RESUMO
Hairy cell leukaemia (HCL) is a rare CD20+ B cell malignancy characterised by rare "hairy" B cells and extensive bone marrow (BM) infiltration. Frontline treatment with the purine analogue cladribine (CDA) results in a highly variable response duration. We hypothesised that analysis of the BM tumour microenvironment would identify prognostic biomarkers of response to CDA. HCL BM immunology pre and post CDA treatment and healthy controls were analysed using Digital Spatial Profiling to assess the expression of 57 proteins using an immunology panel. A bioinformatics pipeline was developed to accommodate the more complex experimental design of a spatially resolved study. Treatment with CDA was associated with the reduction in expression of HCL tumour markers (CD20, CD11c) and increased expression of myeloid markers (CD14, CD68, CD66b, ARG1). Expression of HLA-DR, STING, CTLA4, VISTA, OX40L were dysregulated pre- and post-CDA. Duration of response to treatment was associated with greater reduction in tumour burden and infiltration by CD8 T cells into the BM post-CDA. This is the first study to provide a high multiplex analysis of HCL BM microenvironment demonstrating significant immune dysregulation and identify biomarkers of response to CDA. With validation in future studies, prospective application of these biomarkers could allow early identification and increased monitoring in patients at increased relapse risk post CDA.
Assuntos
Biomarcadores Tumorais/metabolismo , Leucemia de Células Pilosas/patologia , Microambiente Tumoral , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Leucemia de Células Pilosas/imunologia , Leucemia de Células Pilosas/metabolismo , Complexo Principal de Histocompatibilidade/imunologia , Masculino , Pessoa de Meia-Idade , PrognósticoAssuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Leucemia de Células Pilosas/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia de Células Pilosas/imunologia , Leucemia de Células Pilosas/terapia , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos RetrospectivosRESUMO
Hairy cell leukemia (HCL) is an indolent B-cell malignancy with excellent initial response to purine analogs pentostatin or cladribine, but patients are rarely, if ever, cured. Younger patients will usually need repeat chemotherapy which has declining benefits and increasing toxicities with each course. Targeted therapies directed to the BRAF V600E mutation and Bruton's tyrosine kinase may be helpful, but rarely eradicate the minimal residual disease (MRD) which will eventually lead to relapse. Moxetumomab pasudotox (Moxe) is an anti-CD22 recombinant immunotoxin, which binds to CD22 on HCL cells and leads to apoptotic cell death after internalization and trafficking of the toxin to the cytosol. Phase I testing achieved a complete remission (CR) rate of 57% in relapsed/refractory HCL. Most CRs were without MRD and eradication of MRD correlated with prolonged CR duration. Patients were often MRD-free after five years. Important mild-moderate toxicities included capillary leak and hemolytic uremic syndromes which could be prevented and managed conservatively. A phase 3 trial met its endpoint of durable CR with acceptable toxicity, leading to FDA approval of Moxe for relapsed/refractory HCL, under the name Lumoxiti. Moxe combined with rituximab is currently being evaluated in relapsed/refractory HCL to improve the rate of MRD-free CR.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Desenvolvimento de Medicamentos/métodos , Imunotoxinas/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Animais , Toxinas Bacterianas/genética , Ensaios Clínicos como Assunto , Humanos , Imunotoxinas/genética , Leucemia de Células Pilosas/imunologia , Leucemia de Células Pilosas/patologia , Engenharia de Proteínas/métodosAssuntos
COVID-19/complicações , Hipóxia/etiologia , Terapia de Imunossupressão , Leucemia de Células Pilosas/complicações , Leucemia Mieloide Aguda/complicações , Linfoma de Células B/complicações , Linfoma Folicular/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , COVID-19/imunologia , Neoplasias do Colo , Comorbidade , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Humanos , Hipóxia/terapia , Hospedeiro Imunocomprometido , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/imunologia , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/imunologia , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/imunologia , Masculino , Segunda Neoplasia Primária/complicações , Oxigenoterapia , Pandemias , Recidiva , Respiração Artificial , SARS-CoV-2RESUMO
