Associations of Methylene Tetrahydrofolate Reductase Polymorphism and Methotrexate-Related Toxicities in Korean Treated for Malignant Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1607-1607
Author(s):  
Hyangmin Park ◽  
Dok Hyun Yoon ◽  
Youngcheon Song ◽  
Heese Kim ◽  
Youngseol Huh ◽  
...  
Keyword(s):  
Mthfr C677t ◽  
P Value ◽  
High Dose ◽  
Close Monitoring ◽  
High Dose Methotrexate ◽  
C677t Polymorphism ◽  
Mutant Genotype ◽  
Methylene Tetrahydrofolate Reductase ◽  
Dose Methotrexate ◽  
Methylene Tetrahydrofolate

Abstract Abstract 1607 Methotrexate is an antifolate agent commonly used for the treatment of lymphoma. The most common adverse effects include mucositis, myelosuppression, hepatic dysfunction and renal toxicities. It inhibits DNA replication by blocking the conversion of 5,10-methylene tetrahydrofolate to 5-methylene tetrahydrofolate by methylene tetrahydrofolate reductase (MTHFR). MTHFR is a key enzyme in folate metabolism and C677T is one of principal polymorphisms implicated in the metabolism of methotrexate. We aimed to investigate the relationship of the C677T polymorphism with methotrexate concentration in serum as well as methotrexate-associated toxicities. The study cohort included 169 cases treated with regimens containing high dose methotrexate (higher than 1 g/m2) between January 2010 and May 2011. Median age of the patients was 56 years (range, 24–78 years). Concentration of methotrexate was measured daily beginning 48 hours after infusion until the concentration reaches below 0.05 μmol/L. Forty four cases (26.0%) had a wild genotype of CC, 78 (46.2%) a heterozygous genotype of CT, and 47 (27.8%) a homozygous mutant genotype of TT. Mutant cases of TT had significantly higher MTX serum levels when compared with the other genotypes (Table 1) and required significantly longer time for elimination of methotrexate (p=0.011, Table 2). While hematologic toxicities, hepatotoxicities or number of febrile neutropenic episodes did not differ according to the genopypes, TT genotypes had significantly higher MTX levels and higher incidence of nephrotoxicity. Among them, two required therapeutic plasma exchange for prolonged exposure to high levels of methotrexate. Table 1. Concentration of methotrexate at different time points 48 h 72 h 96 h 120 h Wild-type (CC) 0.38 ± 0.47 0.15 ± 0.20 0.08 ± 0.12 0.09 ± 0.10 Heterozygous type (CT) 0.32 ± 0.46 0.12 ± 0.20 0.08 ± 0.11 0.07 ± 0.10 Mutant type (TT) 1.93 ± 5.84 0.92 ± 2.39 0.67 ± 1.25 0.59 ± 0.83 p-value 0.020 0.011 0.002 0.006 * Data expressed as mean ± SEM Table 2. Duration (days) to serum concentration of methotrexate < 0.05 μmol/L MTHFR C677T CC CT TT p-value Duration until methotrexate level < 0.05 μmol/L (days) 4.89 ± 2.95 4.35 ± 2.05 7.66 ± 9.00 0.011 * Data expressed as mean ± SEM Table 3. MTHFR polymorphisms vs. grade 3/4 toxicities Grades 3/4 toxicity MTHFR C677T CC (%) CT (%) TT (%) p-value Hb 27.3 17.9 34.0 0.431 WBC 52.3 61.5 53.2 0.950 PLT 45.5 51.3 53.2 0.465 AST 2.3 10.3 8.5 0.277 ALT 11.4 11.5 10.6 0.911 Total bilirubin 6.8 1.3 4.3 0.532 Creatinine* 0 1.3 10.6 0.006 ANC 47.7 62.8 68.1 0.050 FN episodes** 31.8 37.2 42.6 0.291 Mucositis 15.9 14.1 17.0 0.650 * grade 2 toxicity ** Adverse event positive Our data shows that cases with TT genotype for the MTHFR C677T polymorphism are associated with methotrexate-related renal toxicities. When high dose methotrexate is administered to the patients with TT genoptype, close monitoring for the nephrotoxicity seems to be required. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Renal failure after high-dose methotrexate in a child homozygous for MTHFR C677T polymorphism

2008 ◽  
Vol 50 (1) ◽  
pp. 154-156 ◽  
Author(s):  
Rita Turello ◽  
Katharina Rentsch ◽  
Ermindo Di Paolo ◽  
Maja Beck Popovic
Keyword(s):  
Renal Failure ◽  
Mthfr C677t ◽  
High Dose ◽  
High Dose Methotrexate ◽  
C677t Polymorphism ◽  
Mthfr C677t Polymorphism ◽  
Dose Methotrexate

scholarly journals P0008CASE REPORT: METABOLIC ALKALOSIS RESULTING IN RESPIRATORY COMPROMISE IN A PATIENT UNDERGOING HIGH DOSE METHOTREXATE THERAPY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Darragh O'Donoghue ◽  
Heather Truong ◽  
Heidi Finnes ◽  
Jennifer McDonald ◽  
Nelson Leung
Keyword(s):  
Metabolic Alkalosis ◽  
B Cell Lymphoma ◽  
Methotrexate Therapy ◽  
High Dose ◽  
Close Monitoring ◽  
High Dose Methotrexate ◽  
Respiratory Compromise ◽  
Dose Methotrexate ◽  
Adequate Hydration ◽  
Bicarbonate Infusion

