High-dose chemotherapy with autologous stem cell transplantation for patients with extracranial germ cell tumors - experience of two Brazilian pediatric centers.

Malignant extracranial germ cell tumors (GCTs) are rare in pediatric patients and are usually extremely sensitive to chemotherapy. Relapsed or refractory tumors, although rare, established the need for second-line therapies, including high-dose chemotherapy with autologous stem cell transplantation (HDCT/ASCT). However, there are few data on its use in children with GCTs. We present a retrospective analysis of all patients diagnosed with extracranial GCTs who received HDCT/ASCT at two Brazilian pediatric cancer centers from May 1999 to December 2019. We identified a total of 34 patients with a median age at diagnosis of 2.8 years (range, 0 to 18.8), who received HDCT/ASCT. Most patients (73%) received carboplatin, etoposide and melphalan (CEM) as a HDCT regimen. Fourteen patients received a second-line conventional dose chemotherapy (CDCT), 14 received a third-line CDCT and five received even a fourth-line CDCT prior to HDCT/ASCT. After a median follow-up of 22.7 months (range, 0.3 to 198.1), 16 patients had died after tumor relapse/progression and 2 patients died from HDCT/ASCT toxicity. We observed a 5-year OS of 47.1% and 5-year EFS of 44.1%. The 5-year OS for patients referred for HDCT/ASCT with progressive disease was 10% compared to 62.5% for those who achieved disease control before HDCT/ASCT (p = 0.001). In our experience, heavily pretreated children and adolescents with extracranial GCTs achieved considerable survival rates with HDCT/ASCT since, at least, partial control of their disease was possible before starting HDCT/ASCT. The role of HDCT/ASCT in pediatric patients with GCTs should be investigated in prospective trials.

Tear Film Immunological Profile in Patients with Ocular Graft versus Host Disease.

PURPOSE: To analyze and compare the tear immunological profile in ocular GVHD (oGVHD) patients with that in non-oGVHD patients and to correlate them with ocular surface parameters based on the International Chronic Ocular GVHD Consensus Group (ICCGVHD) diagnostic criteria. METHODS: Tear samples from 20 individuals who underwent allo-hematopoietic stem cell transplantation and were grouped according the presence or absence of oGVHD were analyzed using Bio-Plex assay. RESULTS: IL-8 and MIP-1α levels were significantly higher in tears from oGVHD patients compared with those in tears from non-oGVHD patients (p<0.001 and p=0.001, respectively). Tear IL-8 levels correlated significantly with OSDI criteria (ρ=0.5159, p=0.001), ocular hyperemia (ρ=0.469, p=0.002), and corneal staining (ρ=0.339, p=0.032), whereas tear Mip-1α levels correlated with OSDI score (ρ=0.358, p=0.023). CONCLUSION: We demonstrated higher tear levels of IL-8 and MIP-1α in oGVHD patients and significant correlations between theses cytokines and ocular surface parameters based on the ICCGVHDCG criteria.

Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: children and adolescents.

The Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Children and Adolescents was developed by dietitians, physicians, and pediatric hematologists from 10 Brazilian reference centers in hematopoietic stem cell transplantation. The aim was to emphasize the importance of nutritional status and body composition during treatment, as well as the main characteristics related to patient´s nutritional assessment. This consensus is intended to improve and standardize nutrition therapy during hematopoietic stem cell transplantation. The consensus was approved by the Brazilian Society of Bone Marrow Transplantation.

Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: children and adolescents / Consenso Brasileiro de Nutrição em Transplante de Células-Tronco Hematopoiéticas: crianças e adolescentes

ABSTRACT The Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Children and Adolescents was developed by dietitians, physicians, and pediatric hematologists from 10 Brazilian reference centers in hematopoietic stem cell transplantation. The aim was to emphasize the importance of nutritional status and body composition during treatment, as well as the main characteristics related to patient´s nutritional assessment. This consensus is intended to improve and standardize nutrition therapy during hematopoietic stem cell transplantation. The consensus was approved by the Brazilian Society of Bone Marrow Transplantation.

