RESUMO
Background and Objectives: The treatment of Myeloma after the second relapse is still challenging. The aim of the study was to investigate the outcomes of the POM-DEX regimen in real clinical practice. Materials and Methods: We retrospectively and prospectively analyzed 121 patients with MM treated with POM-DEX in three Italian sites in Tuscany. We assessed the efficacy based on IMWG Uniform Response Criteria in 106 patients who had received at least two courses of the POM-DEX regimen. The median time from diagnosis to use of POM-DEX was 65 months. POM-DEX median use was in the fourth-line therapy. 63.6% were exposed to lenalidomide or thalidomide, 40.5% to bortezomib or carfilzomib or ixazomib, 5.8% to mAbs in the immediately preceding line of therapy. Results: ORR was 43.4%. Median PFS and OS were 8.5 and 14 months. Eighty-nine patients received more than two courses: their median PFS and OS were 11 and 16 months. When used as the third line of therapy, median PFS and OS were 9 and 20 months and, when patients received POM-DEX for more than two courses, median PFS and OS were 14.5 and 22.5 months. Conclusions: POM-DEX is effective in RRMM, regardless of the latest exposure to IMiDs, PIs, and mAbs in the previous line of therapy.
Assuntos
Mieloma Múltiplo , Talidomida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Humanos , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Talidomida/análogos & derivados , Talidomida/uso terapêuticoRESUMO
The high proportion of long-term nonprogressors among chronic lymphocytic leukemia (CLL) patients suggests the existence of a regulatory network that restrains the proliferation of tumor B cells. The identification of molecular determinants composing such network is hence fundamental for our understanding of CLL pathogenesis. Based on our previous finding establishing a deficiency in the signaling adaptor p66Shc in CLL cells, we undertook to identify unique phenotypic traits caused by this defect. Here we show that a lack of p66Shc shapes the transcriptional profile of CLL cells and leads to an upregulation of the surface receptor ILT3, the immunoglobulin-like transcript 3 that is normally found on myeloid cells. The ectopic expression of ILT3 in CLL was a distinctive feature of neoplastic B cells and hematopoietic stem cells, thus identifying ILT3 as a selective marker of malignancy in CLL and the first example of phenotypic continuity between mature CLL cells and their progenitors in the bone marrow. ILT3 expression in CLL was found to be driven by Deltex1, a suppressor of antigen receptor signaling in lymphocytes. Triggering of ILT3 inhibited the activation of Akt kinase upon B-cell receptor (BCR) stimulation. This effect was achieved through the dynamic coalescence of ILT3, BCRs, and phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 into inhibitory clusters at the cell surface. Collectively, our findings identify ILT3 as a signature molecule of p66Shc deficiency in CLL and indicate that ILT3 may functionally contribute to a regulatory network controlling tumor progression by suppressing the Akt pathway.
Assuntos
Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Superfície Celular/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática , Regulação Leucêmica da Expressão Gênica , Humanos , Imunomodulação/genética , Glicoproteínas de Membrana , Receptores de Superfície Celular/genética , Receptores Imunológicos , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/deficiência , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Células-Tronco/metabolismo , Transcriptoma/genética , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima/genéticaRESUMO
Introduction: Carfilzomib, a potent, irreversible, selective proteasome inhibitor has demonstrated consistent results in relapsed/refractory multiple myeloma (RRMM) combined with lenalidomide and dexamethasone (KRd). No prospective studies are yet available that analyzed the efficacy of the KRd combination. Methods: Herein, we report a multicenter prospective observational study on 85 patients who were treated with KRd combination as the second or third line of treatment, according to standard practice. Results: The median age was 61 years; high-risk cytogenetic was found in 26% and renal impairment (estimated glomerular filtration rate (eGFR) <60 ml/min) in 17%. After a median follow-up of 40 months, patients received a median number of 16 cycles of KRd, with a median duration of treatment (DoT) of 18 months (range, 16.1-19.2 months). The overall response rate was 95%, with a high-quality response (≥very good partial remission [VGPR]) in 57% of the patients. The median progression-free survival (PFS) was 36 months (range, 29.1-43.2 months). Achievement of at least VGPR and a previous autologous stem cell transplantation (ASCT) were associated with longer PFS. The median overall survival (OS) was not reached (NR); the 5-year OS rate was 73%. Nineteen patients underwent KRd treatment as a bridge to autologous transplantation, obtaining a post-transplant minimal residual disease (MRD) negativity in 65% of cases. The most common adverse events were hematological, followed by infection and cardiovascular events, rarely G3 or higher, with a discontinuation rate for toxicities of 6%. Our data confirmed the feasibility and safety of the KRd regimen in real life.
