RESUMEN
CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Humanos , Neoplasia Residual/etiología , Piperidinas , SulfonamidasRESUMEN
Highly active BTK inhibitors (BTKis) and the BCL2 inhibitor venetoclax have transformed the therapeutic landscape for chronic lymphocytic leukemia (CLL). Results of prospective clinical trials demonstrate the efficacy of venetoclax to salvage patients with disease progression on BTKis, but data on BTKi therapy after disease progression on venetoclax are limited, especially regarding durability of benefit. We retrospectively evaluated the records of 23 consecutive patients with relapsed/refractory CLL who received a BTKi (ibrutinib, n = 21; zanubrutinib, n = 2) after stopping venetoclax because of progressive disease. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 34 months (range, <1 to 49) and 42 months (range, 2-49), respectively. Prior remission duration ≥24 months and attainment of complete remission or undetectable measurable residual disease on venetoclax were associated with longer PFS after BTKi salvage (P = .044 and P = .029, respectively). BTKi therapy achieved durable benefit for patients with the BCL2 Gly101Val venetoclax resistance mutation (estimated 24-month PFS, 69%). At a median survivor follow-up of 33 months (range, 2-53), 11 patients remained on BTKi and 12 had stopped therapy because of disease progression (n = 8) or toxicity (n = 4). Our findings indicate that BTKi therapy can provide durable CLL control after disease progression on venetoclax.
Asunto(s)
Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Terapia Molecular Dirigida , Proteínas de Neoplasias/antagonistas & inhibidores , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Terapia Recuperativa , Sulfonamidas/uso terapéutico , Adenina/uso terapéutico , Anciano , Anciano de 80 o más Años , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ensayos Clínicos como Asunto/estadística & datos numéricos , Progresión de la Enfermedad , Evaluación de Medicamentos , Resistencia a Antineoplásicos , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Inducción de Remisión , Estudios Retrospectivos , Sulfonamidas/farmacología , Resultado del TratamientoRESUMEN
Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Isoquinolinas/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Purinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Deleción Cromosómica , Cromosomas Humanos Par 17 , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Humanos , Isoquinolinas/efectos adversos , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Purinas/efectos adversos , Recurrencia , Síndrome de Smith-Magenis , Tasa de Supervivencia , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Chronic lymphocytic leukaemia (CLL) remains the most common incurable malignancy of B cells in the western world. Patient outcomes are heterogeneous and can be difficult to predict with current prognostic markers. Here, we used a quantitative label-free proteomic technique to ascertain differences in the B-cell proteome from healthy donors and CLL patients with either mutated (M-CLL) or unmutated (UM-CLL) IGHV to identify new prognostic markers. In peripheral B-CLL cells, 349 (22%) proteins were differentially expressed between normal B cells and B-CLL cells and 189 (12%) were differentially expressed between M-CLL and UM-CLL. We also examined the proteome of proliferating CLL cells in the lymph nodes, and identified 76 (~8%) differentially expressed proteins between healthy and CLL lymph nodes. B-CLL cells show over-expression of proteins involved in lipid and cholesterol metabolism. A comprehensive lipidomic analysis highlighted large differences in glycolipids and sphingolipids. A shift was observed from the pro-apoptotic lipid ceramide towards the anti-apoptotic/chemoresistant lipid, glucosylceramide, which was more evident in patients with aggressive disease (UM-CLL). This study details a novel quantitative proteomic technique applied for the first time to primary patient samples in CLL and highlights that primary CLL lymphocytes display markers of a metabolic shift towards lipid synthesis and breakdown.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Redes y Vías Metabólicas , Biomarcadores , Biopsia , Estudios de Casos y Controles , Biología Computacional , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Lipidómica/métodos , Ganglios Linfáticos/patología , Masculino , Espectrometría de Masas , Metabolómica/métodos , Modelos BiológicosRESUMEN
The number of novel therapies for the treatment of myeloma is rapidly increasing, as are the clinical trials evaluating them in combination with other novel and established therapies. Proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are the most well known and studied classes of novel agents targeting myeloma, with histone deacetylase inhibitors, nuclear export inhibitors and several other approaches also being actively investigated. However, in parallel with the development and clinical use of these novel myeloma therapies is the emergence of novel mechanisms of resistance, many of which remain elusive, particularly for more recently developed agents. Whilst resistance mechanisms have been best studied for proteasome inhibitors, particularly bortezomib, class effects do not universally apply to all class members, and within-class differences in efficacy, toxicity and resistance mechanisms have been observed. Although immunomodulatory agents share the common cellular target cereblon and thus resistance patterns relate to cereblon expression, the unique cell surface antigens to which monoclonal antibodies are directed means these agents frequently exhibit unique within-class differences in clinical efficacy and resistance patterns. This review describes the major classes of novel therapies for myeloma, highlights the major clinical trials within each class and discusses known resistance mechanisms.
