RESUMEN
Severe aplastic anemia (SAA) is a marrow failure disorder with high morbidity and mortality. It is treated with bone marrow transplantation (BMT) for those with fully matched donors, or immunosuppressive therapy (IST) for those who lack such a donor, which is often the case for underrepresented minorities. We conducted a prospective phase 2 trial of reduced-intensity conditioning HLA-haploidentical BMT and posttransplantation cyclophosphamide (PTCy)-based graft-versus-host (GVHD) prophylaxis as initial therapy for patients with SAA. The median patient age was 25 years (range, 3-63 years), and the median follow-up time was 40.9 months (95% confidence interval [CI], 29.4-55.7). More than 35% of enrollment was from underrepresented racial/ethnic groups. The cumulative incidence of grade 2 or 4 acute GVHD on day 100 was 7% (95% CI, not applicable [NA]-17), and chronic GVHD at 2 years was 4% (95% CI, NA-11). The overall survival of 27 patients was 92% (95% CI, 83-100) at 1, 2, and 3 years. The first 7 patients received lower dose total body irradiation (200 vs 400 cGy), but these patients were more likely to have graft failure (3 of 7) compared with 0 of 20 patients in the higher dose group (P = .01; Fisher exact test). HLA-haploidentical BMT with PTCy using 400 cGy total body irradiation resulted in 100% overall survival with minimal GVHD in 20 consecutive patients. Not only does this approach avoid any adverse ramifications of IST and its low failure-free survival, but the use of haploidentical donors also expands access to BMT across all populations. This trial was registered at www.clinicaltrials.gov as NCT02833805.
Asunto(s)
Anemia Aplásica , Enfermedad Injerto contra Huésped , Humanos , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Trasplante de Médula Ósea/efectos adversos , Estudios Prospectivos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Ciclofosfamida/uso terapéuticoRESUMEN
BACKGROUND: Allogeneic blood or marrow transplantation (alloBMT) is a potentially life-saving treatment for individuals with HIV and haematological malignancies; challenges include identifying donors and maintaining antiretroviral therapy (ART). The objectives of our study were to investigate interventions to expand donor options and to prevent ART interruptions for patients with HIV in need of alloBMT. METHODS: This single-arm, interventional trial took place at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (Baltimore, MD, USA). Individuals with HIV who were at least 18 years of age and referred for alloBMT for a standard clinical indication were eligible. The only exclusion criterion was a history of documented resistance to enfuvirtide. We used post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis to expand donor options and an optimised ART strategy of avoiding pharmacoenhancers and adding subcutaneous enfuvirtide during post-transplant cyclophosphamide and during oral medication intolerance. Our primary outcome was the proportion of participants who maintained ART through day 60 after alloBMT. We measured the HIV latent reservoir using a quantitative viral outgrowth assay. This study is registered on ClinicalTrials.gov, NCT01836068. FINDINGS: Between June 1, 2013, and August 27, 2015, nine patients who were referred for transplant provided consent. Two patients had relapsed malignancy before donor searches were initiated. Seven patients had suitable donors identified (two matched sibling, two matched unrelated, two haploidentical, and one single-antigen mismatched unrelated) and proceeded to alloBMT. All patients maintained ART through day 60 and required ART changes (median 1, range 1-3) in the first 90 days. One patient stopped ART and developed HIV rebound with grade 4 meningoencephalitis at day 146. Among six patients who underwent alloBMT and had longitudinal measurements available, the HIV latent reservoir was not detected post-alloBMT in four patients with more than 95% donor chimerism, consistent with a 2·06-2·54 log10 reduction in the HIV latent reservoir. In the two patients with less than 95% donor chimerism, the HIV latent reservoir remained stable. INTERPRETATION: By using post-transplant cyclophosphamide as GVHD prophylaxis, we successfully expanded alloBMT donor options for patients with HIV. Continuing ART with a regimen that includes enfuvirtide post-alloBMT was safe, but life-threatening viral rebound can occur with ART interruption. FUNDING: amfAR (the Foundation for AIDS Research), Johns Hopkins University Center for AIDS Research, and National Cancer Institute.
