Marylou Cardenas-Turanzas

Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study

BACKGROUND Ibrutinib, an orally administered covalent inhibitor of Brutons tyrosine kinase (BTK), is an effective treatment for relapsed chronic lymphocytic leukaemia (CLL). We investigated the activity and safety of the combination of ibrutinib with the monoclonal antibody rituximab in patients with high-risk CLL. METHODS In this single-arm phase 2 study, we enrolled adult patients with high-risk CLL at the MD Anderson Cancer Center (Houston, TX, USA). All enrolled participants had high-risk cytogenetic abnormalities (deletion 17p, TP53 mutation, or deletion 11q) or a short progression-free survival (PFS <36 months) after previous first-line chemoimmunotherapy. Patients with symptomatic disease requiring therapy received 28-day cycles of once-daily ibrutinib 420 mg together with rituximab (375 mg/m(2), intravenously, every week during cycle 1, then once per cycle until cycle 6), followed by continuous daily single-agent ibrutinib 420 mg until disease progression or until toxicities or complications precluded further treatment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov number NCT01520519, and is no longer accruing patients. FINDINGS Between Feb 28, 2012, and Sept 11, 2012, we enrolled 40 patients with CLL with high-risk disease features, 20 of whom had deletion 17p (del[17p]) or TP53 mutations (16 previously treated, four untreated), 13 had relapsed CLL with deletion 11q (del[11q]), and seven a PFS less than 36 months after first-line chemoimmunotherapy. 18-month PFS in all patients was 78·0% (95% CI 60·6-88·5), whereas in those with a del(17p) or TP53 mutation it was 72·4% (45·6-87·6) Toxicity was mainly mild to moderate in severity (grade 1-2). Diarrhoea occurred in ten (25%) patients (grade 1 in nine patients and grade 2 in one), bleeding events in 14 (33%) patients (eight grade 1 and five grade 2), nausea or vomiting in 15 patients (38%) (ten grade 1 and five grade 2), and fatigue in seven (18%) patients (four grade 1 and three grade 2). Five patients (13%) had grade 3 infections (two lung infections, one upper respiratory tract infection, one sepsis, and one mucositis), and no grade 4 or 5 infections occurred. One patient had grade 4 neutropenia. INTERPRETATION The encouraging safety and activity of ibrutinib and rituximab in this population of patients with high-risk CLL merits further investigation of this combination. FUNDING Pharmacyclics Inc, Cancer Prevention and Research Institute of Texas, Leukemia and Lymphoma Society, National Cancer Institute, MD Anderson Cancer Center.

Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities

Early responses to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML)-chronic phase (CP) are associated with improved outcome. We analyzed the impact of such a response on outcomes among patients treated with 4 TKI modalities as frontline therapy in CML-CP. A total of 483 patients who received 400 or 800 mg imatinib, nilotinib, or dasatinib were analyzed. The median follow-up was 72 mo. Landmark analysis at 3 mo by molecular response showed that the cumulative proportions of 3-y event-free survival (EFS) for 3-mo BCR-ABL levels was 95% for those with ≤1%, 98% for >1% to 10%, and 61% for those with >10% (P = .001). The corresponding values by cytogenetic responses were 97% if Ph+ = 0%, 89% if Ph+ = 1% to 35%, and 81% if Ph+ >35% (P = .001). Cytogenetic response at 3 mo significantly discriminated for 3-y overall survival (OS): 98%, 96%, and 92%, respectively (P = .01). In multivariate analysis, young patients, high Sokal index, and treatment with imatinib 400 significantly predicted for poor (>35%) cytogenetic response at 3 mo. Early responses are predictive for EFS and failure-free survival and to a lesser extent OS, regardless of the treatment modality, although therapies other than standard-dose imatinib result in higher rates of deep early responses.

International study of the place of death of people with cancer: a population-level comparison of 14 countries across 4 continents using death certificate data

Background:Where people die can influence a number of indicators of the quality of dying. We aimed to describe the place of death of people with cancer and its associations with clinical, socio-demographic and healthcare supply characteristics in 14 countries.Methods:Cross-sectional study using death certificate data for all deaths from cancer (ICD-10 codes C00-C97) in 2008 in Belgium, Canada, Czech Republic, England, France, Hungary, Italy, Mexico, the Netherlands, New Zealand, South Korea, Spain (2010), USA (2007) and Wales (N=1 355 910). Multivariable logistic regression analyses evaluated factors associated with home death within countries and differences across countries.Results:Between 12% (South Korea) and 57% (Mexico) of cancer deaths occurred at home; between 26% (Netherlands, New Zealand) and 87% (South Korea) occurred in hospital. The large between-country differences in home or hospital deaths were partly explained by differences in availability of hospital- and long-term care beds and general practitioners. Haematologic rather than solid cancer (odds ratios (ORs) 1.29–3.17) and being married rather than divorced (ORs 1.17–2.54) were most consistently associated with home death across countries.Conclusions:A large country variation in the place of death can partly be explained by countries’ healthcare resources. Country-specific choices regarding the organisation of end-of-life cancer care likely explain an additional part. These findings indicate the further challenge to evaluate how different specific policies can influence place of death patterns.