Biologics are potentially immunogenic and can elicit immune response. Complex biologics, such as bispecific antibodies or multi-domain molecules can induce anti-drug antibodies (ADA) with specificity to different domains. Domain specific ADAs may differently affect drug efficacy and safety, and thus, characterization of ADA domain specificity has become a regulatory expectation for multi-domain biologics. Unlike well-established methods for screening, confirmation, titer and neutralizing ADA detection, characterization of ADA domain specificity is an emerging field. The conventional approach for determination of ADA domain specificity is a competitive inhibition with domain-containing molecules. When developing a conventional domain specificity assay for moxetumomab pasudotox, a recombinant anti-CD22 immunotoxin, comprised of two functional domains (CD22-binding fragment and truncated Pseudomonas exotoxin A (PE38), we encountered a bioanalytical challenge. The method was able to detect immunodominant anti-PE38 (ADA-PE) but generated false negative results for low abundant CD22-binding domain ADA (ADA-BD) in a polyclonal sample. Troubleshooting experiments using control samples with varying levels of each ADA subtype demonstrated that a major factor for successful ADA identification was the ratio of the ADA signals contributed by each ADA subtype. To overcome this unique bioanalytical challenge, we developed a novel approach, which ensures detection of a domain-specific ADA subtype regardless of its relative level in a polyclonal ADA sample by evaluating signal inhibition by a respective domain-containing molecule at the condition when signals from all other ADAs are fully blocked. The method has been used for characterization of ADA domain specificity in moxetumomab pasudotox clinical trials, including study 1053, the pivotal Phase III study in hairy cell leukemia patients. It allowed for successful detection of ADA-BD in the presence of immunodominant ADA-PE, enabling accurate determination of domain specificity for moxetumomab pasudotox. The results demonstrated that the method was superior than the conventional approach. The method could be applied broadly to other biologics with two or more domains when there is a need to detect a minor ADA subtype in polyclonal samples.
Assuntos
Anticorpos/isolamento & purificação , Toxinas Bacterianas/imunologia , Monitoramento de Medicamentos/métodos , Exotoxinas/imunologia , Leucemia de Células Pilosas/tratamento farmacológico , Domínios Proteicos/imunologia , ADP Ribose Transferases/imunologia , Anticorpos/sangue , Anticorpos/imunologia , Toxinas Bacterianas/administração & dosagem , Toxinas Bacterianas/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Exotoxinas/administração & dosagem , Exotoxinas/efeitos adversos , Reações Falso-Negativas , Estudos de Viabilidade , Humanos , Imunoensaio/métodos , Leucemia de Células Pilosas/sangue , Leucemia de Células Pilosas/imunologia , Sensibilidade e Especificidade , Resultado do Tratamento , Fatores de Virulência/imunologia , Exotoxina A de Pseudomonas aeruginosaRESUMO
The relationship between hematological malignancy and chemotherapy on the prevalence of antibiotic allergy label (AAL) is ill-defined. We performed a multicenter retrospective case-control study comparing AAL rates among cladribine-treated hairy cell leukemia (C-HCL) cases, non-HCL cladribine-treated controls (control-1), and fludarabine-treated controls (control-2). The prevalence of AALs in C-HCL patients was 60%, compared with control-1 (14%, p < .01) and control-2 patients (25%, p < .01). The predominant phenotype was maculopapular exanthem (92%). The drugs implicated in AAL causality in C-HCL patients included beta-lactams (81%), trimethoprim-sulfamethoxazole (58%), and allopurinol (69%). C-HCL patients demonstrate high rates of AAL, potentially due to immune dysregulation, impacting beta-lactam utilization.
