vitamin-b-12 and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Topics: Child; Humans; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cells, B-Lymphoid; Vitamin B 12

Anemia is a common finding and important cause of morbidity in patients with acute lymphoblastic leukemia (ALL) at diagnosis or during the course of its protracted treatment. We studied profile of anemia in ALL patients on maintenance therapy and evaluated specific micronutrients as cause of this anemia.. ALL patients who were on maintenance therapy and had grade ≥ 2 anemia were recruited for the study. Serum iron studies, folate, and vitamin B12 were done to identify micronutrient deficiency and to initiate supplementation with specific components if found to be deficient. Toxicities, improvement of anemia, micronutrient levels, and disease outcome were studied after 3 months.. From March 2015 to September 2016, 105 ALL patients were found to be on maintenance fulfilling the inclusion criteria. Overall, the proportion of anemia was 80%(N = 84). Majority had normocytic normochromic anemia (71%). Macrocytic anemia was seen in 18% and microcytic hypochromic in 9.5%. In patients with anemia of grade ≥ 2 (N = 84), 38 patients (45%) had biochemical deficiency of serum folate, and 7 (8%) had vitamin B12 deficiency. No biochemical evidence of iron deficiency was found. Supplementation of deficient micronutrients improved anemia: mean hemoglobin significantly increased from 8.06 ± 1.63 to 10.78 ± 1.53 (p < 0.001) at 3 months; and reduced treatment toxicities, mean number of febrile neutropenia episodes (p = 0.007), and treatment interruptions of > 2 weeks (p = 0.002) were lowered. Patients with anemia had significantly more relapses (N = 14,64%) compared to patients without anemia (N = 8,36%), (p = 0.040).. Timely identification and correction of micronutrient deficiencies causing anemia in ALL patients on maintenance can enhance treatment outcomes.

Topics: Adolescent; Adult; Anemia, Macrocytic; Child; Child, Preschool; Dietary Supplements; Female; Folic Acid; Hemoglobins; Humans; Infant; Iron Deficiencies; Male; Micronutrients; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Vitamin B 12; Vitamin B 12 Deficiency; Young Adult

Methotrexate (MTX) is an important anti-folate agent in pediatric acute lymphoblastic leukemia (ALL) treatment. Folinic acid rescue therapy (Leucovorin) is administered after MTX to reduce toxicity. Previous studies hypothesized that Leucovorin could 'rescue' both normal healthy cells and leukemic blasts from cell death. We assessed whether Leucovorin is able to restore red blood cell folate levels after MTX.. We prospectively determined erythrocyte folate levels (5-methyltetrahydrofolate (THF) and non-methyl THF) and serum folate levels in 67 children with ALL before start (T0) and after stop (T1) of HD-MTX and Leucovorin courses.. Erythrocyte folate levels increased between T0 and T1 (mean ± SD: 416.7 ± 145.5 nmol/L and 641.2 ± 196.3 nmol/L respectively, p<0.001). This was due to an increase in 5-methyl THF levels (mean increase: 217.7 ± 209.5 nmol/L, p<0.001), whereas non-methyl THF levels did not change (median increase: 0.6 nmol/L [-9.9-11.1], p = 0.676). Serum folate levels increased between T0 and T1 (median increase: 29.2 nmol/L [32.9-74.0], p<0.001). Results were not significantly affected by age, sex, ALL immunophenotype and MTHFR c.677C>T genotype.. Intracellular folate levels accumulate after HD-MTX and Leucovorin therapy in children with ALL, suggesting that Leucovorin restores the intracellular folate pool. Future studies are necessary to assess concomitant lower uptake of MTX.

