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Context: Ifosfamide (IFA) is an effective antineoplastic for solid tumours in children, although it is associated with high levels of systemic toxicity and causes death in some cases. Objective: Th...

IntroductionThe CYP450 complex participates in the metabolism of ifosfamide, an antineoplastic drug used to treat solid tumors. genes contain several single nucleotide polymorphisms (SNPs) that confer different activity towards the enzyme. The aim of our study was to analyze gene frequencies of allelic variants and their association with ifosfamide blood levels and patient prognosis.Material and methods148 DNA samples from children were analyzed. Genotyping was performed by real-time PCR with TaqMan probes and ifosfamide levels were determined in dried blood drop by UPLCMS/MS.ResultsIfosfamide levels increased according to the genotype, and patients with the variant rs1799853 in CYP2C9 genotype CC had lower levels of ifosfamide (median = 1.8 µmol/l, Q25 0.9–Q75 4.6) compared with patients with genotype TT + CT (median = 2.8 µmol/l, Q25 1.9–Q75 5.1), p < 0.001. In the case of the rs2740574 variant in the CYP3A4 gene, patients with normal genotype (TT) presented median = 1.4 µmol/l, (Q25 0.7–Q75 2.7), while patients with the CC + TC genotype had higher levels of ifosfamide (median = 2.0 µmol/l, Q25 1.0–Q75 4.3), p = 0.024. In addition, patients with CC + CT genotype of this variant had a higher risk of non-response to treatment compared to patients with TT genotype (RR = 1.3, 95% CI: 1.07–1.59, p = 0.03).ConclusionsPolymorphisms in CYP2C9 and CYP3A4 genes are associated with high levels of ifosfamide. In addition, the polymorphism rs2740574 in CYP3A4 was associated with a worse therapeutic response.

Background: Acute graft-versus-host disease (aGVHD) is the most frequent and severe complication after allogeneic hematopoietic stem cell transplantation (HSCT). Objective: To determine if a history of prior infection in the allogeneic HSTC recipient is a risk factor to develop aGVHD. Methods: A retrospective cohort study based on data collected from the Department of Hematopoietic Stem Cell Transplantation at the Instituto Nacional de Pediatria (INP) from January 1998 to December 2016 was performed to identify if prior infection was a predictive risk factor for aGVHD. Results: 27 patients developed aGVHD (36.4%). Median time to aGVHD presentation was 82 days (9 to 273 days). Most patients developed grade III aGVHD. Following the multivariate analysis peripheral blood > bone marrow (OR 12.3; p 8.3 × 106/kg (OR 7.1; p = 0.05), peripheral blood (OR: 11.4; p < 0.001), infection 3 months prior to allogeneic transplant (OR: 4.5; p < 0.03) and CMV infection in the recipient (OR: 4.68; p < 0.03) were significant. Conclusions: Either bacterial infection or CMV infection in the recipient was significant risk factor within the aGVHD recipients; it is important to consider these factors for patients that are going to receive an allogeneic HSCT.

Acute lymphoblastic leukemia (ALL), the most common type of cancer in children worldwide, has one of the highest incidence rates in Mexico. It is a multifactorial disease and different cytokine single nucleotide polymorphisms (SNP), have been associated with ALL expression. Few studies have been published analyzing IFNG +874 T/A and IL2 −330 G/T in this type of leukemia. These SNPs are involved in high or low expression, and are central to cellular immunity, influencing greatly tumor growth. The purpose of this work was to explore the association of IFNG +874 A/T (rs2430561) and IL2 −330 G/T (rs2069762) SNPs with ALL susceptibility and/or protection in 488 Mexican Mestizos patients, as compared to 950 Mexican Mestizo healthy controls. The results demonstrated that IFNG +874 T allele (pc = 0.00004, OR = 0.673) and the TT genotype (pc = 0.00015, OR = 0.349), protect against ALL expression with no specific gender association; however, the TT homozygote genotype (vs. TA+AA) seems more protective in males (pc = 0.00683). IL2 −330 G/T does not contribute to the development of ALL. In healthy Mexicans, the most common genotypes for IL2 and IFNG, are the low cytokine producers, suggesting that the genetic background in this ethnic group, may be partly responsible for the high incidence of ALL. These results show for the first time in Mexicans, the relevant role that IFNG SNP has in the genetic etiology of ALL. Thus, a large group of patients belonging to different ethnicities will be very helpful to study in order to demonstrate if these SNPs contribute to the genetic etiology of ALL, as shown here in Mexican Mestizos.

