mercaptopurine and Lymphopenia

The first and second Medical Research Council UKALL trials have shown that alteration in the timing of methotrexate and 6-mercaptopurine maintenance therapy for the treatment of acute lymphoblastic leukaemia can markedly change drug induced toxicity. Maintenance chemotherapy in both trials used a similar total dosage of these drugs but the timing of their administration was different in the two schedules.

Topics: Child; Child, Preschool; Drug Therapy, Combination; Humans; Infant; Infant, Newborn; Leukemia, Lymphoid; Leukocyte Count; Lymphocytes; Lymphopenia; Mercaptopurine; Methotrexate; Neutropenia; Neutrophils; Remission, Spontaneous; Time Factors

The thiopurine drugs, 6-mercaptopurine and azathioprine, remain the mainstay of immunomodulator therapy for inflammatory bowel disease (IBD). Optimal management depends on achieving therapeutic levels of 6-thioguanine (6-TGN), but measuring thiopurine metabolites is associated with significant cost. Thiopurines cause lymphopenia and an increase in mean corpuscular volume (MCV). It is unclear whether any clinically useful correlation exists between 6-TGN levels and lymphocyte count or MCV.. The aim of this study is to investigate the correlation between 6-TGN levels and lymphocyte count and MCV in thiopurine-treated patients with IBD.. We analysed a prospectively acquired database of 67 patients with IBD treated with thiopurine therapy. The data were analysed looking at the relationship between 6-TGN levels and both lymphocyte count and MCV by using the Spearman's rank correlation coefficient.. Twenty-seven (40%) patients had therapeutic 6-TGN levels. Thirty-three (49%) patients had sub-therapeutic 6-TGN levels. A weak positive correlation between 6-TGN levels and lymphocyte count was demonstrated, but this was not statistically significant (Spearman's R = 0.14, P = 0.23). Spearman's rank correlation coefficient between 6-TGN levels and MCV was statistically significant (R = 0.42, P = 0.0005). MCV >101 fL excluded a subtherapeutic 6-TGN level with positive predictive value of 92%.. There is no specific lymphopenia that can be assumed to indicate a therapeutic 6-TGN level. The relationship between 6-TGN levels and MCV is likely to be clinically relevant. If MCV is elevated, 6-TGN is unlikely to be sub-therapeutic. MCV is a potential surrogate marker which can rule out sub-therapeutic thiopurine metabolites in patients with IBD treated with azathioprine or 6-mercaptopurine.

Topics: Adult; Azathioprine; Biomarkers; Erythrocyte Indices; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphopenia; Male; Mercaptopurine; Retrospective Studies; Thioguanine; Treatment Outcome

To assess the incidence of hemophagocytic lymphohistiocytosis (HLH) in a well-defined population of children with inflammatory bowel disease (IBD) and evaluate the common clinical and laboratory characteristics of individuals with IBD who developed HLH.. We conducted a retrospective study of all children who developed HLH over an 8-year period. The incidence of HLH in patients with IBD was calculated using US census data and a statewide project examining the epidemiology of pediatric IBD.. Among children in Wisconsin, 20 cases of HLH occurred during the study period; 5 cases occurred in children with IBD. Common characteristics include: Crohn's disease (CD), thiopurine administration, fever lasting more than 5 days, lymphadenopathy, splenomegaly, anemia, lymphopenia, and elevated serum triglycerides and ferritin. Of the patients, 4 had primary Epstein-Barr virus infections. The incidence of HLH among all children in Wisconsin was 1.5 per 100 000 per year. The risk was more than 100-fold greater for children with CD (P < .00001).. Pediatric patients with CD are at increased risk for developing HLH; primary Epstein-Barr virus infection and thiopurine administration may be risk factors.

