Introduction:Even in the era of novel targeted therapies for the treatment of Chronic Lymphocytic Leukemia (CLL) patients, such as BTK, PI3K and BCL2 inhibitors, allogeneic hematopoietic stem cell ...transplantations (alloHCT) will remain an important treatment option for a subset of patients with very high risk CLL. The current study focused on the impact of center and procedure-related factors on outcomes after alloHCT, taking into account the impact of patient- and disease-related risk factors.
Patients and Methods:Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analyzed. Their data were collected as part of the EBMT CLL Data Quality Initiative. Outcomes of interest were Event-Free Survival (EFS) up to 5 years after transplantation and mortality in the first 100 days after alloHCT. Outcomes were analyzed by means of the Kaplan-Meier method and Cox proportional hazards models with a frailty (random effects) component to take into account unexplained center heterogeneity. The following factors describing center characteristics or the transplant procedure were analyzed: experience in alloHCT in general and, for CLL specifically, accreditation by the Joint Accreditation Committee-ISCT & EBMT (JACIE), Gross National Income (GNI)/capita based on purchasing power parity (PPP) (GNI/cap), donor type, donor-patient sex-match, type of conditioning, stem cell source and T-cell depletion (TCD).
Results:Five-year EFS of the whole cohort was 37% (95% Confidence Interval, 33%-42%), Day-100 survival was 90% (88%-92%). Experience of the transplant center was measured by the number of all alloHCTs, and alloHCTs for patients with CLL respectively. The median total number of alloHCTs per center per year was 45 (range 0-169) and the median number of CLL alloHCTs was only 2 per center per year (range 0-19). Greater experience with transplantation of patients with CLL (Hazard Ratio (HR) 0.96 per additional transplant, p=0.002), JACIE accreditation (HR 0.7, p=0.045) and a higher GNI/cap (HR 0.4, 95% CI 0.2-0.96, p=0.04) showed a protective impact on 5-year EFS in the Cox model. In vivo TCD with alemtuzumab (HR 1.5 compared to no TCD, p=0.03) and a female donor for a male patient (HR 1.4 compared to a male donor for a male patient, p=0.02) were the only procedure-related factors significantly associated with EFS. Event-Free Survival after in vivo TCD with Anti-Thymocyte-Globulin or after ex vivo TCD was comparable to EFS without TCD (HR 0.9, 0.7-1.3, p=0.6; HR 0.9, 0.5-1.6, p=0.8). Non-myeloablative conditioning did not have a negative impact on 5-year EFS, and exposed patients to a lower risk of non-relapse mortality. Measured and unmeasured center characteristics did not have a significant impact on 100-day mortality.
Even when correcting for patient-, procedure- and center-related characteristics, there was still significant variation in center outcome, expressed by center-specific HRs derived from the frailty models, ranging from 0.6 to 1.2. Their impact is illustrated in a model-based plot for EFS (see Figure) which shows outcomes for three reference patients with the same characteristics who would be transplanted in three centers with the same measured characteristics but with the highest, average and lowest HRs in the dataset. These unexplained center effects likely represent a mixture of differences which could apply to the location of the transplant center, unmeasured characteristics of the patient population transplanted at this center, selection criteria which were not reported and factors determining the success of the transplant procedure which might differ between centers.
Conclusion: We have confirmed that both center- and procedure-related factors have a significant impact on the EFS of patients with CLL undergoing alloHCT. Our results may help to interpret outcomes of single or multicenter studies better. Since non-myeloablative conditioning did not have a negative impact on EFS and exposed patients to a lower risk of non-relapse mortality, this approach should be favored for future alloHCT for CLL.
Probability of Event-Free Survival up to Five Years Post-HCT for three Reference Patients
Contribution: J.S. designed the research and wrote the paper. L.C.d.W conducted the statistical analysis and produced the figure.
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Schetelig:Sanofi: Honoraria. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Dreger:Gilead: Consultancy; Gilead: Speakers Bureau; Janssen: Consultancy; Novartis: Speakers Bureau; Novartis: Consultancy; Roche: Consultancy.