Assuntos
Antibacterianos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hipersensibilidade a Drogas/epidemiologia , Leucemia de Células Pilosas/tratamento farmacológico , Adulto , Idoso , Austrália/epidemiologia , Estudos de Casos e Controles , Cladribina/administração & dosagem , Hipersensibilidade a Drogas/etiologia , Feminino , Seguimentos , Humanos , Leucemia de Células Pilosas/imunologia , Leucemia de Células Pilosas/patologia , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
Hairy cell leukemia (HCL) is a rare, low-grade mature B-cell neoplasm with a characteristic clinical, morphological, immunophenotypic, and more recently described molecular (BRAF p.V600E mutation) profile. It typically affects middle-aged to elderly male who present with pancytopenia and massive splenomegaly. Lymphadenopathy is usually not seen. Atypical presentations such as absence of splenomegaly and presence of lymphadenopathy and leukocytosis, a hypoplastic marrow masquerading as aplastic anemia, pose a diagnostic challenge to both clinician and pathologist. A diligent morphological examination to look for the presence of hairy cells along with flow cytometric immunophenotyping showing consistent bright expression of CD200, in addition to well-described characteristic immunophenotype, helps in correctly diagnosing the case. This can be further confirmed by the consistent presence of V600E point mutation in BRAF gene. The correct identification of HCL in these unusual clinical presentations is of utmost importance owing to a different treatment approach in these cases. We present here four such cases with atypical presentation.
Assuntos
Antígenos CD/genética , Biomarcadores Tumorais/genética , Leucemia de Células Pilosas/diagnóstico , Proteínas Proto-Oncogênicas B-raf/genética , Biomarcadores Tumorais/imunologia , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Imunofenotipagem , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/imunologia , Leucemia de Células Pilosas/patologia , Masculino , Pessoa de Meia-Idade , MutaçãoAssuntos
Imunoterapia , Leucemia de Células Pilosas/mortalidade , Leucemia de Células Pilosas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Leucemia de Células Pilosas/imunologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Taxa de SobrevidaRESUMO
OBJECTIVE: The aberrant expression of CD5 in both HCL and HCL-v is a very rare event. Although a number of CD5 positive HCL and HCL-v cases have been reported, but these are far and few in between. We aimed to review the reported cases of CD5 positive HCL and its variant. METHOD: We hereby report a case of CD5 positive HCL, with variations in PIK3CA and PDGFRA gene, along with a brief review of literature of the cases of CD5 positive HCL and its variant. RESULTS AND CONCLUSION: The current case was positive for CD103, CD11c, CD25, and CD123 which has led the diagnosis to be of typical HCL. With the extensive literature review we found that only 26 cases of hairy cell leukemia [HCL and HCL-v] bearing CD5 expression have been reported so far. The positivity of CD5 is more common in HCL-v as compared to HCL. Additional prospective studies of CD5+ HCL and its variants are required to show whether they are a clinically significant subgroup of lymphoid malignancies. © 2016 International Clinical Cytometry Society.
Assuntos
Antígenos CD5/imunologia , Citometria de Fluxo , Leucemia de Células Pilosas/imunologia , Antígenos CD/imunologia , Feminino , Citometria de Fluxo/métodos , Humanos , Imunofenotipagem , Cadeias alfa de Integrinas/imunologia , Leucemia de Células Pilosas/diagnóstico , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores de IgE/imunologiaAssuntos
Leucemia de Células Pilosas/complicações , Leucemia de Células Pilosas/diagnóstico , Linfocitose/diagnóstico , Linfocitose/etiologia , Esplenomegalia/diagnóstico , Esplenomegalia/etiologia , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cladribina/administração & dosagem , Diagnóstico Diferencial , Feminino , Humanos , Leucemia de Células Pilosas/sangue , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/imunologia , Linfocitose/sangue , Linfocitose/complicações , Linfocitose/tratamento farmacológico , Linfocitose/imunologia , Rituximab/administração & dosagem , Esplenomegalia/tratamento farmacológico , Esplenomegalia/imunologia , Resultado do TratamentoRESUMO
