Functional evaluation indicates physical losses after hematopoietic stem cell transplantation

OBJECTIVE: To perform a function evaluation of patients before and after hematopoietic stem cell transplantation. METHODS: From November 2008 to November 2010, 29 female (58%) and 21 male patients (42%) with median age of 48 years (range: 24-67) were enrolled in this study. Data collection was performed before and after autologous or allogeneic hematopoietic stem cell transplantation. Evaluation instruments included the 2-minute walking test to evaluate gait performance with assessment of the oxygen saturation, heart rate and Borg Scale before and after the test; grip strength for strength evaluation, Schober Test for spine mobility testing and maximum and adapted activity scores of the Human Activity Profile questionnaire to test functionality in daily activities. RESULTS: Fifty patients were evaluated at baseline; six did not undergo hematopoietic stem cell transplantation (three died, one refused and two were excluded). Thus 44/50 (88% - 21 allogeneic and 23 autologous) transplantations were performed. Only 33 of the 44 patients (75%) performed evaluations after transplantation (nine died and two were excluded). Of the patients who performed both evaluations, significantly lower values were found in the evaluation after transplantation for the 2-minute walking test (p-value = 0.004), grip strength of both right and left hands (p-value = 0.004 and p-value < 0.0001, respectively), the Schober Test, and maximum and adapted activity scores (p-value < 0.0001). The heart rate was higher (p-value = 0.01) before the 2-minute walking test and oxygen saturation was higher (p-value = 0.02) after. CONCLUSION: Statistical differences indicate functional impairment after transplantation showing physical losses in this population.

Association between human leukocyte antigens and graft-versus-host disease occurrence after allogenic hematopoietic stem cell transplantation / Associação entre antígenos leucocitários humanos e a ocorrência da doença do enxerto contra o hospedeiro após o transplante alogênico de células-tronco hematopoiéticas

CONTEXT AND OBJECTIVE: Graft-versus-host disease (GVHD) is one of the complications following allogenic stem cell transplantation. This study investigated an association between human leukocyte antigen (HLA) and the occurrence of acute and chronic GVHD in patients who had received stem cell transplantations from HLA-identical siblings. DESIGN AND SETTING: Retrospective study at Hematology and Hemotherapy Center, Universidade Estadual de Campinas (Unicamp). METHODS: The participants were 176 patients whose first transplant was between 1997 and 2009. HLA genotyping was performed serologically and using the polymerase chain reaction with specific primer sequence. RESULTS: Acute GVHD was positively associated with HLA-A10 (P = 0.0007), HLA-A26 (P = 0.002), B55 (P = 0.001), DRB1*15 (P = 0.0211) and DQB1*05 (P = 0.038), while HLA-B16 (P = 0.0333) was more frequent in patients without acute GVHD. Chronic GVHD was positively associated with HLA-A9 (P = 0.01) and A23 (P = 0.0292) and negatively with HLA-A2 (P = 0.0031) and B53 (P = 0.0116). HLA-B35 (P = 0.0373), B49 (P = 0.0155) and B55 (P = 0.0024) were higher in patients with acute GVHD grade 3 or above, than in other patients. In patients with extensive chronic GVHD, HLA-A9 (P = 0.0004), A24 (P = 0.0059) and A26 (P = 0.0411) were higher than in other patients, while HLA-A2 was lower (P = 0.0097). CONCLUSION: This study suggests that HLA can influence the incidence and severity of acute and chronic GVHD. However, a study with a better design and more patients will be needed to confirm these results.

