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1.
Adv Ther ; 40(12): 5383-5398, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37801234

RESUMEN

INTRODUCTION: Brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, is approved for relapsed/refractory B-cell precursor acute lymphoblastic leukemia in adults aged 18+/26+ years in the US/European Union (EU), based on efficacy results from the single-arm ZUMA-3 trial. This study aimed to estimate the relative treatment effects of brexu-cel versus inotuzumab ozogamicin (InO), blinatumomab (blina), and chemotherapies using unanchored matching-adjusted indirect comparison (MAIC) methods. METHODS: Individual patient data from ZUMA-3 and published aggregate level data from two randomized controlled trials, INO-VATE (InO versus chemotherapy) and TOWER (blina versus chemotherapy), were used. Patient-level data from ZUMA-3 were weighted to match the mean of the following prognostic variables at baseline, which were pre-specified based on clinical input, for each comparator population: primary refractory disease, duration of first remission < 12 months, prior stem-cell transplantation, age, performance status, salvage status, bone marrow blast, complex karyotype, and Philadelphia chromosome status. The base case analysis was conducted using the modified intention-to-treat population (i.e., received brexu-cel) from ZUMA-3. Relative treatment effects for overall survival (OS) and event-free survival (EFS) were expressed as hazard ratios (HR) and differences in restricted mean survival time (RMST) with 95% confidence intervals (CI). RESULTS: The base case MAIC results suggested brexu-cel improved OS and EFS compared to blina (OS HR 0.46 [95% CI 0.28, 0.75]; EFS HR 0.37 [95% CI 0.25, 0.56]) and pooled INO-VATE/TOWER chemotherapy (OS HR 0.32 [95% CI 0.18, 0.56]; EFS HR 0.27 [0.18, 0.40]). Brexu-cel also improved OS compared to InO (HR 0.45 [95% CI 0.24, 0.85]). The point estimate for EFS favored brexu-cel over Ino but the difference was not statistically significant (HR 0.67 [95% CI 0.41, 1.10]). Findings were consistent between the HR and RMST analyses. CONCLUSION: Despite limitations, these MAIC results suggest that brexu-cel may improve OS and EFS versus currently used therapies in this population.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inotuzumab Ozogamicina , Inmunoterapia Adoptiva , Inducción de Remisión
2.
J Clin Immunol ; 38(8): 917-926, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30470982

RESUMEN

The results of hematopoietic stem cell transplant (HSCT) for primary immunodeficiency diseases (PID) have been improving over time. Unfortunately, developing countries do not experience the same results. This first report of Brazilian experience of HSCT for PID describes the development and results in the field. We included data from transplants in 221 patients, performed at 11 centers which participated in the Brazilian collaborative group, from July 1990 to December 2015. The majority of transplants were concentrated in one center (n = 123). The median age at HSCT was 22 months, and the most common diseases were severe combined immunodeficiency (SCID) (n = 67) and Wiskott-Aldrich syndrome (WAS) (n = 67). Only 15 patients received unconditioned transplants. Cumulative incidence of GVHD grades II to IV was 23%, and GVHD grades III to IV was 10%. The 5-year overall survival was 71.6%. WAS patients had better survival compared to other diseases. Most deaths (n = 53) occurred in the first year after transplantation mainly due to infection (55%) and GVHD (13%). Although transplant for PID patients in Brazil has evolved since its beginning, we still face some challenges like delayed diagnosis and referral, severe infections before transplant, a limited number of transplant centers with expertise, and resources for more advanced techniques. Measures like newborn screening for SCID may hasten the diagnosis and ameliorate patients' conditions at the moment of transplant.