Accuracy of Colposcopy in the Diagnostic Setting Compared With the Screening Setting

OBJECTIVE: To estimate the accuracy of colposcopy to identify cervical precancer in screening and diagnostic settings. METHODS: As part of a larger clinical trial to evaluate the diagnostic accuracy of optical spectroscopy, we recruited 1,850 patients into a diagnostic or a screening group depending on their history of abnormal findings on Papanicolaou tests. Colposcopic examinations were performed and biopsies specimens obtained from abnormal and normal colposcopic sites for all patients. The criterion standard of test accuracy was the histologic report of biopsies. We calculated sensitivities, specificities, likelihood ratios, receiver operating characteristic curves, and areas under the receiver operating characteristic curves. RESULTS: The prevalence of high-grade squamous intraepithelial lesions (HSIL) or cancer was 29.0% for the diagnostic group and 2.2% for the screening group. Using a disease threshold of HSIL, colposcopy had a sensitivity of 0.983 and a specificity of 0.451 in the diagnostic group when the test threshold was low-grade squamous intraepithelial lesions (LSIL), and a sensitivity of 0.714 and a specificity of 0.813 when the test threshold was HSIL. Using the same HSIL disease threshold, in the screening group, colposcopy had a sensitivity of 0.286 and a specificity of 0.877 when the test threshold was LSIL, and a sensitivity of 0.191 and a specificity of 0.961 when the threshold was HSIL. The colposcopy area under the receiver operating characteristic curve was 0.821 (95% confidence interval 0.79–0.85) in the diagnostic setting compared with 0.587 (95% confidence interval 0.56–0.62) in the screening setting. Changing the disease threshold to LSIL demonstrated similar patterns in the tradeoff of sensitivity and specificity and measure of accuracy. CONCLUSION: Colposcopy performs well in the diagnostic setting and poorly in the screening setting. Colposcopy should not be used to screen for cervical intraepithelial neoplasia. LEVEL OF EVIDENCE: II

International Variation in Place of Death of Older People Who Died From Dementia in 14 European and non-European Countries

OBJECTIVES The objective of this study was to examine variation in place of death of older people dying from dementia in countries across 4 continents. DESIGN Study of death certificate data. METHODS We included deaths of older (65 + years) people whose underlying cause of death was a dementia-related disease (ICD-10: F01, F02, F03, G30) in Belgium, the Netherlands, England, Wales, France, Italy, Spain, Czech Republic, Hungary, New Zealand, United States, Canada, Mexico and South Korea. We examined associations between place of death and sociodemographic factors, social support, and residential and health care system factors. RESULTS Overall, 4.8% of all deaths were from a dementia-related disease, ranging from 0.4% in Mexico to 6.9% in Canada. Of those deaths, the proportion occurring in hospital varied from 1.6% in the Netherlands to 73.6% in South Korea. When controlling for potential confounders, hospital death was more likely for men, those younger than 80, and those married or living in a region with a higher availability of long-term care beds, although this could not be concluded for each country. Hospital death was least likely in the Netherlands compared with other countries. CONCLUSIONS Place of death of older people who died from a dementia-related disease differs substantially between countries, which might point to organizational differences in end-of-life care provision. Increasing the availability of long-term care beds might be important to reduce the number of hospital deaths, while focusing specialized end-of-life care services on married people or those aged 65 to 79 might be crucial for achieving home death. However, proper end-of-life care needs to be ensured in hospitals, should this be the most appropriate end-of-life care setting.

Hematopoietic Cell Transplantation–Specific Comorbidity Index Predicts Inpatient Mortality and Survival in Patients Who Received Allogeneic Transplantation Admitted to the Intensive Care Unit

PURPOSE To investigate the prognostic value of the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) in patients who received transplantation admitted to the intensive care unit (ICU). PATIENTS AND METHODS We investigated the association of HCT-CI with inpatient mortality and overall survival (OS) among 377 patients who were admitted to the ICU within 100 days of allogeneic stem-cell transplantation (ASCT) at our institution. HCT-CI scores were collapsed into four groups and were evaluated in univariate and multivariate analyses using logistic regression and Cox proportional hazards models. RESULTS The most common pretransplantation comorbidities were pulmonary and cardiac diseases, and respiratory failure was the primary reason for ICU admission. We observed a strong trend for higher inpatient mortality and shorter OS among patients with HCT-CI values ≥ 2 compared with patients with values of 0 to 1 in all patient subsets studied. Multivariate analysis showed that patients with HCT-CI values ≥ 2 had significantly higher inpatient mortality than patients with values of 0 to 1 and that HCT-CI values ≥ 4 were significantly associated with shorter OS compared with values of 0 to 1 (hazard ratio, 1.74; 95% CI, 1.23 to 2.47). The factors associated with lower inpatient mortality were ICU admission during the ASCT conditioning phase or the use of reduced-intensity conditioning regimens. The overall inpatient mortality rate was 64%, and the 1-year OS rate was 15%. Among patients with HCT-CI scores of 0 to 1, 2, 3, and ≥ 4, the 1-year OS rates were 22%, 17%, 18%, and 9%, respectively. CONCLUSION HCT-CI is a valuable predictor of mortality and survival in critically ill patients after ASCT.

