather than 45 mg/kg etoposide resulted in less toxicity and a better overall survival due to a lower transplant-related mortality. Bone Marrow Transplantation (2000) 26, 711-716.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Etoposídeo/farmacologia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide/tratamento farmacológico , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Plaquetas/citologia , Bussulfano/administração & dosagem , Bussulfano/farmacologia , Bussulfano/toxicidade , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Ciclofosfamida/farmacologia , Ciclofosfamida/toxicidade , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Etoposídeo/administração & dosagem , Etoposídeo/toxicidade , Feminino , Seguimentos , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Humanos , Lactente , Leucemia Mieloide/complicações , Leucócitos/citologia , Masculino , Pessoa de Meia-Idade , Recidiva , Taxa de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/normas , Resultado do Tratamento
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