Mair Pedro de Souza

Epidemiology of neglected tropical diseases in transplant recipients: review of the literature and experience of a Brazilian HSCT center

The rising success rate of solid organ (SOT) and haematopoietic stem cell transplantation (HSCT) and modern immunosuppression make transplants the first therapeutic option for many diseases affecting a considerable number of people worldwide. Consequently, developing countries have also grown their transplant programs and have started to face the impact of neglected tropical diseases (NTDs) in transplant recipients. We reviewed the literature data on the epidemiology of NTDs with greatest disease burden, which have affected transplant recipients in developing countries or may represent a threat to transplant recipients living in other regions. Tuberculosis, Leprosy, Chagas disease, Malaria, Leishmaniasis, Dengue, Yellow fever and Measles are the topics included in this review. In addition, we retrospectively revised the experience concerning the management of NTDs at the HSCT program of Amaral Carvalho Foundation, a public transplant program of the state of São Paulo, Brazil.

Survival and graft-versus-host disease in patients receiving peripheral stem cell compared to bone marrow transplantation from HLA-matched related donor: retrospective analysis of 334 consecutive patients

The objective of this study was to compare the major transplant outcomes between patients receiving hematopoietic stem cell transplantation (HSCT) from bone marrow (BM) or peripheral blood stem cells (PBSC).

Estudo retrospectivo do tratamento de leucemia mielóide aguda com o transplante de medula óssea: a experiência brasileira

Data from the International Bone Marrow Transplant Registry (IBMTR) contribute for the improvement of Bone Marrow Transplant (BMT) worldwide. We studied the Brazilian experience in BMT for AML to compare this with international data. We performed a retrospective study by sending questionnaires to 16 BMT centers regarding clinical and treatment variables. Statistical analyses concerning autologous BMT (autoBMT) and allogeneic BMT (alloBMT) were performed using the Kaplan-Meier method and the log-rank test. All p-values were two-tailed. We collected data from 731 patients (205 autoBMT and 526 alloBMT). Median overall survival (OS) for autoBMT patients was longer than alloBMT patients (1035 vs. 466 days, p=0.0012). AlloBMT stem cell source (SCS): 73% bone marrow stem cell (BMSC), 23% peripheral blood stem cells (PBSC) and 4% umbilical cord blood. Among the autoBMT patients, the SCS was 63% PBSC, 22% BMSC and 15% both. The SCS did not impact on OS. There was no difference in OS between different FAB classifications in the alloBMT group, but in the autoBMT the M3 patients had longer survival. As expected, the main cause of mortality among autoBMT patients was related to disease relapse (60%), while in the alloBMT, to infection (38%). In both groups we found longer OS in first complete remission (1CR) compared to second (2CR) and other (p<0.0001), and longer OS in de novo AML than in secondary. In the alloBMT group we found more patients with advanced disease (60%), while in the autoBMT group, we found more M3 patients (24%), which could explain the difference in OS. Most of our results are in accordance with IBMTR data. One should consider the fact that this is a retrospective study and our findings should be analysed with caution.

Zika and chikungunya virus infections in hematopoietic stem cell transplant recipients and oncohematological patients

Aedes mosquitoes are well adapted in domestic environments and widespread in tropical regions. Since 2015, Brazil has been experiencing a triple epidemic of dengue (DENV), chikungunya (CHKV), and Zika (ZIKV) viruses. The last 2 viruses are likely following the path of DENV, which has been endemic in most parts of the country since the 1980s. Given this triple epidemic, we proposed a prospective and collaborative study to assess the prevalence, morbidity, and mortality of DENV, CHKV, and ZIKV infections in hematopoietic stem cell transplant (HSCT) recipients and oncohematological patients. A case definition strategy (fever and rash) was used to prompt diagnostic investigation of DENV, ZIKV, and CHKV, which was accomplished by real-time polymerase chain reaction with plasma and urine samples. Clinical follow-up was performed 7 and 30 days after symptom onset. We report here the first cases of ZIKV and CHKV infections diagnosed in this ongoing study. From February to May 2016, 9 of the 26 patients (34.6%) fulfilling case definition criteria were diagnosed with DENV (3 cases), ZIKV (4 cases), or CHKV (2 cases) infections. Prolonged viremia and viruria were observed in dengue and Zika fever cases, respectively. Thrombocytopenia was the most frequent complication. Delayed engraftment was noted in 1 patient who acquired ZIKV 25 days before HSCT. All patients survived without sequelae. With the geographic expansion of arboviruses, donor and recipient screening may become mandatory. Patients living in areas where these viruses are not endemic are also at risk, since these viruses can be transmitted by blood as well as organ or tissue transplantation.

