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1.
Ann Oncol ; 30(4): 542-550, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30799502

RESUMO

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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Fatores Etários , Idoso , Análise de Dados , Progressão da Doença , Estudos de Viabilidade , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Intervalo Livre de Progressão , Tamanho da Amostra
2.
Leukemia ; 30(2): 346-50, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26442611

RESUMO

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.


Assuntos
Anemia Hemolítica Autoimune/induzido quimicamente , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Adenina/análogos & derivados , Adulto , Tirosina Quinase da Agamaglobulinemia , Idoso , Idoso de 80 Anos ou mais , Anemia Hemolítica Autoimune/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Piperidinas , Púrpura Trombocitopênica Idiopática/epidemiologia
4.
Bone Marrow Transplant ; 49(10): 1323-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25068419

RESUMO

Patients who undergo autologous stem cell transplant (ASCT) for hematologic malignancies frequently have multiple comorbidities. The hematopoietic cell transplantation comorbidity index (HCT-CI), a transplant-specific modification of the Charlson comorbidity index, can predict risk of readmission following allogeneic stem cell transplant. Its utility in the autologous setting is unknown. We evaluated 620 patients who underwent ASCT at the Ohio State University from 2007 to 2012 for lymphoma or multiple myeloma (MM) to identify factors associated with readmission. Univariable and multivariable logistic regression were used to estimate the odds of readmission within 30 days of discharge following ASCT. A Cox proportional hazards model was used to evaluate OS. Sixty-four patients were readmitted within 30 days; the most common indications were fever and prolonged gastrointestinal toxicity. MM compared with lymphoma (odds ratio (OR) 1.89, 95% confidence interval (95% CI): 1.06-3.38, P=0.03), HCT-CI⩾3 (OR 1.74, 95% CI: 1.03-2.96, P=0.04) and length of hospitalization ⩾28 days (OR 3.14, 95% CI: 1.26-7.83, P=0.01) remained significantly associated with 30-day readmission in a multivariable model. While the model had excellent fit (P>0.75), its ability to predict individual patients who would be readmitted was less than acceptable (receiver-operator curve=0.64, 95% CI: 0.57-0.71). In a multivariable proportional hazards model, 30-day readmission (hazards ratio (HR) 1.81, 95% CI: 1.04-3.18, P=0.04), length of hospitalization ⩾28 days (HR 4.93, 95% CI: 2.65-9.18, P<0.001) and chemorefractory disease (HR 3.08, 95% CI: 1.74-5.43, P<0.001) were independently associated with inferior OS, but HCT-CI was not. Evaluation of other assessment tools may allow better prediction of outcomes following ASCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Linfoma/mortalidade , Mieloma Múltiplo/mortalidade , Condicionamento Pré-Transplante/mortalidade , Adolescente , Adulto , Idoso , Comorbidade , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/métodos , Adulto Jovem
6.
Bone Marrow Transplant ; 48(9): 1212-7, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23584442

RESUMO

Positron emission tomography/computed tomography (PET/CT)-positive findings before autologous SCT (auto-SCT) are associated with inferior PFS and OS in patients with relapsed Hodgkin's and diffuse large B-cell lymphoma. We classified pre-transplant PET/CT performed before auto-SCT as positive or negative to evaluate the impact of pre-transplant PET/CT in mantle cell lymphoma (MCL). In 29 patients, 17 were PET/CT(-) and 12 were PET/CT(+). PET/CT(+) patients were younger (P=0.04), had lower MCL International Prognostic Index (MIPI, P=0.04) scores, but increased bulky adenopathy >5 cm (45% vs 13%, P=0.09). With a median follow-up of 27 months (range: 5-55 months), 7 patients relapsed (4 in the PET/CT(-) group and 3 in the PET/CT(+) group) with 2 deaths in the PET/CT(+) group without a documented relapse. The estimated 2-year PFS was 64% (95% confidence interval (CI): 0.30-0.85) vs 87% (95% CI: 0.57-0.97) in PET/CT(+) and PET/CT(-) patients, respectively (P=0.054). OS was significantly decreased in PET/CT(+) patients (P=0.007), with 2-year estimates of 60% (95% CI: 0.23-0.84) vs 100% in PET/CT(-) patients. A positive pre-transplant PET/CT is associated with a poor prognosis in patients with MCL. Additional factors may impact the prognostic value of PET/CT, as several PET/CT(+) patients remain in remission.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/cirurgia , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Célula do Manto/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento
8.
Leukemia ; 25(9): 1444-51, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21606960

RESUMO

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.


Assuntos
Antineoplásicos/efeitos adversos , Flavonoides/efeitos adversos , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/efeitos adversos , Síndrome de Lise Tumoral/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Quinases Ciclina-Dependentes/antagonistas & inibidores , Feminino , Flavonoides/farmacocinética , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/tratamento farmacológico , Estadiamento de Neoplasias , Piperidinas/farmacocinética , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Distribuição Tecidual , Resultado do Tratamento
10.
Am J Physiol Heart Circ Physiol ; 278(4): H1335-44, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10749731

RESUMO

To clarify the controversial question of cell-specific distribution of carbonic anhydrase (CA) in the heart, endothelial cells and cardiomyocytes were isolated from porcine and human hearts and were characterized with cell-specific markers. CA activity was found in the microsomal fraction of both cell types. It was shown by Triton X-114 phase separation that both cell types possess a membrane-bound form of CA. These CAs share the same mechanism of membrane-anchoring via glycosylphosphatidylinositol (GPI), which excludes identity with transmembrane isoforms CA IX or CA XII. Western blotting analysis of human microsomes with anti-human CA IV antibodies revealed a marked difference in immunoreactivity. Endothelial CA activity resulted in 11-fold stronger CA IV bands compared with identical amounts of myocytic CA activity, indicating that cardiac endothelium and cardiomyocytes possess immunologically distinct forms of CA. We conclude that in human hearts CA IV is associated with the endothelium, whereas most of the CA in myocytes is not identical with one of the known CA isozymes. This suggests that cardiomyocytic CA is a novel isozyme.


Assuntos
Anidrases Carbônicas/análise , Glicosilfosfatidilinositóis/análise , Isoenzimas/análise , Fibras Musculares Esqueléticas/enzimologia , Miocárdio/enzimologia , Animais , Especificidade de Anticorpos , Biomarcadores , Anidrases Carbônicas/imunologia , Anidrases Carbônicas/metabolismo , Separação Celular , Detergentes , Endotélio/química , Endotélio/citologia , Endotélio/enzimologia , Glicosilação , Ventrículos do Coração/química , Ventrículos do Coração/citologia , Ventrículos do Coração/enzimologia , Humanos , Isoenzimas/imunologia , Isoenzimas/metabolismo , Masculino , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/química , Fibras Musculares Esqueléticas/citologia , Miocárdio/química , Miocárdio/citologia , Cadeias Pesadas de Miosina/análise , Óxido Nítrico Sintase/análise , Óxido Nítrico Sintase Tipo III , Octoxinol , Polietilenoglicóis , Sarcolema/enzimologia , Suínos
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