ABSTRACT
BACKGROUND: The mitogen-activated protein kinase (MAPK)/ERK signaling cascade and the phosphoinosytol-3 phosphate/Akt (PI3K/Akt) pathways are involved in proliferation and differentiation of hematopoietic cells. The frequency of PI3K/Akt and MAPK pathway activation in adult acute lymphoblastic leukemia (ALL) still need to be elucidated. AIMS: To assess the activity and prognostic implications of MAPK/ERK and PI3K/Akt pathways in adult (ALL). METHODS: We examined 28 precursor-B-cell ALL and 6 T-cell primary ALL samples. Flow cytometry was employed to analyze the expression levels of phosphorylated ERK and phosphorylated Akt. RESULTS: Ten out of 15 (67%) ALL fresh samples (7 B-cell, 3 T-cell) showed constitutive p-ERK expression. The p-ERK mean fluorescent index ratio (MFI (R)) showed a tendency to be higher in ALL than in normal T lymphocytes (1.26 [0.74-3.10] vs. 1.08 [1.02-1.21], respectively [p = .069]) and was significantly lower than in leukemic cell lines (median MFI (R) 3.83 [3.71-5.97] [p < .001]). Expression of p-Akt was found in 35% (12/34) (10 B-cell, 2 T-cell). The median MFI (R) expression for p-Akt in primary blast cell was 1.13 (0.48-9.90) compared to 1.01 (1.00-1.20) in normal T lymphocytes (p = ns) and lower than in leukemic cell lines (median MFI (R) 2.10 [1.77-3.40] [p = .037]). Moreover, expression of p-ERK was negatively associated with the expression of CD34 (1.22 [0.74-1.33] vs. 1.52 [1.15-3.10] for CD34(+) and CD34(-) group, respectively, p = .009). CONCLUSION: Our findings suggest that both MAPK/ERK and PI3K/Akt are constitutively activated in adult ALL, indicating a targeted therapy potential for ALL by using inhibitors of these pathways.
Subject(s)
Mitogen-Activated Protein Kinases , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Adolescent , Humans , Mitogen-Activated Protein Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction/physiologyABSTRACT
INTRODUCTION: Measles, mumps, rubella, and even poliomyelitis outbreaks have recently perplexed infectious disease clinicians and epidemiologists globally due to the decline in vaccination coverage rates in children and adults. Measles and yellow fever (YF) have represented an increasing burden on the Brazilian public health system in recent decades. Both diseases are preventable by live-attenuated viral vaccines (LAVV), which have restricted use in hematopoietic cell transplant (HCT) recipients. METHODS: Autologous and allogeneic HCT recipients returning for regular appointments at the outpatient clinic were invited to participate in the study. Patients transplanted for at least 2 years and with a printed copy of the vaccination record were included. RESULTS: We assessed the vaccination records of 273 HCT recipients after the second year of HCT (193 allogeneic and 80 autologous) and observed lower compliance with the YF vaccine (58 patients, 21.2%) than with the measles vaccine (138 patients, 50.5%, p ≤ .0001). This is the largest published series of YF vaccination in HCT recipients so far. No severe adverse events occurred. Although expected, chronic graft-versus-host disease (GVHD) did not affect the compliance with measles (p = .08) or YF vaccination (p = .7). Indeed, more allogeneic recipients received measles vaccine in comparison with autologous patients (p < .0001), suggesting that chronic GVHD was not the main reason for not being vaccinated. Children and allogeneic HCT were more likely to receive measles vaccine. Time elapsed from HCT >5 years favored both measles and YF vaccination. CONCLUSION: A better understanding of the reasons for low compliance with LAVV is necessary to overcome this problem.
Subject(s)
Hematopoietic Stem Cell Transplantation , Measles , Yellow Fever Vaccine , Yellow Fever , Adult , Child , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Immunization, Secondary , Measles/prevention & control , Measles Vaccine/administration & dosage , Vaccination , Viral Vaccines , Yellow Fever/prevention & control , Yellow Fever Vaccine/administration & dosageABSTRACT
Tuberculosis (TB) is a major infectious complication in hematopoietic stem cell transplant (HSCT) recipients in countries with high TB prevalence. Identifying and treating latent tuberculosis infection (LTBI) helps to prevent TB reactivation after transplantation. Few studies have compared the tuberculin skin test (TST) with interferon Gamma release assays (IGRA) to diagnose LTBI in HSCT candidates. We compared TST and QuantiFeron TB gold in tube (QTF-GIT) and prospectively evaluated the incidence of active tuberculosis in 126 HSCT candidates and 58 HSCT recipients with chronic GVHD followed at the outpatient clinic. TB was diagnosed by culture in Mycobacteria media and by commercial real-time PCR kit. Considering the positivity of any test, the prevalence of LTBI was 8.7% in HSCT candidates (11 out of 126) and 12.5% in HSCT recipients with chronic GVHD (6 out of 48). QTF-GIT indeterminate results were detected in 2.4% of the HSCT candidates. Fair to good agreement (K > 0.50) between tests was observed in both cohorts. Cumulative incidence of TB was 3% in the GVHD cohort. TB was diagnosed in 2 chronic GVHD recipients, both cases confirmed by positive culture and PCR. None of the 11 patients with LTBI diagnosed pre-HSCT who received INH prophylaxis developed TB.