RESUMO O Consenso Brasileiro de Nutrição em Transplante de Células-Tronco Hematopoiéticas: crianças e adolescentes foi elaborado com a participação de nutricionistas, médicos nutrólogos e médicos hematologistas pediátricos de 10 centros brasileiros que são referência em transplante de células-tronco hematopoiéticas. O objetivo foi salientar a importância do estado nutricional e da composição corporal durante o tratamento, bem como as principais características relacionadas à avaliação nutricional do paciente. As intenções, ao se estabelecer o consenso, foram aprimorar e padronizar a terapia nutricional durante o transplante de células-tronco hematopoiéticas. O consenso foi aprovado pela Sociedade Brasileira de Transplante de Médula Óssea.

Allogeneic Hematopoietic Stem Cell Transplantation for Children and Adolescents with Acute Myeloid Leukemia in Brazil: A Multicentric Retrospective Study.

The survival rates of children with high-risk acute myeloid leukemia (AML) treated with hematopoietic stem cell transplant (HSCT) range from 60% to 70% in high-income countries. The corresponding rate for Brazilian children with AML who undergo HSCT is unknown. We conducted a retrospective analysis of 114 children with AML who underwent HSCT between 2008 and 2012 at institutions participating in the Brazilian Pediatric Bone Marrow Transplant Working Group. At transplant, 38% of the children were in first complete remission (CR1), 37% were in CR2, and 25% were in CR3+ or had persistent disease. The donors included 49 matched-related, 59 matched-unrelated, and six haploidentical donors. The most frequent source of cells was bone marrow (69%), followed by the umbilical cord (19%) and peripheral blood (12%). The 4-year overall survival was 47% (95% confidence interval [CI] 30%-57%), and the 4-year progression-free survival was 40% (95% CI 30%-49%). Relapse occurred in 49 patients, at a median of 122 days after HSCT. There were 65 deaths: 40 related to AML, 19 to infection, and six to graft versus host disease. In conclusion, our study suggests that HSCT outcomes for children with AML in CR1 or CR2 are acceptable and that this should be considered in the overall treatment planning for children with AML in Brazil. Therapeutic standardization through the adoption of multicentric protocols and appropriate supportive care treatment will have a significant impact on the results of HSCT for AML in Brazil and possibly in other countries with limited resources.

Hematopoietic cell transplantation in pediatric patients with acute leukemias or myelodysplastic syndrome using unrelated adult or umbilical cord blood donors in Brazil.

The choice of alternative donors for HCT for patients without an HLA-matched related donor depends on several factors. We compared major HCT outcomes in 212 consecutive children transplanted at 11 centers in Brazil for acute leukemia or MDS from an HLA-matched unrelated donor (MUD, n = 95), mismatched unrelated donor (MMUD, n = 47) or unrelated umbilical cord blood (UCB, n = 70). Most had ALL (61%), bone marrow (57%) as the graft source and 95% received a MAC regimen. The 3-year OS probability were 57, 55, and 37% after HCT from MUD, MMUD, and UCB, respectively (HR 1.68, 95%CI 1.07-2.63; P = .02). In comparison with MUD, OS was similar after transplantation of a ≥ 6/8 HLA-matched or a high cell dose (>5 × 107 TNC/kg) CB unit (HR 1.41, 95%CI 0.88-2.27; P = .15). NRM was higher for UCB (HR 3.90, 95%CI 1.43-10.7; P = .01) but not for MMUD (HR 1.03, 95%CI 0.53-2.00; P > .20). Advanced disease (HR 2.05, 95%CI 1.26-3.33; P < .001) and UCB with high probability of being < 6/8 HLA-matched (HR 5.34, 95%CI 2.0-13.9; P < .001) were associated with higher mortality. Relapse and acute GVHD were similar among groups, while PGF was higher among UCB transplants (P = .002) and chronic GVHD among MMUD group (HR 2.88, 95% CI 1.05-7.88; P = .04). Our results suggest that in Brazil HCT outcomes performed with MMUD and MUD donors were comparable, while with UCB units < 6/8 HLA-matched were associated with higher NRM for children with acute leukemia or MDS.

Hematopoietic cell transplantation for Diamond Blackfan anemia: A report from the Pediatric Group of the Brazilian Bone Marrow Transplantation Society.