Topics: Adolescent; Antidotes; Child; Child, Preschool; Erythrocytes; Female; Folic Acid; Folic Acid Antagonists; Homocysteine; Humans; Infant; Leucovorin; Male; Metabolic Networks and Pathways; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Vitamin B 12

Inadequate maternal folate intake is associated with increased childhood acute lymphoblastic leukemia (ALL) risk. Folate provides methyl groups for DNA methylation, which is dramatically disrupted in ALL. Whether or not maternal folate (and related B-vitamin) intake during pregnancy may affect ALL risk via influencing DNA methylation is investigated.. Genes in which methylation changes are reported both in response to folate status and in ALL are investigated. Folate-responsive genes (n = 526) are identified from mouse models of maternal folate depletion during pregnancy. Using published data, 2621 genes with persistently altered methylation in ALL are identified. Overall 25 overlapping genes are found, with the same directional methylation change in response to folate depletion and in ALL. Hypermethylation of a subset of genes (ASCL2, KCNA1, SH3GL3, SRD5A2) in ALL is confirmed by measuring 20 patient samples using pyrosequencing. In a nested cohort of cord blood samples (n = 148), SH3GL3 methylation is inversely related to maternal RBC folate concentrations (p = 0.008). Furthermore, ASCL2 methylation is inversely related to infant vitamin B12 levels. (p = 0.016).. Findings demonstrate proof of concept for a plausible mechanism, i.e., variation in DNA methylation, by which low intake of folate, and related B-vitamins during pregnancy may influence ALL risk.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Adaptor Proteins, Signal Transducing; Animals; Basic Helix-Loop-Helix Transcription Factors; DNA Methylation; Erythrocytes; Female; Folic Acid; Humans; Infant; Infant, Newborn; Kv1.1 Potassium Channel; Male; Membrane Proteins; Mice, Inbred C57BL; Mothers; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pregnancy; Vitamin B 12

Methotrexate (MTX) is administered to treat childhood acute lymphoblastic leukemia (ALL). It acts by inhibiting dihydrofolate reductase which reduces methyltetrahydrofolate, a key component in one carbon metabolism, thus reducing cell proliferation. Further perturbations to one carbon metabolism, such as reduced vitamin B. MTX treatment alone significantly increased LINE-1 methylation in SH-SY5Y (p = 0.040) and DAOY (p < 0.001), and increased FKBP5 methylation in MO3.13 cells (p = 0.009).. We conclude that altered DNA methylation of brain/central nervous system cells could be one mechanism involved in MTX treatment-related neurotoxicities and neurocognitive late effects in ALL survivors.

Topics: Antineoplastic Agents; Cell Line, Tumor; DNA Methylation; Humans; Long Interspersed Nucleotide Elements; Methotrexate; Neurons; Neurotoxicity Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tacrolimus Binding Proteins; Vitamin B 12

Folate, vitamins B12 and B6, riboflavin, and methionine are critical nutrients for the one-carbon metabolism cycle involved in DNA synthesis and epigenetic processes. We examined the association between maternal intake of these nutrients before pregnancy and risk of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in a matched case-control study.. Maternal dietary intake and vitamin supplement use in the year before pregnancy was assessed by food frequency questionnaire for 681 ALL cases, 103 AML cases, and 1076 controls. Principal component analysis was used to construct a variable representing combined nutrient intake, and conditional logistic regression estimated the odds ratio (OR) and 95% confidence interval (CI) for the association of ALL and AML with the principal component and each nutrient.. Higher maternal intake of one-carbon metabolism nutrients from food and supplements combined was associated with reduced risk of ALL (OR for one-unit change in the principal component = 0.91, CI 0.84-0.99) and possibly AML (OR for the principal component = 0.83, CI 0.66-1.04). When analyzed separately, intake of supplements high in these nutrients was associated with a reduced risk of ALL in children of Hispanic women only.. In conclusion, these data suggest that higher maternal intake of one-carbon metabolism nutrients may reduce risk of childhood leukemia.

Topics: Adolescent; Adult; California; Carbon; Case-Control Studies; Child; Child, Preschool; Dietary Supplements; Energy Intake; Female; Folic Acid; Hispanic or Latino; Humans; Infant; Infant, Newborn; Logistic Models; Male; Maternal Health; Methionine; Odds Ratio; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pregnancy; Prenatal Care; Riboflavin; Risk Factors; Vitamin B 12; Vitamin B 6

Various micronutrients are essential for optimal functioning of the peripheral nervous system. Serum vitamin E, vitamin B12, and folic acid were estimated in childhood acute lymphoblastic leukemia survivors aged between 5 and 18 years in first continuous remission within 3 years of completion of vincristine-based chemotherapy with and without electrophysiologically defined neuropathy. A total of 80 children were studied. Neuropathy was seen in 27 (33.75%) children electrophysiologically. None of the children had vitamin E deficiency. However, the alpha tocopherol/(cholesterol + triglyceride) ratio was significantly lower in children with neuropathy (P = .05). The prevalence of folate (P = .48) and vitamin B12 (P = .21) deficiency in children with and without neuropathy was not significantly different. Thus, the prevalence of deficiencies of these micronutrients was not significantly different in childhood acute lymphoblastic leukemia survivors with or without electrophysiologically defined neuropathy.

