RESUMO
B-cell prolymphocytic leukaemia (B-PLL) is an aggressive B-cell lymphoproliferative disease with few clinically proven targeted treatments. Due to the rarity of the condition, there is a paucity of clinical trial data and none that involve targeted inhibitors. We present a unique case of relapsed refractory B-PLL treated to a sustained minimal residual disease-negative remission with venetoclax monotherapy, to add to the current evidence base and rationale for future studies using BCL-2 inhibitors in B-PLL.
Assuntos
Leucemia Linfocítica Crônica de Células B , Leucemia Prolinfocítica Tipo Células B , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Prolinfocítica Tipo Células B/diagnóstico , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Leucemia Prolinfocítica Tipo Células B/etiologia , Neoplasia Residual , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonamidas , Proteína Supressora de Tumor p53Assuntos
Leucemia Prolinfocítica Tipo Células B , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Lenalidomida/uso terapêutico , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Piperidinas , Pirazóis , Pirimidinas/uso terapêutico , Rituximab/uso terapêutico , Proteína Supressora de Tumor p53/genéticaRESUMO
A 64-year-old man had a several year history of B prolymphocytic leukaemia (PLL) which behaved indolently and had not required any treatment. Five years after diagnosis, he developed hypoalbuminaemia associated with severe lower-limb oedema, consistent with systemic capillary leak syndrome (SCLS). He recovered spontaneously but went on to have three further increasingly severe and protracted episodes over the subsequent 18 months. There was no identifiable precipitating factor for these episodes, but his peripheral lymphocyte count continued to increase slowly. The start of treatment for his PLL with chemoimmunotherapy was followed by a rapid resolution of residual oedema and normalisation of serum albumin. He has had no further attacks of SCLS in the 14 months since he started therapy for PLL. SCLS is a rare consequence of haematological malignancy which may show an excellent response to treatment of the haematological disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Síndrome de Vazamento Capilar/etiologia , Edema/etiologia , Hipoalbuminemia/etiologia , Leucemia Prolinfocítica Tipo Células B/complicações , Síndrome de Vazamento Capilar/sangue , Síndrome de Vazamento Capilar/diagnóstico , Síndrome de Vazamento Capilar/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Edema/sangue , Edema/diagnóstico , Edema/tratamento farmacológico , Humanos , Hipoalbuminemia/sangue , Hipoalbuminemia/diagnóstico , Leucemia Prolinfocítica Tipo Células B/sangue , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Rituximab/uso terapêutico , Albumina Sérica Humana/análise , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoAssuntos
Adenina/análogos & derivados , Leucemia Prolinfocítica Tipo Células B/patologia , Piperidinas/uso terapêutico , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Adenina/farmacologia , Adenina/uso terapêutico , Idoso , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Leucemia Prolinfocítica Tipo Células B/diagnóstico , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Masculino , Piperidinas/farmacologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/efeitos dos fármacosRESUMO
B cell prolymphocytic leukemia (B-PLL) is a rare and aggressive disease that is associated with poor survival. Although initially asymptomatic patients do not require therapy, most patients will progress and inevitably require treatment. More than 50% of patients with B-PLL carry abnormalities in the TP53 tumor suppressor gene and/or complex karyotype and show resistance to conventional chemotherapy. The efficacy of ibrutinib, a B cell receptor inhibitor, for B-PLL with the TP53 abnormality as second-line therapy was recently demonstrated. We herein report that low-dose ibrutinib as upfront therapy induced a complete response in a B-PLL patient with the TP53 abnormality, whose condition has since remained stable with no recurrence for 12 months. Effective treatments for B-PLL are lacking and given its rarity, prospective comparative therapies are not yet available. This case suggests that upfront therapy with ibrutinib improves the outcome of B-PLL.
