RESUMO
In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE).
Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Neoplasia Residual/diagnóstico , Intervalo Livre de Progressão , Resultado do TratamentoRESUMO
We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10-5 sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172.
Assuntos
Mieloma Múltiplo/diagnóstico , Neoplasia Residual/diagnóstico , Idoso , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Humanos , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , Prognóstico , Intervalo Livre de Progressão , Resultado do TratamentoRESUMO
Natural killer/T cell lymphoma (NKTCL) is a highly aggressive, heterogeneous non-Hodgkin lymphoma resulting from malignant proliferation of cytotoxic natural killer (NK) or T cells. Previous studies demonstrated variable expression of CD38 on NKTCL tumors. Daratumumab, a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, was hypothesized to be a novel therapeutic option for patients with relapsed or refractory (R/R) NKTCL. In the phase 2 NKT2001 study (ClinicalTrials.gov Identifier: NCT02927925) assessing the safety and efficacy of daratumumab, a suboptimal overall response rate was seen in R/R NKTCL patients. One patient, whose tumors did not express CD38, responded to treatment, suggesting that the immunomodulatory activities of daratumumab may be sufficient to confer clinical benefit. To understand the suboptimal response rate and short duration of response, we investigated the immune profile of NKTCL patients from NKT2001 in the context of daratumumab anti-tumor activity. Tumor tissue and whole blood were, respectively, analyzed for CD38 expression and patient immune landscapes, which were assessed via cytometry by time-of-flight (CyTOF), multiparameter flow cytometry (MPFC), clonal sequencing, and plasma Epstein-Barr virus (EBV)-DNA level measurements. Changes observed in the immune profiles of NKTCL patients from NKT2001, including differences in B and T cell populations between responders and nonresponders, suggest that modulation of the immune environment is crucial for daratumumab anti-tumor activities in NKTCL. In conclusion, these findings highlight that the clinical benefit of daratumumab in NKTCL may be enriched by B/T cell-related biomarkers.
Assuntos
Anticorpos Monoclonais , Linfoma Extranodal de Células T-NK , Humanos , Anticorpos Monoclonais/uso terapêutico , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/imunologia , Masculino , Feminino , ADP-Ribosil Ciclase 1 , Pessoa de Meia-Idade , Idoso , Adulto , Glicoproteínas de MembranaRESUMO
BACKGROUND: CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only. METHODS: CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18-65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0-2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants. FINDINGS: Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2-39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]-NE) with daratumumab versus 46·7 months (40·0-NE) with observation only (hazard ratio 0·53, 95% CI 0·42-0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment. INTERPRETATION: Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy. FUNDING: Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/terapia , Transplante de Células-Tronco , Talidomida/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Dexametasona/efeitos adversos , Esquema de Medicação , Europa (Continente) , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Intervalo Livre de Progressão , Transplante de Células-Tronco/efeitos adversos , Talidomida/efeitos adversos , Fatores de Tempo , Transplante Autólogo , Adulto JovemRESUMO
BACKGROUND: Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. METHODS: ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. FINDINGS: 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4-43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46-0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2-82·0) in the D-VMP group and 67·9% (62·6-72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34-0·51]; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [15%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28 [10%]). INTERPRETATION: D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns. FUNDING: Janssen Research & Development.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Bortezomib/administração & dosagem , Melfalan/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Prednisona/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Ásia , Bortezomib/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Europa (Continente) , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , América do Norte , Prednisona/efeitos adversos , América do Sul , Análise de Sobrevida , Resultado do TratamentoRESUMO
Patient-derived xenotransplantation models of human myeloid diseases including acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms are essential for studying the biology of the diseases in pre-clinical studies. However, few studies have used these models for comparative purposes. Previous work has shown that acute myeloid leukemia blasts respond to human hematopoietic cytokines whereas myelodysplastic syndrome cells do not. We compared the engraftment of acute myeloid leukemia cells and myelodysplastic syndrome cells in NSG mice to that in NSG-S mice, which have transgene expression of human cytokines. We observed that only 50% of all primary acute myeloid leukemia samples (n=77) transplanted in NSG mice provided useful levels of engraftment (>0.5% human blasts in bone marrow). In contrast, 82% of primary acute myeloid leukemia samples engrafted in NSG-S mice with higher leukemic burden and shortened survival. Additionally, all of 5 injected samples from patients with myelodysplastic syndrome showed persistent engraftment on week 6; however, engraftment was mostly low (<2%), did not increase over time, and was only transiently affected by the use of NSG-S mice. Co-injection of mesenchymal stem cells did not enhance human myelodysplastic syndrome cell engraftment. Overall, we conclude that engraftment of acute myeloid leukemia samples is more robust compared to that of myelodysplastic syndrome samples and unlike those, acute myeloid leukemia cells respond positively to human cytokines, whereas myelodysplastic syndrome cells demonstrate a general unresponsiveness to them.
