Population-based registries may provide data complementary to that from basic science and clinical intervention studies, all of which are essential for establishing recommendations for the management ...of patients in the real world. The same quality criteria apply for the evidence-based label, and both high representation and good data quality are crucial in registry studies. Registries with high coverage of the target population reduce the impact of selection on outcome and the subsequent problem with extrapolating data to nonstudied populations. Thus, data useful for clinical decision in situations not well covered by clinical studies can be provided. The potential clinical impact of data from population-based studies is exemplified with analyses from the Swedish Acute Leukemia Registry containing more than 3300 acute myeloid leukemia (AML) patients diagnosed between 1997 and 2006 with a median follow-up of 6.2 years on (1) the role of intensive combination chemotherapy for older patients with AML, (2) the impact of allogeneic stem cell transplantation on survival of younger patients with AML, and (3) the continuing problem with early deaths in acute promyelocytic leukemia. We also present the first Web-based dynamic graph showing the complex interaction between age, performance status, the proportion of patients given intensive treatment, early death rate, complete remission rate, use of allogeneic transplants, and overall survival in AML (non-AML).
Acute myeloid leukemia (AML) is most common in the elderly, and most elderly are thought to be unfit for intensive treatment because of the risk of fatal toxicity. The Swedish Acute Leukemia Registry ...covers 98% of all patients with AML (nonacute promyelocytic leukemia) diagnosed in 1997 to 2005 (n = 2767), with a median follow-up of 5 years, and reports eligibility for intensive therapy, performance status (PS), complete remission rates, and survival. Outcomes were strongly age and PS dependent. Early death rates were always lower with intensive therapy than with palliation only. Long-term survivors were found among elderly given intensive treatment despite poor initial PS. Total survival of elderly AML patients was better in the geographic regions where most of them were given standard intensive therapy. This analysis provides unique real world data from a large, complete, and unselected AML population, both treated and untreated, and gives background to treatment decisions for the elderly. Standard intensive treatment improves early death rates and long-term survival compared with palliation. Most AML patients up to 80 years of age should be considered fit for intensive therapy, and new therapies must be compared with standard induction.
Epidemiology and outcome of myeloma are mainly reported from large university centers and collaborative groups, and do not represent 'real-world' patients. The Swedish Myeloma Registry is a ...prospective population-based registry documenting characteristics, treatment and outcome in newly diagnosed myeloma, including asymptomatic and localized forms, with the purpose of improving disease management and outcome. This report presents information on patients diagnosed between 2008 and 2015, including data on first-line treatment in patients diagnosed up to 2014, with a follow up until December 2016. We present age-adjusted incidence, patients' characteristics at baseline, treatment, response, and survival. Baseline data were available with a 97% coverage in 4904 patients (median age 71 years, males 70 years, females 73 years; 72% were 65 years or older), and at 1-year follow up in 3558 patients with symptomatic disease (92% of patients initially reported). The age-adjusted incidence was 6.8 myeloma cases per 100,000 inhabitants per year. Among initially symptomatic patients (n=3988), 77% had osteolytic lesions or compression fractures, 49% had anemia, 18% impaired kidney function, and 13% hypercalcemia. High-dose therapy with autologous stem cell transplantation was given to 77% of patients aged up to 66 years, and to 22% of patients aged 66-70 years. In the study period, 68% received bortezomib, thalidomide, and/or lenalidomide as part of the first-line treatment, rising from 31% in 2008 to 81% in 2014. In active myeloma, the median relative survival of patients aged 65 years or under was 7.7 years, and 3.4 years in patients aged 66 years and over. Patients diagnosed with myeloma in more recent years were associated with significantly higher rates of complete or very good partial remission (
<0.05), and with a significantly higher survival, with a Hazard Ratio (HR) of 0.84 (95%CI: 0.77-0.92;
<0.05). There was a small, but significant survival benefit in patients treated at university hospitals (HR 0.93; 95%CI: 0.87-0.99;
<0.05). We report here on a near complete 'real-world' population of myeloma patients during an 8-year period; a period in which newer drugs were implemented into standard practice. The overall incidence and median age were both higher than in most previous studies, indicating a more complete coverage of older patients. Myeloma survival in Sweden is comparable to other large registry studies, and responses and survival improved during the study period.
APR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose ...(MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246.
APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg.
MTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response.
We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.