Assuntos
Adenina/análogos & derivados , Antineoplásicos/uso terapêutico , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adenina/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Humanos , Leucemia Prolinfocítica Tipo Células B/genética , Masculino , Mutação , Resultado do Tratamento , Proteína Supressora de Tumor p53/genéticaAssuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Leucemia Prolinfocítica Tipo Células B/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Adenina/análogos & derivados , Idoso , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Substituição de Medicamentos , Humanos , Leucemia Prolinfocítica Tipo Células B/diagnóstico , Leucemia Prolinfocítica Tipo Células B/etiologia , Masculino , Piperidinas , Purinas/farmacologia , Purinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Retratamento , Rituximab/farmacologia , Rituximab/uso terapêutico , Sulfonamidas/farmacologia , Resultado do TratamentoAssuntos
Purinas , Quinazolinonas , Indução de Remissão , Rituximab , Proteína Supressora de Tumor p53/genética , Idoso , Feminino , Humanos , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Leucemia Prolinfocítica Tipo Células B/genética , Leucemia Prolinfocítica Tipo Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Purinas/administração & dosagem , Purinas/efeitos adversos , Quinazolinonas/administração & dosagem , Quinazolinonas/efeitos adversos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Reino UnidoAssuntos
Neoplasias Hematológicas/tratamento farmacológico , Janus Quinases/antagonistas & inibidores , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Pirimidinas/administração & dosagem , Sulfonas/administração & dosagem , Quinase Syk/antagonistas & inibidores , Idoso , Feminino , Neoplasias Hematológicas/diagnóstico por imagem , Neoplasias Hematológicas/enzimologia , Humanos , Leucemia Prolinfocítica Tipo Células B/diagnóstico por imagem , Leucemia Prolinfocítica Tipo Células B/enzimologia , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/enzimologia , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Sulfonas/efeitos adversosAssuntos
Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antígenos CD20/imunologia , Antineoplásicos Imunológicos/farmacologia , Proteínas do Sistema Complemento/imunologia , Imunoglobulina A/farmacologia , Leucemia Prolinfocítica Tipo Células B/imunologia , Células Mieloides/imunologia , Animais , Antineoplásicos Imunológicos/imunologia , Células CHO , Cricetulus , Humanos , Imunoglobulina A/imunologia , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Leucemia Prolinfocítica Tipo Células B/patologia , Células Mieloides/patologiaAssuntos
Rearranjo Gênico , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Leucemia Prolinfocítica Tipo Células B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Idoso , Humanos , Leucemia Prolinfocítica Tipo Células B/patologia , Masculino , Piperidinas , PrognósticoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Variação Genética , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Leucemia Prolinfocítica Tipo Células B/genética , Proteína Supressora de Tumor p53/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Comorbidade , Humanos , Leucemia Prolinfocítica Tipo Células B/diagnóstico , Fenótipo , Purinas/administração & dosagem , Quinazolinonas/administração & dosagem , Rituximab/administração & dosagem , Resultado do TratamentoRESUMO
A series of adenosine derivatives bearing a boron cluster were synthesized and evaluated for their cytotoxicity against primary peripheral mononuclear cells from the blood of 17 patients with leukemias (16 CLL and 1 very rare PLL), as well as from 5 healthy donors used as a control. Among the tested agents, two, i.e., compounds 1 and 2, displayed high in vitro cytotoxicity and proapoptotic potential on leukemic cells, with only scarce activity being seen against control cells. Biological tests related to apoptosis revealed the activation of the main execution apoptotic enzyme, procaspase-3, in CLL and PLL cells exposed to compounds 1 and 2. Moreover, the above compounds indicated high activity in the proteolysis of the apoptotic markers PARP-1 and lamin B1, fragmentation of DNA, and the induction of some changes in the expression of the Mcl-1, protein apoptosis regulator in comparison with control cells.
Assuntos
Adenosina/farmacologia , Antineoplásicos/farmacologia , Boro/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Adenosina/síntese química , Adenosina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Boro/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Prolinfocítica Tipo Células B/patologia , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: B-cell prolymphocytic leukemia (B-PLL) is a rare, aggressive leukemia distinct from chronic lymphocytic leukemia, with median survival of only 3 years. B-PLL is resistant to most chemotherapy and newer targeted therapies such as alemtuzumab and thalidomide. Phenylethyl isothiocyanate (PEITC) is a natural compound from horseradish with evidence for therapeutic potential in multiple leukemia types. CASE PRESENTATION: Here we present a case report of a 53-year-old man whose chronic lymphocytic leukemia transformed to end-stage B-PLL, disqualifying him for allogenic stem cell transplantation. He was treated with PEITC followed by salvage R-CHOP (Rituximab, Cyclophosphamide, Hydroxydaunorubicin [doxorubicin hydrochloride], Oncovin [vincristine sulfate], Prednisone or Prednisolone) chemotherapy, which led to normalized white blood cell count and disease stabilization that requalified him for allogenic peripheral stem-cell transplant therapy. We conducted a systematic review to analyze and interpret the potential contribution of PEITC to his unexpectedly favorable R-CHOP response. Following sequential 8 weeks of PEITC/pentostatin and 6 cycles of R-CHOP, the patient received allogenic peripheral blood stem cell transplant on an outpatient basis and remains well at the time of this publication, with no evidence of CD20+ small B-cells. DISCUSSION: Given the limited data for R-CHOP in B-PLL, this patient's recovery suggests presensitization of B-PLL cells toward R-CHOP, potentially justifying further investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Isotiocianatos/administração & dosagem , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Terapia de Salvação , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Significant advances in the diagnosis and treatment of hairy cell leukemia (HCL) have recently been made. Improved distinction of HCL from its mimics though clinical presentations, morphologic and immunophenotypic features, and more recently molecular biology, has highlighted marked differences in treatment response and overall prognosis between these disorders. As our understanding of the unique pathobiology of HCL has grown, exciting new avenues of treatment as well as insight into immune function have been obtained. This review provides an overview of the clinical features and diagnostic attributes of HCL, with contrast to other mature B cell lymphoproliferative disorders with overlapping features.