The morphological and spectroscopic properties of the giant (>60 kpc) Ly alpha nebulae associated with three radio galaxies at z similar to 2.5 (MRC 1558-003, 2025-218 and 0140-257) have been ...investigated using integral field spectroscopic data obtained with the Visible Multi-Object Spectrograph (VIMOS) on VLT.The morphologies are varied. The nebula of one source has a centrally peaked, rounded appearance. In the other two objects, it consists of two spatial components. The three nebulae are aligned with the radio axis within lsim30 degree . The total Ly alpha luminosities are in the range (0.3-3.4) x 10 super(44) erg s super(-1). The Ly alpha spectral profile shows strong variation through the nebulae, with full width at half-maximum (FWHM) values in the range similar to 400-1500 km s super(-1) and velocity shifts V sub(offset) similar to 120-600 km s super(-1).We present an infall model that can successfully explain the morphology, size, surface brightness distribution and the velocity field of the Ly alpha nebula associated with MRC 1558-003. It can also explain why Ly alpha is redshifted relative to other emission lines and the FWHM values of the non-resonant He ii line. This adds further support to our previous conclusion that the quiescent giant nebulae associated with this and other high-redshift powerful radio galaxies are in infall. A problem for this model is the difficulty to reproduce the large Ly alpha FWHM values, which might be the consequence of a different mechanism.We have discovered a giant ( similar to 85 kpc) Ly alpha nebula associated with the radio galaxy MRC 0140-257 at z= 2.64. It shows strikingly relaxed kinematics (FWHM < 300 km s super(-1) and V sub(offset)lsim 120 km s super(-1)), unique among high-z (gsim2) radio galaxies.
Prognostic importance of coronary vessel dominance in patients with ST-elevation myocardial infarction (STEMI) remains uncertain. The aim of this study was to assess influence of coronary vessel ...dominance on the short- and long-term outcome after STEMI.
Coronary angiographic images of consecutive patients presenting with first STEMI were retrospectively reviewed to assess coronary vessel dominance. Patients were followed after STEMI during a median period of 48 (IQR38-61) months for the occurrence of all-cause mortality and the composite of reinfarction and cardiac death. The population comprised 1131 patients of which 971 (86%) patients had a right dominant, 102 (9%) a left dominant, and 58 (5%) a balanced system. After 5 years of follow-up, the cumulative incidence of all-cause mortality was significantly higher in patients with a left dominant system, compared with a right dominant and balanced system (log-rank P = 0.013). Moreover, a left dominant system was an independent predictor for 30-day mortality (OR 2.51, 95% CI 1.11-5.67, P = 0.027) and the composite of reinfarction and cardiac death within 30-days after STEMI (OR 2.25, 95% CI 1.09-4.61, P = 0.028). In patients surviving first 30-days post-STEMI, coronary vessel dominance had no influence on long-term outcome.
A left dominant coronary artery system is associated with a significantly increased risk of 30-day mortality and early reinfarction after STEMI. After surviving the first 30-days post-STEMI, coronary vessel dominance had no influence on long-term outcome.
Background The presence of atrial fibrillation (AF) is related to increased levels of natriuretic peptides. In addition, increased natriuretic peptide levels are predictive of the development of AF. ...However, the role of natriuretic peptides to predict recurrence of AF after radiofrequency catheter ablation (RFCA) is controversial. Objective The study aimed to investigate the role of natriuretic peptides in the prediction of AF recurrence after RFCA for AF. Methods Pre-procedural amino-terminal pro-atrial natriuretic peptide (NT-proANP) and amino-terminal-pro-B-type natriuretic peptide (NT-proBNP) plasma levels were determined in 87 patients undergoing RFCA for symptomatic drug-refractory AF. In addition, a comprehensive clinical and echocardiographic evaluation was performed at baseline. Left atrial volumes, left ventricular volumes, and function (systolic and diastolic) were assessed. During a 6-month follow-up period, AF recurrence was monitored and defined as any registration of AF on electrocardiogram or an episode of AF longer than 30 seconds on 24-hour Holter monitoring. The role of natriuretic peptide plasma levels to predict AF recurrence after RFCA was studied. Results During follow-up, 66 patients (76%) maintained sinus rhythm, whereas 21 patients (24%) had AF recurrence. Patients with AF recurrence had higher baseline natriuretic peptide levels than patients who maintained sinus rhythm (NT-proANP 3.19 nmol/L 2.55-4.28 vs 2.52 nmol/L 1.69-3.55, P = .030; NT-proBNP 156.4 pg/mL 64.1-345.3 vs 84.6 pg/mL 43.3-142.7, P = .036). However, NT-proBNP was an independent predictor of AF recurrence, whereas NT-proANP was not. Moreover, NT-proBNP had an incremental value over echocardiographic characteristics to predict AF recurrence after RFCA. Conclusion Baseline NT-proBNP plasma level is an independent predictor of AF recurrence after RFCA.