Subject(s)
Hematopoietic Stem Cell Transplantation , Tuberculosis , Cohort Studies , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Prospective Studies , Tuberculin Test , Tuberculosis/diagnosis , Tuberculosis/epidemiology , Tuberculosis/etiologyABSTRACT
In this study, we report on major MRD or URD BMT outcomes in pediatric patients with SAA in Brazil. This was a retrospective study, which included 106 patients ≤18 years old who received a first BMT for SAA. All patients received bone marrow as graft source from an MRD (n = 69) or a URD (n = 37). Conditioning regimen was non-myeloablative in 73.6% of cases, and GVHD prophylaxis comprised a calcineurin inhibitor plus methotrexate in 89.6% of patients. After a median follow-up of 4.5 years after BMT, 81 patients are alive, with a 4-year OS of 77% and no statistically significant difference between the MRD and URD groups (82% vs. 69%, respectively; P = .08). Grade III-IV aGVHD at 6 months and cGVHD at 2 years were observed in 8% and 14% of cases, respectively, and were not statistically different between the groups. Twenty-five (23%) patients died at a median of 2.9 months after BMT. Our study showed that 4-year OS after BMT was not statistically different between MRD and URD recipients. This study shows that the outcomes of pediatric patients transplanted for SAA with a URD in Brazil are approaching those of MRD transplants. In contrast, OS after MRD BMT was lower than we would expect based on previous reports. The wide range of preparatory regimens used by the study centers highlights the need for standardized protocols for these children. Our findings provide a benchmark for future studies focused on improving BMT outcomes in this setting in Brazil.
Subject(s)
Anemia, Aplastic/therapy , Bone Marrow Transplantation/methods , Unrelated Donors , Adolescent , Brazil , Child , Child, Preschool , Developing Countries , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , International Cooperation , Male , Retrospective Studies , Severity of Illness Index , Transplantation, Homologous , Treatment Outcome , WashingtonABSTRACT
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.
Subject(s)
Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Lymphopoiesis , Thymus Gland/cytology , Thymus Gland/metabolism , Adolescent , Adult , Case-Control Studies , Female , Graft vs Host Disease/etiology , Hematologic Neoplasms/complications , Hematologic Neoplasms/immunology , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Male , Middle Aged , Receptors, Antigen, T-Cell/metabolism , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/metabolism , Young AdultABSTRACT
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.
Subject(s)
Body Mass Index , Cord Blood Stem Cell Transplantation , Graft vs Host Disease , Leukemia , Nutritional Status , Acute Disease , Adolescent , Adult , Age Factors , Child , Child, Preschool , Disease-Free Survival , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Graft vs Host Disease/pathology , Graft vs Host Disease/physiopathology , Humans , Leukemia/mortality , Leukemia/pathology , Leukemia/physiopathology , Leukemia/therapy , Male , Retrospective Studies , Risk Factors , Sex Factors , Survival RateABSTRACT
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.
ABSTRACT
Dendritic cells (DCs) are antigen-presenting cells that drive immune responses and tolerance and are divided in different subsets: myeloid DCs (mDCs: lineage-; HLA-DR+, 11c+), plasmacytoid dendritic cells (pDCs: HLA-DR+, CD123+), and monocyte-derived DCs (moDC: lineage-, 11c+, 16+). After hematopoietic stem cell transplantation (HSCT), low DC counts in the recipients' peripheral blood (PB) have been associated with worse outcomes, but the relevance of DC graft content remains unclear, and there are few data in the setting of unrelated donor HSCT. We evaluated the DC graft content and monitored DC recovery in PB from 111 HSCT recipients (median age, 17 years; range 1 to 74), who received bone marrow (46%), umbilical cord blood (32%), or PB (22%) from unrelated (81%) or related donors (19%). In 86 patients with sustained allogeneic recovery, patients with higher counts of all DC subsets (pDC, mDC, and moDC) 3 weeks after engraftment had lower incidence of nonrelapse mortality (NMR) and acute graft-versus-host disease (aGVHD) and better survival. pDC counts were associated with more striking results: patients with higher pDC counts had much lower incidences of NRM (3% versus 47%, P < .0001), lower incidence of aGVHD (24% versus 67%, P < .0001), and better overall survival (92% versus 45%, P < .0001). In contrast, higher pDC counts in the graft was associated with an increased risk of aGVHD (55% versus 26%, P = .02). Our results indicate that DC counts are closely correlated with HSCT outcomes and warrant further prospective evaluation and possible early therapeutic interventions to ameliorate severe aGVHD and decrease mortality.