Mucopolysaccharidoses (MPSs) are a heterogeneous group of diseases that have in common the accumulation of glycosaminoglycans (mucopolysaccharides) within the lysosome. The diseases are caused by a deficiency of the enzyme α-L-iduronidase which is responsible for the degradation of glycosaminoglycans (GAGs or mucopolysaccharides). More than 100 mutations in the gene have been reported, resulting in marked clinical/response variability. MPSs usually present as multisystem and progressive clinical disorders which affect psychomotor and cardiovascular development, the cornea and the musculoskeletal system. Seven phenotypically distinct diseases have been described, and MPS type I (MPS-I) is divided into three clinical forms: severe (Hurler syndrome), intermediate (Hurler-Scheie syndrome) or mild (Scheie syndrome). For the treatment of MPS-I, Enzyme Replacement Therapy (ERT) with α-L-iduronidase and Hematopoietic Stem Cells Transplantation (HSCT), separately or in combination, have produced clinical improvement, especially with regards cardiovascular symptoms and psychomotor development. This article presents the long-term (more than seven years) follow-up of monochorionic, diamniotic twins who were diagnosed with MPS-I at an early stage, and treated with ERT (from age 10 months) plus HSCT (from age 18 months). Overall, the treatment has facilitated stable development with an overall good response and better control of symptoms associated with MPS-I., Enzyme replacement therapy; Hematopoietic stem cell transplantation; Monochorionic diamniotic twins; Mucopolysaccharidosis type I; Pediatrics.

Purpose: The objective of this study was to determine whether a comorbidity index could be used to predict mortality in pediatric patients with chemotherapy-treated solid tumors. Methods: Pediatric patients who underwent chemotherapy treatment for solid tumors were included, and demographic, clinical, and comorbidity data were obtained from patient electronic records. Results: A total of 196 pediatric patients with embryonic solid tumors were included. Metastatic tumors were the most frequently observed (n = 103, 52.6%). The most common comorbidities encountered for the Charlson comorbidity index (CCI) were cellulitis (n = 24, 12.2%) and acute renal failure (n = 15, 7.7%). For the Pediatric Comorbidity Index (PCI), the most frequent comorbidities were pneumonia and sepsis, with n = 64 (32.7%) for each. We evaluated established the prognostic values for both indexes using Kaplan-Meier curves, finding that the CCI and PCI could predict mortality with p < 0.0001. Conclusion: Using the PCI, we observed 100% survival in patients without comorbidities, 70% survival in patients with a low degree of comorbidity, and 20% survival in patients with a high degree of comorbidity. Greater discrimination of probability of survival could be achieved using degrees of comorbidity on the PCI than using degrees of comorbidity on the CCI. The application of the PCI for assessing the hospitalized pediatric population may be of importance for improving clinical evaluation.

La incidencia de la enfermedad granulomatosa crónica en reportes internacionales es de 1:250,000; sin embargo, en México se desconoce. En el Instituto Nacional de Pediatría, a partir de 2009 se implementó un proyecto para facilitar el diagnóstico de esa enfermedad. De esa fecha al día de hoy se han estudiado 68 casos, de los que 80% son formas ligadas al cromosoma X, además de que cada vez los casos se han diagnosticado a una edad más temprana. En la actualidad nos encontramos con un nuevo reto: el tratamiento curativo de los pacientes con enfermedad granulomatosa crónica. Comunicamos el caso de un paciente con enfermedad granulomatosa crónica ligada al cromosoma X, trasplantado exitosamente al mes de vida en México.

Total body irradiation (TBI) is conditioning regimen in children with acute lymphoblastic leukemia (ALL) with a very high risk of relapse or in those who have not achieved remission and have relapsed and subsequently received allogenic hematopoietic stem cell transplantation (HSCT). A retrospective evaluation of 33 ALL patients in full remission with an indication of HSCT was performed to evaluate overall survival (OS) and event-free survival (EFS). The inclusion criteria included a myeloablative conditioning regimen of TBI at a dose of 600 cGy. The observed OS at 5 years was 50%, and the EFS of 32% we observed difference in the EFS stem cell origin; the peripheral blood (PB) 60%, and the umbilical cord blood (UC) accounted for 40%. Overall, 45% had a documented chimerism. The OS at 5 years from patients with chimeras was 75%, while those without chimeras had an OS at 5 years of 25%. The mortality in the first 100 days was 24%. A total of 24.2% of children presented with acute graft versus-host disease (GVHD), while 33% had chronic GVHD. Currently, there is no general agreement among all international centers regarding the optimum TBI dose. Our study reports an acceptable range of adverse events with a relatively low dose of 600 cGy.

