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4.
Leukemia ; 32(3): 597-605, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28914261

RESUMEN

Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20-30% of AML cases. This subtype usually responds poorly to conventional therapies, and might become resistant to FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies focusing on resistance mechanisms are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation. We performed high-throughput transcriptomic and proteomic analyses in Pim2-depleted FLT3-ITD AML cells and found that Pim2 predominantly controlled apoptosis through Bax expression and mitochondria disruption. We identified ribosomal protein S6 kinase A3 (RSK2), a 90 kDa serine/threonine kinase involved in the mitogen-activated protein kinase cascade encoded by the RPS6KA3 gene, as a novel Pim2 target. Ectopic expression of an RPS6KA3 allele rescued the viability of Pim2-depleted cells, supporting the involvement of RSK2 in AML cell survival downstream of Pim2. Finally, we showed that RPS6KA3 knockdown reduced the propagation of human AML cells in vivo in mice. Our results point to RSK2 as a novel Pim2 target with translational therapeutic potential in FLT3-ITD AML.


Asunto(s)
Duplicación de Gen , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Secuencias Repetidas en Tándem , Tirosina Quinasa 3 Similar a fms/genética , Animales , Apoptosis , Caspasas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Leucemia Mieloide Aguda/patología , Ratones , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Transcriptoma , Proteína X Asociada a bcl-2/metabolismo
6.
Leukemia ; 31(11): 2326-2335, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28280275

RESUMEN

Alterations in metabolic activities are cancer hallmarks that offer a wide range of new therapeutic opportunities. Here we decipher the interplay between mTORC1 activity and glucose metabolism in acute myeloid leukemia (AML). We show that mTORC1 signaling that is constantly overactivated in AML cells promotes glycolysis and leads to glucose addiction. The level of mTORC1 activity determines the sensitivity of AML cells to glycolysis inhibition as switch-off mTORC1 activity leads to glucose-independent cell survival that is sustained by an increase in mitochondrial oxidative phosphorylation. Metabolic analysis identified the pentose phosphate pathway (PPP) as an important pro-survival pathway for glucose metabolism in AML cells with high mTORC1 activity and provided a clear rational for targeting glucose-6-phosphate dehydrogenase (G6PD) in AML. Indeed, our analysis of the cancer genome atlas AML database pinpointed G6PD as a new biomarker in AML, as its overexpression correlated with an adverse prognosis in this cohort. Targeting the PPP using the G6PD inhibitor 6-aminonicotinamide induces in vitro and in vivo cytotoxicity against AML cells and synergistically sensitizes leukemic cells to chemotherapy. Our results demonstrate that high mTORC1 activity creates a specific vulnerability to G6PD inhibition that may work as a new AML therapy.


Asunto(s)
Glucosafosfato Deshidrogenasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Glucosa/metabolismo , Glucólisis , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/patología , Fosforilación Oxidativa
8.
BMC Health Serv Res ; 16(a): 336, 2016 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-27485349

RESUMEN

BACKGROUND: Healthcare providers-related disparities in adherence to the treatment plan among lymphoma patients are found even in a universal healthcare system, but the mechanism remains unclear. We investigated the association between the type of care center and the relative dose intensity and determined whether it persists after adjustment for patients' recruitment differences. METHODS: Prospective observational cohort study of 294 patients treated with standard protocols for diffuse large B-cell lymphoma (DLBCL) in teaching or community public hospitals or in private centers in the French Midi-Pyrénées region from 2006-2013. To test our assumptions, we used multinomial and mixed-effect logistic models progressively adjusted for patients' biomedical characteristics, socio-spatial characteristics and treatment-related toxicity events. RESULTS: Patients treated using standard protocols in the teaching hospital had more advanced stage and poorer initial prognosis without limitation regarding the distance from the residence to the care center. Patients' recruitment profile across the different types of care center failed to explain the difference in relative dose intensity. Low relative dose intensity was less often observed in teaching hospital than elsewhere. CONCLUSION: We showed that even in a universal healthcare system, disparities in the management of DLBCL patients' do exist according to the types of care center. A main issue may be to find and diffuse the reasons of this benefit in cancer management in the teaching hospital to the other centers.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Disparidades en Atención de Salud , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Cobertura Universal del Seguro de Salud , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Calidad de la Atención de Salud
10.
Clin Exp Allergy ; 46(1): 133-41, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26767494

