Summary Background Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in ...this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m2 ; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov , number NCT01568866. Findings Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3–16·1) in the carfilzomib group and 11·1 months (8·2–14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6–not estimable) in the carfilzomib group versus 9·4 months (8·4–10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio HR 0·53 95% CI 0·44–0·65; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 14% of 463 patients in the carfilzomib group vs 45 10% of 456 patients in the bortezomib group), hypertension (41 9% vs 12 3%), thrombocytopenia (39 8% vs 43 9%), and pneumonia (32 7% vs 36 8%). Interpretation For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. Funding Onyx Pharmaceuticals, Inc., an Amgen subsidiary.
Summary
We have vaccinated 392 patients with two doses of mRNA COMIRNATY vaccine with an overall antibody response of 70% (best in cMPN, worst in CLL). We have then vaccinated 80 patients who did not ...achieve seroconversion or were low responders with a third dose of COMIRNATY vaccine. Our first results show promise, especially for patients on anti‐CD38 therapy.
Optimization of HILIC separation of (lyso)phosphatidylserines, (lyso)phosphatidic acids and other lipids.Acidobasic properties of lipids are correlated with their retention behavior.9HILIC columns ...with different chemistries are compared for the separation of lipid classes.PS, LPS, PA and LPA provide good peak shapes on hydride column at pH 4.Final method is applied for porcine brain and kidney extracts.
The goal of this work is a systematic optimization of hydrophilic interaction liquid chromatography (HILIC) separation of acidic lipid classes (namely phosphatidic acids⿿PA, lysophosphatidic acids⿿LPA, phosphatidylserines⿿PS and lysophosphatidylserines⿿LPS) and other lipid classes under mass spectrometry (MS) compatible conditions. The main parameters included in this optimization are the type of stationary phases used in HILIC, pH of the mobile phase, the type and concentration of mobile phase additives. Nine HILIC columns with different chemistries (unmodified silica, modified silica using diol, 2-picolylamine, diethylamine and 1-aminoanthracene and hydride silica) are compared with the emphasis on peak shapes of acidic lipid classes. The optimization of pH is correlated with the theoretical calculation of acidobasic equilibria of studied lipid classes. The final method using the hydride column, pH 4 adjusted by formic acid and the gradient of acetonitrile and 40mmol/L of aqueous ammonium formate provides good peak shapes for all analyzed lipid classes including acidic lipids. This method is applied for the identification of lipids in real samples of porcine brain and kidney extracts.
Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating ...agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex).
This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016.
A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79%
52%;
= .002). Higher rates of very good partial or complete response rates (64%
39%; hazard ratio HR, 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed.
BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.
The hydrophilic interaction liquid chromatography (HILIC) coupled to a negative-ion electrospray ionization tandem mass spectrometry (ESI-MS/MS) method has been developed for the identification of a ...wide range of gangliosides in biological samples. Gangliosides consist of a backbone of sphingoid base and a polar oligosaccharide chain containing at least one sialic acid. Gangliosides are extracted by chloroform–methanol–water mixture, where an upper aqueous layer containing gangliosides and other polar lipid subclasses is further purified by C18 solid-phase extraction. The optimization of chromatographic conditions includes the column selection, mobile-phase composition, pH value, buffer type, and concentration with the goal to achieve the best chromatographic resolution and MS sensitivity. The identification of gangliosides and other polar lipids is based on accurate m/z values of M–H− ions and fragment ions as well measured by high-resolution MS. The detailed interpretation of MS/MS spectra enables the generalization of fragmentation pathways, which is then used for the differentiation of a, b, and c series of gangliosides. The structural assignment is further confirmed by agreement with the predicted retention behavior in HILIC mode on the basis of the correlation among the ganglioside retention, the number of saccharide units, and their sequence. The final HILIC/ESI-MS/MS method is applied for the analysis of porcine brain, human kidney, lungs, plasma, and erythrocytes resulting in unambiguous identification of 145 ganglioside species from 19 subclasses, which represents the highest number of reported gangliosides. Moreover, 71 sulfatides and 59 polar phospholipids (phosphatidylserines, phosphatidylinositols, lysophosphatidylinositols, and phosphatidylglycerols) are detected within a 15 min run.
In more than 400 older patients with AML who could not receive myeloablative therapy, the incidence of composite complete remission was higher (66.4% vs. 28.3) and the median overall survival was ...longer (14.7 vs. 9.6 months) among patients who received azacitidine plus venetoclax (a B-cell lymphoma 2 antagonist) than among those who received azacitidine alone.
The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). ...The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391.
•KRd has a favorable benefit-risk profile compared with Rd, regardless of baseline cytogenetic risk status, in patients with relapsed MM.•KRd improves but does not abrogate the poor prognosis associated with high-risk cytogenetics in patients with relapsed MM.
The article examines the effectiveness of remote monitoring and the evaluation of facts about patients with hematologic malignancies using telemedicine based on SMART technologies. The project was ...carried out in the Department of Haematooncology of the University Hospital Ostrava. Its objective was to test the efficacy of telemedicine in the treatment of patients with blood cancer. The cost-benefit analysis method was used to evaluate effectiveness, which also confirmed the feasibility of using this method to evaluate the costs and benefits of implementing specific medical projects. The conducted analysis demonstrated the effectiveness of using telemedicine procedures in the treatment of these patients, both in terms of quantifiable and non-quantifiable impacts on the Czech Republic's health system. This was mainly due to a large shortening of the length of the hospitalisation period for patients with problems whose deterioration was discovered by remote monitoring and their treatment could begin promptly. The shortening of the hospitalization period was achieved by around 40%. As a result, the complexity of treatment has been greatly reduced, benefiting both the hospital and, most importantly, the patient. With this prevention, the patient's chances of dying are reduced, as he or she is less likely to develop severe septic diseases. The total average financial savings of the Czech Republic's entire health care system for a patient who does not become septic due to a delayed response to deteriorating health only in hospitalisation, treatment, and medications is approximately USD 2,800.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Over the last few years, treatment principles have been changed towards more targeted therapy for many B-cell lymphoma subtypes and in chronic lymphocytic leukemia (CLL). Immunotherapeutic ...modalities, namely monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cell therapy, commonly use B-cell-associated antigens (CD19, CD20, CD22, and CD79b) as one of their targets. T-cell engagers (TCEs), a subclass of bsAbs, work on a similar mechanism as CAR-T cell therapy without the need of previous T-cell manipulation. Currently, several anti-CD20xCD3 TCEs have demonstrated promising efficacy across different lymphoma subtypes with slightly better outcomes in the indolent subset. Anti-CD19xCD3 TCEs are being developed as well but only blinatumomab has been evaluated in clinical trials yet. The results are not so impressive as those with anti-CD19 CAR-T cell therapy. Antibody-drug conjugates targeting different B-cell antigens (CD30, CD79b, CD19) seem to be effective in combination with mAbs, standard chemoimmunotherapy, or immune checkpoint inhibitors. Further investigation will show whether immunotherapy alone or in combinatory regimens has potential to replace chemotherapeutic agents from the first line treatment.
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