RESUMO
INTRODUCTION: Serum lipid profiles play a crucial role in diagnosing and evaluating cardiovascular diseases. However, the presence of paraprotein can lead to inaccurate dyslipidemia results on automated analyzers. CASE REPORT: A 65-year-old woman whose combined concentrations of HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) consistently surpassed her total serum cholesterol levels over a period of three months presented with unusual lipid component detection. Further analysis revealed the presence of a monoclonal paraprotein, identified as an IgMλ band, with a concentration of 28.0 g/L. The patient was subsequently diagnosed with Waldenström macroglobulinemia. The use of abnormal reaction kinetic curves and the ß quantification method, along with an alternative method that did not suffer from interference, revealed that the monoclonal paraprotein interfered with the measurements of HDL-C, LDL-C, apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB) when using the Roche detection system. This interference led to spurious elevated HDL-C concentrations and falsely decreased apoA-I and apoB concentrations, while the LDL-C results were minimally affected. Although diluting the sample normalized the HDL-C and LDL-C measurements, the interference with the apoA-I and apoB assays persisted. No other common biochemical tests were interfered with this paraprotein. CONCLUSION: Caution is advised when using a homogenous method for direct measurement of HDL-C and LDL-C in patients with monoclonal paraprotein. Techniques to recognize and eliminate this interference are available. However, immunoturbidimetric detection of apoA-I and apoB levels is also susceptible to this interference, which is not readily removable.
Assuntos
Dislipidemias , Paraproteínas , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/complicações , Idoso , Feminino , Paraproteínas/análise , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/complicações , HDL-Colesterol/sangue , LDL-Colesterol/sangueRESUMO
Waldenström macroglobulinemia (WM) is a type of B-cell lymphoma that produces IgM. Our study aimed to investigate the role of CXCL13, a chemokine essential for B lymphocytes, in the evaluation of treatment response and prognosis in WM. We collected serum samples and clinical data from 72 WM patients, with 69 patients receiving systemic therapy and 3 patients opting not to receive treatment. Serum CXCL13 levels at baseline and after six months of treatments were measured by enzyme-linked immunosorbent assay. The median serum level of CXCL13 was 1 539.2 pg/ml (range 10.0-21 389.9) at baseline and significantly decreased to 123.1 pg/ml (range 0.0-6 741.5) after 6 months of treatments. At baseline, higher CXCL13 levels were associated with lower hemoglobin levels (p = 0.001), higher ß2-microglobulin levels (p = 0.001), lower albumin levels (p = 0.046), and higher IPSS-WM scores (p = 0.013). After 6 months of treatment, patients who achieved PR/VGPR had significantly lower CXCL13 levels compared to those with SD (70.2 pg/ml vs 798.6 pg/ml, p = 0.002). The median follow-up period was 40 months (range 4.2-188). Eight patients died during the follow-up period. Overall survival differed based on CXCL13 levels. When grouped by baseline CXCL13 levels, the median OS was 60.0 months in patients with serum CXCL13 > 2 000 pg/ml, while it was not reached in patients with low CXCL13 levels (p < 0.001). Based on CXCL13 levels after the treatments, the median OS was 74.0 months in patients with serum CXCL13 > 200 pg/ml, while it was not reached in patients with CXCL13 ≤ 200 pg/ml. In a subgroup of 28 patients with a series of serum samples, the increase of serum CXCL13 level was associated with disease progression or the start of next-line therapy (p < 0.001). Our study concludes that serum CXCL13 levels decrease in WM patients treated with various regimens and correlate with treatment response. Detecting serum CXCL13 at baseline or after treatment help in predicting prognosis.