Assuntos
Antineoplásicos/administração & dosagem , Bortezomib/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Mieloma Múltiplo/diagnóstico , Resultado do TratamentoRESUMO
Systemic amyloidosis arises from monoclonal CD38+ plasma cells that produce misfolded immunoglobulin light chains, which form amyloid fibrils that are deposited into different tissues, leading to organ damage. Daratumumab is a human IgG/k monoclonal antibody that targets CD38, a glycoprotein uniformly expressed on human plasma cells. Daratumumab has been utilized in recent years with unprecedented responses in multiple myeloma. In patients with relapsed or refractory AL amyloidosis, daratumumab has shown promising efficacy in terms of hematologic responses and improvement in organ function. Here, we report real-life treatment with Daratumumab in 33 AL amyloidosis patients treated within the Regional Tuscan Myeloma network at 5 centers with associated MGUS or SMM (n = 15) or symptomatic MM (n = 18). Patients were treated at relapsed/refractory disease stages (n = 29) with a median of one previous line of therapy or at diagnosis (n = 4). Daratumumab showed good efficacy, representing 60% of good hematological responses and 50% of organ responses in a real-life population of patients with an acceptable toxicity profile.
Assuntos
Transformação Celular Viral , Infecções por Vírus Epstein-Barr/complicações , Linfoma de Células B/diagnóstico , Linfoma de Células B/etiologia , Plasmocitoma/complicações , Plasmocitoma/virologia , Idoso , Infecções por Vírus Epstein-Barr/diagnóstico , Humanos , Linfoma de Células B/tratamento farmacológico , Masculino , Plasmócitos/patologia , Plasmócitos/virologia , Plasmocitoma/diagnóstico , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Ativação ViralRESUMO
Bortezomib was the first proteasome inhibitor (PI) discovered and demonstrated great efficacy in myeloma, both in vitro and in patients. However, still many patients ultimately relapse and there is the need for novel therapies. A second generation of PI have been discovered, potentially more effective ands some also orally administered. Carfilzomib is an irreversible proteasome inhibitor that showed great efficacy in clinical studies. Ixazomib is an oral compound that has been introduced recently in the therapeutic spectrum. Novel agents such as Marizomib seem promising in the fact that can also pass through the blood brain barrier and maybe effective also in CNS muyeloma. This review focus on all proteasome inhibitors available in clinics and the new ones coming soon.
Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Animais , Ácidos Borônicos/farmacologia , Ácidos Borônicos/uso terapêutico , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Neoplasias do Sistema Nervoso Central/metabolismo , Descoberta de Drogas , Humanos , Lactonas/farmacologia , Lactonas/uso terapêutico , Mieloma Múltiplo/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Inibidores de Proteassoma/farmacologia , Pirróis/farmacologia , Pirróis/uso terapêutico , Treonina/análogos & derivados , Treonina/farmacologia , Treonina/uso terapêuticoRESUMO
Abnormality of the B-cell receptor (BCR) signaling is correlated to origin of many B-cell malignancies. Bruton's tyrosine kinase (BTK), is described as a possible target in a many B-cell neoplasms. Ibrutinib is the most used inhibitor of BTK and has great tolerability and efficacy in chronic lymphocytic leukemia. This review summarizes results with ibrutinib in clinical trials and novel BTK inhibitors of interest.