We report a very rare case of a 45-year-old Japanese male patient with hairy cell leukemia-Japanese variant (HCL-JV) expressing CD27. The patient showed a high number of abnormal peripheral lymphocytes, thrombocytopenia, and severe splenomegaly but no lymphadenopathy. Histology of the resected spleen showed small-sized lymphoma cells diffusely infiltrating the red pulp without follicle formation. By immunohistochemistry, lymphoma cells were negative for CD3, CD5, CD8, CD10, CD34, cyclin-D1, and annexin A1 but positive for CD20 and BCL2. BRAF V600E mutation was not observed. Bone marrow aspirate showed preserved normal hematopoietic cells with invasion of lymphoma cells in an interstitial pattern without obvious nodules. The cells had abundant pale cytoplasm and round nuclei with inconspicuous nucleoli. After natural drying, the cells had unevenly distributed microvilli. Flow cytometric analysis demonstrated positivity for CD11a, CD11c, CD19, CD20, CD22, CD27, surface IgG, and λ but not for CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD21, CD23, CD25, CD30, CD34, CD38, CD43, CD56, CD57, CD103, IgD, IgM, and κ. Monoclonal expansion of B cells was confirmed by an immunoglobulin heavy chain (IgH) rearrangement band as demonstrated by Southern blot hybridization. The lymphoma cells had unevenly distributed long, large, and broad-based microvilli, which resembled splenic diffuse red pulp small B cell lymphoma (SDRPL) cells. CD27 expression is extremely rare in HCL-JV, but the young age of the patient and high peripheral WBC counts were similar to HCL-JV, which suggests, in this case, an intermediate disease between SDRPL and HCL-JV.
Assuntos
Linfócitos B/patologia , Leucemia de Células Pilosas/metabolismo , Neoplasias Esplênicas/diagnóstico , Linfócitos B/imunologia , Humanos , Imuno-Histoquímica/métodos , Imunofenotipagem/métodos , Leucemia de Células Pilosas/imunologia , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Esplênicas/imunologia , Neoplasias Esplênicas/patologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoAssuntos
Antineoplásicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Indóis/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos B/ultraestrutura , Cladribina/uso terapêutico , Gerenciamento Clínico , Resistencia a Medicamentos Antineoplásicos , Feminino , Expressão Gênica , Humanos , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/imunologia , Leucemia de Células Pilosas/patologia , Masculino , Mutação , Pentostatina/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/imunologia , Recidiva , Indução de Remissão , Fatores Sexuais , VemurafenibRESUMO
Unusual clinical manifestations and associations with auto-immunity or other systemic disorders are uncommon clinical features of hairy cell leukemia (HCL). The exact prevalence of these rare associations is difficult to determine as they are mostly published as anecdotal case reports and generally not included in larger published series. This chapter deals with uncommon clinical manifestations and rare sites of involvement in HCL. It also summarizes the association with systemic hemato-oncological disorders as well as second malignancies, based on review of the relevant literature and from personal experience.
Assuntos
Anemia Hemolítica Autoimune/diagnóstico , Síndrome Antifosfolipídica/diagnóstico , Síndrome de Behçet/diagnóstico , Leucemia de Células Pilosas/diagnóstico , Doenças Linfáticas/diagnóstico , Esplenomegalia/diagnóstico , Trombocitopenia/diagnóstico , Anemia Hemolítica Autoimune/complicações , Anemia Hemolítica Autoimune/imunologia , Anemia Hemolítica Autoimune/patologia , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Síndrome de Behçet/complicações , Síndrome de Behçet/imunologia , Síndrome de Behçet/patologia , Osso e Ossos/imunologia , Osso e Ossos/patologia , Feminino , Humanos , Leucemia de Células Pilosas/complicações , Leucemia de Células Pilosas/imunologia , Leucemia de Células Pilosas/patologia , Fígado/imunologia , Fígado/patologia , Linfonodos/imunologia , Linfonodos/patologia , Doenças Linfáticas/complicações , Doenças Linfáticas/imunologia , Doenças Linfáticas/patologia , Masculino , Fatores Sexuais , Pele/imunologia , Pele/patologia , Esplenomegalia/complicações , Esplenomegalia/imunologia , Esplenomegalia/patologia , Trombocitopenia/complicações , Trombocitopenia/imunologia , Trombocitopenia/patologiaRESUMO