Background Although most patients who improve in clinical status after cardiac resynchronization therapy (CRT) also show a significant left ventricular (LV) reverse remodeling, some patients do not ...show echocardiographic improvement. The aim of the present study was to evaluate the degree of agreement between clinical and echocardiographic response to CRT in a large cohort of heart failure patients, and to evaluate the characteristics of patients with clinical response but without echocardiographic response. Methods In 440 consecutive heart failure patients (mean age 66 ± 11 years, 81% men) treated with CRT, agreement between clinical and echocardiographic responses at 6 months of follow-up were evaluated. The combined clinical response was defined as: ≥1-point New York Heart Association functional class improvement or ≥15% increase in 6-minute walk test. Echocardiographic response was defined by a reduction in LV end-systolic volume (LVESV) ≥15%. Results At 6 months of follow-up, clinical response was observed in 84% (n = 370) of the patients. Significant reduction in LVESV was noted in 63% (n = 276). The majority of patients who improved clinically did show LV reverse remodeling (72%, n = 268). Importantly, 28% (n = 102) of patients who improved clinically did not show significant LV reverse remodeling. The patients with clinical response but without echocardiographic response had more often ischemic heart failure as compared to patients with positive clinical and echocardiographic response (69.6% vs 57.5%; P = .021). Moreover, patients with such discordant responses had more narrow QRS complex (148 ± 31 vs 159 ± 31 milliseconds; P = .004), and showed less LV dyssynchrony than patients with concordant positive responses (90 ± 77 vs 171 ± 105 milliseconds; P < .001). Conclusions Although there is a good concordance between echocardiographic and clinical response to CRT, up to 28% of the population experienced clinical response without significant LV reverse remodeling. Subjects with such discrepant responses have more frequently ischemic heart failure and show more narrow QRS complex and less LV dyssynchrony than patients with both clinical and echocardiographic response.
Mechanisms linking occupational heat exposure with chronic diseases have been proposed. However, evidence on occupational heat exposure and cancer risk is limited.
We evaluated occupational heat ...exposure and female breast cancer risk in a large Spanish case-control study. We enrolled 1,738 breast cancer cases and 1,910 frequency-matched population controls. A Spanish job-exposure matrix, MatEmEsp, was used to assign estimates of the proportion of workers exposed (
≥ 25% for at least 1 year) and work time with heat stress (wet bulb globe temperature ISO 7243) for each occupation. We used three exposure indices: ever versus never exposed, lifetime cumulative exposure, and duration of exposure (years). We estimated ORs and 95% confidence intervals (CI), applying a lag period of 5 years and adjusting for potential confounders.
Ever occupational heat exposure was associated with a moderate but statistically significant higher risk of breast cancer (OR 1.22; 95% CI, 1.01-1.46), with significant trends across categories of lifetime cumulative exposure and duration (
= 0.01 and 0.03, respectively). Stronger associations were found for hormone receptor-positive disease (OR ever exposure = 1.38; 95% CI, 1.12-1.67). We found no confounding effects from multiple other common occupational exposures; however, results attenuated with adjustment for occupational detergent exposure.
This study provides some evidence of an association between occupational heat exposure and female breast cancer risk.
Our results contribute substantially to the scientific literature. Further investigations are needed considering multiple occupational exposures.
Introduction.
Ibrutinib is a first-in-class, oral, once-a-day Bruton's tyrosine kinase inhibitor that achieves high overall response rates and durable remissions in patients with chronic lymphocytic ...leukemia (CLL) including those with high-risk features (unmutated IGHV, TP53 abnormalities, 11q deletion). Survival with continuous single-agent ibrutinib in previously-untreated CLL patients is comparable to an age-matched general population (Figure 1). IBRORS is an observational, retrospective, multicentre study to describe the characteristics and clinical outcomes of patients with CLL treated with single-agent ibrutinib in routine clinical practice in Spain. This present analysis reviews the subset of patients in IBRORS who received ibrutinib as the first-line of treatment. This series includes a significant number of patients with high risk cytogenetic/molecular alterations (del17p/TP53 M), which corresponds with the approved indication for first-line CLL patients in Spain at the time.
