Francisco J.P. Aranha

Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: An individual patient data meta-analysis of nine randomized trials

PURPOSE Considerable uncertainty exists regarding relative effects of allogeneic peripheral blood stem cells transplantation (PBSCT) versus bone marrow transplantation (BMT) on outcomes of patients with hematologic malignancies. PATIENTS AND METHODS To provide the totality of research evidence related to the effects of PBSCT versus BMT, we conducted an individual-patient data meta-analysis using data from nine randomized trials enrolling 1,111 adult patients. RESULTS Compared with BMT, PBSCT led to faster neutrophil (odds ratio [OR] = 0.31; 95% CI, 0.25 to 0.38; P < .00001) and platelet engraftment (OR = 0.52; 95% CI, 0.44 to 0.61; P < .00001). PBSCT was associated with a significant increase in the development of grade 3-4 acute graft-versus-host disease (GVHD; OR = 1.39; 95% CI, 1.03 to 1.88) and extensive (47% v 31% at 3 years; OR = 1.89; 95% CI, 1.47 to 2.42; P < .000001) and overall chronic GVHD (68% v 52% at 3 years; OR = 1.92; 95% CI, 1.47 to 2.49; P < .000001), but not grade 2-4 acute GVHD (54% v 53%; P = .49). PBSCT was associated with a decrease in relapse (21% v 27% at 3 years; OR = 0.71; 95% CI, 0.54 to 0.93; P = .01) in both late-stage-(33% v 51% at 3 years; OR = 0.59; 95% CI, 0.38 to 0.93; P = .02) and early-stage-disease patients (16% v 20% at 3 years; OR = 0.69; 95% CI, 0.49 to 0.98; P = .04). Nonrelapse mortality was not different between groups. Overall and disease-free survival were only statistically significantly improved in patients with late-stage disease (overall survival: 46% v 31% at 3 years; OR = 0.64; 95% CI, 0.46 to 0.90; P = .01; disease-free survival: 41% v 27% at 3 years; OR = 0.63 95% CI, 0.45 to 0.87; P = .01). CONCLUSION PBSCT is associated with a decreased relapse rate in hematologic malignancies and improvement in overall and disease-free survival in patients with late-stage disease. PBSCT is also associated with a significant risk of extensive chronic GVHD.

A high angiopoietin-2/angiopoietin-1 ratio is associated with a high risk of septic shock in patients with febrile neutropenia

IntroductionEndothelial barrier breakdown is a hallmark of septic shock, and proteins that physiologically regulate endothelial barrier integrity are emerging as promising biomarkers of septic shock development. Patients with cancer and febrile neutropenia (FN) present a higher risk of sepsis complications, such as septic shock. Nonetheless, these patients are normally excluded or under-represented in sepsis biomarker studies. The aim of our study was to validate the measurement of a panel of microvascular permeability modulators as biomarkers of septic shock development in cancer patients with chemotherapy-associated FN.MethodsThis was a prospective study of diagnostic accuracy, performed in two distinct in-patient units of a university hospital. Levels of vascular endothelial growth factor A (VEGF-A), soluble fms-like tyrosine kinase-1 (sFlt-1) and angiopoietin (Ang) 1 and 2 were measured after the onset of neutropenic fever, in conditions designed to mimic the real-world use of a sepsis biomarker, based on our local practice. Patients were categorized based on the development of septic shock by 28 days as an outcome.ResultsA total of 99 consecutive patients were evaluated in the study, of which 20 developed septic shock and 79 were classified as non-complicated FN. VEGF-A and sFlt-1 levels were similar between both outcome groups. In contrast, Ang-2 concentrations were increased in patients with septic shock, whereas an inverse finding was observed for Ang-1, resulting in a higher Ang-2/Ang-1 ratio in patients with septic shock (5.29, range 0.58 to 57.14) compared to non-complicated FN (1.99, range 0.06 to 64.62; P = 0.01). After multivariate analysis, the Ang-2/Ang-1 ratio remained an independent factor for septic shock development and 28-day mortality.ConclusionsA high Ang-2/Ang-1 ratio can predict the development of septic shock in cancer patients with febrile neutropenia.