Assuntos
Quimiocina CXCL13 , Macroglobulinemia de Waldenstrom , Humanos , Quimiocina CXCL13/sangue , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/mortalidade , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Prognóstico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do Tratamento , Rituximab/uso terapêutico , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Taxa de SobrevidaAssuntos
Adenina/análogos & derivados , Antineoplásicos/uso terapêutico , Evolução Clonal , Piperidinas/uso terapêutico , Linfoma Plasmablástico/etiologia , Inibidores de Proteínas Quinases/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adenina/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Bortezomib/uso terapêutico , Ciclofosfamida/administração & dosagem , Progressão da Doença , Doxorrubicina/administração & dosagem , Evolução Fatal , Feminino , Humanos , Imunoglobulina M/sangue , Cadeias kappa de Imunoglobulina/sangue , Linfonodos/patologia , Fator 88 de Diferenciação Mieloide/genética , Proteínas de Neoplasias/sangue , Linfoma Plasmablástico/sangue , Linfoma Plasmablástico/tratamento farmacológico , Linfoma Plasmablástico/patologia , Prednisona/administração & dosagem , Vincristina/administração & dosagem , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/patologiaRESUMO
Patients with asymptomatic/smouldering Waldenström macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow-up of 9·5 [8·1-11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and ß2 -microglobulin (ß2 M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time-to-progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88WT ) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7-8·7) vs. 4·7 (2·4-7·7) years for the MYD88L265P cohort, n = 42; P = 0·11]. The presence of C-X-C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4WT vs. 5·6 years for CXCR4MUT , P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age-, sex- and calendar year-matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and ß2 M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre-emptive intervention in this patient population.
Assuntos
Hemoglobinas/análise , Fator 88 de Diferenciação Mieloide/genética , Macroglobulinemia de Waldenstrom/genética , Microglobulina beta-2/sangue , Idoso , Biomarcadores/análise , Progressão da Doença , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Valor Preditivo dos Testes , Receptores CXCR4/genética , Estudos Retrospectivos , Fatores de Risco , Sobrevida , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/patologiaRESUMO
Errors in laboratory medicine occur in the preanalytical, analytical, and postanalytical phases. The errors are mostly detected in the preanalytical period. However, analytical errors are still an important source of error, despite their frequency is reduced significantly in years thanks to developments in laboratories. In this case, an analytical error was noticed during the verification of a patient's results. The direct bilirubin of a 66-year-old male patient admitted to the emergency department was higher than the total bilirubin. The patient's symptoms were fatigue and dyspnoea. Albumin and haemoglobin (Hb) concentrations of the patient were significantly low. After considering the patient's demographics and laboratory results, the laboratory specialist suspected a paraproteinemia interference. Total protein was performed as a reflective test. The albumin/globulin ratio was reversed. Thereafter, serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) were performed as another reflective tests, respectively. SPEP and IFE results were in favour of monoclonal gammopathy. The patient was directed to a haematologist, underwent a bone marrow biopsy, and the result was reported as Waldenstrom's macroglobulinemia with plasma cell differentiation expressing IgM-Kappa. The patient went on a chemotherapy protocol, and his condition has been improved in subsequent months. Detection of analytical errors is of great importance, like in our case, and may be used as a tool to identify patients who have not yet been diagnosed. The laboratory specialist must dominate the entire process of each test in the laboratory, be aware of the limitations of tests, and turn these disadvantages into advantages when necessary.
Assuntos
Bilirrubina/sangue , Paraproteínas/metabolismo , Macroglobulinemia de Waldenstrom/sangue , Idoso , Humanos , MasculinoRESUMO
Waldenstrom macroglobulinemia (WM) is a rare type of non-Hodgkin lymphoma with great heterogeneity, and the data of peripheral blood T-lymphocyte subsets in WM are limited. This study aimed to investigate the clinical correlation and distribution of circulating T-lymphocyte subsets in newly diagnosed WM patients. We retrospectively searched medical records for 86 newly diagnosed WM patients. Comparisons of the absolute CD3+ T-lymphocyte count (ACD3C), CD4+ T-lymphocyte count (ACD4C), CD8+ T-lymphocyte count (ACD8C), and CD4+/CD8+ T-lymphocyte ratio (CD4+/CD8+) as continuous parameters in different groups were calculated. Univariate and multivariate analyses were used to assess prognostic factors for overall survival (OS) and progression-free survival (PFS). Young patients (<65 years) had lower ACD8C levels and a higher CD4+/CD8+ ratio. And the lower level of ß2-microglobulin (<3 mg/L) was associated with a higher CD4+/CD8+ ratio. With a median follow-up of 25 months, the univariate survival analysis showed that CD4+/CD8+ ratio inversion (CD4+/CD8+<1.5) was associated with shorter OS and PFS, and multivariate analysis confirmed that inverted CD4+/CD8+ ratio could be an independent adverse prognostic factor for OS and PFS. Additionally, initial treatment with rituximab or bortezomib significantly improved the PFS and OS of CD4+/CD8+ inversion patients but did not affect normal CD4+/CD8+ patients. We show that low circulating CD4+/CD8+ ratio at diagnosis is an adverse prognostic factor in WM patients and that first-line therapy which included rituximab or bortezomib significantly improved PFS and OS for patients with CD4+/CD8+ ratio less than 1.5.