Assuntos
Citocinas/metabolismo , Sobrevivência de Enxerto/imunologia , Hospedeiro Imunocomprometido , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/metabolismo , Animais , Transplante de Medula Óssea , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Síndromes Mielodisplásicas/terapia , Transplante HeterólogoRESUMO
The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival. Myelopoiesis increased and was coupled with a reduction in B lymphopoiesis and compromised erythropoiesis, suggesting that hematopoietic lineage/progression was altered. Treatment of mice with acute myeloid or lymphoblastic leukemia with a pharmacologic inhibitor of the synthesis of duodenal serotonin, a hormone suppressing osteoblast numbers, inhibited loss of osteoblasts. Maintenance of the osteoblast pool restored normal marrow function, reduced tumor burden, and prolonged survival. Leukemia prevention was attributable to maintenance of osteoblast numbers because inhibition of serotonin receptors alone in leukemic blasts did not affect leukemia progression. These results suggest that osteoblasts play a fundamental role in propagating leukemia in the marrow and may be a therapeutic target to induce hostility of the niche to leukemia blasts.
Assuntos
Progressão da Doença , Leucemia/patologia , Osteoblastos/patologia , Animais , Contagem de Células , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Osteoblastos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Pirimidinas/farmacologia , Pirimidinas/uso terapêuticoRESUMO
The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16+ and granzyme B+ NK cells, and higher frequency of TIM-3+ and HLA-DR+ NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells.
RESUMO
BACKGROUND: The skin commensal and opportunistic pathogen Staphylococcus epidermidis is a leading cause of hospital-acquired and biomaterial-associated infections. The polysaccharide intercellular adhesin (PIA), a homoglycan composed of ß-1,6-linked N-acetylglucosamine residues, synthesized by enzymes encoded in icaADBC is a major functional factor in biofilm accumulation, promoting virulence in experimental biomaterial-associated S. epidermidis infection. Extracellular mucous layer extracts of S. epidermidis contain another major polysaccharide, referred to as 20-kDa polysaccharide (20-kDaPS), composed mainly out of glucose, N-acetylglucosamine, and being partially sulfated. 20-kDaPS antiserum prevents adhesion of S. epidermidis on endothelial cells and development of experimental keratitis in rabbits. Here we provide experimental evidence that 20-kDaPS and PIA represent distinct molecules and that 20-kDaPS is implicated in endocytosis of S. epidermidis bacterial cells by human monocyte-derived macrophages. RESULTS: Analysis of 75 clinical coagulase-negative staphylococci from blood-cultures and central venous catheter tips indicated that 20-kDaPS is expressed exclusively in S. epidermidis but not in other coagulase-negative staphylococcal species. Tn917-insertion in various locations in icaADBC in mutants M10, M22, M23, and M24 of S. epidermidis 1457 are abolished for PIA synthesis, while 20-kDaPS expression appears unaltered as compared to wild-type strains using specific anti-PIA and anti-20-kDaPS antisera. While periodate oxidation and dispersin B treatments abolish immuno-reactivity and intercellular adhesive properties of PIA, no abrogative activity is exerted towards 20-kDaPS immunochemical reactivity following these treatments. PIA polysaccharide I-containing fractions eluting from Q-Sepharose were devoid of detectable 20-kDaPS using specific ELISA. Preincubation of non-20-kDaPS-producing clinical strain with increasing amounts of 20-kDaPS inhibits endocytosis by human macrophages, whereas, preincubation of 20-kDaPS-producing strain ATCC35983 with 20-kDaPS antiserum enhances bacterial endocytosis by human macrophages. CONCLUSIONS: In conclusion, icaADBC is not involved in 20-kDaPS synthesis, while the chemical and chromatographic properties of PIA and 20-kDaPS are distinct. 20-kDaPS exhibits anti-phagocytic properties, whereas, 20-kDaPS antiserum may have a beneficial effect on combating infection by 20-kDaPS-producing S. epidermidis.
