Dose Folinic Acid Research Articles

Impact of Folinic Acid Dosing on Efficacy and Toxicity of High-Dose Methotrexate in Central Nervous System Lymphoma

Treatment of primary central nervous system lymphoma (PCNSL) is centered around a backbone of high-dose methotrexate (HDMTX) with folinic acid (FA) rescue. Higher FA doses were associated with treatment failure in several retrospective studies in acute lymphatic leukemia (ALL), leading to the adoption of lower FA doses in ALL treatment protocols. In PCNSL, FA doses have varied widely, guidelines and consensus statements generally do not address FA dosing, and the effect of FA dosing on treatment outcomes has not been assessed. We retrospectively analyzed the medical records of patients treated at our institute for PCNSL between the years 2014 and 2022 to address this question. Patient characteristics are listed in table 1. Complete dosing data was available for 36 patients. The median number of HDMTX doses administered was 6.5 (range, 2-9;), with an average dose of 3.9 g/m 2 (SD +/- 0.74; range, 2.7-5.0). Per the local protocol, IV FA rescue began 24 hours after each MTX infusion at a fixed dose of 50 mg four times daily and continued until MTX clearance. The average cumulative dose of FA administered per treatment was 322 mg/m 2 (SD +/- 141; range, 140-700). 33 patients (92%) achieved either a partial or complete response on MRI following induction treatment. Three (8%) had progressive disease. 26 patients (72%) proceeded with consolidation treatment. Of these, 16 (44%) underwent autologous hematopoietic stem cell transplant. At a median follow up of 1.6 years (range, 0.3-8.1), 12 patients (33%) suffered progressive disease, disease relapse, or death. The 2-year PFS probability for the entire cohort was estimated at 64.5% (95% confidence interval [CI], 49.4-84.1%), and the 2-year OS as 70.7% (95% CI 56.0-89.2%). In univariate Cox regression analysis, average FA dose during MTX treatment was a significant predictor of both PFS and OS, with hazard ratios (HR) of 2.22 (95% CI 1.39-3.55; p < 0.001) and 2.07 (95% CI 1.31-3.29; p = 0.002), respectively, for each 100 mg/m 2 increase. The FA dose during the first treatment cycle, before assessment of response, was also significantly associated with worse PFS (HR 1.56; 95% CI 1.24-1.96; p < 0.001) and OS (HR 1.41; 95% CI 1.14-1.74; p = 0.001). A trend towards worse PFS and OS was seen with male gender, elevated serum LDH, and deep structure involvement. A Cox multivariate regression analysis using the variables age, gender, serum LDH, deep structure involvement, and the average MTX and FA doses, identified FA dose as an independent prognostic factor for PFS, with an estimated hazard ratio (HR) of 2.23 for each 100 mg/m 2 increase (95% CI, 1.25-3.97; p = 0.006). A smaller effect was seen when the FA dose during only the first treatment cycle was examined (HR 1.55; 95% CI 1.16-2.08; p = 0.003). Involvement of deep structures was also significantly associated with worse PFS, with an estimated HR of 8.59 (95% CI, 1.28-57.5; p = 0.027), and there was a borderline significant trend for worse PFS with male gender and elevated LDH. None of the examined variables were identified as statistically significant predictors of OS in the multivariate analysis. Logistic regression with 2-year PFS as the dependent variable was used to define a cutoff value of 350 mg/m 2 for FA dose. The group of patients who received FA doses above and below this threshold showed significantly different PFS curves (figure 1). The 2-year PFS probability was estimated at 56.6% (95% CI, 35.4-90.5%) for patients who received doses of FA above this threshold, and 70.5% (95% CI, 51.7%-96.2%) for patients who received doses below it. We identified no effect of FA dosing on hematologic, renal, hepatic, or gastrointestinal toxicity at the dose ranges examined. In summary, we found that high FA doses were associated with inferior PFS in PCNSL. Such high doses may be avoided through use of lower individual doses of FA, such as 15 mg/m 2 or 25 mg fixed doses as have been used in some protocols, rather than the 50 mg or higher doses used in our and other's practice. Our conclusions are moderated by the study's limitations, which include a small sample size limited to a single center and a retrospective design. However, they suggest that optimizing FA dosing in treatment of PCNSL might improve treatment efficacy without excess toxicity. Future larger and prospective studies will be required to better define the range of MTX and FA doses at which the balance between prevention of treatment toxicity and preservation of treatment efficacy is preserved.

