RESUMEN
Patients with acute myeloid leukaemia (AML) who lack a matched sibling or unrelated donor commonly undergo transplantation from a donor matched at 9/10 HLA-A, -B, -C, -DRB1, -DQB1 alleles, and it is unclear if a specific locus mismatch is preferable to any other. We therefore studied 937 patients with AML in complete remission transplanted using a reduced intensity conditioning regimen from an unrelated donor mismatched at a single allele. In a multivariate analysis, patient age, adverse karyotype and patient cytomegalovirus (CMV) seropositivity were correlated with decreased leukaemia free survival (LFS) and overall survival (OS). There was no significant difference in LFS or OS between patients transplanted from donors mismatched at HLA-A, -B, -C or -DRB1 in comparison to a HLA-DQB1 mismatched transplant. In a multivariate analysis, patients transplanted with a HLA-A mismatched donor had higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM) than patients transplanted with a HLA-DQB1 mismatched donor. Patient CMV seropositivity was associated with an increase in NRM and acute GVHD and reduced LFS and OS, regardless of donor CMV status. For CMV seropositive patients lacking a fully matched donor, alternative GVHD and CMV prophylaxis strategies should be considered.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/terapia , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Donante no EmparentadoRESUMEN
BACKGROUND: The novel proteasome inhibitor carfilzomib alone or in combination with other agents is already one of the standard therapies for relapsed and/or refractory multiple myeloma (MM) patients and produces impressive response rates in newly diagnosed MM as well. However, carfilzomib-related cardiovascular adverse events (CVAEs) - including hypertension (all grades: 12.2%; grade ≥3: 4.3%), heart failure (all grades: 4.1%; grade ≥3: 2.5%) and ischemic heart disease (all grades: 1.8%; grade ≥3: 0.8%) - may lead to treatment suspensions. At present, there are neither prospective studies nor expert consensus on the prevention, monitoring and treatment of CVAEs in myeloma patients treated with carfilzomib. METHODS: An expert panel of the European Myeloma Network in collaboration with the Italian Society of Arterial Hypertension and with the endorsement of the European Hematology Association aimed to provide recommendations to support health professionals in selecting the best management strategies for patients, considering the impact on outcome and the risk-benefit ratio of diagnostic and therapeutic tools, thereby achieving myeloma response with novel combination approaches whilst preventing CVAEs. RESULTS: Patients scheduled to receive carfilzomib need a careful cardiovascular evaluation before treatment and an accurate follow-up during treatment. CONCLUSIONS: A detailed clinical assessment before starting carfilzomib treatment is essential to identify patients at risk for CVAEs, and accurate monitoring of blood pressure and of early signs and symptoms suggestive of cardiac dysfunction remains pivotal to safely administer carfilzomib without treatment interruptions or dose reductions.
Asunto(s)
Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/terapia , Mieloma Múltiple/tratamiento farmacológico , Oligopéptidos/efectos adversos , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/prevención & control , Árboles de Decisión , Humanos , Monitoreo Fisiológico , Oligopéptidos/uso terapéuticoRESUMEN
Human γδ T cells are innate-like T cells which are able to kill a broad range of tumour cells and thus may have potential for cancer immunotherapy. The activating receptor natural killer group 2 member D (NKG2D) plays a key role in regulating immune responses driven by γδ T cells. Here, we explored whether recombinant immunoligands consisting of a CD20 single-chain fragment variable (scFv) linked to a NKG2D ligand, either MHC class I chain-related protein A (MICA) or UL16 binding protein 2 (ULBP2), could be employed to engage γδ T cells for tumour cell killing. The two immunoligands, designated MICA:7D8 and ULBP2:7D8, respectively, enhanced cytotoxicity of ex vivo-expanded γδ T cells against CD20-positive lymphoma cells. Both Vδ1 and Vδ2 γδ T cells were triggered by MICA:7D8 or ULBP2:7D8. Killing of CD20-negative tumour cells was not induced by the immunoligands, indicating their antigen specificity. MICA:7D8 and ULBP2:7D8 acted in a dose-dependent manner and induced cytotoxicity at nanomolar concentrations. Importantly, chronic lymphocytic leukaemia (CLL) cells isolated from patients were sensitized by the two immunoligands for γδ T cell cytotoxicity. In a combination approach, the immunoligands were combined with bromohydrin pyrophosphate (BrHPP), an agonist for Vδ2 γδ T cells, which further enhanced the efficacy in target cell killing. Thus, employing tumour-directed recombinant immunoligands which engage NKG2D may represent an attractive strategy to enhance antitumour cytotoxicity of γδ T cells.
