Treosulfan-Based Conditioning Regimen In Pediatric Hematopoietic Stem Cell Transplantation: A Retrospective Analysis on Behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC).

Increasing data on treosulfan-based conditioning regimens before hematopoietic stem cell transplantation (HSCT) demonstrate the consistent benefits of this approach, particularly regarding acute toxicity. This study aimed to describe the results of treosulfan-based conditioning regimens in children, focusing on toxicity and outcomes when used to treat both malignant and nonmalignant diseases. This retrospective observational study of pediatric patients treated in Spain with treosulfan-based conditioning regimens before HSCT was based on data collection from electronic clinical records. We studied a total of 160 treosulfan-based conditioning HSCTs to treat nonmalignant diseases (n = 117) or malignant diseases (n = 43) in 158 children and adolescents. The median patient age at HSCT was 5.1 years (interquartile range, 2 to 10 years). The most frequent diagnoses were primary immunodeficiency (n = 42; 36%) and sickle cell disease (n = 42; 36%) in the nonmalignant disease cohort and acute lymphoblastic leukemia (n = 15; 35%) in the malignant disease cohort. Engraftment occurred in 97% of the patients. The median times to neutrophil engraftment (17 days versus 14 days; P = .008) and platelet engraftment (20 days versus 15 days; P = .002) were linger in the nonmalignant cohort. The 1-year cumulative incidence of veno-occlusive disease was 7.98% (95% confidence interval [CI], 4.6% to 13.6%), with no significant differences between cohorts. The 1-year cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) was higher in the malignant disease cohort (18% versus 3.2%; P = .011). Overall, the malignant cohort had both a higher total incidence (9% versus 3%; P < .001) and a higher 2-year cumulative incidence (16% versus 1.9%; P < .001) of total chronic GVHD. The 2-year cumulative transplantation-related mortality was 15%, with no difference between the 2 cohorts. The 5-year overall survival was 80% (95% CI, 72% to 86%) and was higher in the nonmalignant cohort (87% versus 61%; P = .01). The 2-year cumulative incidence of relapse was 25% in the malignant cohort. The 5-year cumulative GVHD-free, relapse-free survival rate was 60% (95% CI, 51% to 70%) and was higher in the nonmalignant cohort (72% versus 22%; P < .001). A treosulfan-based radiation-free conditioning regimen is feasible, achieving a high engraftment rate and 5-year overall survival, and is an emerging option for the first HSCT in nonmalignant diseases.

Personalized Medicine in Infant Population with Cancer: Pharmacogenetic Pilot Study of Polymorphisms Related to Toxicity and Response to Chemotherapy.

BACKGROUND: Pharmacogenetics is a personalized medicine tool that aims to optimize treatments by adapting them to each individual's genetics, maximizing their efficacy while minimizing their toxicity. Infants with cancer are especially vulnerable, and their co-morbidities have vital repercussions. The study of their pharmacogenetics is new in this clinical field. METHODS: A unicentric, ambispective study of a cohort of infants receiving chemotherapy (from January 2007 to August 2019). The genotypes of 64 patients under 18 months of age were correlated with severe drug toxicities and survival. A pharmacogenetics panel was configured based on PharmGKB, drug labels, and international experts' consortiums. RESULTS: Associations between SNPs and hematological toxicity were found. Most meaningful were: MTHFR rs1801131 GT increasing the anemia risk (OR 1.73); rs1517114 GC, XPC rs2228001 GT, increasing neutropenia risk (OR 1.50 and 4.63); ABCB1 rs1045642 AG, TNFRSF11B rs2073618 GG, CYP2B6 rs4802101 TC and SOD2 rs4880 GG increasing thrombocytopenia risk (OR 1.70, 1.77, 1.70, 1.73, respectively). Regarding survival, MTHFR rs1801133 GG, TNFRSF11B rs2073618 GG, XPC rs2228001 GT, CYP3A4 rs2740574 CT, CDA rs3215400 del.del, and SLC01B1 rs4149015 GA were associated with lower overall survival probabilities (HR 3.12, 1.84, 1.68, 2.92, 1.90, and 3.96, respectively). Lastly, for event-free survival, SLC19A1 rs1051266 TT and CDA rs3215400 del.del increased the relapse probability (HR 1.61 and 2.19, respectively). CONCLUSIONS: This pharmacogenetic study is a pioneer in dealing with infants under 18 months of age. Further studies are needed to confirm the utility of the findings in this work to be used as predictive genetic biomarkers of toxicity and therapeutic efficacy in the infant population. If confirmed, their use in therapeutic decisions could improve the quality of life and prognosis of these patients.

Pharmacogenetics in Neuroblastoma: What Can Already Be Clinically Implemented and What Is Coming Next?

Pharmacogenetics is one of the cornerstones of Personalized Precision Medicine that needs to be implemented in the routine of our patients' clinical management in order to tailor their therapies as much as possible, with the aim of maximizing efficacy and minimizing toxicity. This is of great importance, especially in pediatric cancer and even more in complex malignancies such as neuroblastoma, where the rates of therapeutic success are still below those of many other types of tumors. The studies are mainly focused on germline genetic variants and in the present review, state of the art is presented: which are the variants that have a level of evidence high enough to be implemented in the clinic, and how to distinguish them from the ones that still need validation to confirm their utility. Further aspects as relevant characteristics regarding ontogeny and future directions in the research will also be discussed.

Pharmacogenetics implementation in the clinics: information and guidelines for germline variants.

The aim of this work was to supply an overview of the germline Pharmacogenetics that can be already implemented in the oncology clinical practice. An explanation of the three pillars considered necessary for determining which genetic polymorphisms should be used has been provided. These are PharmGKB single nucleotide polymorphism (SNP)-Drug Clinical Annotations with levels of evidence 1 or 2; the genetic information provided in the drug labels by the drug regulatory main agencies (Food and Drug Administration and European Medicines Agency, mainly); and the guidelines elaborated by international expert consortia (mainly Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group). A summary of the relevant SNPs and the recommendations on how to apply their results has also been compiled.