OBJECTIVES: The aim of this study was to analyze the outcomes of children with Diamond-Blackfan anemia (DBA) treated in Brazil with hematopoietic cell transplantation (HCT). METHODS: We performed a retrospective analysis of 44 pediatrics patients transplanted between 1990 and 2018. The median age of patients was 5 years, and 57% were male. Twenty-five received their first HCT from an HLA-matched sibling donor (MSD), 12 from a HLA matched unrelated bone marrow donor (MUD 10/10, n = 12) and 7 other HLA mismatched donors (MMD). RESULTS: After a median follow-up of 4 years, estimate 5-year overall survival (OS) for the entire cohort was 70%, 80% for MSD group, 73% for MUD, and 29% for MMD. Thirty-eight out of the 44 evaluable patients engrafted successfully. Primary and secondary graft failure was observed in five and three patients, respectively. Rates of grade II-IV and III-IV acute graft-versus-host disease (aGVHD) were 25% and 18%, respectively. Nine patients developed chronic GVHD (cGVHD). CONCLUSION: Overall survival rates observed after HLA matched donors transplant for DBA were comparable to those reported from higher-income countries and international registries.

Allogeneic Bone Marrow Transplants for Pediatric Severe Aplastic Anemia: Real-world Data comparing Matched Related and Unrelated Donors in a Developing Country. Retrospective study on behalf of the Pediatric Hematopoietic Stem Cell Transplant Working Group of the Brazilian Bone Marrow Transplantation Society (SBTMO) and the Brazil-Seattle Consortium (Gedeco).

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.

Transplantation of Hematopoietic Stem Cells for Primary Immunodeficiencies in Brazil: Challenges in Treating Rare Diseases in Developing Countries.

The results of hematopoietic stem cell transplant (HSCT) for primary immunodeficiency diseases (PID) have been improving over time. Unfortunately, developing countries do not experience the same results. This first report of Brazilian experience of HSCT for PID describes the development and results in the field. We included data from transplants in 221 patients, performed at 11 centers which participated in the Brazilian collaborative group, from July 1990 to December 2015. The majority of transplants were concentrated in one center (n = 123). The median age at HSCT was 22 months, and the most common diseases were severe combined immunodeficiency (SCID) (n = 67) and Wiskott-Aldrich syndrome (WAS) (n = 67). Only 15 patients received unconditioned transplants. Cumulative incidence of GVHD grades II to IV was 23%, and GVHD grades III to IV was 10%. The 5-year overall survival was 71.6%. WAS patients had better survival compared to other diseases. Most deaths (n = 53) occurred in the first year after transplantation mainly due to infection (55%) and GVHD (13%). Although transplant for PID patients in Brazil has evolved since its beginning, we still face some challenges like delayed diagnosis and referral, severe infections before transplant, a limited number of transplant centers with expertise, and resources for more advanced techniques. Measures like newborn screening for SCID may hasten the diagnosis and ameliorate patients' conditions at the moment of transplant.

The influence of cell concentration at cryopreservation on neutrophil engraftment after autologous peripheral blood stem cell transplantation

ABSTRACT Background: Peripheral blood stem cell concentrations are traditionally adjusted to 20-40 × 106 leukocytes/mL prior to freezing. This low cell concentration at cryopreservation implies larger volumes with more dimethyl sulfoxide being used, and higher cost and toxicity at the time of transplant. Higher cell concentrations have been reported but this is not widely accepted. Moreover, the influence of cell concentration on engraftment has not been well documented. Therefore, this study retrospectively analyzed the influence of peripheral blood stem cell concentration at freezing on engraftment after autologous hematopoietic stem cell transplantation. Method: Leukapheresis products were plasma-depleted and cryopreserved with 5% dimethyl sulfoxide, 6% hydroxyethylamide solution and 4% albumin in a −80 °C freezer. Individual patient data from hospital records were reviewed. Results: Fifty consecutive patients with oncological diseases underwent 88 leukaphereses. Median age was six years (range: 1-32 years) and median weight was 19 kg (range: 8-94 kg). Median leukocyte concentration was 109 × 106/mL at collection and 359 × 106 (range: 58-676 × 106) at freezing with 78% viability (range: 53-95%); leukocyte recovery after thawing was 95% (range: 70-100%). In multivariate analysis, cell concentration (p-value = 0.001) had a negative impact on engraftment. Patients infused with bags frozen with <200 × 106 leukocytes/mL engrafted after a median of nine days (range: 8-12 days), 200-400 × 106 leukocytes/mL after 11 days (range: 9-20 days); 400-600 × 106 leukocytes/mL after 12 days (range: 8-19 days) and with cell concentrations >600 × 106 leukocytes/mL, engraftment was after 14 days (range: 13-22 days). Conclusion: In patients with adequate CD34 cell collections, total leukocyte concentrations of 282 × 106/mL, freezing with 5% dimethyl sulfoxide and 6% hydroxyethylamide solution without a controlled-rate freezer, and storing cells at −80 ºC yielded excellent engraftment. Further increases in cell concentration may delay engraftment, without affecting safety.

