Nas duas últimas décadas, houve uma mudança radical na terapia e na evolução do mieloma múltiplo(MM), neoplasia hematológica ainda considerada fatal. As pesquisas e investimentos em medicamentos que interferem com a fisiopatogenia e com o microambiente medular estão permitindo o controle e a regressão do clone plasmocitário maligno, mudando as perspectivas da doença. A idéia nova de usar uma droga velha, a talidomida, tem-se mostrado efetiva no MM. Em 1997, apostando nos efeitos imunomoduladores e antiangiogênicos da talidomida, foram iniciados ensaios clínicos para MM refratários. A partir daí, outras ações sobre o plasmócito e microambiente medular foram eficazes contra a doença, não somente em refratários ou recaídos, mas também como terapia de indução e/ou de manutenção da remissão. No Serviço de Hematologia do Hospital de Clínicas de Porto Alegre foram acompanhados 35 portadores de mieloma múltiplo, em uso de doses baixas (100 mg) de talidomida, pelas indicações: 13-manutenção pós-TMO, 11-pós-indução, 5-recaída, 4-refratariedade e 2-terapia de indução. O estudo vigorou entre março/01 a dez/03. Os parâmetros avaliados foram: nível Hb, pico da imunoglobulina sérica ou urinária e o número de plasmócitos na medula óssea. As medidas foram tomadas pré-talidomida e após 3, 6 e 12 meses. A taxa de imunoglobulina foi o padrão ouro para avaliação de resposta. Os resultados: a dose terapêutica tolerada em 48% dos pacientes foi 100 mg; 65% dos tratados para induzir remissão (11 pacientes) apresentaram melhora entre 25%-50% no nível da imunoglobulina sérica; 87,5% daqueles que usaram para manutenção de remissão (13 pós-TMO/ 11 pós-indução) mantiveram o mesmo plateau inicial.
Purpose- Everolimus is an oral antineoplastic agent that targets the raptor mammalian target of rapamycin (mTORC1). The phosphatidylinositol 3-kinase/mTOR signal transduction pathway has been demonstrated to be activated in tumor samples from patients with Hodgkin Lymphoma (HL). The goal of this study was to evaluate the response, time of response, toxicity and overall survival in patients with refractory disease using everolimus out of clinical trial, in a compassionate use.
Patients and Methods- Patients were eligible if they had refractory and active Hodgkin disease. Patients received everolimus 10 mg PO daily. Dose reductions were allowed. Time to response assessement was defined by each center until progression (this was defined by each doctor, some have considered to keep the drug until clinical progression and not radiological progression of the disease). Patients could remain on drug until progression or toxicity.
Results- Thirty three patients were enrolled. Median age at the time of everolimus start was 29 years (range, 20-70). Patients had received a median of 5 prior therapies (range, 3-7) , 81% had undergone prior autologous stem cell transplant and 4 patients had undergone alogenic trasnplantation. The ORR was 51% (95% CI: 24-71%) with 14 patients achieving a PR, 3 patient achieving a CR and 10 with stable disease. Thirteen patients used the drug for more than 1 year. Patients received a median of 14 cycles of therapy and 3 remains on therappy at 36 months showing a great tolerability of the drug. The median DR for the responders (CR/PR) was 10 months. The most commons site effects were trombocitopenia and hypercholesterolemia. Three patients had pulmonar toxicity. The adverse events grade III and IV ocurred in 30% of the patients.
Conclusions- Everolimus has single-agent activity in relapsed/refractory HL, even in real lyfe and clinical practice and provides proof-of-concept that targeting the mTOR pathway in HL is clinically relevant.
Disclosures
Off Label Use: everolimus for refractory hodgkin lymphoma.
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