Hairy cell leukaemia is a rare chronic neoplastic B-cell lymphoproliferation that characteristically involves blood, bone marrow and spleen with liver, lymph node and skin less commonly involved. Histologically, the cells have a characteristic appearance with pale/clear cytoplasm and round or reniform nuclei. In the spleen, the infiltrate involves the red pulp and is frequently associated with areas of haemorrhage (blood lakes). The cells stain for B-cell related antigens as well as with antibodies against tartrate-resistant acid phosphatase, DBA44 (CD72), CD11c, CD25, CD103, CD123, cyclin D1 and annexin A1. Mutation of BRAF -V600E is present and antibody to the mutant protein can be used as a specific marker. Bone marrow biopsy is essential in the initial assessment of disease as the bone marrow may be inaspirable or unrepresentative of degree of marrow infiltration as a result of the tumour associated fibrosis preventing aspiration of the tumour cell component. Bone marrow biopsy is important in the assessment of therapy response but in this context staining for CD11c and Annexin A1 is not helpful as they are also markers of myeloid lineage and identification of low level infiltration may be obscured. In this context staining for CD20 may be used in conjunction with morphological assessment and staining of serial sections for cyclin D1 and DBA44 to identify subtle residual infiltration. Staining for CD79a and CD19 is not recommended as these antibodies will identify plasma cells and can lead to over-estimation of disease. Staining for CD20 should not be used in patients following with anti-CD20 based treatments. Down regulation of cyclin D1 and CD25 has been reported in patients following BRAF inhibitor therapy and assessment of these antigens should not be used in this context. Histologically, hairy cell leukaemia needs to be distinguished from other B-cell lymphoproliferations associated with splenomegaly including splenic marginal zone lymphoma, splenic diffuse red pulp small B-cell lymphoma and hairy cell leukaemia variant. This can be done by assessment of the spleen but as this is now rarely performed in this disorder distinction is almost always possible by a combination of morphological and immunophenotypic studies on bone marrow trephine biopsy, which can be supplemented by assessment of BRAF-V600E mutation assessment in borderline cases.
Assuntos
Medula Óssea/patologia , Leucemia de Células Pilosas/diagnóstico , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Baço/patologia , Fosfatase Ácida/genética , Fosfatase Ácida/imunologia , Antígenos CD/genética , Antígenos CD/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Medula Óssea/imunologia , Ciclina D1/genética , Ciclina D1/imunologia , Diagnóstico Diferencial , Expressão Gênica , Humanos , Imuno-Histoquímica , Isoenzimas/genética , Isoenzimas/imunologia , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/imunologia , Leucemia de Células Pilosas/patologia , Fígado/imunologia , Fígado/patologia , Linfonodos/imunologia , Linfonodos/patologia , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/imunologia , Linfoma de Zona Marginal Tipo Células B/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/imunologia , Pele/imunologia , Pele/patologia , Baço/imunologia , Fosfatase Ácida Resistente a TartaratoRESUMO
Hairy cell leukemia (HCL) cells engage in complex cellular and molecular interactions with accessory cells, matrix proteins, and various cytokines in the bone marrow and spleen, collectively referred to as the tissue microenvironment. Chemokine receptors and adhesion molecules are critical players for homing and retention within these microenvironments. Engagement of B cell antigen receptors and CD40 on HCL cells promote survival and proliferation. In this chapter, we summarize the current knowledge about the cellular and molecular interactions between HCL cells and their supportive tissue microenvironment, and provide insight into new therapeutic approaches targeting B cell receptor signaling in HCL.
