RESUMO
Graft-versus-host disease-associated angiomatosis (GVHD-AA) is an uncommon manifestation of chronic GVHD consisting of friable vascular proliferations. Using fluorescence in situ hybridization, we demonstrate the presence of donor-derived endothelial cells within areas of GVHD-AA. This is the first documented occurrence of a benign neoplastic growth in relationship to a form of chronic GVHD.
Assuntos
Angiomatose/etiologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Escleroderma Sistêmico/etiologia , Quimeras de Transplante , Quimera , Doença Crônica , Células Endoteliais , Feminino , Humanos , Cromossomos Sexuais , Transplante HomólogoRESUMO
Currently, granulocyte colony stimulating factor (G-CSF) remains the standard mobilizing agent for peripheral blood stem cell (PBSC) donors, allowing the safe collection of adequate PBSCs from the vast majority of donors. However, G-CSF mobilization can be associated with some significant side effects and requires a multi-day dosing regimen. The other cytokine approved for stem cell mobilization, granulocyte-macrophage colony stimulating factor (GM-CSF), alters graft composition and may reduce the development of graft-versus-host disease, but a significant minority of donors fails to provide sufficient CD34+ cells with GM-CSF and some experience unacceptable toxicity. AMD3100 is a promising new mobilizing agent, which may have several advantages over G-CSF for donor mobilization. As it is a direct antagonist of the interaction between the chemokine stromal-derived factor-1 and its receptor CXCR4, AMD3100 mobilizes PBSCs within hours rather than days. It is also well tolerated, with no significant side effects reported in any of the clinical trials to date. Studies of autologous and allogeneic transplantation of AMD3100 mobilized grafts have demonstrated prompt and stable engraftment. Here, we review the current state of stem cell mobilization in normal donors and discuss novel strategies for donor stem cell mobilization.
Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Benzilaminas , Transplante de Medula Óssea , Ciclamos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Compostos Heterocíclicos/efeitos adversos , Compostos Heterocíclicos/farmacologia , Humanos , Proteínas Recombinantes , Segurança , Doadores de Tecidos , Transplante HomólogoRESUMO
In an otherwise eligible patient with relapsed lymphoma, inadequate mobilization of hematopoietic stem cells (HSCs) is a limiting factor to proceeding with an autologous hematopoietic cell transplantation (auto-HCT). Multiple strategies have been used to mobilize an adequate number of HSCs with no obvious front-line strategy. We report a single institutional experience mobilizing HSCs using four different approaches in lymphoma patients. We prospectively collected mobilization outcomes on patients planned to undergo auto-HCT at Ohio State University. We report results of first mobilization attempts for all relapsed or refractory lymphoma patients between 2008 and 2014. We identified 255 lymphoma patients who underwent mobilization for planned auto-HCT. The 255 lymphoma patients underwent the following front line mobilization strategies: 95 (37%) G-CSF alone, 38 (15%) chemomobilization (G-CSF+chemotherapy), 97 (38%) preemptive day 4 plerixafor, and 25 (10%) rescue day 5 plerixafor. As expected, there were significant differences between cohorts including age, comorbidity indices, histology, and amount of prior chemotherapy. After controlling for differences between groups, the odds of collecting 2 × 106/kg HSCs on the first day of collection and 5 × 106/kg HSCs in total was the highest in the cohort undergoing chemomobilization. In conclusion, our experience highlights the effectiveness of chemomobilization.
Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma/terapia , Adulto , Idoso , Antígenos CD34/análise , Antineoplásicos/administração & dosagem , Benzilaminas , Contagem de Células , Ciclamos , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/normas , Células-Tronco Hematopoéticas/citologia , Compostos Heterocíclicos/administração & dosagem , Humanos , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante Autólogo , Adulto JovemRESUMO
High-dose melphalan followed by autologous stem cell transplantation remains the standard of care for eligible patients with multiple myeloma, but disease response and toxicity, including severe mucositis, varies among patients. Our randomized trial investigated duration of cryotherapy (2 and 6 h) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate that 2-h is at least as effective as 6-h cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified that fat-free mass, hematocrit, and creatinine clearance were significant covariates, as reported previously. Furthermore, we observed the rs4240803 SLC7A5 polymorphism was significantly associated with pharmacokinetic variability, and pharmacokinetics was associated with both mucositis and neutropenia. However, melphalan exposure was not associated with progression-free or overall survival in our dataset. These findings contribute to ongoing efforts to personalize melphalan dosing in transplant patients.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Crioterapia/métodos , Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Estomatite/prevenção & controle , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacocinética , Terapia Combinada , Creatinina/metabolismo , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/genética , Masculino , Melfalan/efeitos adversos , Melfalan/farmacocinética , Pessoa de Meia-Idade , Polimorfismo Genético , Estomatite/induzido quimicamente , Taxa de Sobrevida , Fatores de TempoRESUMO
Quantitative polymerase chain reaction (QPCR) for cytomegalovirus (CMV) is emerging as the preferred screening method for detection of CMV viremia in patients following allogeneic bone marrow and peripheral blood stem cell transplant. However, there are currently no universally accepted QPCR treatment thresholds at which to start pre-emptive therapy. We report here results of a pre-emptive therapy strategy using ganciclovir (GCV) 5 mg/kg initiated once daily (ODG) delayed till a threshold CMV load of > or =10 000 copies/ml whole blood in clinically stable patients. Sixty-nine at risk patients underwent allogeneic stem cell transplant. 48/69 (70%) patients had an initial episode of CMV viremia. 5/48 (10%) cleared viremia without requiring treatment. 28/43 (65%) patients requiring treatment initiated treatment with ODG. 17/28 (61%) patients successfully cleared CMV viremia on ODG, 10/28 (36%) patients required dose escalation to twice daily GCV for increasing viral loads. There were two cases of CMV disease (colitis) and no deaths due to CMV disease in patients initiating treatment with ODG. We conclude delaying pre-emptive therapy with ODG until whole blood QPCR> or =10 000 copies/ml is a safe and effective strategy for CMV viremia after allogeneic stem cell transplant in clinically stable patients.
Assuntos
Antivirais/administração & dosagem , Transplante de Medula Óssea , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus , Ganciclovir/administração & dosagem , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco de Sangue Periférico , Adulto , Idoso , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/etiologia , DNA Viral/sangue , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Transplante Homólogo , Carga Viral/métodosRESUMO
Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and have important roles in hematopoietic engraftment, GvHD and graft-versus-leukemia responses following allogeneic hematopoietic cell transplantation (HCT). In addition, pDCs mediate antiviral immunity, particularly as they are the body's primary cellular source of type I interferon. Given their pleiotropic roles, pDCs have emerged as cells that critically impact transplant outcomes, including overall survival. In this article, we will review the pre-clinical and clinical literature, supporting the crucial roles that pDCs assume as key immune effector cells during HCT.
Assuntos
Células Dendríticas/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunidade Celular , Imunidade Inata , Plasmócitos/imunologia , Aloenxertos , Humanos , Viroses/etiologia , Viroses/imunologiaRESUMO
PURPOSE: To assess the clinical toxicity and outcome associated with a comprehensive supportive care approach in poor-risk breast cancer (BrCA) patients with high-dose chemotherapy (HDC). PATIENTS AND METHODS: One hundred twenty-five consecutive patients with stages II, III or metastatic breast cancer received HDC between February 1992 and June 1994. Recipients received 4 days of continuous infusion of cyclophosphamide 1.5 g/m2/d, thiotepa 125 mg/m2/d, and carboplatin 200 mg/m2/d followed by infusion of bone marrow or peripheral-blood stem cells (PBSC) and recombinant human growth factor (rhu-GF) support. Patients received similar supportive care that included administration of prophylactic antibiotics, management of neutropenic fevers, and transfusion support. RESULTS: There were 38 women with stage II or III (27 patients with > or = 10 lymph nodes), four with stage IIIB, and 83 with metastatic breast cancer. The median age