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1.
Rinsho Ketsueki ; 60(9): 1243-1256, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31597850

RESUMO

Multiple myeloma is a malignant plasma cell neoplasm that is incurable despite significant progress in treatment over the past several decades. The incorporation of novel agents and combinations into the MM treatment paradigm has resulted in improved survival and tolerability, as well as deeper responses including achieving a minimal residual disease negative state. The addition of new treatment options and combinations has added complexity in treatment selection for myeloma patients. The current strategy for newly diagnosed myeloma involves induction, consolidation, and maintenance therapy. However, nearly all myeloma patients will develop refractory disease. This highlights the need for more effective therapies targeting the myeloma cells and their microenvironment. In this article, we summarize current management of transplant eligible and ineligible newly diagnosed patients in both the upfront and relapsed refractory setting, highlighting risk adapted strategies. We also summarize emerging therapies, such as immune and targeted approaches, as well as drugs with novel mechanisms of action. Emerging strategies offer individualized treatment options and may ultimately offer the possibility of a cure for myeloma patients.


Assuntos
Mieloma Múltiplo/terapia , Gerenciamento Clínico , Humanos , Imunoterapia , Terapia de Alvo Molecular , Microambiente Tumoral
2.
Clin Lymphoma Myeloma Leuk ; 17(5): 296-304.e2, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28343904

RESUMO

BACKGROUND: Patients with multiple myeloma (MM) and other plasma cell disorders are highly susceptible to influenza infections, which are major causes of morbidity in this population, despite the routine administration of a seasonal influenza vaccination. Existing data are limited by small and retrospective studies, which suggest poor seroprotection rates of < 20% after standard influenza vaccination in patients with MM. PATIENTS AND METHODS: Patients with plasma cell dyscrasia (n = 51) were treated with a 2-dose series of high-dose inactivated trivalent influenza vaccine during the 2014 to 2015 influenza season. Laboratory-confirmed influenza infections were identified through seasonal surveillance, sera were collected for influenza hemagglutination antibody inhibition (HAI) titer assays, and logistic regression models were used to identify the clinical correlates to the HAI serologic responses. RESULTS: Influenza vaccine was well tolerated, without any vaccine-related grade ≥ 2 adverse events. Only 3 patients (6%) experienced laboratory-confirmed influenza. The rates of HAI seroprotection against all 3 vaccine strains (A/California/7/2009 [H1N1] pdm09-like virus; A/Texas/50/2012 [H3N2]-like virus; and a B/Massachusetts/2/2012-like virus) increased from 4% at baseline to 49% and 65% after 1 and 2 doses, respectively. The risk factors associated with a lower likelihood of HAI serologic response included plasma cell disorder requiring therapy, less than a partial response found on disease response assessment, and active conventional chemotherapy. Alternatively, active therapy with an immunomodulatory drug alone or with a proteasome inhibitor was associated with a greater likelihood of an HAI serologic response. CONCLUSION: These data have demonstrated that, in contrast to the historically poor results with standard influenza vaccination, this novel high-dose booster vaccination strategy leads to high rates of seroprotection. Randomized controlled studies are needed to compare this novel strategy to the standard vaccination strategy.


Assuntos
Imunização Secundária/métodos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Mieloma Múltiplo/imunologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Macroglobulinemia de Waldenstrom/imunologia
3.
Nat Med ; 22(11): 1351-1357, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27723723

RESUMO

Most human cancers, including myeloma, are preceded by a precursor state. There is an unmet need for in vivo models to study the interaction of human preneoplastic cells in the bone marrow microenvironment with non-malignant cells. Here, we genetically humanized mice to permit the growth of primary human preneoplastic and malignant plasma cells together with non-malignant cells in vivo. Growth was largely restricted to the bone marrow, mirroring the pattern in patients with myeloma. Xenografts captured the genomic complexity of parental tumors and revealed additional somatic changes. Moreover, xenografts from patients with preneoplastic gammopathy showed progressive growth, suggesting that the clinical stability of these lesions may in part be due to growth controls extrinsic to tumor cells. These data demonstrate a new approach to investigate the entire spectrum of human plasma cell neoplasia and illustrate the utility of humanized models for understanding the functional diversity of human tumors.