Impact of Folinic Acid Dosing on Efficacy and Toxicity of High-Dose Methotrexate in Central Nervous System Lymphoma

IntroductionHigh-dose methotrexate (HDMTX)-based regimens are the treatment of choice in primary central nervous system lymphoma (PCNSL). Folinic acid (FA) rescue is used to mitigate the toxic effects of MTX on normal cells. However, the optimal dosing of FA in PCNSL remains uncertain. MethodsWe analyzed the relationship between FA dosing and treatment efficacy and toxicity in a cohort of 36 PCNSL patients treated at our institute between the years 2014 and 2022. A combination of univariate and multivariate analyses using known prognostic factors were used to determine the association between FA dosing and treatment outcomes. ResultsWe found that higher per-treatment cumulative FA doses were associated with inferior progression-free survival (PFS), with a hazard ratio (HR) of 2.2 for each 100 mg/m2 increase in FA dose. We identified a threshold of 350 mg/m2/treatment, above which there was a significant reduction in PFS. Notably, lower FA doses did not result in increased toxicity. ConclusionOur findings suggest that optimizing FA dosing to avoid very high rescue doses may improve treatment outcomes in PCNSL patients receiving HDMTX. Further prospective studies are warranted to validate these findings.

Korisnost ponovljenih merenja nivoa leka nakon infuzije visoke doze metotreksata za planiranje lečenja kod pedijatrijske leukemije

Introduction: Although high-dose Methotrexate (MTX) is a successful chemotherapeutic agent used in the treatment of acute lymphoblastic leukemia in childhood, life-threatening toxic effects are rarely seen. Therefore, frequent follow-up of drug levels is recommended. The study researched the necessity of drug level measurement and a minimum safe number of measurements. Materials and Methods: The files of pediatric patients with Acute Lymphoblastic Leukemia receiving high-dose MTX treatment in a single center between 2018 and 2021 were retrospectively reviewed. The treatment protocol was: 3000 mL/m2 alkaline hydration fluid was continued until the 72nd hour together with 2 gr/m2 continuous MTX infusion in the low-risk group and 5 gr/m2 in moderate and high-risk groups, and 15 mg/m2 /dose folinic acid was given at the 42nd, 48th and 54th hours. Findings: 456 MTX treatments were evaluated in 114 patients. Similar results (p > 0.05) were obtained in the MTX level measurements performed at the 24th, 42nd, 48th, and 54th hours after MTX administration. In the repeated measurements, the data at the 42nd hour were similar (p = 0.021). The number of cases that were > 150 µmol/L at the 24th hour of methotrexate infusion and above 1 µmol/L at the 42nd, 48th, and 52nd hours were found to be similar in the repeated measurements. Conclusion: Although recommended, frequent follow-up of MTX levels might not always indicate toxicity. In centers with limited laboratory facilities, the MTX level measured at the 42nd hour in the first treatment might be a practical approach to guide the management of other MTX treatments.

Reduced dose folinic acid rescue after rapid high-dose methotrexate clearance is not associated with increased toxicity in a pediatric cohort

PurposeLow doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity.MethodsWe reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 μmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected.ResultsRapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given.ConclusionA pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.