was 44 years (range, 27 to 61). Grade II or greater nonhematologic toxicities included diarrhea (66%), stomatitis (33%), hepatic venoocclusive disease (VOD) (5%), and pulmonary toxicity (4%). Myeloid and platelet engraftment was comparable between bone marrow and PBSC recipients (P > .1). Infectious complications were rare and consisted of gram-negative bacteremia (1.6%), gram-positive bacteremia (1.6%), fungemia (1.6%), and documented or suspected aspergillosis infection (3%). There was one treatment-related death secondary to severe VOD. CONCLUSION: A comprehensive supportive care approach was associated with a low treatment-related mortality rate of less than 1%. With the observed reduction in treatment-related mortality, it is reasonable to evaluate the efficacy of HDC in women with less than 10 positive nodes and stage II disease in well-designed clinical trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Análise Atuarial , Adulto , Algoritmos , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Carboplatina/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Análise de Sobrevida , Tiotepa/administração & dosagem , Transplante Autólogo , Resultado do TratamentoRESUMO
We retrospectively reviewed the results of transplanting peripheral blood progenitor cell (PBPC) allografts from HLA-matched sibling donors mobilized using various hematopoietic cytokines. Patients had received allografts mobilized with Granulocyte colony-stimulating factor (G-CSF) (G, N = 65) alone, G plus Granulocyte-macrophage colony stimulating factor (GM-CSF) (G/GM, N = 70), or GM-CSF alone at 10 or 15 microg/kg/day (GM, N = 10 at 10 microg/kg/day and 21 at 15 microg/kg/day). The CD34+ and CD3+ cell content of grafts were significantly lower following GM alone compared to G alone (P < 0.001 and 0.04, respectively). Nonhematopoietic toxicity observed in donors precluded dose escalation of GM-CSF beyond 10 microg/kg/day. Hematopoietic recovery was similar among all three groups. Grades II-IV acute graft-versus-host disease (GVHD) was observed in only 13% of patients in the GM alone group compared to 49 and 69% in the G alone or G/GM groups, respectively (P < 0.001). In a multivariate analysis, receipt of PBPC mobilized with GM alone was associated with a lower risk of grades II-IV acute GVHD (hazard ratio 0.21; 95% CI 0.073, 0.58) compared to G alone or G/GM. There were no differences in relapse risk or overall survival among the groups. Donor PBPC grafts mobilized with GM-CSF alone result in prompt hematopoietic engraftment despite lower CD34+ cell doses and may reduce the risk of grades II-IV acute GVHD following HLA-matched PBPC transplantation.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Doença Aguda , Adolescente , Adulto , Idoso , Antígenos CD34 , Complexo CD3 , Contagem de Células , Avaliação de Medicamentos , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/toxicidade , Fator Estimulador de Colônias de Granulócitos e Macrófagos/toxicidade , Mobilização de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/métodos , Estudos Retrospectivos , Risco , Irmãos , Transplante HomólogoRESUMO
OBJECTIVE: The human bone marrow contains mesenchymal stem cells capable of differentiating along multiple mesenchymal cell lineages. Using a non-human primate model, we sought to determine whether the systemic infusion of baboon-derived mesenchymal stem cells was associated with toxicity and whether these cells were capable of homing to and persisting within the bone marrow. MATERIALS AND METHODS: Five baboons (Papio anubis) were administered lethal irradiation followed by intravenous autologous hematopoietic progenitor cells combined with either autologous (n = 3) or allogeneic (n = 2) mesenchymal stem cells that had been expanded in culture. In four of these baboons, the mesenchymal stem cells were genetically modified with a retroviral vector encoding either the enhanced green fluorescent protein gene (n = 3) or the human placental alkaline phosphatase gene (n = 1) for tracking purposes. A sixth animal received only intravenous gene marked autologous mesenchymal stem cells but no hematopoietic stem cells or conditioning irradiation. RESULTS: Following culture, baboon mesenchymal stem cells appeared morphologically as a homogeneous population of spindle-shaped cells that were identified by the monoclonal antibodies SH-3 and SH-4. These cells did not express the hematopoietic markers CD34 or CD45. Baboon mesenchymal stem cells isolated from primary culture were capable of differentiating along both adipogenic and osteogenic lineages. There was no acute or chronic toxicity associated with the intravenous infusion of mesenchymal stem cells. In all five recipients of gene marked mesenchymal stem cells, transgene was detected in post-transplant bone marrow biopsies. In two animals receiving autologous mesenchymal stem cells, including the one non-conditioned recipient, transgene could be detected over 1 year following infusion. In one recipient of allogeneic gene marked mesenchymal stem cells, transgene was detected in the bone marrow at 76 days following infusion. CONCLUSION: These data demonstrate that baboon mesenchymal stem cells: 1) are not associated with significant toxicity when administered intravenously, 2) are capable of homing to the bone marrow following intravenous infusion, and 3) have the capacity to establish residence within the bone marrow for an extended duration following systemic administration.
