RESUMEN
PR1, an HLA-A2-restricted peptide derived from both proteinase 3 and neutrophil elastase, is recognized on myeloid leukemia cells by cytotoxic T lymphocytes (CTLs) that preferentially kill leukemia and contribute to cytogenetic remission. To evaluate safety, immunogenicity and clinical activity of PR1 vaccination, a phase I/II trial was conducted. Sixty-six HLA-A2+ patients with acute myeloid leukemia (AML: 42), chronic myeloid leukemia (CML: 13) or myelodysplastic syndrome (MDS: 11) received three to six PR1 peptide vaccinations, administered subcutaneously every 3 weeks at dose levels of 0.25, 0.5 or 1.0 mg. Patients were randomized to the three dose levels after establishing the safety of the highest dose level. Primary end points were safety and immune response, assessed by doubling of PR1/HLA-A2 tetramer-specific CTL, and the secondary end point was clinical response. Immune responses were noted in 35 of 66 (53%) patients. Of the 53 evaluable patients with active disease, 12 (24%) had objective clinical responses (complete: 8; partial: 1 and hematological improvement: 3). PR1-specific immune response was seen in 9 of 25 clinical responders versus 3 of 28 clinical non-responders (P=0.03). In conclusion, PR1 peptide vaccine induces specific immunity that correlates with clinical responses, including molecular remission, in AML, CML and MDS patients.
Asunto(s)
Vacunas contra el Cáncer/inmunología , Antígeno HLA-A2/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Péptidos/inmunología , Biomarcadores , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Epítopos de Linfocito T/inmunología , Femenino , Antígeno HLA-A2/química , Humanos , Memoria Inmunológica , Inmunofenotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Péptidos/administración & dosificación , Péptidos/efectos adversos , Análisis de Supervivencia , Especificidad del Receptor de Antígeno de Linfocitos T , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del Tratamiento , VacunaciónRESUMEN
The PR1 peptide, derived from the leukemia-associated antigens proteinase 3 and neutrophil elastase, is overexpressed on HLA-A2 in acute myeloid leukemia (AML). We developed a high-affinity T-cell receptor-like murine monoclonal antibody, 8F4, that binds to the PR1/HLA-A2 complex, mediates lysis of AML and inhibits leukemia colony formation. Here, we explored whether 8F4 was active in vivo against chemotherapy-resistant AML, including secondary AML. In a screening model, coincubation of AML with 8F4 ex vivo prevented engraftment of all tested AML subtypes in immunodeficient NSG (NOD scid IL-2 receptor γ-chain knockout) mice. In a treatment model of established human AML, administration of 8F4 significantly reduced or eliminated AML xenografts and extended survival compared with isotype antibody-treated mice. Moreover, in secondary transfer experiments, mice inoculated with bone marrow from 8F4-treated mice showed no evidence of AML engraftment, supporting the possible activity of 8F4 against the subset of AML with self-renewing potential. Our data provide evidence that 8F4 antibody is highly active in AML, including chemotherapy-resistant disease, supporting its potential use as a therapeutic agent in patients with AML.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Femenino , Supervivencia de Injerto/efectos de los fármacos , Antígeno HLA-A2/inmunología , Humanos , Elastasa de Leucocito/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Persona de Mediana Edad , Mieloblastina/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) can be induced when GM-CSF is used as an adjuvant to solid tumor vaccination. Neutralizing anti-GM-CSF IgG has been associated with pulmonary alveolar proteinosis (PAP), and secondary PAP has been linked to myeloid leukemia. We studied 69 patients with acute myeloid leukemia, chronic myeloid leukemia and myelodysplastic syndrome, including 19 patients who received GM-CSF with peptide antigen and incomplete Freund's adjuvant in a vaccine trial for the presence or induction of anti-GM-CSF antibodies. Anti-GM-CSF IgG were present in 36 (52%) patients with myeloid leukemia compared to only 1 of 33 (3%) healthy subjects (P=0.008) and in none of 6 patients with lymphoid leukemia (P=0.0001). Antibody titers were unaffected by vaccination. Anti-GM-CSF IgA and IgM were found in 33 and 20% of patients, respectively; IgA from two patients neutralized GM-CSF. Strikingly, while anti-GM-CSF IgG titers were higher in patients with active disease (n=52) versus those in complete remission (n=14, P=0.0009), GM-CSF expression was not increased in either group. These data are first to show that anti-GM-CSF antibodies of multiple isotypes are present in patients with active myeloid leukemia without PAP and may be useful markers of disease activity.
