ABSTRACT
BACKGROUND: Haemato-oncology patients are likely to be referred later to palliative care than patients with solid tumours, despite experiencing similar symptom burden. Patients prior to stem cell transplant may benefit from symptom control, advance care planning and shared decision-making, and previous studies have demonstrated feasibility and benefit of such a service. However, the views of patients are not yet established, and are vital to ensure acceptability of the service. AIMS: To identify areas where a palliative care team may help to support patients being considered for a stem cell transplant, and to explore the attitudes and perceptions of patients towards palliative care at this time. DESIGN: A qualitative study including interviews (N = 12) and a focus group (N = 4) for patients pre- and post-transplant, using a semi-structured format via telephone, online video-conferencing and face-to-face discussions. Recordings were transcribed and analysed using thematic analysis. SETTING: A tertiary cancer centre in the UK. FINDINGS: Themes identified were the following: Identified needs, Information and decision-making, Importance of relationships, Changing perceptions of what palliative care means, and The future. Patients associate palliative care with terminal care due to indirect experiences. Patients were open to palliative care once its purpose was explained and described emotional and physical needs relevant to early palliative care. CONCLUSIONS: The involvement of early palliative care alongside haematology treatment prior to stem cell transplant may improve quality of life for patients and facilitate shared decision-making at a crucial stage of treatment. Early palliative care should be offered alongside haematology care around the time of stem cell transplant, with information provided to patients regarding its role.
Subject(s)
Hematopoietic Stem Cell Transplantation , Palliative Care , Attitude of Health Personnel , Humans , Qualitative Research , Quality of LifeABSTRACT
BACKGROUND: CH5126766 (also known as VS-6766, and previously named RO5126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations. METHODS: We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or metastatic solid tumours. For the basket dose-expansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4·0 mg or 3·2 mg CH5126766 three times per week; (2) 4·0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4·0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509. FINDINGS: Between June 5, 2013, and Jan 10, 2019, 58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2·3 months (IQR 1·6-3·5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4·0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3·2 mg CH5126766 three times per week. 4·0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%]), hypoalbuminaemia (six [11%]), and fatigue (four [7%]). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11·6-47·8]) of 26 response-evaluable patients in the basket expansion achieved objective responses. INTERPRETATION: To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation. FUNDING: Chugai Pharmaceutical.
Subject(s)
Coumarins/administration & dosage , Drug-Related Side Effects and Adverse Reactions/pathology , Multiple Myeloma/drug therapy , Protein Kinase Inhibitors/administration & dosage , Administration, Oral , Adult , Aged , Coumarins/adverse effects , Dose-Response Relationship, Drug , Drug-Related Side Effects and Adverse Reactions/classification , Female , Humans , MAP Kinase Signaling System/drug effects , Male , Middle Aged , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Protein Kinase Inhibitors/adverse effects , raf Kinases/genetics , ras Proteins/geneticsABSTRACT
BACKGROUND: Multiple myeloma (MM) remains incurable despite recent therapeutic advances. RAS mutations are frequently associated with relapsed/refractory disease. Efforts to target the mitogen-activated protein kinase (MAPK) pathway with the MEK inhibitor, trametinib (Tra) have been limited by toxicities and the development of resistance. Dexamethasone (Dex) is a corticosteroid commonly used in clinical practice, to enhance efficacy of anti-myeloma therapy. Therefore, we hypothesised that the combination of Tra and Dex would yield synergistic activity in RAS-mutant MM. METHODS: The response of human MM cell lines to drug treatment was analysed using cell proliferation assays, Western blotting, Annexin V and propidium iodide staining by flow cytometry and reverse phase protein arrays. The efficacy of trametinib and dexamethasone treatment in the MM.1S xenograft model was assessed by measuring tumor volume over time. RESULTS: The Tra/Dex combination demonstrated synergistic cytotoxicity in KRASG12A mutant lines MM.1S and RPMI-8226. The induction of apoptosis was associated with decreased MCL-1 expression and increased BIM expression. Reverse phase proteomic arrays revealed suppression of FAK, PYK2, FLT3, NDRG1 and 4EBP1 phosphorylation with the Tra/Dex combination. Notably, NDRG1 expression was associated with the synergistic response to Tra/Dex. MM cells were sensitive to PDK1 inhibition and IGF1-induced signalling partially protected from Tra/Dex treatment, highlighting the importance of this pathway. In the MM.1S tumor xenograft model, only the combination of Tra/Dex resulted in a significant inhibition of tumor growth. CONCLUSIONS: Overall Tra/Dex demonstrates antiproliferative activity in RAS-mutant MM cell lines associated with suppression of pro-survival PDK1 signalling and engagement of apoptotic pathways. Our data support further investigation of this combination in RAS-mutant MM.