Asunto(s)
Enfermedad Injerto contra Huésped/epidemiología , Trasplante de Células Madre Hematopoyéticas , Síndromes de Inmunodeficiencia/terapia , Enfermedades Raras/terapia , Brasil/epidemiología , Diagnóstico Tardío , Países en Desarrollo , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Síndromes de Inmunodeficiencia/epidemiología , Síndromes de Inmunodeficiencia/mortalidad , Lactante , Recién Nacido , Masculino , Tamizaje Neonatal , Enfermedades Raras/epidemiología , Enfermedades Raras/mortalidad , Análisis de Supervivencia
5.
Transplantation ; 89(11): 1336-40, 2010 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-20351629

RESUMEN

BACKGROUND: A pilot study was conducted to determine whether conditioning using selective targeting of hematopoietic cells with an alpha-particle emitter, bismuth-213 ((213)Bi)-labeled anti-CD45 monoclonal antibody (mAb) is sufficient to overcome the major histocompatibility barrier in a canine model of dog leukocyte antigen-haploidentical hematopoietic cell transplantation (HCT). METHODS: Six dogs were administered 0.5 mg/kg (213)Bi-labeled anti-CD45 mAb (dose (213)Bi=2.26-4.9 mCi/kg) in six to eight injections. For postgrafting immunosuppression, all dogs received cyclosporine and mycophenolate mofetil. RESULTS: All dogs had initial donor engraftment, with three of six dogs having sustained engraftment to last point of follow-up. Two dogs receiving 2.26 and 3.25 mCi/kg of (213)Bi rejected their grafts at day +127 and +125, respectively, whereas dogs receiving (213)Bi doses of 3.3 mCi/kg or greater achieved high level donor chimerism. CONCLUSION: The results suggest that nonmyeloablative conditioning with (213)Bi-labeled anti-CD45 mAb could be applicable to major histocompatibility haploidentical HCT without excessive nonhematologic regimen-related toxicity.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Bismuto , Supervivencia de Injerto/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Antígenos Comunes de Leucocito/inmunología , Radioisótopos , Animales , Medios de Cultivo Condicionados , Perros , Haploidia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Neutrófilos/citología , Trombocitopenia/epidemiología , Trasplante Homólogo/inmunología , Trasplante Homólogo/métodos
6.
Cytotherapy ; 12(1): 113-5, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-19878083
7.
Blood ; 112(8): 3088-98, 2008 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-18559976

RESUMEN

The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell-like DLBCL, but not nongerminal center B cell-like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.


Asunto(s)
Linfoma de Células B Grandes Difuso/genética , Mutación , Proteína p53 Supresora de Tumor/genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Análisis Mutacional de ADN , Doxorrubicina/administración & dosificación , Exones , Femenino , Humanos , Cooperación Internacional , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Prednisolona/administración & dosificación , Pronóstico , Resultado del Tratamiento , Vincristina/administración & dosificación
8.
Transplantation ; 82(3): 332-9, 2006 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-16906030

