mercaptopurine and Bone-Marrow-Diseases

Probably, the most important and potentially lethal adverse event of azathioprine (AZA) and mercaptopurine (MP) is myelosuppression. Our aim was to conduct a review of AZA/MP-induced myelotoxicity in inflammatory bowel disease (IBD) patients.. Bibliographical searches were performed in MEDLINE/EMBASE. The studies evaluating thiopurine-induced myelotoxicity in patients with IBD were reviewed. The cumulative incidence and the incidence rate of AZA/MP-induced myelotoxicity were calculated by a meta-analysis.. In total, 66 studies (8,302 patients) were included. The cumulative incidence of AZA/MP-induced myelotoxicity was 7% (95% confidence interval [CI] 6-8%). The incidence rate (per patient and year of treatment) of the drug-induced myelotoxicity was 3% (95% CI 3-4%). The risk was roughly similar with AZA and with MP (7%vs 9%). The duration of AZA/MP treatment in patients with myelotoxicity ranged from 12 days to 27 yr. The cumulative incidence of infections among AZA/MP-induced myelotoxicity patients was 6.5%. The cumulative incidence of severe myelotoxicity was 1.1% (incidence rate 0.9%). Three deaths were reported due to myelotoxicity (cumulative incidence 0.06%, 95% CI 0.02-0.17%). The risk of death among patients who developed myelotoxicity was 0.94% (95% CI 0.32-2.70%).. The incidence rate of myelotoxicity in IBD patients receiving AZA/MP is approximately 3% per patient and year of treatment. Although bone marrow toxicity may develop at any time after starting the therapy, this happens more frequently during the first months. The incidence rate of severe myelotoxicity is less than 1% per patient and year of treatment, and the mortality risk is less than 0.1% (which means that the risk of death among IBD patients who develop myelotoxicity is approximately 1%).

Topics: Azathioprine; Bone Marrow Diseases; Humans; Inflammatory Bowel Diseases; Leukopenia; Mercaptopurine

Topics: Bone Marrow Diseases; Child; Drug Resistance; Female; Guanine Nucleotides; Humans; Leukemia, Lymphoid; Male; Mercaptopurine; Methyltransferases; Thionucleotides

Topics: Alopecia; Aminopterin; Antimetabolites; Antineoplastic Agents; Arthritis, Rheumatoid; Azathioprine; Bone Marrow Diseases; Chlorambucil; Clinical Trials as Topic; Cyclophosphamide; Cystitis; Female; Herpes Zoster; Humans; Jaundice; Mechlorethamine; Mercaptopurine; Methotrexate

6-Mercaptopurine (6-MP) is an effective maintenance medication in patients with ulcerative colitis (UC), but toxic effects like myelosuppression limit its clinical benefit. In the blood, 6-thioguanine (6-TGN) is formed from 6-MP and mediates the therapeutic efficacy and most of the toxicities of 6-MP. The level of 6-TGN depends on the activity of thiopurine methyltransferase (TPMT), inherited as 1 of its 3 polymorphic forms with low, moderate, or normal/high activity. Accordingly, the 6-MP dose needs to be pharmacogenetically guided.. Patients with quiescent UC received 6-MP as maintenance therapy and 6-TGN was assayed as its concentrations in red blood cells (RBCs) done by high-performance liquid chromatography. In a preliminary investigation, 30 mg/day 6-MP (n = 50) was given orally over 12 weeks to determine the time course of blood 6-TGN level. Then 257 patients were given 6-MP at 15-80 mg/day in a stepwise manner based on RBC 6-TGN, white blood cell count, and body weight to monitor 6-MP efficacy and safety profiles.. At 30 mg/day 6-MP, RBC 6-TGN peaked over 4-8 weeks. In the main dosing study, the mean RBC 6-TGN level in patients who remained in remission during the 1-year observation time (n = 151) was 322.3 +/- 119.5 pmole/8 x 10(8) RBC versus 204.8 +/- 78.7 pmole/8 x 10(8) RBC in patients (n = 19) who relapsed (P < 0.001). Bone marrow suppression was seen almost exclusively at high 6-TGN concentration ranges. Further, a regression plot showed an inverse relationship between 6-TGN levels in RBC and TPMT enzyme activity.. By regularly measuring RBC 6-TGN in patients with quiescent UC receiving 6-MP as maintenance therapy, we could monitor bone marrow suppression as well as other toxic side effects. Potentially, this strategy should enable physicians to avoid thiopurine-related adverse effects and identify individuals who may benefit most from 6-MP maintenance therapy.

