Multiple myeloma (MM) patients risk diagnostic delays and irreversible organ damage. In those with newly diagnosed myeloma, we explored the presenting symptoms to identify early signals of MM and ...their relationships to organ damage. The symptoms were recorded in patients' own words at diagnosis and included diagnostic time intervals. Those seen by a haematologist >6 months prior to MM diagnosis were classified as precursor disease (PD). Most (962/977) patients provided data. Back pain (38%), other pain (31%) and systemic symptoms (28%) predominated. Patients rarely complain of 'bone pain', simply 'pain'. Vertebral fractures are under-recognised as pathological and are the predominant irreversible organ damage (27% of patients), impacting the performance status (PS) and associated with back pain (odds ratio (OR) 6.14 CI 4.47-8.44), bone disease (OR 3.71 CI 1.88-7.32) and age >65 years (OR 1.58 CI 1.15-2.17). Renal failure is less frequent and associated with gastrointestinal symptoms (OR 2.23 CI1.28-3.91), age >65 years (OR 2.14 CI1.28-3.91) and absence of back pain (OR 0.44 CI 0.29-0.67). Patients with known PD (
= 149) had fewer vertebral fractures (
= 0.001), fewer adverse features (
= 0.001), less decline in PS (
= 0.001) and a lower stage (
= 0.04) than 813 with de novo MM. Our data suggest subgroups suitable for trials of 'symptom-directed' screening: those with back pain, unexplained pain, a general decline in health or low-impact vertebral compression fractures.
The COVID-19 pandemic has resulted in the rapid development of a range of vaccines against SARS-CoV-2. Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare but life-threatening ...complication of primarily adenoviral-based vaccines associated with the presence of antibodies to a PF4/polyanion neoepitope and measured by using enzyme-linked immunosorbent assays. Presented are serial anti–PF4/polyanion antibody, platelet, and D-dimer measurements in a large cohort of patients and their relation to relapse. Overall, 51% of patients using the Stago assay had persistently positive anti–PF4/polyanion levels 100 days' postdiagnosis, whereas 94% of patients monitored by using the Immucor assay remain positive. The median duration of positivity of the PF4 assay is 87 days, with 72% of patients remaining positive after a median follow-up of 105 days. The use of plasma exchange seemed to reduce anti–PF4/polyanion levels and increase platelet counts in the acute setting more rapidly than other therapies. The rate of relapse in this study was 12.6%, with all relapsed cases exhibiting persistently positive PF4 antibodies and falling platelet counts. Only one patient had extension of their thrombosis. Overall, despite the persistence of PF4 antibodies in 72% of patients, the rate of relapse was low and did not seem to result in recrudescence of the aggressive clinical picture seen at index presentation. Monitoring of these patients in the UK cohort is ongoing and will aid in definition of the natural history of this novel condition.
•72% of patients remain positive for PF4 antibodies at 100 days; differences exist in antibody persistence dependent on assay used.•Relapse rate is 12.6%, predominantly taking the form of recurrent thrombocytopenia, and all occurred within 90 days of presentation.
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Introduction: Carfilzomib (20/36mg/m2) triplets with Lenalidomide-Dexamethasone (KRd), or Cyclophosphamide-Dexamethasone (KCd) are safe and effective in patients with newly diagnosed multiple ...myeloma(NDMM). The higher dose of 56mg/m2 is effective as a doublet with Dexamethasone in the relapsed setting, but there is limited data on this dose in triplet combinations in the frontline setting.
Aim: The CARDAMON study evaluated KCd with bi-weekly carfilzomib (56mg/m2) as induction in NDMM patients, and the benefit of ASCT versus K56Cd consolidation followed by carfilzomib maintenance. Co-primary endpoints were major response (≥VGPR rate) to 4 induction cycles of K56Cd, and 2-year PFS for ASCT versus K56Cd consolidation. Here we report interim analysis of the first primary endpoint of ≥VGPR rate to K56Cd induction.
Methods: Transplant eligible ND patients received 4 x 28d cycles of K56Cd (carfilzomib:20/56mg/m2, IV d1, 2, 8, 9, 15, 16, cyclophosphamide 500mg orally d1, 8, 15 and dexamethasone 20mg d1, 2, 8, 9, 15, 16). Responding patients with a successful stem cell harvest (PBSCH) were randomised to autologous stem cell transplant (ASCT) or 4 more cycles of K56Cd as consolidation, followed by 18 months carfilzomib maintenance (K56 days 1, 8, 15) for both arms. Trial recruitment completed in July 2019. Response was assessed by IMWG criteria; all patients had MRD testing by multi-parameter flow cytometry (10-5) after PBSCH. Adverse risk genetics was any one of t(4;14), t(14;16), t(14,20) or del(17p).