Asunto(s)
Antígenos CD20/metabolismo , Citotoxicidad Inmunológica , Inmunoterapia/métodos , Linfoma/terapia , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Anticuerpos de Cadena Única/uso terapéutico , Linfocitos T/fisiología , Antígenos CD20/inmunología , Difosfatos/uso terapéutico , Quimioterapia Combinada , Proteínas Ligadas a GPI/genética , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Inmunización , Péptidos y Proteínas de Señalización Intercelular/genética , Linfoma/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Anticuerpos de Cadena Única/genética , Células Tumorales CultivadasAsunto(s)
Infecciones Bacterianas/epidemiología , Infecciones Bacterianas/microbiología , Tercer Molar/microbiología , Boca/microbiología , Trasplante de Células Madre , Adolescente , Adulto , Anciano , Aloinjertos , Autoinjertos , Infecciones Bacterianas/etiología , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Antineoplásicos/uso terapéutico , Bortezomib/uso terapéutico , Quimioterapia de Consolidación , Mieloma Múltiple/terapia , Trasplante de Células Madre , Adulto , Anciano , Antineoplásicos/efectos adversos , Bortezomib/efectos adversos , Ensayos Clínicos Fase III como Asunto , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Trasplante AutólogoRESUMEN
For young patients with high-risk CLL, BTK-/PI3K-inhibitors or allogeneic stem cell transplantation (alloHCT) are considered. Patients with a low risk of non-relapse mortality (NRM) but a high risk of failure of targeted therapy may benefit most from alloHCT. We performed Cox regression analyses to identify risk factors for 2-year NRM and 5-year event-free survival (using EFS as a surrogate for long-term disease control) in a large, updated EBMT registry cohort (n= 694). For the whole cohort, 2-year NRM was 28% and 5-year EFS 37%. Higher age, lower performance status, unrelated donor type and unfavorable sex-mismatch had a significant adverse impact on 2-year NRM. Two-year NRM was calculated for good- and poor-risk reference patients. Predicted 2-year-NRM was 11 and 12% for male and female good-risk patients compared with 42 and 33% for male and female poor-risk patients. For 5-year EFS, age, performance status, prior autologous HCT, remission status and sex-mismatch had a significant impact, whereas del(17p) did not. The model-based prediction of 5-year EFS was 55% and 64%, respectively, for male and female good-risk patients. Good-risk transplant candidates with high-risk CLL and limited prognosis either on or after failure of targeted therapy should still be considered for alloHCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Linfocítica Crónica de Células B/terapia , Adulto , Factores de Edad , Anciano , Donantes de Sangre , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Factores de Riesgo , Factores Sexuales , Análisis de Supervivencia , Trasplante Homólogo , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
Even with the availability of targeted drugs, allogeneic hematopoietic cell transplantation (allo-HCT) is the only therapy with curative potential for patients with CLL. Cure can be assessed by comparing long-term survival of patients to the matched general population. Using data from 2589 patients who received allo-HCT between 2000 and 2010, we used landmark analyses and methods from relative survival analysis to calculate excess mortality compared with an age-, sex- and calendar year-matched general population. Estimated event-free survival, overall survival and non-relapse mortality (NRM) 10 years after allo-HCT were 28% (95% confidence interval (CI), 25-31), 35% (95% CI, 32-38) and 40% (95% CI, 37-42), respectively. Patients who passed the 5-year landmark event-free survival (N=394) had a 79% probability (95% CI, 73-85) of surviving the subsequent 5 years without an event. Relapse and NRM contributed equally to treatment failure. Five-year mortality for 45- and 65-year-old reference patients who were event-free at the 5-year landmark was 8% and 47% compared with 3% and 14% in the matched general population, respectively. The prospect of long-term disease-free survival remains an argument to consider allo-HCT for young patients with high-risk CLL, and programs to understand and prevent late causes of failure for long-term survivors are warranted, especially for older patients.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/terapia , Adolescente , Adulto , Factores de Edad , Anciano , Aloinjertos , Niño , Supervivencia sin Enfermedad , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Sociedades Médicas , Tasa de Supervivencia , Factores de TiempoAsunto(s)