Platelet glycoprotein Ibα polymorphisms modulate the risk for myocardial infarction

Platelet glycoprotein Iba (GPIba) gene polymorphisms have been reported to affect the risk of developing coronary heart disease. Here, within the GPIba gene, we determine the association between the variable number of tandem repeats (VNTR), the -5C/T Kozak sequence dimorphism, and the human platelet antigen (HPA)-2 polymorphisms with occurrence of myocardial infarction (MI). Patients (n=180) presenting survivors of MI were compared to 180 controls matched by age, gender, and race. Carriers of VNTR-CD genotype had a 2-fold higher risk for MI compared to controls.The prevalence of VNTR-BC was lower among patients than among controls (P=.007). These data are in agreement with recent reports of increased plug formation by human platelets containing VNTRCD but no other VNTR genotypes. Among patients, the number of vessels severely occluded was greater among carriers of the D-allele (P=.019) or VNTR-CD (P=.026) and lower among carriers of the C-allele (P=.003) or VNTR-CC (P=.0009) compared to non-carriers of these alleles. No influence was seen with the Kozak or HPA-2 polymorphisms. Determination of VNTR of the GPIba gene may prove useful for identifying high-risk individuals for MI.

Cytomegalovirus (CMV) genotype in allogeneic hematopoietic stem cell transplantation

BackgroundBased on sequence variation in the UL55 gene that encodes glycoprotein B (gB), human cytomegalovirus (CMV) can be classified into four gB genotypes. Previous studies have suggested an association between CMV gB genotype and clinical outcome in patients who underwent an allogeneic hematopoietic stem cell transplant (HSCT). The goals of this study were identify patients with active infection caused by CMV in recipients of HSCT; determine the prevalence of CMV genotypes in the study group; correlate genotype with CMV disease, acute GVHD and overall survival.MethodsThe diagnosis of active CMV infection after allogeneic HSCT was detected by antigenemia (AGM) and/or nested-PCR (N-PCR). Positive samples from patients with active CMV infection were submitted to genotyping using N-PCR to amplify a region of UL55, followed by restriction analysis based on HinfI and RsaI digestion. Real-time PCR (qPCR) was used to determine the viral load during active CMV infection and antiviral treatment.ResultsSixty-three allogeneic HSCT recipients were prospectively evaluated; 49/63 (78%) patients were infected with CMV genotypes – gB1 19/49 (39%), gB2 17/49 (35%), gB3 3/49 (6%), gB4 7/49 (14%) – and 3 (6%) had mixed CMV genotypes (gB1 + gB3, gB1 + gB4 and gB2 + gB4). Characterized by gastrointestinal disease, CMV disease occurred in 3/49 (6.1%) patients, who had CMV gB3 genotype. These gB3 genotype patients presented an increasing AGM number, mean 125 (± 250) (P = 0.70), and qPCR copies/ml, mean 37938 (SD ± 50542) (P = 0.03), during antiviral treatment, when compared with other CMV genotypes. According to CMV genotypes, stratified overall survival was 55% for gB1, 43% for gB2; 0% for gB3 and 57% for gB4 (P = 0.03).ConclusionsOne of the restrictions of the presented study was the low number of CMV gB sub-cohorts). However, we demonstrated that the frequency of active CMV infection in this HSCT population was high, and the most prevalent genotype in these patients with active CMV infection was gB1 and gB2 genotype (74%). In Brazil, HSCT recipients seem to carry mainly gB1 and gB2 CMV genotype.

Associação entre HLA e leucemia em uma população brasileira de etnia mista

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%IC = 0.94-10.44; P = 0.03; OR = 3.61; 95%IC = 0.47-27.64, respectively), than in controls. In patients with AML, the frequency of HLA-B7 (P = 0.01; OR = 2.41; 95%IC = 1.25-4.67) was higher than in controls. The presence of HLA-B45 (P= 0.01; OR = 3.29; 95%IC = 1.46-7.40), HLA-DRB1*04 (P = 0.002; OR = 2.17; 95%IC = 1.36-3.46) and HLA-DRB1*08 (P = 0.004; OR = 2.36; 95%IC = 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.

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.