Assuntos
Medula Óssea , Mesoderma/citologia , Papio , Transplante de Células-Tronco , Células-Tronco/citologia , Fosfatase Alcalina/genética , Animais , Anticorpos Monoclonais , Antígenos CD34/análise , Medula Óssea/química , Separação Celular , Células Cultivadas , DNA Recombinante/análise , Ensaio de Imunoadsorção Enzimática , Feminino , Proteínas de Fluorescência Verde , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Antígenos Comuns de Leucócito/análise , Proteínas Luminescentes/genética , Masculino , Mesoderma/imunologia , Reação em Cadeia da Polimerase , Transfecção , TransgenesRESUMO
Bronchiolitis obliterans syndrome (BOS) remains an important complication following allo-SCT. The development of this condition portends a higher morbidity and mortality but the effect on heath-related quality of life (HRQL) is unknown. The aim of this study was to determine whether the development of BOS impacted HRQL compared with patients without BOS. This Institutional Review Board-approved prospective study analyzed 126 patients who underwent allo-SCT at our institution. Patients were administered three HRQL survey tools (SF-36, European Organization for Research and Treatment of Cancer QLQ-c30 and St George Respiratory Questionnaire (SGRQ)) before transplant and then again at 6 months, 1 year and 2 years after transplant. Patients were analyzed in three groups determined by highest chronic GVHD (cGVHD) severity and BOS status. Overall, our study group had improving HRQL after transplant when measured over time, measured by the SF-36 with stable HRQL, when measured by the SGRQ total score and QLQ-c30. Patients that developed BOS had significantly worse HRQL scores measured by the SGRQ and the SF-36 physical composite score. This difference was not explained by the severity of cGVHD that patients with BOS developed.
Assuntos
Bronquiolite Obliterante/epidemiologia , Qualidade de Vida , Transplante de Células-Tronco , Inquéritos e Questionários , Adulto , Idoso , Aloenxertos , Bronquiolite Obliterante/etiologia , Doença Crônica , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
The impact of extramedullary disease (EMD) in AML on the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) is unknown. Using data from the Center for International Blood and Marrow Transplant Research, we compared the outcomes of patients who had EMD of AML at any time before transplant, with a cohort of AML patients without EMD. We reviewed data from 9797 AML patients including 814 with EMD from 310 reporting centers and 44 different countries, who underwent alloHCT between and 1995 and 2010. The primary outcome was overall survival (OS) after alloHCT. Secondary outcomes included leukemia-free survival (LFS), relapse rate and treatment-related mortality (TRM). In a multivariate analysis, the presence of EMD did not affect either OS (hazard ratio 1.00, 95% confidence interval (CI) 0.91-1.09), LFS (0.98, 0.89-1.09), TRM (relative risk 0.92, 95% CI 0.80-1.16, P=0.23) or relapse (relative risk=1.03, 95% CI, 0.92-1.16; P=0.62). Furthermore, the outcome of patients with EMD was not influenced by the location, timing of EMD, or intensity of conditioning regimen. The presence of EMD in AML does not affect transplant outcomes and should not be viewed as an independent adverse prognostic feature.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Neoplasias Meníngeas , Segunda Neoplasia Primária , Sarcoma Mieloide , Neoplasias Cutâneas , Adolescente , Adulto , Idoso , Aloenxertos , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/terapia , Pessoa de Meia-Idade , Segunda Neoplasia Primária/mortalidade , Segunda Neoplasia Primária/terapia , Sarcoma Mieloide/mortalidade , Sarcoma Mieloide/terapia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/terapiaRESUMO
