RESUMO
Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10-8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10-7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.
Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/genética , Oncogenes , Alelos , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Proteínas de Choque Térmico HSP40/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a RNARESUMO
The results of the MURANO trial showed encouraging progression-free survival (PFS) and overall survival (OS) in relapsed/refractory chronic lymphocytic leukemia (RR-CLL) patients treated with venetoclax-rituximab (VEN-R). A retrospective analysis was performed to evaluate the efficacy and safety of VEN-R within the Polish Adult Leukemia Study Group (PALG) centers. The study group included 117 patients with RR-CLL (with early relapse after immunochemotherapy or bearing TP53 aberrations) treated with VEN-R in 2019-2023 outside clinical trials. Patients were treated with a median of 2 (range 1-9) previous lines of therapy. Twenty-two participants were previously treated with BTKi (18.8% out of 117). The median follow-up was 20.3 months (range 0.27-39.1). The overall response rate (ORR) was 95.3% in the group of patients in whom a response to treatment was assessed and 86.3% for all patients. Twenty patients (17.1% out of 117) achieved a complete response (CR), 81 (69.2%) achieved a partial response (PR), and in 5 patients (4.3%), disease progression was noted (assessed as the best response during treatment). The median PFS in the whole cohort was 36.97 (95% CI 24.5, not reached) months, and the median OS was not reached (95% CI 27.03, not reached). Thirty-six patients died during the follow-up, 10 (8.5%; 27.8% of deaths) due to COVID-19 infection. All grade neutropenia (n = 87/117, 74.4%; grade 3 or higher n = 67/117, 57.3%) was the most common treatment adverse event. Forty-five patients (38.5%) remained on treatment, and twenty-two (18.8%) completed 24 months of therapy, while it was discontinued in fifty cases (42.7%). In this real-world setting of early access in very high-risk RR-CLL patients, the VEN-R regimen was associated with shorter median PFS compared with the results of the MURANO trial. This outcome, however, could be attributed to patients' exposure to SARS-CoV-2 infection and the aggressive course of the disease as very high-risk patients, after multiple lines of prior therapies, were included in the Polish Ministry of Health reimbursement program.
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COVID-19 , Leucemia Linfocítica Crônica de Células B , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , COVID-19/etiologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Polônia/epidemiologia , Recidiva , Estudos Retrospectivos , Rituximab , SARS-CoV-2 , Resultado do Tratamento , Ensaios Clínicos como AssuntoRESUMO
Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10-9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3- B cells, CD5+IgD- cells, IgM- cells, IgD-IgM- cells, and CD4-CD8- PBMCs (p = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent pathways.
Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Leucócitos Mononucleares/patologia , Biomarcadores , Imunoglobulina M , AutofagiaRESUMO
OPINION STATEMENT: The better understanding of the biology of chronic lymphocytic leukemia (CLL) gained over the past decade has led to the development and introduction of several targeted drugs, with an demonstrable improvement in the prognosis for this currently incurable condition. Currently, Bruton's tyrosine kinase (BTK) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, venetoclax, and CD20 monoclonal antibodies are the key elements in the treatment of both previously untreated and relapsed/refractory CLL patients. Ibrutinib was the first BTK inhibitor approved for clinical use, and showed excellent efficacy and an acceptable safety profile. Following this, the better-tolerated second-generation irreversible BTK inhibitors acalabrutinib and zanubrutinib have been introduced for the treatment of lymphoid malignancies, and acalabrutinib was approved for CLL. When used as single drugs, BTK inhibitors are given continuously until unacceptable toxicity or disease progression; however, when combined with venetoclax and/or CD20 antibodies, they induce deeper response and can be given for a limited time. Recently, promising new reversible BTK inhibitors pirtobrutinib and nemtabrutinib were discovered, and these seem to be more active and better tolerated than their irreversible predecessors. However, they are in an early phase of development and are not currently approved for CLL. The phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib and duvelisib are highly effective in patients with relapsed CLL, including high-risk disease. The major limitations for their use are adverse events, mostly of autoimmune origin (hepatitis, enteritis/colitis, and pneumonitis). Otherwise, cellular therapies like allogeneic hematopoietic stem cell transplantation and chimeric antigen receptor (CAR) T cells and bispecific monoclonal antibodies offer promise for patients who have failed BTK inhibitors and venetoclax treatment. In the coming years, it is likely that novel targeted therapies will replace immunochemotherapy regimens in most patients.
