RESUMEN
BACKGROUND: Ibrutinib therapy is safe and effective in patients with chronic lymphocytic leukemia (CLL). Currently, ibrutinib is administered continuously until disease progression. Combination regimens with ibrutinib are being developed to deepen response which could allow for ibrutinib maintenance (IM) discontinuation. Among untreated older patients with CLL, clinical investigators had the following questions: (i) does ibrutinib + venetoclax + obinutuzumab (IVO) with IM have superior progression-free survival (PFS) compared with ibrutinib + obinutuzumab (IO) with IM, and (ii) does the treatment strategy of IVO + IM for patients without minimal residual disease complete response (MRD- CR) or IVO + IM discontinuation for patients with MRD- CR have superior PFS compared with IO + IM. DESIGN: Conventional designs randomize patients to IO with IM or IVO with IM to address the first objective, or randomize patients to each treatment strategy to address the second objective. A sequential multiple assignment randomized trial (SMART) design and analysis is proposed to address both objectives. RESULTS: A SMART design strategy is appropriate when comparing adaptive interventions, which are defined by an individual's sequence of treatment decisions and guided by intermediate outcomes, such as response to therapy. A review of common applications of SMART design strategies is provided. Specific to the SMART design previously considered for Alliance study A041702, the general structure of the SMART is presented, an approach to sample size and power calculations when comparing adaptive interventions embedded in the SMART with a time-to-event end point is fully described, and analyses plans are outlined. CONCLUSION: SMART design strategies can be used in cancer clinical trials with adaptive interventions to identify optimal treatment strategies. Further, standard software exists to provide sample size, power calculations, and data analysis for a SMART design.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Factores de Edad , Anciano , Análisis de Datos , Progresión de la Enfermedad , Estudios de Factibilidad , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Supervivencia sin Progresión , Tamaño de la MuestraAsunto(s)
Dominios C2/genética , Resistencia a Antineoplásicos/genética , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Mutación , Fosfolipasa C gamma/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/genética , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa , Humanos , Leucemia Linfocítica Crónica de Células B/genética , PiperidinasRESUMEN
Chronic lymphocytic leukemia (CLL) mainly affects older people: the median age at diagnosis is > 70 years. Elderly patients with CLL are heterogeneous with regard both to the biology of their disease and aging. Following the diagnosis of CLL in an elderly individual, careful risk assessment is essential when treatment options are evaluated. This includes not only clinical staging and evaluation of disease-specific prognostic biomarkers such as 17p deletion and TP53 mutation, but also of comorbidities, physical capacity, nutritional status, cognitive capacity, ability to perform activities of daily living and social support. Comorbidity scoring and geriatric assessment tools are helpful in achieving such multidimensional evaluation in a systematic manner. The introduction of new drugs including novel monoclonal antibodies and kinase inhibitors offers enhanced opportunities for the treatment of elderly patients with CLL. This position paper of a Task Force of the International Society of Geriatric Oncology (SIOG) reviews currently available evidence relevant to such patients. All types of elderly patient (i.e. chronological age > 65-70 years) are considered, from robust (fit) to vulnerable (unfit) to the terminally ill. Among the topics covered are the following: (i) the relationship between chronological age, prognosis and survival, (ii) assessment of biological aging, (iii) biological age as a determinant of treatment feasibility and tolerance and (iv) tailoring of both first and further-line treatment to the circumstances of the individual patient.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/terapia , Anciano , Anciano de 80 o más Años , Manejo de la Enfermedad , Evaluación Geriátrica , Humanos , Inmunoterapia , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/mortalidad , Oncología Médica , Estadificación de Neoplasias , Pronóstico , Medición de Riesgo , Resultado del TratamientoRESUMEN
The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Carioferinas/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Animales , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Xenoinjertos , Humanos , Ratones , Invasividad Neoplásica , Tasa de Supervivencia , Resultado del Tratamiento , Proteína Exportina 1RESUMEN
Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AICs). Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase approved for the treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib, as participants in therapeutic clinical trials at The Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment-emergent AIC cases were identified. Before starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment-emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment-emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy.