CONTEXTO E OBJETIVO: A doença do enxerto contra o hospedeiro (DECH) é uma das complicações pós-transplante alogênico de células progenitoras hematopoéticas. Este estudo investigou uma associação entre o antígeno leucocitário humano (HLA) e a ocorrência de DECH aguda e crônica, em pacientes que receberam transplantes de irmãos HLA-idênticos. TIPO DE ESTUDO E LOCAL: Estudo retrospectivo no Centro de Hematologia e Hemoterapia da Universidade Estadual de Campinas (Unicamp). MÉTODOS: Os participantes foram 176 pacientes cujo primeiro transplante foi entre 1997 e 2009. A tipagem HLA foi realizada por sorologia e reação em cadeia da polimerase (PCR) com sequência específica de primers. RESULTADOS: A DECH aguda foi associada positivamente com HLA-A10 (P = 0,0007), HLA-A26 (P = 0,002), B55 (P = 0,001), DRB1*15 (P = 0,0211) e DQB1*05 (P = 0,038), enquanto HLA-B16 (P = 0,0333) foi mais frequente em pacientes sem DECH aguda. A DECH crônica foi associada positivamente com HLA-A9 (P = 0,01) e A23 (P = 0,0292) e, negativamente, com HLA-A2 (P = 0,0031) e B53 (P = 0,0116). HLA-B35 (P = 0,0373), B49 (P = 0,0155) e B55 (P = 0,0024) estavam aumentados em pacientes com DECH aguda grau 3 ou maior, em comparação aos outros pacientes. Em pacientes com DECH crônica extensa, HLA-A9 (P = 0,0004), A24 (P = 0,0059) e A26 (P = 0,0411) estavam aumentados em comparação aos outros pacientes, enquanto HLA-A2 estava diminuído (P = 0,0097). CONCLUSÕES: Este estudo sugere que o HLA pode influenciar a ocorrência de DECH aguda e crônica e a sua gravidade. No entanto, um estudo com melhor desenho e com mais pacientes será necessário para confirmar esses resultados.

Importance of killer immunoglobulin-like receptors in allogeneic hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation is the treatment of choice for many hematologic diseases, such as multiple myeloma, bone marrow aplasia and leukemia. Human leukocyte antigen (HLA) compatibility is an important tool to prevent post-transplant complications such as graft rejection and graft-versus-host disease, but the high rates of relapse limit the survival of transplant patients. Natural Killer cells, a type of lymphocyte that is a key element in the defense against tumor cells, cells infected with viruses and intracellular microbes, have different receptors on their surfaces that regulate their cytotoxicity. Killer immunoglobulin-like receptors are the most important, interacting consistently with human leukocyte antigen class I molecules present in other cells and thus controlling the activation of natural killer cells. Several studies have shown that certain combinations of killer immunoglobulin-like receptors and human leukocyte antigens (in both donors and recipients) can affect the chances of survival of transplant patients, particularly in relation to the graft-versusleukemia effect, which may be associated to decreased relapse rates in certain groups. This review aims to shed light on the mechanisms and effects of killer immunoglobulin-like receptors - human leukocyte antigen associations and their implications following hematopoietic stem cell transplantation, and to critically analyze the results obtained by the studies presented herein.

Leucemia mieloide crônica e outras doenças mieloproliferativas crônicas / Chronic myeloid leukemia and other chronic myeloproliferative disorders

A leucemia mieloide crônica (LMC) é uma doença clonal da medula óssea caracterizada pela presença do cromossomo Philadelphia (Ph), resultante da translocação entre os cromossomos 9 e 22. O gene híbrido assim formado, BCR-ABL codifica proteínas com atividade de tirosinoquinases que regulam o crescimento celular. A partir da década de 80, o transplante alogênico de células-tronco hematopoéticas (TCTH) se tornou tratamento de escolha para pacientes com idade menor que 55 anos de idade e doador compatível. Não obstante, a partir do advento dos inibidores de tirosinoquinases, drogas de alta eficácia e baixa toxicidade, houve uma mudança no algoritmo de tratamento da LMC. As indicações do TCTH foram restritas em decorrência da mortalidade relacionada a este procedimento e o mesilato de imatinibe tornou-se o novo tratamento de escolha para esta enfermidade. No Brasil e possivelmente em outros países em desenvolvimento, as condições socioeconômicas fazem com que o TCTH ainda seja considerado como primeira linha de tratamento em algumas situações. O TCTH permanece indicado nas doenças (ou neoplasias) mieloproliferativas, como a mielofibrose primária em situações de alto risco e pacientes portadores de policitemia vera ou trombocitose essencial que tenham evoluído para mielofibrose com características de alto risco.

Chronic myeloid leukemia (CML) is a clonal disease of the bone marrow characterized by the presence of Philadelphia chromosome (Ph) which results from translocation between chromosome nine and 22. The hybrid gene, BCR-ABL, encodes proteins with tyrosine kinase activity that regulate cell growth. From the 80ïs allogeneic hematopoietic stem cell transplantation (HSCT) has become the treatment of choice for patients younger than 55 years of age and donor. However, from the advent of tyrosine kinase inhibitors, drugs of high efficacy and low toxicity, there was a change in the treatment algorithm of CML. The indications of HSCT have been restricted as a result of mortality related to this procedure and imatinib mesylate has become the new treatment of choice for this disease. In Brazil and possibly in other developing countries, socio-economic conditions make HSCT still feasible as first-line treatment in some situations. The HSCT remains indicated for Ph negative myeloproliferative disorders such as high risk myelofibrosis or patients with polycythemia vera or essential thrombocytosis that have evolved to myelofibrosis with high-risk features.