Subject(s)
Antineoplastic Agents/therapeutic use , Dexamethasone/therapeutic use , Multiple Myeloma/drug therapy , Pyridones/therapeutic use , Pyrimidinones/therapeutic use , Apoptosis , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Drug Synergism , Drug Therapy, Combination , Gene Expression Regulation, Neoplastic , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , MAP Kinase Kinase Kinases/antagonists & inhibitors , Multiple Myeloma/genetics , Mutation/genetics , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , Receptors, Glucocorticoid/antagonists & inhibitors , Signal Transduction , ras Proteins/geneticsSubject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Multiple Myeloma/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bortezomib/administration & dosage , Bortezomib/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Female , Humans , Male , Middle Aged , Multiple Myeloma/pathology , Panobinostat/administration & dosage , Panobinostat/adverse effects , Retrospective StudiesABSTRACT
BACKGROUND: The introduction of central venous catheters has advanced medical care, particularly in hemato-oncology. However these can be associated with an increased thrombotic risk. Previous studies have compared the rate of thrombotic events between peripherally- inserted (PICCs) and long term skin tunneled catheters (LTSTCs) noting fewer complications associated with the latter, though this has rarely translated into clinical practice. The objectives of our study was to compare the cumulative incidence of thrombotic events between peripherally-inserted and long term skin tunneled venous catheters. PATIENTS/METHODS: We performed a retrospective, single center cohort analysis of patients with hematological malignancies who had either a PICC or LTSTC line inserted between January 2010 through January 2013. Cumulative incidences of thrombotic events were compared between the two groups, and post-thrombotic complications were also examined. RESULTS: 346 patients had a PICC inserted with cumulative incidence of symptomatic thrombosis of 5.8%, while 237 patients had a LTSTC inserted with a cumulative incidence of 1.7% (p = 0.003). Post-thrombotic complication rates, particularly infection, were higher in the PICC group compared to the LTSTC group (p = 0.597). CONCLUSIONS: Our study showed that the incidence of thrombotic events in hemato-oncology patients was significantly lower in those who had a LTSTC compared to PICC line. As the use of central venous lines increases in hemato-oncology patient care, a randomized trial comparing PICCs and LTSTCs is necessary to address which venous access is most appropriate in this cohort of patients, with minimal risk of morbidity and mortality.
ABSTRACT
Despite widespread use of Pegylated forms of Inteferon in the management of Myeloproliferative Neoplasms (MPN), most clinicians have experience predominantly with peginterferon alfa-2a (Pegasys). Third generation pegylated IFNα, ropeginterferon alfa-2b (ropegIFN; Besremi), was recommended by the European Medicine Authority (EMA) for treatment of Polycythaemia Vera (PV) following a Phase III trial (PROUD-PV / CONTINUATION-PV). FDA approval for PV, regardless of treatment history, was subsequently granted in November 2021. We hereby demonstrate the safety and tolerability of ropegIFN in a series of MPN patients at variable doses. It corroborates reports of efficacy of ropegIFN in patients with PV and use in pregnancy.
ABSTRACT
Advanced systemic mastocytosis (AdvSM) is a rare myeloid neoplasm associated with poor overall survival (OS). This study (NCT04695431) compared clinical outcomes between patients with AdvSM treated with avapritinib in the Phase 1 EXPLORER (NCT0256198) and Phase 2 PATHFINDER (NCT03580655) trials (N = 176) and patients treated with best available therapy (BAT; N = 141). A multi-center, observational, retrospective chart review study was conducted at six study sites (four European, two American) to collect data from patients with AdvSM who received BAT; these data were pooled with data from EXPLORER and PATHFINDER. Comparisons between outcomes of OS, duration of treatment (DOT), and maximum reduction in serum tryptase were conducted between the treatment cohorts, with adjustment for key covariates. The results indicated that the avapritinib cohort had significantly better survival (adjusted hazard ratio (HR) (95% confidence interval (CI)): 0.48 (0.29, 0.79); p = 0.004) and significantly longer DOT (HR: 0.36 (0.26, 0.51); p < 0.001) compared to the BAT cohort. Additionally, the mean difference in percentage maximum reduction in serum tryptase levels was 60.3% greater in the avapritinib cohort (95% CI: -72.8, -47.9; p < 0.001). With no randomized controlled trials comparing avapritinib to BAT, these data offer crucial insights into the improved efficacy of avapritinib for the treatment of AdvSM.