Asunto(s)
Autoanticuerpos/sangre , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Síndromes Mielodisplásicos/diagnóstico , Vacunas contra el Cáncer/inmunología , Estudios de Casos y Controles , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Humanos , Isotipos de Inmunoglobulinas/sangre , Isotipos de Inmunoglobulinas/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Leucemia Mieloide Aguda/inmunología , Síndromes Mielodisplásicos/inmunología , VacunaciónRESUMEN
We analyzed the clinical factors associated with late cytomegalovirus (CMV) reactivation in a group of 269 consecutive recipients of allogeneic stem cell transplant (SCT) for hematological malignancies. Eighty-four subjects (31%) experienced late CMV reactivation, including 64 with prior early reactivation and 20 with isolated late reactivation. Multivariate analyses were conducted in patients with early CMV reactivation to identify factors associated with late recurrence. Important risk factors included lymphoid diagnosis, occurrence of graft-versus-host disease (GVHD), greater number of episodes of early reactivation, persistent day 100 lymphopenia and the use of a CMV-seronegative donor graft. We combined these risk factors in a predictive model to identify those at relatively low, intermediate and high risk. The low-risk group (15% cumulative incidence, CI) encompassed patients without early CMV reactivation, and subjects transplanted for a myeloid malignancy from a matched-related (MR) donor without subsequent acute GVHD. The high-risk patients (73% CI) met all of the following criteria: (1) received an MR graft but developed GVHD, or received a non-MR graft irrespective of GVHD; (2) had more than two episodes of early reactivation; and (3) received a CMV-seronegative graft and/or remained persistently lymphopenic at day 100 after SCT. The remaining patients had an intermediate incidence of 32%.
Asunto(s)
Infecciones por Citomegalovirus/etiología , Neoplasias Hematológicas/terapia , Trasplante de Células Madre/efectos adversos , Adolescente , Adulto , Anciano , Femenino , Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/inmunología , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia , Factores de Riesgo , Linfocitos T/inmunología , Factores de Tiempo , Trasplante HomólogoRESUMEN
BACKGROUND: Umbilical cord blood (CB) is a promising source of hematopoietic stem cells for allogeneic transplantation. However, delayed engraftment and impaired immune reconstitution remain major limitations. Enrichment of donor grafts with CB T cells expanded ex vivo might facilitate improved T-cell immune reconstitution post-transplant. We hypothesized that CB T cells could be expanded using paramagnetic microbeads covalently linked to anti-CD3 and anti-CD28 Ab. METHODS: CB units were divided into three fractions: (1) cells cultured without beads, (2) cells cultured with beads and (3) cells cultured with beads following CD3+ magnetic enrichment. All fractions were cultured for 14 days in the presence of IL-2 (200 IU/mL). RESULTS: A mean 100-fold expansion (range 49-154) of total nucleated cells was observed in the CD3+ magnetically enriched fraction. Following expansion, CB T cells retained a naive and/or central memory phenotype and contained a polyclonal TCR diversity demonstrated by spectratyping. DISCUSSION: Our data provide evidence that naive and diverse CB T cells may be expanded ex vivo and warrant additional studies in the setting of human CB transplantation.