Assuntos
Leucemia de Células Pilosas/diagnóstico , Leucemia Prolinfocítica Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Macroglobulinemia de Waldenstrom/diagnóstico , Antineoplásicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Diagnóstico Diferencial , Fadiga/diagnóstico , Fadiga/patologia , Feminino , Humanos , Indóis/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/patologia , Leucemia de Células Pilosas/cirurgia , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Leucemia Prolinfocítica Tipo Células B/patologia , Leucemia Prolinfocítica Tipo Células B/cirurgia , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Zona Marginal Tipo Células B/cirurgia , Masculino , Mutação , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Fatores Sexuais , Esplenectomia , Esplenomegalia/diagnóstico , Esplenomegalia/patologia , Esplenomegalia/cirurgia , Sulfonamidas/uso terapêutico , Vemurafenib , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/patologia , Macroglobulinemia de Waldenstrom/cirurgiaAssuntos
Neoplasias do Sistema Nervoso Central/secundário , Leucemia Prolinfocítica Tipo Células B/patologia , Idoso de 80 Anos ou mais , Encéfalo/patologia , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Evolução Fatal , Humanos , Leucemia Prolinfocítica Tipo Células B/diagnóstico , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Resultado do TratamentoRESUMO
This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced B-cell chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (B-PLL) to definitely describe the impact of this antibody in clinical routine use. Data were collected from 208 consecutive, mainly pretreated, patients with CLL (n = 202), and B-PLL (n = 6) who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) in various settings were assessed, and toxicities were documented. In these routine patients, a comparably low cumulative dose of alemtuzumab (median, 403 mg) was applied. In CLL, overall response rate was 32 %, and various pre-therapeutic parameters were predictive for inferior response, among them, the prior administration of ≥3 therapy lines (P < 0.001), refractoriness to fludarabine (P = 0.002), and bulky lymphadenopathy (P = 0.003). PFS and OS after start of alemtuzumab were 6.2 and 21.0 months, respectively. Bulky lymphadenopathy was the prominent risk factor for both inferior PFS (P < 0.001) and OS (P = 0.002). In B-PLL, four patients experienced a fatal outcome, whereas two patients had some benefit with alemtuzumab. The main adverse effects were CMV reactivation (20 %) and a broad spectrum of infections, which together were the main reasons for treatment interruption and/or premature termination. In conclusion, alemtuzumab administered even at low dose levels was effective but overall considerably toxic in routine CLL patients. We emphasize that alemtuzumab remains an important therapeutic option in subsets of CLL patients.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alemtuzumab , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Prolinfocítica Tipo Células B/mortalidade , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaAssuntos
Células Sanguíneas/patologia , Leucemia Prolinfocítica Tipo Células B/tratamento farmacológico , Leucemia Prolinfocítica Tipo Células B/patologia , Pentostatina/uso terapêutico , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Células Sanguíneas/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Testes Hematológicos , Humanos , Leucemia Prolinfocítica Tipo Células B/sangue , MasculinoRESUMO
BACKGROUND: B-Cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. Clinical treatment of CLL is often limited due to drug resistance and severe therapy-induced toxicities. We hypothesized that the omega 3 (n-3) fatty acids, eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), would increase the sensitivity of malignant B-lymphocytes to anti-cancer drugs doxorubicin, vincristine and/or fludarabine in vitro and that increased sensitivity is achieved by alterations in cell-cycle progression leading to growth inhibition and/or enhanced cell death. We further postulate that enhanced sensitivity is dependent on the formation of lipid peroxides and to the generation of reactive oxygen species (ROS). METHODS: In the present study, B-CLL-derived leukemic cell lines EHEB and MEC-2 and the B-Prolymphocytic leukemic-derived (PLL) cell line JVM-2 were tested for in vitro sensitivity against doxorubicin, vincristine or fludarabine in the presence or absence of vehicle, arachidonic acid (omega 6), EPA or DHA. Cell cycle analysis and Annexin-V assays were performed to determine cell cycle progression and % apoptotic cells, respectively. Assays for malondialdehyde, a measure of lipid peroxidation, and DCF fluorescence assays, a measure of intracellular ROS, were performed to determine if enhanced sensitivity of cells to the drugs by n-3 was dependent on the formation of ROS. RESULTS: Our results indicated that: 1) EPA and DHA differentially sensitized B-leukemic cell lines EHEB, JVM-2 and MEC-2 to doxorubicin, vincristine and fludarabine in vitro; 2) n-3 alone and with drug treatment increased cell death and induced G2/M arrest in a cell-type specific manner; 3) lipid peroxidation increased in the presence of n-3; 4) there was higher lipid peroxidation in MEC-2 cells in presence of DHA and doxorubicin than with either alone; 5) n-3 increased generation of ROS in MEC-2, and 6) the addition of vitamin-E abrogated the increase in ROS generation and chemo-sensitivity of MEC-2 to doxorubicin by DHA. CONCLUSION: N-3's are promising chemo-sensitizing agents for the treatment of CLL. Selective enhancement of chemo-sensitivity of EHEB, JVM-2 and MEC-2 to drugs by n-3 that is not dependent on increased lipid peroxidation and ROS generation indicates alternative mechanisms by which n-3 enhances chemo-sensitivity.