RESUMEN

BACKGROUND: We previously described a reduced-intensity hematopoietic cell transplantation (HCT) regimen in dog leukocyte antigen (DLA)-haploidentical littermate recipients consisting of 450 cGy total body irradiation (TBI) and anti-CD44 monoclonal antibody (mAb) S5 before and mycophenolate mofetil (MMF)/cyclosporine (CSP) after HCT. METHODS: We tested a nonmyeloablative regimen of mAb S5 and 200 cGy TBI with postgrafting MMF/CSP in 44 DLA-haploidentical recipients using eight different regimens. Ten dogs also received escalating doses of donor lymphocyte infusion (DLI) alone or with pentostatin to convert to complete donor chimerism. RESULTS: All dogs achieved initial engraftment between one to two weeks after HCT with peripheral blood mononuclear cell (PBMC) donor chimerism ranging from 2% to 98% (median 37%) on day +35. Twenty-five (57%) dogs rejected their donor grafts at a median of seven (range; 1-19) weeks after HCT. Low levels of PBMC donor chimerism at three weeks predicted graft rejection. DLI neither facilitated conversion to full donor chimerism after HCT nor prevented rejection. Higher total nucleated cells, CD4+, CD8+, and CD14+ cell subset numbers in the PBMC graft were associated with stable full donor engraftment. Dogs given higher cell subset doses of infused PBMC achieved longer duration of mixed chimerism. CONCLUSIONS: Nonmyeloablative conditioning with 200 cGy TBI and anti-CD44 mAb was sufficient for initial uniform engraftment across DLA haplotype-mismatched barriers. However, sustained donor engraftment was seen in only 43% of recipients. Graft composition and donor-dominant chimerism early after HCT may be the most important factors for sustained donor engraftment.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Receptores de Hialuranos/inmunología , Inmunoterapia , Leucocitos/inmunología , Células Madre/inmunología , Animales , Recuento de Células , Quimera/inmunología , Perros , Relación Dosis-Respuesta a Droga , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Enfermedad Injerto contra Huésped/inmunología , Haploidia , Inmunosupresores/farmacología , Leucocitos/efectos de la radiación , Modelos Animales , Células Mieloides/citología , Células Mieloides/efectos de la radiación , Células Madre/efectos de los fármacos , Factores de Tiempo , Acondicionamiento Pretrasplante , Trasplante Homólogo/inmunología
9.
Leuk Lymphoma ; 45(10): 2071-8, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15370252

RESUMEN

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Although the presence of p53 gene mutations has been considered as a bad prognostic feature in DLBCL, its clinical significance is still controversial. The aims of this study were: detect the presence of mutations in exons 5 to 9 of the p53 gene and correlate it to prognosis in DLBCL. Fifty-one DLBCL patients were enrolled in this study. Expression of p53 was evaluated by immunohistochemistry. The screening of p53 mutations was performed using PCR-SSCP methods. Cases showing a mobility shift on SSCP electrophoresis were analyzed by automatic sequencing. We could identify 8 missense mutations in 6 of 48 cases (12.5%). In addition, we found a known polymorphism at codon 213 and 2 instances of silent mutations. Of all mutations/polymorphisms found, 7 (64%) were localized in codons previously described as p53 hot spots in NHL cases. Of the remaining alterations (4 or 36%), 2 mutations were localized in codons previously described as hot spots for p53 in other tumors and 2 (codon 142 of the exon 5 and codon 195 of the exon 6), in codons not described as hot spots for p53 up to now. The presence of missense mutations in exons 5 to 9 of p53 gene had adverse impact on overall survival (P = 0.020). Cox's Regression Model identified that high-risk International Prognostic Index (IPI) and p53 gene mutations have independent negative impact on OS. Therefore, the association of IPI with cellular factors, such as p53 mutation, can be very helpful in deciding when we should indicate more aggressive therapies in patients with DLBCL, to somehow increase the chance of cure in these patients.


Asunto(s)
Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Mutación , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Exones , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Linfoma de Células B/mortalidad , Linfoma de Células B Grandes Difuso/mortalidad , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento
10.
Leuk Lymphoma ; 45(3): 539-45, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15160916

RESUMEN

Many patients with follicular lymphoma (FL) achieve response after treatment but complete remission (CR) rates are very low. Thus the majority of them will relapse, mainly those in advanced stage disease, due to the persistence of residual disease. Therefore, this study had the following aims: to determine the presence of bcl-2/IgH rearrangement in peripheral blood of early and advanced stage FL patients after treatment and to correlate it with their clinical situation at the same moment. We obtained 100 consecutive peripheral blood samples from 30 FL cases and conducted molecular studies using two separate semi-nested PCRs for MBR and mcr rearrangements. These semi-nested PCRs for bcl-2/IgH rearrangement were able to detect one positive cell among 10,000 normal cells. Clinical and molecular evolution of patients diagnosed as early stage disease suggested that molecular response could be obtained even with conventional chemotherapy or radiotherapy. In this group of patients, 64% achieved molecular response in some point during follow-up. However, only 23% of patients diagnosed as advanced stage disease reached molecular response when treated with chemotherapy (with or without radiotherapy). Due to the low number of subjects assessed in this study, we only found a tendency to significance when clinical stage at the diagnosis was associated to molecular response (P = 0.095). We observed 100% of concordance between clinical remission and molecular response in patients after bone marrow transplantation or in those cases treated with monoclonal antibody anti-CD20. This retrospective study, performed in a restricted number of patients, suggests that molecular response can be obtained in FL patients diagnosed at early stage disease, even with conventional chemotherapy and radiotherapy. In advanced stage disease, concordance between clinical remission and molecular response was observed in the majority of patients after bone marrow transplantation or in those cases treated with monoclonal antibody anti-CD20. The prognostic significance of this data should be confirmed with extended follow-up and in a larger number of patients.