Human mesenchymal stem cells (MSCs) are capable of differentiating into multiple mesenchymal lineages including chondrocytes, osteocytes, adipocytes, and marrow stromal cells. Using a nonhuman primate model, we evaluated nonhuman primate MSCs as targets for gene therapy. Baboon MSCs (bMSCs) cultured from bone marrow aspirates appeared as a homogeneous population of spindle-shaped cells. bMSCs were capable of differentiating into adipocytes and osteocytes in vitro and chondrocytes in vivo. bMSCs were genetically modified with a bicistronic vector encoding the human erythropoietin (hEPO) gene and the green fluorescent protein (GFP) gene. Transduction efficiencies ranged from 72 to 99% after incubation of MSCs with retroviral supernatant. Transduced cells produced from 1.83 x 10(5) to 7.12 x 10(5) mIU of hEPO per 10(6) cells per 24 hr in vitro before implantation. To determine the capacity of bMSCs to express hEPO in vivo, transduced bMSCs were injected intramuscularly in NOD/SCID mice. In a separate experiment, transduced bMSCs were loaded into immunoisolatory devices (IIDs) and surgically implanted into either autologous or allogeneic baboon recipients. Human EPO was detected in the serum of NOD/SCID mice for up to 28 days and in the serum of five baboons for between 9 and 137 days. NOD/SCID mice experienced sharp rises in hematocrit after intramuscular injection of hEPO-transduced bMSCs. The baboon that expressed hEPO for 137 days experienced a statistically significant (p < 0.04) rise in its hematocrit. These data demonstrate that nonhuman primate MSCs can be engineered to deliver a secreted and biologically active gene product. Therefore, human MSCs may be an effective target for future human gene therapy trials.
Assuntos
Eritropoetina/genética , Eritropoetina/metabolismo , Terapia Genética/métodos , Mesoderma/citologia , Mesoderma/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Adulto , Animais , Diferenciação Celular , Células Cultivadas , Feminino , Proteínas de Fluorescência Verde , Hematócrito , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Modelos Genéticos , Papio , Fenótipo , Retroviridae/genética , Fatores de Tempo , Transdução GenéticaRESUMO
Preparative regimens used prior to bone marrow transplantation (BMT) in patients with malignancies must mediate engraftment and eradicate malignant cells without producing significant extramedullary toxicities. The first agents to be tested in BMT preparative regimens, total body irradiation (TBI) and cyclophosphamide (Cy), were ineffective as single agents, but resulted in long-term disease-free survival in some leukemic patients when combined. However, Cy/TBI regimens are associated with significant acute and chronic toxicities as well as technical constraints involving the administration of radiation. Accordingly, a nonradiation-based regimen consisting of Cy and busulfan (Bu) was developed. Regimens using either a 4-day course (BuCy4) or a 2-day course (BuCy2) of Cy have been shown to have significant antileukemic effects. In general, however, BuCy regimens do not appear to result in greater antileukemic activity or lower treatment-related toxicity than Cy/TBI regimens. New preparative regimens are currently being developed to lower the incidence of disease recurrence after BMT. One such regimen consists of BuCy plus etoposide. At our institution, we are currently testing the efficacy and toxicity of regimens in which cytarabine or diaziquone are administered in combination with Bu and Cy. It is hoped that these new preparative regimens will enhance the antileukemic effects of BMT without significantly increasing treatment-related toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea/métodos , Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Aziridinas/administração & dosagem , Benzoquinonas/administração & dosagem , Bussulfano/efeitos adversos , Ciclofosfamida/efeitos adversos , Citarabina/administração & dosagem , Monitoramento de Medicamentos , Humanos , Pré-Medicação , Irradiação Corporal TotalRESUMO
In the past decade, we have witnessed significant advances in ex vivo hematopoietic stem cell culture expansion, progressing to the point where clinical trials are being designed and conducted. Preclinical milestone investigations provided data to enable expansion of portions of hematopoietic grafts in a clinical setting, indicating safety and feasibility of this approach. Data derived from current clinical trials indicate successful reconstitution of hematopoiesis after myeloablative chemoradiotherapy using infusion of ex vivo-expanded perfusion cultures. Future avenues of exploration will focus upon refining preclinical and clinical studies in which cocktails of available cytokines, novel molecules and sophisticated expansion systems will explore expansion of blood, marrow and umbilical cord blood cells.
Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Mobilização de Células-Tronco Hematopoéticas/tendências , Transplante de Células-Tronco/métodos , Técnicas de Cultura de Células/métodos , Células-Tronco Hematopoéticas/citologia , Humanos , Transplante de Células-Tronco/tendências , Doadores de TecidosRESUMO
A 19-year-old male underwent allogeneic BMT for severe aplastic anaemia (SAA) from his HLA- and blood group-identical sister. He was conditioned with cyclophosphamide (CY) and single fraction total lymphoid irradiation (TLI). GVHD prophylaxis consisted of FK506 and a short course of methotrexate. The patient failed to achieve durable trilineage hematopoietic engraftment. There was no significant myeloid response to GM-CSF or G-CSF. Evaluation of FACS-sorted peripheral T cells from the patient by fluorescence in situ hybridization (FISH) revealed mixed chimerism (44% host origin). Fifty-three days after the first BMT, he was treated with G-CSF primed, unmanipulated PBSC transfusions (5.28 x 10(8)/kg mononuclear, 4.28 x 10(6)/kg CD34+, 292.51 x 10(6)/kg CD3+ cells) from his original donor without reconditioning. FK506 was continued at the same dose. Neutrophil recovery to 0.5 x 10(9)/l and platelet engraftment to 20 x 10(9)/l was achieved 11 and 27 days following the first dose of allogeneic PBSC transfusion, respectively. On day 23 a repeat FISH on the patient's sorted peripheral T lymphocytes revealed 91% donor origin T cells. The patient is currently well with a stable engraftment 6 months following allogeneic PBSC transfusion, with no signs of acute of chronic GVHD.
Assuntos
Anemia Aplástica/terapia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Adulto , Separação Celular , Rejeição de Enxerto , Sobrevivência de Enxerto , Células-Tronco Hematopoéticas/patologia , Humanos , Masculino , Transplante HomólogoRESUMO
In contrast to allogeneic bone marrow transplantation (allo-BMT), there is a paucity of data on cytomegalovirus (CMV) infection and preemptive therapy (PT) strategies following allogeneic peripheral blood stem cell (allo-PBSC) transplantation. We report here on the patterns of CMV infection in a cohort of 225 patients following sibling donor allo-PBSC transplantation. In an attempt to reduce neutropenia, we used intravenous low-dose short-course (LDSC) ganciclovir (GCV) 5 mg/kg once daily for 21 days as preemptive therapy. A total of 165 recipient-donor pairs were CMV seropositive. An initial episode of viremia (detected by shell vial/tube culture) occurred in 75/165 (45%) at a median of day +35 (17-445) post allo-PBSC. In all, 58 patients received PT with LDSC GCV. Among 58, 55 (94%) completed the 21-day course of PT. A second episode of viremia occurred in 19/58 (33%) at day+80 (50-174) and a third episode in 5/58 (9%) at day+134 (103-218). Among patients receiving LDSC GCV, 5/58(9%) developed disease (four pneumonia, one colitis) at day+211 (63-487). No patient on LDSC GCV exhibited a decline in their ANC below 500/microl and none required growth factors. LDSC GCV is extremely well tolerated and cost-effective as PT for CMV viremia following allo-PBSC transplantation.
Assuntos
Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/administração & dosagem , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Antivirais/toxicidade , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/etiologia , Ganciclovir/uso terapêutico , Ganciclovir/toxicidade , Humanos , Incidência , Pessoa de Meia-Idade , Neutropenia/prevenção & controle , Transplante de Células-Tronco de Sangue Periférico/métodos , Prevenção Secundária , Irmãos , Transplante Homólogo , Viremia/prevenção & controleRESUMO
Three patients who developed acute onset of cerebral blindness within 5-47 days of BMT using tacrolimus (FK506) as primary GVHD prophylaxis are described. This syndrome has been described with the use of cyclosporin A (CsA) and FK506 in solid organ transplant recipients. CsA-induced cerebral blindness has also been noted in BMT recipients but to date there have been no reports of this complication in BMT patients receiving FK506. We have noted a striking similarity in the clinical and radiographic presentations between these patients and those with CsA-associated cerebral blindness. Reversibility within 1-2 weeks of onset and the potential for substitution of CsA for FK506 in these patients is described.