Asunto(s)
Antígenos CD/metabolismo , Sangre Fetal/citología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/metabolismo , Antígenos CD28/metabolismo , Complejo CD3/metabolismo , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Células Cultivadas , Trasplante de Células Madre de Sangre del Cordón Umbilical , Trasplante de Células Madre Hematopoyéticas , Humanos , Activación de Linfocitos/inmunología , Linfocitos T/citología , Linfocitos T/inmunologíaAsunto(s)
Colon Sigmoide/parasitología , Enfermedad Injerto contra Huésped/diagnóstico , Infecciones por Uncinaria/diagnóstico , Leucemia Promielocítica Aguda/complicaciones , Leucemia Promielocítica Aguda/parasitología , Transfusión de Linfocitos/efectos adversos , Trasplante de Células Madre/efectos adversos , Trasplante Homólogo/efectos adversos , Adulto , Ancylostomatoidea , Animales , Diagnóstico Diferencial , Exantema , Humanos , Inmunosupresores/uso terapéutico , Masculino , Inducción de Remisión , Donantes de TejidosRESUMEN
The purpose of the study was to determine the feasibility and efficacy of a reduced intensity conditioning regimen of fludarabine and melphalan for allogeneic transplantation in patients with multiple myeloma. From August 1996 to December 2000, 22 patients received a reduced intensity conditioning regimen with fludarabine and melphalan. Median age was 51 years (range, 45-64), median time from initial therapy to transplant was 36 months (range, 3-135 months). Disease phase prior to transplant was primary refractory in two patients, refractory relapse in 11 patients, sensitive relapse in eight patients and initial remission consolidation in one patient. The median number of prior therapies was five (range, 1-7), and median beta 2 microglobulin prior to transplant was 3.0 mg/l (range, 1.0-7.3). All patients received unmanipulated grafts from either HLA matched sibling donors (n = 13) or matched unrelated donors (n = 9). Eighteen patients received fludarabine 30 mg/m(2) for 4 days with melphalan 140 mg/m(2) as a single dose and four patients received fludarabine 25 mg/m(2) for 5 days with melphalan 90 mg/m(2) daily for 2 days. All 21 patients evaluable for engraftment achieved a neutrophil count of >0.5 x 10(9)/l after a median of 12 days (range, 9-24), 18 patients achieved platelet transfusion independence after a median of 14 days (range, 8-47). All engrafting patients had 100% donor cell engraftment. Seven patients achieved a complete remission. Six patients are currently alive with a median follow-up of 15 months (range, 10-47 months). The actuarial survival and progression-free survival is 30 +/- 11% and 19 +/- 9% at 2 years. Non-relapse mortality at 100 days was 19 +/- 10% and 40 +/- 10% at 1 year. Fludarabine/melphalan combinations are feasible and allow consistent engraftment of allogeneic progenitor cells from both related and unrelated donors in patients with multiple myeloma and should be explored in patients with less advanced disease.
Asunto(s)
Melfalán/administración & dosificación , Mieloma Múltiple/terapia , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/toxicidad , Trasplante de Médula Ósea/métodos , Trasplante de Médula Ósea/mortalidad , Supervivencia sin Enfermedad , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/mortalidad , Trasplante de Células Madre de Sangre Periférica/métodos , Trasplante de Células Madre de Sangre Periférica/mortalidad , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/mortalidad , Trasplante Homólogo/mortalidad , Resultado del TratamientoRESUMEN
The myelodysplastic syndromes (MDSs) are characterized by bilineage or trilineage dysplasia. Although diagnostic criteria are well established for MDS, a significant number of patients have blood and bone marrow findings that make diagnosis and classification difficult. Flow cytometric immunophenotyping is an accurate and highly sensitive method for detection of quantitative and qualitative abnormalities in hematopoietic cells. Flow cytometry was used to study hematopoietic cell populations in the bone marrow of 45 patients with straightforward MDS. The results were compared with those obtained in a series of patients with aplastic anemia, healthy donors, and patients with a history of nonmyeloid neoplasia in complete remission. The immunophenotypic abnormalities associated with MDS were defined, and the diagnostic utility of flow cytometry was compared, with morphologic and cytogenetic evaluations in 20 difficult cases. Although morphology and cytogenetics were adequate for diagnosis in most cases, flow cytometry could detect immunophenotypic abnormalities in cases when combined morphology and cytogenetics were nondiagnostic. It is concluded that flow cytometric immunophenotyping may help establish the diagnosis of MDS, especially when morphology and cytogenetics are indeterminate. (Blood. 2001;98:979-987)