Assuntos
Relação CD4-CD8 , Macroglobulinemia de Waldenstrom/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Rituximab/administração & dosagem , Taxa de Sobrevida , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/mortalidade , Microglobulina beta-2/análiseRESUMO
Zanubrutinib is a potent, second-generation Bruton's tyrosine kinase inhibitor that is currently being investigated in patients with B-cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the PKs of zanubrutinib and identify the potential impact of intrinsic and extrinsic covariates on zanubrutinib PK. Data across nine clinical studies of patients with B-cell malignancies and data of healthy volunteers (HVs) were included in this analysis, at total daily doses ranging from 20 to 320 mg. In total, 4,925 zanubrutinib plasma samples from 632 subjects were analyzed using nonlinear mixed-effects modeling. Zanubrutinib PKs were adequately described by a two-compartment model with sequential zero-order then first-order absorption, and first-order elimination. A time-dependent residual error model was implemented in order to better capture the observed maximum concentration variability in subjects. Baseline alanine aminotransferase and health status (HVs or patients with B-cell malignancies) were identified as statistically significant covariates on the PKs of zanubrutinib. These factors are unlikely to be clinically meaningful based on a sensitivity analysis. No statistically significant differences in the PKs of zanubrutinib were observed based on age, sex, race (Asian, white, and other), body weight, mild or moderate renal impairment (creatinine clearance ≥ 30 mL/minute as estimated by Cockcroft-Gault), baseline aspartate aminotransferase, bilirubin, tumor type, or use of acid-reducing agents (including proton pump inhibitors). These results support that no dose adjustment is considered necessary based on the aforementioned factors.
Assuntos
Leucemia de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Variação Biológica da População , Estudos de Casos e Controles , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Feminino , Voluntários Saudáveis , Humanos , Leucemia de Células B/sangue , Linfoma de Células B/sangue , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Macroglobulinemia de Waldenstrom/sangue , Adulto JovemRESUMO
DISEASE OVERVIEW: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. DIAGNOSIS: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in the majority of IgM MGUS patients. RISK STRATIFICATION: Age, hemoglobin level, platelet count, ß2 microglobulin, LDH and monoclonal IgM concentrations are characteristics that are predictive of outcomes. RISK-ADAPTED THERAPY: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogues are active but usage is declining in favor of less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine. MANAGEMENT OF REFRACTORY DISEASE: Bortezomib, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection.
Assuntos
Macroglobulinemia de Waldenstrom , Fatores Etários , Humanos , Imunoglobulina M/sangue , L-Lactato Desidrogenase/sangue , Mutação de Sentido Incorreto , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Contagem de Plaquetas , Medição de Risco , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/tratamento farmacológicoRESUMO
We report the case of a man with a primary diagnosis of Waldenström macroglobulinemia. He secondarily presented a diffuse large B cell lymphoma (DLBCL) located in the nasal fossae, which relapsed later in the eye. The diagnosis of these two malignancies is based on a multidisciplinary biological approach using new sensitive and specific techniques. These techniques revealed that the two diseases harbor different B cell clones, indicating a distinct origin. This observation highlights the importance of targeted biological techniques for the diagnosis of these two rare hemopathies. It also shows that it is possible to prove the independent nature of the two tumor clones, thus allowing optimized therapeutic management.
