mercaptopurine and Hepatic-Veno-Occlusive-Disease

Sinusoidal obstruction syndrome (SOS) of the liver is a complication of chemotherapy most often encountered with hematopoietic stem cell transplant due to high-dose conditioning regimens, but it can also occur with regimens outside of the transplant setting. Mild-to-moderate SOS is a well-described 6-thioguanine toxicity; however, it has rarely been reported as secondary to 6-mercaptopurine, a related thiopurine. This report details a case of a 10-year-old male with T-cell acute lymphoblastic leukemia who developed severe SOS during maintenance therapy with 6-mercaptopurine, and a review of the related literature.

Topics: Child; Hepatic Veno-Occlusive Disease; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Thioguanine

Several lympholytic and cytotoxic agents are used in acute lymphoblastic leukemia (ALL) polychemotherapy. Genetic variants for cellular components involved in the pharmacokinetics and pharmacodynamics of these drugs can influence the pharmacological response, and molecular characterization of these genetic variants could be helpful for the comprehension of the mechanisms of resistance or increased sensitivity. The purpose of this review is to carry out an update of recent publications on genes that might influence ALL treatment in terms of outcome and/or toxicity and to underlie the role of genetic variants, particularly single nucleotide polymorphisms (SNP), in predicting clinical response, with particular reference to the current protocol for ALL therapy used in Italy, AIEOP-BFM ALL 2009.

Topics: Alkaloids; Antineoplastic Agents; Benzamides; Child; Glucocorticoids; Hepatic Veno-Occlusive Disease; Humans; Imatinib Mesylate; Mercaptopurine; Methotrexate; Nucleotides; Pharmacogenetics; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Thioguanine; Vincristine

Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy.. In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks.. PEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Drug Interactions; Female; Hepatic Veno-Occlusive Disease; Humans; Infant; Kaplan-Meier Estimate; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proportional Hazards Models

The Children's Cancer Group 1952 (CCG-1952) clinical trial studied the substitution of oral 6-thioguanine (TG) for 6-mercaptopurine (MP) and triple intrathecal therapy (ITT) for intrathecal methotrexate (IT-MTX) in the treatment of standard-risk acute lymphoblastic leukemia. After remission induction, 2027 patients were randomized to receive MP (n = 1010) or TG (n = 1017) and IT-MTX (n = 1018) or ITT (n = 1009). The results of the thiopurine comparison are as follows. The estimated 7-year event-free survival (EFS) for subjects randomized to TG was 84.1% (+/- 1.8%) and to MP was 79.0% (+/- 2.1%; P = .004 log rank), although overall survival was 91.9% (+/- 1.4%) and 91.2% (+/- 1.5%), respectively (P = .6 log rank). The TG starting dose was reduced from 60 to 50 mg/m(2) per day after recognition of hepatic veno-occlusive disease (VOD). A total of 257 patients on TG (25%) developed VOD or disproportionate thrombocytopenia and switched to MP. Once portal hypertension occurred, all subjects on TG were changed to MP. The benefit of randomization to TG over MP, as measured by EFS, was evident primarily in boys who began TG at 60 mg/m(2) (relative hazard rate [RHR] 0.65, P = .002). The toxicities of TG preclude its protracted use as given in this study. This study is registered at http://clinicaltrials.gov as NCT00002744.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Hepatic Veno-Occlusive Disease; Humans; Hypertension, Portal; Infant; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

Thiopurine metabolism was investigated in children with acute lymphoblastic leukemia treated in the United Kingdom Medical Research Council trial ALL97. This trial compared the efficacy and toxicity of thioguanine (INN, thioguanine) versus mercaptopurine.. Consecutive children were randomized to receive thioguanine or mercaptopurine during maintenance chemotherapy. Toxicity data were collected by an adverse event-reporting system with follow-up questionnaires. Red blood cell thiopurine methyltransferase (TPMT) activity and thioguanine nucleotide concentrations were measured by standard techniques.. Of the children, 748 were randomized to thioguanine and 744 were randomized to mercaptopurine. There was no difference in the event-free survival rate between the 2 groups (80% and 81%, respectively, at 5 years). Thioguanine was associated with veno-occlusive disease (VOD) of the liver in 95 children, and persistent splenomegaly as a result of portal hypertension developed in 43 children. TPMT activity was significantly lower in the children in whom VOD developed, with a median of 13.4 U (range, 5.8-23 U) compared with 15.2 U (range, 5.3-27) in a control group of 161 leukemia patients in whom VOD did not develop (median difference, 1.8 U; 95% confidence interval, 0.9-2.7 U; P = .0001). TPMT activity in children with persistent splenomegaly was also lower than that in control subjects (median difference, 1.6 U; 95% confidence interval, 0.3-2.8 U; P = .012). There was no difference in red blood cell thioguanine nucleotide concentrations.. Thioguanine was associated with liver damage in 11% of children randomized to thioguanine without an improvement in event-free survival rate. The association of lower TPMT activity with thioguanine-related liver damage could provide a means of identifying at-risk patients.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Disease-Free Survival; Female; Hepatic Veno-Occlusive Disease; Humans; Hypertension, Portal; Infant; Infant, Newborn; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Splenomegaly; Thioguanine

