levoleucovorin and Pancytopenia

To conduct a systematic literature review and meta-analysis to estimate the incidence of anaemia, leucopoenia, neutropenia and thrombocytopenia associated with MTX plus folic acid among patients with rheumatic diseases.. We searched MEDLINE, PubMed and EMBASE through August 2016 for all randomized controlled clinical trials with a MTX monotherapy arm. We excluded randomized controlled clinical trials for cancer and included only double-blind studies that reported on haematologic adverse events. Studies were excluded if patients did not receive folic acid or leucovorin supplementation. Full text articles were assessed by two independent reviewers. Incidence estimates were calculated using random-effects models.. Of 1601 studies identified, 30 (1.87%) were included, representing 3858 patients; all had RA. Seventeen trials reported on anaemia (n = 2032), 17 reported on leucopoenia (n = 2220), 16 reported on neutropenia (n = 2202) and 12 reported on thrombocytopenia (n = 1507). The incidence for any anaemia was 2.55% (95% CI 0.60-5.47%), any leucopoenia 1.17% (95% CI 0.16-2.80%), any neutropenia 1.77% (95% CI 0.33-4.00%), and any thrombocytopenia 0.19% (95% CI 0.00-0.86%). Four cases of severe anaemia were reported, as defined by authors, along with three cases of severe neutropenia. No cases of severe leucopoenia, severe thrombocytopenia or pancytopenia were reported.. Cytopenias are an uncommon side effect of low-dose MTX with folic acid supplementation among RA patients. Further research is needed to reach a more precise estimate.

Topics: Anemia; Antirheumatic Agents; Arthritis, Rheumatoid; Folic Acid; Humans; Leucovorin; Leukopenia; Methotrexate; Neutropenia; Pancytopenia; Randomized Controlled Trials as Topic; Rheumatic Diseases; Severity of Illness Index; Thrombocytopenia; Vitamin B Complex

Intoxication by pyrimethamine is rare compare to these of patients who ingest a massive dose of amino-4-quinoleine. Clinic manifestations can be delayed and they are specially based on haematologic disorder as shown by literature data. Others organs can be concerned. The authors would like to present the case of a patient with a severe pancytopenia accompanied with: ocular blow like hyperhaemia of conjunctiva then iris siderosis. skin attack as Gũnther's disease. Etiologic treatment by folinic acid is the only deduction. Recovery is complete.

Topics: Acute Disease; Adult; Antidotes; Antimalarials; Conjunctival Diseases; Folic Acid Antagonists; Humans; Hyperemia; Hyperpigmentation; Iris Diseases; Leucovorin; Male; Pancytopenia; Porphyria, Erythropoietic; Pyrimethamine; Siderosis

Methotrexate is an anticancer drug from the antimetabolite class. It is also used in gynecology and obstetrics and is the molecule of choice for the medical treatment of ectopic pregnancies. We report a case of toxidermia associated with severe pancytopenia induced by methotrexate for ectopic pregnancy.. A 30-year-old Malagasy (African) woman was admitted to the Emergency and Intensive Care Department for probable toxidermia following injection of 75 mg of methotrexate for an ectopic pregnancy. She had developed generalized erythema, which started 48 hours after the injection. The secondary onset of phlyctenular maculopapular skin lesions, generalized purpura, and erosions of the oral mucosa in a context of febrile jaundice prompted her hospitalization. On admission, the patient presented with febrile neutropenia, pancytopenia, renal failure, and hepatic cytolysis. She received transfusions of fresh whole blood, erythromycin, and amphotericin B. The course was fatal within 2 days of hospitalization. The patient died of multiple organ failure.. Our case is mainly distinguished by the lack of use of granulocyte growth factors and folinic acid. In the event of severe reactions to methotrexate, the management should be multidisciplinary and as much as possible within an intensive care unit.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Leucovorin; Methotrexate; Pancytopenia; Pregnancy; Pregnancy, Ectopic

Topics: Adult; Antidotes; Drug-Related Side Effects and Adverse Reactions; Early Diagnosis; Hemorrhage; Humans; Immunosuppressive Agents; Leucovorin; Male; Methotrexate; Mucous Membrane; Pancytopenia; Psoriasis; Skin; Treatment Outcome; Withholding Treatment