Asunto(s)
Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasoma/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Resistencia a Antineoplásicos , Humanos , Factores Inmunológicos/uso terapéutico , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Mutación , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismoRESUMEN
Intra-tumor genetic heterogeneity is a hallmark of cancer. The ability to monitor and analyze these sub-clonal cell populations can be considered key to successful treatment, particularly in the modern era of targeted therapies. Although advances in sequencing technologies have significantly improved our ability to analyze the mutational landscape of tumors, this utility is reduced when considering small, but clinically significant sub-clones, that is, those representing <10% of the tumor burden. We have developed a high-throughput method that utilizes a 17-probe labeled bacterial artificial chromosome contig to quantify sub-clonal populations of cells based on deletion of a single locus. Chronic lymphocytic leukemia (CLL) cells harboring deletion of the short arm of chromosome 17 (del17p), an important prognostic marker for CLL were used to demonstrate the technique. Sub-clones of del17p cells were quantified and isolated from heterogeneous CLL populations using fluorescence in situ hybridization in suspension (FISH-IS) and the locus specific probe set. Using the combination of FISH-IS with the locus-specific probe set enables automated analysis of tens of thousands of cells, accurately quantifying and isolating cells carrying a del17p. Based on the fluorescence intensity of 17p probes, 17p (TP53) deleted cells were identified and sorted using flow cytometric techniques, and enrichment was demonstrated using single nucleotide polymorphism analysis. The ability to separate sub-clones of cells based on genetic heterogeneity, independent of the clone size, highlights the potential application of this method not only in the diagnostic and prognostic setting, but also as an unbiased approach to enable further detailed genetic analysis of the sub-clone with deep sequencing approaches. © 2017 International Society for Advancement of Cytometry.
Asunto(s)
Citometría de Flujo/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Hibridación Fluorescente in Situ/métodos , Leucemia Linfocítica Crónica de Células B/patología , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Células Clonales/patología , Heterogeneidad Genética , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Mutación/genética , Pronóstico , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Chronic lymphocytic leukaemia (CLL) frequently responds to chemoimmunotherapy combining cytotoxic chemotherapy and monoclonal antibodies. However, CLL is associated with significant genetic heterogeneity, and some high-risk forms are known to be chemo-resistant and associated with early relapse. AIMS: To review the current treatment paradigm of patients with high-risk disease, in particular those with del(17p) and TP53 variants. RESULTS: A 'watch and wait' approach is recommended for all patients who are asymptomatic. When symptomatic, fluorescence in situ hybridisation testing should be performed and gene sequencing considered subsequently to identify del(17p) and TP53 variants respectively. In the front-line setting, treatment within a clinical trial is the preferred option. In the relapsed or refractory setting, patients with del(17p) or TP53 aberrations should be offered treatment with a novel agent, such as ibrutinib, idelalisib-rituximab or venetoclax. However, of note, at the date of this publication venetoclax is not PBS reimbursed, and ibrutinib will not be reimbursed until 1 December 2017. CONCLUSION: Testing for del(17p) and TP53 variants identifies high-risk CLL that requires specialist management.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Terapia Molecular Dirigida , Purinas/uso terapéutico , Quinazolinonas/uso terapéutico , Rituximab/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Australia , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Guías como Asunto , Humanos , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/inmunología , Proteína p53 Supresora de Tumor/genética , Espera VigilanteAsunto(s)
Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Integrina alfa4/genética , Leucemia Linfocítica Crónica de Células B/genética , Anciano de 80 o más Años , Anemia/complicaciones , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Linfocitosis/complicaciones , Masculino , MutaciónRESUMEN
Mantle cell lymphoma (MCL) is a rare but aggressive form of non-Hodgkin's lymphoma. Involvement of the kidney is an infrequent occurrence in patients with MCL and can be the result of direct infiltration or paraneoplastic glomerulopathy. Proliferative glomerulonephritis, membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis have previously been reported in association with MCL. We report a 55-year-old woman who developed nephrotic syndrome due to biopsy proven minimal change disease (MCD) in association with MCL. Proteinuria decreased with prednisolone treatment and MCD remains in remission without any immunosuppressant after the treatment of the underlying MCL.