Assuntos
Macrófagos/imunologia , Macrófagos/microbiologia , Fagocitose , Polissacarídeos Bacterianos/metabolismo , Staphylococcus epidermidis/imunologia , Staphylococcus epidermidis/metabolismo , Células Cultivadas , Elementos de DNA Transponíveis , Perfilação da Expressão Gênica , Humanos , Peso Molecular , Mutagênese Insercional , Polissacarídeos Bacterianos/química , Polissacarídeos Bacterianos/genética , Polissacarídeos Bacterianos/imunologiaRESUMO
Bacterial adherence to eukaryotic cells is highly contributing to microbial pathogenesis. Bacterial adhesins, macromolecules, and glycosaminoglycan chains of the endothelial cell surface have been implicated in staphylococcal attachment. Our research group has isolated an antigenic polysaccharidic component of Staphylococcus epidermidis extracellular layer, known as 20-kDa PS (PS), and showed that antibodies against this polysaccharide protect from infections. Therefore, the role of PS in S. epidermidis adherence to endothelial cells was studied. For this purpose we examined the impact of PS on the ability of two S. epidermidis strains (a PS-producing and a non-PS-producing strain) to adhere to human endothelial cells in the presence or absence of specific antibodies to this polysaccharide. Hence, it is established that exogenous chondroitin sulfate (CS) decreases, in part, the S. epidermidis' attachment to endothelial cells and the antagonistic binding effect of CS and PS was also studied. The results obtained demonstrate that PS facilitates the adherence of S. epidermidis to both strains. CS abolished the PS-induced adherence in PS-producing strain and partially in the non-PS-producing one. Conclusively, the adherence of S. epidermidis to human endothelial cells is associated with its extracellular PS component and it is suggested that the bacterial binding via glycosaminoglycan chains is an important mechanism underlining the PS-induced binding to endothelial cells.
Assuntos
Aderência Bacteriana/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/microbiologia , Espaço Extracelular/química , Muco/química , Polissacarídeos Bacterianos/farmacologia , Staphylococcus epidermidis/citologia , Biotina/metabolismo , Sulfatos de Condroitina/farmacologia , Contagem de Colônia Microbiana , Espaço Extracelular/efeitos dos fármacos , Humanos , Muco/efeitos dos fármacos , Padrões de Referência , Coloração e Rotulagem , Staphylococcus epidermidis/efeitos dos fármacos , Staphylococcus epidermidis/isolamento & purificaçãoRESUMO
The extracellular slime of Staphylococcus epidermidis contains, amongst various macromolecules, an acidic polysaccharide (PS) of a molecular mass of 20 kDa with significant antigenic and biological properties. The isolation procedure used so far includes multiple fractionations in anion-exchange chromatographic columns before its final purification by gel filtration chromatography. This protocol is laborious, time-consuming and includes the risk of unnecessary loss of PS quantities. Because of the significance of this PS, a modified protocol resulting in an easier and quicker isolation procedure was developed. Furthermore, identification, purity, charge density and molecular integrity of the isolated polysaccharide were evaluated by a reverse-polarity capillary electrophoresis method.
Assuntos
Eletroforese Capilar/métodos , Polissacarídeos Bacterianos/isolamento & purificação , Staphylococcus epidermidis/química , Formiatos/química , Concentração de Íons de Hidrogênio , Polissacarídeos Bacterianos/químicaRESUMO
PURPOSE: In relapsed and/or refractory multiple myeloma, daratumumab reduced the risk of progression or death by > 60% in POLLUX (daratumumab/lenalidomide/dexamethasone [D-Rd]) and CASTOR (daratumumab/bortezomib/dexamethasone [D-Vd]). Minimal residual disease (MRD) is a sensitive measure of disease control. Sustained MRD negativity and outcomes were evaluated in these studies. METHODS: MRD was assessed via next-generation sequencing (10-5) at suspected complete response (CR), 3 and 6 months following confirmed CR (POLLUX), 6 and 12 months following the first dose (CASTOR), and every 12 months post-CR in both studies. Sustained MRD negativity (≥ 6 or ≥ 12 months) was evaluated in the intention-to-treat (ITT) and ≥ CR populations. RESULTS: The median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR. In the ITT population, MRD-negativity rates were 32.5% versus 6.7% for D-Rd versus lenalidomide and dexamethasone (Rd) and 15.1% versus 1.6% for D-Vd versus bortezomib and dexamethasone (Vd; both P < .0001). Higher MRD negativity rates were achieved in ≥ CR patients in POLLUX (D-Rd, 57.4%; Rd, 29.2%; P = .0001) and CASTOR (D-Vd, 52.8%; Vd, 17.4%; P = .0035). More patients in the ITT population achieved sustained MRD negativity ≥ 6 months with D-Rd versus Rd (20.3% v 2.1%; P < .0001) and D-Vd versus Vd (10.4% v 1.2%; P < .0001), and ≥ 12 months with D-Rd versus Rd (16.1% v 1.4%; P < .0001) and D-Vd versus Vd (6.8% v 0%). Similar results for sustained MRD negativity