The most important challenges in acute promyelocytic leukemia (APL) is preventing early death and reducing long-term events, such as second neoplasms (s-NPLs). We performed a retrospective analysis of 2670 unselected APL patients, treated with PETHEMA "chemotherapy based" and "chemotherapy free" protocols. Only de novo APL patients who achieved complete remission (CR) and completed the three consolidation cycles were enrolled into the analysis. Out of 2670 APL patients, there were 118 (4.4%) who developed s-NPLs with the median latency period (between first CR and diagnosis of s-NPL) of 48.0 months (range 2.8-231.1): 43.3 (range: 2.8-113.9) for s-MDS/AML and 61.7 (range: 7.1-231.1) for solid tumour. The 5-year CI of all s-NPLs was of 4.43% and 10 years of 7.92%. Among s-NPLs, there were 58 cases of s-MDS/AML, 3 cases of other hematological neoplasms, 57 solid tumours and 1 non-identified neoplasm. The most frequent solid tumour was colorectal, lung and breast cancer. Overall, the 2-year OS from diagnosis of s-NPLs was 40.6%, with a median OS of 11.1 months. Multivariate analysis identified age of 35 years (hazard ratio = 0.2584; p < 0.0001) as an independent prognostic factor for s-NPLs. There were no significant differences in CI of s-NPLs at 5 years between chemotherapy-based vs chemotherapy-free regimens (hazard ratio = 1.09; p = 0.932). Larger series with longer follow-up are required to confirm the potential impact of ATO+ATRA regimens to reduce the incidence of s-NPLs after front-line therapy for APL.
- MeSH
- akutní promyelocytární leukemie * diagnóza farmakoterapie epidemiologie MeSH
- dospělí MeSH
- incidence MeSH
- lidé MeSH
- patologická kompletní odpověď MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- sekundární malignity * farmakoterapie MeSH
- tretinoin MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities. PATIENTS AND METHODS: ALPINE (ClinicalTrials.gov identifier: NCT03734016) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled. RESULTS: Between November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib. CONCLUSION: Zanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.
- MeSH
- adenin terapeutické užití MeSH
- B-buněčný lymfom * farmakoterapie MeSH
- chronická lymfatická leukemie * farmakoterapie MeSH
- fibrilace síní * MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
CONTEXT: The Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib, was designed for high BTK specificity and minimal toxicity. SEQUOIA (NCT03336333) is a global, open-label, randomized phase 3 study in treatment-naïve patients with CLL/SLL without del(17p) who were unsuitable for fludarabine/cyclophosphamide/rituximab. DESIGN: Patients were randomized to receive zanubrutinib (160 mg twice daily) or bendamustine (day 1-2: 90 mg/m2) and rituximab (cycle 1: 375 mg/m2; cycles 2-6: 500 mg/m2); stratification factors were age (<65 years vs ≥65 years), Binet Stage, IGHV mutation, and geographic region. MAIN OUTCOME MEASURES: Primary endpoint was an independent review committee (IRC)-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed (INV) PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: From October 31, 2017, to July 22, 2019, 479 patients were enrolled (zanubrutinib=241; BR=238). Baseline characteristics (zanubrutinib vs BR): median age, 70.0 years versus 70.0 years; unmutated IGHV, 53.4% versus 52.4%; del(11q), 17.8% versus 19.3%. With median follow-up of 26.2 months, PFS was significantly prolonged with zanubrutinib by IRC (HR 0.42; 2-sided P<.0001) and INV (HR 0.42; 2-sided P=.0001). Zanubrutinib treatment benefit occurred across age, Binet stage, bulky disease, del(11q) status, and unmutated IGHV (HR 0.24; 2-sided P<.0001), but not mutated IGHV (HR 0.67; 2-sided P=.1858). For zanubrutinib versus BR, 24-month PFS-IRC=85.5% versus 69.5%; ORR-IRC=94.6% versus 85.3%; complete response rate=6.6% versus 15.1%; ORR-INV=97.5% versus 88.7%; and 24-month OS=94.3% versus 94.6%. Select adverse event (AE) rates (zanubrutinib vs BR): atrial fibrillation (3.3% vs 2.6%), bleeding (45.0% vs 11.0%), hypertension (14.2% vs 10.6%), infection (62.1% vs 55.9%), and neutropenia (15.8% vs 56.8%). Treatment discontinuation due to AEs (zanubrutinib vs BR)=20 patients (8.3%) versus 31 patients (13.7%); AEs leading to death=11 patients (4.6%) versus 11 patients (4.8%). No sudden deaths occurred. CONCLUSIONS: In summary, zanubrutinib significantly improved PFS-IRC versus BR and was well tolerated, supporting the potential utility of frontline zanubrutinib in treatment-naïve CLL/SLL.