Subject(s)
Mastocytosis, Systemic , Humans , Mastocytosis, Systemic/drug therapy , Pyrazoles/therapeutic use , Pyrroles , Retrospective Studies , Triazines , Tryptases/therapeutic useSubject(s)
Intestinal Perforation/chemically induced , Multiple Myeloma/drug therapy , Thalidomide/adverse effects , Aged , Aged, 80 and over , Diverticulitis/diagnostic imaging , Diverticulitis/surgery , Female , Humans , Intestinal Perforation/diagnostic imaging , Intestinal Perforation/etiology , Male , Middle Aged , Multiple Myeloma/complications , Retrospective Studies , Thalidomide/administration & dosage , Tomography, X-Ray ComputedSubject(s)
Bile Acids and Salts/metabolism , Diarrhea/chemically induced , Malabsorption Syndromes/complications , Malabsorption Syndromes/drug therapy , Multiple Myeloma/drug therapy , Thalidomide/analogs & derivatives , Aged , Female , Humans , Lenalidomide , Male , Middle Aged , Thalidomide/adverse effectsABSTRACT
Supplemental Digital Content is available in the text.
ABSTRACT
OBJECTIVE: Current therapies for multiple myeloma, which include corticosteroids, increase risk of avascular necrosis. The aim of this study was to assess incidental detection of femoral head avascular necrosis on routine whole body MRI including diffusion weighted MRI. METHODS: All whole body MRI studies, performed on patients with known multiple myeloma between 1 January 2010 to 1 May 2017 were assessed for features of avascular necrosis. RESULTS: 650 whole body MR scans were analysed. 15 patients (6.6%) had typical MR features of avascular necrosis: 2/15 (13.3%) had femoral head collapse, 4/15 (26.7%) had bilateral avascular necrosis and 9/15 (60%) were asymptomatic. CONCLUSION: This is the first report of avascular necrosis detected on routine whole body MRI in patients with multiple myeloma. Targeted review of femoral heads in multiple myeloma patients undergoing whole body MR is recommended, including in patients without symptoms. ADVANCES IN KNOWLEDGE: Whole body MR which includes diffusion-weighted MRI is extremely sensitive for evaluation of bone marrow. Although whole body MRI is primarily used for evaluation of multiple myeloma disease burden, it also presents an unique opportunity to evaluate the femoral heads for signs of avascular necrosis which can predate symptoms.
Subject(s)
Diffusion Magnetic Resonance Imaging , Femur Head Necrosis/diagnostic imaging , Multiple Myeloma/diagnostic imaging , Whole Body Imaging , Adrenal Cortex Hormones/adverse effects , Adult , Aged , Antineoplastic Agents/adverse effects , Early Diagnosis , Female , Femur Head Necrosis/chemically induced , Humans , Incidental Findings , Male , Middle Aged , Multiple Myeloma/drug therapy , Retrospective Studies , Risk FactorsABSTRACT
Marginal zone lymphomas (MZLs) account for between 5% and 17% of all non-Hodgkin's lymphomas. MZLs consist of 3 different subtypes with extranodal being the most commonly reported, representing 50-70% of MZL, followed by splenic (20%) and nodal (10%). Median age at presentation varies between these lymphoma sub-types, ranging between 50 and 69 years, with an overall greater incidence noted in males compared to females. Given the rarity of these lymphomas, epidemiologic data has been sparse, although it has been suggested the aetiology is multi-factorial including ethnicity and geographical factors. Other reported associations include autoimmune disease and infection, with Helicobacter pylori and Campylobacter psittaci, being the most commonly reported pathogens. Larger population studies are required to investigate the role of these environmental factors further as these can direct the future management of these lymphomas, through the use of more effective targeted treatments.
Subject(s)
Environmental Exposure/adverse effects , Lymphoma, B-Cell, Marginal Zone , Age of Onset , Aged , Helicobacter Infections/epidemiology , Helicobacter Infections/immunology , Helicobacter pylori/immunology , Humans , Lymphoma, B-Cell, Marginal Zone/epidemiology , Lymphoma, B-Cell, Marginal Zone/immunology , Lymphoma, B-Cell, Marginal Zone/microbiology , Middle AgedABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is a high-grade, aggressive disease that typically presents with widespread lymphadenopathy and active 'B' symptoms, making it easy to recognise and manage. However, a small proportion of patients can present with no evidence of lymphadenopathy or organomegaly, with the disease confined to the bone marrow; this presentation is also known as 'Primary Bone Marrow DLBCL'. Subsequently, diagnosis can be a challenge, resulting in delayed treatment and an overall poorer prognosis. Given the rarity of this disease, we wished to describe a patient who presented initially with fevers associated with isolated thrombocytopenia and was later diagnosed with this condition. Unfortunately, due to the aggressive nature of this disease, subsequent treatment was unsuccessful. Overall, we felt that in future cases of fevers with thrombocytopenia, clinicians should include this rare lymphoma subtype as part of the differential diagnosis, as early identification and treatment can be associated with a favourable outcome.