Inmunoterapia/métodos , Neoplasias/terapia , Terapia Combinada , Humanos , Neoplasias/inmunologíaRESUMEN
Despite new treatment modalities, the clinical outcome in a substantial number of patients with multiple myeloma (MM) has yet to be improved. Antibody-based targeted therapies for myeloma patients could make use of the HM1.24 antigen (CD317), a surface molecule overexpressed on malignant plasma cells and efficiently internalized. Here, a novel immunotoxin, HM1.24-ETA', is described. HM1.24-ETA' was generated by genetic fusion of a CD317-specific single-chain Fv (scFv) antibody and a truncated variant of Pseudomonas aeruginosa exotoxin A (ETA'). HM1.24-ETA' inhibited growth of interleukin 6 (IL-6)-dependent and -independent myeloma cell lines. Half-maximal growth inhibition was observed at concentrations as low as 0.3 nM. Target cell killing occurred via induction of apoptosis and was unaffected in co-culture experiments with bone marrow stromal cells. HM1.24-ETA' efficiently triggered apoptosis of freshly isolated/cryopreserved cells of patients with plasma cell leukemia and MM and was active in a preclinical severe combined immunodeficiency (SCID) mouse xenograft model. Importantly, HM1.24-ETA' was not cytotoxic against CD317-positive cells from healthy tissue (monocytes, human umbilical vein endothelial cells). These results indicate that CD317 may represent a promising target structure for specific and efficient immunotoxin therapy for patients with plasma cell tumors.
Asunto(s)
ADP Ribosa Transferasas/farmacología , Toxinas Bacterianas/farmacología , Exotoxinas/farmacología , Inmunotoxinas/farmacología , Mieloma Múltiple/tratamiento farmacológico , Factores de Virulencia/farmacología , ADP Ribosa Transferasas/química , Animales , Anticuerpos Monoclonales Humanizados/química , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Antígenos CD/inmunología , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Toxinas Bacterianas/química , Epítopos , Exotoxinas/química , Femenino , Proteínas Ligadas a GPI/inmunología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Inmunotoxinas/química , Inmunotoxinas/inmunología , Células Jurkat , Ratones , Ratones SCID , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Factores de Virulencia/química , Ensayos Antitumor por Modelo de Xenoinjerto , Exotoxina A de Pseudomonas aeruginosaAsunto(s)
Anticuerpos Monoclonales Humanizados/inmunología , Antígenos CD19/inmunología , Fragmentos Fc de Inmunoglobulinas/inmunología , Células Asesinas Naturales/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Femenino , Humanos , Masculino , Cultivo Primario de CélulasRESUMEN
Bispecific antibodies (bsab) offer a promising approach for optimizing antibody-based therapies. In the present study, [(CD20)(2)xCD16], a recombinant CD20- and CD16-directed bsab in the tribody format, was designed to optimize recruitment of FcγRIII (CD16)-positive effector cells. [(CD20)(2)xCD16] retained the antigen specificities of the parental monoclonal antibodies and binding to FcγRIIIa was not compromised by the F/V polymorphism at amino-acid position 158. [(CD20)(2)xCD16] mediated potent lysis of lymphoma cell lines and freshly isolated tumor cells from patients, even at low picomolar concentrations (â¼10 pM). Irrespective of the CD16a allotype, potency as well as efficacy of lysis obtained with the tribody was significantly higher than lysis triggered by rituximab. Tumor cell killing also occurred when autologous NK cells were used as effector cells. Compared with rituximab, the tribody demonstrated depletion of autologous B cells in ex vivo whole blood assays at 100-fold lower antibody concentration. In mice with a reconstituted humanized hematopoietic system, established by transplantation of human CD34-positive cord blood cells, this novel tribody significantly depleted autologous human B cells. Thus, tribodies such as [(CD20)(2)xCD16], recruiting CD16-positive effector cells, may represent promising candidates for clinical development.