We report a case of a child with pre-B cell acute lymphoblastic leukemia undergoing maintenance chemotherapy with 6-mercaptopurine and methotrexate (MTX) who developed sinusoidal obstruction syndrome after being treated with ciprofloxacin for BK viremia. This case represents a rare complication of maintenance therapy with MTX and 6-mercaptopurine, and suggests a drug interaction between ciprofloxacin and MTX.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biopsy; Child; Drug Interactions; Hepatic Veno-Occlusive Disease; Humans; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Multimodal Imaging; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (HSCT), but membranous glomerulopathy (MG) has rarely been described as a manifestation of chronic GVHD. We report two cases of MG in children who underwent allogeneic HSCT. The clinical findings were characterized by edema of the lower extremities and nephrotic proteinuria in one case and hypertension, hematuria and edema with non-nephrotic proteinuria in the other one. Renal biopsy was consistent with MG and appropriate immunosuppressive therapy was prescribed. Both patients achieved complete remission and are alive without renal disease 4 and 2 years after the diagnosis of MG. The normal levels of albumin and non-nephrotic proteinuria in one of the two cases raise the question of whether the real incidence of MG after HSCT is underestimated. Therefore, we strongly suggest regular urine analysis during the follow-up of children undergoing HSCT in order to diagnose MG early.

Topics: Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Edema; Glomerulonephritis, Membranous; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Transplantation Conditioning; Transplantation, Homologous; Vincristine

The case records of 99 consecutive children with acute lymphoblastic leukaemia who received either 6-thioguanine (6-TG) or 6-mercaptopurine (6-MP) as maintenance therapy for at least 1 year were reviewed for hepatic veno-occlusive disease (VOD). Overall, 12% of those on 6-TG developed VOD (all boys). Isolated persistent thrombocytopenia appeared to be the earliest indicator of incipient VOD. Multivariate analysis identified male sex and 6-TG as risk factors. In all cases, VOD was mild and reversible on withdrawing 6-TG or replacing it with 6-MP. The data implicate a sex-linked polymorphic variation in xenobiotic pathways of thiopurine metabolism in the pathogenesis of VOD.

Topics: Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Hepatic Veno-Occlusive Disease; Humans; Logistic Models; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sex Factors; Thioguanine; Xenobiotics

Veno-occlusive disease (VOD) is an entity described as a triad of pathologic findings including ascites, tender hepatomegaly, and elevated liver enzymes. The prognosis of patients suffering from VOD is highly variable, ranging from slow resolution to the need for liver transplant. The histopathology of VOD has been described by light and electron microscopy. However, the pathogenesis of VOD is still largely unclear. In the present case study, we report the significant findings in a case of pediatric VOD following chemotherapy. We studied the liver biopsy by light and electron microscopes. In addition to previous reported findings of occlusion of the central vein with endothelial cell damage, proliferation and activation of stellate cells, and collagen deposition in the central vein wall, there were prominent activated macrophages within the lumen and wall of central veins. The following mechanism of VOD was proposed: Tissue damage activates monocytes through monocyte chemoattractant protein-1. The secretory macrophages release TGF-beta, which promotes proliferation of stellate cells to cause collagenous thickening of the central vein. The activated stellate cells produce collagen. The normal drainage of the Space of Disse and sinusoids draining into the central vein are blocked by the fibrosis. This leads to extravasated RBCs trapped within the thickened central vein wall and impaction of RBCs in the sinusoids.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Female; Hepatic Veno-Occlusive Disease; Humans; Liver; Macrophages; Mercaptopurine; Methotrexate; Microscopy, Electron; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine