RESUMEN
BACKGROUND: Sickle cell disease is characterized by the painful recurrence of vaso-occlusive events. Gene therapy with the use of LentiGlobin for sickle cell disease (bb1111; lovotibeglogene autotemcel) consists of autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified ß-globin gene, which produces an antisickling hemoglobin, HbAT87Q. METHODS: In this ongoing phase 1-2 study, we optimized the treatment process in the initial 7 patients in Group A and 2 patients in Group B with sickle cell disease. Group C was established for the pivotal evaluation of LentiGlobin for sickle cell disease, and we adopted a more stringent inclusion criterion that required a minimum of four severe vaso-occlusive events in the 24 months before enrollment. In this unprespecified interim analysis, we evaluated the safety and efficacy of LentiGlobin in 35 patients enrolled in Group C. Included in this analysis was the number of severe vaso-occlusive events after LentiGlobin infusion among patients with at least four vaso-occlusive events in the 24 months before enrollment and with at least 6 months of follow-up. RESULTS: As of February 2021, cell collection had been initiated in 43 patients in Group C; 35 received a LentiGlobin infusion, with a median follow-up of 17.3 months (range, 3.7 to 37.6). Engraftment occurred in all 35 patients. The median total hemoglobin level increased from 8.5 g per deciliter at baseline to 11 g or more per deciliter from 6 months through 36 months after infusion. HbAT87Q contributed at least 40% of total hemoglobin and was distributed across a mean (±SD) of 85±8% of red cells. Hemolysis markers were reduced. Among the 25 patients who could be evaluated, all had resolution of severe vaso-occlusive events, as compared with a median of 3.5 events per year (range, 2.0 to 13.5) in the 24 months before enrollment. Three patients had a nonserious adverse event related or possibly related to LentiGlobin that resolved within 1 week after onset. No cases of hematologic cancer were observed during up to 37.6 months of follow-up. CONCLUSIONS: One-time treatment with LentiGlobin resulted in sustained production of HbAT87Q in most red cells, leading to reduced hemolysis and complete resolution of severe vaso-occlusive events. (Funded by Bluebird Bio; HGB-206 ClinicalTrials.gov number, NCT02140554.).
Asunto(s)
Anemia de Células Falciformes/terapia , Terapia Genética , Vectores Genéticos , Trasplante de Células Madre Hematopoyéticas , Hemoglobinas/genética , Lentivirus , Trasplante de Células Madre , Globinas beta/genética , Adolescente , Adulto , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/complicaciones , Niño , Femenino , Hemoglobina Fetal , Hemoglobinas/análisis , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Grado de Desobstrucción Vascular , Adulto JovenRESUMEN
IFN-γ is a pleiotropic cytokine that plays a controversial role in regulatory T cell (Treg) activity. In this study, we sought to understand how IFN-γ receptor (IFN-γR) signaling affects donor Tregs following allogeneic hematopoietic cell transplant (allo-HCT), a potentially curative therapy for leukemia. We show that IFN-γR signaling inhibits Treg expansion and conversion of conventional T cells (Tcons) to peripheral Tregs in both mice and humans. Mice receiving IFN-γR-deficient allo-HCT showed markedly reduced graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects, a trend associated with increased frequencies of Tregs, compared with recipients of wild-type allo-HCT. In mice receiving Treg-depleted allo-HCT, IFN-γR deficiency-induced peripheral Treg conversion was effective in preventing persistent GVHD while minimally affecting GVL effects. Thus, impairing IFN-γR signaling in Tcons may offer a promising strategy for achieving GVL effects without refractory GVHD. Similarly, in a human PBMC-induced xenogeneic GVHD model, significant inhibition of GVHD and an increase in donor Tregs were observed in mice cotransferred with human CD4 T cells that were deleted of IFN-γR1 by CRISPR/Cas9 technology, providing proof-of-concept support for using IFN-γR-deficient T cells in clinical allo-HCT.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia , Ratones , Humanos , Animales , Linfocitos T Reguladores , Trasplante Homólogo , Leucocitos Mononucleares , Ratones NoqueadosRESUMEN
Transfusion-dependent ß-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).
Asunto(s)
Anemia de Células Falciformes/terapia , Sistemas CRISPR-Cas , Hemoglobina Fetal/biosíntesis , Edición Génica/métodos , Terapia Genética , Proteínas Represoras/genética , Talasemia beta/terapia , Adulto , Anemia de Células Falciformes/genética , Femenino , Hemoglobina Fetal/genética , Humanos , Proteínas Represoras/metabolismo , Adulto Joven , Talasemia beta/genéticaRESUMEN
Although Dara-VCD (daratumumab-bortezomib-cyclophosphamide-dexamethasone) has revolutionized the treatment of newly diagnosed Amyloid Light chain (AL) amyloidosis, patients with stage IIIb disease were excluded in the pivotal trial. We performed a multicentre retrospective cohort study to investigate the outcomes of 19 consecutive patients treated with Dara-VCD front-line therapy who had stage IIIb AL at diagnosis. More than two thirds presented with New York Heart Association Class III/IV symptoms, and had a median of two organs involved (range, 2-4). The haematologic overall response rate was 100%, with 17/19 patients (89.5%) achieving a very good partial response (VGPR) or better. Haematologic responses were achieved rapidly, as evidenced by 63% of evaluable patients with involved serum free light chains (iFLC) < 2 mg/dl and the difference between involved and uninvolved serum free light chains (dFLC) <1 mg/dl at three months. Among 18 evaluable patients, 10 (56%) achieved a cardiac organ response and six (33%) cardiac VGPR or better. The median time to first cardiac response was 1.9 months (range, 0.4-7.3). At a median follow-up of 12 months for surviving patients, estimated one-year overall survival was 67.5% [95% confidence interval (CI), 43.8-84.7]. The incidence of grade 3 or higher infections was 21%, with no infection-related mortality thus far. In summary, Dara-VCD has a promising efficacy and safety profile in stage IIIb AL, and should be studied in prospective trials.
Asunto(s)
Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Humanos , Bortezomib/efectos adversos , Ciclofosfamida/efectos adversos , Dexametasona/efectos adversos , Estudios Prospectivos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Although descriptions of quality of life and patient reports of mood in sickle cell disease (SCD) have become more common in the literature, less is known about psychiatric illness prevalence, presentation, and treatment, particularly for adults. We provide a narrative review of what is known about common and debilitating psychiatric conditions such as depression, anxiety, and cognitive impairment, specifically for adults with SCD. We discuss the limitations of the current evidence, make provisional recommendations, and identify opportunities for research and improved care.
Asunto(s)
Anemia de Células Falciformes , Ansiedad , Disfunción Cognitiva , Depresión , Adulto , Humanos , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/epidemiología , Anemia de Células Falciformes/psicología , Ansiedad/epidemiología , Disfunción Cognitiva/epidemiología , Comorbilidad , Calidad de Vida , Depresión/epidemiologíaRESUMEN
In multiple myeloma (MM), frequent mutations of NRAS, KRAS, or BRAF are found in up to 50% of newly diagnosed patients. The majority of the NRAS, KRAS, and BRAF mutations occur in hotspots causing constitutive activation of the corresponding proteins. Thus, targeting RAS mutation in MM will increase therapeutic efficiency and potentially overcome drug resistance. We identified germinal center kinase (GCK) as a novel therapeutic target in MM with RAS mutation. GCK knockdown (KD) in MM cells demonstrated in vitro and in vivo that silencing of GCK induces MM cell growth inhibition, associated with blocked MKK4/7-JNK phosphorylation and impaired degradation of IKZF1/3, BCL-6, and c-MYC. These effects were rescued by overexpression of a short hairpin RNA (shRNA)-resistant GCK, thereby excluding the potential off-target effects of GCK KD. In contrast, overexpression of shRNA-resistant GCK kinase-dead mutant (K45A) inhibited MM cell proliferation and failed to rescue the effects of GCK KD on MM growth inhibition, indicating that GCK kinase activity is critical for regulating MM cell proliferation and survival. Importantly, the higher sensitivity to GCK KD in RASMut cells suggests that targeting GCK is effective in MM, which harbors RAS mutations. In accordance with the effects of GCK KD, the GCK inhibitor TL4-12 dose-dependently downregulated IKZF1 and BCL-6 and led to MM cell proliferation inhibition accompanied by induction of apoptosis. Here, our data identify GCK as a novel target in RASMut MM cells, providing a rationale to treat RAS mutations in MM. Furthermore, GCK inhibitors might represent an alternative therapy to overcome immunomodulatory drug resistance in MM.
Asunto(s)
Silenciador del Gen , Quinasas del Centro Germinal/genética , Mieloma Múltiple/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas ras/genética , Animales , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Terapia Genética , Quinasas del Centro Germinal/metabolismo , Humanos , Ratones SCID , Terapia Molecular Dirigida , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Mutación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Hematopoietic cell transplantation (HCT) recipients have reduced antibody titers to tetanus, diphtheria, and pertussis. Tdap is approved for revaccinating adult HCT recipients in the United States, whereas DTaP is not approved in this population. To our knowledge, no studies to date have compared responses to DTaP versus Tdap in adult HCT patients. We conducted a retrospective study comparing responses to DTaP versus Tdap vaccines in otherwise similar adult HCT patients in order to determine if one of these vaccines elicits superior antibody responses. METHODS: We evaluated 43 allogeneic and autologous transplant recipients as a combined cohort and as separate subsets for vaccine specific antibody titers and proportion of strong vaccine responders. Subset analysis focused on the autologous transplant recipients. RESULTS: Higher median antibody titers were found to all vaccine components among DTaP recipients (diphtheria p = .021, pertussis p = .020, tetanus p = .007). DTaP recipients also had more strong responders to diphtheria and pertussis (diphtheria p = .002, pertussis p = .006). Among the autologous HCT recipient subset, there were more strong responders to diphtheria (p = .036). CONCLUSIONS: Our data shows that post-HCT vaccination with DTaP leads to higher antibody titers and more strong responders, which suggests that DTaP is more effective than Tdap in HCT recipients.
Asunto(s)
Vacunas contra Difteria, Tétanos y Tos Ferina Acelular , Difteria , Trasplante de Células Madre Hematopoyéticas , Tétanos , Tos Ferina , Adulto , Humanos , Anticuerpos Antibacterianos , Difteria/prevención & control , Vacuna contra Difteria, Tétanos y Tos Ferina , Inmunización Secundaria , Estudios Retrospectivos , Tétanos/prevención & control , Receptores de Trasplantes , Estados Unidos , Vacunación , Tos Ferina/prevención & control , Tos Ferina/epidemiologíaRESUMEN
The outbreak of coronavirus disease 2019 (COVID-19) has disproportionately affected patients with comorbidities, including recipients of solid organ and hematopoietic stem cell transplants (SCT). Upon recovery from COVID-19, the degree of the immunological protection from reinfection remains unclear. Here we describe a 33-year-old patient with erythropoietic protoporphyria (EPP) who had undergone liver transplantation with splenectomy followed by allogeneic SCT in 2013 after an initial failed liver and umbilical cord transplant. The patient developed mild upper respiratory symptoms in the spring of 2020 and was found to have anti-SARS-CoV2 antibodies suggesting past infection. A comprehensive analysis of T cell functionality in peripheral blood from this patient revealed robust in vitro responses against SARS CoV2 antigens Spike (S) 1 and 2, membrane (M) and nucleoprotein (NP), comparable to the reactivity against common antigens from CMV, EBV, Ad and BK viruses, while only low reactivity was seen in healthy donors without documented history of COVID-19. Moreover, the patient displayed a marked recognition of counterpart antigens from related human coronaviruses (hCoVs) 229E, OC43, NL63 and HKU1. Thus, despite lifelong immunosuppression, this survivor of COVID-19 retained a remarkable degree of immunocompetence and showed broad-spectrum T cell memory specific for SARS-CoV2 and related hCoVs including less studied hCoV M and NP antigens. The study highlights the role of cellular immunity after natural COVID-19 infection, suggesting broader use of T cell assays as a tool for risk stratification, measurement of immunocompetence and/or post-infection or post-vaccination protection, and possible T cell-based adoptive immunotherapy strategies in high-risk patients.
Asunto(s)
COVID-19 , Coronavirus Humano OC43 , Trasplante de Células Madre Hematopoyéticas , Adulto , Anticuerpos Antivirales , Humanos , Hígado , ARN Viral , SARS-CoV-2 , Linfocitos TRESUMEN
BACKGROUND: Cytomegalovirus (CMV) reactivation is associated with significant morbidity and mortality after an allogeneic hematopoietic cell transplant (AHCT), and graft versus host disease (GVHD) increases the risk of CMV reactivation. Letermovir is approved for CMV prophylaxis in CMV-seropositive patients, but has only been studied through day 100 post-transplantation in the registration trial. Its efficacy in preventing CMV in patients with GVHD requiring treatment beyond the day 100 milestone has not been studied. METHODS: We retrospectively analyzed all patients who underwent an AHCT at a single center over a period of 24 months, and identified a cohort of 20 patients who received extended duration of letermovir (beyond 100 days) after the diagnosis of GVHD. The primary end point was the incidence of clinically significant CMV infection, defined as onset of CMV disease or initiation of preemptive therapy with alternative antiviral agents. RESULTS: In this high-risk cohort, only one patient (5%) developed a clinically significant CMV infection, requiring preemptive therapy. No patients developed CMV organ disease. Three additional patients developed CMV viremia of ≥150 IU/mL while on letermovir and after the onset of GVHD, and none required additional treatment. Receipt of post-transplant cyclophosphamide (PTCy) and low CD4 count after the development of GVHD were associated with breakthrough CMV viremia while on extended duration letermovir. CONCLUSIONS: Extended duration letermovir was efficacious in preventing clinically significant CMV infections in patients with GVHD.
Asunto(s)
Acetatos/uso terapéutico , Infecciones por Citomegalovirus , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Quinazolinas/uso terapéutico , Antivirales/uso terapéutico , Citomegalovirus , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/prevención & control , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Humanos , Estudios RetrospectivosRESUMEN
Sickle cell disease (SCD) affects 100,000 Americans and causes significant psychiatric illness and poor quality of life in many domains, including infertility. Hematopoietic cell transplantation (HCT) is the only available cure for SCD, but it can entail chronic toxicities, including psychiatric conditions, such as depression and anxiety, and sterility in both men and women. There is scant literature on fertility or psychiatric outcomes for patients with SCD receiving HCT, and none considering the additive ramifications of the stresses of SCD, transplantation, and infertility. Financial toxicity is a significant concern for all patients undergoing HCT. Treatment for infertility is also very expensive, and access to fertility services is variable in the United States, adding to the medical and quality of life burden for this patient population. Here we review the relevant areas of SCD and infertility, SCD and psychiatric wellness, access to care, and infertility and quality of life. Collectively, these data suggest that the group of patients with SCD who undergo HCT and experience infertility are at particularly high risk for poor quality of life, worsening psychiatric health, and poor access to adequate fertility treatment.
Asunto(s)
Anemia de Células Falciformes , Trasplante de Células Madre Hematopoyéticas , Infertilidad , Anemia de Células Falciformes/terapia , Femenino , Accesibilidad a los Servicios de Salud , Humanos , Infertilidad/etiología , Infertilidad/terapia , Masculino , Calidad de Vida , Estados UnidosRESUMEN
In patients undergoing stem cell transplantation (SCT), nonadherence has potential for significant medical impact and potentially life-threatening complications. No study thus far has demonstrated an effective way to predict adherence in SCT recipients. A structured rating scale, the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT), has been shown to predict psychosocial outcomes and medical morbidity in solid organ transplant recipients. We assessed the SIPAT in SCT recipients. We hypothesized that the SIPAT rating would be associated with nonadherence to the post-SCT regimen. We retrospectively studied SCT recipients who had psychiatric evaluations with the SIPAT before SCT. The primary outcome was nonadherence, defined a priori as at least 1 life-threatening nonadherence event in the first 6 months post-transplant. Association of the SIPAT with outcomes was evaluated by logistic regression, and an optimal cutoff score was determined using a receiver operating characteristic curve. Of 85 patients (mean age 47 years; range, 18 to 74 years), 56 (66%) were male, and 43 (50.5%) received autologous SCT. Eighteen (21%) patients were nonadherent. The SIPAT rating, treated as a continuous variable and controlling for autologous versus allogeneic SCT, was significantly associated with nonadherence (per 1 point; odds ratio [OR], 1.162; P< .0001). Allogeneic SCT also conferred a significantly increased risk of nonadherence (OR, 14.184; P= .005). Multivariate analysis stratifying for allogeneic versus autologous transplantation and controlling for age, sex, and disease confirmed an independent association between the SIPAT score and nonadherence. A cutoff score of 18 provided optimal specificity (89.6%) and sensitivity (55.6%) for nonadherence. Nonadherence rates were 58.8% and 11.8% for subjects with SIPAT ratings of 18 and above or 17 and below, respectively (relative risk = 4.98, P < .0001). Psychosocial risk as quantified by the SIPAT correlated with SCT recipients' adherence to the post-transplant regimen, suggesting that this instrument can contribute to medical risk stratification models. Further study should evaluate long-term mortality data and the effects of intervention on psychosocial risks.
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Trasplante de Células Madre Hematopoyéticas/psicología , Cooperación del Paciente/psicología , Adolescente , Adulto , Anciano , Aloinjertos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psicología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The immunomodulatory drugs, lenalidomide and pomalidomide yield high response rates in multiple myeloma patients, but are associated with a high rate of thrombocytopenia and increased risk of secondary hematologic malignancies. Here, we demonstrate that the immunomodulatory drugs induce self-renewal of hematopoietic progenitors and upregulate megakaryocytic colonies by inhibiting apoptosis and increasing proliferation of early megakaryocytic progenitors via down-regulation of IKZF1. In this process, the immunomodulatory drugs degrade IKZF1 and subsequently down-regulate its binding partner, GATA1. This results in the decrease of GATA1 targets such as ZFPM1 and NFE2, leading to expansion of megakaryocytic progenitors with concomitant inhibition of maturation of megakaryocytes. The down-regulation of GATA1 further decreases CCND1 and increases CDKN2A expression. Overexpression of GATA1 abrogated the effects of the immunomodulatory drugs and restored maturation of megakaryocytic progenitors. Our data not only provide the mechanism for the immunomodulatory drugs induced thrombocytopenia but also help to explain the higher risk of secondary malignancies and long-term cytopenia induced by enhanced cell cycling and subsequent exhaustion of the stem cell pool.
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Apoptosis/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Factor de Transcripción Ikaros/biosíntesis , Factores Inmunológicos/farmacología , Megacariocitos/metabolismo , Femenino , Células Madre Hematopoyéticas/citología , Humanos , Masculino , Megacariocitos/citologíaRESUMEN
Persistent low levels of disease in bone marrow, an immunoprivileged tissue, are responsible for relapse following allogeneic hematopoietic cell transplantation. Using mouse models carrying primary human acute lymphoblast leukemia derived from MLL-AF9-overexpressing human hematopoietic stem cells, we demonstrate that allogeneic lymphocyte infusion (ALI)-mediated graft-vs.-leukemia effects selectively spare leukemia cells in the bone marrow. The resistance of leukemia cells to ALI within bone marrow is due to the immunosuppressive status of the tissue, as ALI achieved a significantly increased complete remission rate when leukemia cells were dislodged from bone marrow by treatment with a CXCR4 antagonist AMD3100. Adoptive transfer experiments confirmed that the frequency of leukemia-initiating cells in bone marrow was significantly decreased in the recipients treated with ALI plus AMD3100 compared to those receiving ALI only. These findings indicate that the immunoprivileged nature of bone marrow is largely responsible for relapse after immunotherapies, and that treatment with AMD3100 may offer a clinically-practical approach to improving the outcome of adoptive allogeneic cell therapy.
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Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Receptores CXCR4/antagonistas & inhibidores , Animales , Bencilaminas , Línea Celular Tumoral , Ciclamas , Compuestos Heterocíclicos/uso terapéutico , Xenoinjertos , Humanos , Inmunoterapia Adoptiva/métodos , Transfusión de Linfocitos/métodos , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Trasplante HomólogoRESUMEN
Proliferative GN with monoclonal IgG deposits is an increasingly recognized form of GN, but its relation to hematologic malignancy remains poorly understood. Filgrastim, an analog for granulocyte colony-stimulating factor produced by recombinant DNA technology, is frequently used to stimulate bone marrow release of hematopoietic progenitor cells in preparation for stem cell transplant. We report an exceptional case of proliferative GN with monoclonal IgG2λ deposits in a young man whose disease progressed slowly to CKD, which was followed by a preemptive kidney transplant. The patient developed recurrent GN in the allograft and clinically detectable plasma cell neoplasm 9 years after the first renal manifestations. Contemporaneous with filgrastim administration for stem cell mobilization, the patient's slowly progressive GN underwent severe crescentic transformation, leading to rapidly progressive and irreversible allograft failure. This report explores the spectrum of GN with monoclonal IgG deposits and the pathophysiologic role of granulocyte colony-stimulating factor in exacerbation of preexisting GN.
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Filgrastim/efectos adversos , Glomerulonefritis Membranoproliferativa/inducido químicamente , Glomerulonefritis Membranoproliferativa/patología , Inmunoglobulina G , Trasplante de Riñón , Complicaciones Posoperatorias/inducido químicamente , Complicaciones Posoperatorias/patología , Adulto , Humanos , Masculino , RecurrenciaAsunto(s)
Anemia de Células Falciformes/terapia , Eliminación de Componentes Sanguíneos , Médula Ósea , Terapia Genética , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Compuestos Heterocíclicos/administración & dosificación , Adulto , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/metabolismo , Autoinjertos , Bencilaminas , Ciclamas , Femenino , Compuestos Heterocíclicos/efectos adversos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Acute graft-versus-host disease (GVHD) remains a barrier to more widespread application of allogeneic haemopoietic stem-cell transplantation. Vorinostat is an inhibitor of histone deacetylases and was shown to attenuate GVHD in preclinical models. We aimed to study the safety and activity of vorinostat, in combination with standard immunoprophylaxis, for prevention of GVHD in patients undergoing related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation. METHODS: Between March 31, 2009, and Feb 8, 2013, we did a prospective, single-arm, phase 1/2 study at two centres in the USA. We recruited adults (aged ≥18 years) with high-risk haematological malignant diseases who were candidates for reduced-intensity conditioning haemopoietic stem-cell transplantation and had an available 8/8 or 7/8 HLA-matched related donor. All patients received a conditioning regimen of fludarabine (40 mg/m(2) daily for 4 days) and busulfan (3.2 mg/kg daily for 2 days) and GVHD immunoprophylaxis of mycophenolate mofetil (1 g three times a day, days 0-28) and tacrolimus (0.03 mg/kg a day, titrated to a goal level of 8-12 ng/mL, starting day -3 until day 180). Vorinostat (either 100 mg or 200 mg, twice a day) was initiated 10 days before haemopoietic stem-cell transplantation until day 100. The primary endpoint was the cumulative incidence of grade 2-4 acute GVHD by day 100. This trial is registered with ClinicalTrials.gov, number NCT00810602. FINDINGS: 50 patients were assessable for both toxic effects and response; eight additional patients were included in the analysis of toxic effects. All patients engrafted neutrophils and platelets at expected times after haemopoietic stem-cell transplantation. The cumulative incidence of grade 2-4 acute GVHD by day 100 was 22% (95% CI 13-36). The most common non-haematological adverse events included electrolyte disturbances (n=15), hyperglycaemia (11), infections (six), mucositis (four), and increased activity of liver enzymes (three). Non-symptomatic thrombocytopenia after engraftment was the most common haematological grade 3-4 adverse event (nine) but was transient and all cases resolved swiftly. INTERPRETATION: Administration of vorinostat in combination with standard GVHD prophylaxis after related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation is safe and is associated with a lower than expected incidence of severe acute GVHD. Future studies are needed to assess the effect of vorinostat for prevention of GVHD in broader settings of haemopoietic stem-cell transplantation. FUNDING: Merck, Leukemia and Lymphoma Society, National Institutes of Health, St Baldrick's Foundation, Michigan Institute for Clinical and Health Research.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Inhibidores de Histona Desacetilasas/administración & dosificación , Ácidos Hidroxámicos/administración & dosificación , Inmunosupresores/administración & dosificación , Ácido Micofenólico/análogos & derivados , Tacrolimus/administración & dosificación , Acondicionamiento Pretrasplante , Enfermedad Aguda , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Estudios Prospectivos , Trasplante Homólogo , VorinostatRESUMEN
Rapamycin (RAPA) inhibits the mechanistic target of rapamycin (mTOR), a crucial immune system regulator. Dendritic cells (DC) generated in RAPA (RAPA-DC) enrich for CD4(+) forkhead box p3 (FoxP3(+)) regulatory T cells and induce T cell apoptosis by an unknown mechanism. RAPA-DC also promote experimental allograft survival, yet paradoxically secrete increased IL-12, crucial for the generation of IFN-γ(+) CD4(+) T cells. However, IFN-γ is pro-apoptotic and IL-12-driven IFN-γ inhibits experimental graft-versus-host disease (GVHD). We hypothesized that IL-12(hi) RAPA-DC would facilitate IFN-γ-mediated apoptosis of alloreactive T cells and, unlike control (CTR)-DC, would reduce lethal GVHD. Following LPS stimulation, RAPA-DC exhibited decreased MHCII and co-stimulatory molecules and contained a significant population of CD86(lo) IL-12(hi) cells. Consistent with our hypothesis, both unstimulated and LPS-stimulated RAPA-DC enhanced alloreactive CD4(+) T cell apoptosis in culture. Augmented T cell apoptosis was ablated by IFN-γ neutralization or using T cells lacking the IFN-γ receptor, and it was associated with increased expression of Fas and cleaved caspase 8. DC production or responses to IFN-γ were not important to increased apoptotic functions of RAPA-DC. LPS-stimulated IL-12p40(-/-) RAPA-DC induced lower levels of T cell apoptosis in culture, which was further decreased with addition of anti-IFN-γ. Finally, whereas CTR-DC accelerated mortality from GVHD, LPS-treated RAPA-DC significantly prolonged host survival. In conclusion, increased apoptosis of allogeneic CD4(+) T cells induced by LPS-stimulated IL-12(hi) RAPA-DC is mediated in vitro through IFN-γ and in part by increased IL-12 expression. Enhanced production of IL-12, the predominant inducer of IFN-γ by immune cells, is a probable mechanism underlying the capacity of LPS-treated RAPA-DC to reduce GVHD.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Apoptosis/inmunología , Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Interleucina-12/inmunología , Sirolimus/uso terapéutico , Animales , Antibióticos Antineoplásicos/inmunología , Diferenciación Celular , Proliferación Celular , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Sirolimus/inmunologíaRESUMEN
Hematopoietic stem cell transplantation is the only curative treatment for many malignant hematologic diseases, with an often critical graft-versus-leukemia effect. Despite peritransplant prophylaxis, GVHD remains a significant cause of posthematopoietic stem cell transplantation morbidity and mortality. Traditional therapies have targeted T cells, yet immunostimulatory dendritic cells (DCs) are critical in the pathogenesis of GVHD. Furthermore, DCs also have tolerogenic properties. Monitoring of DC characteristics may be predictive of outcome, and therapies that target DCs are innovative and promising. DCs may be targeted in vivo or tolerogenic (tol) DCs may be generated in vitro and given in the peritransplant period. Other cellular therapies, notably regulatory T cells (T(reg)) and mesenchymal stem cells, mediate important effects through DCs and show promise for the prevention and treatment of GVHD in early human studies. Therapies are likely to be more effective if they have synergistic effects or target both DCs and T cells in vivo, such as tolDCs or T(reg). Given the effectiveness of tolDCs in experimental models of GVHD and their safety in early human studies for type 1 diabetes, it is crucial that tolDCs be investigated in the prevention and treatment of human GVHD while ensuring conservation of graft-versus-leukemia effects.
Asunto(s)
Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Leucemia/inmunología , Trasplante de Células Madre Hematopoyéticas , Tolerancia Inmunológica , Linfocitos T Reguladores/inmunología , Animales , Células Dendríticas/patología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/terapia , Enfermedad Injerto contra Huésped/patología , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Humanos , Linfocitos T Reguladores/patología , Trasplante HomólogoRESUMEN
This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m(2) (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704.