Terapêutica citoprotetora em pacientes tratados com quimio e/ou radioterapia anti neoplásica

In recent years, cytoprotective agents have been developed to protect normal cells from the toxic effects of chemotherapy and radiotherapy. The ideal cytoprotectant is that which is able to allow intensification of chemotherapy; protects a broad spectrum of normal tissues and organs when used with a variety of chemotherapeutic agents; confers specific protection for normal tissues; preserves anti tumour activity and has little or manageable toxicity of its own. A cytoprotectant is administered prior to cytotoxic therapy, in contrast to the colony stimulant factors and Leucovorin, which are administered after chemotherapy to rescue the bone marrow and stimulate haematological recovery. Currently there are three cytoprotectors: two chemotherapy-specific (Dexrazoxane and Mesna) and one broad-spectrum (Amifostine). The authors discuss the main properties and usefulness of these drugs in Oncohematology.

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.

Experiência brasileira utilizando terapia sequencial de alta dose seguido de transplante autólogo de célula-tronco hematopoética para linfomas malignos

A proposta deste trabalho foi avaliar a eficacia da HDS seguida do transplante autologo como terapia de salvamento atraves da sobrevida global, livre de doenca e livre de progressao bem como sua toxicidade. Realizou-se estudo retrospectivo com 106 pacientes com LNH de alto grau de malignidade entre 1998 e 2006. A mediana de idade foi 45 anos (8-65); 62% homens; DLBCL, 78%; 12%, T e anaplasico e 9%, linfoma da zona do manto; 87%, celulas B; 83% estadios III-IV; 63% com sintomas B; 32% com infiltracao da medula ossea ao diagnostico; 62% com grande massa e 42% com IPI de alto risco ou intermediario. Apos alta dose de ciclofosfamida (HDCY), nove pacientes faleceram. Oitenta pacientes realizaram o transplante, sendo que 47% estavam em RC e 15% faleceram devido a toxicidade. A sobrevida global foi de 45% em oito anos para estes pacientes. Trinta e cinco pacientes nao realizaram o transplante por causas diversas. Sobrevida global para todos os pacientes foi de 42%, DLBCL, 40%; T-cell, 40% e zona do manto, 20% (P=NS). Pacientes que obtiveram RC apos HDCY tiveram melhor sobrevida global e livre de progressao (38% e 17%, respectivamente) do que os que permaneceram em PD (P<0.0001). O modelo de Cox resultou que o numero de linhas terapeuticas antes da HDCY (RR 1.41 IC 95%: 1.04-1.90, P=0.02) e PD antes da HDCY (RR 2.70, IC 95%: 1.49-4.91, P<0.001) e apos HDCY (RR 5.38, IC 95%: 2.93-9.87, P<0.0001). Nosso estudo sugere que HDS e um metodo eficiente de tratamento para melhorar o status e reduzir a massa tumoral. Em relacao a toxicidade, e factivel, especialmente em pacientes de prognostico ruim

Brazilian Experience Using High-Dose Sequential Chemotherapy Followed by Autologous Hematopoietic Stem Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma

PURPOSE We evaluate the effectiveness and toxicity of high-dose sequential chemotherapy (HDS) as salvage therapy in patients with advanced-stage Hodgkin lymphoma. PATIENTS AND METHODS We performed a retrospective analysis on 77 patients receiving HDS between 1998 and 2006. Patients enrolled were in disease progression or relapsed disease, or did not achieve a complete remission after first-line treatment. HDS consisted of the sequential administration of cyclophosphamide and granulocyte colony-stimulating factor with stem cell harvesting, followed by methotrexate plus vincristine and etoposide. RESULTS The majority of patients had stage III/IV (64%) and B symptoms (71.4%). Disease status improvement after HDS was observed in 24 of 57 patients (42%) previously in disease progression or relapse. HDS-related deaths occurred in 8 of 77 patients (10.4%). Four patients (5.2%) developed acute myeloid leukemia/myelodysplastic syndrome. Overall, disease-free and progression-free survival was 27%, 57%, and 25%, respectively. CONCLUSION Despite the treatment-related mortality, HDS is feasible, with satisfactory response rates, even in patients with poor prognosis.