Asunto(s)
Trasplante de Médula Ósea , Ciclofosfamida/uso terapéutico , Infecciones por VIH/complicaciones , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Adulto , Terapia Antirretroviral Altamente Activa , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/métodos , Terapia Combinada , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Estudios de Factibilidad , Femenino , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del Tratamiento , Carga ViralRESUMEN
Based on our previous study of the combination of sorafenib with 5-azacytidine (AZA) in relapsed/refractory patients with FLT3 mutated acute myeloid leukemia (AML), we hypothesized that the combination would be efficacious and well tolerated in untreated patients with FLT3 mutated AML who are unsuitable for standard chemotherapy due to advanced age or lack of fitness. Newly diagnosed patients with untreated FLT3 mutated AML who underwent frontline therapy on 2 separate protocols of AZA plus sorafenib were analyzed. The clinical trials were registered at clinicaltrials.gov (NCT02196857 and NCT01254890). Overall, 27 patients with untreated FLT3 mutated AML (median age of 74 years, range, 61-86) were enrolled. The overall response rate was 78% (7 [26%] CR, 12 [44%] CRi/CRp, and 2 [7%] PR). Patients received a median of 3 treatment cycles (1-35). The median duration of CR/CRp/CRi is 14.5 months (1.1-28.7 months). Three (11%) responding patients (1 CR, 2 CRi) proceeded to allogeneic stem cell transplant. The median follow-up for surviving patients was 4.1 months (3.0-17.3 months). The median overall survival for the entire group was 8.3 months, and 9.2 months in the 19 responders. The regimen was well tolerated in elderly patients with untreated FLT3 mutated AML with no early deaths.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/terapia , Tirosina Quinasa 3 Similar a fms/genética , Factores de Edad , Anciano , Anciano de 80 o más Años , Azacitidina/uso terapéutico , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Mutación , Inducción de Remisión , Terapia Recuperativa/métodos , Sorafenib/uso terapéutico , Trasplante de Células Madre , Análisis de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Recurrent cytogenetic abnormalities have provided the backbone for prognosticating acute myeloid leukemia and predicting response to consolidative therapies for decades. However, more than 45% of acute myeloid leukemia patients have normal cytogenetics on both karyotype and fluorescence in situ hybridization at diagnosis. Increasingly utilized next-generation sequencing has led to the discovery of numerous recurrent molecular mutations in acute myeloid leukemia, which can currently be identified in 97.3% of patients. Despite the prevalence of dozens of these recurrent lesions, only NMP1, CEBPA, KIT, FLT3-ITD, and TP53 have been incorporated into widely accepted risk-stratification schemas, such as the 2017 National Comprehensive Cancer Network guidelines. Here we review the most frequent molecular genetic abnormalities, their utility in predicting relapse and survival, and their function as markers of minimal residual disease. We also provide a summary of sixteen common recurrent molecular abnormalities about which sufficient data exists ( Table 1 ).
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Leucemia Mieloide/genética , Leucemia Mieloide/terapia , Mutación , Enfermedad Aguda , Humanos , Leucemia Mieloide/patología , Recurrencia Local de Neoplasia , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Pronóstico , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
FMS-like tyrosine kinase-3 (FLT3) tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia (AML). We hypothesized that FLT3/internal tandem duplication (ITD) leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here, we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated and anti-leukemia effects were more pronounced compared with either drug alone. ERK reactivation was also observed following inhibition of other tyrosine kinase-driven cancer cells, including EGFR-mutant lung cancer, HER2-amplified breast cancer, and BCR-ABL leukemia. These studies reveal an adaptive feedback mechanism in tyrosine kinase-driven cancers associated with reactivation of ERK signaling in response to targeted inhibition. Cancer Res; 77(20); 5554-63. ©2017 AACR.