Assuntos
Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Linfoma de Células B , Antineoplásicos/uso terapêutico , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/etiologia , Fosfatidilinositol 3-Quinases , PrognósticoRESUMO
Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.
Assuntos
Apirase/genética , Perfilação da Expressão Gênica/métodos , Proteínas Mitocondriais/genética , Mieloma Múltiplo/mortalidade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Proteínas de Ligação a RNA/genética , Idoso , Feminino , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Análise de SobrevidaRESUMO
We evaluated the association between germline genetic variants located within the 3'-untranlsated region (polymorphic 3'UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3'-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis.
Assuntos
Regiões 3' não Traduzidas/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Mieloma Múltiplo/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Análise de SobrevidaRESUMO
BACKGROUND: Ibrutinib, an inhibitor of the Bruton's kinase (BTK), is characterized by high efficacy in the therapy of patients with relapsed and refractory chronic lymphocytic leukemia (RR-CLL). AIMS: To analyze the potential significance of the mutational status of selected 30 genes on the disease outcome in 45 patients with RR-CLL using custom-made gene panel and sequencing on Illumina MiSeq FGx platform. RESULTS: The highest rate of mutations was observed in TP53 (n = 18; 40.0%), NOTCH1 (n = 13; 28.8%), SF3B1 (n = 11; 24.4%), ATM (n = 7; 15.6%), MED12 (n = 6, 13.3%), CHD2 (n = 5; 11.1%), XPO1 (n = 5; 11.1%), NFKBIE (n = 5; 11.1%), BIRC3 (n = 4; 8.9%), SPEN (n = 4; 8.9%), POT1 (n = 4; 8.9%), EGR2 (n = 3; 6.7%), and RPS15 (n = 3; 6.7%). With a median observation time of 45.9 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. The 36-month estimated rate of PFS and OS were 64% and 68.2%, respectively. The overall response rate was noted in 23 patients (51.1%), while twenty (44.4%) patients achieved stability. Progression was noted in 2 (4.5%) cases. Analyzed molecular factors had no impact on PFS and OS. CONCLUSION: Despite accumulation of several poor prognostic factors in our real-life cohort of heavily pretreated patients with CLL, ibrutinib treatment showed long-term clinical benefit.
Assuntos
Adenina/análogos & derivados , Biomarcadores Tumorais/genética , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Terapia de Alvo Molecular , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Recidiva , Resultado do TratamentoRESUMO
Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation.
Assuntos
Proteínas de Transporte/genética , Desequilíbrio de Ligação , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Idoso , Receptor Constitutivo de Androstano , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Mieloma Múltiplo/terapia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p < 0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta-analyzed with data from a previously published genome-wide association study (GWAS). The SNPs rs13409 (located in the 3'UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome-wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk.
Assuntos
Predisposição Genética para Doença/genética , MicroRNAs/genética , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Sítios de Ligação/genética , Estudos de Casos e Controles , Europa (Continente) , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Mieloma/genética , RNA Mensageiro/genética , RiscoRESUMO
Richter transformation (RT) is defined as developing an aggressive lymphoma in 2-10% of patients suffering from chronic lymphocytic leukemia (CLL). So far, no complex analysis of RT demographics and treatment outcomes has been performed in Poland. Thus, the retrospective analysis of 124 patients with RT from Polish hematology centers was designed. Ninety-nine patients with diffuse large B-cell lymphoma (DLBCL-RT) were identified. The median overall survival (OS) for DLBCL-RT was 17.3 months, while for Hodgkin lymphoma (HL-RT)-21.3 months. In multivariate analysis, the independent factors of worse OS for DLBCL-RT were: prior CLL therapy, ECOG stage ≥2, and elevated serum LDH activity. Patients who proceeded to hematopoietic stem cell transplantation (HSCT) achieved better results. The median OS in allogeneic HSCT recipients was not reached, while in autologous HSCT median OS was 51.3 months. In conclusion, our study represents the largest dataset of patients diagnosed with RT in Poland and confirms its dismal prognosis.
Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Adulto , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Polônia , Estudos Retrospectivos , Resultado do Tratamento , Prognóstico , Linfoma Difuso de Grandes Células B/patologia , Transformação Celular Neoplásica/patologiaRESUMO
A diagnosis of typical chronic lymphocytic leukemia (CLL) requires the presence of ≥5000 clonal B-lymphocytes/µL, the coexistence of CD19, CD20, CD5, and CD23, the restriction of light chain immunoglobulin, and the lack of expression of antigens CD22 and CD79b. Atypical CLL (aCLL) can be distinguished from typical CLL morphologically and immunophenotypically. Morphologically atypical CLL cells have been defined mainly as large, atypical forms, prolymphocytes, or cleaved cells. However, current aCLL diagnostics rely more on immunophenotypic characteristics rather than atypical morphology. Immunophenotypically, atypical CLL differs from classic CLL in the lack of expression of one or fewer surface antigens, most commonly CD5 and CD23, and the patient does not meet the criteria for a diagnosis of any other B-cell lymphoid malignancy. Morphologically atypical CLL has more aggressive clinical behavior and worse prognosis than classic CLL. Patients with aCLL are more likely to display markers associated with poor prognosis, including trisomy 12, unmutated IGVH, and CD38 expression, compared with classic CLL. However, no standard or commonly accepted criteria exist for differentiating aCLL from classic CLL and the clinical significance of aCLL is still under debate. This review summarizes the current state of knowledge on the morphological, immunophenotypic, and genetic abnormalities of aCLL.
RESUMO
BACKGROUND: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. METHODS: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. RESULTS: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. CONCLUSIONS: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. IMPACT: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.
Assuntos
Estudo de Associação Genômica Ampla , Mieloma Múltiplo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 × 10-6 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.
Assuntos
Mieloma Múltiplo/genética , Homeostase do Telômero , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Polimorfismo de Nucleotídeo Único , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Telômero/genéticaRESUMO
Introduction: During recent years, the introduction of novel drugs, particularly small molecule inhibitors, has led to remarkable progress in both previously untreated and relapsed/refractory (RR) patients in chronic lymphocytic leukemia (CLL). However, further research is necessary to find an optimal cure that responds to the individual needs of the patient. Areas covered: This review discusses new agents in phase 1 and 2 clinical trials currently underway in CLL patients. A literature review of the MEDLINE database for articles in English concerning novel drugs, clinical trials, phase 1, phase 2 and CLL was conducted via PubMed. Publications from 2000 through January 2020 were scrutinized. Conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association and American Society of Clinical Oncology were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. The search also included clinical trials registered in clinicaltrials.gov. Expert opinion: The use of BTK and PI3Kδ inhibitors and BCL-2 antagonist have changed the treatment strategy of CLL. Several clinical trials with novel, unapproved agents are currently ongoing. Their findings should define the role of these novel drugs in the treatment of patients with previously untreated and RR CLL.
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Antineoplásicos/administração & dosagem , Drogas em Investigação/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Desenvolvimento de Medicamentos , Drogas em Investigação/farmacologia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidoresRESUMO
Introduction: During recent years, therapy in chronic lymphocytic leukemia (CLL) has changed dramatically. The introduction of small molecule inhibitors has shown remarkable clinical efficacy in both previously untreated and relapsed CLL patients. However, these therapies are associated with an increased risk of specific adverse events. Selection of the best therapeutic approach for patients with CLL should be based on an assessment of general condition, comorbidities, and most importantly, the individual risk of serious side effects.Areas covered: The review presents available data about the occurrence, prophylaxis and management of the most common and clinically most relevant adverse events associated with novel therapy in CLL.Expert opinion: The incorporation of novel drugs, such as B-cell receptor inhibitors and venetoclax, a selective inhibitor of B-cell lymphoma, influences the CLL management paradigm. An individualized approach to CLL is now possible with targeted therapies. The appropriate and optimal use of current therapies requires a precise understanding of their mechanisms of action, efficacy and adverse effect profiles. A fuller understanding of the prophylaxis and management of specific adverse events stemming from CLL therapy could minimize its associated morbidity and mortality. Next-generation agents with improved efficacy and better safety profiles will further advance outcomes for patients with CLL.