- MeSH
- B-buněčný lymfom * farmakoterapie MeSH
- bendamustin hydrochlorid terapeutické užití MeSH
- chronická lymfatická leukemie * farmakoterapie patologie MeSH
- cyklofosfamid terapeutické užití MeSH
- inhibitory proteinkinas * škodlivé účinky MeSH
- lidé MeSH
- piperidiny škodlivé účinky MeSH
- proteinkinasa BTK MeSH
- protokoly antitumorózní kombinované chemoterapie * škodlivé účinky MeSH
- pyrazoly škodlivé účinky MeSH
- pyrimidiny škodlivé účinky MeSH
- rituximab terapeutické užití MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
- MeSH
- dítě MeSH
- etnicita MeSH
- krevní nemoci * epidemiologie terapie MeSH
- lidé MeSH
- nádory * epidemiologie terapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
War refugees and veterans have been known to frequently develop neuropsychiatric conditions including depression, post-traumatic stress disorder (PTSD), and anxiety disorders that tend to leave a long-lasting scar and impact their emotional response system. The shear stress, trauma, and mental breakdown from overnight displacement, family separation, and killing of friends and families cannot be described enough. Victims often require years of mental health support as they struggle with sleep difficulties, recurring memories, anxiety, grief, and anger. Everyone develops their coping mechanism which can involve dependence and long-term addiction to alcohol, drugs, violence, or gambling. The high prevalence of mental health disorders during and after the war indicates an undeniable necessity for screening those in need of treatment. For medical health professionals, it is crucial to identify such vulnerable groups who are prone to developing neuropsychiatric morbidities and associated risk factors. It is pivotal to develop and deploy effective and affordable multi-sectoral collaborative care models and therapy, which primarily depends upon family and primary care physicians in the conflict zones. Herein, we provide a brief overview regarding the identification and management of vulnerable populations, alongside discussing the challenges and possible solutions to the same.
On the 24th of February 2022, the Russian Federation began an unprovoked invasion of Ukraine, marking the biggest military attack in Europe since the second world war. Over 4 million people have fled their homeland within the first month of the war and have triggered a large refugee crisis with impacts far beyond the Ukrainian border. People in the neighboring countries have shown tremendous support by stepping forward to donate food, clothes, medications, money, and other essential supplies. The governments and other regional stakeholders have also been supportive in accommodating and easing regulations for the incoming refugees. Herein, we summarize the humanitarian measures and medical donations that have been made by European countries as they stepped up their efforts to provide refugees with all necessary basic services. We further highlight potential oncoming challenges in Ukraine and the host countries along with relevant solutions to these challenges. The current scenario highlights the need for multi-party and multi-level collaborations (both public and private) to tackle the emerging situation.
BACKGROUND: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL. METHODS: We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided α of 0·05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment. FINDINGS: Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26·2 months (IQR 23·7-29·6), median progression-free survival per independent review committee was not reached in either group (group A 95% CI not estimable [NE] to NE; group B 28·1 months to NE). Progression-free survival was significantly improved in group A versus group B (HR 0·42 [95% CI 0·28 to 0·63]; two-sided p<0·0001). The most common grade 3 or worse adverse event was neutropenia (27 [11%] of 240 patients in group A, 116 [51%] of 227 in group B, and 17 [15%] of 111 patients in group C). Serious adverse events occurred in 88 (37%) of 240 patients in group A, 113 (50%) of 227 patients in group B, and 45 (41%) of 111 patients in group C. Adverse events leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and three (3%) of 111 patients in group C, most commonly due to COVID-19 (four [2%] of 240 patients in group A), diarrhoea, and aspiration pneumonia (two each [1%] of 227 patients in group B). INTERPRETATION: Zanubrutinib significantly improved progression-free survival versus bendamustine-rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL. FUNDING: BeiGene.