Asunto(s)
Inmunofenotipificación , Síndromes Mielodisplásicos/diagnóstico , Adulto , Anciano , Anemia Aplásica/diagnóstico , Anemia Aplásica/patología , Antígenos CD/análisis , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Análisis Citogenético , Células Precursoras Eritroides/inmunología , Células Precursoras Eritroides/patología , Femenino , Citometría de Flujo , Humanos , Masculino , Megacariocitos/inmunología , Megacariocitos/patología , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Células Mieloides/inmunología , Células Mieloides/patologíaRESUMEN
Allogeneic hematopoietic transplantation is an effective therapy for a range of malignancies. High doses of myelosuppressive chemotherapy or radiation have been used in preparative regimens with the goal of preventing graft rejection and eradicating malignancy. Much of the benefit of transplantation, however, results from graft-versus-malignancy effects, mediated by donor immunocompetent cells. An alternative approach is to utilize less toxic, nonmyeloablative preparative regimens to achieve engraftment and allow graft-versus-malignancy effects to develop. This strategy reduces the risk of treatment-related mortality and allows transplantation for elderly or medically infirm patients not eligible for myeloablative therapy. Nonmyeloablative preparative regimens appear promising in diagnoses sensitive to graft-versus-malignancy effects and provide a platform for further development of cellular immunotherapy. Controlled clinical trials are warranted to define the role of nonmyeloablative allogeneic transplants in a range of hematologic malignancies and selected solid tumors.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Efecto Injerto vs Tumor , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Agonistas Mieloablativos/uso terapéutico , Neoplasias/terapia , Acondicionamiento Pretrasplante/normas , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/métodosRESUMEN
Leukemia is susceptible to immune-mediated therapies such as allogeneic stem-cell transplantation, donor lymphocyte infusion, and interferon. The clinical effectiveness of these immune-based modalities has encouraged interest in vaccine therapies for leukemia. Substantial progress has recently been made in basic immunology, allowing scientifically based vaccination strategies to be developed. The discovery of leukemia- specific and leukemia-associated antigens will allow antigen-specific therapeutic strategies to be developed. Vaccination with genetically modified leukemia cells and the use of dendritic cells in various vaccination approaches are all promising avenues of study for development of effective leukemia vaccines.
Asunto(s)
Vacunas contra el Cáncer/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Leucemia Mieloide Aguda/inmunología , Animales , Antígenos de Neoplasias/inmunología , Células Dendríticas/inmunología , Humanos , Proteínas de Neoplasias/inmunologíaRESUMEN
Myelodysplastic syndrome (MDS) and T-cell large granular lymphocytic disease (T-LGL) are bone marrow failure disorders. Successful use of immunosuppressive agents to treat cytopenia in MDS and LGL suggests a common pathophysiology for the two conditions. Of 100 patients with initial diagnoses of either MDS or T-LGL referred to the National Institutes of Health for immunosuppressive treatment of cytopenia, nine had characteristics of both T-LGL and MDS (T-LGL/MDS). Fifteen patients with T-LGL received cyclosporin (CSA) (10 responses). Eight out of nine patients with T-LGL/MDS received CSA (two responses) and one patient received ATG (one response). Of 76 patients with MDS, eight received CSA (one response) and 68 received ATG (21 responses). The response to immunosuppression was significantly lower in patients with T-LGL/MDS and MDS than in patients with T-LGL disease alone (28% vs. 66%, P = 0.01). The proportion of T-helper cells and T-suppressor cells with an activated phenotype (HLA-DR(+)) was increased in patients with T-LGL, T-LGL/MDS and MDS, but the increase in activated T-suppressor cells in patients with T-LGL/MDS was not statistically significant. Autoreactive T cells may suppress haematopoiesis and contribute to the cytopenia in T-LGL and some patients with MDS, leading to T-LGL/MDS. The lower response rate of MDS or T-LGL/MDS to immunosuppression, compared with T-LGL alone, may reflect the older age and intrinsic stem cell abnormalities in MDS and T-LGL/MDS patients.