Acute renal injury after high-dose methotrexate is independent of folinic acid dose

Acute renal injury after high-dose methotrexate is independent of folinic acid dose

A single assessment of methotrexate levels at 42 hours permits safe administration and early discharge in children with lymphoblastic lymphoma and leukemia receiving high-dose methotrexate

High-dose methotrexate (HDMTX) is an important component of treatment in pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Optimal rescue therapy is essential for the safe administration of HDMTX. A cost-effective strategy that does not compromise safety is necessary for low- and middle-income countries. Consecutive admissions for HDMTX in children with ALL and LL over 12 months were analyzed. The dose of HDMTX was 3 g/m2 in B-ALL and B-LL and 5 g/m2 in T-ALL and T-LL. A methotrexate level was measured at 42 hours of starting HDMTX infusion (T42-MTX). Three doses of folinic acid at T42, T48, and T54 and alkalinized hydration till T54 were administered if T42-MTX <1 µM. A total of 282 cycles of HDMTX that were administered in 71 patients were analyzed. T42-MTX was <1 µM in 266 (94.3%) cycles. T42-MTX was ≥1 µM in 12% and 3% of cycles of HDMTX administered at a dose of 5 g/m2 and 3 g/m2, respectively (p = .074). The median duration of hospitalization for HDM was three days and did not differ with the dose of HDMTX administered (p = .427). Mucositis, delayed recovery of blood counts, and hospitalization for reversible toxicity occurred after 21 (7.4%), 28 (9.9%), and 19 (6.7%) cycles of HDMTX, respectively. Mucositis was greater following the administration of 5 g/m2 of HDMTX. A single T42-MTX measurement permits the safe administration of HDMTX and an expedited discharge from the hospital within three days in more than 90% of children with ALL/LL.

Folinic acid over rescue of high dose methotrexate: How problematic citations conserve discredited concepts

BackgroundThe outdated axiom that the dose of Folinic acid (FA) rescue used after high dose Methotrexate (HDMTX) should be kept to a minimum in order to prevent a reduction of prognosis (“over rescue”) continues to be expressed even though the concept has been seriously challenged.Study aim The ways “problematic citations” are used to support an old theory, such as this, was examined. ResultsTen patterns of “problematic citation” use were identified. In 8 of these patterns the articles used were scientifically sound and the problem was with the articles citing them. However in 2 other pattens, the articles and their conclusions were flawed and citing them, apparently, resulted from accepting the presented data or conclusions as sound and valid. The patterns were 1. Claims based on data that are not present in the cited article. 2. Selective inclusion of data from cited articles. 3. Citation of misleading data presented only in the abstract. 4. Reporting trends as statistically significant. 5. Copying the citations used by others without checking the article. 6. Acceptance of illusionary truth in spite of knowledge to the contrary. 7. Citation of reports not relevant to the population under discussion 8. Presenting opinions as facts without any citation. 9. Selective presentation of data sets that support the thesis while ignoring the data sets that show the opposite results. 10. Use of a title expressing what the authors intended to show but not what was found. ImplicationsThe containing acceptance of this old insupportable conjecture, in part, because of “problematic citations” has resulted in unnecessary neurocognitive damage to patients and may have resulted in the misconception that it is the outcome of HDMTX that may have lead to its abandonment in favour of more toxic therapies. Realisation that this is a significant problem in data analysis should lead authors and reviewers to be even more carefully in checking all references. The importance of high-quality reviews is clearly evident. The effect of “Canonization of false facts” is a serious impairment to the acceptance of new hypotheses that better express reality and could lead to improved treatment results. Authors are advised only to cite articles they have read in entirety not relying on the title, abstract or previous use and to check the content of citations before submission.

Protocol concordance and impact of protocol deviations on selected outcomes in delivery of high-dose methotrexate in acute lymphoblastic leukemia in Sri Lanka.