Asunto(s)
Cromosomas Humanos Par 14 , Cromosomas Humanos Par 18 , Linfoma Folicular/patología , Neoplasia Residual/patología , Células Neoplásicas Circulantes/patología , Translocación Genética , Reordenamiento Génico , Genes bcl-2 , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Neoplasia Residual/genética , Reacción en Cadena de la Polimerasa/normas , Pronóstico , Estudios Retrospectivos
11.
Leuk Lymphoma ; 45(2): 331-8, 2004 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15101720

RESUMEN

The aims of this study were: 1) to identify the type of bcl-2 rearrangement in a Brazilian group of FL patients and 2) to correlate it to clinical features, International Prognostic Index (IPI), histological subtype, response to treatment and clinical outcome. We reviewed the diagnosis of 48 patients with FL and investigated the type of bcl-2 gene rearrangement using DNA from paraffin-embedded tumor samples obtained at the time of diagnosis. In 30 cases, we also obtained consecutive peripheral blood samples to search for the presence of bcl-2/IgH rearrangement. Molecular analysis identified 41 (86%) patients with MBR and 5 (10%) patients with mcr rearrangement. In this study, the type of rearrangement was not associated with clinical characteristics or IPI. In addition, the type of rearrangement did not have an impact on response to initial treatment or on clinical outcome. However, we found an association between the type of rearrangement and the histological subtype of FL, i.e., none of mcr-positive patients presented histological grade I (p = 0.043). In this study, we could not demonstrate a relationship between the type of bcl-2 rearrangement and the response to treatment or outcome. However, we found a relationship between the type of rearrangement and FL histological subtype, information not previously reported.


Asunto(s)
Reordenamiento Génico , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Anciano , Clonación Molecular , ADN/química , ADN/genética , ADN/metabolismo , Supervivencia sin Enfermedad , Electroforesis en Gel de Agar , Femenino , Humanos , Inmunoglobulinas/genética , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , Factores de Tiempo
12.
Leuk Lymphoma ; 44(1): 149-51, 2003 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-12691156

RESUMEN

Primary malignant breast lymphoma (PBL) is a rare disease with an incidence of 0.04-0.5% of all malignant breast neoplasms. The majority of cases are B-cell lymphomas and the most common histologic type is diffuse large B-cell lymphoma (DLCL). In this study, we report our experience with three cases of PBL. The treatment was the same currently indicated for early stage aggressive NHL, i.e. anthracycline based chemotherapy followed by the involved field radiation therapy. Unfortunately, two patients underwent mastectomy to carry out correct diagnosis. The three patients are alive without any evidence of relapse after 24, 67 and 135 months of follow-up. Considering that aggressive NHL is very sensitive to chemotherapy, mastectomy should be avoided to preserve the quality of life of these patients, once surgery does not change the good prognosis of PBL.


Asunto(s)
Neoplasias de la Mama/terapia , Linfoma no Hodgkin/terapia , Anciano , Antibióticos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/diagnóstico , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/terapia , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/terapia , Linfoma no Hodgkin/diagnóstico , Mastectomía , Persona de Mediana Edad , Radioterapia Adyuvante , Procedimientos Innecesarios
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