Assuntos
Medula Óssea , Proliferação de Células , Microambiente Celular , Camundongos , Modelos Animais , Mieloma Múltiplo , Plasmócitos/citologia , Lesões Pré-Cancerosas , Microambiente Tumoral , Animais , Humanos , Camundongos Transgênicos , Transplante de Neoplasias
4.
N Engl J Med ; 374(6): 555-61, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26863356

RESUMO

Antigen-driven selection has been implicated in the pathogenesis of monoclonal gammopathies. Patients with Gaucher's disease have an increased risk of monoclonal gammopathies. Here we show that the clonal immunoglobulin in patients with Gaucher's disease and in mouse models of Gaucher's disease-associated gammopathy is reactive against lyso-glucosylceramide (LGL1), which is markedly elevated in these patients and mice. Clonal immunoglobulin in 33% of sporadic human monoclonal gammopathies is also specific for the lysolipids LGL1 and lysophosphatidylcholine (LPC). Substrate reduction ameliorates Gaucher's disease-associated gammopathy in mice. Thus, long-term immune activation by lysolipids may underlie both Gaucher's disease-associated gammopathies and some sporadic monoclonal gammopathies.


Assuntos
Doença de Gaucher/imunologia , Glucosilceramidas/imunologia , Imunoglobulinas/imunologia , Lisofosfatidilcolinas/imunologia , Mieloma Múltiplo/imunologia , Paraproteinemias/imunologia , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Doença de Gaucher/complicações , Glucosilceramidas/análise , Humanos , Lisofosfatidilcolinas/análise , Camundongos
5.
Clin Cancer Res ; 15(1): 355-60, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19118065

RESUMO

PURPOSE: Thalidomide and its more potent immunomodulatory derivative lenalidomide enhance rituximab-mediated antibody-dependent cell-mediated cytotoxicity. We therefore evaluated lenalidomide and rituximab in symptomatic Waldenstrom's macroglobulinemia (WM) patients naive to either agent. EXPERIMENTAL DESIGN: Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1 week off) along with rituximab (375 mg/m(2)/wk) dosed on weeks 2 to 5 and 13 to 16. Sixteen patients were enrolled, 12 of whom were previously untreated. RESULTS: Unexpectedly, we observed an acute decrease in hematocrit in 13 of 16 patients (median hematocrit decrease, 4.8%), which was attributable to lenalidomide patients and which led to cessation of further enrollment on this study. Lenalidomide-related anemia was observed even at doses as low as 5 mg/d and occurred in the absence of hemolysis or other cytopenias. The overall response and major response (<50% decrease in serum IgM) rates were 50% and 25%, respectively, on an intent-to-treat basis. With a median follow-up of 31.3 months, 4 of 8 responding patients have progressed with a median time to progression of 18.9 months. CONCLUSION: Lenalidomide produces unexpected but clinically significant acute anemia in patients with WM. In comparison with our previous study with thalidomide and rituximab in an analogous patient population, the responses achieved in WM patients with lenalidomide and rituximab appear less favorable.


Assuntos
Anemia/induzido quimicamente , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Talidomida/análogos & derivados , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Imunoglobulina M/sangue , Lenalidomida , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Rituximab , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Trombocitopenia/induzido quimicamente
6.
Blood ; 113(16): 3673-8, 2009 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-19015393

