To explore the preferences of Spanish healthcare professionals (haematologists and hospital pharmacists) for the treatment selection of active Chronic Lymphocytic Leukaemia (CLL) patients at first ...relapse, condition that mainly afflicts older adults.
A discrete choice experiment (DCE) was conducted among haematologists and hospital pharmacists. A literature review and a focus group informed the DCE design. CLL treatment settings were defined by seven attributes: four patient/disease-related attributes (age, functional status, comorbidities, and risk of the disease) and three treatment-related attributes (efficacy hazard ratio of progression-free survival, HR-PFS, rate of discontinuations due to adverse events and cost). A mixed-logit model was used to determine choice-based preferences. Relative importance (RI) of attributes was calculated and compared between stakeholders. Willingness-to-pay (WTP) was estimated through the DCE. Besides, nine ad-hoc questions were posed, to explore more in depth CLL treatment decision making.
A total of 130 participants (72 haematologists and 58 hospital pharmacists) answered the DCE. All attributes were significant predictors of preferences (p < 0.05) in the multinomial model. Higher RI was obtained for treatment-related attributes: the highest rated being ‘cost’ (23.8%) followed by ‘efficacy’ (20.9%). Regarding patient-related attributes, the highest RI was obtained for ‘age’ (18.1%). No significant differences (p > 0.05) in RI between haematologists and pharmacists were found. WTP for the treatment was higher for younger CLL patients. Ad-hoc questions showed that patient age and functional status influence treatment decisions.
For healthcare professionals, ‘cost’ and ‘efficacy’ (treatment-related attributes) and age (patient-related attribute) are the main factors that determine CLL treatment selection at first relapse. WTP decreases as patient's age increases.
Frailty is a crucial indicator in determining the well-being of older adults in terms of their health. With the growing number of elderly people, the demand for geriatricians is increasing, which ...means that they have less time to spend with each patient. The current methods for frailty assessment use simple tests that are time-consuming and do not require specific medical expertise. To address this issue, this paper proposes the use of social robots to assess frailty autonomously. It presents a practical proposal that defines the robot's behavior and explains the design and implementation concepts. Finally, it discusses some of the challenges that may arise from introducing social robots as frailty evaluators.
Objective
Somatic mutations in ASXL1 seem to have a negative prognostic impact in patients with several myeloid neoplasms, including myelofibrosis (MF). The aim of this work was to determine the ...prevalence and profile of ASXL1 mutations in MF.
Methods
We analyzed mutations in ASXL1 in 70 consecutive MF patients from 8 Spanish hospitals by means of Sanger sequencing, as well as JAK2, CALR, and MPL mutations.
Results
ASXL1 mutations were found in 16/70 (23%) of cases, most commonly p.Gly646TrpfsX12 (5/16). Most mutations (13/16) were frameshift mutations. Of 54 ASXL1‐ wild‐type patients, 32 (59%) had at least one single nucleotide polymorphism (SNP), 27 of them had g.78128C>T, g.79017A>C, and g.79085T>C triple SNP (TSNP) patients. The 5‐yr overall survival probability of TSNP patients was 67% (95% CI, 43–91%) vs. 90% (95% CI, 77–100%) in ASXL1‐WT patients (P = 0.152).
Conclusion
ASXL1 mutations were found in 23% of cases, p.Gly646TrpfsX12 being the most frequent. About 85% of mutations were found only in individual cases and 46% had not previously been reported, a pattern also seen in other series. Fifty percent of ASXL1‐WT patients had a combination of three specific SNPs that might have a prognostic correlation that needs to be determined in larger series.
Cadherin-13 (CDH13) is a newly characterized cadherin molecule responsible for selective cell recognition and adhesion, the expression of which is decreased by methylation in a variety of human ...cancers, indicating that the CDH13 gene functions as a tumor suppressor gene. Although defective progenitor-stromal adhesion is a well-recognized feature of chronic myeloid leukemia (CML), the role of CDH13 abnormalities has not been evaluated in this disease.
We examined the methylation status of the CDH13 promoter in 179 chronic phase (CP)-CML patients and in 52 advanced-phase samples and correlated it with mRNA expression using methylation-specific polymerase chain reaction (PCR) and reverse transcriptase PCR.
Aberrant de novo methylation of the CDH13 promoter region was observed in 99 (55%) of 179 of CP-CML patients, and 90 of the patients failed to express CDH13 mRNA (P <.0001). Advanced-stage samples (n = 52) showed concordant methylation results with their corresponding CP tumors, indicating that CDH13 methylation was not acquired during the course of the disease. Nevertheless, absence of CDH13 expression was more frequently observed among Sokal high-risk patients (P =.01) and was also independently associated with a shorter median progression-free survival time (P =.03) and poor cytogenetic response to interferon alfa treatment (P =.0001).