Topics: Autoimmune Diseases; Blood Cell Count; Bone Marrow; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Interactions; Folic Acid; Humans; Leucovorin; Lung Injury; Medication Errors; Methotrexate; Pancytopenia; Risk Factors

Methotrexate toxicity in mucocutaneous areas is usually not associated with tissue eosinophilia. We describe a case of acute methotrexate-induced mucocutaneous erosions with interface dermatitis and eosinophils. A 76-year-old African-American woman with a history of bullous pemphigoid on methotrexate therapy presented with lower extremity cellulitis, developing oral and cutaneous erosions during hospitalization after daily dosage of methotrexate. Shallow circular cutaneous erosions were found on chest, abdomen and limbs. Laboratory results showed pancytopaenia and elevated liver function tests. Skin biopsy revealed irregular acanthotic epidermis with interface dermatitis, individual dyskeratotic cells and superficial perivascular lymphocytic infiltrate with numerous eosinophils. Methotrexate was stopped and leucovorin was administered, leading to improvement. The histopathological changes in acute mucocutaneous toxicity range from pauci-inflammatory erosions with dyskeratotic keratinocytes to interface dermatitis and infrequently seen eosinophils. This case exemplifies that interface dermatitis with a marked eosinophilic infiltrate can be found in the setting of acute mucocutaneous methotrexate toxicity.

Topics: Aged; Drug Eruptions; Eosinophilia; Female; Humans; Leucovorin; Methotrexate; Mouth Mucosa; Pancytopenia; Pemphigoid, Bullous; Treatment Outcome

Topics: Aged; Anti-Bacterial Agents; Exanthema; Febrile Neutropenia; Female; Folic Acid; Humans; Leucovorin; Methotrexate; Necrosis; Pancytopenia; Rheumatic Fever; Skin; Stomatitis

Low-dose methotrexate (ld-MTX) that is administered during rheumatoid arthritis (RA) treatment has hematological adverse effects such as pancytopenia, although rare. Although well-established and widely used for hematological adverse effects caused by high-dose MTX, leucovorin (folinic acid) treatment does not have an agreed-upon administration for ld-MTX-induced pancytopenia. Here, we aimed to figure out whether there was any difference in response time between the regimens with and without folinic acid prescribed to our patients who developed pancytopenia while on MTX therapy, and to identify risk factors for its development. Our cases were collectively assessed together with other rare cases available in the literature that were reported in a similar manner with an explicitly indicated response time, in days. Thereupon, we looked for any difference in response time between the regimens with and without folinic acid. In total, ten of our patients experienced pancytopenia while on ld-MTX treatment. Mean day on which hematological response was achieved was as follows: 7 days in one patient on folic acid monotherapy, 6 days in three patients on granulocyte-colony stimulating factor (G-CSF) monotherapy, 4.5 days in two patients on leucovorin monotherapy, and 4 days in the remaining three patients who were treated with G-CSF + folinic acid/leucovorin. When we collectively evaluated our patients and the patients with an explicitly stated response duration in the literature (15 patients) and compared regimens including folinic acid to those without folinic acid, duration until response/recovery from pancytopenia was significantly shorter in folinic acid group than that in the group without folinic acid (5.47 ± 2.9 days vs 10 ± 3.77 days, p = 0.002). Treatment modalities including folinic acid (leucovorin) either with or without G-CSF result in a shorter recovery/response time compared to other agents. Leucovorin should definitely be considered and applied in rescue therapy for ld-MTX-associated side effects.