RESUMO

We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenström macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m(2) per day for 5 days) of fludarabine and 8 infusions (375 mg/m(2) per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n = 2), very good partial response (n = 14), partial response (n = 21), and minor response (n = 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P = .017) and those achieving at least a very good partial response (P = .049). Grade 3 or higher toxicities included neutropenia (n = 27), thrombocytopenia (n = 7), and pneumonia (n = 6), including 2 patients who died of non-Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short- and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Vidarabina/análogos & derivados , Macroglobulinemia de Waldenstrom/dietoterapia , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/induzido quimicamente , Síndromes Mielodisplásicas/mortalidade , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/mortalidade , Neutropenia/induzido quimicamente , Neutropenia/mortalidade , Pneumonia/induzido quimicamente , Pneumonia/mortalidade , Estudos Prospectivos , Rituximab , Taxa de Sobrevida , Trombocitopenia/induzido quimicamente , Trombocitopenia/mortalidade , Fatores de Tempo , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Macroglobulinemia de Waldenstrom/mortalidade
7.
Blood ; 112(12): 4452-7, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18713945

RESUMO

Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Waldenstrom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m(2) per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n = 1), partial response (n = 15), and major response (n = 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P = .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalidomide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie,

Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Talidomida/administração & dosagem , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptores de IgG/genética , Rituximab , Talidomida/efeitos adversos , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/genética
8.
Blood ; 112(12): 4683-9, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18216294

RESUMO

Waldenström macroglobulinemia (WM) is a B-cell malignancy characterized by an IgM monoclonal gammopathy and bone marrow (BM) infiltration with lymphoplasmacytic cells (LPCs). Excess mast cells (MCs) are commonly present in WM, and provide growth and survival signals to LPCs through several TNF family ligands (CD40L, a proliferation-inducing ligand [APRIL], and B-lymphocyte stimulator factor [BLYS]). As part of these studies, we demonstrated that WM LPCs secrete soluble CD27 (sCD27), which is elevated in patients with WM (P < .001 vs healthy donors), and serves as a faithful marker of disease. Importantly, sCD27 stimulated expression of CD40L on 10 of 10 BM MC samples and APRIL on 4 of 10 BM MC samples obtained from patients with WM as well as on LAD2 MCs. Moreover, the SGN-70 humanized monoclonal antibody, which binds to CD70 (the receptor-ligand partner of CD27), abrogated sCD27 mediated up-regulation of CD40L and APRIL on WM MCs. Last, treatment of severe combined immunodeficiency-human (SCID-hu) mice with established WM using the SGN-70 antibody blocked disease progression in 12 of 12 mice, whereas disease progressed in all 5 untreated mice. The results of these studies demonstrate a functional role for sCD27 in WM pathogenesis, along with its utility as a surrogate marker of disease and a target in the treatment of WM.


Assuntos
Ligante CD27/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Macroglobulinemia de Waldenstrom/etiologia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Biomarcadores Tumorais/metabolismo , Ligante CD27/imunologia , Ligante CD27/fisiologia , Estudos de Casos e Controles , Células Cultivadas , Humanos , Mastócitos/metabolismo , Mastócitos/patologia , Camundongos , Camundongos SCID , Plasmócitos/metabolismo , Plasmócitos/patologia , Ligação Proteica , Carga Tumoral , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologia , Macroglobulinemia de Waldenstrom/metabolismo , Macroglobulinemia de Waldenstrom/patologia , Macroglobulinemia de Waldenstrom/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Clin Lymphoma Myeloma ; 7 Suppl 5: S199-206, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17877845

RESUMO

Waldenström's macroglobulinemia is a B-cell disorder characterized by bone marrow infiltration with lymphoplasmacytic cells and demonstration of an immunoglobulin M monoclonal gammopathy. Despite advances in therapy, Waldenström's macroglobulinemia remains incurable. As such, novel therapeutic agents are needed for the treatment of Waldenström's macroglobulinemia. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of Waldenström's macroglobulinemia so as to better target therapeutics for this malignancy. Importantly, as part of these efforts, we have prioritized the development of stem cell-sparing drugs because autologous stem cell transplantation remains a viable salvage option in Waldenström's macroglobulinemia. These efforts have led to the development of several novel agents for treating Waldenström's macroglobulinemia, including bortezomib; monoclonal antibodies and/or blocking protein targeting CD40, CD52, or CD70, a proliferation-inducing ligand and B-lymphocyte stimulator; the immunomodulator thalidomide as an enhancer of rituximab activity, as well as agents interfering with stem cell factor, phosphatidylinositol 3-kinase/Akt, phosphodiesterase, cholesterol, and protein kinase C beta signaling. This report provides an update on biologic studies and clinical efforts for the development of these novel agents in the treatment of Waldenström's macroglobulinemia.