Results: 281 pts were registered between 06/2015 and 07/2019; we report outcomes for 252 patients who either completed induction or came off study before end of induction. Median age was 58yrs(33-74), 91% ECOG 0-1, 45.2% ISS I, 24.7% adverse risk (48.5% when including 1p/1q+). Best response at end of induction or after PBSCH (n=250) was: ≥VGPR 59.2%, ORR 87.6%. ≥VGPR rate in adverse risk patients was 53.4% vs 61.9% in standard risk(SR), (p=0.25), ORR was similar: adverse risk, 87.9% vs standard risk, 88.1%. Post-PBSCH, 24.1% of patients were MRD-negative (patients who were withdrawn due to insufficient induction response or toxicity and those with an inconclusive result were grouped with the MRD-positive). Of 19 patients in sCR/CR, 9 were MRD-negative(47.4%) while 40/110 (36.4%) of VGPR patients were MRD-negative. MRD-negative rates in adverse and standard risk patients were 22.8% and 24.7% respectively. 10 patients progressed during or at end of induction, and 12 were withdrawn for toxicity.
There were 4 deaths during induction, one from myocardial infarction, the other 3 from cardiac arrest, associated with bronchopneumonia and sepsis. During induction, 114 serious adverse events (SAEs) were reported in 72/252 patients, notable ones were thrombotic microangiopathy (2), grade 3 cardiac ischaemia (4), infection (16.3%, mainly lung), renal impairment (6), G3 hypertension (3), thromboembolism(2). Specific guidance for hypertension management was incorporated. 25% of patients are currently reported to have received a dose modification during induction. Full details of adverse events and dose intensity will be presented at the meeting.
Conclusion: K56Cd is an effective induction regimen in NDMM patients, and has equivalent MRD negative rates in adverse and standard risk disease. The SAE profile is in keeping with published safety data with carfilzomib.
Yong:Sanofi: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Autolus: Consultancy; Janssen: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Popat:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria; Takeda: Honoraria, Other: travel, accommodations, expenses. Ramasamy:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NAPP Pharmaceuticals Ltd.: Research Funding; Janssen-Cilag Ltd.: Research Funding; Oncopeptides and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chapman:Takeda: Honoraria. Benjamin:Allogene: Research Funding; Gilead: Honoraria; Novartis: Honoraria; Pfizer: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Servier: Research Funding; Eusapharm: Consultancy. Owen:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel/ meeting support.
Carfilzomib is used with cyclophosphamide as 1st line treatment for myeloma
PURPOSE:To evaluate the computed tomographic (CT) predictors of a clinically significant yield from microbiological tests in patients with a tree-in-bud pattern.
MATERIALS AND METHODS:CT examinations ...in 53 patients (male=34; mean age=52.9±17.3 y) with a tree-in-bud pattern in whom a diagnostic test (sputum analysis, bronchoalveolar lavage or nasopharyngeal aspirates) had been performed within 2 weeks were identified. The following CT patterns were independently quantified by 2 thoracic radiologiststree-in-bud, bronchiectasis, bronchial wall thickening, consolidation, ground-glass opacification, and nodules. The presence of cavitation (in nodules and/or consolidation) was recorded. Patient charts were reviewed for the presence of a clinically significant positive microbiological result.
RESULTS:A clinically significant causal organism was present in 25/53 (47%) patients. The median extent of a tree-in-bud pattern was 5 range=1 to 16 (maximum range=0 to 18), and cavitation was present in 14/53 (26%) patients (cavitating nodules=8, cavitation in consolidation=3, and cavitation in consolidation and nodules=3). There was no independent linkage between the extent of a tree-in-bud pattern and the identification of a clinically significant organism. The microbiological yield was significantly higher if there was coexistent cavitation in nodules or consolidation 11/14 (79%) vs. 14/39 (39%); P=0.005. On stepwise logistic regression, the only CT predictor of a clinically significant microbiological yield was cavitation on CT (odds ratio=9.7; 95% confidence interval=1.9, 49.9; P<0.01); the extent of a tree-in-bud pattern, concurrent use of antibiotics, age, and sex were not independently linked to a significant microbiological yield.
CONCLUSIONS:A specific clinically significant microbiological diagnosis was obtained in approximately 50% of patients with a tree-in-bud pattern. The microbiological yield rises strikingly when a tree-in-bud pattern coexists with cavitation (in nodules or consolidation) but is not predicted by ancillary CT signs or clinical parameters.