Asunto(s)
Anticuerpos Biespecíficos/uso terapéutico , Citotoxicidad Celular Dependiente de Anticuerpos , Antígenos CD20/inmunología , Leucemia de Células B/terapia , Linfoma de Células B/terapia , Receptores de IgG/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Animales Recién Nacidos , Especificidad de Anticuerpos , Femenino , Sangre Fetal/citología , Sangre Fetal/metabolismo , Humanos , Células Asesinas Naturales/inmunología , Leucemia de Células B/inmunología , Depleción Linfocítica , Linfoma de Células B/inmunología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Receptores de IgG/metabolismoRESUMEN
Minimal residual disease (MRD) after allogeneic stem cell transplantation (SCT) for Ph+ acute lymphoblastic leukemia (ALL) is predictive of relapse. Imatinib administration subsequent to SCT may prevent relapse, but the role of scheduling and its impact on outcome are not known. In a prospective, randomized multicenter trial, we compared the tolerability and efficacy of post-transplant imatinib administered either prophylactically (arm A; n=26) or following detection of MRD (arm B; n=29). Prophylactic imatinib significantly reduced the incidence of molecular recurrence after SCT compared with MRD-triggered imatinib (40% vs 69%; P=0.046). Median duration of PCR negativity was 26.5 and 6.8 months, respectively (P=0.065). Five-year survival in both interventional groups was high (80 and 74.5%), despite premature discontinuation of imatinib in the majority of patients because of poor tolerability. Relapse probability was significantly higher in patients who became MRD positive (P=0.017). In conclusion, post-transplant imatinib results in a low relapse rate, durable remissions and excellent long-term outcome in patients with BCR-ABL1-positive ALL irrespective of whether it is given prophylactically or MRD-triggered. Reappearance of BCR-ABL1 transcripts early after SCT or at higher levels identifies a small subset of patients who do not benefit sufficiently from imatinib, and in whom alternative approaches should be explored.
Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Neoplasia Residual , Piperazinas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pirimidinas/uso terapéutico , Trasplante de Células Madre , Adolescente , Adulto , Antineoplásicos/efectos adversos , Benzamidas/efectos adversos , Terapia Combinada , Femenino , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Piperazinas/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirimidinas/efectos adversos , Análisis de Supervivencia , Adulto JovenRESUMEN
OBJECTIVES: In this study, we compared a classic single-platform (SP) method applying beads for enumeration of CD45+ or CD34+ cells with a new device allowing direct volumetric measurements of stem and progenitor cells. BACKGROUND: Following apheresis and cyropreservation, the precise enumeration of CD34+ cells as key parameter of graft quality is mandatory for the clinical course after transplantation. Currently, flow cytometry with SP technique represents the 'gold standard' for such determinations. METHODS/MATERIALS: Fresh samples, 14 from mobilised peripheral blood (PB), 9 from apheresis products (AP) and 13 samples from frozen-thawed (FT) haematopoietic progenitor cell grafts, were analysed for CD34+ cells, CD45+ cells, and in frozen-thawed samples for viability by a bead-based flow cytometric method and in parallel by a direct, volumetric flow cytometric method. RESULTS: Comparison of CD34+ analyses revealed a significant correlation (P < 0·01) for each material between both techniques with r = 0·95 (PB), r = 0·933 (AP) and r = 0·929 (FT). Also, for analysis of CD45+ cells µL(-1) , the measured numbers evaluated with the different techniques did not significantly differ for all three materials analysed. In frozen-thawed samples, the analysis of viability was comparable for both techniques. CONCLUSIONS: The results of this study demonstrate that a direct volumetric analysis of CD34+ cells µL(-1) or CD45+ cells µL(-1) is feasible. This technique represents a simple and economical approach for standardisation of progenitor and stem cell analyses.
Asunto(s)
Antígenos CD34/análisis , Recuento de Células Sanguíneas/métodos , Citometría de Flujo/métodos , Células Madre Hematopoyéticas , Adulto , Anciano , Eliminación de Componentes Sanguíneos , Conservación de la Sangre , Criopreservación , Femenino , Citometría de Flujo/instrumentación , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/química , Humanos , Antígenos Comunes de Leucocito/análisis , Masculino , Microesferas , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica/métodos , Reproducibilidad de los ResultadosAsunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Citotoxicidad Inmunológica , Antígenos de Histocompatibilidad Clase I/uso terapéutico , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Células Asesinas Naturales/inmunología , Linfoma/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , ADP-Ribosil Ciclasa 1/metabolismo , Antígenos CD20/metabolismo , Proteínas Ligadas a GPI/uso terapéutico , Humanos , Ligandos , Linfoma/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismoRESUMEN
Antibody-drug conjugates (ADC) represent promising agents for targeted cancer therapy. To allow rational selection of human antibodies with favorable characteristics for ADC development a screening tool was designed obviating the need of preparing individual covalently linked conjugates. Therefore, α-kappa-ETA' was designed as a fusion protein consisting of a human kappa light chain binding antibody fragment and a truncated version of Pseudomonas exotoxin A. α-kappa-ETA' specifically bound to human kappa light chains of human or human-mouse chimeric antibodies and Fab fragments. Antibody-redirected α-kappa-ETA' specifically inhibited proliferation of antigen-expressing cell lines at low toxin and antibody concentrations. Selected antibodies that efficiently delivered α-kappa-ETA' in the novel assay system were used to generate scFv-based covalently linked immunotoxins. These molecules efficiently triggered apoptosis of target cells, indicating that antibodies identified in our assay system can be converted to functional immunoconjugates. Finally, a panel of human epidermal growth factor receptor (EGFR) antibodies was screened--demonstrating favorable characteristics with antibody 2F8. These data suggest that antibodies with potential for Pseudomonas exotoxin A-based ADC development can be identified using the novel α-kappa-ETA' conjugate.