Assuntos
Antineoplásicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Inibidores de Proteases/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Animais , Humanos
10.
Exp Hematol ; 35(9): 1366-75, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17761288

RESUMO

A significant impairment in understanding the biology and advancing therapeutics for Waldenstrom's macroglobulinemia (WM) has been the lack of a representative cell line and animal model. We, therefore, report on the establishment of the BCWM.1 cell line, which was derived from the long-term culture of CD19(+) selected bone marrow lymphoplasmacytic cells isolated from an untreated patient with WM. BCWM.1 cells morphologically resemble lymphoplasmacytic cells (LPC) and propagate in RPMI-1640 medium supplemented with 10% fetal bovine serum. Phenotypic characterization by flow cytometric analysis demonstrated typical WM LPC characteristics: CD5(-), CD10(-), CD19(+), CD20(+), CD23(+), CD27(-), CD38(+), CD138(+), CD40(+), CD52(+), CD70(+), CD117(+), cIgM(+), cIgG(-), cIgA(-), ckappa(-), clambda(+), as well as the survival proteins APRIL and BLYS, and their receptors TACI, BCMA and BAFF-R. Enzyme-linked immunosorbent assay studies demonstrated secretion of IgMlambda and soluble CD27. Karyotypic and multicolor fluorescence in situ hybridization studies did not demonstrate cytogenetic abnormalities. Molecular analysis of BCWM.1 cells confirmed clonality by determination of IgH rearrangements. Inoculation of BCWM.1 cells in human bone marrow chips implanted in severe combined immunodeficient-hu mice led to rapid engraftment of tumor cells and serum detection of human IgM, lambda, and soluble CD27. These studies support the use of BCWM.1 cells as an appropriate model for the study of WM, which in conjunction with the severe combined immunodeficient-hu mouse model may be used as a convenient model for studies focused on both WM pathogenesis and development of targeted therapies for WM.


Assuntos
Linhagem Celular , Modelos Animais de Doenças , Transplante Heterólogo , Macroglobulinemia de Waldenstrom/patologia , Animais , Células Cultivadas , Sobrevivência de Enxerto , Humanos , Camundongos , Camundongos SCID , Camundongos Transgênicos
11.
Clin Cancer Res ; 13(11): 3320-5, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17545538

RESUMO

PURPOSE: Waldenstrom's macroglobulinemia (WM) is a B-cell disorder. Despite advances in the therapy, WM remains incurable. As such, novel therapeutic agents are needed for the treatment of WM. EXPERIMENTAL DESIGN: In this multicenter study, 27 patients with WM received up to eight cycles of bortezomib at 1.3 mg/m(2) on days 1, 4, 8, and 11. All but one patient had relapsed/or refractory disease. RESULTS: Following therapy, median serum IgM levels declined from 4,660 to 2,092 mg/dL (P < 0.0001). The overall response rate was 85%, with 10 and 13 patients achieving minor and major responses, respectively. Responses were prompt and occurred at median of 1.4 months. The median time to progression for all responding patients was 7.9 (range, 3-21.4+) months. The most common grade III/IV toxicities occurring in > or =5% of patients were sensory neuropathies (22.2%), leukopenia (18.5%), neutropenia (14.8%), dizziness (11.1%), and thrombocytopenia (7.4%). Sensory neuropathies resolved or improved in nearly all patients following cessation of therapy. CONCLUSIONS: The results of these studies show that bortezomib is an active agent in relapsed and refractory WM.