Asunto(s)
Leucemia de Células T/complicaciones , Síndromes Mielodisplásicos/complicaciones , Adulto , Factores de Edad , Anciano , Anemia Refractaria/complicaciones , Anemia Refractaria/genética , Anemia Refractaria/inmunología , Anemia Refractaria con Exceso de Blastos/complicaciones , Anemia Refractaria con Exceso de Blastos/genética , Anemia Refractaria con Exceso de Blastos/inmunología , Anemia Sideroblástica/complicaciones , Anemia Sideroblástica/genética , Anemia Sideroblástica/inmunología , Femenino , Reordenamiento Génico de Linfocito T , Humanos , Inmunofenotipificación , Cariotipificación , Leucemia de Células T/genética , Leucemia de Células T/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
A reduced-intensity preparative regimen consisting of melphalan and a purine analog was evaluated for allogeneic transplantation in 86 patients who had a variety of hematologic malignancies and were considered poor candidates for conventional myeloablative therapies because of age or comorbidity. Seventy-eight patients received fludarabine 25 mg/m(2) daily for 5 days in combination with melphalan 180 mg/m(2) (n = 66) or 140 mg/m(2) (n = 12). Eight patients received cladribine 12 mg/m(2) continuous infusion for 5 days with melphalan 180 mg/m(2). The median age was 52 years (range, 22-70 years). Disease status at transplantation was either first remission or first chronic phase in 7 patients, untreated first relapse or subsequent remission in 16 patients, and refractory leukemia or transformed chronic myelogenous leukemia in 63 patients. Nonrelapse mortality rates on day 100 were 37.4% for the fludarabine/melphalan combination and 87.5% for the cladribine/melphalan combination. The median percentage of donor cells at 1 month in 75 patients was 100% (range, 0%-100%). The probability of grade 2-4 and 3-4 acute graft-versus-host disease was 0.49 (95% CI, 0.38-0.60) and 0.29 (95% CI, 0.18-0.41), respectively. Disease-free survival at 1 year was 57% for patients in first remission or chronic phase and 49% for patients with untreated first relapse or in a second or later remission. On multivariate analysis the strongest predictor for disease-free survival was a good or intermediate risk category. In summary, fludarabine/melphalan combinations are feasible in older patients with associated comorbidities, and long-term disease control can be achieved with reduced-intensity conditioning in this population.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cladribina/uso terapéutico , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Melfalán/uso terapéutico , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Enfermedad Aguda , Adenosina/efectos adversos , Adenosina/análogos & derivados , Adenosina/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedad Crónica , Cladribina/administración & dosificación , Cladribina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/diagnóstico , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Melfalán/administración & dosificación , Melfalán/efectos adversos , Persona de Mediana Edad , Tasa de Supervivencia , Quimera por Trasplante , Acondicionamiento Pretrasplante , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/mortalidad , Vidarabina/administración & dosificación , Vidarabina/efectos adversosRESUMEN
Although the immune system has long been implicated in the control of cancer, evidence for specific and efficacious immune responses in human cancer has been lacking. In the case of chronic myelogenous leukemia (CML), either allogeneic bone marrow transplant (BMT) or interferon-alpha2b (IFN-alpha2b) therapy can result in complete remission, but the mechanism for prolonged disease control is unknown and may involve immune anti-leukemic responses. We previously demonstrated that PR1, a peptide derived from proteinase 3, is a potential target for CML-specific T cells. Here we studied 38 CML patients treated with allogeneic BMT, IFN- alpha2b or chemotherapy to look for PR1-specific T cells using PR1/HLA-A*0201 tetrameric complexes. There was a strong correlation between the presence of PR1-specific T cells and clinical responses after IFN-alpha and allogeneic BMT. This provides for the first time direct evidence of a role for T-cell immunity in clearing malignant cells.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Serina Endopeptidasas/inmunología , Linfocitos T Citotóxicos/inmunología , Circulación Sanguínea , Trasplante de Médula Ósea , Citotoxicidad Inmunológica , Efecto Injerto vs Leucemia , Humanos , Interferón-alfa/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Mieloblastina , Fragmentos de Péptidos/inmunología , Inducción de RemisiónRESUMEN