Topics: Adolescent; alpha-Tocopherol; Child; Child, Preschool; Female; Folic Acid; Folic Acid Deficiency; Humans; Male; Micronutrients; Peripheral Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prevalence; Survivors; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin E; Vitamin E Deficiency

Topics: Female; Folic Acid; Humans; Induction Chemotherapy; Male; Nutritional Status; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vitamin B 12

Topics: Female; Folic Acid; Humans; Induction Chemotherapy; Male; Nutritional Status; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vitamin B 12

To evaluate pre-treatment undernutrition, and folate and B12 deficiency in children with acute lymphoblastic leukemia, and their correlation with complications and outcome of induction chemotherapy.. Observational study.. Tertiary care teaching hospital in Northern India.. 50 children with acute lymphoblastic leukemia.. Children were assessed for nutritional status (Weight for age Z-score, serum albumin, folate and B12) at presentation, and were followed-up during induction for bone marrow response, counts and outcome. Folate and B12 were repeated twice at monthly intervals after induction. Univariate and multivariate analyses were done to determine the association of nutritional parameters with the outcome variables.. Baseline undernutrition was observed in 66%, hypo-albuminemia in 32.6%, folate deficiency in 41.3% and B12 deficiency in 36.9% of included children. Significant decline in folate levels was noted on serial assays during chemotherapy (P=0.001). Folate deficient children had higher risk for delayed marrow recovery and counts on day 14 (P=0.007 and P=0.001). Hypoalbuminemia (P=0.04), B12 deficiency (P=0.001) and folate (P=0.03) deficiency were associated with toxic deaths during induction.. Baseline nutritional deficiencies negatively influence the outcome and occurrence of complications during induction chemotherapy in children with acute lymphoblastic leukemia.

Topics: Child; Child, Preschool; Female; Folic Acid; Humans; Induction Chemotherapy; Male; Nutritional Status; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein-Energy Malnutrition; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

We investigated whether paternal dietary intake of folate before conception is associated with the risk of childhood acute lymphoblastic leukemia (ALL) in a nationwide case-control study.. Data on dietary folate intake during the 6 months before the child's conception were collected from 285 case fathers and 595 control fathers using a dietary questionnaire. Nutrient intake was quantified using a customized computer software package based on Australian food composition databases. Data on folate intake were analyzed using unconditional logistic regression, adjusting for study-matching variables, total energy, and potentially confounding variables. In a subset of 229 cases and 420 controls, data on vitamin B6 and vitamin B12 intake were also analyzed.. No consistent associations were seen with paternal dietary intake of folate or vitamin B6. Higher levels of paternal dietary vitamin B12 were appeared to be associated with an increased risk of childhood ALL, with those in the highest tertile of consumption having an OR of 1.51 (0.97, 2.36). The use of supplements containing folate and vitamins B6 or B12 was rare.. We did not find any biologically plausible evidence that paternal nutrition in the period leading up to conception was associated with childhood ALL. Our finding for vitamin B12 may be a chance finding, given the number of analyses performed, or be attributable to participation bias because parents with a tertiary education had the lowest level of B12 intake and tertiary education was more common among control than case parents.

Topics: Adolescent; Adult; Australia; Case-Control Studies; Child; Child, Preschool; Diet; Dietary Supplements; Fathers; Female; Folic Acid; Humans; Infant; Infant, Newborn; Logistic Models; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Surveys and Questionnaires; Vitamin B 12; Vitamin B 6; Vitamin B Complex