Assuntos
Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Pirazinas/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adulto , Idoso , Medula Óssea/efeitos dos fármacos , Bortezomib , Ensaios Clínicos como Assunto , Feminino , Humanos , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Tempo , Resultado do Tratamento
12.
Clin Lymphoma Myeloma ; 7(4): 286-90, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17324336

RESUMO

BACKGROUND: Polymorphisms in FcgammaRIIa and FcgammaRIIIa receptors are associated with responses to the CD20-directed immunoglobulin G1 (IgG1) monoclonal antibody rituximab among patients with indolent lymphoma. At odds with the aforementioned clinical observations has been the finding that IgG1 binding is impacted by polymorphisms in FcgammaRIIIa but not FcgammaRIIa. One possibility for this discrepancy might involve linkage of polymorphisms between FcgammaRIIa and FcgammaRIIIa. MATERIALS AND METHODS: As such, we performed allelespecific polymerase chain reaction and directed sequencing of the genomic DNA coding region of FcgammaRIIA and FcgammaRIIIA for 52 healthy individuals. RESULTS: Two common polymorphisms were observed for FcgammaRIIA (at positions 27 and 131) and FcgammaRIIIA (at positions 48 and 158). Importantly, we observed linkage among polymorphisms within and between FcgammaRIIa and FcgammaRIIIa, including the expression of histidine at FcgammaRIIa-131 and valine at FcgammaRIIIa, both of which are associated with enhanced responses to rituximab. The results of these studies demonstrate that there is wide linkage within and between polymorphisms in FcgammaRIIa and FcgammaRIIIa and might provide an explanation for why polymorphisms at FcgammaRIIa are associated with rituximab responses despite a lack of impact on IgG1 binding. CONCLUSION: Knowledge of such linkages could facilitate the development of diagnostic tests aimed at identifying patients who might be more suitable for treatment with rituximab and possibly other therapeutic antibodies.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos CD20/imunologia , Antígenos CD/genética , Ligação Genética , Linfoma não Hodgkin/tratamento farmacológico , Receptores de IgG/genética , Adulto , Idoso , Anticorpos Monoclonais Murinos , Antígenos CD20/genética , Feminino , Genótipo , Humanos , Imunoglobulina G/imunologia , Linfoma não Hodgkin/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Rituximab , Resultado do Tratamento
13.
Am J Hematol ; 82(1): 83-4, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16955461

RESUMO

While a familial predisposition may exist in up to 20% of patients with Waldenström's Macroglobulinemia (WM), the precipitating cause of this B-cell malignancy remains unknown in most patients. In previous studies, an association between hepatitis C virus (HCV) infection and WM has been suggested as etiological. This relationship has been the subject of debate, however, with some studies demonstrating increased incidence of HCV infection among WM patients and other studies showing no such association exists. This discordance might be attributable to the analytical method used, HCV antibody detection, which might be ineffective in patients with immunosuppression. We therefore analyzed the prevalence of HCV in a large population of WM patients utilizing both an HCV antibody detection immunoassay as well as qualitative polymerase chain reaction assay to directly detect HCV presence in serum samples. None of 100 randomly tested WM patients in this study tested positive for HCV by either analytical method. Our results therefore demonstrate a lack of association between HCV and WM.


Assuntos
Hepacivirus , Anticorpos Anti-Hepatite C/sangue , Hepatite C/sangue , RNA Viral/sangue , Macroglobulinemia de Waldenstrom/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hepatite C/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Macroglobulinemia de Waldenstrom/etiologia
14.
Arch Ophthalmol ; 124(11): 1601-6, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17102008