High-dose chemotherapy combined with autologous peripheral blood stem cell transplantation has shown promise as treatment for recurrent or persistent epithelial ovarian cancer. We evaluated the stem cell mobilization regimen of high-dose ifosfamide plus etoposide in 32 patients with epithelial ovarian cancer, who had a positive second-look laparatomy or recurrent disease. Ifosfamide was given at 10 g/m2 by continuous i.v. from days 1 to 3. Etoposide was given at 150 mg/m2 every 12 h for six doses on days 1-3. Filgrastim was given at 10 microg/kg/d s.c. from day 5 until the completion of peripheral blood stem cell harvest. Fourteen of 32 patients had measurable or evaluable disease before mobilization therapy and were assessed for response. In nine (64%) of the 14 patients, treatment response was demonstrated, and these patients received a second cycle of mobilization therapy. The target CD34+ cell dose (>8 x 106 cells/kg) was achieved with a median of one apheresis (range 1-5). A median of 25.1 (range 8.0-122.5) x 106 CD34+ cells/kg body weight was collected. Non-hematologic toxicity was limited to grade 2 renal dysfunction in one patient and grade 2 hepatic dysfunction in three patients. In this patient group, high-dose ifosfamide plus etoposide with filgrastim support was well tolerated, lead to successful stem cell harvest and had antitumor activity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/terapia , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas , Neoplasias Ováricas/terapia , Adulto , Eliminación de Componentes Sanguíneos , Terapia Combinada , Etopósido/administración & dosificación , Femenino , Filgrastim , Humanos , Ifosfamida/administración & dosificación , Mesna/uso terapéutico , Persona de Mediana Edad , Proteínas Recombinantes , Trasplante AutólogoRESUMEN
It is often difficult to distinguish myelodysplastic syndrome (MDS) from severe aplastic anemia (SAA) because both can present with profoundly hypocellular bone marrows. The distinction matters because although both conditions are complicated by pancytopenia, the risk of progression to acute leukemia is much greater in MDS. This chapter reexamines the relationship between SAA and MDS. The clinical and morphological features and pathophysiology of AA (including moderate and severe forms of acquired AA) are compared with MDS and hypoplastic MDS, with particular reference to new observations implicating autoimmune processes in both conditions. SAA and hypoplastic MDS (HMDS) are discussed in the light of these findings and attempts to separate nonevolving bone marrow failure syndromes from marrow failure progressing to acute leukemia are reviewed. The weight of evidence supports a common pathophysiology and, more speculatively, a common etiology for at least some forms of AA and MDS.
Asunto(s)
Anemia Aplásica/diagnóstico , Síndromes Mielodisplásicos/diagnóstico , Anemia Aplásica/genética , Anemia Aplásica/patología , Anemia Aplásica/terapia , Médula Ósea/patología , Diagnóstico Diferencial , Humanos , Inmunosupresores/uso terapéutico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/terapia , Pancitopenia , Linfocitos T/inmunologíaRESUMEN
A 34-year-old woman with diffuse mediastinal B cell large cell lymphoma presented 60 days after high-dose chemotherapy and autologous stem cell transplantation, and post-transplant immunotherapy with interleukin-2, with skin necrosis in the ears and extremities. Extensive work-up revealed the presence of cryofibrinogenemia and associated thrombotic vasculopathy. The patient was successfully treated with corticosteroids and therapeutic plasma exchange. However, she had recurrence of large cell lymphoma a few weeks later and died of progressive disease. Cryfibrinogenemia and skin necrosis may have occurred secondary to the imminent relapse, or as a rare complication of high-dose chemotherapy or treatment with interleukin-2.
Asunto(s)
Crioglobulinemia/etiología , Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso/complicaciones , Enfermedades de la Piel/etiología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Crioglobulinemia/patología , Crioglobulinas/efectos adversos , Resultado Fatal , Femenino , Fibrinógenos Anormales/efectos adversos , Humanos , Linfoma de Células B Grandes Difuso/terapia , Necrosis , Recurrencia , Enfermedades de la Piel/patología , Trasplante AutólogoRESUMEN
An immune-mediated graft-versus-malignancy effect is important to prevent relapse after allogeneic bone marrow transplant for a range of hematologic malignancies and potentially some solid tumors. Graft-versus-leukemia (GVL) effects as seen in response to donor lymphocyte infusions have been most prominent against indolent malignancies including chronic myelogenous leukemia, chronic lymphocytic leukemia, and low-grade lymphoma. Acute myelogenous leukemia and multiple myeloma may also respond. An alternative strategy for allogeneic transplantation is to avoid the toxicity of high-dose chemoradiotherapy and use a relatively nontoxic, nonablative preparative regimen to achieve engraftment, allowing subsequent infusion of additional donor lymphocytes to mediate GVL. Fludarabine-based nonablative chemotherapy agents, using standard dose combinations, produce moderate myelosuppression but are sufficiently immunosuppressive to allow engraftment of an allogeneic hematopoietic transplant and generation of graft-versus-malignancy effects.