Methods.
Adult patients diagnosed with CLL treated with single-agent ibrutinib in first-line, or at first or second relapse since its commercialization in Spain (between January 2016 to January 2019) were included in the IBRORS study. Clinical characteristics of patients, efficacy and tolerability of ibrutinib as first-line treatment were analyzed here. A Kaplan-Meier analysis was performed for overall survival (OS) and progression-free survival (PFS).
Results.
84 patients, from a total of 269 included in IBRORS, received single-agent ibrutinib as first-line treatment. The median age was 71.3 years (range 63-77) at the time of ibrutinib initiation. 56.3% of patients presented with an intermediate/high-risk Rai-Binet stage, and the majority of patients (98.6%) had an ECOG PS of 0-1. 91.7% of patients had at least 1 high risk molecular cytogenetic factor (unmutated IGHV, TP53 abnormalities, 11q deletion or complex karyotype) described in table 1.
Baseline comorbidities of patients are described in table 2. Concomitant medication included anticoagulants (9.5% patients; vitamin K antagonist n=4, Apixaban n=1 and LMWH n=3 patients), antiplatelet agents (11.9% patients), and antihypertensives (50% patients).
The overall response rate (ORR) was 79.5%; 14/84 (16.6%) achieved a complete response (CR), 14/84 (16.6%) achieved CR unconfirmed, 27/84 (32.14%) achieved a partial response (PR) and 12/84 (14.2%) a PR + lymphocytosis. The median PFS and OS were not reached, and the estimated PFS at 24 months was 84.5% (73.4-95.6%). OS and PFS curves are represented in figure 2.
The PFS of each patient subgroup with high-risk cytogenetic characteristics was similar to that of all patients in the first-line cohort: del17p/TP53 mutation (HR = 0.963 95% CI 0.188-4.928; p = 0.964), del11q (HR = 0.042 95% CI 0.000-682.736; p=0.521), unmutated IGHV (HR = 0.391 95% CI 0.110-1.394; p = 0.148).
The median duration of exposure to ibrutinib was 17.3 (11.9-25.6) months. Dose reduction of ibrutinib occurred in 17/84 (20.2%) patients, 8/84 (9.52%) due to toxicity (4 hematologic toxicity and 4 non-hematologic toxicity). 27/84 (32.1%) patients had temporary interruption of treatment. 15/84 (17.8%) patients permanently discontinued ibrutinib including 6 (7.14%) patients due to progression, 4 (4.76%) due to toxicity and 5 for other reasons.
Safety:
49/84 (58.3%) patients developed at least one adverse event (AE), while 12/84 (14.2%) patients developed at least one serious adverse event (SAE). Twelve (14.3%) patients reported at least one haematological toxicity while 53 patients (63.1%) recorded at least one non-haematological toxicity. Only 1 patient experienced grade 3 atrial fibrillation, which did not lead to discontinuation. The most common AEs are described in table 3.
Conclusion.
This population of previously-untreated CLL patients, enriched for high-risk genomic features, reflects the initial approval of ibrutinib for the treatment of first-line patients with del17p in Spain. Single-agent Ibrutinib as the first-line treatment in this real world population was effective regardless of risk factors and well tolerated, with a low rate of discontinuation due to toxicity. Findings are consistent with those reported in clinical trials.
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Loscertales:AbbVie: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; AstraZeneca: Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria. Arguiñano:AbbVie: Honoraria; Janssen: Honoraria; BMS-Celgene: Honoraria; Novartis: Honoraria. Hernandez-Rivas:Janssen: Membership on an entity’s Board of Directors or advisory committees; Abbvie: Membership on an entity’s Board of Directors or advisory committees; Roche: Membership on an entity’s Board of Directors or advisory committees; AstraZeneca: Membership on an entity’s Board of Directors or advisory committees; Gilead: Membership on an entity’s Board of Directors or advisory committees; Celgene/BMS: Membership on an entity’s Board of Directors or advisory committees; Rovi: Membership on an entity’s Board of Directors or advisory committees. Pérez Persona:Amgen: Consultancy; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Jannsen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy. Loriente:Janssen Cilag: Current Employment. Villanueva:Janssen Cilag: Current Employment.
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