Associação entre HLA e leucemia em uma população brasileira de etnia mista / Association between HLA and leukemia in a mixed Brazilian population

OBJETIVOS: O objetivo deste estudo foi investigar a freqüência de antígenos HLA Classe I e de alelos HLA Classe II em 164 pacientes com vários tipos de leucemias: 35 pacientes com LLA (leucemia linfóide aguda), 50 com LMA (leucemia mielóide aguda) e 78 com LMC (leucemia mielóide crônica). MÉTODOS: A tipagem HLA Classe I foi realizada por microlinfocitotoxicidade e a de Classe II por PCR-SSP (polymerase chain reaction - sequence specific of primers), ambas da One Lambda (Canoga Park, CA, US). RESULTADOS: Em pacientes com LLA, as freqüências das variantes HLA-B45 e HLA-B56 foram maiores (P = 0,02; OR = 3,13; 95 por centoIC = 0,94-10,44; P = 0,03; OR = 3,61; 95 por centoIC = 0,47-27,64, respectivamente), quando comparadas com controles. Nos pacientes com LMA, a freqüência de HLA-B7 (P = 0,01; OR = 2,41; 95 por centoIC = 1,25-4,67) foi maior que em controles. A presença de HLA-B45 (P= 0,01; OR = 3,29; 95 por centoIC = 1,46-7,40) e de HLA-DRB1*04 (P = 0,002; OR = 2,17; 95 por centoIC = 1,36-3,46) e HLA-DRB1*08 (P = 0,004; OR = 2,36; 95 por centoIC = 1,34-4,16) foi associada ao maior risco de desenvolver LMC. CONCLUSÃO: Nossos resultados sugerem que variantes HLA conferem susceptibilidade a algumas formas de leucemia e podem prover novas ferramentas para a investigação da genética e etiologia desta doença.

OBJECTIVE: The main purpose of this study was to investigate the class I HLA antigens and class II HLA allele frequencies in 164 patients with leukemia: 35 patients with ALL (acute lymphoid leukemia), 50 with AML (acute myeloid leukemia) and 78 with CML (chronic myeloid leukemia). METHODS: The genotyping of class I HLA was performed by microlymphocytotoxicity and of class II by PCR-SSP (polymerase chain reaction - sequence specific of primers) (One Lambda, Canoga Park, CA, USA). RESULTS: In patients with LLA, frequencies of HLA-B45 and HLA-B56 were higher (P = 0.02; OR = 3.13; 95 percentIC = 0.94-10.44; P = 0.03; OR = 3.61; 95 percentIC = 0.47-27.64, respectively), than in controls. In patients with AML, the frequency of HLA-B7 (P = 0.01; OR = 2.41; 95 percentIC = 1.25-4.67) was higher than in controls. The presence of HLA-B45 (P= 0.01; OR = 3.29; 95 percentIC = 1.46-7.40), HLA-DRB1*04 (P = 0.002; OR = 2.17; 95 percentIC = 1.36-3.46) and HLA-DRB1*08 (P = 0.004; OR = 2.36; 95 percentIC = 1.34-4.16) was associated to increased risk of CML developing. CONCLUSION: Our results suggest that variants of HLA confer susceptibility to the same forms of leukemia, and could provide new tools for the investigation of genetics and etiology of this disease.

