RESUMO
Extramedullary disease (EMD) is a high-risk feature of multiple myeloma (MM) and remains a poor prognostic factor even in the era of novel immunotherapies. Here we applied spatial transcriptomics (tomo-seq [n=2] and 10X Visium [n=12]), and single-cell RNA sequencing (scRNAseq [n=3]) to a set of 14 EMD biopsies to dissect the three-dimensional architecture of tumor cells and their microenvironment. Overall, the infiltrating immune and stromal cells showed both intra- and inter-patient variation with no uniform distribution over the lesion. We observed substantial heterogeneity at the copy number level within plasma cells, including the emergence of new subclones in circumscribed areas of the tumor, consistent with genomic instability. We further identified spatial expression differences of GPRC5D and TNFRSF17, two important antigens for bispecific antibody therapy. EMD masses were infiltrated by various immune cells, including T-cells. Notably, exhausted TIM3+/PD-1+ T-cells diffusely co-localized with MM cells, whereas functional and activated CD8+ T-cells showed a focal infiltration pattern along with M1 macrophages in otherwise tumor-free regions. This segregation of fit and exhausted T-cells was resolved in the case of response to T-cell engaging bispecific antibodies. MM cells and microenvironment cells were embedded in a complex network that influenced immune activation and angiogenesis, and oxidative phosphorylation represented the major metabolic program within EMD lesions. In summary, spatial transcriptomics has revealed a multicellular ecosystem in EMD with checkpoint inhibition and dual targeting as potential new therapeutic avenues.
RESUMO
Survivor testimonies link survival in deadly POW camps, Gulags, and Nazi concentration camps to the formation of close friendships with other prisoners. To provide evidence free of survival bias on the importance of social ties for surviving the Holocaust, we study individual histories of 30 thousand Jewish prisoners who entered the Auschwitz-Birkenau concentration camp on transports from the Theresienstadt ghetto. We ask whether the availability of potential friends among fellow prisoners on a transport influenced the chances of surviving the Holocaust. Relying on multiple proxies of preexisting social networks and varying social-linkage composition of transports, we uncover a significant survival advantage to entering Auschwitz with a larger group of potential friends.
Assuntos
Holocausto , Prisioneiros , Humanos , Amigos , Judeus , Aplicação da LeiRESUMO
Induction therapy followed by CD34+ cell mobilisation and autologous transplantation represents standard of care for multiple myeloma (MM). However, the anti-CD38 monoclonal antibodies daratumumab and isatuximab have been associated with mobilisation impairment, yet the mechanism remains unclear. In this study, we investigated the effect of three different regimens (dara-VCd, isa-KRd and VTd) on CD34+ cells using flow cytometry and transcriptomics. Decreased CD34+ cell peak concentration and yields, longer collection and delayed engraftment were reproduced after dara-VCd/isa-KRd versus VTd induction in 34 patients in total. Using flow cytometry, we detected major changes in the proportion of apheresis product and bone marrow CD34+ subsets in patients treated with regimens containing anti-CD38 therapy; however, without any decrease in CD38high B-lymphoid progenitors in both materials. RNA-seq of mobilised CD34+ cells from 21 patients showed that adhesion genes are overexpressed in CD34+ cells after dara-VCd/isa-KRd and JCAD, NRP2, MDK, ITGA3 and CLEC3B were identified as potential target genes. Finally, direct in vitro effect of isatuximab in upregulating JCAD and CLEC3B was confirmed by quantitative PCR. These findings suggest that upregulated adhesion-related interactions, rather than killing of CD34+ cells by effector mechanisms, could be leading causes of decreased mobilisation efficacy in MM patients treated with anti-CD38 therapy.
Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Antígenos CD34/análise , Medula Óssea/química , Citometria de Fluxo , Mobilização de Células-Tronco Hematopoéticas , ADP-Ribosil Ciclase 1RESUMO
OBJECTIVES: Cluster of differentiation 38 (CD38) is a key target on multiple myeloma (MM) cells. This multi-centre, Phase 1, single-agent study (NCT04000282) investigated SAR442085, a novel fragment crystallisable (Fc)-modified anti-CD38 monoclonal antibody (mAb), with enhanced affinity towards Fc-gamma receptor on effector cells in patients with relapsed and/or refractory (RR) MM. METHODS: This study comprised two parts: Part-A (dose-escalation involving anti-CD38 mAb pre-treated and naïve patients) and Part-B (dose expansion). Primary endpoints were maximum tolerated dose and recommended Phase 2 dose (RP2D). RESULTS: Thirty-seven heavily pre-treated patients were treated in Part A. Part-B (dose-expansion) was not studied. Seven dose-limiting toxicities were reported at DL3, DL5, DL6, and DL7. RP2D was determined to be 5-7·5 mg/kg. Most common treatment-emergent adverse events were infusion-related reactions in 70·3% (26/37) patients. Grade ≥3 thrombocytopenia was reported in 48·6% (18/37). Overall response rate was 70% in anti-CD38 mAb naïve and 4% in anti-CD38 pre-treated patients, with a median progression-free survival of 7·62 (95%CI: 2·858; not calculable) months and 2·79 (95%CI: 1·150; 4·172) months and, respectively. CONCLUSIONS: The efficacy of SAR442085 was promising in anti-CD38 mAb naïve patients but did not extend to the larger cohort of anti-CD38 mAb pre-treated patients. This observation, along with transient high-grade thrombocytopenia, could potentially limit its clinical use.
RESUMO
Gene expression is a fundamental process that enables cells to produce specific proteins in a timely and spatially dependent manner. In eukaryotic cells, the complex organization of the cell body requires precise control of protein synthesis and localization. Certain mRNAs encode proteins with an N-terminal signal sequences that direct the translation apparatus toward a specific organelle. Here, we focus on the mechanisms governing the translation of mRNAs, which encode proteins with an endoplasmic reticulum (ER) signal in human cells. The binding of a signal-recognition particle (SRP) to the translation machinery halts protein synthesis until the mRNA-ribosome complex reaches the ER membrane. The commonly accepted model suggests that mRNA that encodes a protein that contains an ER signal peptide continuously repeats the cycle of SRP binding followed by association and dissociation with the ER. In contrast to the current view, we show that the long mRNAs remain on the ER while being translated. On the other hand, due to low ribosome occupancy, the short mRNAs continue the cycle, always facing a translation pause. Ultimately, this leads to a significant drop in the translation efficiency of small, ER-targeted proteins. The proposed mechanism advances our understanding of selective protein synthesis in eukaryotic cells and provides new avenues to enhance protein production in biotechnological settings.
RESUMO
Cancer immunotherapies utilizing genetically engineered T cells have emerged as powerful personalized therapeutic agents showing dramatic preclinical and clinical results, particularly in hematological malignancies. Ectopically expressed chimeric antigen receptors (CARs) reprogram immune cells to target and eliminate cancer. However, CAR T cell therapy's success depends on the balance between effective anti-tumor activity and minimizing harmful side effects. To improve CAR T cell therapy outcomes and mitigate associated toxicities, scientists from different fields are cooperating in developing next-generation products using the latest molecular cell biology and synthetic biology tools and technologies. The immunotherapy field is rapidly evolving, with new approaches and strategies being reported at a fast pace. This comprehensive literature review aims to provide an up-to-date overview of the latest developments in controlling CAR T cell activity for improved safety, efficacy, and flexibility.
Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Linfócitos T , Neoplasias/terapia , Imunoterapia , Receptores de Antígenos de Linfócitos TRESUMO
We performed real world evidence (RWE) analysis of daratumumab, lenalidomide and dexamethasone (Dara-Rd) versus lenalidomide and dexamethasone (Rd) treatment in relapsed/refractory multiple myeloma patients (RRMM). In total, 240 RRMM patients were treated with Dara-Rd from 2016 to 2022 outside of clinical trials in all major Czech hematology centers. As a reference, 531 RRMM patients treated with Rd were evaluated. Patients' data were recorded in the Czech Registry of Monoclonal Gammopathies (RMG). Partial response (PR) or better response (ORR) was achieved in significantly more patients in Dara-Rd than in Rd group (91.2% vs. 69.9%; p < 0.001). The median progression free survival (PFS) was 26.9 months in the Dara-Rd and 12.8 months in the Rd group (p < 0.001). Median overall survival (OS) was not reached in the Dara-Rd compared to 27.2 months in the Rd group (p = 0.023). In patients with 1-3 previous treatment lines, there was significant PFS benefit of Dara-Rd compared to Rd (median PFS not reached vs. 13.2 months; p < 0.001). In patients with > 3 previous treatment lines, there was no significant PFS benefit of Dara-Rd treatment (7.8 months vs. 9.9 months; p = 0.874), similarly in patients refractory to PI + IMIDs (11.5 months vs. 9.2 months; p = 0.376). In RWE conditions, the median PFS in RRMM patients treated with Dara-Rd is shorter when compared to clinical trials. In heavily pretreated RRMM patients, efficacy of Dara-Rd treatment is limited; best possible outcomes of Dara-Rd are achieved in minimally pretreated patients.
Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Lenalidomida/uso terapêutico , Dexametasona/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
During innate immune responses, myeloid differentiation primary response 88 (MyD88) functions as a critical signaling adaptor protein integrating stimuli from toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family and translates them into specific cellular outcomes. In B cells, somatic mutations in MyD88 trigger oncogenic NF-κB signaling independent of receptor stimulation, which leads to the development of B-cell malignancies. However, the exact molecular mechanisms and downstream signaling targets remain unresolved. We established an inducible system to introduce MyD88 to lymphoma cell lines and performed transcriptomic analysis (RNA-seq) to identify genes differentially expressed by MyD88 bearing the L265P oncogenic mutation. We show that MyD88L265P activates NF-κB signaling and upregulates genes that might contribute to lymphomagenesis, including CD44, LGALS3 (coding Galectin-3), NFKBIZ (coding IkBƺ), and BATF. Moreover, we demonstrate that CD44 can serve as a marker of the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) and that CD44 expression is correlated with overall survival in DLBCL patients. Our results shed new light on the downstream outcomes of MyD88L265P oncogenic signaling that might be involved in cellular transformation and provide novel therapeutical targets.
Assuntos
Linfoma Difuso de Grandes Células B , NF-kappa B , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Galectina 3/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Mutação , Perfilação da Expressão Gênica , Fatores de Transcrição de Zíper de Leucina Básica/genética , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
Multiple myeloma (MM) is characterized by malignant plasma cell infiltration of the bone marrow. In extramedullary multiple myeloma (EMD), a subclone of these cells migrates out of the bone marrow. Out of 4 985 MM patients diagnosed between 2005 and 2017 in the Czech Republic, we analyzed 234 secondary EMD patients to clarify risk factors of secondary EMD development. We found younger age [<65 years; odds ratio (OR) 4·38, 95% confidence interval (CI): 2·46-7·80, P < 0·0001], high lactate dehydrogenase (LDH) levels (>5 µkat/l; OR 2·07, 95% CI: 1·51-2·84, P < 0·0001), extensive osteolytic activity (OR 2·21, 95% CI: 1·54-3·15, P < 0·001), and immunoglobulin A (IgA; OR 1·53, 95% CI: 1·11-2·11, P = 0·009) or the non-secretory type of MM (OR 2·83; 95% CI: 1·32-6·04, P = 0·007) at the time of MM diagnosis to be the main risk factors for secondary EMD development. Newly diagnosed MM (NDMM) patients with subsequent EMD had inferior median progression-free (PFS) and overall (OS) survival when compared to NDMM patients without future EMD [mPFS: 13·8 months (95% CI: 11·4-16·3) vs 18·8 months (95% CI: 17·7-19·9), P = 0·006; mOS: 26·7 months (95% CI: 18·1-35·4) vs 58·7 months (95% CI: 54·8-62·6), P < 0·001]. We found that NDMM patients with specific risk factors associated with secondary EMD development have a more aggressive disease course before secondary EMD develops.
