Severe Complications Due to THFR SNP in ALL T Type Recent Diagnosed Teenager, after Induction Protocol with Methotrexate: Case Report
Melendi GA1, Hernández A1, Picón A1, Chiesa I2, Maria S Perez2, Hernández Y1, Pablo Moreno1 and Gustavo Cardigni1
1Sanatorio Trinidad Palermo, Pediatric Intensive Care Unit, South America
2Medicine genomic, Laboratorio Manlab, USA
Submission: March 01, 2017; Published: June 01, 2017
*Corresponding author: Guillermina AM, Sanatorio Trinidad Palermo, Pediatric Intensive Care Unit, South America.
How to cite this article: Melendi GA, Hernández A, Picón A, Chiesa I, Maria S P. Severe Complications Due to THFR SNP in ALL T Type Recent Diagnosed
Teenager, after Induction Protocol with Methotrexate: Case Report. Acad J Ped Neonatol. 2017; 4(4): 555701. DOI: 10.19080/AJPN.2017.04.555701
Severe drugs toxicities in pediatric ALL patients could cause life-threatening situations and consequent PICU admition. Genomics and pharmacogenomics bring new insights on management and treatment. We describe a ALL pediatric patient with severe bone marrow aplasia with high blood levels of methotrexate after a standard IV dose for ALL induction block treatment.
Abbrevations: ALL: Acute Lymphoblastic Leukemia; GATLA: Grupo Argentino de Tratamiento de la Leucemia Aguda; LTC: Long Term Catheter; MTHFR: Methylene Tetra Hydrofolate Reductase; PICU: Pediatric Intensive Care Unit; qPCR: quantitive Protein C Reactive; SNPs: Single Nucleotide Polimorphisms; TPN: Total Parenteral Nutricion; WBC: White Blood Cell Count
There are 370 registered acute lymphoblastic leukemia (ALL) cases per year in Argentina, 30% of which will be admitted in PICU at some point of their disease history. Methotrexate is one of the drugs that ALL patients will be early exposed. Its metabolism by the MTFHR (methylene tetra hydrofolate reductase) is key to its clearance [1-4]. Over the past decades, the medical advance of genomics and pharmacogenetics enhanced the knowledge of drugs toxicity.
A 13-year-old teenager with recently ALL diagnose, is admitted to PICU with shock clinical signs after the first exposure to IV
methotrexate (2gr) the patient initially required vasoactive drugs, antibiotic therapy and supplementary oxygen. Methotrexate toxicity was suspected therefore blood levels were measure, over 4 times expected levels were found. Folinic Acid rescue treatment started .
Due to severe mucositis total parenteral nutrition was needed.
White blood cell count descended since addition, after fifteen days
at PICU the patient started with pancytopenia that persisted for
26 days; fever was associated therefore deep infection protocol
was followed. Skin and mucosa infection by Fusarium sp. And
Candida albicans in blood cultures were found. Total PICU days
of stay were 61, days with TPN 35, antibiotics and antifungal were
45 Figure 1.
MTHFR’s Single nucleotide polimorphisms (SNPs) were
analyzed, a mutation A1298C a (glutamic acid/ alanine change)
was found. The patient continued with an alternative ALL
treatment protocol, achieving remission. No PICU admission was
Two MTHFR SNPs are associated with severe methotrexate
toxicity, C677T and A1298C. Both, widely described in the
literature as methotrexate metabolism inhibitor. Associated clinical
manifestations are leucopenia and mucocitis from moderated
to severe. [1-8]. The patient described in this Case Report was
found hetorocygote for the A1298C SNP. Felice et al. described the
association of mutations above with high risk of severe leucopenia
in a pediatric population, encompassing different countries in a
multicentre international study . Latest recommendations on
SNPs screening are not in GATLA protocols. SNPs for THFR are
found mostly in jew population, Argentina has 1:238 6th highest
ratio of Jews population per habitant in the world. The cost of the
assay in Argentina, in a private clinical laboratory is around 40 US
dollars (Man Lab, Argentina). Here and now, critical ill patients
can benefit on their disease prognosis with the current knowledge
on epigenetics, pharmacogenetics, custom biologics treatment,
therefore these approaches are not the future any more, they
are the present, therefore we should think about them also as