O transplante alogênico de células-tronco hematopoéticas no tratamento do Mieloma Múltiplo / Allogeneic hematopoietic stem cell transplant for Multiple Myeloma

O mieloma múltiplo (MM) é uma neoplasia hematológica incurável com uma sobrevida mediana de três anos com a utilização de tratamento convencional. O transplante de células-tronco hematopoéticas alogênico (TCTH-alo) pode curar alguns pacientes, mas está associado com uma alta mortalidade relacionada ao transplante (MRT) podendo atingir mais de 40 por cento. As vantagens do TCTH-alo são a capacidade de coletar um enxerto livre de mieloma e o efeito enxerto-versus-mieloma (EVM). Entretanto, apesar destes fatores, a cura é rara. As recidivas ocorrem em uma taxa de 7 por cento ao ano em seguimentos prolongados. A doença do enxerto contra o hospedeiro (GVHD) pode também ser um problema, necessitando de tratamento específico e prejudicando a qualidade de vida. Novas técnicas para melhorar os resultados do TCTH-alo para o MM incluem a consideração do status do paciente, a eficácia e a toxicidade do tratamento de indução, o tipo do enxerto e o regime de condicionamento utilizado. Recentemente foi incluído o transplante autólogo seguido pelo transplante alogênico não mieloablativo e o TCTH- alo com depleção de células T e subseqüente infusão de linfócitos do doador. A utilização de novas estratégias terapêuticas direcionadas para a regulação do ciclo celular poderá prolongar a sobrevida dos pacientes e melhorar a qualidade de vida se comparada com os atuais resultados do transplante, que ainda apresentam claros benefícios na sobrevida.

Multiple myeloma (MM) is a incurable hematological malignancy with an average survival of 3 years with conventional therapy. Allogeneic hematopoietic cell transplantation (allo - HCT) may cure some patients, but has been associated with a high transplantation-related-mortality (TRM) of over 40 percent. The potential advantages of allo - HCT are the ability to collect myeloma free stem cells and the graft - versus - myeloma effect. But, despite these factors, long term cure is rare. Relapse continues at a rate of approximately 7 percent per year with long term follow-up. The graft-versus-host disease (GVHD) can also be a problem, requiring therapy and impairing quality of life. Approaches to improve the outcome of allo - HCT for MM include consideration of patient status, efficacy and toxicity of induction therapy, source of hematopoietic graft, and conditioning regimens. Recent attempts to improve outcome include autologous hematopoietic cell transplantation (AHCT) followed by non - myeloablative allogeneic transplantation, and allo-HCT with T depletion and subsequent donor lymphocyte infusions. With the use of strategies directed at cell signaling, patients' lives can be prolonged, and the quality of their lives can be improved compared with the current approach that transplantation provides, despite its survival benefit.

Addition of exogenous cytokines in mixed lymphocyte culture for selecting related donors for bone marrow transplantation

CONTEXT: Mixed lymphocyte culturing has led to conflicting opinions regarding the selection of donors for bone marrow transplantation. The association between a positive mixed lymphocyte culture and the development of graft-versus-host disease (GVHD) is unclear. The use of exogenous cytokines in mixed lymphocyte cultures could be an alternative for increasing the sensitivity of culture tests. OBJECTIVE: To increase the sensitivity of mixed lymphocyte cultures between donor and recipient human leukocyte antigen (HLA) identical siblings, using exogenous cytokines, in order to predict post-transplantation GVHD and/or rejection. TYPE OF STUDY: Prospective study. SETTING: Bone Marrow Transplantation Unit, Universidade Estadual de Campinas. PARTICIPANTS: Seventeen patients with hematological malignancies and their respective donors selected for bone marrow transplantation procedures. PROCEDURES: Standard and modified mixed lymphocyte culturing by cytokine supplementation was carried out using donor and recipient cells typed for HLA. MAIN MEASUREMENTS: Autologous and allogenic responses in mixed lymphocyte cultures after the addition of IL-4 or IL-2. RESULTS: In comparison with the standard method, average responses in the modified mixed lymphocyte cultures increased by a factor of 2.0 using IL-4 (p < 0.001) and 6.4 using IL-2 (p < 0.001), for autologous donor culture responses. For donor-versus-recipient culture responses, the increase was by a factor of 1.9 using IL-4 (p < 0.001) and 4.1 using IL-2 (p < 0.001). For donor-versus-unrelated culture responses, no significant increase was observed using IL-4, and a mean response inhibition of 20 percent was observed using IL-2 (p < 0.001). Neither of the cytokines produced a significant difference in the unrelated control versus recipient cell responses. CONCLUSION: IL-4 supplementation was the best for increasing the mixed lymphocyte culture sensitivity. However, IL-4 also increased autologous responses, albeit less intensively than IL-2. Thus, with this loss of specificity we believe that it is not worth modifying the traditional mixed lymphocyte culture method, even with IL-4 addition