RESUMO

OBJECTIVES: To determine the earliest retinal changes associated with Waldenström macroglobulinemia (WM) and to ascertain the serum IgM and serum viscosity (SV) levels at which these changes occur. METHODS: Patients with WM were evaluated using indirect ophthalmoscopy with scleral depression, laser Doppler retinal blood flow measurements, and serum IgM and SV determinations. Hemodynamic findings were compared with those of a group of age-matched controls. A retinopathy severity scale was developed, and the associated IgM and SV values were related to particular morphologic changes. RESULTS: A total of 46 patients with WM and 14 age-matched, healthy controls participated in the study. Patients exhibited far-peripheral hemorrhages and venous dilation with increasing SV and IgM values. Central retinal changes were associated with significantly higher SV values. Retinal vessel diameter increased with increasing serum IgM and SV levels. The mean IgM level of patients with the earliest retinal changes was 5442 mg/dL. The mean SV level was 3.1 cP. CONCLUSIONS: Retinal manifestations of hyperviscosity syndrome occur at lower serum IgM and SV levels than previously reported. Indirect ophthalmoscopy with scleral depression along with retinal vessel diameter measurements are able to detect the earliest hyperviscosity syndrome-related complications and should be considered in the treatment of patients with WM.


Assuntos
Viscosidade Sanguínea , Doenças Retinianas/diagnóstico , Vasos Retinianos/patologia , Macroglobulinemia de Waldenstrom/diagnóstico , Velocidade do Fluxo Sanguíneo , Feminino , Humanos , Imunoglobulina M/sangue , Fluxometria por Laser-Doppler , Masculino , Pessoa de Meia-Idade , Oftalmoscopia , Doenças Retinianas/sangue , Doenças Retinianas/fisiopatologia , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/fisiopatologia
15.
Clin Lymphoma Myeloma ; 6(6): 478-83, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16796779

RESUMO

BACKGROUND: Alemtuzumab is a monoclonal antibody used in the treatment of CD52-expressing B-cell malignancies, including Waldenstrom's macroglobulinemia (WM). Recent studies demonstrate high levels of alemtuzumab activity in relapsed/refractory disease. One potential target of alemtuzumab is bone marrow mast cells (BMMCs), which provide growth and survival signaling for WM lymphoplasmacytic cells. PATIENTS AND METHODS: We therefore examined BMMCs (FceRI+, CD117+) from WM and other mast cell (MC) disorders for expression of CD52. RESULTS: We identified cell surface antigen expression by multicolor flow cytometric analysis and found CD52 expressed on human mast-derived cell line-1 (HMC-1) and LAD2 MC lines, on BMMC from 13 of 15 patients with WM, and on BMMCs from 4 of 4 patients with systemic mastocytosis (SM). None of 4 healthy donors expressed CD52. Reverse-transcriptase polymerase chain reaction analysis confirmed CD52 expression in the HMC-1 and LAD2 MC lines, in BMMCs from 14 of 15 patients with WM, and 3 of 3 patients with SM. CD52 transcripts were also detected in BMMCs from 6 of 6 healthy donors, despite the absence of CD52 cell surface expression. Importantly, we observed high levels of alemtuzumab-mediated, antibody-dependent, cell-mediated cytotoxicity against LAD2 MCs and BMMCs from patients with WM and SM. CONCLUSION: These studies demonstrate that CD52 is widely expressed on human MCs and WM bone marrow lymphoplasmacytic cells and provide the preclinical rationale for the use of alemtuzumab in the treatment of WM and possibly other MC-related disorders.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antígenos CD/imunologia , Antígenos de Neoplasias/imunologia , Células da Medula Óssea/imunologia , Glicoproteínas/imunologia , Mastócitos/imunologia , Mastocitose/tratamento farmacológico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Alemtuzumab , Anticorpos Monoclonais Humanizados , Antígenos CD/genética , Antígenos de Neoplasias/genética , Apoptose/efeitos dos fármacos , Células da Medula Óssea/patologia , Antígeno CD52 , Glicoproteínas/genética , Humanos , Mastócitos/efeitos dos fármacos , Mastócitos/patologia , Mastocitose/imunologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Macroglobulinemia de Waldenstrom/imunologia
16.
Blood ; 107(9): 3442-6, 2006 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-16410453

