RESUMEN
CAR-T cells are genetically modified human lymphocytes and gene therapy medicinal products. They are developed to treat cancers that express a membrane antigen targeted by the CAR. The FDA approved the two first-in-class medicinal products in 2017 and EMA in August 2018; both are autologous CAR-T cells targeting CD19 that is expressed at the surface of normal B-cells throughout their differentiation, and on B-cell lymphoid malignancies. Clinical efficacy was demonstrated for B-cell acute lymphoblastic leukemias, non-Hodgkin's lymphoma and chronic lymphocytic leukemia, although the marketing authorizations are less liberal in terms of indications. Manufacturing of these personalized treatments necessitates that a novel organization and supply chain be set in place, to ensure product preservation, patient safety and compliance with complex regulatory requirements. Side effects are commensurate with clinical efficacy and can be life-threatening: proper management imposes tight coordination between various specialists, particularly between hematologists and intensive care practitioners. High pricing for these treatments is part of a long-term trend for increasing costs of innovations in hematology and oncology; it questions the ability of healthcare systems to sustain their reimbursement.
Asunto(s)
Inmunoterapia Adoptiva , Neoplasias/terapia , Receptores Quiméricos de Antígenos/inmunología , Antígenos CD19/inmunología , Humanos , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunologíaRESUMEN
This corrects the article DOI: 10.1038/bmt.2012.225.
RESUMEN
BACKGROUND: The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune-mediated graft-versus-leukaemia effects. Previous studies have suggested a strong association between graft-versus-host disease (GVHD) occurrence and graft-versus-leukaemia effects after allogeneic hematopoietic cell transplantation. METHODS: Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient-year within sequential 90-day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time-dependent covariate. RESULTS: The study included data from 1068 patients given single (n = 567) or double (n = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II-IV acute (HR = 0.8, P = 0.1) and chronic (HR = 0.65, P = 0.1) GVHD decreased relapse risk. However, grade II-IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P < 0.001) and late (HR = 4.9, P < 0.001) mortality after UCBT. CONCLUSIONS: The occurrence of grade II-IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft-versus-leukemia effect of GVHD.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Enfermedad Injerto contra Huésped , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Anciano , Suero Antilinfocítico/uso terapéutico , Femenino , Humanos , Inmunosupresores/uso terapéutico , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Adulto JovenRESUMEN
Since a significant proportion of diabetic patients have clinical or subclinical neuropathy, there may be concerns about the use of local anaesthetics. The present study was designed to determine and compare the effects of articaine, a widely used anaesthetic in dental practice, and lidocaine on the resting and axonal stimulation-evoked release of [3H]noradrenaline ([3H]NA) in prefrontal cortex slices and the release of [3H]NA in spinal cord slices prepared from non-diabetic and streptozocin (STZ)-induced diabetic (glucose level=22.03±2.31mmol/l) rats. The peak of allodynia was achieved 9 weeks after STZ-treatment. Articaine and lidocaine inhibited the stimulation-evoked release in a concentration-dependent manner and increased the resting release by two to six times. These effects indicate an inhibitory action of these anaesthetics on Na+- and K+-channels. There was no difference in clinically important nerve conduction between non-diabetic and diabetic rats, as measured by the release of transmitter in response to axonal stimulation. The uptake and resting release of NA was significantly higher in the brain slices prepared from diabetic rats, but there were no differences in the spinal cord. For the adverse effects, the effects of articaine on K+ channels (resting release) are more pronounced compared to lidocaine. In this respect, articaine has a thiophene ring with high lipid solubility, which may present potential risks for some patients.