Diretrizes para o diagnóstico, classificação, profilaxia e tratamento da doença enxerto contra hospedeiro crônica

A falta de criterios diagnosticos padronizados, amplamente utilizados, pode comprometer tanto a avaliacao real da incidencia da doenca contra hospedeiro cronica bem como a correlacao de sua gravidade com a taxa de mortalidade pos-transplante. Na I Reuniao de Diretrizes da Sociedade Brasileira de Transplante de Medula Ossea, realizada em junho de 2009, o Grupo de Estudos de DECH Brasil - Seattle (GEDECH), baseado na realidade dos Centros brasileiros, apresentou as recomendacoes para diagnostico, classificacao, profilaxia e tratamento da doenca enxerto contra hospedeiro cronica propostas pelo National Institutes of Health. Estas propostas incluiram padronizacao das caracteristicas utilizadas no diagnostico e ferramentas para a pontuacao dos orgaos envolvidos e avaliacao global da gravidade a serem utilizados em estudos clinicos da doenca enxerto contra hospedeiro cronica. Estes criterios sao uteis para uma melhor analise da incidencia desta doenca, alem de poder avaliar a gravidade do comprometimento de um orgao ou sitio envolvido e a influencia na mortalidade tardia do transplante. A profilaxia e os tratamentos propostos para esta importante complicacao dos transplantes de celulas-tronco hematopoeticas foram discutidos e graduados de acordo com niveis de evidencia estabelecidos pelo National Institutes of Health.

Transplante de células-tronco hematopoéticas em crianças e adolescentes com leucemia aguda: experiência de duas instituições Brasileiras

Hematopoietic Stem Cell transplantation (HSCT) is the treatment of choice for patients with high-risk leukemia. In spite of this, relapse remains a major cause of death of these patients. Our objective was to analyze the outcomes of patients with acute leukemia submitted to hematopoietic stem cell transplantation in two Brazilian institutions. A retrospective study of 208 patients transplanted between 1990 and 2007 with a median age of 9 years (range: 1-18 years) was made. One hundred and nineteen patients had acute lymphocytic leukemia (ALL) and 89 had acute myeloid leukemia (AML). Early disease was considered for CR1 and CR2 cases and advanced disease >CR3 and refractory and relapse disease. Ninety patients are alive between 258 and 6068 days after hematopoietic stem cell transplantation (M: 1438 days). The overall survival (OS) was 45% (3 years) and event free survival (EFS) was 39% (3 years). Primary graft failure occurred in 14/195 patients (8%). There were no differences in the overall survival and event free survival between patients with acute lymphocytic leukemia and acute myeloid leukemia, between sources of cells used or between those who developed acute or chronic graft-versus-host disease (GVHD). When comparing transplants from related and unrelated donors, there was no difference in the overall survival. Patients with acute lymphocytic leukemia receiving the total body irradiation (TBI) conditioning regimen had better overall survival and event free survival (p<0.001). One hundred and eighteen patients died between 0 and 1654 days after hematopoietic stem cell transplantation (M: 160 days). Transplantation-related-mortality (TRM) at D+100 was 16% and cumulative incidence of relapse was 40% (3 years). Patients with advanced disease had lower 3-year overall survival and event free survival (p<0.001). Multivariate analysis showed that disease status was the most significant factor associated with higher event free survival and overall survival . Our results show that children and adolescents transplanted with early disease can achieve considerable overall survival and also highlights the inefficacy of hematopoietic stem cell transplantation for patients with advanced disease.

