RESUMEN
BACKGROUND: In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT. PATIENTS AND METHODS: We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles. RESULTS: The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12-9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression. CONCLUSIONS: BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.
Asunto(s)
Bortezomib/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Vorinostat/uso terapéutico , Bortezomib/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Enfermedades Gastrointestinales/etiología , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Tasa de Supervivencia , Trasplante Autólogo , Resultado del Tratamiento , Vorinostat/efectos adversosRESUMEN
DNA methyltransferase inhibitors sensitize leukemia cells to chemotherapeutics. We therefore conducted a phase 1/2 study of mitoxantrone, etoposide and cytarabine following 'priming' with 5-10 days of decitabine (dec/MEC) in 52 adults (median age 55 (range: 19-72) years) with relapsed/refractory acute myeloid leukemia (AML) or other high-grade myeloid neoplasms. During dose escalation in cohorts of 6-12 patients, all dose levels were well tolerated. As response rates appeared similar with 7 and 10 days of decitabine, a 7-day course was defined as the recommended phase 2 dose (RP2D). Among 46 patients treated at/above the RP2D, 10 (22%) achieved a complete remission (CR), 8 without measurable residual disease; five additional patients achieved CR with incomplete platelet recovery, for an overall response rate of 33%. Seven patients (15%) died within 28 days of treatment initiation. Infection/neutropenic fever, nausea and mucositis were the most common adverse events. While the CR rate compared favorably to a matched historic control population (observed/expected CR ratio=1.77), CR rate and survival were similar to two contemporary salvage regimens used at our institution (G-CLAC (granulocyte colony-stimulating factor (G-CSF); clofarabine; cytarabine) and G-CLAM (G-CSF; cladribine; cytarabine; mitoxantrone)). Thus, while meeting the prespecified efficacy goal, we found no evidence that dec/MEC is substantially better than other cytarabine-based regimens currently used for relapsed/refractory AML.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Azacitidina/uso terapéutico , Biomarcadores , Citarabina , Decitabina , Resistencia a Antineoplásicos , Etopósido , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Mitoxantrona , Clasificación del Tumor , Recurrencia , Resultado del Tratamiento , Adulto JovenRESUMEN
HLA-B*49:39 allele is characterised by 1 amino acid substitution in the alpha 1 domain.
Asunto(s)
Alelos , Exones , Antígenos HLA-B/genética , Trasplante de Células Madre Hematopoyéticas , Leucemia/terapia , Polimorfismo de Nucleótido Simple , Sustitución de Aminoácidos , Secuencia de Bases , Codón/química , Femenino , Expresión Génica , Antígenos HLA-B/inmunología , Haplotipos , Prueba de Histocompatibilidad , Humanos , Leucemia/inmunología , Leucemia/patología , Masculino , Núcleo Familiar , Linaje , Reacción en Cadena de la Polimerasa , Alineación de Secuencia , Análisis de Secuencia de ADN , Donantes de TejidosRESUMEN
Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission. Seventy-one patients (median age: 56 years) received CloBu4. At day 30 after HCT, 90% achieved morphologic remission. The incidence of non-relapse mortality and relapse at 2 years was 25% and 55%, respectively. The 2-year overall survival (OS) and event-free survival (EFS) were 26% and 20%, respectively. Patients entering HCT in PIF had significantly greater EFS than those in relapse (34% vs 8%; P<0.01). Multivariate analysis comparing CloBu4 with a contemporaneous cohort (Center for International Blood and Marrow Transplantation Research) of AML not in remission receiving other myeloablative conditioning (n=105) demonstrated similar OS (HR: 1.33, 95% confidence interval: 0.92-1.92; P=0.12). HCT with myeloablative CloBu4 is associated with high early response rates and may produce durable remissions in select patients with AML not in remission.
Asunto(s)
Nucleótidos de Adenina/administración & dosificación , Arabinonucleósidos/administración & dosificación , Busulfano/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Acondicionamiento Pretrasplante , Adulto , Anciano , Aloinjertos , Clofarabina , Supervivencia sin Enfermedad , Femenino , Humanos , Quimioterapia de Inducción , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
HLA-C*15:103 allele is characterised by one amino acid substitution in the alpha 2 domain.