RESUMEN

BACKGROUND: Mastocytosis is difficult to diagnose, especially when systemic mast cell activation symptoms are not present or involve only one extracutaneous organ. OBJECTIVE: The main objective was to evaluate the accuracy of the bone marrow tryptase level in the diagnosis of systemic mastocytosis in patients with a clinical suspicion of mastocytosis. METHODS: We included all adult patients evaluated in our centre between December 2009 and 2013 for suspected mastocytosis as part of a standardized procedure and who had a bone marrow and serum tryptase assay on the same day. The diagnosis of systemic mastocytosis was established on the basis of the World Health Organization criteria as the gold standard. The accuracy of the bone marrow tryptase level in the diagnosis of systemic mastocytosis was assessed by a receiver operating characteristics curve analysis. The different sensitivity and specificity values, corresponding to the set of possible bone marrow tryptase level cut-off values, were estimated with 95% confidence intervals. RESULTS: Seventy-three patients were included. The diagnosis of systemic mastocytosis was established in 43 patients (58.9%). The median bone marrow tryptase level was 423 µg/L [95% CI: 217-868] in the systemic mastocytosis group and 7.5 µg/L [95% CI: 4.6-17.1] in the non-systemic mastocytosis group (P < 0.001). A cut-off value of 50 µg/L for bone marrow tryptase identified systemic mastocytosis with a sensitivity of 93.0% [95% CI: 80.9-98.5%] and a specificity of 90.0% [95% CI: 73.5-97.9%]. CONCLUSION AND CLINICAL RELEVANCE: The bone marrow tryptase level appears to be a valuable diagnostic criterion for confirming systemic mastocytosis. If this diagnosis can reliably be excluded by evaluation of the bone marrow tryptase level, there would be no need to perform a bone marrow biopsy.


Asunto(s)
Médula Ósea/enzimología , Médula Ósea/patología , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/enzimología , Triptasas/metabolismo , Adolescente , Adulto , Anciano , Biomarcadores , Biopsia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Reproducibilidad de los Resultados , Triptasas/sangre , Adulto Joven
11.
Blood Cancer J ; 5: e297, 2015 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-25794133

RESUMEN

Relevant preclinical mouse models are crucial to screen new therapeutic agents for acute myeloid leukemia (AML). Current in vivo models based on the use of patient samples are not easy to establish and manipulate in the laboratory. Our objective was to develop robust xenograft models of human AML using well-characterized cell lines as a more accessible and faster alternative to those incorporating the use of patient-derived AML cells. Five widely used AML cell lines representing various AML subtypes were transplanted and expanded into highly immunodeficient non-obese diabetic/LtSz-severe combined immunodeficiency IL2Rγc(null) mice (for example, cell line-derived xenografts). We show here that bone marrow sublethal conditioning with busulfan or irradiation has equal efficiency for the xenotransplantation of AML cell lines. Although higher number of injected AML cells did not change tumor engraftment in bone marrow and spleen, it significantly reduced the overall survival in mice for all tested AML cell lines. On the basis of AML cell characteristics, these models also exhibited a broad range of overall mouse survival, engraftment, tissue infiltration and aggressiveness. Thus, we have established a robust, rapid and straightforward in vivo model based on engraftment behavior of AML cell lines, all vital prerequisites for testing new therapeutic agents in preclinical studies.