17 Background: In Sri Lanka, children with acute lymphoblastic leukemia are treated on the UKALL 2011 protocol, which includes high-dose methotrexate (HDMTX) in high risk patients. Safe delivery of HDMTX is challenging in low resource settings, where deviation from accepted guidelines can occur frequently and result in toxicity, subsequent treatment delays, and in extreme cases, death. The goal of this study was to compare current practices to the treatment and supportive care details described in the protocol to identify the incidence and impact of guideline-discordant care to deliver HDMTX more safely children with cancer in Sri Lanka. Methods: We reviewed medical records to assess guideline concordance in 4 critical aspects of HDMTX delivery: 2 consecutive alkaline urine pH readings in the 2-hour period before starting HDMTX, 24-hour duration of MTX infusion (as opposed to early stop), the first dose of folinic acid administered later than 36 hours from start of HDMTX infusion (no inappropriately early rescue), and the administration of at least 3 folinic acid doses per course (appropriate duration of rescue). We analyzed how each deviation influenced AKI (creatinine increase of 0.3 mg/dL or more), infection, and treatment delays (defined as recovery delayed 7 days or longer from the 14 days expected between courses of HDMTX). Results: We analyzed 309 HDMTX courses in 91 patients younger than 20 years, including 105 girls (34%). In 83 courses (27%) alkaline urine was not documented prior to the start of MTX. Infusion time was less than 24 hours in 239 courses (77%), most of which finished 20-21 hours. In 37 courses (12%), the first folinic acid dose was given inappropriately early, and in 25 courses (8%) less than 3 doses of folinic acid were given. There were 2 episodes of AKI, 43 infections, 11 treatment delays and one death. None of the 4 guideline deviations were significantly associated with AKI or treatment delays. Patient sex was also not associated with any difference in guideline discordance or outcome (p&gt;0.1 in all cases). Conclusions: Significant deviations from HDMTX administration guidelines were common, especially early completion of infusion. However, outcomes were not impacted so quality standards may require adjustment to focus only on extreme deviations likely to impact patient outcomes.

Folate: Friend or Foe? An investigation into the opposing roles of folate in glioma

Survival rates in patients with glioblastoma have shown little improvement over the last 40 years due to the heterogeneity of tumours and the difficulty of specifically targeting the tumour whilst sparing surrounding healthy tissue. Altered gene methylation is often observed in glioma cells, and methylating agents such as folate may reverse aberrant methylation. Folate treatment has shown a beneficial effect, reducing risk of certain cancers (colorectal, breast, squamous cell carcinoma), whereas other studies have shown detrimental effects following folate treatment, whereby proliferation of cancer increased (mammary, prostate). The aim of this study was to investigate the opposing roles of folate in glioma. The glioma cell lines 1321N1, U87 MG and non-cancerous glial SVGp12 cells were grown in folate deficient, folic or folinic acid supplemented media and compared to standard cell culture media. Cell viability, apoptosis and cell cycle analysis along with methylation status and protein expression of the genes of interest; PTEN, FOLR1, RFC, PCFT, and MTHFR were analysed to determine differences between cell lines following treatment. Folic and folinic acid behaved differently depending on the concentration used and the cell lines treated. Low folic acid at 5 µg/ml significantly increased cell viability and protein expression levels in the U87 MG and SVGp12 cell lines, whilst the high dose of folinic acid (35 µg/ml) resulted in significant decreased cell viability, increased apoptotic activity and down regulation of the folate transporters in the 1321N1, U87 MG and SVGp12 cell lines. Folate treatment did not significantly alter cell cycle phase. Altered methylation of genes specific for folate metabolism and transport did not explain the cytotoxic effects of folate in cell lines. In conclusion folinic acid rather than folic acid supplementation should be investigated further to elucidate the mechanism of potential cytotoxic effects in glioma.

The Clinical Importance of Drug Monitoring: Methotrexate-Induced Acute Renal Failure

Plasma concentrations of methotrexate (MTX) represent the best predictive value of its toxicity. Monitoring of the MTX is a common practice that allows identifying patients with acute toxicity and adjusting the dose of folinic acid, and establishing immediate corrective actions. However, the main adverse effects that must be found after a patient treated with this drug are myelosuppression, mucositis of the entire gastrointestinal tract, renal failure and in some cases neurological alterations.

High Frequency of Bone Marrow Depression During Congenital Toxoplasmosis Therapy in a Cohort of Children Identified by Neonatal Screening in Minas Gerais, Brazil.