Abstract 3241
Leukemia cells are believed to arise from leukemia stem cells (LSC). It is also known that LSC are responsible for relapse in certain types of leukemia, such as acute myeloid leukemia ...(AML). However, the existence and role of LSC in acute lymphoblastic leukemia (ALL) is unclear. CD9 was reported to be a marker for LSC in B-ALL using cell lines (Nishida H. et al., 2009). CD9 is a tetraspanin and is believed to be involved in cell adhesion, motility, and signaling events. It is also involved in metastasis; however, the mechanisms are unknown. Since childhood ALL is a heterogeneous group of diseases and cell lines can be different from primary leukemia cells, we tested the role of CD9 as a candidate LSC marker using primary precursor B (preB) ALL cells from pediatric patients. Two methods, Raman spectroscopy and serial transplantation of sorted leukemia cells in NOD/SCID/IL2R g null (NSG) mice, were used to confirm LSC. Raman spectroscopy is a laser-based technique for the single cell analysis of intrinsic molecular vibrations reflecting cellular biochemical information. It can provide a quantitative assessment of the levels of DNA, RNA, proteins, lipids, and carbohydrates in the cell, as well as molecular-level conformational changes. Previous studies by our group showed that unique Raman fingerprints were identified in normal blood cells, ALL cells, and stem cells, including hematopoietic stem cells and embryonic stem cells. Four preB ALL samples were stained for CD9 and sorted by flow cytometry. ALL samples were obtained from patients at diagnosis or freshly harvested from NSG mice engrafted with primary leukemia samples. All samples showed heterogeneous expression of CD9. CD9 high-positive cells and negative cells were flow sorted. Raman spectra of freshly sorted CD9 high-positive and negative cells were obtained. 10 to 20 cells were analyzed in each sample. CD34 positive cells, which were isolated from normal donors, were also analyzed by Raman spectroscopy as a control. No unique Raman fingerprints were identified to separate CD9 high-positive cells from negative cells using Principal Component Analysis (PCA). Furthermore, CD9 high-positive and negative cells from three preB ALL samples were transplanted into NSG mice via intra-bone marrow injection. Equal cell numbers (5×105 to 1.5×106 cells) were used for positive and negative samples in each injection. The majority of the mice from both groups (transplanted with CD9 high-positive or negative cells) developed leukemia 3 to 4 months after injection. Leukemia phenotype was confirmed to be the same as the original leukemia. In conclusion, although CD9 was shown to be a marker for LSC in B-ALL cell lines, it does not appear to be an LSC marker in primary preB ALL. Since childhood preB ALL is a heterogeneous group of diseases, larger cohorts are necessary to confirm our findings. Raman spectroscopy may be a useful screening tool for analysis of cellular intrinsic markers.
No relevant conflicts of interest to declare.
Abstract 3269
The one-bead-one-compound (OBOC) combinatorial library method was invented by Kit Lam to identify cancer cell surface targeting ligands (Peng L et al. Nat. Chem. Biol. 2006, Aina OH et ...al., Mol. Pharm. 2007). Using this method, LLP2A, a ligand against activated a4b1 integrin, was discovered that targets malignant lymphoma with high affinity and specificity (Peng L et al., Mol Cancer Ther. 2008). We tested whether childhood acute lymphoblastic leukemia (ALL) cells expressed activated a4b1 integrin and bound to LLP2A using primary leukemia cells and leukemia cells engrafted in NOD/SCID/IL2Rg null (NSG) mice. Expression of activated a4b1 integrin was observed in three primary leukemia samples (1 T-ALL, 1 precursor B (preB) ALL, and 1 relapsed preB ALL) by the rainbow beads (color-coded polystyrene bead mixture displaying unique ligands against known receptors such as a4b1, a3b1, avb3, a5b1 integrins (Luo J et al., J. Comb. Chem. 2008). To quantify activated a4b1 integrin expression, primary leukemia cells were analyzed by flow cytometry using biotinylated LLP2A/streptavidin-PE. Nine samples (7 preB ALL and 2 relapsed preB ALL) were analyzed. All samples, except for one relapsed preB ALL sample, showed expression of activated a4b1 integrin at different levels. In order to determine the specificity of activated a4b1 integrin expression, hematopoietic stem cells from three normal bone marrow (BM) samples were analyzed and showed very low levels of activated a4b1 integrin expression. Furthermore, we have identified 32 analogues of LLP2A using three fresh preB ALL samples to screen two LLP2A-focused libraries. Peptide microarrays using a polystyrene slide coated with neutravidin and biotinylated ligands will be prepared with these analogues. We will determine the binding affinity and specificity of these analogues to a series of primary ALL cells. Binding specificity to leukemia cells will be determined by excluding ligands which bind to normal hematopoietic progenitor (CD34) cells. The property of the selected ligands will be tested in vivo using NSG mice engrafted with primary ALL cells. Updated results with these new ligands will be presented at the meeting.
No relevant conflicts of interest to declare.
The deal to sell Northumbrian Water to Cheung Kong Infrastructure (CKI), combined with the softened stance of the water industry's watchdog, Ofwat, towards mergers and acquisitions, suggests a period ...of consolidation in Britain's fragmented water industry. There is strong support in the industry for the number of companies to come down from the present 21 to around 10, although there is some doubt about whether sufficient infrastructure funds will come back to the industry after the credit crunch.
Interviews Steve Ridgway, who joined the Virgin Atlantic airline company in 1989 after becoming close friends with Richard Branson during the attempt of the "Virgin Atlantic Challenger" to break the ...Atlantic crossing record. He is now the chief executive and is attempting to keep the company going despite the industrial turbulence caused by its pilots over pay rises.
Interviews David Price, the chief executive of Chemring. Despite the government's cuts in defence, this defence group, which makes explosives, munitions, flares and countermeasures, is maintaining a ...growth rate which is in double figures.
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