Asunto(s)
ADP Ribosa Transferasas/inmunología , Toxinas Bacterianas/inmunología , Exotoxinas/inmunología , Cadenas kappa de Inmunoglobulina/aislamiento & purificación , Inmunotoxinas/aislamiento & purificación , Factores de Virulencia/inmunología , ADP Ribosa Transferasas/uso terapéutico , Animales , Toxinas Bacterianas/uso terapéutico , Línea Celular , Citotoxicidad Inmunológica , Ensayo de Inmunoadsorción Enzimática , Receptores ErbB/inmunología , Exotoxinas/uso terapéutico , Citometría de Flujo , Humanos , Fragmentos Fab de Inmunoglobulinas/química , Fragmentos Fab de Inmunoglobulinas/aislamiento & purificación , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Cadenas kappa de Inmunoglobulina/química , Cadenas kappa de Inmunoglobulina/uso terapéutico , Inmunotoxinas/química , Inmunotoxinas/uso terapéutico , Ratones , Modelos Moleculares , Neoplasias/inmunología , Neoplasias/terapia , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/uso terapéutico , Factores de Virulencia/uso terapéutico , Exotoxina A de Pseudomonas aeruginosaRESUMEN
The efficacy and safety of CD52 antibody alemtuzumab to treat severe acute GVHD in 18 consecutive patients refractory to standard high-dose corticosteroid therapy is reported. Patients (age range 13-68 years) had developed acute GVHD grade III and IV with gut and/or liver involvement after stem cell transplantation from family donors (n= 7) or HLA-matched unrelated donors (n=11), including five donors with one or two HLA mismatches. Initially, in three patients, start doses of alemtuzumab in the range of 70-80 mg were applied and repeated after 3 to 4 weeks. Impressive responses were seen, but virus reactivation and bacterial infections were frequent. In an attempt to reduce this complication, the next nine patients received a reduced starting dose of 20-33 mg, and the last six patients received 3-13 mg repeated every 2-3 weeks. Seventeen of 18 patients responded to alemtuzumab, six patients are alive with a median follow-up of 108 weeks. Chronic GVHD was observed frequently. Although pronounced lymphocyte depletion requiring close monitoring for signs of infections seems inevitable for efficacy, alemtuzumab given in moderate doses has a substantial activity not only in intestinal but also in severe acute GVHD of the liver.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/inmunología , Inmunosupresores/uso terapéutico , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Anciano , Alemtuzumab , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/administración & dosificación , Anticuerpos Antineoplásicos/efectos adversos , Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Infecciones Bacterianas/complicaciones , Antígeno CD52 , Enfermedades Gastrointestinales/complicaciones , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades Gastrointestinales/inmunología , Glicoproteínas/metabolismo , Enfermedad Injerto contra Huésped/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/terapia , Hepatopatías/complicaciones , Hepatopatías/tratamiento farmacológico , Hepatopatías/inmunología , Depleción Linfocítica/efectos adversos , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del Tratamiento , Virosis/complicaciones , Adulto JovenAsunto(s)
Antígenos CD36/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Isoanticuerpos/inmunología , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/cirugía , Trasplante Autólogo , Adulto , Antígenos CD36/deficiencia , Humanos , Linfoma de Células B Grandes Difuso/sangre , Masculino , Recuento de Plaquetas , Resultado del TratamientoRESUMEN
In this multicenter study, 30 patients undergoing matched related or unrelated allogeneic stem-cell transplantation for leukemia were treated with palifermin, and retrospectively compared to a matched control group. Palifermin recipients transplanted with an unrelated donor showed a significant reduction of severity, incidence and duration of oral mucositis WHO grades 2-4. In addition, in the palifermin group the use of opioid analgesics and the duration of total parenteral nutrition decreased, whether stem cells were used from matched related or unrelated donors. No beneficial influence of palifermin on the incidence and severity of acute GVHD (aGVHD) was apparent. The incidence and duration of febrile neutropenia, documented infections, hematopoietic recovery or overall survival remained unchanged. The most common adverse effects included rash or erythema, generally mild and transient in appearance. Thus, the administration of palifermin was generally well tolerated and safe, and significantly reduced oral mucositis whereas--regardless of donor status--no effect on the incidence and severity of aGVHD was seen.