Assuntos
Mieloma Múltiplo/fisiopatologia , Idoso , Feminino , Humanos , Masculino , Mieloma Múltiplo/mortalidade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de SobrevidaRESUMO
Natural killer (NK) cells are part of a phylogenetically old defense system, which is characterized by its strong cytolytic function against physiologically stressed cells such as tumor cells and virus-infected cells. Their use in the treatment of hematological malignancies may be more advantageous in several ways when compared with the already established T lymphocyte-based immunotherapy. Given the different mechanisms of action, allogeneic NK cell products can be produced in a non-personal based manner without the risk of the formidable graft-versus-host disease. Advanced manufacturing processes are capable of producing NK cells relatively easily in large and clinically sufficient numbers, useable without subsequent manipulations or after genetic modifications, which can solve the lack of specificity and improve clinical efficacy of NK cell products. This review summarizes the basic characteristics of NK cells and provides a quick overview of their sources. Results of clinical trials in hematological malignancies are presented, and strategies on how to improve the clinical outcome of NK cell therapy are discussed.
Assuntos
Neoplasias Hematológicas , Neoplasias , Neoplasias Hematológicas/terapia , Humanos , Fatores Imunológicos , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Células Matadoras Naturais , Neoplasias/terapiaRESUMO
We assessed the outcomes of pomalidomide and dexamethasone treatment in relapsed/refractory multiple myeloma (RRMM) patients with ≥1 prior line of therapy. We analyzed the data of all RRMM patients treated with pomalidomide and dexamethasone at nine Czech centers between 2013 and 2018. The source of the data was the Registry of Monoclonal Gammopathies of the Czech Republic. Primary endpoints included response rates based on International Myeloma Working Group criteria and survival measures, including progression-free survival (PFS) and overall survival (OS). Secondary endpoints were toxicities and previous treatment patterns, including refractory to lenalidomide, and their impact on final outcomes. The overall response rate was 51.8% and the clinical benefit rate (including patients with minimal response) was 67.1%, with 0.6% of complete responses, 8.5% of very good partial responses, and 42.1% of partial responses (PR). Overall, 16.5% of patients had a minimal response, and 32.3% had stable disease /progression. Median PFS was 8.8 months and the median OS was 14.2 months. In patients who achieved ≥PR, the median PFS and OS were significantly longer compared to non-responders (median PFS (12.1 vs. 4.5 months, p≤0.001 respectively), median OS (22.1 vs. 7.7 months, p≤0.001, respectively). The most frequent adverse events (AEs) were neutropenia (29.9%) and anemia (18.9%), non-hematological AEs included infections (14.6%) and fatigue (7.3%). Our analysis confirmed the effectiveness of pomalidomide and dexamethasone in a real-world setting. This therapy achieved reasonable outcomes comparable to the data from clinical trials even though this was an unbiased cohort of patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Mieloma Múltiplo , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , República Tcheca/epidemiologia , Dexametasona/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Dados de Saúde Coletados RotineiramenteRESUMO
Extramedullary multiple myeloma (EMD) is an aggressive disease; malignant plasma cells lose their dependence in the bone marrow microenvironment and migrate into tissues. EMD is a negative prognostic factor of survival. Using flow cytometry and next-generation sequencing, we aimed to identify antigens and microRNAs (miRNAs) involved in EMD pathogenesis. Flow cytometry analysis revealed significant differences in the level of clonal plasma cells between MM and EMD patients, while the expression of CD markers was comparable between these two groups. Further, miR-26a-5p and miR-30e-5p were found to be significantly down-regulated in EMD compared to MM. Based on the expression of miR-26a-5p, we were able to distinguish these two groups of patients with high sensitivity and specificity. In addition, the involvement of deregulated miRNAs in cell cycle regulation, ubiquitin-mediated proteolysis and signaling pathways associated with infections or neurological disorders was observed using GO and KEGG pathways enrichment analysis. Subsequently, a correlation between the expression of analyzed miRNAs and the levels of CD molecules was observed. Finally, clinicopathological characteristics as well as CD antigens associated with the prognosis of MM and EMD patients were identified. Altogether, we identified several molecules possibly involved in the transformation of MM into EMD.