Subject(s)
Bone Marrow Transplantation/adverse effects , Cord Blood Stem Cell Transplantation/adverse effects , Dendritic Cells/pathology , Graft vs Host Disease/mortality , Hematologic Neoplasms/mortality , Hematopoietic Stem Cell Transplantation/adverse effects , Transplantation Conditioning , Acute Disease , Adolescent , Adult , Aged , Cell Count , Cell Lineage/immunology , Child , Child, Preschool , Dendritic Cells/classification , Dendritic Cells/immunology , Female , Graft vs Host Disease/drug therapy , Graft vs Host Disease/etiology , Graft vs Host Disease/immunology , Hematologic Neoplasms/immunology , Hematologic Neoplasms/pathology , Hematologic Neoplasms/therapy , Humans , Immunosuppressive Agents/therapeutic use , Infant , Male , Middle Aged , Myeloablative Agonists/therapeutic use , Siblings , Survival Analysis , Transplantation, Homologous , Unrelated DonorsABSTRACT
OBJECTIVES: 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). METHODS: All consecutive HSCT patients using BM or PBSC from an HLA-matched related donors for haematological malignancies after high intensity conditioning at seven Brazilian transplant centres between January 2008 and December 2009 were retrospectively evaluated. RESULTS: In the study period, 334 patients were treated in the centres and included in the evaluation. The cumulative incidence of grades II-IV and III-IV acute graft-versus-host disease (GVHD) at one year was 36.7% and 9.7% for BM recipients and 34.4% and 15.1% for PBSC recipients, respectively (not statistically different). The cumulative incidence of chronic GVHD at three years was 53.7% and 79.8% (HR 1.93; 95% CI 1.38-2.69, P < 0.001) for BM and PBSC, respectively. Median overall survival was 2.85 and 2.39 years for BM and PBSC recipients, respectively (HR 1.19; 95% CI, 0.84-1.68, P = 0.34). CONCLUSIONS: Our results confirm previous findings of increased chronic GVHD incidence in patients receiving PBSC when compared to patients receiving BM as the graft source in HSCT. Acute GVHD incidence, progression-free survival and overall survival were not different between the groups.
Subject(s)
Bone Marrow Transplantation , Graft vs Host Disease/mortality , Hematologic Neoplasms/mortality , Hematologic Neoplasms/therapy , Peripheral Blood Stem Cell Transplantation , Tissue Donors , Adolescent , Adult , Aged , Allografts , Child , Child, Preschool , Disease-Free Survival , Female , Follow-Up Studies , Graft vs Host Disease/etiology , Humans , Infant , Male , Middle Aged , Retrospective Studies , Survival RateABSTRACT
BACKGROUND AND OBJECTIVES: The management of chronic myeloid leukemia (CML) has changed radically since the introduction of imatinib therapy. The decision of whether to offer a patient a hematopoietic stem cell transplant (HSCT) must be based on the probability of success of the procedure. The aim of this retrospective analysis of 1,084 CML patients who received an allogeneic HSCT in 10 Brazilian Centers between February 1983 and March 2003 was to validate the EBMT risk score. DESIGN AND METHODS: The study population comprised 647 (60%) males and 437 (40%) females, with a median age of 32 years old (range 1 - 59); 898 (83%) were in chronic phase, 146 (13%) were in accelerated phase and 40 (4%) were in blast crisis; 151 (14%) were younger than 20 years old, 620 (57%) were between 20 and 40 and 313 (29%) were older than 40; 1,025 (94%) received an HLA fully matched sibling transplant and only 59 (6%) received an unrelated transplant. In 283 cases (26%) a male recipient received a graft from a female donor. The interval from diagnosis to transplantation was less than 12 months in 223 (21%) cases and greater in 861 (79%). The overall survival, disease-free survival, transplant-related mortality and relapse incidence were 49%, 50%, 45% and 25%, respectively. RESULTS: Of the 1084 patients, 179 (17%) had a risk score of 0 or 1, 397 (37%) had a score of 2, 345 (32%) had a score of 3, 135 (12%) had a score of 4 and 28 (2%) a score of 5 or 6. The overall survival (OS) rate in patients with risk scores 0-1 and 2 was similar (58% and 55%, respectively) but significantly better than that in patients with scores 3 or more (score 3 - 44%, 4 - 36 % and 5-6 - 27%, respectively) pp<0.001). Disease-free survival (DFS) and transplant related mortality (TRM) in a patients with a score of 3 or more were 46% and 49%, respectively and the relapse rate beyond score 5-6 was 77%. Disease status had a negative impact on all outcomes (OS, DFS, TRM, and relapse). The OS rate for male recipients of a graft from a female donor was 40% compared to 52% among the other donor-recipient pairs (p=0.004). DFS and TRM were significant for disease phase and female donor-male recipient (p<0.001 and p<0.003, respectively). In our experience, age and interval between diagnosis and transplant did influence OS, DFS, TRM, and relapse rate. INTERPRETATION AND CONCLUSIONS: Our results validate the EBMT risk score in the context of a developing country and confirm its usefulness for making point decisions in the imatinib era.