Assuntos
Carcinoma de Células de Transição/diagnóstico , Neoplasias Oculares/secundário , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Neoplasias da Bexiga Urinária/diagnóstico , Macroglobulinemia de Waldenstrom/diagnóstico , Idoso , Carcinoma de Células de Transição/sangue , Carcinoma de Células de Transição/complicações , Diagnóstico Diferencial , Neoplasias Oculares/sangue , Neoplasias Oculares/diagnóstico , Testes Hematológicos , Humanos , Imunoglobulina M/análise , Imunoglobulina M/sangue , Imunofenotipagem , Achados Incidentais , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/complicações , Masculino , Gamopatia Monoclonal de Significância Indeterminada/sangue , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/patologia , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/complicações , Urotélio/patologia , Baixa Visão/diagnóstico , Baixa Visão/etiologia , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/complicações , Macroglobulinemia de Waldenstrom/patologiaRESUMO
CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.
Assuntos
Linfócitos B/efeitos dos fármacos , Paraproteinemias/tratamento farmacológico , Rituximab/uso terapêutico , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ataxia/tratamento farmacológico , Ataxia/etiologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Linfócitos B/patologia , Crioglobulinas/análise , Feminino , França/epidemiologia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/imunologia , Humanos , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oftalmoplegia/tratamento farmacológico , Oftalmoplegia/etiologia , Paraproteinemias/sangue , Paraproteinemias/imunologia , Paraproteinemias/terapia , Parestesia/tratamento farmacológico , Parestesia/etiologia , Estudos Retrospectivos , Síndrome , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/imunologiaRESUMO
Ibrutinib may inhibit intestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B-cell malignancies received single doses of EE/LN (30/150 µg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single-dose ibrutinib plus single-dose midazolam). Systemic induction was assessed at steady-state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) were derived using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady-state, the Cmax and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion.
Assuntos
Adenina/análogos & derivados , Anticoncepcionais Orais/administração & dosagem , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Piperidinas/administração & dosagem , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adenina/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Bupropiona/administração & dosagem , Bupropiona/farmacocinética , Anticoncepcionais Orais/farmacocinética , Interações Medicamentosas , Etinilestradiol/administração & dosagem , Etinilestradiol/farmacocinética , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/metabolismo , Levanogestrel/administração & dosagem , Levanogestrel/farmacocinética , Linfoma de Zona Marginal Tipo Células B/sangue , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma de Célula do Manto/sangue , Linfoma de Célula do Manto/metabolismo , Taxa de Depuração Metabólica , Midazolam/administração & dosagem , Midazolam/farmacocinética , Pessoa de Meia-Idade , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/metabolismoRESUMO
We aimed to detect the MYD88L265P and CXCR4S338X mutations in cell-free DNA (cfDNA) in patients with Waldenström macroglobulinemia (WM). We collected peripheral blood and paired bone marrow aspirates from 27 WM patients (including 16 patients with newly diagnosed WM, 3 patients with WM in relapse and 8 patients with WM during treatment). cfDNA was extracted from peripheral blood using a QIAamp Circulating Nucleic Acid Kit. The MYD88L265P and CXCR4S338X mutations were detected by real-time allele-specific PCR (AS-PCR) in cfDNA and genomic DNA (gDNA) extracted from bone marrow aspirates. The sensitivity of real-time AS-PCR for detecting MYD88L265P in cfDNA was determined using a serial dilution of 10%, 2%, 0.4% and 0.08% MYD88L265P cfDNA in wild-type cfDNA. Among the 27 patients, MYD88L265P was detected in 88.9% of them in gDNA and in 85.2% of them in cfDNA, with a concordance rate of 96.3%. The concordance rates were 93.8%, 100% and 100% in patients with newly diagnosed WM, patients with WM in relapse and patients with WM during treatment, respectively. The sensitivity of real-time AS-PCR for detecting MYD88L265P in cfDNA was 0.4%. CXCR4S338X was detected in 6.3% of the 16 newly diagnosed WM patients in both gDNA and cfDNA, with a concordance rate of 100.0%. It is feasible to apply cfDNA to detect MYD88L265P and CXCR4S338X in WM patients with a high concordance rate.
