A Retrospective Cohort Study: The Influence of MTHFR C677T and A1298C on the High-dose Methotrexate-Related Toxicities in Pediatric Patients With Non-Hodgkin Lymphoma

Pediatric NHL Clinical Trial

Official title:

A Retrospective Cohort Study: The Influence of MTHFR C677T and A1298C on the High-dose Methotrexate-Related Toxicities in Pediatric Patients With Non-Hodgkin Lymphoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04283955
• Other study ID #: SCCCG-NHL-2017
• Status: Completed
• Start date: March 1, 2014
• Est. completion date: March 1, 2019

Study information

• Verified date: February 2020
• Source: Sun Yat-sen University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

We hypothesized that polymorphism MTHFR C677T and A1298C should be associated with HD-MTX-related toxicities in children with NHL. Therefore, we aimed to retrospectively explore their relationships in this analysis.

Description:

INTRODUCTION: Non-Hodgkin lymphoma (NHL), the fourth most common malignancy across the pediatric age spectrum, is a heterogeneous group of lymphoid malignancies. In children, NHL comprises four main wide categories: lymphoblastic lymphoma (LBL), Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and anaplastic large cell lymphoma (ALCL). The current overall survival rate of pediatric NHL exceeds 80% due to dramatic progress in developing risk-adapted curative therapy (1), in which methotrexate (MTX) plays a crucial part.

MTX is used to treat a variety of cancers. A high-dose MTX (HD-MTX) regimen, referred to the administration of a dosage ranging from 0.5g/m2 to 12.0g/m2 or even higher, is commonly used to treat childhood acute lymphoblastic leukemia (ALL), lymphoma and pediatric osteosarcoma. Despite its wide range of therapeutic efficacy, the toxicities of HD-MTX including reversible myelosuppression, nausea, vomiting, diarrhea, hepatotoxicity, nephrotoxicity, neurotoxicity, and particularly oral mucositis should not be neglected. Accumulating pharmacogenetic studies have revealed that polymorphisms of enzymes involved in folate pathway could lead to variability in response to MTX and HD-MTX-related toxicities in various malignancies. The most two extensively studied SNPs of MTHFR in relation to the toxicities of MTX are the C677T variant (Ala222Val, rs1801133) and A1298C variant (Glu 429Ala, rs1801131), both dampening the enzyme activity by 40-70%.

However, limited evidence is available in pediatric NHL, with results varying considerably in different studies. Therefore, the aim of this retrospective study was to evaluate the influence of C677T and A1298C polymorphisms on HD-MTX-related toxicities in children with NHL treated according to BFM-modified protocols.

PATIENTS & METHODS：We reviewed the medical records of all pediatric patients who were diagnosed as NHL and received HD-MTX-based chemotherapy at the dose of 5g/m2 in Sun Yat-sen University Cancer Center between March 2014 and March 2019. Data were analyzed by chi-square test.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 93
• Est. completion date: March 1, 2019
• Est. primary completion date: March 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

Inclusion Criteria: patients who were:

• Aged = 18 years old;

• Diagnosed as the four main types of NHL, including lymphoblastic lymphoma (LBL), Burkitt's lymphoma (BL), anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL);

• Treated with HD-MTX therapy at the dose of 5g/m2;

• Genotyped by PCR following Sanger with respect to MTHFR C677T and A1298C

• With complete medical records.

Exclusion Criteria: patients who were:

• Aged >18 years old;

• Diagnosed as cancer types other than the four main types of NHL;

• Treated with no HD-MTX therapy or at the dose other than 5g/m2;

• Not genotyped by PCR following Sanger with respect to MTHFR C677T and A1298C

• With incomplete medical records .

Related Conditions & MeSH terms

• Lymphoma, Non-Hodgkin
• Pediatric NHL

Intervention

Drug:
• High-dose MTX based chemotherapy
Patients received MTX therapy at the dose of 5g/m2 for 24 hours. Each dose of HD-MTX therapy was followed by 6~7 times of leucovorin rescue 12 hours after the end of MTX infusion, at the dose of 15 mg/ m2 every 6 hours. The plasma MTX levels were monitored at 0, 24, 48, 72 hours from the initiation of HD-MTX infusion. To maintain the urine pH at approximately 7~8, intravenous hydration and alkalization at the dose of 1,500ml/ m2 per day were achieved 12 hours prior to the initiation of HD-MTX administration (D0) and 3,000ml/ m2 per day lasted for the following 3 days (D1 to D3). CF was used to rinse mouth to prevent oral mucositis from D1 to D3. We closely monitored the volume and pH of the urine via routine test from D0 to D4.

Locations

Country	Name	City	State
China	Sun Yat-sen University Cancer Center	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Sun Yat-sen University

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Observations of HD-MTX-related toxicities	We recorded the toxicities that occurred to the patients after the MTX infusion, including hematological suppression, hepatotoxicity, nephrotoxicity, oral mucositis, vomiting and diarrhea.	3 weeks