RESUMO

Waldenström macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of lymphoplasmacytic cells into bone marrow and the presence of an IgM monoclonal gammopathy. As part of the Third International Workshop on WM, held October 7 to 10, 2004 in Paris, France, a consensus panel charged with providing treatment recommendations for WM updated its recommendations on both frontline and salvage therapies. The panel considered encouraging results from recent studies that addressed the use of extended-dose rituximab as well as other treatment options: therapy with either nucleoside analogs and alkylator agents, rituximab in combination with nucleoside analogs, nucleoside analogs plus alkylator agents, or combination chemotherapies, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or cyclophosphamide and dexamethasone. The panel determined that these were reasonable treatment options for WM patients and such therapeutic approaches were likely to yield results that are at least as good as if not better than the currently recommended use of single-agent alkylator, nucleoside analog, or standard-dose rituximab therapy. Such approaches were deemed to be reasonable treatment for WM patients in both the upfront and salvage settings, though randomized studies addressing the efficacy and toxicity of such novel approaches over previously established standard of care options are needed.


Assuntos
Macroglobulinemia de Waldenstrom/terapia , Alquilantes/administração & dosagem , Alquilantes/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Humanos , Nucleosídeos/administração & dosagem , Nucleosídeos/uso terapêutico , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Rituximab , Terapia de Salvação , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico
17.
Clin Lymphoma ; 5(4): 246-9, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15794857

RESUMO

CD5, CD10, and CD23 are cell surface antigens used to distinguish B-cell disorders. The expression of these antigens and their clinical significance in Waldenstrom's macroglobulinemia (WM), an uncommon B-cell disorder, remains to be clarified. We therefore determined expression of CD5, CD10, and CD23 by flow cytometric analysis on bone marrow lymphoplasmacytic cells (CD19+ k/l light chain restricted) for 171 serially biopsied patients with findings of the consensus panel definition of WM. Importantly, we also correlated laboratory and clinical data, as well as existence of a familial history of a B-cell disorder in view of reports suggesting familial predisposition in WM. These studies demonstrated tumor cell expression of CD5, CD10, and CD23 in 15 of 171 patients (9%), 11 of 161 patients (7%), and 37 of 105 patients (35%), respectively. Coexpression of CD23 with CD5 or CD10 was common. Tumor Lymphoplasmacytic from 10 of 15 (66%) and 3 of 11 (27%) patients with WM that expressed CD5 and CD10, respectively, also showed expression of CD23 (P = 0.01 and P = 0.08, respectively). Among patients with CD23 expression, increased serum immunoglobulin (Ig) M levels were observed compared with patients without CD23 expression (P = 0.05). No differences in age at diagnosis; presence of adenopathy and/or splenomegaly; bone marrow involvement; serum IgA, IgB, and b2 macroglobulin levels; hematocrit; platelet count; or familial history of WM or a related B-cell disorder were observed among patients with and without CD5, CD10, and CD23 expression. These studies demonstrate that CD5, CD10, and CD23 are commonly found in WM and that their expression should not exclude the diagnosis of WM. Moreover, expression of CD23 may define a clinically distinct subset of patients with WM.


Assuntos
Antígenos CD5/biossíntese , Perfilação da Expressão Gênica , Neprilisina/biossíntese , Receptores de IgE/biossíntese , Macroglobulinemia de Waldenstrom/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/patologia
18.
J Clin Oncol ; 23(3): 474-81, 2005 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-15659493