Our aim was to address the hypothesis that maternal dietary intake of folate during pregnancy is inversely associated with risk of acute lymphoblastic leukemia (ALL) in the offspring. Dietary intake of folate, vitamins B6 and B12 in the last 6 mo of pregnancy from 333 cases and 695 frequency-matched controls were assessed using a food frequency questionnaire. Data were analyzed using unconditional logistic regression, adjusting for study matching variables, total energy, and potentially confounding variables. Higher levels of dietary folate and B12 appeared to be associated with a decreased risk of ALL. Higher levels of vitamin B6 were associated with an increased risk. The strongest associations of ALL with these variables were seen when mothers consumed alcohol in pregnancy. Our findings are consistent with a modest protective effect of higher dietary intake of folate and vitamin B12 against ALL in the offspring, more particularly among women who drank alcohol during pregnancy. These findings are consistent with previous reports of the protective effects of a maternal diet high in fruit, vegetables, and nondairy protein sources. The vitamin B6 findings are not consistent with evidence that it is a protective factor against other cancers, and may be a chance finding.

Topics: Acute Disease; Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; Diet; Female; Folic Acid; Humans; Infant; Logistic Models; Maternal Nutritional Physiological Phenomena; Nutrition Assessment; Odds Ratio; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pregnancy; Prospective Studies; Risk Factors; Surveys and Questionnaires; Vitamin B 12; Vitamin B 6

This study aims to identify folate-metabolism-related genetic risk factors for low bone mineral density (BMD) during/after pediatric acute lymphoblastic leukemia (ALL) treatment.. We investigated the influence of methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C) and methionine synthase reductase (MTRR 66A > G) single nucleotide polymorphisms (SNPs) on total body BMD (BMD(TB)) and lumbar spine BMD (BMD(LS)) in 83 patients. Homocysteine, folate and vitamin B12 were determined. BMD was measured repeatedly using dual-energy X-ray absorptiometry in patients ≥ 4 years (n = 68).. Carriers of the MTHFR 677 T-allele showed a lower baseline BMD(TB) than non-carriers (-0.38 SDS vs. +0.55 SDS, p = 0.01) and BMD(TB) remained lower during/after treatment. MTHFR 677C>T did not influence treatment-related loss of BMD(TB) (p = 0.39). The MTRR 66 G-allele carriers showed a trend towards a lower BMD(TB) compared with non-carriers. Combining these two SNPs, patients carrying ≥ 2 risk alleles had a significantly lower BMD(TB) (-1.40 SDS) than patients with one (-0.80 SDS) or no risk alleles (-0.31 SDS). Although carriers of the MTHFR 1298A > C had higher homocysteine levels, this SNP was not related to BMD(TB). BMD(LS) of carriers was similar to non-carriers of the investigated SNPs.. The MTHFR 677C>T SNP and the MTRR 66A >G SNP were identified as determinants of impaired BMD(TB) in childhood ALL patients.

Topics: Absorptiometry, Photon; Adolescent; Biomarkers, Tumor; Bone Density; Case-Control Studies; Child; Child, Preschool; Ferredoxin-NADP Reductase; Folic Acid; Fractures, Bone; Genotype; Germ Cells; Homocysteine; Humans; Infant; Methylenetetrahydrofolate Reductase (NADPH2); Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Vitamin B 12

Topics: Autistic Disorder; Biological Transport; Brain; Cognition Disorders; District of Columbia; Folic Acid; Genomic Instability; Humans; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, N-Methyl-D-Aspartate; Vitamin B 12

The cause of majority of acute leukemias is unknown, but likely to involve interaction of environment, hematopoitic development and weak susceptibility loci within an individual's genetic constitution. The present study evaluates the association between plasma levels of homocysteine, folate and vitamin B12 and acute lymphoblastic leukemia.. Plasma levels of homocysteine, folate and vitamin B12 were compared between cases of acute lymphoblastic leukemia and age and sex matched normal controls. Homocysteine levels were measured by solid immunoassay, while folate and vitamin B12 levels were determined by radioassay.. Folate levels were significantly among cases as compared to control group (8.56 +/- 4.35) vs (14.04 +/- 2.62) ng/ml, P< 0.001). Although individually vitamin B12 and homocysteine were not significant different between cases and controls, the combined effect of all three parameters was significantly different (P< 0.001), with 83.3% of correct classification of cases and controls was obtained by discriminate function analysis.. The data provide evidence for the role of folate, vitamin B12 and homocysteine levels in acute lymphoblastic leukemia, suggesting that gene-environment interaction may be an important factor in the development of acute lymphoblastic leukemia.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Discriminant Analysis; Female; Folic Acid; Homocysteine; Humans; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vitamin B 12