Our data indicate that the silencing of CDH13 expression by aberrant promoter methylation occurs at an early stage in CML pathogenesis and probably influences the clinical behavior of the disease.
Introduction: Discontinuation of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has become part of routine clinical practice in recent years, thanks to growing evidence on their ...feasibility and safety. However, and despite adequate patient selection based on current recommendations, loss of response is observed in approximately 50% of patients. In this scenario, efforts are focused on finding strategies to increase the rate of successful discontinuations. Ponatinib has shown to induce deeper molecular responses compared with imatinib, but its risk of arterial occlusive events (AOE) limits its use in first line at its standard dose of 45mg. The risk of AOEs appears to be dose-related and following the results of the OPTIC study, dose reduction to 15mg in patients with good response is an increasingly popular strategy. Under these premises it has been postulated that a consolidation with ponatinib 15mg may increase the proportion of patients who could discontinue treatment successfully. Our aim is to evaluate the efficacy and safety of one year of consolidation therapy with ponatinib 15mg on treatment-free remission (TFR) rate in patients with CML who have achieved a deep molecular response with imatinib. Material and Methods: A multicenter open-label, single-arm, phase II, exploratory, prospective clinical trial (NCT 04043676) was conducted including patients with philadelphia-positive CML who met discontinuation criteria according to European LeukemiaNet recommendations, had received 4 years or more of imatinib therapy, with a documented grade 4 molecular response (MR4) at least 12 months prior to study entry. Uncontrolled arterial hypertension, active cardiovascular disease, or concomitant medication with potential for QTc prolongation were exclusion criteria. The study has two main phases: ponatinib consolidation (48 weeks), and ponatinib TFR phase (48 weeks); where patients remain without treatment. During the TFR phase, patients with a confirmed loss of MR4 or a single value above major molecular response (MMR) were scheduled to restart treatment with a TKI at investigator's discretion. The present abstract reports the results of the primary endpoint of the study; the proportion of patients with no loss of MR4 at the end of the TFR phase. Results: A total of 23 patients started treatment with ponatinib 15mg. One patient subsequently failed screening due to a major protocol deviation. Baseline patient characteristics were as follows: median age was 51.8 years (range 26-74), 65.2% were male. Ninety-five percent were Caucasian and 5% were Hispanic, ECOG was 0 in 83% and 1 in 17%, Sokal was low in 69.5%, intermediate in 17.5% and unknown in 13%. Eighteen patients were receiving imatinib 400mg daily (82%) at study entry, 2 patients 800mg and two 200mg. Median time on prior imatinib was 10 years (range 4-17), with a median time on MR4 of 3.6 years (range 1.9-13.3). Prior to initiation 13 patients (56.5%) had a grade 5 molecular response, 4 had a 4.5 molecular response (26%) and the remainder had a MR4. The adverse events (AEs) reported with ponatinib are summarized in Table 1, the most frequent being constipation (30%), asthenia (26%), myalgias and arthralgias (26% respectively) and skin rash (17%). A high rate of SARS-CoV2 infections was reported during the treatment period (26%), which should be interpreted considering that the study took place during the COVID-19 pandemic. Three patients out of 22 (13.6%) had serious AEs with ponatinib leading to treatment discontinuation; thrombophlebitis, erectile dysfunction, and intermittent claudication. Of the patients who entered the TFR phase, 14/19 (74%) continue with MMR without requiring treatment after a median follow-up of 12 months (68% with MR4) (table 1). Six patients (31%) lost MR4, five of them required reintroduction of an TKI (4 imatinib, 1 dasatinib; median time to reintroduction 5.4 months). All patients with MR4 loss were receiving the 400 mg dose of imatinib at study entry. All patients who restarted treatment recovered MMR. The sixth patient lost MR4 while maintaining an MMR without requiring treatment reinduction to date. Conclusions: Consolidation with 12 months of ponatinib 15mg in this study shows a high discontinuation success rate with an adequate safety profile, although not free of AEs. The results make this approach attractive for the design of further randomized clinical trials.
INTRODUCTION
Most patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) are of advanced age and it is often difficult to identify those who may benefit from specific ...treatment strategies. The comprehensive geriatric assessment (CGA) is considered the gold standard tool to classify older patients according to their frailty profile. A multidisciplinary approach that includes a geriatrician is essential. CGA can be helpful in personalizing the treatment plan and detecting conditions that may be reversible through geriatric interventions. Our objective is to evaluate the impact of CGA on therapeutic decisions in patients with AML and MDS.