The influence of cell concentration at cryopreservation on neutrophil engraftment after autologous peripheral blood stem cell transplantation.

BACKGROUND: Peripheral blood stem cell concentrations are traditionally adjusted to 20-40 × 106 leukocytes/mL prior to freezing. This low cell concentration at cryopreservation implies larger volumes with more dimethyl sulfoxide being used, and higher cost and toxicity at the time of transplant. Higher cell concentrations have been reported but this is not widely accepted. Moreover, the influence of cell concentration on engraftment has not been well documented. Therefore, this study retrospectively analyzed the influence of peripheral blood stem cell concentration at freezing on engraftment after autologous hematopoietic stem cell transplantation. METHOD: Leukapheresis products were plasma-depleted and cryopreserved with 5% dimethyl sulfoxide, 6% hydroxyethylamide solution and 4% albumin in a -80 °C freezer. Individual patient data from hospital records were reviewed. RESULTS: Fifty consecutive patients with oncological diseases underwent 88 leukaphereses. Median age was six years (range: 1-32 years) and median weight was 19 kg (range: 8-94 kg). Median leukocyte concentration was 109 × 106/mL at collection and 359 × 106 (range: 58-676 × 106) at freezing with 78% viability (range: 53-95%); leukocyte recovery after thawing was 95% (range: 70-100%). In multivariate analysis, cell concentration (p-value = 0.001) had a negative impact on engraftment. Patients infused with bags frozen with <200 × 106 leukocytes/mL engrafted after a median of nine days (range: 8-12 days), 200-400 × 106 leukocytes/mL after 11 days (range: 9-20 days); 400-600 × 106 leukocytes/mL after 12 days (range: 8-19 days) and with cell concentrations >600 × 106 leukocytes/mL, engraftment was after 14 days (range: 13-22 days). CONCLUSION: In patients with adequate CD34 cell collections, total leukocyte concentrations of 282 × 106/mL, freezing with 5% dimethyl sulfoxide and 6% hydroxyethylamide solution without a controlled-rate freezer, and storing cells at -80 °C yielded excellent engraftment. Further increases in cell concentration may delay engraftment, without affecting safety.

Adherence and immune response to revaccination following hematopoietic stem cell transplantation at a pediatric onco-hematology reference center.

BACKGROUND: Revaccination after hematopoietic stem cell transplantation (HSCT) is necessary to compensate for the loss of immunological memory. The aims of this study were to evaluate the adherence to revaccination schedule and the humoral immune response to different vaccine antigens in HSCT pediatric and young adult patients. METHODS: Patients submitted to HSCT for over 3 years were recruited. After written informed consent, a questionnaire was filled in, the vaccination card was analyzed, a blood sample was collected and tested by ELISA for diphtheria, Haemophilus influenzae type b (Hib), hepatitis A, hepatitis B, tetanus, measles, rubella, and varicella antibodies. RESULTS: Sixty-three patients (mean age at HSCT, 10.7 years) were evaluated. Forty-one (65%) were male; 34 (54%) had allogeneic and 29 (46%), autologous HSCT. Complete adherence to diphtheria revaccination was found in 79.4% patients and seropositivity was found in 92% of those who completed the revaccination schedule; for Hib, 68.3% adherence and 95.3% seropositivity were observed; for hepatitis A, 63.5% adherence and 92.5% seropositivity; for 3 doses of hepatitis B, 86.8% adherence and 79.2% seropositivity; for tetanus, 79.4% adherence and 100% seropositivity; for measles and rubella, 17.5% adherence and 100% seropositivity; for varicella, 7.9% adherence and 100% seropositivity. The existence of a Vaccination Center for Special Immunobiologicals in patients' municipality was positively associated with completed vaccine schedule; on the other hand, chronic GVHD was negatively associated with revaccination adherence. CONCLUSION: Hematopoietic stem cell transplantation patients showed good seropositivity rates after complete vaccination schedule. However, a low coverage rate was observed for live attenuated antigens.