Assuntos
Antígenos CD40/imunologia , Regulação Leucêmica da Expressão Gênica , Leucemia de Células Pilosas/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Microambiente Tumoral/imunologia , Adenina/análogos & derivados , Antineoplásicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/patologia , Antígenos CD40/genética , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/imunologia , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/patologia , Piperidinas , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Quinazolinonas/uso terapêutico , Receptores de Antígenos de Linfócitos B/genética , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Transdução de Sinais , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/imunologiaRESUMO
Success in the treatment of patients with hairy cell leukemia (HCL) over the last several decades is largely due to the high efficacy of the nucleoside analogs, cladribine and pentostatin. However, the relapse-free survival curves have not shown a plateau and many patients treated with these agents will eventually relapse. Although better understanding of the pathogenic mechanisms in HCL have led to effective and novel options for the treatment of relapse, long term durability of the responses obtained with these agents still remains unclear. Combination of nucleoside analogs with monoclonal antibodies such as rituximab has been shown to be safe and effective and has the potential to supersede the nucleoside analogs as the frontline strategy. Such chemo-immunotherapy approaches are under further investigation and will have to be assessed with socioeconomic considerations in mind. Other novel monoclonal antibodies, approved for the treatment of other lymphoid neoplasms, may also be considered for future studies of chemo-immunotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cladribina/uso terapêutico , Imunoterapia/métodos , Leucemia de Células Pilosas/tratamento farmacológico , Pentostatina/uso terapêutico , Rituximab/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Humanos , Leucemia de Células Pilosas/imunologia , Leucemia de Células Pilosas/mortalidade , Leucemia de Células Pilosas/patologia , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/imunologia , Recidiva , Indução de Remissão , Análise de SobrevidaRESUMO
Hairy cell leukemia (HCL) is an indolent B-cell malignancy effectively treated but not often cured by purine analog therapy; after multiple courses of purine analogs, patients can become purine analog resistant and in need of alternative therapies. Complete remission to single-agent purine analog is often accompanied by minimal residual disease (MRD), residual HCL cells detectable by immunologic methods, considered a risk factor for eventual relapse. Several different non-chemotherapy approaches are being used to target relapsed and refractory HCL, including inhibitors of BRAF, but so far only monoclonal antibody (MAb)-based approaches have been reported to eliminate MRD in a high percentage of patients. One of the MAb-based options for HCL currently under clinical investigation involves recombinant immunotoxins, containing a fragment of a MAb and a bacterial toxin. The bacterial toxin, a highly potent fragment from Pseudomonas exotoxin, catalytically ADP-ribosylates elongation factor 2 (EF2), resulting in protein synthesis inhibition and apoptotic cell death. Recombinant immunotoxins tested in HCL patients include LMB-2, targeting CD25, and BL22, targeting CD22. An affinity matured version of BL22, termed moxetumomab pasudotox (formerly HA22 or CAT-8015) achieved high CR rates in phase I, and is currently undergoing multicenter Phase 3 testing. Phase I testing was without dose-limiting toxicity, although 2 patients had grade 2 hemolytic uremic syndrome (HUS) with transient grade 1 abnormalities in platelets and creatinine. Preclinical work is underway to identify residues on moxetumomab pasudotox leading to immunogenicity. Moxetumomab pasudotox is undergoing pivotal testing for relapsed and refractory HCL.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Toxinas Bacterianas/uso terapêutico , Exotoxinas/uso terapêutico , Imunoconjugados/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Cladribina/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Leucemia de Células Pilosas/imunologia , Leucemia de Células Pilosas/mortalidade , Leucemia de Células Pilosas/patologia , Mutação , Neoplasia Residual , Pentostatina/uso terapêutico , Fator 2 de Elongação de Peptídeos/antagonistas & inibidores , Fator 2 de Elongação de Peptídeos/genética , Fator 2 de Elongação de Peptídeos/imunologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/imunologia , Indução de Remissão , Análise de SobrevidaRESUMO
Hairy cell leukemia (HCL) is characterized by underexpression of the intracellular signaling molecule RhoH. Reconstitution of RhoH expression limits HCL pathogenesis in a mouse model, indicating this could represent a new therapeutic strategy. However, while RhoH reconstitution is theoretically possible as a therapy, it is technically immensely challenging as an appropriately functional RhoH protein needs to be specifically targeted. Because of this problem, we sought to identify druggable proteins on the HCL surface that were dependent upon RhoH underexpression. One such protein was identified as CD38. Analysis of 51 HCL patients demonstrated that 18 were CD38-positive. Interrogation of the clinical record of 23 relapsed HCL patients demonstrated those that were CD38-positive had a mean time to salvage therapy 71 months shorter than patients who were CD38-negative. Knockout of the CD38 gene in HCL cells increased apoptosis, inhibited adherence to endothelial monolayers, and compromised ability to produce tumors in vivo. Furthermore, an anti-CD38 antibody proved effective against pre-existing HCL tumors. Taken together, our data indicate that CD38 expression in HCL drives poor prognosis by promoting survival and heterotypic adhesion. Our data also indicate that CD38-positive HCL patients might benefit from treatments based on CD38 targeting.