Thymopoiesis in Pre- and Post-Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) is an important therapeutic option for some hematological diseases. However, patients who undergo HSCT acquire a state of immunodeficiency that causes significant mortality. Reconstitution of thymic function is needed to support the immune system. One way to measure thymic function is through T-cell receptor excision circle (TREC) quantification. TRECs are generated by T-cell receptor gene rearrangements during T-cell maturation in the thymus and represent a reliable marker for thymic output. In this study, we aimed to assess aging and malignant hematological diseases as two important factors that may influence thymic output before HSCT. We observed that patients before HSCT presented signal joint TREC (sjTREC) numbers lower than 606.55 copies/μg DNA (low values) compared with healthy individuals, with an odds ratio (OR) of 12.88 [95% confidence interval (CI): 5.26–31.53; p < 0.001]. Our results showed that a group of older individuals (≥50 years old), comprising both healthy individuals and patients, had an OR of 10.07 (95% CI: 2.80–36.20) for low sjTREC values compared with younger individuals (≤24 years old; p < 0.001). Multiple logistic regression analysis confirmed that both older age (≥50 years old) and malignant hematological diseases and their treatments were important and independent risk factors related to thymic function impairment (p < 0.001). The median sjTREC value for patients of all ages was significantly lower than the sjTREC median for the subgroup of older healthy individuals (≥50 years old; p < 0.001). These data suggested that patients before HSCT and healthy individuals exhibited age-dependent thymic impairment, and that prior treatment for hematological diseases may exacerbate aging-related deterioration of natural thymic function. Furthermore, we analyzed these patients 9 months post-HSCT and compared patients who underwent autologous HSCT with those who underwent allogeneic HSCT. Both groups of patients achieved sjTREC copy numbers similar to those of healthy individuals. We did not find a close relationship between impaired thymic function prior to HSCT and worse thymic recovery after HSCT.

Low Body Mass Index Is Associated with Increased Risk of Acute GVHD after Umbilical Cord Blood Transplantation in Children and Young Adults with Acute Leukemia: A Study on Behalf of Eurocord and the EBMT Pediatric Disease Working Party

Body mass index (BMI) may influence outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of BMI on survival in children undergoing HSCT is not well defined, with conflicting results being reported on this issue. We analyzed 855 patients age 2 to 20 years with diagnosis of acute leukemia who underwent umbilical cord blood transplantation (UCBT) from 1990 to 2015. Patients were classified according to BMI as normal (fifth to 85th percentile), underweight (less than fifth percentile), overweight (85th to 95th percentile), and obese (>95th percentile) using growth charts for age and sex. All patients received single-unit UCBT after a myeloablative conditioning regimen. Diagnosis was acute lymphoblastic leukemia in 68% of the patients. Sixty-one percent of patients (n = 523) were in the normal BMI category, 11% (n = 96) were underweight, 16% (n = 137) overweight, and 12% (n = 99) obese. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was 35% (32% to 38%). According to pretransplantation BMI, aGVHD was 46% (33% to 59%) for underweight, 34% (31% to 42%) for normal, 36% (18% to 38%) for overweight, and 27% (15% to 37%) for obese (P = .04). In multivariate analysis, a BMI less than the fifth percentile was associated with higher incidence of acute grade II to IV GVHD compared with normal-BMI patients (hazard ratio,  1.61; 95% confidence interval, 1.15 to 2.26; P = .006). Our results show that being underweight at the time of transplantation is associated with an increased risk of aGVHD, highlighting the importance of nutritional status before UCBT.

Transplante de células-tronco hematopoéticas em linfoma Hodgkin

Hodgkins Lymphoma is a hematologic malignancy with a wide range of therapeutic options that must be chosen according to the stage and the prognostic classification of each patient. The overall survival of patients treated for classic Hodgkins Lymphoma is increasing significantly, with current cure rates being between 80% and 85%. Nevertheless, 20% to 25% are refractory to the initial treatment and about 30% relapse after having reached a complete response. Patients that have failed standard therapy still have a second chance of cure if they present chemosensitivity to cure schemes, followed by one type of hematopoietic stem cell transplantation (TCTH). Autologous TCTH is an attractive strategy for Hodgkins Lymphoma patients that fail in the conventional standard therapy. The results in terms of overall survival and disease-free survival are higher than the cure schemes with conventional chemotherapy. This procedure addresses the cure in 50% of chemosensitive patients in second remission, and can lead to lasting remissions for those with more than two lines of treatment. Today, allogeneic TCTH, basically with reduced intensity conditioning (RIC) is indicated for patients with premature relapse after autologous TCTH or for young patients refractory to one or more lines of conventional treatment.