Topics: Adolescent; Anemia; Azathioprine; Crohn Disease; Epstein-Barr Virus Infections; Ferritins; Fever; Humans; Immunosuppressive Agents; Incidence; Lymphatic Diseases; Lymphohistiocytosis, Hemophagocytic; Lymphopenia; Mercaptopurine; Retrospective Studies; Splenomegaly; Triglycerides; Wisconsin

Myelosuppression occurs in 2-7% of inflammatory bowel disease (IBD) patients treated with azathioprine, and can be associated with reduced activity of thiopurine methyltransferase (TPMT) in some patients. It has been proposed that pretreatment assessment of TPMT status reduces the incidence of toxicity and is cost-effective.. To determine if screening for TPMT status predicts side-effects to azathioprine in patients with IBD and to ascertain whether screening by TPMT enzyme activity or genotype is superior.. Sequential IBD patients were identified and azathioprine tolerance recorded. Blood was collected for measurement of TPMT activity and TPMT*3C, TPMT*3A and TPMT*2 genotypes.. Of 130 patients, 25% stopped azathioprine because of toxicity. Four patients experienced severe myelosuppression (WCC < 2). Eleven of 17 patients with reduced TPMT activity were heterozygotes, including one patient with marked TPMT deficiency who experienced severe myelosuppression. There was no association between intermediate TPMT deficiency and any side-effect.. Moderate reduction of TPMT activity in heterozygotes was not associated with toxicity, but very low TPMT activity caused severe myelosuppression in one patient. This would have been predicted by measuring TPMT activity but not by genotyping. Measurement of TPMT activity may therefore be superior to genotype in predicting severe myelosuppression.

Topics: Clinical Enzyme Tests; Cost-Benefit Analysis; Female; Gastrointestinal Agents; Genetic Techniques; Genotype; Humans; Inflammatory Bowel Diseases; Lymphopenia; Male; Mass Spectrometry; Mercaptopurine; Methyltransferases; Polymerase Chain Reaction; Sensitivity and Specificity

Lymphopenia induced by treatment for acute lymphoblastic leukaemia is analysed and discussed in relation to the type and incidence of infection occurring in those patients during complete remission. Blood lymphocytes can be placed into three largely independent groups: (1) those lymphocytes susceptible to long-term depletion following irradiation; (2) those lost from the blood during and for a short period after maintenance chemotherapy with methotrexate and 6-mercaptopurine; and (3) the remainder which are not depleted by irradiation or maintenance chemotherapy. The number of cells in each compartment varies from child to child and probably with age but on average is about 1.2 x 10(9)/1. for group 1, 0.7 x 10(9)/1. for group 2 and 0.4 x 10(9)/1. for group 3. Conventional lymphocyte typing crosses these barriers in that: Group 1 consists mainly of E-rosetting cells and cells which show a mitotic response to phytohaemagglutinin; Group 2 also contains E-rosetting cells but contains a major proportion of blood lymphocytes with surface immunoglobulin and essentially all antibody dependent cytotoxic lymphocyte (K-cell) activity; Group 3 comprises E-rosetting cells and a few immunoglobulin-staining cells.

Topics: Antimetabolites, Antineoplastic; Humans; Immunosuppression Therapy; Leukemia, Lymphoid; Lymphocytes; Lymphopenia; Mercaptopurine; Methotrexate; Radiation Injuries; Radiotherapy

Topics: Acute Disease; BCG Vaccine; Central Nervous System Diseases; Humans; Immunosuppression Therapy; Immunotherapy; Leukemia, Lymphoid; Leukocyte Count; Lymphocytes; Lymphopenia; Mercaptopurine; Methotrexate; Neutropenia

Topics: Animals; Antibody Formation; Antilymphocyte Serum; Erythrocytes; Hydrocortisone; Immunosuppressive Agents; Lymphopenia; Male; Mercaptopurine; Mice; Rabbits; Sheep; Skin Transplantation; Spleen; Transplantation Immunology

Topics: Adolescent; Adult; Aged; Asparaginase; Azaserine; Burkitt Lymphoma; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Child; Drug Hypersensitivity; Escherichia coli; Female; Humans; Leukemia, Lymphoid; Leukopenia; Lymphoma, Non-Hodgkin; Lymphopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Neoplasms; Pancreatitis; Thrombocytopenia