Assuntos
ADP-Ribosil Ciclase 1/fisiologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos de Neoplasias/fisiologia , Imunoglobulina G/uso terapêutico , Leucemia de Células Pilosas/imunologia , Glicoproteínas de Membrana/fisiologia , Terapia de Alvo Molecular , ADP-Ribosil Ciclase 1/análise , ADP-Ribosil Ciclase 1/imunologia , Animais , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/imunologia , Apoptose , Adesão Celular , Células Endoteliais/citologia , Feminino , Técnicas de Inativação de Genes , Humanos , Leucemia de Células Pilosas/mortalidade , Leucemia de Células Pilosas/terapia , Masculino , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Proteínas de Neoplasias/fisiologia , Transplante de Neoplasias , Prognóstico , Terapia de Salvação , Fatores de Transcrição/fisiologia , Transfecção , Proteínas rho de Ligação ao GTP/fisiologiaRESUMO
Although the coexistence of hairy cell leukemia with sarcoidosis has been reported in a few cases in the literature, in our case the patient had been diagnosed and followed about 10 years with sarcoidosis and massive splenomegaly. It has been demonstrated that T helper 1 cells exist in organs influenced by sarcoidosis. These cells produce IL-2 and IFN-γ and induce a nonspecific inflammatory response and granuloma formation. Also these cytokines may play a role in the development of hairy cell leukemia.Key words: hairy cell leukemia -â sarcoidosis - massive splenomegaly.
Assuntos
Leucemia de Células Pilosas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Sarcoidose/imunologia , Baço/imunologia , Idoso , Citocinas , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Leucemia de Células Pilosas/complicações , Ativação Linfocitária , Sarcoidose/complicaçõesRESUMO
Detection of high-frequency BRAF V600E mutations in hairy cell leukemia (HCL) has important diagnostic utility. However, the requisite analytic performance for a clinical assay to routinely detect BRAF V600E mutations in HCL has not been clearly defined. In this study, we sought to determine the level of analytic sensitivity needed for formalin-fixed, paraffin-embedded (FFPE) and frozen samples and to compare the performance of 2 allele-specific polymerase chain reaction (PCR) assays. Twenty-nine cases of classic HCL, including 22 FFPE bone marrow aspirates and 7 frozen specimens from blood or bone marrow were evaluated using a laboratory-developed allele-specific PCR assay and a commercially available allele-specific quantitative PCR assay-myT BRAF Ultra. Also included were 6 HCL variant and 40 non-HCL B-cell lymphomas. Two cases of classic HCL, 1 showing CD5 expression, were truly BRAF V600E-negative based on negative results by PCR and sequencing despite high-level leukemic involvement. Among the remaining 27 specimens, V600E mutations were detected in 88.9% (17/20 FFPE; 7/7 frozen) and 81.5% (15/20 FFPE; 7/7 frozen), for the laboratory-developed and commercial assays, respectively. No mutations were detected among the 46 non-HCL lymphomas. Both assays showed an analytic sensitivity of 0.3% involvement in frozen specimens and 5% in FFPE tissue. On the basis of these results, an assay with high analytic sensitivity is required for the clinical detection of V600E mutations in HCL specimens. Two allele-specific PCR assays performed well in both frozen and FFPE bone marrow aspirates, although detection in FFPE tissue required 5% or more involvement.