Topics: Aged; Aged, 80 and over; Antirheumatic Agents; Arthritis, Rheumatoid; Disease Management; Female; Folic Acid; Granulocyte Colony-Stimulating Factor; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Pancytopenia; Retrospective Studies; Rheumatology

We report a case of a 79-year-old man who developed severe therapy-related pancytopenia from tegafur uracil(UFT)and Leucovorin(LV)as adjuvant chemotherapy for ascending colon cancer. Laparoscopic right hemicolectomy resection was performed for the ascending colon cancer. Pathohistological analysis revealed that the ascending colon tumor was moderately differentiated tubular adenocarcinoma(T3, N1, M0, and Stage III a). Postoperative adjuvant chemotherapy with UFT and LV was administered. After 2 courses of chemotherapies, severe thrombocytopenia(Grade 4)and neutropenia(Grade 4)were noted. Platelet and granulocyte-colony stimulating factor(G-CSF)were transfused. Furthermore, red blood cell transfusions were given for anemia(Grade 3). Dihydropyrimidine dehydrogenase(DPD)deficiency was suspected as the cause of the pancytopenia, and the ratio of dihydrouracil(DHU)and uracil(URA)was measured. However, the result was negative for DPD deficiency. Bone marrowaspiration revealed that therapy-related leukemia(TRL)and therapy-related myelodysplastic syndrome(T-MDS)were not the causes of the pancytopenia either. A total of 230 units of platelet transfusions and 20 units of red blood cell transfusions have been given for 32 weeks, and the patient currently requires routine blood transfusions. Fortunately, infection and bleeding never occurred. Subsequently, the patient should be monitored carefully.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colon, Ascending; Colonic Neoplasms; Granulocyte Colony-Stimulating Factor; Humans; Leucovorin; Male; Pancytopenia; Platelet Transfusion; Tegafur

Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease.

Topics: Amino Acid Metabolism, Inborn Errors; Amino Acid Sequence; Anemia, Megaloblastic; Base Sequence; Biopterins; Brain; Female; Folic Acid; Folic Acid Deficiency; Humans; Infant; Leucovorin; Magnetic Resonance Imaging; Male; Models, Molecular; Molecular Sequence Data; Pancytopenia; Pedigree; Protein Conformation; Sequence Homology, Amino Acid; Tetrahydrofolate Dehydrogenase

In addition to the well-known signs of methotrexate toxicity, rare cutaneous side effects have been described. These cutaneous signs may provide a diagnostic clue into the diagnosis of toxicity as well as facilitate early and aggressive therapy. We describe the case of a 37-year-old male, with a diagnosis of psoriasis, who developed characteristic signs and symptoms of acute methotrexate toxicity after receiving an unknown amount of intravenous methotrexate. The patient experienced a distinct change in the morphology of his existing psoriatic plaques, which became ulcerated and necrotic in the week following the methotrexate injection. Shortly after the development of cutaneous erosions, the patient developed pancytopenia, which ultimately led to his death. Ulceration and necrosis of cutaneous psoriasis plaques may serve as a herald for the impending development of life-threatening pancytopenia in patients with acute methotrexate toxicity.

Topics: Acute Kidney Injury; Adult; Azithromycin; Biopsy; Fatal Outcome; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Leucovorin; Male; Methotrexate; Mucositis; Necrosis; Pancytopenia; Plasma; Psoriasis; Recombinant Proteins; Self Medication; Skin Ulcer; Trimethoprim, Sulfamethoxazole Drug Combination

Pancytopenia is a rare but serious adverse effect of low-dose methotrexate (MTX) sodium therapy, and this case report describes a very early-onset of pancytopenia and cutaneous lesions after three days of ingestion. A 64-year-old man was presented to Emergency Department with weakness, fever, poor appetite, nausea, and vomiting after he had had accidentally ingested MTX tablets (2.5 mg) twice a day for the last three days. On initial examination, several painful lesions in his oral mucosa and a cutaneous ulceration on his right foot were also observed. He had severe pancytopenia, poor kidney functions, and abnormal coagulation parameters. The blood level of MTX was found to be within therapeutic range. He was treated with leucovorine, intravenous antibiotics, and appropriate blood transfusions; he was discharged from hospital without any sequela. Pancytopenia associated with low-dose (cumulative dose of 15 mg in 3 days) MTX therapy had not been reported previously. The Naranjo probability scale showed pancytopenia and skin ulcer associated with low-dose MTX therapy as probable adverse reactions. Risk factors for pancytopenia such as renal insufficiency, hypoalbuminemia, low folate levels, concomitant infections, concomitant use of drugs, and folate supplementation were not identified in our patient. Although pancytopenia associated with low-dose MTX therapy is not expected as early as 3 days after initiation of the therapy, physicians should also be aware of this life threatening adverse effect during the very first days of MTX therapy for rheumatoid arthritis patients.