Asunto(s)
Factor 7 de Crecimiento de Fibroblastos/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia/terapia , Estomatitis/prevención & control , Adolescente , Adulto , Femenino , Factor 7 de Crecimiento de Fibroblastos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
Systemic candidiasis is a rare but life threatening complication in immunosuppressed patients undergoing allogeneic SCT. Combination of new antifungal agents may improve outcome in this patient population. Here, triple anti-mycotic therapy is described in an relapsed ALL patient in urgent need of allogeneic bone marrow transplantation. The patient with T-cell acute lymphoblastic leukemia of thymic differentiation achieved remission after treatment according to the German ALL protocol 07/03. Two months after the consolidation therapy relapse occurred requiring high dose chemotherapy with allogeneic stem cell transplantation. One day after start of the conditioning regimen the patient showed skin manifestations typical for septic mycosis and blood cultures became positive for Candida krusei while on fluconazole prophylaxis. Because of the limited sensibility of fluconazole resistant candida species to liposomal amphotericin B and the high mortality rate in patients with systemic candidiasis, voriconazole was added immediately to liposomal amphotericin B. Since fever did not resolve and the conditioning therapy for allogeneic transplantation was not yet completed caspofungin was added. Skin manifestation responded to this triple anti-mycotic combination and peripheral blood stem cells from an unrelated donor were transplanted. With the triple antifungal therapy the patient finally became afebrile, skin manifestations showed complete resolution and blood cultures became negative. Three months after the onset of systemic candidiasis the patient was fully active with no signs of fungal infection and in haematological and molecular remission. Mycotic sepsis at the start of myeloablative conditioning therapy in heavily pretreated acute leukemia patients is usually considered as not allowing successful allogeneic transplantation. Thus this case demonstrates, that allogeneic stem cell transplantation is feasible in patients presenting with systemic candidiasis if combined antifungal therapy with liposomal amphotericin B, caspofungin and voriconazole is given.
Asunto(s)
Antifúngicos/uso terapéutico , Trasplante de Médula Ósea , Candidiasis/terapia , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Adulto , Anfotericina B/administración & dosificación , Anfotericina B/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Candidiasis/inmunología , Caspofungina , Quimioterapia Combinada , Equinocandinas , Humanos , Huésped Inmunocomprometido , Leucemia-Linfoma de Células T del Adulto/inmunología , Leucemia-Linfoma de Células T del Adulto/terapia , Lipopéptidos , Liposomas , Masculino , Péptidos Cíclicos/uso terapéutico , Pirimidinas/uso terapéutico , Trasplante Homólogo , Triazoles/uso terapéutico , VoriconazolRESUMEN
Graft-versus-host disease (GvHD) caused by alloreactive T cells within the graft is a major drawback of allogeneic BMT, but depletion of T cells leads to higher rates of relapse, opportunistic infections and graft failure. Therefore, selective removal of GvHD-inducing alloreactive T cells might be beneficial. We describe here the separation of alloresponsive T cells, based on carboxyfluorescein succimidyl ester labeling, in vitro allostimulation and FACS-sorting. In vivo effects of the separated cell populations were investigated in the context of allogeneic BMT in murine models: in vitro resting T cells were shown to survive in the allogeneic host and retain immunoreactivity against 'third-party' antigens. As demonstrated in two different transplantation models, elimination of proliferating cells significantly reduces GvHD but offers no advantages to using T-cell-depleted bone marrow alone concerning engraftment and tumor control. Transplanting T cells that proliferate in response to tumor antigens in vitro may narrow down the spectrum of antigens recognized by T cells and therefore reduce GvHD while maintaining graft-facilitating function and tumor control. Therefore, selecting tumor-reactive T cells on the basis of their proliferative response in vitro may be beneficial for the recipient, less time consuming than T-cell cloning and still reduce the extent of GvHD.