METHODS
From January 2018 to April 2021, 97 elderly patients with AML and MDS, who were candidates to receive any treatment, were systematically evaluated through the CGA, which includes validated instruments to assess comorbidity, polypharmacy, functional status, geriatric syndromes, mood, cognition and social state. According to the CGA, the patients were classified into 3 frailty categories: fit, medium fit and unfit.
RESULTS
The mean age was 78 years (range 67-90); 55% were men, 50 patients (51,5%) with AML and 47 (37.1%) with MDS (Table 1). Diagnoses were classified according to the 2017 WHO's AML criteria: 7 (7.2%) patients had AML and related neoplasm (unclassifiable), 11 (11.3%) AML with recurrent genetic abnormalities, 14 (14.4%) AML NOS, 18 (18.5%) AML with dysplasia-related changes and 6 (6.2%) Therapy Related Myeloid Neoplasm. According to 2017 WHO's MDS criteria: 13 (13.4%) had MDS-EB, 11 (11.4%) CMML, 2 (2.1%) MDS-RS, 1 (1%) MDS with isolated del (5q), 8 (8.2%) MDS-MLD, 5 (5.1%) MDS-RS-MLD and 1 (1%) MDS unclassifiable. R-IPSS assessment for MDS was: 2 patients (6.1%) very low, 7 (21.2%) low, 10 (30.3%) intermediate, 9 (27.27%) high, and 5 (15.15%) very high risk. As for CMML prognostic, CPSS was: 4 (44.4%) high, 3 int-1(33.3%) and 2 (22.2%) low. For AML, 2017 European Leukemia Network (ELN) categories were 23 (37.7%) favorable, 24 (39.3%) intermediate and 14 (22.9%) adverse. According to the CGA, in AML, 23 (46%) patients were classified as fit, 23 (46%) as medium fit and 4 (8%) as unfit. In the MDS, 25 (54.2%), 14 (29.8%) and 8 (17%) were fit, medium fit and unfit, respectively. Regarding treatment, a total of 85.4% of fit, 78.9% of medium fit and 45.5% of unfit patients received hemato-specific treatment (p 0.03). According to the CGA category, 35.4% of fit, 50% of medium fit and 100% of unfit patients required intervention (p 0.001). Furthermore, for the CGA domains taken into consideration, depression and cognitive deficit were detected in 31 (32%) and 9 (9.3%) of patients, respectively. Also, 5 (5,2%) and 17 (17.5%) of patients had basic activities of daily livings (bADL) and instrumental activities of daily livings (iADL) deficiencies, respectively. This indicates dependence on assistance for tasks such as managing finances, use the phone, prepare meals or manage medicines. Regarding Charlson Comorbidity Index (CCI), 55 (56,7%) of patients scored ≥2 and 6 (6.2%) of patients had falls (Table 1). In addition, 48.5% of patients (54% AML) required intervention in different measures by physiotherapy, nutrition, pharmacy, psychology, social work or palliative treatment.
Geriatric assessed frailty categories were a powerful OS predictor and could discriminate three different groups regarding OS. Patients classified as fit had better median overall survival (OS;1.8 years 95% CI 1.4-2.1) compared to medium fit (1.1 y 95% CI 0.8-1.4) and unfit patients (0.8 y 95% CI 0.3-1.3) (p 0.016; Figure 1). Multivariate analysis performed included gender, age CGA categories and hemato-specific treatment showed that medium fit and unfit categories were associated with poor survival, independent of hemato-specific treatment, age and gender (HR 2.1; 95% CI, 1.1-4.2; p 0.022 and HR 2.4; 95% CI, 0.98-5.99; p 0.05)
CONCLUSIONS
Incorporating CGA within a multidisciplinary approach provides the opportunity to better classify patients according to frailty profiles to guide interventions and treatment decisions. CGA showed efficacy in predicting survival and demonstrates potential implications for shaping the decision-making process for hematologic therapies
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Sureda: Roche: Other: Support for attending meetings and/or travel; GSK: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Consultancy; Bluebird: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Arnan: BMS/Celgene: Consultancy, Other: Participation in clinical trials; Takeda: Other: Participation in clinical trials; Novartis: Consultancy, Other: Participation in clinical trials; Astellas: Other: Participation in clinical trials; Jazz: Other: Participation in clinical trials.
The emergence of clonal chromosomal abnormalities in Philadelphia-negative cells during treatment with imatinib in patients with Philadelphia-positive chronic myeloid leukemia has been reported. We ...add information to this issue presenting a series of 29 patients in complete cytogenetic response after imatinib treatment, three of whom developed clonal aberrations.
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