Asunto(s)
Anemia Hemolítica Autoinmune/inducido químicamente , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Púrpura Trombocitopénica Idiopática/inducido químicamente , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Adenina/análogos & derivados , Adulto , Agammaglobulinemia Tirosina Quinasa , Anciano , Anciano de 80 o más Años , Anemia Hemolítica Autoinmune/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Piperidinas , Púrpura Trombocitopénica Idiopática/epidemiologíaAsunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos/genética , Flavonoides/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Piperidinas/uso terapéutico , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/genética , Deleción Cromosómica , Análisis Citogenético , Proteínas de Unión al ADN/genética , Humanos , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/mortalidad , Recurrencia Local de Neoplasia/genética , Proteínas Serina-Treonina Quinasas/genética , Factores de Riesgo , Tasa de Supervivencia , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Tumor lysis syndrome (TLS) has been described in over 40% of patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. We conducted a retrospective analysis to determine predictive factors for TLS. In 116 patients, the incidence of TLS was 46% (95% CI: 36-55%). In univariable analysis, female gender, greater number of prior therapies, Rai stages III-IV, adenopathy ≥ 10 cm, splenomegaly, del(11q), decreased albumin and increased absolute lymphocyte count, white blood cell count (WBC), ß2-microglobulin, and lactate dehydrogenase were associated (P < 0.05) with TLS. In multivariable analysis, female gender, adenopathy ≥ 10 cm, elevated WBC, increased ß2-microglobulin, and decreased albumin were associated with TLS (P < 0.05). With respect to patient outcomes, 49 and 44% of patients with and without TLS, respectively, responded to flavopiridol (P = 0.71). In a multivariable analysis, controlling for number of prior therapies, cytogenetics, Rai stage, age and gender, progression-free survival (PFS) was inferior in patients with TLS (P = 0.01). Female patients and patients with elevated ß2-microglobulin, increased WBC, adenopathy ≥ 10 cm and decreased albumin were at highest risk and should be monitored for TLS with flavopiridol. TLS does not appear to be predictive of response or improved PFS in patients receiving flavopiridol.
Asunto(s)
Antineoplásicos/efectos adversos , Flavonoides/efectos adversos , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Piperidinas/efectos adversos , Síndrome de Lisis Tumoral/etiología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Femenino , Flavonoides/farmacocinética , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estadificación de Neoplasias , Piperidinas/farmacocinética , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Distribución Tisular , Resultado del TratamientoRESUMEN
Rituximab has modest activity in relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma but is associated with tumor necrosis factor-alpha (TNF-alpha) release that can cause CLL proliferation and inhibit apoptosis. We examined whether disruption of TNF-alpha by etanercept improves response to rituximab in CLL. Eligible patients had previously treated CLL with performance status 0-3. Patients received etanercept 25 mg subcutaneously twice weekly (weeks 1-5) and rituximab 375 mg/m(2) intravenously thrice weekly (weeks 2-5) using a phase I/II design. Primary end points were response and toxicity. The 36 enrolled patients had a median of two prior treatments; 50% were fludarabine refractory and 22% had del(17p13.1). Of the 34 response-evaluable patients, 10 (29%) responded, including 9 partial responses and 1 complete remission. Response was not affected by prior rituximab or fludarabine-refractory status, but no patients with del(17p13.1) responded. Median progression-free survival for responders was 9.0 months (range 1-43). Ten patients have had treatment-free intervals exceeding 12 months, including four who have remained untreated for 32, 43, 46 and 56 months. Adverse events were mild, including mild infusion reactions, transient cytopenias and grade 3 infections in 14% of the patients. The combination of etanercept and thrice weekly rituximab produces durable remissions in non-del(17p13.1) CLL patients and is well tolerated.