Outbreak of Fusarium oxysporum infections in children with cancer: an experience with 7 episodes of catheter-related fungemia.

BACKGROUND: Fusarium species are widely spread in nature as plant pathogens but are also able to cause opportunistic fungal infections in humans. We report a cluster of Fusarium oxysporum bloodstream infections in a single pediatric cancer center. METHODS: All clinical and epidemiological data related to an outbreak involving seven cases of fungemia by Fusarium oxysporum during October 2013 and February 2014 were analysed. All cultured isolates (n = 14) were identified to species level by sequencing of the TEF1 and RPB2 genes. Genotyping of the outbreak isolates was performed by amplified fragment length polymorphism fingerprinting. RESULTS: In a 5-month period 7 febrile pediatric cancer patients were diagnosed with catheter-related Fusarium oxysporum bloodstream infections. In a time span of 11 years, only 6 other infections due to Fusarium were documented and all were caused by a different species, Fusarium solani. None of the pediatric cancer patients had neutropenia at the time of diagnosis and all became febrile within two days after catheter manipulation in a specially designed room. Extensive environmental sampling in this room and the hospital did not gave a clue to the source. The outbreak was terminated after implementation of a multidisciplinary central line insertion care bundle. All Fusarium strains from blood and catheter tips were genetically related by amplified fragment length polymorphism fingerprinting. All patients survived the infection after prompt catheter removal and antifungal therapy. CONCLUSION: A cluster with, genotypical identical, Fusarium oxysporum strains infecting 7 children with cancer, was most probably catheter-related. The environmental source was not discovered but strict infection control measures and catheter care terminated the outbreak.

Pilot study on the efficacy of combined intraoral and extraoral low-level laser therapy for prevention of oral mucositis in pediatric patients undergoing hematopoietic stem cell transplantation.

OBJECTIVE AND BACKGROUND DATA: Studies suggest that intraoral low-level laser therapy (LLLT) can ameliorate oral mucositis in adult patients receiving high-dose chemotherapy. The objective of this study was to evaluate the use of a combined protocol of intraoral and extraoral LLLT in children undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Twelve children undergoing HSCT were treated four times a week with a combined protocol of intraoral and extraoral LLLT, for a mean duration of 22 days. Clinical and functional mucositis scores were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). These scores were compared with a matched retrospective control group of 12 children who did not receive LLLT during HSCT. RESULTS: Clinical mucositis scores were significantly lower in the LLLT group than in the control group (p = 0.004). Incidence of ulcerative oral mucositis was also significantly lower in the LLLT group (p = 0.027). Functional limitation associated with diet/swallowing was less severe in the LLLT group; however, this was not statistically significant. CONCLUSIONS: This study indicates that a combined protocol of intraoral and extraoral application of LLLT can reduce the severity of oral mucositis in pediatric patients undergoing HSCT. Randomized double-blind clinical trials with a larger number of subjects are needed to further test such combined protocols.

Rapid, low-cost MR imaging protocol to document central nervous system and sinus abnormalities prior to pediatric hematopoietic stem cell transplantation.

Patients undergoing bone marrow transplant (BMT) are at risk for infectious complications, including those of the sinus. Central nervous system (CNS) abnormalities related to the chemotherapy or radiation that the patient received for the treatment of underlying malignancy or to transplant-related effects are also commonly seen. The only effective way to differentiate pre- and post-transplant causes is to have a baseline evaluation prior to the admission for transplant. The current method used to evaluate these patients is head CT. However, CT is not accurate to demonstrate CNS abnormalities and exposes the patient to radiation. MRI, despite better sensitivity for white matter abnormalities, has not been routinely used because of the higher cost and longer duration of the exam. Therefore, we designed a fast, low-cost and radiation-free MRI-based protocol to simultaneously evaluate sinus and brain abnormalities.