The Performance of Human Papillomavirus High-Risk DNA Testing in the Screening and Diagnostic Settings

Objective: We sought to evaluate the performance of the human papillomavirus high-risk DNA test in patients 30 years and older. Materials and Methods: Screening (n = 835) and diagnosis (n = 518) groups were defined based on prior Papanicolaou smear results as part of a clinical trial for cervical cancer detection. We compared the Hybrid Capture II (HCII) test result with the worst histologic report. We used cervical intraepithelial neoplasia (CIN) 2/3 or worse as the reference of disease. We calculated sensitivities, specificities, positive and negative likelihood ratios (LR+ and LR−), receiver operating characteristic (ROC) curves, and areas under the ROC curves for the HCII test. We also considered alternative strategies, including Papanicolaou smear, a combination of Papanicolaou smear and the HCII test, a sequence of Papanicolaou smear followed by the HCII test, and a sequence of the HCII test followed by Papanicolaou smear. Results: For the screening group, the sensitivity was 0.69 and the specificity was 0.93; the area under the ROC curve was 0.81. The LR+ and LR− were 10.24 and 0.34, respectively. For the diagnosis group, the sensitivity was 0.88 and the specificity was 0.78; the area under the ROC curve was 0.83. The LR+ and LR− were 4.06 and 0.14, respectively. Sequential testing showed little or no improvement over the combination testing. Conclusions: The HCII test in the screening group had a greater LR+ for the detection of CIN 2/3 or worse. HCII testing may be an additional screening tool for cervical cancer in women 30 years and older. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2865–71)

Collecting direct non-health care and time cost data: application to screening and diagnosis of cervical cancer.

Background . Data on direct non-health care and time costs are rarely collected, though the incorporation of such data is essential for performing cost-effectiveness analyses according to established guidelines. Objectives . To explore the challenges involved in collecting and analyzing these data from patients enrolled in a clinical trial. Methods . Through the use of a pilot study, the authors designed a questionnaire to collect these costs. They used this questionnaire in a clinical trial conducted at a comprehensive cancer center and a public community hospital. Patients in the trial were undergoing screening or diagnostic procedures through a clinical protocol designed to measure the effectiveness of fluorescence and reflectance spectroscopy for detecting cervical precancers. Direct non-health care costs were adjusted to 2003 constant dollars. Results . The authors successfully collected direct non-health care and time cost data, thus demonstrating the feasibility of acquiring such data. Compared to patients receiving diagnostic services for cervical cancer, those receiving screening services for the same condition in both settings incurred lower direct non-health care costs and time costs, as defined in the questionnaire. Compared to patients receiving either service at the comprehensive cancer center, those seeking either service at the public community hospital incurred lower direct non-health care costs and time costs. When outliers were removed, total direct non-health care costs and time costs substantially decreased for diagnostic patients in the comprehensive cancer center; total direct non-health care costs and time costs for other subgroups remained essentially unchanged. Conclusions . Direct non-health care and time cost data can be collected within a large-scale clinical trial. The setting (community v. specialty hospital) and population (patients receiving screening v. diagnostic examination) makes a difference regarding the cost totals. The order of magnitude of the final result depends on the context in which the non-health care and time cost data will be used.

The combination of hyper-CVAD plus nelarabine as frontline therapy in adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma: MD Anderson Cancer Center experience

The combination of hyper-CVAD plus nelarabine as frontline therapy in adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma: MD Anderson Cancer Center experience

Hospital Versus Home Death: Results from the Mexican Health and Aging Study

CONTEXT Characterizing where people die is needed to inform palliative care programs in Mexico. OBJECTIVES To determine whether access to health care influences the place of death of older Mexicans and examine the modifying effects of demographic and clinical characteristics. METHODS We analyzed 2001 baseline and 2003 follow-up data from the Mexican Health and Aging Study. Cases included adults who completed the baseline interview and died before the follow-up interview and for whom a proxy interview was obtained in 2003. The main outcome variable was the place of death (hospital vs. home). The predictors of the place of death were identified using logistic regression analysis. RESULTS The study group included 473 deceased patients; 52.9% died at home. Factors associated with hospital death were having spent at least one night in a hospital during the last year of life (odds ratio [OR]: 6.73; 95% confidence interval [CI]: 3.29, 13.78) and dying in a city other than the city of usual residence (OR: 4.68, 95% CI: 2.56, 8.57). Factors associated with home death were not having health care coverage (OR: 2.78, 95% CI: 1.34, 5.88), living in a city of less than 100,000 residents (OR: 2.44, 95% CI: 1.43, 4.17), and older age (OR: 1.03, 95% CI: 1.01, 1.05). CONCLUSION Older Mexicans with access to health care services were more likely to die in the hospital even after controlling for important clinical and demographic characteristics. Findings from the study may be used to plan the provision of accessible end-of-life hospital and home-based services.