were observed among ≥ CR patients. More patients in the daratumumab-containing arms achieved MRD negativity and sustained MRD negativity, which were associated with prolonged progression-free survival. CONCLUSION: Daratumumab-based combinations induce higher rates of sustained MRD negativity versus standard of care, which are associated with durable remissions and prolonged clinical outcomes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Anticorpos Monoclonais/administração & dosagem , Bortezomib/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Dexametasona/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Humanos , Lenalidomida/administração & dosagem , Estudos Multicêntricos como Assunto , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia , Neoplasia Residual/diagnóstico , Avaliação de Resultados em Cuidados de Saúde/métodos , Intervalo Livre de Progressão , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with ≥1 prior line received Rd (lenalidomide, 25 mg, on Days 1-21 of each 28-day cycle; dexamethasone, 40 mg, weekly) ± daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35-0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10-5; 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31-0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42-0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Idoso , Anticorpos Monoclonais/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Seguimentos , Humanos , Lenalidomida/administração & dosagem , Masculino , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida , Talidomida/administração & dosagemRESUMO
High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10-5) was assessed via the clonoSEQ® assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Deleção Cromossômica , Mieloma Múltiplo , Translocação Genética , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cromossomos Humanos , Análise Citogenética , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Recidiva , Taxa de SobrevidaRESUMO
BACKGROUND: Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019). METHODS: Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT). All subjects had relapsed/refractory multiple myeloma and had previously undergone ASCT with less than 1 year progression-free survival (PFS). RESULTS: ASCT + CTL019 was safe and feasible, with most toxicity attributable to ASCT and no severe cytokine release syndrome. Two of 10 subjects exhibited significantly longer PFS after ASCT + CTL019 compared with prior ASCT (479 vs. 181 days; 249 vs. 127 days). Correlates of favorable clinical outcome included peak CTL019 frequency in bone marrow and emergence of humoral and cellular immune responses against the stem-cell antigen Sox2. Ex vivo treatment of primary myeloma samples with a combination of CTL019 and CAR T cells against the plasma cell antigen BCMA reliably inhibited myeloma colony formation in vitro, whereas treatment with either CAR alone inhibited colony formation inconsistently. CONCLUSION: CTL019 may improve duration of response to standard multiple myeloma therapies by targeting and precipitating secondary immune responses against myeloma-propagating cells. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02135406. FUNDING: Novartis, NIH, Conquer Cancer Foundation.
Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Melfalan/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/uso terapêutico , Idoso , Antígeno de Maturação de Linfócitos B/imunologia , Terapia Combinada/métodos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunidade Celular/efeitos dos fármacos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Agonistas Mieloablativos/uso terapêutico , Receptores de Antígenos de Linfócitos T/administração & dosagem , Receptores de Antígenos de Linfócitos T/imunologia , Fatores de Transcrição SOXB1/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Transplante Autólogo , Resultado do TratamentoRESUMO
Staphylococcus epidermidis is a leading cause of hospital-acquired and biofilm-associated infections. Interactions of peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages with planktonic or biofilm phase S. epidermidis cells were studied. Biofilm phase bacteria exhibited higher attachment, as well as, a 10-fold higher intracellular survival in monocyte-derived macrophages than their planktonic counterparts. Stimulation of PBMCs and monocyte-derived macrophages was performed with live or formalin-fixed bacterial cells. Supernatant concentration of selected cytokines was measured by Luminex(®) xMAP(™) technology at different time points. As compared to planktonic phase, biofilm phase bacteria elicited lower amounts of proinflammatory cytokines and Th1 response cytokines, such as TNFα, IL-12p40, IL-12p70 and IFN-γ, whereas they enhanced production of IL-8, GM-CSF and IL-13. This phenomenon was independent of formalin pretreatment. Taken together, these results may contribute to interpretation of observed silent course of biofilm-associated infections.