Asunto(s)
Linfoma de Células del Manto/complicaciones , Nefrosis Lipoidea/complicaciones , Síndrome Nefrótico/etiología , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Glucocorticoides/uso terapéutico , Humanos , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/tratamiento farmacológico , Metotrexato/uso terapéutico , Persona de Mediana Edad , Síndrome Nefrótico/tratamiento farmacológico , Prednisolona/uso terapéutico , Prednisona/uso terapéutico , Vincristina/uso terapéuticoRESUMEN
Cholesterol has many critical functions in cells. It is a key component of membranes and cell-signalling processes, and it functions as a chemical precursor in several biochemical pathways, such as Vitamin D and steroid synthesis. Cholesterol has also been implicated in the development and progression of various cancers, in which it is thought to promote cell proliferation, migration, and invasion. Chronic lymphocytic leukemia (CLL) is an example of a lipid-avid cancer that relies on lipid metabolism, rather than glycolysis, to fuel cell proliferation. However, data regarding the role of cholesterol in CLL are conflicting. Studies have shown that dyslipidaemia is more common among CLL patients than age-matched healthy controls, and that CLL patients who take cholesterol-lowering drugs, such as statins, appear to have improved survival rates. Therefore, defining the roles of cholesterol in CLL may highlight the importance of monitoring and managing hyperlipidaemia as part of the routine management of patients with CLL. In this review, we discuss the roles of cholesterol in the context of CLL by examining the literature concerning the trafficking, uptake, endogenous synthesis, and intracellular handling of this lipid. Data from clinical trials investigating various classes of cholesterol and lipid-lowering drugs in CLL are also discussed.
RESUMEN
PURPOSE: The CAPTIVATE study investigated first-line ibrutinib plus venetoclax for chronic lymphocytic leukemia in 2 cohorts: minimal residual disease (MRD)-guided randomized discontinuation (MRD cohort) and Fixed Duration (FD cohort). We report outcomes of fixed-duration ibrutinib plus venetoclax in patients with high-risk genomic features [del(17p), TP53 mutation, and/or unmutated immunoglobulin heavy chain (IGHV)] in CAPTIVATE. PATIENTS AND METHODS: Patients received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day). FD cohort patients (n = 159) received no further treatment. Forty-three MRD cohort patients with confirmed undetectable MRD (uMRD) after 12 cycles of ibrutinib plus venetoclax received randomized placebo treatment. RESULTS: Of 195 patients with known status of genomic risk features at baseline, 129 (66%) had ≥1 high-risk feature. Overall response rates were >95% regardless of high-risk features. In patients with and without high-risk features, respectively, complete response (CR) rates were 61% and 53%; best uMRD rates: 88% and 70% (peripheral blood) and 72% and 61% (bone marrow); 36-month progression-free survival (PFS) rates: 88% and 92%. In subsets with del(17p)/TP53 mutation (n = 29) and unmutated IGHV without del(17p)/TP53 mutation (n = 100), respectively, CR rates were 52% and 64%; uMRD rates: 83% and 90% (peripheral blood) and 45% and 80% (bone marrow); 36-month PFS rates: 81% and 90%. Thirty-six-month overall survival (OS) rates were >95% regardless of high-risk features. CONCLUSIONS: Deep, durable responses and sustained PFS seen with fixed-duration ibrutinib plus venetoclax are maintained in patients with high-risk genomic features, with similar PFS and OS to those without high-risk features. See related commentary by Rogers, p. 2561.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Piperidinas/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéuticoRESUMEN
Many cancers rely on glucose as an energy source, but it is becoming increasingly apparent that some cancers use alternate substrates to fuel their proliferation. Chronic lymphocytic leukaemia (CLL) is one such cancer. Through the use of flow cytometry and confocal microscopy, low levels of glucose uptake were observed in the OSU-CLL and HG3 CLL cell lines relative to highly glucose-avid Raji cells (Burkitt's lymphoma). Glucose uptake in CLL cells correlated with low expression of the GLUT1 and GLUT3 receptors. In contrast, both CLL cell lines and primary CLL cells, but not healthy B cells, were found to rapidly internalise medium- and long-chain, but not short-chain, fatty acids (FAs). Differential FA uptake was also observed in primary cells taken from patients with unmutated immunoglobulin heavy variable chain usage (IGHV) compared with patients with mutated IGHV. Delipidation of serum in the culture medium slowed the proliferation and significantly reduced the viability of OSU-CLL and HG3 cells, effects that were partially reversed by supplementation with a chemically defined lipid concentrate. These observations highlight the potential importance of FAs in the pathogenesis of CLL and raise the possibility that targeting FA utilisation may represent a novel therapeutic and prognostic approach in this disease.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/metabolismo , Metabolismo de los Lípidos , Anciano , Linfocitos B/metabolismo , Linfocitos B/patología , Línea Celular Tumoral , Ácidos Grasos/metabolismo , Femenino , Glucosa/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana EdadRESUMEN
Chronic lymphocytic leukaemia (CLL) is a malignant lymphoproliferative disorder characterised by the accumulation of dysfunctional B-lymphocytes in the blood and lymphoid tissues. It is a clonally complex disease with a high degree of both intra-tumoural and inter-patient heterogeneity. This variability leads to a wide range of clinical outcomes and highlights the critical need for accurate prognostic tests in CLL. With the advent of a range of new targeted agents for CLL in recent years, there is also a clinical need for improved predictive tests to therapy. This review of laboratory testing in CLL focuses on emerging technologies for prognostication including single nucleotide polymorphism microarray for karyotypic analysis, targeted next generation sequencing analysis of the immunoglobulin heavy chain variable region gene as well as genes recurrently mutated in the disease such as TP53, and detection of minimal residual disease.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/diagnóstico , Polimorfismo de Nucleótido Simple/genética , Técnicas de Laboratorio Clínico , Secuenciación de Nucleótidos de Alto Rendimiento , Cariotipificación , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Neoplasia Residual , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Análisis de Secuencia de ADNRESUMEN
Covalent Bruton tyrosine kinase inhibitors (BTKi's) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency. To define the characteristics and outcomes of patients with double class-resistant disease, we retrospectively analyzed 17 patients who developed progressive disease (PD) on both TA classes for CLL (venetoclax, then BTKi, n=12; BTKi, then venetoclax, n = 5). The cohort was heavily pretreated (median lines of prior therapy, 4) and enriched for adverse disease genetics (complex karyotype, 12 of 12 tested [100%]; del(17p)/TP53 mutations, 15 of 17 [88%]). The median time to progression on prior venetoclax was 24 months (range, 6-94 months) and was 25 months (range, 1-55 months) on prior BTKi. Progression on second-line TA was manifest as progressive CLL in 11 patients and as Richter transformation in 6. The median overall survival after progression on second-line TA was 3.6 months (95% confidence interval, 2-11 months). Patients with double class-resistant CLL have a dismal prognosis, representing a group of high unmet need.
Asunto(s)
Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Linfoma de Células B Grandes Difuso , Antineoplásicos/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Estudios RetrospectivosRESUMEN
PURPOSE: CAPTIVATE (NCT02910583), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL). METHODS: Previously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety. RESULTS: One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, -1.6 to 10.9]; P = .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time. CONCLUSION: The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.