Assuntos
MicroRNAs , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/genética , MicroRNAs/genética , Sequenciamento de Nucleotídeos em Larga Escala , Microambiente TumoralRESUMO
Remarkable advances have been achieved in the treatment of multiple myeloma (MM) in the last decade, which saw targeted immunotherapy, represented by anti-CD38 monoclonal antibodies, successfully incorporated across indications. However, myeloma is still considered curable in only a small subset of patients, and the majority of them eventually relapse. B-cell maturation antigen (BCMA) is expressed exclusively in mature B lymphocytes and plasma cells, and represents an ideal new target for immunotherapy, presented by bispecific antibody (bsAb) constructs, antibody-drug conjugates (ADCs) and chimeric antigen receptor T (CAR-T) cells. Each of them has proved its efficacy with the potential for deep and long-lasting responses as a single agent therapy in heavily pretreated patients. As a result, belantamab mafodotin was approved by the United States Food and Drug Administration for the treatment of relapsed/refractory MM, as the first anti-BCMA agent. In the present review, we focus on monoclonal antibodies targeting BCMA - bsAbs and ADCs. The data from preclinical studies as well as first-in-human clinical trials will be reviewed, together with the coverage of their constructs and mechanisms of action. The present results have laid the groundwork for the ongoing or upcoming clinical trials with combinatory regimens, which have always been a cornerstone in the treatment of MM.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Sistemas de Liberação de Medicamentos , Imunoconjugados/uso terapêutico , Imunoterapia Adotiva , Mieloma Múltiplo/terapia , Proteínas de Neoplasias/antagonistas & inibidores , Antígeno de Maturação de Linfócitos B/imunologia , Humanos , Mieloma Múltiplo/imunologia , Proteínas de Neoplasias/imunologia , Plasmócitos/imunologiaRESUMO
Plasma cell leukaemia (PCL) is a rare and very aggressive plasma cell disorder. Preventing a dismal outcome of PCL requires early diagnosis with appropriate analytical tools. Therefore, the investigation of 33 patients with primary and secondary PCL was done when the quantity of circulating plasma cells (PCs) using flow cytometry (FC) and morphology assessment was evaluated. The phenotypic profile of the PCs was also analysed to determine if there is an association with clinical outcomes and to evaluate the prognostic value of analysed markers. Our results revealed that FC is an excellent method for identifying circulating PCs as a significantly higher number was identified by FC than by morphology (26·7% vs. 13·5%, P = 0·02). None of secondary PCL cases expressed CD19 or CD20. A low level of expression with similar positivity of CD27, CD28, CD81 and CD117 was found in both PCL groups. A decrease of CD44 expression was detected only in secondary PCL. Expression of CD56 was present in more than half of PCL cases as well as cytoplasmic nestin. A decreased level of platelets, Eastern Cooperative Oncology Group score of 2-3 and lack of CD20+ PC were associated with a higher risk of death. FC could be incorporated in PCL diagnostics not only to determine the number of circulating PCs, but also to assess their phenotype profile and this information should be useful in patients' diagnosis and possible prognosis.