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Antineoplásicos/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/efeitos adversos , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Sulfonamidas/uso terapêuticoRESUMO
PURPOSE: High-dose methylprednisolone (HDMP) with or without anti-CD20 antibody treatment in the pre B-cell receptor inhibitor (BCRi) era was used as potential salvage therapy for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (r/r CLL/SLL) patients bearing the 17p deletion. PATIENTS AND METHODS: Outcomes were compared in retrospect between r/r patients treated with HDMP (n = 20), ibrutinib (n = 39) and idelalisib with rituximab (n = 14). RESULTS: Higher overall response rates were found in those patients undergoing BCRi therapy compared to HDMP (79.2% vs. 0%; p < 0.0001), along with longer median progression-free survival (not reached vs. 24.1 months; p < 0.01). Nevertheless, there were no differences in the overall survival (HDMP 35.87 months vs. not reached; p = 0.58). CONCLUSION: HDMP treatment was significantly inferior in terms of response rate and progression-free survival in r/r CLL/SLL patients with the 17p deletion, and may only be used whenever novel compounds are unavailable.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcr/antagonistas & inibidores , Terapia de Salvação , Proteína Supressora de Tumor p53/genética , Adenina/administração & dosagem , Adenina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Piperidinas/administração & dosagem , Prognóstico , Purinas/administração & dosagem , Quinazolinonas/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida , Proteína Supressora de Tumor p53/metabolismoRESUMO
Cereblon (CRBN) is crucial for antiproliferative and immunomodulatory properties of immunomodulatory drugs. The objective of this study was to verify whether germline single nucleotide polymorphisms (SNPs) in the CRBN gene may influence response to lenalidomide in multiple myeloma (MM). Fourteen tagging SNPs covering the genetic variability in the CRBN gene region were genotyped in 167 Polish patients with refractory/relapsed MM treated with lenalidomide-based regimens. We found that carriers of minor alleles of two studied CRBN SNPs rs1714327G > C (OR = 0.26; 95% CI = 0.1-0.67; p = .0055, Bonferroni corrected p = .033) and rs1705814T > C (OR = 0.22; 95% CI = 0.07-0.65; p = .0063, Bonferroni corrected p = .037) were significantly associated with lower probability of achievement at least partial remission while treated with lenalidomide-based regimens, using the dominant inheritance model. Moreover, one of these SNPs, namely rs1705814T > C, was correlated with shorter progression-free survival (HR = 2.49; 95%CI = 1.31-4.74, p = .0054, Bonferroni corrected p = .033). It is suggested that selected germline CRBN allelic variants (rs1714327G > C and rs1705814T > C) affect lenalidomide efficacy in patients with relapsed/refractory MM.
Assuntos
Mieloma Múltiplo , Proteínas Adaptadoras de Transdução de Sinal/genética , Humanos , Lenalidomida , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Peptídeo Hidrolases/genética , Testes Farmacogenômicos , Polimorfismo Genético , Intervalo Livre de Progressão , Talidomida/uso terapêutico , Ubiquitina-Proteína LigasesRESUMO
BACKGROUND/AIM: To study the long-term clinical efficacy and tolerability of ibrutinib monotherapy in real-world relapsed and refractory chronic lymphocytic leukemia (RR-CLL) patients outside clinical trials. PATIENTS AND METHODS: Clinical data of 171 RR-CLL patients treated with ibrutinib were collected within the observational study of the Polish Adult Leukemia Study Group. RESULTS: Median patient age was 64 years. Patients were pretreated with 3 (1-10) median lines of therapy, while 42 (24.6%) had 17p deletion. The median observation time was 40 months (range=1-59 months), while median ibrutinib monotherapy reached 37.5 months (range=0.4-59.2 months). Response was noted in 132 (77.2%) patients. The estimated 5-year progression-free survival (PFS) and overall survival (OS) rates were 61.1% (95%CI=49.3-70.9%) and 56.8% (95%CI=45.6-66.6%), respectively. At the time of analysis 97 (56.7%) remained under ibrutinib monotherapy. CONCLUSION: Ibrutinib is clinically effective and tolerable as a monotherapy in real-world RR-CLL patients.