Asunto(s)
Neuronas Adrenérgicas/efectos de los fármacos , Carticaína/farmacología , Norepinefrina/fisiología , Anestesia Local , Animales , Axones/efectos de los fármacos , Encéfalo/efectos de los fármacos , Carticaína/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Lidocaína/metabolismo , Lidocaína/farmacología , Masculino , Conducción Nerviosa/efectos de los fármacos , Norepinefrina/metabolismo , Corteza Olfatoria/citología , Ratas , Ratas Wistar , Médula Espinal/citología , Estreptozocina/farmacologíaRESUMEN
Unrelated cord blood transplantation (UCBT) after a reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly patients and those with co-morbidities without an HLA-identical donor, although post-transplant relapse remains a concern in high-risk acute myeloid leukemia (AML) patients. HLA incompatibilities between donor and recipient might enhance the alloreactivity of natural killer (NK) cells after allogeneic hematopoietic stem-cell transplantation (HSCT). We studied the reconstitution of NK cells and KIR-L mismatch in 54 patients who underwent a RIC-UCBT for AML in CR in a prospective phase II clinical trial. After RIC-UCBT, NK cells displayed phenotypic features of both activation and immaturity. Restoration of their polyfunctional capacities depended on the timing of their acquisition of phenotypic markers of maturity. The incidence of treatment-related mortality (TRM) was correlated with low CD16 expression (P=0.043) and high HLA-DR expression (P=0.0008), whereas overall survival was associated with increased frequency of NK-cell degranulation (P=0.001). These features reflect a general impairment of the NK licensing process in HLA-mismatched HSCT and may aid the development of future strategies for selecting optimal UCB units and enhancing immune recovery.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/inmunología , Recuperación de la Función/inmunología , Sistema de Registros , Acondicionamiento Pretrasplante , Adulto , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
We investigated the use of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of advanced Hodgkin lymphoma (HL). Sixty-two consecutive HL patients underwent haplo-HSCT. Unmanipulated stem cells and post-transplant cyclophosphamide were given to all patients as GVHD prophylaxis. At 100 days, the cumulative incidence of grades 2-3 and grades 3-4 acute GVHD was 23% and 4%, respectively. The chronic GVHD (cGVHD) cumulative incidence was 16%, with one patient experiencing severe cGVHD. The 3-year OS, PFS, relapse rates and 1-year non-relapse mortality (NRM) were 63%, 59%, 21% and 20%, respectively. Uncontrolled disease status and high hematopoietic cell transplantation comorbidity index (HCT-CI) were associated with lower OS, whereas PBSC was an independent protective factor. Uncontrolled disease and HCT-CI >2 was predictive for NRM. Finally, disease status other than CR was predictive of relapse. In conclusion, haplo-HSCT is a valid treatment in advanced HL, offering excellent rates of survival and acceptable toxicities.
Asunto(s)
Ciclofosfamida/uso terapéutico , Enfermedad de Hodgkin/terapia , Trasplante Haploidéntico/métodos , Adulto , Anciano , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad de Hodgkin/mortalidad , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica , Pronóstico , Análisis de Supervivencia , Trasplante Haploidéntico/mortalidad , Adulto JovenAsunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Inhibidores de la Calcineurina/uso terapéutico , Ciclofosfamida/uso terapéutico , Cistitis/tratamiento farmacológico , Cistitis/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Poliomavirus/patogenicidad , Acondicionamiento Pretrasplante/efectos adversos , Antineoplásicos Alquilantes/farmacología , Inhibidores de la Calcineurina/efectos adversos , Inhibidores de la Calcineurina/farmacología , Ciclofosfamida/farmacología , Cistitis/patología , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Estudios Retrospectivos , Acondicionamiento Pretrasplante/métodosAsunto(s)
Enfermedad de Hodgkin/terapia , Recurrencia Local de Neoplasia/terapia , Trasplante de Células Madre , Adolescente , Adulto , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenAsunto(s)
Trasplante de Médula Ósea , Trasplante de Células Madre de Sangre Periférica , Células Madre/citología , Acondicionamiento Pretrasplante , Adolescente , Adulto , Factores de Edad , Anciano , Ensayos Clínicos Fase II como Asunto , Estudios de Cohortes , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia/terapia , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Síndromes Mielodisplásicos/terapia , Factores de Tiempo , Trasplante Homólogo , Resultado del TratamientoAsunto(s)
Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante Haploidéntico/efectos adversos , Adolescente , Adulto , Anciano , Estudios de Cohortes , Ciclofosfamida/uso terapéutico , Femenino , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Depleción Linfocítica , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenAsunto(s)
Ciclofosfamida/administración & dosificación , Ciclosporina/administración & dosificación , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Tacrolimus/administración & dosificación , Adulto , Aloinjertos , Ciclofosfamida/efectos adversos , Ciclosporina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tacrolimus/efectos adversosRESUMEN
Unmanipulated haploidentical transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy) represents an alternative for patients with high-risk diseases lacking HLA-identical donor. Although it provides low incidences of GVHD, the efficacy of Haplo-SCT is still questioned, especially for patients with myeloid malignancies. Thus, we analyzed 60 consecutive patients with refractory (n=30) or high-risk CR (n=30) AML or myelodysplastic syndromes (MDSs) who underwent PT-Cy Haplo-SCT. The median age was 57 years (22-73 years), hematopoietic cell transplantation comorbidity index was ⩾3 in 38 patients (63%) and Haplo-SCT was the second allogeneic transplantation for 10 patients (17%). Although most of patients received PBSC as graft source (n=48, 80%), we found low incidences of grade 3-4 acute (2%) and severe chronic GVHD (4%). Among patients with high-risk CR diseases, 1-year non-relapse mortality, cumulative incidence of relapse, progression-free and overall survivals were 20%, 32%, 47% and 62%, respectively. In patients with refractory disease, corresponding results were 34%, 35%, 32% and 37%, respectively. We conclude that PT-Cy Haplo-SCT could provide promising anti-leukemic effect even in the setting of very advanced diseases. Thus, it represents a viable alternative for high-risk AML/MDS patients without HLA-identical donor.
Asunto(s)
Ciclofosfamida/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Trasplante de Células Madre , Enfermedad Aguda , Adulto , Anciano , Aloinjertos , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidadRESUMEN
BACKGROUND: Patients with advanced B-cell non-Hodgkin's lymphoma (NHL) refractory to initial chemotherapy or relapsing after autologous stem-cell transplantation have a poor prognosis. Allogeneic stem-cell transplantation after reduced-intensity conditioning (RIC) regimen can be a therapeutic option. However, the high incidence of relapse remains a challenging issue. We speculated that the incorporation of (90)Y-Ibritumomab tiuxetan into a fludarabine-based RIC regimen would improve the lymphoma control without overwhelming toxicity. Our aim was to evaluate the safety of (90)Y-Ibritumomab tiuxetan in association with such a regimen in a prospective multicenter phase II trial. PATIENTS AND METHODS: Thirty-one patients with advanced lymphoma from five distinct institutions were included between February 2008 and October 2010. Thirty patients in complete or partial response after failure of a median of 3 (range, 2-4) previous chemotherapy regimens including autologous transplant in 29 were evaluable for nonrelapse mortality (NRM) at day 100 post-transplant that was the primary end point. RESULTS: With a median follow-up of 32 months (range, 29-60 months), the 2-year event-free and overall survivals of the whole study group were both 80% [95 confidence interval (CI) 60.8% to 90.5%). The 100-day and 2-year post-transplant cumulative incidences of NRM were 3.3% (95% CI 0.2% to 14.9%) and 13.3% (95% CI 5.4% to 33.2%), respectively. The 2-year cumulative incidence of relapse was 6.7% (95% CI 1.7% to 25.4%). The cumulative incidences of grade II-IV and extensive chronic graft-versus-host disease were 27% and 14%, respectively. CONCLUSIONS: For chemosensitive advanced high-risk B-cell lymphoma, the addition of (90)Y-Ibritumomab tiuxetan to a RIC regimen based on fludarabine, busulfan and antithymocyte globulin followed by allogeneic transplant is safe and highly effective. clinicaltrials.gov: NCT00607854.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Busulfano/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Vidarabina/análogos & derivados , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped , Humanos , Linfoma de Células B/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estudios Prospectivos , Terapia Recuperativa , Trasplante de Células Madre , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del Tratamiento , Vidarabina/uso terapéuticoRESUMEN
Allo-SCT is regularly performed in advanced lymphoma. Haploidentical family donors are a valuable source of hematopoietic stem cells and transplants from these donors, using T-repleted grafts, has recently been successfully reported. We report on 49 patients with refractory lymphoma who received T-repleted haploidentical SCT with a non-myeloablative regimen and post-transplant CY. The median time to recover ANC >0.5 × 10e9/L and transfusion independent plt count >20 × 10e9/L was 20 days (range 14-38) and 26 days (range 14-395). The probability to reach ANC >0.5 × 10e9/L at 30 days was 87% and transfusion independent plt count >20 × 10e9/L at 100 days was 87%. The cumulative incidence of grade 2-4 acute GVHD (aGVHD) was 25.6% (95% confidence interval (CI): 12.9-38.3%) and the cumulative incidence of chronic GVHD (cGVHD) was 5.2% (95% CI: 0-12.4%). The median follow-up is 20.6 months (range 12-54), and the projected 2-year OS and PFS were 71 and 63%. The relapse rate was 18.7% (95% CI: 7.6-29.8%) and the median time to relapse was 4.4 months (range 1.1-8.3). At 2 years, cumulative incidence of NRM was 16.3% (95% CI: 5.9-26.8%). T-repleted Haploidentical transplantation with post-infusion CY is a feasible and effective therapy in the poor prognosis of advanced lymphoma patients.