Assuntos
Antineoplásicos/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Estrutura Molecular , Piperidinas , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Pirazóis/química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
Suppression of the cytotoxic T cell (CTL) immune response has been proposed as one mechanism for immune evasion in cancer. In this study, we have explored the underlying basis for CTL suppression in the context of B cell malignancies. We document that human B cells have an intrinsic ability to resist killing by freshly isolated cytotoxic T cells (CTLs), but are susceptible to lysis by IL-2 activated CTL blasts and CTLs isolated from immunotherapy-treated patients with chronic lymphocytic leukemia (CLL). Impaired killing was associated with the formation of dysfunctional non-lytic immune synapses characterized by the presence of defective linker for activation of T cells (LAT) signaling and non-polarized release of the lytic granules transported by ADP-ribosylation factor-like protein 8 (Arl8). We propose that non-lytic degranulation of CTLs are a key regulatory mechanism of evasion through which B cells may interfere with the formation of functional immune synapses by CTLs.
Assuntos
Linfócitos B/metabolismo , Grânulos Citoplasmáticos/metabolismo , Exocitose , Sinapses Imunológicas/metabolismo , Leucemia Linfocítica Crônica de Células B/imunologia , Linfócitos T Citotóxicos/metabolismo , Fatores de Ribosilação do ADP/metabolismo , Linfócitos B/imunologia , Células Cultivadas , Humanos , Sinapses Imunológicas/imunologia , Sinapses Imunológicas/ultraestrutura , Linfócitos T Citotóxicos/imunologia , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab27 de Ligação ao GTPRESUMO
The introduction of novel agents in multiple myeloma therapy has dramatically improved survival in latest years. Great progress has also been detected in particular poor clinical situation such as acute renal failure in which survival was dismal in the past. Treatment with bortezomib, thalidomide and dialysis associated with high cut-off (HCO) filters can recover more than two thirds of myeloma patients with an end stage renal failure. Novel proteasome inhibitors and immunomodulating agents (IMID's) are even more promising in this set of patients. Aim of this review is to provide an overview of treatments of multiple myeloma patients with acute renal failure coming from most recent clinical trials.
Assuntos
Antineoplásicos/uso terapêutico , Falência Renal Crônica/terapia , Mieloma Múltiplo/terapia , Diálise Renal/métodos , Humanos , Falência Renal Crônica/complicações , Mieloma Múltiplo/complicaçõesRESUMO
Multiple myeloma survival has significantly improved in the latest years due to a broad spectrum of novel agents available for treatment. The introduction of thalidomide, bortezomib, and lenalidomide together with autologous stem-cell transplantation has considerably increased complete remission rate and progression-free survival resulting ultimately in prolonged survival in myeloma patients. Moreover, novel strategies of treatment such as consolidation and maintenance are being used to further implement responses. Finally, a number of new drugs such as carfilzomib and pomalidomide are already in clinical practice, making the future of myeloma patients brighter.
RESUMO
Median age at diagnosis for chronic lymphocytic leukaemia (CLL) patients is now 72 years, thus a consistent number of patients may not tolerate standard doses i.v. of fludarabine, cyclophosphamide and rituximab (FCR), the best available therapy, due to unacceptable myelotoxicity and risk of severe infections. We studied safety and efficacy of the addition of rituximab to the oral low-dose FC regimen (old-FCR) in a selected population of 30 elderly (median age 75, 15 untreated, 15 treated with 1 prior therapy) CLL patients. Complete remission (CR) rate was 80% in the untreated patients (overall response rate, ORR 93%), and 30% in pretreated patients (ORR 74%). Progression free survivals (PFS) were 45 months and 30 months in the untreated and treated patients, respectively. In patients achieving CR, old-FCR led to PFS of 67 months. Moreover, haematological toxicity was mild (grade 3-4: 15%) and patients were treated mostly in outpatient clinic. Old-FCR could be a good therapy option for elderly CLL patients outside clinical trials, larger studies are needed to confirm our findings.