Asunto(s)
Antineoplásicos/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Antineoplásicos/efectos adversos , Células de la Médula Ósea/efectos de los fármacos , Línea Celular Tumoral , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones
12.
Leuk Res ; 39(3): 296-306, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25601157

RESUMEN

Hypomethylating agents are able to prolong the overall survival of some patients diagnosed with acute myeloid leukemia. The aim of this study was to evaluate the clinical use of azacitidine as front-line therapy in unfit acute myeloid leukemia (AML) patients and to develop a clinical prediction model to identify which patients may benefit more from the drug. One hundred and ten untreated unfit AML patients received front-line azacitidine therapy in Spain, and response and survival were evaluated in them following European LeukemiaNet (ELN) guidelines. A clinical prediction rule was obtained from this population that was validated and refined in 261 patients treated in France, Austria and Italy. ELN response was achieved in 21.0% of the 371 patients (CI95% 17.0-25.5) and did not depend on bone marrow blast cell percentage. Median overall survival was 9.6 months (CI95% 8.5-10.8) and 40.6% of the patients were alive at 1 year (CI95% 35.5-45.7). European ALMA score (E-ALMA), based on performance status, white blood cell counts at azacitidine onset and cytogenetics, discriminated three risk groups with different survival and response rates. Azacitidine seems a reasonable therapeutic option for most unfit AML patients, i.e. those displaying a favorable or intermediate E-ALMA score.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Estudios de Validación como Asunto
15.
Leukemia ; 28(2): 293-301, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23748345

RESUMEN

Phosphorylation by Akt on Ser 280 was reported to induce cytoplasmic retention and inactivation of CHK1 with consequent genetic instability in PTEN-/- cells. In acute myeloid leukemia cells carrying the FLT3-internal tandem duplication (ITD) mutation, we observed high rates of FLT3-ITD-dependent CHK1 Ser 280 phosphorylation. Pharmacological inhibition and RNA interference identified Pim1/2, not Akt, as effectors of this phosphorylation. Pim1 catalyzed Ser 280 phosphorylation in vitro and ectopic expression of Pim1/2-induced CHK1 phosphorylation. Ser 280 phosphorylation did not modify CHK1 localization, but facilitated its cell cycle and resistance functions in leukemic cells. FLT3, PIM or CHK1 inhibitors synergized with DNA-damaging agents to induce apoptosis, allowing cells to bypass the etoposide-induced G2/M arrest. Consistently, etoposide-induced CHK1-dependent phosphorylations of CDC25C on Ser 216 and histone H3 on Thr11 were decreased upon FLT3 inhibition. Accordingly, ectopic expression of CHK1 improved the resistance of FLT3-ITD cells and maintained histone H3 phosphorylation in response to DNA damage, whereas expression of unphosphorylated Ser 280Ala mutant did not. Finally, FLT3- and Pim-dependent phosphorylation of CHK1 on Ser 280 was confirmed in primary blasts from patients. These results identify a new pathway involved in the resistance of FLT3-ITD leukemic cells to genotoxic agents, and they constitute the first report of CHK1 Ser 280 regulation in myeloid malignancies.


Asunto(s)
Leucemia Mieloide Aguda/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Duplicación de Gen , Humanos , Espacio Intracelular/metabolismo , Leucemia Mieloide Aguda/genética , Fosforilación , Transporte de Proteínas , Serina/metabolismo , Transducción de Señal , Tirosina Quinasa 3 Similar a fms/metabolismo
16.
Leukemia ; 27(11): 2129-38, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23568147