Assuntos
Cegueira/etiologia , Transplante de Medula Óssea , Encéfalo/efeitos dos fármacos , Imunossupressores/efeitos adversos , Tacrolimo/efeitos adversos , Adulto , Ciclosporina/efeitos adversos , Feminino , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
We report a patient who underwent two allogeneic bone marrow transplants for chronic myelogenous leukemia, initially in 1984 and again after relapse in 1990, who developed an identical pulmonary syndrome at a similar interval following each transplant. The patient presented with a non-productive cough, bilateral inspiratory crackles, and multiple patchy infiltrates on chest X-ray. Pulmonary function testing revealed a restrictive abnormality but no obstructive defects. The appearance of this pulmonary disorder after each transplant coincided with the development of chronic graft-versus-host disease. In both instances, this pulmonary syndrome completely reversed with corticosteroid therapy. The patient's chest computed tomographic scan and lung biopsy specimens were consistent with the diagnosis of bronchiolitis obliterans with organizing pneumonia (BOOP). While bronchiolitis obliterans has been reported following allogeneic transplant, BOOP has not previously been reported in this setting.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Bronquiolite Obliterante/etiologia , Pneumonia/etiologia , Adulto , Bronquiolite Obliterante/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/cirurgia , Leucemia Mieloide de Fase Crônica/cirurgia , Masculino , Pneumonia/tratamento farmacológico , Prednisona/uso terapêutico , Síndrome , Transplante HomólogoRESUMO
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) have been observed after bone marrow transplantation (BMT), typically occurring 1-6 months following BMT. We describe two patients who developed TTP very early after BMT while receiving intravenous FK506. They were treated with platelet support and plasma exchange (PE) using either fresh frozen plasma (FFP) or cryosupernatant fraction of plasma (CFP), resulting in remission of TTP activity.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Púrpura Trombocitopênica Trombótica/etiologia , Tacrolimo/efeitos adversos , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Transfusão de Plaquetas , Púrpura Trombocitopênica Trombótica/terapiaRESUMO
Severe regimen-related toxicity often complicates second transplant procedures performed in patients with hematological malignancies that have relapsed after an initial hematopoietic stem cell (HSC) transplant. Therefore, we studied the safety and efficacy of a reduced-intensity fludarabine and melphalan based conditioning regimen in 11 patients who had relapsed following an autologous (n = 7) or allogeneic (n = 4) HSC transplant. All patients received allogeneic peripheral blood HSC from either an HLA-identical (n = 7) or an HLA-mismatched (n = 4) relative. Diagnoses included AML (n = 9), ALL (n = 1), or Hodgkin's disease (n = 1). Only one patient was in complete remission at the time of second transplant. The median interval between first transplant and relapse was 163 days (range 58-1885). Recipients of HLA-mismatched transplants received antithymocyte globulin in addition to fludarabine and melphalan as part of the conditioning regimen. All 11 patients received acute GVHD prophylaxis consisting of tacrolimus and methotrexate. Ten of 11 patients achieved hematopoietic engraftment with a median time to absolute neutrophil count >0.5 x 10(9)/l and to platelet count of >20 x 10(9)/l of 14 and 19 days, respectively. All engrafting patients achieved 100% donor chimerism on initial analysis, except for one with persistent leukemia at day +19. Two patients experienced grade 3 regimen-related toxicity, manifesting as acute renal failure. Acute GVHD grades 2-4 occurred in two recipients and chronic GVHD in four. The 100-day mortality from all causes was 36%. Ten of 11 patients (91%) died a median of 140 days (range 9-996) after the second transplant. The causes of death included relapse (n = 5), sepsis (n = 4), and idiopathic pneumonia syndrome (n = 1). One patient with AML survives in remission at 880 days post-transplant. We conclude that fludarabine- and melphalan-based conditioning promotes full donor chimerism, even following HLA-mismatched transplants. However, the regimen may be more beneficial when applied to patients undergoing allogeneic HSC transplantation earlier in their disease course.