Abstract Background and Aims High dose Methotrexate (HDMTX) is an important component of several modern oncological/haematological treatment protocols due to its central nervous system penetrance. Nephrotoxicity represents a significant adverse effect and can limit therapeutic options. Therefore, strategies to prevent this are paramount. Urinary alkalinisation and large volume resuscitation to maintain adequate hydration and urine output are the typical strategies. Urinary alkalinisation prevents tubular precipitation of methotrexate and therefore, a strict urinary pH target of 7 is maintained via a continuous bicarbonate infusion. Method We describe a case report, of Iatrogenic metabolic alkalosis leading to respiratory compromise in a patient receiving HDMTX from Mayo Clinic, Rochester. Results We present the case of a 76-year-old woman with a Diffuse Large B-Cell Lymphoma with CNS involvement who presented for elective admission for her 1st cycle of HDMTX. She received 7g of Methotrexate at dosing of 8 g/m2. She received the standard urinary alkalinisation with pre- and post-hydration. Her baseline HCO3- was 28 mEq/L. Her 48 hour MTX level was elevated at 1.2 so the urinary alkalinisation protocol was continued until &lt;0.1 mcmol/L. On day 4, she developed frequent episodes of apnoea. Her ABG demonstrated a metabolic alkalaemia pH 7.54, pCO 53, pO2 91, HCO3 45. She was transferred to the ICU for close monitoring. Her bicarbonate infusion was discontinued and she received acetazolamide. Her bicarbonate improved to 31 after 12 hours. She had a significant improvement in her respiratory status with no further episodes of apnoea. Her bicarbonate infusion was restarted due to elevated MTX levels. She was discharged home with no further complications. Conclusion Iatrogenic Metabolic alkalosis leading to respiratory compromise represents a rare but important complication of urinary alkalinsation protocols for High-dose Methotrexate therapy.

scholarly journals Influence of Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphism on High-Dose Methotrexate-Related Toxicities in Pediatric Non-Hodgkin Lymphoma Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Suying Lu ◽  
Xiaoqin Zhu ◽  
Wei Li ◽  
Huimou Chen ◽  
Dalei Zhou ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Oral Mucositis ◽  
Methylenetetrahydrofolate Reductase ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Mutant Genotype ◽  
Non Hodgkin Lymphoma ◽  
Dose Methotrexate

PurposeThis retrospective study aimed to investigate the relationships between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C and high-dose methotrexate (HD-MTX)-related toxicities in pediatric non-Hodgkin lymphoma (NHL) patients.Patients and MethodsWe reviewed the medical records of 93 NHL patients aged under 18 years who received HD-MTX therapy at the dose of 5 g/m2 with 24-h infusion at Sun Yat-sen University Cancer Center between 2014 and 2019.ResultsThere were 61 males and 32 females, with a median age of 8.8 years (0.9–15.8 years). The tumor types included lymphoblastic lymphoma (n = 38), Burkitt’s lymphoma (n = 31), anaplastic large cell lymphoma (n = 18), diffuse large B-cell lymphoma (n = 6). Overall, 355 courses of HD-MTX therapy were prescribed. All patients were rescued with calcium folinate 12 h after the end of MTX infusion. We found that plasma MTX levels &gt; 0.2 μmol/L at 48 h post-infusion increased the risk of developing oral mucositis (2.4% VS. 9.5%, P = 0.018). Also, patients carrying the C677T and T677T genotypes had tendencies to be more susceptible to oral mucositis (P = 0.034). Patients harboring mutant 677T allele were more likely to develop leucopenia (38.5 vs. 50.3%, P = 0.025) and thrombocytopenia (22.0 vs. 32.4%, P = 0.028). For polymorphism A1298C, the mutant genotype played a protective role in vomiting (11.1 vs. 4.3%, P = 0.018) but increased the risk of anemia (23.8 vs. 41.7%, P &lt; 0.001) and leucopenia (38.1 vs. 50.3%, P = 0.021).ConclusionChildhood NHL patients harboring C677T genotype were more vulnerable to oral mucositis, leucopenia, and thrombocytopenia, while those with A1298C genotype were at a decreased risk of vomiting and more likely to develop anemia and leucopenia.