RESUMEN

Previous reports demonstrate that metformin, an anti-diabetic drug, can decrease the risk of cancer and inhibit cancer cell growth. However, its mechanism in cancer cells is still unknown. Metformin significantly blocks cell cycle and inhibits cell proliferation and colony formation of leukemic cells. However, the apoptotic response to metformin varies. Furthermore, daily treatment with metformin induces apoptosis and reduces tumor growth in vivo. While metformin induces early and transient activation of AMPK, inhibition of AMPKα1/2 does not abrogate anti-proliferative or pro-apoptotic effects of metformin. Metformin decreases electron transport chain complex I activity, oxygen consumption and mitochondrial ATP synthesis, while stimulating glycolysis for ATP and lactate production, pentose phosphate pathway for purine biosynthesis, fatty acid metabolism, as well as anaplerotic and mitochondrial gene expression. Importantly, leukemic cells with high basal AKT phosphorylation, glucose consumption or glycolysis exhibit a markedly reduced induction of the Pasteur effect in response to metformin and are resistant to metformin-induced apoptosis. Accordingly, glucose starvation or treatment with deoxyglucose or an AKT inhibitor induces sensitivity to metformin. Overall, metformin elicits reprogramming of intermediary metabolism leading to inhibition of cell proliferation in all leukemic cells and apoptosis only in leukemic cells responding to metformin with AKT phosphorylation and a strong Pasteur effect.


Asunto(s)
Apoptosis/efectos de los fármacos , Hipoglucemiantes/farmacología , Leucemia/tratamiento farmacológico , Leucemia/patología , Metformina/farmacología , Mitocondrias/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Western Blotting , Proliferación Celular/efectos de los fármacos , Cromatografía Liquida , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Humanos , Técnicas para Inmunoenzimas , Ácido Láctico/metabolismo , Leucemia/metabolismo , Ratones , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Fosforilación/efectos de los fármacos , ARN Interferente Pequeño/genética , Espectrometría de Masa por Ionización de Electrospray , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Leukemia ; 27(7): 1479-86, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23321953

RESUMEN

The mTORC1 signaling pathway is constitutively activated in almost all acute myelogenous leukemia (AML) patients. We conducted a phase Ib trial combining RAD001 (everolimus), an allosteric inhibitor of mTORC1, and conventional chemotherapy, in AML patients under 65 years of age at first relapse (clinical trial NCT 01074086). Increasing doses of RAD001 from 10-70 mg were administrated orally on days 1 and 7 (d1 and d7) of a 3+7 daunorubicin+cytarabine conventional induction chemotherapy regimen. Twenty-eight patients were enrolled in this trial. The treatment was well tolerated with <10% toxicity, mainly involving the gastrointestinal tract and lungs. In this phase Ib trial, the RAD001 maximum tolerated dose was not reached at 70 mg. Sixty-eight percent of patients achieved CR, of which 14 received a double induction. Eight subsequently were intensified with allogeneic-stem cell transplant. Strong plasma inhibition of P-p70S6K was observed after RAD001 administration, still detectable at d7 (d7)at the 70 mg dosage. CR rates in patients with RAD001 areas under or above the curve median were 53% versus 85%. A 70 mg dose of RAD001 at d1 and d7 of an induction chemotherapy regimen for AML has acceptable toxicity and may improve treatment.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/efectos adversos , Daunorrubicina/efectos adversos , Everolimus , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Transducción de Señal/efectos de los fármacos , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Resultado del Tratamiento , Adulto Joven
18.
Ann Oncol ; 24(4): 1032-7, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23235801

RESUMEN

BACKGROUND: The superiority of a chemotherapy with doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) in comparison with cyclophosphamide, doxorubicin, vincristin and prednisone plus radiotherapy for young patients with localized diffuse large B-cell lymphoma (DLBCL) was previously demonstrated. We report the results of a trial which evaluates the role of rituximab combined with ACVBP (R-ACVBP) in these patients. PATIENTS AND METHODS: Untreated patients younger than 66 years with stage I or II DLBCL and no adverse prognostic factors of the age-adjusted International Prognostic Index were randomly assigned to receive three cycles of ACVBP plus sequential consolidation with or without the addition of four infusions of rituximab. RESULTS: A total of 223 patients were randomly allocated to the study, 110 in the R-ACVBP group and 113 in the ACVBP group. After a median follow-up of 43 months, our 3-year estimate of event-free survival was 93% in the R-ACVBP group and 82% in the ACVBP group (P = 0.0487). Three-year estimate of progression-free survival was increased in the R-ACVBP group (95% versus 83%, P = 0.0205). Overall survival did not differ between the two groups with a 3-year estimates of 98% and 97%, respectively (P = 0.686). CONCLUSION: In young patients with low-risk localized DLBCL, rituximab combined with three cycles of ACVBP plus consolidation is significantly superior to ACVBP plus consolidation alone.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/administración & dosificación , Prednisona/efectos adversos , Rituximab , Resultado del Tratamiento , Vindesina/administración & dosificación , Vindesina/efectos adversos
19.
Leukemia ; 27(2): 325-35, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22902361