Asunto(s)
Alelos , Exones , Antígenos HLA-C/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia/terapia , Polimorfismo de Nucleótido Simple , Donante no Emparentado , Anciano , Sustitución de Aminoácidos , Secuencia de Bases , Niño , Codón/química , Femenino , Genotipo , Antígenos HLA-C/inmunología , Prueba de Histocompatibilidad , Humanos , Leucemia/inmunología , Leucemia/patología , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa , Dominios Proteicos , Alineación de Secuencia , Análisis de Secuencia de ADN , Resultado del TratamientoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/administración & dosificación , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Doxorrubicina/análogos & derivados , Mieloma Múltiple/tratamiento farmacológico , Adolescente , Adulto , Anciano , Doxorrubicina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Terapia Neoadyuvante , Polietilenglicoles/administración & dosificación , Recurrencia , Trasplante de Células Madre , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo , Adulto JovenRESUMEN
We aimed to examine whether doses of melphalan higher than 200 mg/m(2) improve response rates when used as conditioning before autologous transplant (ASCT) in multiple myeloma (MM) patients. Patients with MM, n=131, were randomized to 200 mg/m(2) (mel200) vs 280 mg/m(2) (mel280) using amifostine pretreatment. The primary end point was the proportion of patients achieving near complete response (⩾nCR). No treatment-related deaths occurred in this study. Responses following ASCT were for mel200 vs mel280, respectively, ⩾nCR 22 vs 39%, P=0.03, ⩾PR 57 vs 74%, P=0.04. The hazard of mortality was not statistically significantly different between groups (mel200 vs mel280; hazard ratio (HR)=1.15 (95% confidence interval (CI), 0.62-2.13, P=0.66)) nor was the rate of progression/mortality (HR=0.81 (0.52-1.27, P=0.36)). The estimated PFS at 1 and 3 years were 83 and 46%, respectively, for mel200 and 78 and 54%, respectively, for mel280. Amifostine and mel280 were well tolerated, with no grade 4 regimen-related toxicities and only one grade 3 mucositis (none with mel200) and three grade 3 gastrointestinal (GI) toxicities (two in mel200). Hospitalization rates were more frequent in the mel280 group (59 vs 43%, P=0.08). Mel280 resulted in a higher major response rate (CR+nCR) and should be evaluated in larger studies.
Asunto(s)
Melfalán/administración & dosificación , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Trasplante de Células Madre , Acondicionamiento Pretrasplante , Adulto , Anciano , Autoinjertos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Tasa de SupervivenciaRESUMEN
HLA-B*50:20 contains seven nucleotide substitutions leading to four amino acid changes in the alpha-2 domain.
Asunto(s)
Genes MHC Clase II , Antígenos HLA-B/química , Alelos , Sustitución de Aminoácidos , Secuencia de Bases , Exones/genética , Antígenos HLA-B/genética , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Conformación Proteica , Estructura Terciaria de Proteína , Alineación de Secuencia , Homología de Secuencia de Ácido NucleicoRESUMEN
Bone marrow-derived mesenchymal stromal cells (BM-MSCs) play a fundamental role in the BM microenvironment (BME) and abnormalities of these cells may contribute to acute myeloid leukemia (AML) pathogenesis. The aim of the study was to characterize the cytokine and gene expression profile, immunophenotype and cytogenetics of BM-MSCs from AML patients compared to normal BM-MSCs from healthy donors. AML BM-MSCs showed decreased monocyte chemoattractant protein-1 levels compared to normal BM-MSCs. AML BM-MSCs expressed similar ß1 integrin, CD44, CD73, CD90 and E-cadherin compared to normal BM-MSCs. Cytogenetic analysis revealed chromosomal aberrations in AML BM-MSCs, some overlapping with and others distinct from their corresponding AML blasts. No significant difference in gene expression was detected between AML BM-MSCs compared to normal BM-MSCs; however, comparing the differences between AML and MSCs from AML patients with the differences between normal hematopoietic cells and normal MSCs by Ingenuity pathway analysis showed key distinctions of the AML setting: (1) upstream gene regulation by transforming growth factor beta 1, tumor necrosis factor, tissue transglutaminase 2, CCAAT/enhancer binding protein alpha and SWItch/Sucrose NonFermentable related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; (2) integrin and interleukin 8 signaling as overrepresented canonical pathways; and (3) upregulation of transcription factors FBJ murine osteosarcoma viral oncogene homolog and v-myb avian myeloblastosis viral oncogene homolog. Thus, phenotypic abnormalities of AML BM-MSCs highlight a dysfunctional BME that may impact AML survival and proliferation.
Asunto(s)
Médula Ósea/patología , Aberraciones Cromosómicas , Leucemia Mieloide Aguda/genética , Células Madre Mesenquimatosas , Microambiente Tumoral/genética , Adulto , Anciano , Animales , Diferenciación Celular/genética , Proliferación Celular/genética , Análisis Citogenético , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Ratones , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteína Glutamina Gamma Glutamiltransferasa 2 , TranscriptomaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/patología , Células de la Médula Ósea/citología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Femenino , Humanos , Quimioterapia de Inducción , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Recuento de Plaquetas , Pronóstico , Inducción de RemisiónRESUMEN
Allo-SCT can result in long-term remission in patients with multiple myeloma (MM), although its overall role in disease management remains controversial. We evaluated lenalidomide monotherapy response and tolerability among 18 patients with MM who progressed or relapsed after Allo-SCT, who were enrolled a median of 12 months (range 3-104) following transplant. Treatment duration of lenalidomide was 8 months (range 1-57). Ten patients required dose reductions from 25 to 5-20 mg at a median of three cycles (range 1-12): eight for neutropenia, one for thrombocytopenia and one for myalgias and weakness. Serious adverse events (N=5) included H1N1 influenza (2), bacterial pneumonia (2) and fever, myalgia and hypoxia. Two patients died at 3 and 5 months of gastrointestinal or hepatic GVHD occurring within 1 month of dosing. Responses included complete response (CR) (5), very good partial response (2), partial response (PR) (3), minimal response (1) and stable disease (2) for an overall response rate (≥ PR) of 56%. Ten patients discontinued therapy for progressive disease (PD) at a median of 8.5 (1-43) months. Six patients died from PD. Five patients remained on therapy at 39 months (range 14-57), with four in CR. Lenalidomide for relapse of MM after Allo-SCT can result in extended disease control (>12 months) in 50% of patients.
Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Mieloma Múltiple/terapia , Talidomida/análogos & derivados , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Progresión de la Enfermedad , Femenino , Humanos , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/etiología , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/terapia , Estudios Prospectivos , Inducción de Remisión , Talidomida/administración & dosificación , Talidomida/efectos adversos , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
HLA-B*44:101 and HLA-B*57:48 are characterized by amino acid substitutions in the alpha 2 domain.
Asunto(s)
Alelos , Bases de Datos de Ácidos Nucleicos , Antígenos HLA-B/genética , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Población BlancaRESUMEN
HLA-C*12:92 contains one amino acid exchange in the T-cell receptor binding region.
Asunto(s)
Alelos , Aminoácidos/genética , Antígenos HLA-C/química , Antígenos HLA-C/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Exones/genética , Antígenos HLA-C/metabolismo , Humanos , Datos de Secuencia Molecular , Unión Proteica , Estructura Terciaria de Proteína , Alineación de SecuenciaAsunto(s)
ADP-Ribosil Ciclasa 1/metabolismo , Antígenos CD34/metabolismo , Crisis Blástica/terapia , Células Precursoras de Granulocitos/patología , Leucemia Mieloide Aguda/terapia , Adulto , Anciano , Anciano de 80 o más Años , Animales , Crisis Blástica/diagnóstico , Crisis Blástica/genética , Estudios de Casos y Controles , Terapia Combinada , Análisis Citogenético , Femenino , Citometría de Flujo , Células Precursoras de Granulocitos/metabolismo , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Pronóstico , Receptores de Interleucina-2/fisiología , Inducción de Remisión , Adulto JovenRESUMEN
The novel HLA-C allele HLA-C*07:147 contains one nucleotide substitution in exon 2 leading to an amino acid change in the alpha 1 domain from phenylalanine to leucine.
Asunto(s)
Alelos , Sustitución de Aminoácidos , Antígenos HLA-C/genética , Mutación Missense , Humanos , Estructura Terciaria de ProteínaRESUMEN
The novel HLA-B*27:67 contains three nucleotide substitutions in exon 2 leading to two amino acid changes.
Asunto(s)
Antígenos HLA-B/genética , Alelos , Secuencia de Bases , Sitios de Unión , Incompatibilidad de Grupos Sanguíneos , Exones , Antígenos HLA-B/química , Haplotipos , Prueba de Histocompatibilidad/métodos , Humanos , Modelos Genéticos , Datos de Secuencia Molecular , Nucleótidos/genética , Péptidos/química , Estructura Terciaria de Proteína , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido Nucleico , Células Madre/citologíaRESUMEN
One of the major hurdles for the development of gene therapy for Fanconi anemia (FA) is the increased sensitivity of FA stem cells to free radical-induced DNA damage during ex vivo culture and manipulation. To minimize this damage, we have developed a brief transduction procedure for lentivirus vector-mediated transduction of hematopoietic progenitor cells from patients with Fanconi anemia complementation group A (FANCA). The lentiviral vector FancA-sW contains the phosphoglycerate kinase promoter, the FANCA cDNA, and a synthetic, safety-modified woodchuck post transcriptional regulatory element (sW). Bone marrow mononuclear cells or purified CD34(+) cells from patients with FANCA were transduced in an overnight culture on recombinant fibronectin peptide CH-296, in low (5%) oxygen, with the reducing agent, N-acetyl-L-cysteine (NAC), and a combination of growth factors, granulocyte colony-stimulating factor (G-CSF), Flt3 ligand, stem cell factor, and thrombopoietin. Transduced cells plated in methylcellulose in hypoxia with NAC showed increased colony formation compared with 21% oxygen without NAC (P<0.03), showed increased resistance to mitomycin C compared with green fluorescent protein (GFP) vector-transduced controls (P<0.007), and increased survival. Thus, combining short transduction and reducing oxidative stress may enhance the viability and engraftment of gene-corrected cells in patients with FANCA.