Vacuolar myelopathy (VM) in leukemia is rare. We report a boy with leukemia who developed isolated central nervous system (CNS) relapse during reinduction therapy. 5 months after cranial radiotherapy, he gradually developed quadriparesis. Magnetic resonance imaging revealed an intramedullary lesion which extended through the cervical spine. Serum vitamin B12, folic acid, cerebrospinal fluid methyl malonic acid were normal. Viral screening by ELISA was negative. He had lymphopenia, and reduced immunoglobulins, from a cardiac arrest. Biopsy revealed VM. He responded to weekly vitamin B12 treatment but on the 6th week of the therapy he died after developing periventricular, gliotic, hyperintense lesions in the brain.

Topics: Central Nervous System Neoplasms; Child; Humans; Magnetic Resonance Imaging; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Spinal Cord Diseases; Vitamin B 12

To evaluate the influence of pretreatment plasma folate concentrations on methotrexate exposure in children with acute lymphoblastic leukemia/non-Hodgkin lymphoma treated with high-dose methotrexate, we assessed time profiles of plasma homocysteine, folate, and vitamin B(12) concentrations in children treated with high-dose methotrexate with leucovorin rescue.. We analyzed 98 treatment courses. The study endpoints were to determine how methotrexate exposure is related to homocysteine accumulation and whether it is influenced by pretreatment plasma folate.. Peak concentrations of homocysteine increased from the start of the intravenous infusion through cessation of methotrexate therapy up to time point t(42), when this trend was reversed by administration of folinic acid. The area under the curve (AUC) for plasma homocysteine showed decreasing course-to-course tendencies with a statistically significant decrease only between courses 1 and 2 (P 10 nmol/L. Correspondingly, in the courses with low initial folate, peak plasma concentrations of methotrexate were significantly higher than in courses with high precourse concentrations of plasma folate.. Endogenous pretreatment plasma folate modulates the magnitude of the methotrexate effect, providing support for a "folate overrescue" concept.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Folic Acid; Homocysteine; Humans; Infant; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vitamin B 12; Vitamin B Complex

The effects of methotrexate (inhibiting dihydrofolate reductase) and nitrous oxide (inactivating methionine synthase) on intracellular folate coenzyme levels of leukemic cells were studied. Blast cells from 10 cases of acute myeloid leukemia (AML) and 5 cases of acute lymphoid leukemia (ALL) were incubated with 5 x 10(-8) M [3H] 5-formyltetrahydrofolate (5-formylTHF) for 18 h to label intracellular folate pools, which were subsequently quantitated by high performance liquid chromatography (HPLC). In AML, 5-methylTHF made up 53% of the total folate pool followed by 10-formylTHF (26%), 5-formylTHF (10%), THF (9%) and DHF (1%). Cells from ALL differed from AML (p less than 0.05) with respect to 10-formylTHF (17%) and DHF (10%). Exposure to nitrous oxide (8 h) caused an equal decrease of 10-formylTHF and 5-formylTHF in both AML (30%) and ALL (45%), whereas 5-methylTHF increased (130%). Methotrexate (4 h, 10(-6) M) caused an accumulation of DHF and a decrease of 5-methylTHF in both AML (32%) and ALL (12%). A specific reduction of the 10-formylTHF (50%) and 5-formylTHF (25%) pools was noticed in ALL. Exposure to nitrous oxide prior to methotrexate treatment aggravated the reduction of 10-formylTHF and 5-formylTHF presumably by impaired replenishment from the 5-methylTHF pool. In conclusion, this study demonstrates a significant difference in folate coenzyme distribution between cells from AML and ALL. Moreover it is shown that nitrous oxide and methotrexate treatment of leukemic cells cause an accumulation of 5-methylTHF and DHF respectively at the expense of other folate forms. The presence of substantial amounts of DHF in cells from ALL together with the specific reduction of 10-formylTHF (necessary for purine synthesis) during MTX treatment may in part explain the efficacy of methotrexate in the treatment of ALL.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Enzyme Activation; Folic Acid; Folic Acid Antagonists; Humans; Leukemia, Myeloid, Acute; Methotrexate; Nitrous Oxide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured; Vitamin B 12