There are few studies reporting frequency and control of adverse events associated with congenital toxoplasmosis treatment. The objective of this study is to describe treatment adherence and adverse hematologic events in a cohort of children identified with congenital toxoplasmosis in Minas Gerais, Brazil. Children were treated with sulfadiazine, pyrimethamine and folinic acid and were evaluated clinically and by laboratory tests at regular intervals. Of 146,307 live newborns who participated in the Neonatal Screening Program in Minas Gerais in 2006-2007, 190 had congenital toxoplasmosis. Among the 171 children whose treatment data were available, 73.1% completely adhered to antiparasitic therapy. Hematologic adverse events (macrocytic anemia and/or neutropenia and/or thrombocytopenia) were diagnosed in 44% of them. The most common adverse event was neutropenia (31%). In most cases, it was not severe and reversed after increase in folinic acid dosage (25.7%) or temporary treatment suspension (1.8%). No infections were observed in association with neutropenic events. Significant associations were detected between macrocytic anemia and lower weight Z score at first medical appointment (P = 0.03), and between severe neutropenia (<500/mm) and lower weight Z score toward the end of treatment (P = 0.04). The high frequency of hematologic adverse events found, especially in malnourished children, highlight the importance of careful monitoring of these children throughout treatment, as well as considering nutritional aspects and the need for higher doses of folinic acid. With adequate monitoring, antiparasitic treatment was feasible and relatively safe in the setting of this large screening program for congenital toxoplasmosis.

Neurotoxicity after high-dose methotrexate (MTX) is adequately explained by insufficient folinic acid rescue.

To challenge the view that the dose of folinic acid rescue after high-dose methotrexate (MTX) has no significance in the prevention of neurotoxicity and to present the minority view that neurotoxicity can be prevented by an adequate dose of folinic acid, without compromising treatment results. Several fallacies that led to the misunderstanding of post MTX neurotoxicity are presented. Data mining using search engines was used to find relevant publications, and an e-mail survey of more than 60 authors of articles in this field was performed. All relevant articles identified were read in their entirety. Examples of clinical studies with neurotoxicity following inadequate rescue are given. Some studies demonstrated no neurotoxicity when adequate doses of folinic acid rescue were started 24-36 h after the start of HDMTX rescue even after mega doses of MTX. Rescue started after 42 h was associated with neurotoxicity except in patients with low serum MTX levels after 24 and 36 h. ALL protocols with neurotoxicity, especially BFM-like protocols, are presented. Protocol is reported in which single protocol changes prevented neurotoxicity. From the published data, when folinic acid rescue is given in a sufficiently high enough dose and is started 24-36 h after the beginning of the methotrexate exposure, and virtually all forms of post MTX neurotoxicity can be prevented without compromising therapeutic results.

The basis for folinic acid treatment in neuro-psychiatric disorders

Multiple factors such as genetic and extraneous causes (drugs, toxins, adverse psychological events) contribute to neuro-psychiatric conditions. In a subgroup of these disorders, systemic folate deficiency has been associated with macrocytic anemia and neuropsychiatric phenotypes. In some of these, despite normal systemic levels, folate transport to the brain is impaired in the so-called cerebral folate deficiency (CFD) syndromes presenting as developmental and psychiatric disorders. These include infantile-onset CFD syndrome, infantile autism with or without neurologic deficits, a spastic-ataxic syndrome and intractable epilepsy in young children expanding to refractory schizophrenia in adolescents, and finally treatment-resistant major depression in adults. Folate receptor alpha (FRα) autoimmunity with low CSF N(5)-methyl-tetrahydrofolate (MTHF) underlies most CFD syndromes, whereas FRα gene abnormalities and mitochondrial gene defects are rarely found. The age at which FRα antibodies of the blocking type emerge, determines the clinical phenotype. Infantile CFD syndrome and autism with neurological deficits tend to be characterized by elevated FRα antibody titers and low CSF MTHF. In contrast, in infantile autism and intractable schizophrenia, abnormal behavioral signs and symptoms may wax and wane with fluctuating FRα antibody titers over time accompanied by cycling changes in CSF folate, tetrahydrobiopterin (BH4) and neurotransmitter metabolites ranging between low and normal levels. We propose a hypothetical model explaining the pathogenesis of schizophrenia. Based on findings from clinical, genetic, spinal fluid and MRI spectroscopic studies, we discuss the neurochemical changes associated with these disorders, metabolic and regulatory pathways, synthesis and catabolism of neurotransmitters, and the impact of oxidative stress on the pathogenesis of these conditions. A diagnostic algorithm and therapeutic regimens using high dose folinic acid, corticosteroids and milk-free diet is presented which has proven to be beneficial in providing adequate folate to the brain and decreasing the FRα autoantibody titer in those positive for the antibody.