Assuntos
Contagem de Células Sanguíneas , Citometria de Fluxo/métodos , Leucemia Plasmocitária/sangue , Células Neoplásicas Circulantes , Plasmócitos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Antígenos de Neoplasias/análise , Contagem de Células Sanguíneas/métodos , Medula Óssea/patologia , Células da Medula Óssea/química , Detecção Precoce de Câncer , Reações Falso-Negativas , Feminino , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Leucemia Plasmocitária/mortalidade , Masculino , Pessoa de Meia-Idade , Plasmócitos/química , Plasmócitos/ultraestrutura , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: We have performed a head to head comparison of all-oral triplet combination of ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and refractory multiple myeloma (RRMM) in the routine clinical practice. METHODS: A total of 344 patients treated with IRD (N = 127) or RD (N = 217) were selected for analysis from the Czech Registry of Monoclonal Gammopathies (RMG). Descriptive statistics were used to assess patient's characteristics associated with the respective therapy. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS). Survival endpoints were plotted using Kaplan-Meier methodology at 95% Greenwood confidence interval. Univariable and multivariable Cox proportional hazards models were used to evaluate the effect of treatment regimens and the significance of uneven variables. Statistical tests were performed at significance level 0.05. RESULTS: In the whole cohort, median PFS for IRD was 17.5 and for RD was 11.5 months favoring the all-oral triplet, p = 0.005; in patients within relapse 1-3, the median PFS was 23.1 vs 11.6 months, p = 0.001. The hazard ratio for PFS was 0.67 (95% confidence interval [CI] 0.51-0.89, p = 0.006). The PFS advantage translated into improved OS for patients treated with IRD, median 36.6 months vs 26.0 months (p = 0.008). The overall response rate (ORR) was 73.0% in the IRD group vs 66.2% in the RD group with a complete response rate (CR) of 11.1% vs 8.8%, and very good partial response (VGPR) 22.2% vs 13.9%, IRD vs RD respectively. The IRD regimen was most beneficial in patients ≤75 years with ISS I, II, and in the first and second relapse. Patients with the presence of extramedullary disease did not benefit from IRD treatment (median PFS 6.5 months). Both regimens were well tolerated, and the incidence of total as well as grade 3/4 toxicities was comparable. CONCLUSIONS: Our analysis confirms the results of the TOURMALINE-MM1 study and shows benefit of all-oral triplet IRD treatment versus RD doublet. It demonstrates that the addition of ixazomib to RD improves key survival endpoints in patients with RRMM in a routine clinical setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos de Boro/farmacologia , Compostos de Boro/uso terapêutico , República Tcheca/epidemiologia , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Glicina/análogos & derivados , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Lenalidomida/farmacologia , Lenalidomida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Estudos Prospectivos , Sistema de Registros/estatística & dados numéricosRESUMO
BACKGROUND: High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) is routinely used in various hematologic malignancies. However, dimethylsulfoxide contained in cryopreserved grafts can cause adverse events (AEs). STUDY DESIGN AND METHODS: Forty-three ASCTs were performed with Sepax 2 washed grafts between 7/2016 and 10/2019. The aim of this study was to determine whether washing out dimethyl sulfoxide (DMSO) from transplants using the Sepax 2 (S-100) device is safe and reduces the incidence of DMSO-associated AEs. RESULTS: The washing procedure was automated and that resulted in the satisfactory recovery of total nucleated cells, CD34+ cells, and colony forming units of granulocyte and macrophages (85%, 80%, and 84%, medians). Time to engraftment of leukocytes, granulocytes, and platelets as well as the number of neutropenic days did not differ when compared to 20 consecutive ASCTs without washing. The AE occurrence was lower compared to unwashed grafts: 81% versus 78% during and shortly after grafts administration, 76% versus 69% in the following day. CONCLUSION: We conclude that the washing of cryopreserved transplants using Sepax 2 was feasible with a high recovery of hematopoietic cells, did not influence time to engraftment, and resulted in the satisfactory reduction of AEs and improved tolerance of the procedure.