Topics: Anti-Bacterial Agents; Antirheumatic Agents; Blood Transfusion; Dose-Response Relationship, Drug; Humans; Injections, Intravenous; Leucovorin; Male; Methotrexate; Middle Aged; Pancytopenia; Skin Ulcer; Vitamin B Complex

We report on a case of methotrexate (MTX) intoxication occurring in a 19-year-old man treated for a leukemia. Exchange-transfusion (ET) was performed in attempt to remove the MTX from the body. This exchange-transfusion was unable to decrease the MTX plasma concentration. This inefficacy of ET in MTX intoxication is in contradiction with previously reported recommendations. However, this result is easily explained by MTX pharmacokinetics parameters.

Topics: Acute Kidney Injury; Adult; Antidotes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Diuretics; Drug Overdose; Exchange Transfusion, Whole Blood; Furosemide; Humans; Leucovorin; Male; Methotrexate; Pancytopenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Failure

Topics: Adult; Anesthesia, Obstetrical; Cesarean Section; Female; Folic Acid Deficiency; Humans; Leucovorin; Pancytopenia; Pregnancy; Pregnancy Complications, Hematologic

To determine which risk factors are associated with serious pancytopenia associated with low dose methotrexate (MTX) therapy.. All Ottawa area rheumatologists, hematologists and dermatologists were surveyed to obtain cases of pancytopenia associated with low dose MTX therapy between 1981 and 1991. Pancytopenia was defined as white blood cells < 3.5 x 10(9)/l and platelets < 140 x 10(9)/l and hemoglobin < 100 g/l. A case control method was used to evaluate risk factors.. Fifteen cases of pancytopenia were identified from returned questionnaires (93% response rate) and from reviewing the medical records of 2 major teaching hospitals. All patients were hospitalized, had MTX therapy discontinued and were treated: 12 patients received transfusions, 8 leucovorin therapy, and 4 folic acid. Two patients died, only 1 directly due to MTX therapy. Identified risk factors were (1) elevated BUN or creatinine levels, (2) increasing mean corpuscular volume values, (3) increased age and (4) concomitant trimethoprim-sulfamethoxazole therapy.. Pancytopenia associated with low dose MTX therapy is a life threatening adverse effect often associated with known risk factors. A change in monitoring guidelines and patient education are suggested as means of risk reduction.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Arthritis, Psoriatic; Arthritis, Rheumatoid; Blood Urea Nitrogen; Canada; Creatinine; Dose-Response Relationship, Drug; Female; Folic Acid; Health Surveys; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Pancytopenia; Psoriasis; Risk Factors; Surveys and Questionnaires; Trimethoprim, Sulfamethoxazole Drug Combination

An AIDS patient with cerebral toxoplasmosis had a folate deficiency-induced acute pancytopenia, which was rapidly reversed by the administration of folic acid. This observation is particularly important as a possible preventive therapy to be given to all HIV-infected patients because of the anti-folic activity of the majority of anti-infectious agents used during the course of this disease and the many potential sites of hematopoietic involvement. The patient's condition is stressed because the undernourished subject is at greater risk for this type of manifestation.

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Adult; Brain Diseases; Folic Acid Antagonists; Folic Acid Deficiency; HIV-1; Humans; Leucovorin; Male; Pancytopenia; Pyrimethamine; Toxoplasmosis

Agranulocytosis and aplastic anaemia associated with sulphasalazine are well recognised, but pancytopenia caused by acute megaloblastic arrest of haemopoiesis while taking sulphasalazine has not previously been described. We report three patients who, after taking sulphasalazine for over two years, suddenly developed severe pancytopenia with gross megaloblastic changes in the marrow. In two patients there was a good response to high dose oral folic acid but the third required folinic acid. The mechanism appears to be acute folate deficiency, and the requirement for folinic acid in one case suggests that the known inhibition of folate metabolism by sulphasalazine also contributes. The syndrome appears to be associated with high dosage and slow acetylator status. The drug has been successfully restarted at reduced dosage with folate supplements in two patients both of whom were slow acetylators. In the third case, whose acetylator status is not known, progression of her disease led to colectomy.