The metabolic basis for developmental disorders due to defective folate transport

Folates are essential in the intermediary metabolism of amino acids, synthesis of nucleotides and for maintaining methylation reactions. They are also linked to the production of neurotransmitters through GTP needed for the synthesis of tetrahydrobiopterin. During pregnancy, folate is needed for fetal development. Folate deficiency during this period has been linked to increased risk of neural tube defects. Disturbances of folate metabolism due to genetic abnormalities or the presence of autoantibodies to folate receptor alpha (FRα) can impair physiologic processes dependent on folate, resulting in a variety of developmental disorders including cerebral folate deficiency syndrome and autism spectrum disorders. Overall, adequate folate status has proven to be important during pregnancy as well as neurological development and functioning in neonates and children. Treatment with pharmacologic doses of folinic acid has led to reversal of some symptoms in many children diagnosed with cerebral folate deficiency syndrome and autism, especially in those positive for autoantibodies to FRα. Thus, as the brain continues to develop throughout fetal and infant life, it can be affected and become dysfunctional due to a defective folate transport contributing to folate deficiency. Treatment and prevention of these disorders can be achieved by identification of those at risk and supplementation with folinic acid.

IMPROVING THE PRACTICE OF PRESCRIBING FOLINIC ACID RESCUE POST HIGH DOSE METHOTREXATE CHEMOTHERAPY

Aim To reduce the incidence of omitted or delayed doses of IV folinic acid rescue following the implementation of electronic prescribing. High dose methotrexate (MTX) is a component of some paediatric chemotherapy regimens. IV folinic acid rescue started 24–42 hours after MTX (dependent on protocol) is essential to avoid toxicity. Since the introduction of electronic prescribing (EP) there has been an increase in the number of delayed doses of folinic acid. Prior to the introduction of EP, this rescue was prescribed alongside the chemotherapy on the paper chart, allowing nurses to enter the folinic acid start time at the same time as starting the MTX. It is not possible to do this with the EP system. Method A list of all patients who have received high dose methotrexate since December 2012 was compiled and drugs charts reviewed to check the folinic acid prescription and administration. An audit tool was created to collect the data. Any new patients prescribed high dose methotrexate were audited prospectively. In addition the Trust incident database was interrogated for all previous reports of omitted/delayed doses of folinic acid to ensure all cases were captured. Several changes including checklists, paper and electronic based prompts have been implemented in an effort to resolve the problem. A retrospective audit and ongoing review of new prescriptions is being completed, identifying the compliance with the new measures and percentage of prescriptions where folinic acid has been prescribed and given at the correct time. Results In the ten month period prior to EP, 100% of prescriptions for folinic acid were complete and administered correctly. This reduced to 83% immediately following the introduction of EP. After the introduction of the first set of measures this increased to 94%. Conclusion Since the implementation of EP ongoing changes to the prescribing of folinic acid are helping to reduce the incidents of delayed and omitted doses. Continuous monitoring will enable deficiencies in our systems to be highlighted and resolved in a timely fashion in order to avoid a potentially serious adverse event. Further changes to our procedures are currently being evaluated, with an expectation that 100% compliance will be achieved.

Follow-up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome.

BackgroundKearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome that presents with profound cerebral folate deficiency and other features. Preliminary data support the notion that folinic acid therapy might be useful in the treatment of KSS patients. Our aim was to assess the clinical and neuroimaging outcomes of KSS patients receiving folinic acid therapy.MethodsPatients: We recruited eight patients with diagnoses of KSS. Four cases were treated at 12 de Octubre Hospital, and the other two cases were treated at Sant Joan de Déu Hospital. Two patients refused to participate in the treatment protocol.Methods: Clinical, biochemical and neuroimaging data (magnetic resonance imaging or computed tomography scan) were collected in baseline conditions and at different time points after the initiation of therapy. Cerebrospinal fluid 5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence detection. Large-scale mitochondrial DNA deletions were analysed by Southern blot.Treatment protocol: The follow-up periods ranged from one to eight years. Cases 1–4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8 received 3 mg/kg/day.ResultsNo adverse effects of folinic acid treatment were observed. Cerebral 5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline conditions. Moreover, all three patients who accepted lumbar puncture after folinic acid therapy exhibited complete recoveries of their decreased basal cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases neurologically improved after folinic therapy. Disease worsened in the other patients.Post-treatment neuroimaging was performed for the 6 cases that received folinic acid therapy. One patient exhibited improvements in white matter abnormalities. The remaining patients displayed progressions in subcortical cerebral white matter, the cerebellum and cerebral atrophy.ConclusionsFour patients exhibited clinical and radiological progression of the disease following folinic acid treatment. Only one patient who was treated in an early stage of the disease exhibited both neurological and radiological improvements following elevated doses of folinic acid, and an additional patient experienced neurological improvement. Early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of KSS.Trial registrationEudracT2007-00-6748-23Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0217-2) contains supplementary material, which is available to authorized users.

PP-081 SEVERE RENAL FAILURE DUE TO HIGH DOSE METHOTREXATE IN ACUTE LYMPHOBLASTIC LEUKEMIA ASSOCIATED WITH PREDISPOSING FACTORS: CASE REPORT

Introduction: High dose methotrexate induced acute tubular damages is an important oncologic emergency in spite of preventive supportive treatment such as closely monitoring, leucovorin, hydration and alkalization. We report a case of severe renal insufficiency due to Hyper-CVAD in an acute lymphoblastic leukemia (ALL) with contributing factors such as diabetes and hypertension. Case: Hyper-CVAD was started to a 45 years old male ALL patient. He had diagnosis of diabetes mellitus and hypertension previously. After high-dose methotrexate infusion, preventive treatments such as adequate hydration and optimal dose folinic acid were given. Initially, the value of creatinine was 0.82 mg/dL. Despite preventive treatment, on the twelfth day of chemotherapy, creatinine value began to increase rapidly and acute renal failure occurred. Creatinine increased to 7.76 mg/dL and he became anuric. Dialysis and adequate supportive treatments were started immediately. He was monitored in the intensive care unit because of worsening of general condition. On the eighth day of acute renal failure the patient’s urine output has begun and septic shock improved during the course. The patient was discharged eventually. Discussion: High-dose methotrexate induced acute renal failure is a rare condition according to the other side effects of methotrexate. This rare side effect, in the presence of underlying predisposing factors may be more frequent and more severe. As in our case, even at normal creatinine values, while applying high-dose methotrexate we believe patients must be monitored closely for toxicity, adequate dose and duration of preventive treatment must be done and if possible dose adjustment would be appropriate especially in the presence of predisposing conditions to renal failure such as diabetes and hypertension.

