Activation and expansion of CD8(+) T effector cells in patients with chronic graft-versus-host disease.

We tested the hypothesis that changes in the phenotype of CD8(+) T cells from patients with chronic graft-versus-host disease (cGVHD) correlate with disease activity, and resolve or normalize in clinically tolerant patients successfully withdrawn from immunosuppression therapy (IST). No significant difference was found in the absolute CD8(+) T cell counts among cGVHD patients, tolerant patients, and healthy controls. However, compared with healthy normal controls, CD8(+) T cells from cGVHD patients had decreased expression of the IL-7 receptor and an increase in effector T cells, Ki-67, and perforin expression and apoptosis, suggesting that activation, differentiation, and proliferation of host-reactive CD8(+) effector T cells is a mechanism by which cGVHD is sustained and persists. The increase in effector T cells was most prominent in older patients and patients who were cytomegalovirus seropositive before transplantation. Use of IST was associated with a decreased number of CD45RA(-) CD8(+) effector T cells, a decreased expression of Ki-67, and an increased expression of CD95 (Fas). Together, these results demonstrate that CD8(+) T cells in patients with cGVHD are characterized by an increased level of activation and proliferation, and an expansion of effector cells that appear to be selectively sensitive to IST compared with other CD8(+) T cells. In GVHD-free tolerant patients, CD8(+) T cells showed an increased expression of granzyme and HLA-DR molecules compared with CD8(+) T cells from healthy controls, indicating that clinical tolerance in these patients can occur without full normalization of the CD8(+) T cell phenotype.

Association of busulfan and cyclophosphamide conditioning with sleep disorders after hematopoietic stem cell transplantation.

New indications and conditioning regimens for hematopoietic stem cell transplantation (HSCT) have emerged in the last 10 years. Previous studies have shown the association of HSCT with late effects such as sleep disorders. The aim of this study was to determine the prevalence and factors associated with sleep disorders following HSCT in a population considering these new trends. Sixty-one individuals 1-10 years after allogeneic HSCT were surveyed using the DSM-IV-TR criteria for sleep disorders. Factors related to conditioning and graft-versus-host disease were collected from medical records. A prevalence of sleep disorders of 26.2% was found. Busulfan-cyclophosphamide conditioning was an independent risk factor in a multivariate analysis (relative risk, RR: 3.74, 95% CI: 1.1-12.6; p = 0.03), which also included sex (RR: 2.37, 95% CI: 1.0-5.7; p = 0.05) and age (RR: 1.03, 95% CI: 0.99-1.07; p = 0.11). Sleep disorders were frequent following HSCT. Patients who were treated with busulfan-cyclophosphamide had a higher risk of developing this complication. Female sex was also possibly a risk factor.

Variation in supportive care practices in hematopoietic cell transplantation.

Hematopoietic cell transplantation is an elective procedure that results in prolonged immune suppression and high treatment-related morbidity and mortality. Transplant centers and physicians use a variety of prophylaxis and monitoring strategies to prevent or minimize complications. Little is known about the variability in these practices. We conducted an international Internet-based survey of 526 physicians to describe the spectrum of supportive care practices employed. Consistency in pretransplant cardiac (96%) and pulmonary (95%) screening, informed consent documentation (93%), and use of antifungal prophylaxis (92%) was observed. Greater heterogeneity was seen in use of myelogenous growth factors, empiric antibiotic therapy, protective isolation procedures, posttransplant monitoring, and environmental and social restrictions. Although some practice differences were associated with physician characteristics and transplant type, most practice variation remained unexplained. These results suggest a need for well-designed observational and interventional studies to provide data about which supportive care practices improve outcomes. For practices proved to be beneficial, publication of guidelines and incorporation of monitoring into quality improvement initiatives may help standardize practices.

Leucemia mielóide aguda: o olhar dos anos 2000 no Serviço de Hematologia do Hospital de Clínicas de Porto Alegre-RS / Acute myeloid leukemia from the year 2000 point of view Hematology Service - Hospital de Clínicas de Porto Alegre-RS