Background: In Mexico, AML survival is referred in 30%. Our aim was to evaluate results with ADE protocol as induction treatment in children with non-M3 AML in a public Mexican institution. Method: We included patients with AML in a single institution between 2005 and 2013. All non-M3-AML patients received ADE as induction therapy (cytarabine 100 mg/m2 in continuous infusion from day 1 to 7, daunorrubicin 30 mg/m2 days 1, 3, 5 and etoposide 100 mg/m2 over days 1 to 5). Patients received antibiotic prophylaxis and strict scheduled appointments to assure adherence and prevent avoidable emergencies. Main Results: Eighteen patients were included. Median age was 106 months. One patient died at diagnosis so 17 were eligible for induction results analysis; eleven needed two cycles and six patients three. Remission rate was 100%. Analyzing non-M3 patients overall survival was 80.2% at 100 months. No fatal complications were observed. Stratifying by number of cycles we observe that patients receiving one ADE cycle had a 0% overall survival at short follow up, with 2 ADE cycles 80% at 100 months and with 3 cycles 100% at 60 months. Conclusion: ADE induction therapy showed improved results in overall survival compared with other standard regimens. Following the protocol we obtained 100% remission. This is an important achievement in our population. Our focus must be to ameliorate maintenance final results. These results should be reproduced in other hospitals in Mexico and other countries.

Background Fanconi anemia (FA) is a condition characterized by congenital malformations, low height, and progressive bone marrow failure during childhood, genomic instability and hypersensitivity to DNA cross-linking agents. Bone marrow transplantation (BMT), is currently the only treatment capable to restore normal hematopoiesis and improve survival of these patients. To achieve a successful allogeneic BMT, a normal T-cell immunity reconstitution is required.1,2 Objective To describe the kinetics of immune reconstitution in six patients with FA after BMT, having used a reduce intensity conditioning regimen, well as associated infections during the post-transplant process. Methods We describe the distribution in peripheral blood of CD3+ T lymphocytes, CD16 +/CD56+ NK cells, CD4+ helper T lymphocytes, CD8+ cytotoxic T lymphocytes and CD19+/CD20+ B cells, in six patients with FA, after BMT from an HLA-matching sibling and complete chimerism, on days +90, +120, +150, +180, +210 and +360. The conditioning regimen employed consisted of fludarabine (Flu) 150 mg/m2, cyclophosphamide 20 mg/kg and rabbit anti-thymocyte globulin (r-ATG) 20 mg/kg. Infection was determined by a positive reaction of the DNA polymerase chain to Cytomegalovirus (CMV), Epstein-Barr virus, Adenovirus and BK virus (BKV), as well as galactomannan antigen and antibodies against Candida sp, or positive bacterial cultures. Results We observed different kinetics regarding the recovery of different lymphocyte subpopulations, starting from day +90. CD16+/CD56+ NK cells recovered first, between days 90 and 120, followed by CD8+ T lymphocytes between day +120 and +150, CD19+/CD20+ B cells between day +180 and +210, and finally, CD4+ T lymphocytes starting from day 210. Five patients presented infection in the post-BMT stage. Four patients before +90, developed CMV infection, based on positive reaction of the CMV polymerase chain. All patient responses to ganciclovir therapy and no CMV disease were documented. The fifth patient presented with meningitis due to Lysteria monocitogenes and BKV hemorrhagic cystitis at day +153; this patient had the diagnosis of chronic-graft versus host disase, and was treated with ampicillin, rifampicin and intravenous immunoglobulin, evolving satisfactorily. All patients remain alive and well. Discussion Most patients in our report developed CMV infection, as being reported with FLU and anti-thymocyte globulin combination. We observed a later reconstitution in comparison with patients in whom lower doses of r-ATG ( Conclusion Immunological reconstitution after a BMT in FA patients is determinant for morbidity and mortality, mainly due to opportunistic infections and GVHD. We observed that recovery kinetics of different lymphocyte populations is different in cases in which higher doses of r-GAT are used, also an early detection and prompt treatment of opportunistic infections may be determinant for patient's survival. Conflict-of-interest disclosure: The authors declare they have nothing to disclose. Correspondence: Gerardo López-Hernández. loherge@gmail.com BibliographyOgonek J, Kralj Juric M, Ghimire S, Varanasi PR, Holler E, Greinix H, et al. Immune reconstitution after allogenic hematopoietic stem cell transplantation. Front immunol. 2016; 7 (507):1-15.Smith AR, Wagner JE. Current clinical management of Fanconi anemia. Expert Rev Hematol. 2012; 5 (5): 513-522.Perlingeiro-Beltrame M, Malvezzi M, Bonfim C, Tadeu Covas D, Pasquini R. Immune reconstitution in patients with Fanconi anemia after allogeneic bone marrow transplantation. Cytotherapy. 2014; 0: 1e14. Disclosures No relevant conflicts of interest to declare.