Assuntos
Ácidos Nucleicos Livres/genética , Mutação de Sentido Incorreto , Fator 88 de Diferenciação Mieloide/genética , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores CXCR4/genética , Macroglobulinemia de Waldenstrom/genética , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Ácidos Nucleicos Livres/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/sangue , Proteínas de Neoplasias/sangue , Receptores CXCR4/sangue , Sensibilidade e Especificidade , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/terapiaRESUMO
INTRODUCTION: After tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 were introduced for the treatment of chronic myeloid leukemia, clinical outcomes have improved dramatically. However, together with the increase in the survival rate, a more frequent occurrence of secondary malignancies has been observed as well. TKIs have been demonstrated to be a risk factor of malignancies such as non-Hodgkin lymphoma, prostate cancer, and skin cancer. However, lymphoplasmacytic lymphoma (LPL) has never been reported as a secondary malignancy after TKI treatment in chronic myeloid leukemia (CML). PATIENT CONCERNS: An 81-year-old male patient diagnosed with CML and treated with TKIs for a long period (15 years) was admitted due to a chief complaint of abdominal pain. A large abdominal mass was detected by imaging that included computed tomography. DIAGNOSIS: LPL was confirmed from biopsies after ultrasonography and sigmoidoscopy. Serum IgM level was increased and M protein and monoclonal gammopathy, IgM_kappa light chain type were detected. INTERVENTIONS: The patient received six cycles of R-CHOP chemotherapy. OUTCOMES: After chemotherapy, he showed response. The sizes of the abdominal mass and lymph nodes decreased; moreover, serum M protein and IgM levels decreased, as well. CONCLUSION: Herein, for the first time, we describe a patient who developed LPL as a secondary malignancy after administration of TKIs for the treatment of CML. Our observations indicate the importance of awareness of this secondary malignancy that can develop in CML patients treated with TKIs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Segunda Neoplasia Primária , Macroglobulinemia de Waldenstrom , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biópsia/métodos , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Humanos , Imunoglobulina M/sangue , Masculino , Segunda Neoplasia Primária/sangue , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/patologia , Prednisona/administração & dosagem , Radiografia Abdominal/métodos , Rituximab/administração & dosagem , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Vincristina/administração & dosagem , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/etiologia , Macroglobulinemia de Waldenstrom/patologiaAssuntos
Autoanticorpos/sangue , Síndromes Paraneoplásicas/imunologia , Pênfigo/imunologia , Macroglobulinemia de Waldenstrom/complicações , Idoso , Autoanticorpos/imunologia , Desmocolinas/imunologia , Evolução Fatal , Humanos , Lábio , Masculino , Mucosa Bucal/imunologia , Mucosa Bucal/patologia , Síndromes Paraneoplásicas/sangue , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/patologia , Pênfigo/sangue , Pênfigo/diagnóstico , Pênfigo/patologia , Língua , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/imunologiaRESUMO
Rituximab-containing regimens are commonly used for frontline therapy in patients with symptomatic Waldenström macroglobulinemia (WM). We had observed that a portion of WM patients experienced deepening of response months to years after therapy completion. We carried a retrospective study aimed at describing this phenomenon. We gathered baseline data, and responses at end of induction, end of maintenance and best response. Deepening of response was defined as ≥25% decrease in serum IgM achieved at a later time from therapy completion. Of 178 patients included, 116 (65%) received maintenance therapy and 62 (35%) were observed. In patients who received maintenance, 44 (38%) had ≥25% decrease in serum IgM level after the end of maintenance with a median time from end of maintenance to lowest IgM level of 1.6 years (range 0.1-7.9 years). In patients who were observed, 19 (31%) had ≥25% decrease in serum IgM level after the end of induction with a median time from end of induction to lowest IgM level of 1.6 years (range 0.2-5.1 years). Baseline hemoglobin <11.5 g/dL, bone marrow involvement ≥50%, CXCR4 mutations and serum IgM ≥4000 mg/dL were associated with lower odds of deepening of response after therapy completion. Deepening of response was associated with better progression-free survival (PFS; HR 0.46, 95% CI 0.26-0.80; P = .006) and better survival after frontline treatment initiation (SAFTI; HR 0.21, 95% CI 0.06-0.73; P = .01). In conclusion, deepening of response occurs in one third of WM patients after completing rituximab-containing regimens and was associated with better PFS and SAFTI.