Clonal heterogeneity and evolution has major implications for disease progression and relapse in acute myeloid leukemia (AML). To model clonal dynamics in vivo, we serially transplanted 23 AML cases ...to immunodeficient mice and followed clonal composition for up to 15 months by whole-exome sequencing of 84 xenografts across two generations. We demonstrate vast changes in clonality that both progress and reverse over time, and define five patterns of clonal dynamics: Monoclonal, Stable, Loss, Expansion and Burst. We also show that subclonal expansion in vivo correlates with a more adverse prognosis. Furthermore, clonal expansion enabled detection of very rare clones with AML driver mutations that were undetectable by sequencing at diagnosis, demonstrating that the vast majority of AML cases harbor multiple clones already at diagnosis. Finally, the rise and fall of related clones enabled deconstruction of the complex evolutionary hierarchies of the clones that compete to shape AML over time.
Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually ...relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.
•Whole-exome sequencing of CLL patients who relapsed after FCR treatment revealed frequent mutations in RPS15.•RPS15 mutations are likely to be early clonal events and confer poor prognosis.
In multiple myeloma (MM), advancements in treatments and toxicity management have enhanced survival rates. This, coupled with shifting age demographics in MM, necessitates an updated understanding of ...infection risks in MM patients compared to the general population. Using Swedish population-based registries, we investigated the incidence of infections in 8,672 Swedish symptomatic MM patients diagnosed 2008-2021 and 34,561 matched controls. Overall, MM patients had a 5-fold risk (hazard ratio (HR) = 5.30; 95%, Confidence Interval = CI 5.14-5.47) of developing any clinically significant infection compared to matched controls. Bacterial infections represented a 5-fold (HR 4.88; CI 4.70-5.07) increased risk, viral and fungal infections 7-fold compared to controls. The 1st year after MM diagnosis the risk of infections compared to controls was 7 –fold (HR 6.95; CI 6.61-7.30) and remained elevated up to 5 years after the myeloma diagnosis. The risk of infection compared to controls remained 5-fold in MM patients with follow-up till 2022. Preceding MM diagnosis, the risk compared to matched controls was significantly increased up to four years before MM diagnosis (HR1.16; CI 1.05-1.28). Among MM patients, 8% had died within 2 months of diagnosis and infection contributed to 32% of all deaths. After 1 year, 20% MM patients had died, and infection-related mortality was 27%. Our data constitute the largest population-based study to date on the risk of infections compared to the normal population in the era of modern MM therapies and confirms that infections still represent a major threat to patients and underscores importance of preventive strategies.
Radiology plays a key role in the diagnosis of bronchiectasis, defined as permanent dilatation of the bronchial lumen. Volumetric thin-section multidetector computed tomography is an excellent ...noninvasive modality to evaluate bronchiectasis. Bronchiectasis is categorised by morphological appearance. Cylindrical bronchiectasis has a smooth tubular configuration and is the most common form. Varicose bronchiectasis has irregular contours with alternating dilating and contracting lumen. Cystic bronchiectasis is the most severe form and exhibits saccular dilatation of bronchi. Bronchial dilatation is the hallmark of bronchiectasis and is evaluated in relation to the accompanying pulmonary artery. A broncho-arterial ratio exceeding 1:1 should be considered abnormal. Normal bronchi are narrower in diameter the further they are from the lung hila. Lack of normal bronchial tapering over 2 cm in length, distal from an airway bifurcation, is the most sensitive sign of bronchiectasis. Findings commonly associated with bronchiectasis include bronchial wall thickening, mucus plugging and tree-in-bud opacities. Bronchiectasis results from a myriad of conditions, with post-infectious bronchiectasis being the most common. Imaging can sometimes discern the cause of bronchiectasis. However, in most cases it is nonspecific or only suggestive of aetiology. While morphological types are nonspecific, the distribution of abnormality offers clues to aetiology.
Bronchiectasis is a chronic progressive condition with significant disease burden and frequent exacerbations, for which the diagnosis relies on cross-sectional imaging.The major imaging findings include bronchial dilatation, bronchial contour abnormalities and visualisation of the normally invisible peripheral airways.Bronchiectasis is the end result of various conditions, including immunodeficiencies, mucociliary disorders and infections. Imaging is often nonspecific with regard to aetiology but can be suggestive.Distribution of abnormality in the lung offers helpful clues for establishing aetiology.
To review the cross-sectional imaging appearance of bronchiectasis and the common associated findings.To get a sense of how radiology can aid in establishing the aetiology of bronchiectasis.
PDF