Background Hematopoietic stem cell transplantation (HSCT) is used in pediatric patients with acute leukemia, after a relapse to bone marrow, or in first remission in case of high risk disease. If necessary, 75% of the cases do not have a compatible related donor and it is not always possible to have a compatible unrelated donor or an umbilical cord blood unit. Therefore, using haploidentical alternative donors of hematopoietic stem cells (HSC) is becoming more frequent. Objective The purpose of this is to report the results of haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide (PTCy) in a group of pediatric patients, which lacks a related HLA compatible donor, at the National Pediatrics Institute in México City, México, in the period between January 2012 thru December 2016. Methods We retrospectively reviewed 27 patients´ files Results Fourteen patients (51.6%) presented complete and sustained chimerism. Overall survival is presented in Figure 1. Graft failure occurred (48.1%) more frequently in the group of patients in whom bone marrow was used as a source of HSC (p=0.26). Nine patients with complete chimera, whose HSC source turned out to be PB, presented acute-GVHD III-IV (p = 0.06). Four of the patients whom presented full engraftment died, three of them due to infectious processes (cytomegalovirus pneumonia, AH1N1 pneumonia, abdominal sepsis secondary to intestinal perforation and E. coli sepsis), before +100-day post-transplantation. All these patients presented acute-GVHD III-IV. The fourth patient who died, also the cause was infectious (pulmonary sepsis secondary to Morganella morganii), thirteen months after the transplant and without history of GVHD. Of the thirteen patients who presented primary graft failure, seven of them are alive and without evidence of tumoral activity Discussion Haploidentical transplantation with PTCy is a feasible therapeutic option in pediatric patients with malignant hematological diseases who require a HSCT and do not have a matched sibling or unrelated donor available. Conflict-of-interest disclosure: The authors declare they have nothing to disclose. Correspondence: Gerardo López-Hernández. loherge@gmail.com BibliographyKlein OR, Buddenbaum J, Tucker N, et al. Nonmyeloablative Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Pediatric and Young Adult Patients with High-Risk Hematologic Malignancies. Biol Blood Marrow Transplant. 2017; 23(2): 325-332.González-Llano O, González-López EE, Ramírez-Cázares AC, et al. Haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide in children and adolescents with hematological malignancies. Pediatr Blood Cancer. 2016; 63: 2033-2037.Robinson TM, O'Donnell PV, Fuchs EJ, Luznik L. Haploidentical bone marrow and stem cell transplantation: experience with post-transplantation cyclophosphamide. Semin Hematol. 2016; 53(2): 90-97.Fuchs EJ, Huang XJ, Miller JS. HLA-haploidentical stem cell transplantation for hematologic malignancies. Biol Blood Marrow Transplant. Biol Blood Marrow Transplant. 2010; 16 (1 Suppl): S57-S63. Disclosures No relevant conflicts of interest to declare.

Objectives Hematopoietic stem cell transplantation (HSCT) from a matched sibling donor (MSD) is the preferred initial treatment for children with severe aplastic anemia (SAA). Unfortunately, only about 30% of patients have a suitable human leukocyte antigen-matched sibling. Methods We have analyzed the outcome of 42 patients who received HSCT (22 MSD and 20 alternative donors (AD)) for SAA at the seven major pediatric HSCT centers in Mexico between 2001 and 2013. Results With a median follow-up of 30 months (range, 0.4-144), the 5-year overall survival in children transplanted from MSD was 86.4 + 7.3 vs. 49.5 + 11% for children after AD-HSCT (P = 0.013). The cumulative incidence of treatment-related mortality (TRM) was in the MSD-HSCT 9.1 + 3.9% vs. 47.6 + 9.1% in the AD-HSCT context (P = 0.007). Infectious complications contributed to death (91%) of most patients who received AD-HSCT. Discussion Even when the results of patients given MSD-HSCT are adequate, there is still much room for improvement particularly in children allografted with AD and in the supportive care. The development of an economicwise designed prospective project with MSD or matched unrelated donor HSCTs as a first line of treatment of children with SAA as a unified national trial could address these issues.