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Feminino , Seguimentos , Humanos , Imunoglobulina M/sangue , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Paraproteínas/análise , Intervalo Livre de Progressão , Receptores CXCR4/genética , Estudos Retrospectivos , Rituximab/administração & dosagem , Análise de Sobrevida , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/patologiaAssuntos
Viscosidade Sanguínea/imunologia , Imunoglobulina M/sangue , Troca Plasmática/métodos , Rituximab/administração & dosagem , Macroglobulinemia de Waldenstrom , Idoso de 80 Anos ou mais , Exame de Medula Óssea/métodos , Diagnóstico Diferencial , Feminino , Humanos , Imunoeletroforese/métodos , Fatores Imunológicos/administração & dosagem , Mieloma Múltiplo/diagnóstico , Fator Reumatoide/sangue , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/fisiopatologia , Macroglobulinemia de Waldenstrom/terapiaRESUMO
PURPOSE: To image retinal blood vessels in patients with Waldenström's macroglobulinemia using optical coherence tomography (OCT). METHODS: Retrospective case series examining fundus photographs and OCT scans of 16 eyes in eight patients with Waldenström's macroglobulinemia. Analyses included intravascular OCT reflectivity profiles and vessel diameters, and their relation to total immunoglobulin M (IgM) levels. RESULTS: In six out of eight patients, cross-sectional OCT scans of larger retinal vessels (diameter > 100 µm) showed normal intravascular reflectivity and retrovascular shadowing. In two patients with the highest total IgM > 60 g/l, altered intravascular reflectivity, distinct anterior and posterior vessel wall reflexes, and retrovascular hyposhadowing were seen. Normalization of the OCT reflectivity in these patients occurred after reduction of total IgM to < 17 g/l and was accompanied by decreasing venous tortuosity and disappearance of retinal haemorrhages and cotton wool spots. CONCLUSION: This study found that Waldenström's macroglobulinemia and total IgM > 60 g/l were associated with abnormal intravascular reflectivity and retrovascular shadowing on OCT. Awareness of these signs of hyperviscosity could potentially enable earlier detection of critical conditions in patients with Waldenström's macroglobulinemia and improve the assessment of severity and treatment effect.
Assuntos
Vasos Retinianos/patologia , Tomografia de Coerência Óptica , Macroglobulinemia de Waldenstrom/fisiopatologia , Idoso , Estudos Transversais , Feminino , Humanos , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Vasos Retinianos/diagnóstico por imagem , Estudos Retrospectivos , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/diagnóstico por imagemAssuntos
Proteínas Sanguíneas/análise , Eletroforese , Imunoeletroforese , Idoso , Anticorpos Monoclonais/análise , Anticorpos Monoclonais/sangue , Biomarcadores , Viscosidade Sanguínea , Eletroforese/métodos , Feminino , Humanos , Imunoeletroforese/métodos , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/diagnósticoRESUMO
We investigated the feasibility of using next-generation sequencing (NGS) technique using molecular barcoding technology to detect MYD88 L265P mutation in unselected peripheral blood mononuclear cells (PBMCs) in 52 patients with Waldenström's macroglobulinemia [1] and 21 patients with IgM-monoclonal gammopathy of undetermined significance (MGUS). The NGS technique successfully detected the MYD88 L265P in unselected PBMCs at a sensitivity of 0.02%, which was ×5 higher than that of AS-PCR. All the results between paired BM and PB samples from 2 IgM MGUS and 4 untreated WM patients matched completely. MYD88 L265P mutation was detected in 14/21 (66.7%), 14/19 (73.7%), and 10/33 (30.3%) with the median mutant allele burden of 0.36% (range, 0.06-2.85%), 0.48% (range, 0.02-32.3%), and 0.16% (range, 0.02-33.8%), in IgM-MGUS, untreated WM, and previously treated WM, respectively. Multiple linear regression analysis identified an absolute peripheral lymphocyte count as the positive predictor of PB mutant allele burden (R2 = 0,72, P<0.0001). Our non-invasive, simple NGS method has the potential to detect MYD88 L265P mutations in PBMCs of IgM MGUS and WM patients, which may especially utilized for monitoring minimal residual tumor burden after treatment.