Asunto(s)
Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/enzimología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzamidas/administración & dosificación , Benzamidas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Difenilamina/administración & dosificación , Difenilamina/análogos & derivados , Difenilamina/farmacología , Femenino , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Distribución Aleatoria , Sorafenib , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Aminopiridinas/uso terapéutico , Benzotiazoles/uso terapéutico , Biomarcadores/análisis , Médula Ósea/efectos de los fármacos , Médula Ósea/enzimología , Médula Ósea/patología , Línea Celular Tumoral , Ensayos Clínicos como Asunto , Dasatinib , Expresión Génica , Cabello/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/enzimología , Células Madre Hematopoyéticas/patología , Humanos , Indazoles , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/patología , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Pigmentación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Sorafenib , Sulfonamidas/uso terapéutico , Tiazoles/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Patients received 5-azacytidine (AZA) 75 mg/m(2) intravenously daily for 7 days and sorafenib 400 mg orally twice daily continuously; cycles were repeated at ~1-month intervals. Forty-three acute myeloid leukemia (AML) patients with a median age of 64 years (range, 24-87 years) were enrolled; 37 were evaluable for response. FMS-like tyrosine kinase-3 (FLT3)-internal tandem duplication (ITD) mutation was detected in 40 (93%) patients, with a median allelic ratio of 0.32 (range, 0.009-0.93). They had received a median of 2 prior treatment regimens (range, 0-7); 9 had failed prior therapy with a FLT3 kinase inhibitor. The response rate was 46%, including 10 (27%) complete response with incomplete count recovery (CRi), 6 (16%) complete responses (CR), and 1 (3%) partial response. The median time to achieve CR/CRi was 2 cycles (range, 1-4), and the median duration of CR/CRi was 2.3 months (range, 1-14.3 months). Sixty-four percent of patients achieved adequate (defined as >85%) FLT3 inhibition during their first cycle of therapy. The degree of FLT3 inhibition correlated with plasma sorafenib concentrations. FLT3 ligand levels did not rise to levels seen in prior studies of patients receiving cytotoxic chemotherapy. The combination of AZA and sorafenib is effective for patients with relapsed AML and FLT-3-ITD. This trial was registered at clinicaltrials.gov as #NCT01254890.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Secuencias Repetidas en Tándem/genética , Tirosina Quinasa 3 Similar a fms/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Azacitidina/administración & dosificación , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Pronóstico , Inducción de Remisión , Sorafenib , Tasa de Supervivencia , Adulto Joven , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidoresRESUMEN
Acute myelogenous leukemia (AML) patients with FLT3/ITD mutations have an inferior survival compared to AML patients with wild-type (WT) FLT3, primarily because of an increased relapse rate. Allogeneic transplantation represents a postremission therapy that is effective at reducing the risk of relapse for many cases of poor-risk AML. Whether or not allogeneic transplantation in first complete remission (CR) can improve outcomes for patients with FLT3/ITD AML remains controversial. Our institution has adopted a policy of pursuing allogeneic transplantation, including the use of alternate donors, for FLT3/ITD AML patients in remission. As part of an instituional review board-approved study, we performed a review of the clinical data from November 1, 2004, to October 31, 2008, on all adult patients under the age of 60 presenting in consecutive fashion to the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins with newly diagnosed non-M3 AML. We followed their outcomes through August 1, 2010. During the study period, 133 previously untreated AML patients between the ages of 20 and 59 were diagnosed and received induction and consolidation therapy at our institution. Of these 133 patients, 31 (23%) harbored an FLT3/ITD mutation at diagnosis. The median overall survival (OS) from the time of diagnosis for the FLT3/ITD AML patients was compared to the OS of the entire cohort and found to be comparable (19.3 months versus 15.5 months, P = .56). Historically, OS for FLT3/ITD AML patients is significantly worse than for AML patients lacking this mutation. However, the OS for the 31 FLT3/ITD patients reported here was comparable to the 102 patients with WT FLT3 over the same 4-year time period. One difference that might have contributed to the surprising outcomes for the FLT3/ITD group is our aggressive pursuit of allogeneic bone marrow transplant (BMT) in CR1 within this group (60% of FLT3/ITD versus 17% with WT). Our single-institution study of consecutively treated AML patients supports the hypothesis that allogeneic transplant in early CR1 improves the long-term outcomes for FLT3/ITD AML.