RESUMO

PURPOSE: Rituximab is an important therapeutic for Waldenstrom's macroglobulinemia (WM). Polymorphisms in FcgammaRIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell-mediated cytotoxicity, and may therefore influence responses to rituximab. PATIENTS AND METHODS: Sequence analysis of the entire coding region of FcgammaRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known. RESULTS: Variations in five codons of FcgammaRIIIA were identified. Two were commonly observed (FcgammaRIIIA-48 and FcgammaRIIIA-158) and predicted for amino acid polymorphisms at FcgammaRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcgammaRIIIA-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcgammaRIIIA-158F/F were always FcgammaRIIIA-48L/L, and patients with either FcgammaRIIIA-L/R or -L/H always expressed at least one valine at FcgammaRIIIA-158 (P < or = .001). The response trend was higher for patients with FcgammaRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcgammaRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcgammaRIIIA-48L/L were higher when at least one valine was present at FcgammaRIIIA-158 (P = .057), thereby supporting a primary role for FcgammaRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, no significant differences in the median time to progression and progression-free survival were observed when patients were grouped according to their FcgammaRIIIA-48 and -158 polymorphisms. CONCLUSION: The results of these studies therefore support a predictive role for FcgammaRIIIA-158 polymorphisms and responses to rituximab in WM.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos CD/genética , Antineoplásicos/uso terapêutico , Perfilação da Expressão Gênica , Polimorfismo Genético , Receptores de IgG/genética , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Murinos , Antineoplásicos/farmacologia , Códon , Progressão da Doença , Intervalo Livre de Doença , Feminino , Proteínas Ligadas por GPI , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Rituximab , Resultado do Tratamento
19.
Clin Lymphoma ; 5(3): 205-7, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15636699

RESUMO

Waldenstrom's macroglobulinemia (WM) is an incurable B-cell malignancy. Interestingly, an unusual response activity was observed in 5 patients with WM that appeared related to their use of sildenafil, a phosphodiesterase inhibitor used to treat erectile dysfunction. One patient demonstrated a complete remission, and 4 other patients demonstrated less dramatic, but also unexpected, responses associated with sildenafil. In view of these findings, WM tumor cells were culture-sorted with sildenafil at pharmacologically achievable levels and apoptosis was demonstrated in tumor cells from all 5 patients. These studies suggest that sildenafil may be an active agent in the treatment of WM.


Assuntos
Piperazinas/uso terapêutico , Vasodilatadores/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Purinas , Citrato de Sildenafila , Sulfonas , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/patologia
20.
Semin Oncol ; 30(2): 110-5, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12720118

RESUMO

This presentation represents consensus recommendations for the clinicopathological definition of Waldenstrom's macroglobulinemia (WM), which were prepared in conjunction with the Second International Workshop held in Athens, Greece during September 2002. WM is an uncommon lymphoproliferative disorder characterized primarily by bone marrow infiltration and IgM monoclonal gammopathy. It should be considered a distinct clinicopathological entity rather than a clinical syndrome secondary to IgM secretion. The underlying pathological diagnosis in WM is lymphoplasmacytic lymphoma as defined by the World Health Organization (WHO) and Revised European-American Lymphoma (REAL) classification criteria. The concentration of monoclonal IgM can vary widely in WM and it is not possible to define a concentration that reliably distinguishes WM from monoclonal gammopathy of undetermined significance (MGUS) and other lymphoproliferative disorders. A diagnosis of WM can therefore be made irrespective of IgM concentration if there is evidence on a bone marrow trephine biopsy of bone marrow infiltration by lymphoplasmacytic lymphoma with predominantly an intertrabecular pattern, supported by appropriate immunophenotypic studies. Simple criteria to distinguish patients with symptomatic WM who require therapy from those with asymptomatic WM and MGUS were also proposed. Patients with clinical features attributable to IgM monoclonal gammopathy but no overt evidence of lymphoma are considered to constitute a distinct clinical group and the term "IgM-related disorders" is proposed.


Assuntos
Macroglobulinemia de Waldenstrom/classificação , Macroglobulinemia de Waldenstrom/diagnóstico , Antígenos CD5 , Aberrações Cromossômicas , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Imunofenotipagem , Linfoma/imunologia , Guias de Prática Clínica como Assunto , Macroglobulinemia de Waldenstrom/imunologia , Macroglobulinemia de Waldenstrom/patologia
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