A leucemia mielóide aguda (LMA) representa uma preocupação para os especialistas, porque perfaz um percentual alto das leucemias no adulto e o sucesso terapêutico ainda é insatisfatório. A partir do ano 2000, o Serviço de Hematologia do Hospital de Clínicas de Porto Alegre definiu estratégias para diagnóstico, tratamento e seguimento das LMAs, de acordo com o subtipo FAB, idade, citogenética e performance status (ECOG). Todos os casos de LMA "de novo"não promielocítica, em adultos (15 a 65 anos) foram acompanhados prospectivamente, desde outubro de 2001, data da implantação do protocolo c,ompreendendo três fases de tratamento: indução com o tradicional "7+3", citarabina 100 mg/m²/dia em infusão contínua em 7d, e daunorrubicina 60 mg/m²/dia em 3d e citarabina intratecal no D1 nas LMA M4 e M5. Após a recuperação medular, segue a consolidação idêntica à indução e posteriormente a intensificação com dois ou três ciclos de altas doses de citarabina 6 g/m²/dia por três dias. Foram diagnosticados, entre outubro/01 e dezembro/05, 69 pacientes portadores de LMA e destes, 39 com LMA "de novo"e idade entre 15 e 65 anos. Neste grupo foram analisadas a taxa de remissão, a taxa de recaída, a refratariedade e o tempo de sobrevida global. No final da observação foram encontrados: a taxa de indução de remissão 75 por cento; aconteceram 12 (40 por cento) recaídas, 7 (19 por cento) foram refratários ao tratamento. A sobrevida global foi 37 por cento em 56 meses, representando um incremento aos resultados obtidos no Serviço na década passada.

Acute myeloid leukemia (AML) is still a concern for hematologists as it represents a significant percentage of adult leukemias and the therapeutic success rates are unsatisfactory. In 2000, the Hematology Department of Hospital de Clínicas de Porto Alegre defined strategies for the diagnosis, treatment and follow up of AML patients according to the FAB subtype classification, age, cytogenetic tests and performance status (ECOG). Patients with promyelocytic leukemia are treated using the AIDA (GIMEMA) protocol with those older than 65 years receiving palliative therapy using hydroxyurea, oral etoposide, thalidomide, subcutaneous cytarabine or an association of drugs. Since October 2001 all our "de novo"AML patients aged 15 to 65 years with non-promyelocytic acute leukemia were prospectively followed up. At diagnosis we start a three phase treatment protocol: induction with a classical "7+3"therapy regimen, that is continuous infusion of 100 mg/m²/day cytarabine for 7 days, 60 mg/m²/day daunorubicin for 3 days and on day 1 an intrathecal cytarabine in AML M4 and M5 cases. After bone marrow recovery, if complete remission is achieved, follow ups involve an identical "7+3"consolidation phase followed by two or three high dose cycles of 6 g/m²/day cytarabine for 3 days. A group of 39 patients diagnosed between October 2001 and December 2005 was followed up until June 2006. Our objectives were to evaluate the effectiveness of the protocol for remission, relapse rates and overall survival. The rate of complete remission was 75 percent. Relapse occurred in 12/29 (40 percent) patients and the overall survival rate at 56 months was 37 percent, showing an improvement on our results of previous decades.

Talidomida e mieloma múltiplo: verificação dos efeitos terapêuticos através de parâmetros clínico e laboratoriais / Thalidomide and multiple myeloma: therapy evaluation using clinical and laboratorial parameters

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 por cento dos pacientes foi 100 mg; 65 por cento dos tratados para induzir remissão (11 pacientes) apresentaram melhora entre 25 por cento-50 por cento no nível da imunoglobulina sérica; 87,5 por cento daqueles que usaram para manutenção de remissão (13 pós-TMO/ 11 pós-indução) mantiveram o mesmo plateau inicial.

Over the last two decades, we have seen a radical change intherapy and progression of multiple myeloma, a malignanthematologic disease that is still considered fatal. Recentinvestment and research on mechanisms that interfere in thephysiopathogenesis and bone marrow microenvironment areturning control and regression of the malignant plasma cellclone into something achievable, which may change expectationsrelated to this disease. The new idea of using an old drug,thalidomide, has shown to be effective in multiple myeloma. In1997, using the known effects of immunomodulation and antiangiogenesisof this drug, clinical trials were started in patients with unresponsive disease. Other therapeutic interventions inthe bone marrow microenvironment and plasma cells have beenadded and proved to be efficacious, not only as a therapy forrefractory patients, but also for induction and/or remissionmaintenance therapy. Thirty-five patients with multiple myelomawere treated with low-dose thalidomide (100 mg) and followedup. .... The study tookplace in the Hematology and Bone Marrow Transplantationservice of the Hospital de Clínicas de Porto Alegre, from March2001 to December 2003. Hemoglobin levels, serum or urineimmunoglobulin peaks and bone marrow plasma cell countswere evaluated. These parameters were assessed before startingwith the drug and after 3.6 and 12 months of usage. Theimmunoglobulin level was considered the gold standard toevaluate the response. The results showed that 100 mg was thetolerable dose for 51% of the patients. Sixty-five percent of thosewho used thalidomide for induction therapy showed a 25 to 50%improvement in immunoglobulin serum levels and 90% of thepatients on maintenance therapy (13 after bone marrowtransplantation, 11 after induction), sustained the sameimmunoglobulin levels of the initial plateau.