Challenging the clinical relevance of folinic acid over rescue after high dose methotrexate (HDMTX)

The hypothesisThe use of adequate folinic acid rescue (in clinically relevant doses) after high dose methotrexate will prevent neurotoxicity without reducing treatment results. MethodsA literature search was performed to test the hypothesis that no evidence for the existence of folinic acid over-rescue of high-dose methotrexate (MTX) in clinically relevant situations exists (evidence that too much folinic acid reduced cure rate). Empirical dataExamples of folinic acid over-rescue after lower doses of MTX were found and has been cited as evidence of over rescue of high dose MTX. Mega doses of folinic acid, used when toxic levels of MTX occurred, also could neutralize the MTX effect. Data were found to support the contention that higher levels of MTX require disproportionally higher folinic acid doses for rescue. Careful examination of the available studies after HDMTX yielded more convincing alternative explanations for reduction in cure rate than over rescue. Little convincing evidence for the existence of over rescue after HDMTX was found. DiscussionThe rescue of high-dose MTX with an appropriate dose of folinic acid that can prevent toxicity, especially neurotoxicity, was not shown to reduce the therapeutic effect. No evidence was found that higher doses of folinic acid after high dose MTX reduces the therapeutic effect. Consequences of the hypothesisAcceptance of the hypothesis can prevent harm being caused (especially brain damage) by reversing the trend of dose reduction in FA rescue. The recognition that the use of higher folinic acid doses is safe, can prevent neurotoxicity, and does not reduce prognosis has important implications for the development of effective non toxic treatment protocols.

The Correlation Between Dose of Folinic Acid and Neurotoxicity in Children and Adolescents Treated for Osteosarcoma With High-dose Methotrexate (HDMTX)

This study has been performed to examine the currently used doses of folinic acid (FA) and to determine the importance of the dose of FA in preventing subtle neurotoxicity. Thirty osteosarcoma patients were an appropriate population studied as they have no intrinsic neurological involvement. The neuropsychological and psychosocial status was tested in 2 groups of patients treated with similar protocols containing repeated doses of high-dose methotrexate, but different doses of FA. The patients received 300 to 600 mg/m or 120 to 250 mg/m FA in their protocols. Eighteen tests or subtests of neuropsychological assessment were tested. Eleven of 18 tests were significant at the P=0.025 level favoring the group treated with high dose of FA. There were no clear results in the psychosocial measures with only a single measure of self-esteem (understanding) being significantly higher (P=0.024) in the group treated with high dose of FA, other measures had no statistical significance. A correlation between a higher dose of FA after high-dose methotrexate and a better neuropsychological status was clearly shown. The doses of FA used in the low FA group, 120 to 250 mg/m, were similar to those used by several groups treating children with leukemia; some have used even lower doses and report gross neurotoxicity.

Folinic Acid Supplementation in Higher Doses is Associated with Graft Rejection in Pediatric Hematopoietic Stem Cell Transplantation

Folinic acid is widely used in hematopoietic stem cell transplantation (SCT), mainly to reverse antifolate effects of such drugs as methotrexate and cotrimoxazole but also empirically to reduce toxicity and support hematopoietic recovery. However, concerns have been raised in oncohematology about reduced curative rates associated with folinic acid administration. The clinical impact of folinic acid with regard to graft-versus-host disease (GVHD), relapse, and rejection in pediatric SCT is largely undetermined. In this single-center retrospective study we investigated folinic acid administration in 87 children undergoing SCT between 2007 and 2010. Data on folinic acid dosage and duration were analyzed along with SCT parameters using univariate and multivariate statistics. Folinic acid treatment was not correlated with relapse or GVHD grades ≥ II. However, significantly higher folinic acid doses until day +21 post-SCT had been administered to patients rejecting their grafts (P < .005). In a subanalysis of nonmalignant disease and reduced-intensity conditioning (RIC) SCTs, higher total folinic acid doses were found to be associated with rejection (P = .015 and P = .026). Multivariate analysis identified RIC (odds ratio, 19.9; P < .01) and an early total folinic acid dose of >185 mg/m2 (odds ratio, 11.4; P = .03) as risk factors for graft rejection. Late folinic acid treatment had no impact on relapse, GVHD, and rejection. To conclude, administration of folinic acid in pediatric SCT seems safe in terms of relapse and GVHD. However, it should be carried out with caution, especially in patients with nonmalignant conditions and those receiving RIC to avoid graft rejection.