Asunto(s)
Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , Piperidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adenina/farmacología , Adenina/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Estudios de Cohortes , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Piperidinas/farmacología , Sulfonamidas/farmacología , Análisis de SupervivenciaRESUMEN
Paraneoplastic manifestations in malignant pleural mesothelioma are rare. We report a case of malignant pleural mesothelioma associated with minimal change disease (MCD). A 58-year-old man with occupational exposure to asbestos presented with severe peripheral edema, heavy proteinuria, and acute renal failure shortly after the diagnosis of mesothelioma had been confirmed. The renal biopsy demonstrated MCD. The underlying pathogenesis of this association remains unknown.
Asunto(s)
Lesión Renal Aguda/etiología , Mesotelioma/complicaciones , Mesotelioma/patología , Neoplasias Pleurales/complicaciones , Neoplasias Pleurales/patología , Lesión Renal Aguda/patología , Lesión Renal Aguda/terapia , Humanos , Masculino , Mesotelioma/terapia , Persona de Mediana Edad , Nefrosis Lipoidea/etiología , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/terapia , Neoplasias Pleurales/terapiaRESUMEN
Cardiac amyloidosis is a progressive disorder and is sometimes difficult to diagnose even when suspected in the appropriate clinical setting. We present an interesting case of rapidly progressive light-chain cardiac amyloidosis and highlights the importance of close monitoring even when the initial biopsy and imaging findings are not pathognomonic for amyloidosis. (Level of Difficulty: Beginner.).
RESUMEN
PURPOSE: In the phase III DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy versus ofatumumab [median (m) progression-free survival (PFS), 13.3 vs. 9.9 months (HR, 0.52; P < 0.0001); overall response rate [ORR], 74% vs. 45% (P < 0.0001)], with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial. PATIENTS AND METHODS: Patients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety. RESULTS: As of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or TP53 mutations had similar outcomes [ORR, 77% (20/26); mPFS, 14.7 months]. Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%). CONCLUSIONS: Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Estudios Cruzados , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Isoquinolinas/administración & dosificación , Isoquinolinas/efectos adversos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Purinas/administración & dosificación , Purinas/efectos adversos , Terapia Recuperativa , Tasa de SupervivenciaRESUMEN
The cryopreservation of peripheral blood mononuclear cells (PBMCs) is a routine research laboratory process, enabling long-term storage of primary patient blood samples. Retrospective analysis of these samples has the potential to identify markers that may be associated with prognosis and response to treatment. To draw valid biological conclusions from this type of analysis, it is essential to ensure that any observed changes are directly related to the pathology of the disease rather than the preservation process itself. Therefore, we have investigated 15 cell surface markers that are relevant to chronic lymphocytic leukemia (CLL) on matched fresh and thawed samples to determine the effect of cryopreservation on their detection. We found that the number of CLL cells positive for the markers CD22, CD40, CD49d, CD54, CD69, and CXCR3 was decreased significantly after cryopreservation. In addition, the mean fluorescence intensity of 10 of the 15 markers changed significantly after cryopreservation. These findings demonstrate that care must be taken when interpreting this type of analysis on thawed samples.
Asunto(s)
Antígenos CD/análisis , Antígenos de Neoplasias/análisis , Artefactos , Biomarcadores de Tumor/análisis , Conservación de la Sangre/métodos , Criopreservación , Citometría de Flujo , Inmunofenotipificación , Leucemia Linfocítica Crónica de Células B/sangre , Receptores CXCR/análisis , Epítopos/análisis , Reacciones Falso Negativas , Citometría de Flujo/métodos , Humanos , Inmunofenotipificación/métodos , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
Chronic lymphocytic leukemia (CLL) remains the most common leukemia in the Western world. Whilst its disease course is extremely heterogeneous (ranging from indolent to aggressive), current methods are unable to accurately predict the clinical journey of each patient. There is clearly a pressing need for both improved prognostication and treatment options for patients with this disease. Whilst molecular studies have analyzed both genetic mutations and gene expression profiles of these malignant B-cells, and as a result have shed light on the pathogenesis of CLL, proteomic studies have been largely overlooked to date. This review summarizes our current knowledge of the proteomics of CLL, and discusses some of the issues in CLL proteomic research, such as reproducibility and data interpretation. In addition, we look ahead to how proteomics may significantly help in the development of a successful treatment for this currently incurable disease.