- MeSH
- bendamustin hydrochlorid MeSH
- chronická lymfatická leukemie * farmakoterapie patologie MeSH
- COVID-19 * MeSH
- lidé MeSH
- piperidiny MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- pyrazoly MeSH
- pyrimidiny MeSH
- rituximab MeSH
- sekvoj * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
Deep learning (DL) methods have in recent years yielded impressive results in medical imaging, with the potential to function as clinical aid to radiologists. However, DL models in medical imaging are often trained on public research cohorts with images acquired with a single scanner or with strict protocol harmonization, which is not representative of a clinical setting. The aim of this study was to investigate how well a DL model performs in unseen clinical datasets-collected with different scanners, protocols and disease populations-and whether more heterogeneous training data improves generalization. In total, 3117 MRI scans of brains from multiple dementia research cohorts and memory clinics, that had been visually rated by a neuroradiologist according to Scheltens' scale of medial temporal atrophy (MTA), were included in this study. By training multiple versions of a convolutional neural network on different subsets of this data to predict MTA ratings, we assessed the impact of including images from a wider distribution during training had on performance in external memory clinic data. Our results showed that our model generalized well to datasets acquired with similar protocols as the training data, but substantially worse in clinical cohorts with visibly different tissue contrasts in the images. This implies that future DL studies investigating performance in out-of-distribution (OOD) MRI data need to assess multiple external cohorts for reliable results. Further, by including data from a wider range of scanners and protocols the performance improved in OOD data, which suggests that more heterogeneous training data makes the model generalize better. To conclude, this is the most comprehensive study to date investigating the domain shift in deep learning on MRI data, and we advocate rigorous evaluation of DL models on clinical data prior to being certified for deployment.
- MeSH
- deep learning * MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozek diagnostické zobrazování MeSH
- neuronové sítě (počítačové) MeSH
- reprodukovatelnost výsledků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Melflufen is a novel peptide-drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. It has emerged as a potential new multiple myeloma treatment, particularly for late-stage forms of the disease. Here we describe the rationale and design of OCEAN (NCT03151811), a randomized, head-to-head, superiority, open-label, global, Phase III study evaluating the efficacy and safety of melflufen + dexamethasone versus pomalidomide + dexamethasone. Eligible patients with relapsed refractory multiple myeloma have received 2-4 previous treatments and are refractory to both lenalidomide and their last treatment. Patients are excluded if they have previously received pomalidomide. The primary endpoint is progression-free survival, and key secondary endpoints include overall response rate, duration of response and overall survival.
- MeSH
- chemorezistence MeSH
- dexamethason terapeutické užití MeSH
- doba přežití bez progrese choroby MeSH
- fenylalanin analogy a deriváty terapeutické užití MeSH
- klinické zkoušky, fáze III jako téma MeSH
- lenalidomid škodlivé účinky MeSH
- lidé MeSH
- melfalan analogy a deriváty terapeutické užití MeSH
- mnohočetný myelom farmakoterapie patologie MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- randomizované kontrolované studie jako téma MeSH
- recidiva MeSH
- thalidomid analogy a deriváty terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- protokol klinické studie MeSH
The t(14;16) translocation, found in 3%-5% of newly diagnosed (ND) multiple myeloma (MM), has been associated with adverse outcomes. However, the studies establishing the characteristics of t(14;16) included solely small cohorts. The goal of the current international, multicenter (n = 25 centers), retrospective study was to describe the characteristics and outcomes of t(14;16) patients in a large, real-world cohort (n = 223). A substantial fraction of patients had renal impairment (24%) and hemoglobin <10 g/dL (56%) on initial presentation. Combined therapy of both immunomodulatory drug and proteasome inhibitor (PI) in the first line was used in 35% of patients. Autologous stem cell transplantation was performed in 42% of patients. With a median follow up of 4.1 years (95% CI 3.7-18.7), the median progression-free survival (PFS) and overall survival (OS) from first line therapy were 2.1 years (95% CI 1.5-2.4) and 4.1 years (95% CI 3.3-5.5), respectively. Worse OS was predicted by age > 60 years (HR = 1.65, 95% CI [1.05-2.58]), as well as revised International Scoring System (R-ISS) 3 (vs R-ISS 2; HR = 2.59, 95% CI [1.59-4.24]). In conclusion, based on the largest reported cohort of t(14;16) patients, quarter of this subset of MM patients initially presents with renal failure, while older age and the R-ISS 3 predict poor survival.
- MeSH
- doba přežití bez progrese choroby MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetný myelom genetika mortalita MeSH
- retrospektivní studie MeSH
- translokace genetická MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