RESUMEN

Several receptor tyrosine kinases (TKs) are involved in the pathogenesis of acute myeloid leukemia (AML). Here, we have assessed the expression of the Recepteur d'Origine Nantais (RON) in leukemic cell lines and samples from AML patients. In a series of 86 AML patients, we show that both the full length and/or the short form (sf) of RON are expressed in 51% and 43% of cases, respectively. Interestingly, sfRON is not expressed in normal CD34+ hematopoietic cells and induces part of its oncogenic signaling through interaction with the Src kinase Lyn. sfRON-mediated signaling in leukemic cells also involves mTORC1, the proapoptotic bcl2-family member, BAD, but not the phosphatidylinositol 3-kinase/Akt pathway. Furthermore, the expression of sfRON was specifically downregulated by 5-azacytidine (AZA). Conversely, AZA could induce the expression of sfRON in sfRON-negative leukemic cells suggesting that the activity of this drug in AML and myelodysplastic syndromes could involve modulation of TKs. cMET/RON inhibitors exhibited an antileukemic activity exclusively in AML samples and cell lines expressing sfRON. These results might support clinical trials evaluating cMET/RON inhibitors in AML patients expressing sfRON.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Azacitidina/farmacología , Western Blotting , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Citometría de Flujo , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Inmunoprecipitación , Indoles/farmacología , Leucemia Mieloide Aguda/metabolismo , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Persona de Mediana Edad , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacología , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Adulto Joven , Proteína Letal Asociada a bcl/genética , Proteína Letal Asociada a bcl/metabolismo , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismo
20.
Ann Oncol ; 23(10): 2687-2695, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22767588

RESUMEN

BACKGROUND: This study explored the efficacy and safety of rituximab as treatment of clinical or molecular residual disease after autologous stem-cell transplantation (ASCT) in follicular lymphoma (FL). PATIENTS AND METHODS: Forty patients with CD20+ FL and clinically (group A, n = 14) or clono-specific PCR-detectable (group B, n = 25) residual disease persisting 3 months after ASCT received rituximab 375 mg/m² once weekly for 4 weeks. RESULTS: Response rate at day 50 was 36% [90% confidence interval (CI) 15-61] in group A (World Health Organization criteria) and 52% (90% CI 34-70) in group B (conversion PCR-undetectable status to undetectable status). The best response rate was 71% [nine complete responses (CRs) and one partial response] in group A and 76% in group B. At 36 months, all 10 responses persisted in group A, whereas 46% of patients in group B still had PCR-undetectable disease. Furthermore, 68% of patients in group B were still in clinical CR. Rituximab after ASCT was safe with few grade 3-4 toxic effects (15% patients), mainly acute reactions and infections. CONCLUSION: Rituximab induced a high rate of durable CRs in patients with clinically detectable disease, as well as durable eradication of PCR-detectable disease in patients with FL after ASCT. Continued molecular responses assessed with a highly sensitive and clono-specific PCR technique were correlated with an excellent disease control.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Linfoma Folicular/tratamiento farmacológico , Neoplasia Residual , Adolescente , Adulto , Anciano , Humanos , Linfoma Folicular/patología , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Estudios Prospectivos , Rituximab , Adulto Joven
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