Topics: Adolescent; Adult; Bone Marrow; Female; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Male; Pancytopenia; Sulfasalazine

Topics: Abscess; Breast Diseases; Cough; Drug Combinations; Erythrocytes; Erythrocytes, Abnormal; Female; Folic Acid; Folic Acid Antagonists; Humans; Leucovorin; Megaloblasts; Methotrexate; Middle Aged; Neutrophils; Pancytopenia; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Low dose pulse MTX was associated with the development of pancytopenia in six patients with RA. Two patients died. Factors implicated in the occurrence of this complication were renal impairment in five patients, medication errors by two patients, preexisting marrow injury from occult alcoholism in one patient, and an apparent idiosyncratic reaction to the drug in another. Medication errors were associated with the use of five or more medications, and the unusual schedule of administration of low dose MTX may also have been contributory. From a consideration of the clinical pharmacokinetics of MTX, we suggest other factors that may predispose to the occurrence of marrow toxicity: the presence of hypoalbuminemia, interactions between MTX and other protein bound or weakly acidic drugs, and the repetitive dosing schedule of low dose MTX. Based on our experience, patients with impaired renal function (creatinine greater than or equal to 2.0 mg/dL) should not receive MTX. Renal function should be monitored regularly during treatment with MTX, and blood counts should be observed carefully if a new drug is added or substituted. A 5 mg test dose of MTX before initiating weekly therapy may identify patients with severe hypersensitivity to the drug. The potential risks of using MTX in a patient unwilling to accept blood products should be acknowledged and discussed with the patient. Furthermore, we recommend the use of leucovorin if pancytopenia occurs, even if low or undetectable serum levels of MTX are present.

Topics: Adult; Aged; Arthritis, Rheumatoid; Bone Marrow; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Pancytopenia; Risk

Seventy-two patients with neoplastic disease in a variety of anatomic sites were treated with sequential methotrexate (MTX) and 5-fluorouracil (5-FU) followed by leucovorin (LV) rescue. Treatment consisted of MTX, 160 mg/m2 as a 10-min infusion; 5-FU, 600 mg/m2 as a bolus 90 min later; and LV, a minimum of 25 mg/m2 or 15 mg/m2 p.o. q.6h. X 4, repeated at 1- or 2-wk intervals. Responses of any type included 4 of 24 colon cancers, 3 of 12 stomach cancers, 0 of 6 pancreas cancers, 1 of 2 gallbladder cancers, 4 of 6 breast cancers, 1 of 1 uterus cancer, 2 of 2 selected lung cancers, 1 of 1 parotid cancer, 1 of 2 sarcomas, and 0 of 6 ovary cancers. Response appeared to increase survival. The best-quality responses were observed in patients with stomach, breast, and parotid tumors. Toxicities included anemia requiring transfusion (20%), anorexia during treatment with LV (16%), moderate thrombocytopenia (12%), grade 3 stomatitis (12%), moderate granulocytopenia (10%), severe conjunctivitis (6%), severe gastroenteritis (6%), vomiting (6%), anamnestic reactions (6%), possible renal failure (4%), and possible pulmonary failure (2%). One patient had life-threatening gastroenteritis and reappearance of a grade 1 to 2 skin reaction of the entire treatment field more than 5 yr after radiotherapy. Patients with prior cis-platin therapy had a 50% risk of life-threatening pancytopenia. The results encourage controlled primary trials testing intensification of the sequential combinations with parallel investigations of MTX alone with and without diminished doses of LV.

Topics: Aged; Anemia; Conjunctivitis; Drug Evaluation; Drug Therapy, Combination; Fluorouracil; Gastrointestinal Neoplasms; Humans; Intestinal Obstruction; Leucovorin; Methotrexate; Pancytopenia; Probability; Stomatitis

Topics: Female; Humans; Leucovorin; Liver Cirrhosis; Middle Aged; Pancytopenia; Triamterene

Topics: Aminopterin; Anemia, Aplastic; Biomedical Research; Bone Marrow; Folic Acid; Leucovorin; Pancytopenia