RESUMEN
Although preliminary data suggests that ibrutinib may increase risk of atrial fibrillation (AF), the incidence of AF in a general cohort of chronic lymphocytic leukemia (CLL) patients is unknown. We evaluated the prevalence of AF at CLL diagnosis and incidence of AF during follow-up in 2444 patients with newly diagnosed CLL. A prior history of AF was present at CLL diagnosis in 148 (6.1%). Among the 2292 patients without history of AF, 139 (6.1%) developed incident AF during follow-up (incidence approximately 1%/year). Older age (p < .0001), male sex (p = .01), valvular heart disease (p = .001), and hypertension (p = .04) were associated with risk of incident AF on multivariate analysis. A predictive model for developing incident AF constructed from these factors stratified patients into 4 groups with 10-year rates of incident AF ranging from 4% to 33% (p < .0001). This information provides context for interpreting rates of AF in CLL patients treated with novel therapies.
Asunto(s)
Fibrilación Atrial/epidemiología , Fibrilación Atrial/etiología , Leucemia Linfocítica Crónica de Células B/complicaciones , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/diagnóstico , Comorbilidad , Femenino , Humanos , Incidencia , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Piperidinas , Prevalencia , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Factores de Riesgo , Adulto JovenRESUMEN
Patients with chronic lymphocytic lymphoma (CLL) with high-risk cytogenetics [del(11q)(q22.3) or del(17p)(p13.1)] have limited therapeutic options and their prognosis remains poor. This analysis was conducted to determine the clinical activity of lenalidomide in patients with high-risk disease. Relapsed/refractory patients with CLL enrolled in a phase II clinical trial who had del(11q)(q22.3) or del(17p)(p13.1) were included in this analysis. Patients received single agent lenalidomide for 21 days of the 4 week treatment cycle. The overall response rate among patients with high-risk cytogenetics was 38%, with 19% of patients achieving a complete response. Median progression-free survival was 12.1 months, which is higher than demonstrated with other agents in comparable patient populations. In addition, the estimated 2-year survival probability was 58%, demonstrating that the responses achieved with lenalidomide are durable, even in patients with CLL with high-risk disease with poor risk cytogenetics.
Asunto(s)
Antineoplásicos/uso terapéutico , Deleción Cromosómica , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 17 , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Talidomida/análogos & derivados , Adulto , Anciano , Citogenética , Supervivencia sin Enfermedad , Humanos , Lenalidomida , Persona de Mediana Edad , Pronóstico , Recurrencia , Riesgo , Talidomida/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Lenalidomide, an oral immunomodulatory drug that is similar to thalidomide but has a different safety profile, has clinical activity in relapsed or refractory multiple myeloma. METHODS: Patients in the United States and Canada who had received at least one previous therapy for multiple myeloma but who required additional treatment were randomly assigned to receive either 25 mg of lenalidomide or placebo on days 1 to 21 of a 28-day cycle. Both groups also received 40 mg of oral dexamethasone on days 1 to 4, 9 to 12, and 17 to 20 for the first four cycles. After the fourth cycle, 40 mg of dexamethasone was administered only on days 1 to 4. Safety, clinical response, time to progression, and overall survival were assessed. RESULTS: We assigned 177 patients to the lenalidomide group and 176 to the placebo group. Complete, near-complete, or partial responses occurred in 108 patients (61.0%) in the lenalidomide group and in 35 patients (19.9%) in the placebo group (P<0.001); complete responses occurred in 14.1% and 0.6%, respectively (P<0.001). The median time to progression was 11.1 months in the lenalidomide group and 4.7 months in the placebo group (P<0.001). Median overall survival times in the two groups were 29.6 months and 20.2 months, respectively (P<0.001). Grade 3 or 4 adverse events were reported in 85.3% of the lenalidomide group and in 73.1% of the placebo group; these events resulted in study discontinuation in 19.8% and 10.2%, respectively. Grade 3 or 4 neutropenia and venous thromboembolism were more common in the lenalidomide group than in the placebo group (41.2% vs. 4.6% and 14.7% vs. 3.4%, respectively; P<0.001 for both comparisons). CONCLUSIONS: Lenalidomide plus dexamethasone is superior to placebo plus dexamethasone in patients with relapsed or refractory multiple myeloma. (ClinicalTrials.gov number, NCT00056160 [ClinicalTrials.gov].).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/uso terapéutico , Glucocorticoides/uso terapéutico , Factores Inmunológicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Recurrencia , Análisis de Supervivencia , Talidomida/efectos adversos , Talidomida/uso terapéuticoRESUMEN
The availability of new agents for multiple myeloma (MM) provides an opportunity to further improve response rates through the development of new combination regimens. Such new agents include pegylated liposomal doxorubicin (PLD) and the immunomodulatory drugs thalidomide and lenalidomide, all of which have demonstrated efficacy and safety in the treatment of newly diagnosed and relapsed/refractory MM. Based on their complementary mechanisms of action and nonoverlapping toxicity profiles, PLD and the immunomodulatory drugs might provide incremental benefits when used in combined treatment regimens. Thus, they have been evaluated in clinical studies that combine PLD/vincristine/dexamethasone and thalidomide (DVd-T) or PLD/vincristine/dexamethasone and lenalidomide (DVd-R) as well as in a study combining bortezomib with PLD and thalidomide. Results of all these studies have included high overall response rates, with improved rates of complete/near complete response compared with similar regimens that do not include chemotherapy (ie, immunomodulatory drugs plus dexamethasone). This article provides the clinical rationale for the use of PLD in combination with immunomodulatory drugs to treat patients with MM and summarizes the clinical experience with these combinations to date. Notably, the early phase I/II study results have been sufficiently encouraging to warrant further investigation in additional large-scale, phase II/III studies. Future clinical trials should focus on determining the optimal dose and schedule for each of these agents when used in combination and whether the addition of other new agents provides an additional response benefit.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Doxorrubicina/análogos & derivados , Mieloma Múltiple/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Talidomida/análogos & derivados , Talidomida/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos como Asunto , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Lenalidomida , Mieloma Múltiple/diagnóstico , Polietilenglicoles/efectos adversos , Recurrencia , Tasa de Supervivencia , Talidomida/efectos adversos , Resultado del TratamientoRESUMEN
Many novel agents and new combinations (including bortezomib, thalidomide, and lenalidomide) have been developed in recent years for the treatment of multiple myeloma (MM), creating major shifts in therapeutic management. Achieving complete response (CR)/near CR (nCR) generally serves as a reliable clinical surrogate for overall treatment outcome, ie, prolonged survival. Indeed, some newer induction regimens are yielding similar median time to disease progression effects compared with transplantation. Thus, it can be a dilemma whether a patient with CR/nCR needs to be subjected to the potential morbidity associated with transplantation after induction therapy. Combining new agents with chemotherapy-based regimens appears to offer higher overall response and CR/nCR rates than similar combinations that do not include chemotherapy. We review the preclinical and clinical rationale for combining bortezomib with pegylated liposomal doxorubicin for the treatment of MM. The synergistic interaction in sensitizing each other toward myeloma cells in vitro and their complementary in vivo activities have justified clinical studies. We summarize data for completed and ongoing phase I/II trials of this combination. To date, results have been sufficiently encouraging to initiate an international, multicenter, randomized, phase III trial comparing bortezomib with or without pegylated liposomal doxorubicin in patients with relapsed/refractory MM. The results of this trial will confirm whether the rationale for combining bortezomib with pegylated liposomal doxorubicin is validated by improved clinical outcome, ie, improved time to progression, for patients with MM.