Assuntos
Crioprotetores/efeitos adversos , Dimetil Sulfóxido/efeitos adversos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Adulto , Idoso , Criopreservação/instrumentação , Criopreservação/métodos , Crioprotetores/isolamento & purificação , Dimetil Sulfóxido/isolamento & purificação , Feminino , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Humanos , Masculino , Pessoa de Meia-Idade , Transplante AutólogoRESUMO
OBJECTIVES: This study compared the use of bortezomib in different combination regimens in newly diagnosed multiple myeloma (NDMM) patients who were transplant ineligible. PATIENTS AND METHODS: We analyzed data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group (CMG) to provide real-world evidence of outcome for 794 newly diagnosed MM transplant ineligible patients. The most frequently used regimen was VCd (bortezomib-cyclophosphamide-dexamethasone) (47.5%) over VMP (bortezomib-melphalan-prednisone) (21.7%), BDd (bortezomib-doxorubicin-dexamethasone) (9.8%), and VTd (bortezomib-thalidomide-dexamethasone) (2.9%). RESULTS: The overall response rate (ORR) was 69.2% (478/691), including 12.6% (≥ CR); 34.7% very good partial responses (VGPR); and 21.9% partial responses (PR). Among triplet regimens, VMP was the most effective regimen compared to VCd, BDd, and VTd. Median PFS was 22.3 vs. 18.5 vs. 13.7 vs. 13.8 mo, (P = .275), respectively, and median OS was 49 vs. 41.7 vs. 37.9 vs. 32.2 mo (P = .004), respectively. The most common grade 3-4 toxicities were anemia in 17.4% and infections in 18% of patients. CONCLUSION: Our study confirmed that bortezomib-based treatment is effective and safe in NDMM transplant ineligible patients, especially VMP, which was identified as superior between bortezomib-based induction regimens not only in clinical trials, but also in real clinical practice.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Melfalan/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Prednisona/uso terapêutico , Sistema de Registros , Idoso , Idoso de 80 Anos ou mais , Ciclofosfamida/uso terapêutico , República Tcheca , Dexametasona/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)-piperaquine (APQ) Eurartesim® during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap. METHODS: Participants were recruited through Health Care Provider's safety registry in 15 centres across 6 European countries in the period 2013-2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett's (QTcB) or Fridericia's (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females. RESULTS: Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m2 (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p < 0.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF > 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%). CONCLUSIONS: APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries. Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942.
Assuntos
Artemisininas/uso terapêutico , Doenças Transmissíveis Importadas/prevenção & controle , Malária Falciparum/prevenção & controle , Quinolinas/uso terapêutico , Adolescente , Adulto , Idoso , Bélgica , Criança , Pré-Escolar , Combinação de Medicamentos , Feminino , França , Alemanha , Humanos , Itália , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Espanha , Reino Unido , Adulto JovemRESUMO
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.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunoconjugados/uso terapêutico , Imunoterapia/métodos , Linfoma de Células B/tratamento farmacológico , Transtornos Linfoproliferativos/tratamento farmacológico , Animais , Humanos , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologiaRESUMO
Travelling with chronic diseases is no longer unusual. More and more chronically ill people are embarking on long-distance trips, sometimes under thoroughly adventurous conditions. Tour operators have long adapted to this need and are constantly offering new destinations. The experiences of the last decades have led to a considerable increase in safety standards and care for travelers. Today, an averagely mobile person can travel to almost any destination in the world. Nevertheless, the more relevant chronic illnesses are, the greater the health risks of a trip. Particularly due to reduced body defenses, infectious diseases pose an increased health risk during long-distance travel. In this overview, exemplary diseases are discussed.