Analysis of high-dose methotrexate with rituximab versus other treatment regimens for primary central nervous system (CNS) lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2090-2090
Author(s):  
Scott Michael Lindhorst ◽  
Frances McSherry ◽  
Annick Desjardins ◽  
Henry S. Friedman ◽  
Katherine B. Peters
Keyword(s):  
Treatment Regimen ◽  
Alternative Treatment ◽  
Survival Rates ◽  
Primary Cns Lymphoma ◽  
Cns Lymphoma ◽  
P Value ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Treatment Regimens ◽  
Dose Methotrexate

2090 Background: The most effective and least toxic treatment regimen for primary CNS lymphoma is a matter of debate. Most current regimens utilize various doses of high-dose methotrexate combined with other agents. The utility of deferred radiation is also under study. Methods: We evaluated 28 patients with primary CNS lymphoma treated with methotrexate 3.5 g/m2 and rituximab, as well as alternative regimens. Median, 12-month, and 24-month survival were compared for the various treatment regimens, as well as for patients who received radiation and those who did not. Results: Survival rates were significantly better in the methotrexate-rituximab treatment cohort than the other regimens examined (Log-Rank p-value 0.0437). 12-month survival for the methotrexate-rituximab cohort was 72.7% (95% CI, 37.1% to 90.3%) versus the alternative treatment cohort 12-month survival of 49.4% (95% CI, 23.7% to 70.8%). 24-month survival for the methotrexate-rituximab cohort was 72.7% (95% CI, 37.1% to 90.3%) versus the alternative treatment cohort 24-month survival of 39.5% (95% CI, 14.9% to 63.6%). Median survival for the alternative treatment cohort was 11 months (95% CI, 2.2 to 28.6), while the median survival for the methotrexate-rituximab regimen was not reached. Stratified by radiation, survival rates were significantly better in the radiation cohort than the cohort without radiation (Log-Rank p-value 0.0040). 12-month survival for the radiation cohort was 90% (95% CI, 47.3% to 98.5%) versus the cohort without radiation 12-month survival of 40.5% (95% CI, 17.7% to 62.3%). 24-month survival for the radiation cohort was 90% (95% CI, 47.3% to 98.5%) versus the cohort without radiation 24-month survival of 33.7% (95% CI, 12.9% to 56.1%). Median follow-up for all patients was 21.5 months (95% CI, 16 to 42.1). Conclusions: The combination of methotrexate at 3.5 g/m2 with rituximab is a valid treatment regimen for primary CNS lymphoma. Patients may be spared toxicity by using a methotrexate dose of 3.5 g/m2 rather than 8 g/m2. The addition of radiation provided a significant survival advantage in this observational study, however, radiation deferred until progression may be a viable alternative.

scholarly journals Use of the extracorporeal detoxification methods for methotrexate elimination

2021 ◽  
Vol 17 (8) ◽  
pp. 90-94
Author(s):  
R.Yu. Sobko ◽  
T.T. Borachok ◽  
T.B. Oranskyi ◽  
M.O. Kovalov ◽  
Kh.M. Zapotochna ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Clinical Case ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr C677t ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Urine Alkalinization ◽  
Intravenous Hydration

The article considers a clinical case of a 12-year-old child with osteosarcoma of the left tibia, T1N0M0G3, treated with high-dose methotrexate 12 g/m2. As a result of delayed elimination of methotrexate, the patient developed acute liver failure. The ALT level increased to 4790 U/L, AST — to 4320 U/L, which indicates life-threatening acute liver damage. There was no coagulopathy, significant increase in bilirubin, and hepatic encephalopathy. The timely use of efferent therapy allowed avoiding the complete course of acute liver failure. The patient received intravenous hydration therapy and urine alkalinization with 3000 ml/m2/day of 5% glucose in combination with 20 μmol NaHCO3/L and 20 μmol KCl/L. The urine output was more than 600 ml/m2/6 hours. Additionally, antidote therapy with calcium folinate was administered. In this case, we used continuous venous-venous hemodiafiltration using Prismaflex. After the first session, which lasted for 78 hours, there was a re-increase in serum methotrexate concentration and ALT, AST levels, which indicates a large volume of distribution of methotrexate and the need for long-term extracorporeal therapy. Therefore, the second session of continuous venous-venous hemodiafiltration was provided. After the second session, there was no re-increase in methotrexate level in the blood and the transaminases and total bilirubin returned to normal levels. Additionally, the patient was tested for homocysteine levels for hyperhomocysteinemia, as well as 4 genes that also determine the predisposition to hyperhomocysteinemia — methylenetetrahydrofolate reductase gene MTHFR C677T, A1298C, methionine synthase MTRR, and MTR. The presence of elevated levels of homocysteine, as well as heterozygosity of these genes, indicate a slow excretion of methotrexate or a complete delay in its excretion. Our patient presented the negative results of these tests. Conclusions. This clinical case indicates the effectiveness of continuous venous-venous hemodiafiltration in combination with intravenous hydration, urine alkalinization, and antidote therapy in the treatment of hepatotoxicity of high-dose methotrexate on the background of delayed excretion.

Sign in / Sign up

Export Citation Format

Share Document