Asunto(s)
Leucemia Mieloide Aguda/terapia , Tirosina Quinasa 3 Similar a fms/genética , Adulto , Detección Precoz del Cáncer , Diagnóstico Precoz , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
We examined in vivo FLT3 inhibition in acute myeloid leukemia patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib, comparing newly diagnosed acute myeloid leukemia patients with relapsed patients. Because we noted that in vivo FLT3 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly diagnosed patients, we investigated whether plasma FLT3 ligand (FL) levels could influence the efficacy of FLT3 inhibition in these patients. After intensive chemotherapy, FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly diagnosed patients, whereas they rose to a mean of 1148 pg/mL in the relapsed patients. FL levels rose even higher with successive courses of chemotherapy, to a mean of 3251 pg/mL after the fourth course. In vitro, exogenous FL at concentrations similar to those observed in patients mitigated FLT3 inhibition and cytotoxicity for each of 5 different FLT3 inhibitors (lestaurtinib, midostaurin, sorafenib, KW-2449, and AC220). The dramatic increase in FL level after chemotherapy represents a possible obstacle to inhibiting FLT3 in this clinical setting. These findings could have important implications regarding the design and outcome of trials of FLT3 inhibitors and furthermore suggest a rationale for targeting FL as a therapeutic strategy.
Asunto(s)
Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas de la Membrana/fisiología , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Antineoplásicos/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Bencenosulfonatos/farmacología , Bencenosulfonatos/uso terapéutico , Carbazoles/farmacología , Carbazoles/uso terapéutico , Células Cultivadas , Antagonismo de Drogas , Furanos , Humanos , Indazoles/farmacología , Indazoles/uso terapéutico , Concentración 50 Inhibidora , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/patología , Proteínas de la Membrana/sangre , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/farmacología , Estudios Multicéntricos como Asunto , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piperazinas/farmacología , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Piridinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Sorafenib , Estaurosporina/análogos & derivados , Estaurosporina/farmacología , Estaurosporina/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. PATIENTS AND METHODS In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m(2) by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m(2) IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. RESULTS Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. CONCLUSION Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Adulto , Anciano , Bencenosulfonatos/administración & dosificación , Citarabina/administración & dosificación , Estudios de Factibilidad , Femenino , Humanos , Idarrubicina/administración & dosificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Mutación/genética , Estadificación de Neoplasias , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/administración & dosificación , Sorafenib , Tasa de Supervivencia , Resultado del Tratamiento , Adulto Joven , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a driver of the disease and therefore as a target for therapy. We report the characterization of AC220, a second-generation FLT3 inhibitor, and a comparison of AC220 with the first-generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib, and sunitinib. AC220 exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity, and in animal models is efficacious at doses as low as 1 mg/kg given orally once daily. The data reveal that the combination of excellent potency, selectivity, and pharmacokinetic properties is unique to AC220, which therefore is the first drug candidate with a profile that matches the characteristics desirable for a clinical FLT3 inhibitor.
Asunto(s)
Benzotiazoles/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Bencenosulfonatos/farmacología , Benzotiazoles/farmacocinética , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Carbazoles/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Furanos , Humanos , Ratones , Ratones Desnudos , Ratones SCID , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacocinética , Fosforilación/efectos de los fármacos , Piperazinas/farmacología , Pronóstico , Mapeo de Interacción de Proteínas , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Piridinas/farmacología , Quinazolinas/farmacología , Sorafenib , Estaurosporina/análogos & derivados , Estaurosporina/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Etopósido/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Quinolonas/administración & dosificación , Administración Oral , Edad de Inicio , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Farnesiltransferasa/antagonistas & inhibidores , Células HL-60 , Humanos , Células Jurkat , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/epidemiología , Células Tumorales Cultivadas , Células U937RESUMEN
Constitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) play an important role in leukaemogenesis. We have examined, by cDNA microarray analysis, the changes in gene expression induced by FLT3/ITD or constitutively activated wild type FLT3 signalling. A limited set of genes was consistently affected by FLT3 inhibition. In confirmation of their FLT3 dependence, these genes returned toward pretreatment levels of expression after reversal of FLT3 inhibition. Several of the most significantly affected genes are involved in the RAS/mitogen-activated protein kinase, Janus kinase/signal transducer and activator of transcription and phosphatidylinositol 3 kinase (PI3K)/AKT pathways. These data suggest that constitutively activated FLT3 works through multiple signal transduction pathways. PIM1, MYC and CCND3 were chosen from this gene set to explore their biological roles. Knock-down of these genes by small interfering RNA showed that these genes play important roles in constitutively activated FLT3 expressing cells. The alterations of the gene expression profiles in these cells help to further elucidate the mechanisms of FLT3-mediated leukaemogenesis.