Topics: Adolescent; Adult; Aged; Bone Marrow; Bone Marrow Diseases; Colitis, Ulcerative; Drug Monitoring; Erythrocytes; Humans; Immunosuppressive Agents; Leukapheresis; Mercaptopurine; Mesalamine; Methyltransferases; Middle Aged; Prednisolone; Thioguanine; Treatment Outcome; Young Adult

In order to evaluate the role of Mitoxantrone in the therapy of non-Hodgkin's lymphoma (NHL) (intermediate-high grade malignancy) a series of successive phase II-III studies were performed in a multicenter cooperative group. The first phase II study consisted of Mitoxantrone alone administered at 14 mg/m2 i.v. on day 1 and repeated every 3 weeks for six times. Fifteen refractory or relapsed patients (pts) entered the study, and an overall response of 54% (CR 4 pts, PR 4 pts) was obtained. 7 pts progressed or remained stable disease (NR). The second phase II consisted of Mitoxantrone in combination with Etoposide and Prednisone (VeMP). Twenty pts were treated and a complete remission (CR) of 50% with 1 partial remission (PR) were obtained with an overall response of 55%. The third phase II study consisted of 13 pts with refractory or relapsed disease treated with Mitoxantrone, Cis-platinum, Etoposide and Prednisone (CEMP); an overall response of 62% was obtained with an acceptable toxicity. This was not superior to other conventional salvage regimens. On this background a phase III study with VEMP (Etoposide, Cyclophosphamide, Mitoxantrone, Prednisone) was started as first line therapy for pts presenting one or more of following criteria: Performance Status (P.S.) 2-3, aggressive histology at stage I-IIE or advanced stage in old pts, low grade histology with B-symptoms stage in III-IV, age over 65 years. Until now 64 pts entered this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Cyclophosphamide; Drug Administration Schedule; Etoposide; Female; Gastrointestinal Diseases; Humans; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Middle Aged; Mitoxantrone; Prednisolone; Prednisone; Remission Induction; Salvage Therapy; Survival Analysis; Treatment Outcome; Vincristine

On study CCG-161 of the Childrens Cancer Study Group (CCSG), 631 children with acute lymphoblastic leukemia (ALL) at low risk for relapse were randomized to receive monthly pulses of vincristine-prednisone (VCR-PDN ) during maintenance therapy in addition to standard therapy with mercaptopurine (6MP) and methotrexate (MTX), and either cranial irradiation during consolidation or intrathecal (IT) MTX every 3 months during maintenance. All patients received six doses of IT MTX during induction and consolidation. With a minimum follow-up time of 4.25 years, 76.7% receiving VCR-PDN were in continuous complete remission at 5 years, in contrast to 63.9% receiving GMP-MTX alone (P = .002). The difference in relapse-free survival was due primarily to bone marrow relapse (P = .0008), and in boys also to testicular relapse (P = .003). Among the nonirradiated patients, the 5-year disease-free survival (DFS) was 79.4% for patients randomized to the VCR-PDN pulses, in contrast to 61.2% for the patients randomized to receive 6MP-MTX alone (P = .0002). Among the irradiated patients, the DFS was not significantly different. Of the four combinations of maintenance and CNS therapy studied, the highest DFS was achieved with VCR-PDN pulses and maintenance IT MTX.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Brain Neoplasms; Child, Preschool; Combined Modality Therapy; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Random Allocation; Recurrence; Remission Induction; Survival Rate; Testicular Neoplasms; Vincristine

In a comparison of treatments for standard-risk acute lymphoblastic leukaemia in children (UKALL III), there were no differences in remission lengths between regimens with or without second-line drugs (cytosine arabinoside and asparaginase) and with continuous or discontinuous mercaptopurine. The number of infections was significantly lower when maintenance followed the less immunosuppressive modified induction period and when there were 1-week gaps each month in the administration of mercaptopurine. As in the previous trial, a higher rate of relapse in boys was found to be due partly to testicular and partly to bone marrow relapse. Cell-typing by the FAB system showed that the proportion of patients still in their first remission at 5 years was very much higher in L1 than in L2 cases.

Topics: Adolescent; Antineoplastic Agents; Asparaginase; Bone Marrow Diseases; Child; Child, Preschool; Clinical Trials as Topic; Cytarabine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant; Leukemia, Lymphoid; Male; Mercaptopurine; Neoplasm Recurrence, Local; Prognosis; Sex Factors; Testicular Neoplasms; Time Factors

Topics: Alopecia; Aminopterin; Antimetabolites; Antineoplastic Agents; Arthritis, Rheumatoid; Azathioprine; Bone Marrow Diseases; Chlorambucil; Clinical Trials as Topic; Cyclophosphamide; Cystitis; Female; Herpes Zoster; Humans; Jaundice; Mechlorethamine; Mercaptopurine; Methotrexate

Topics: Adenocarcinoma; Anemia; Bone Marrow Diseases; Carcinoma, Squamous Cell; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Colonic Neoplasms; Humans; Leukopenia; Lung Neoplasms; Mercaptopurine; Nausea; Neoplasms; Rectal Neoplasms; Stomach Neoplasms; Thrombocytopenia; Vomiting

Mercaptopurine (6MP) and methotrexate are the cornerstones of maintenance therapy in pediatric patients with acute lymphoblastic leukemia. However, although bone marrow suppression and liver dysfunction are common side effects of these antimetabolites, 6MP-induced hypoglycemia during the maintenance phase is rare. Guidelines and international protocols are well established for the management of bone marrow suppression and liver dysfunction, but promptly identifying 6MP-induced hypoglycemia is the key to its control. Here we report 2 cases of leukemia that developed hypoglycemia during the maintenance phase. Both patients were boys younger than 6 years of age and both suffered symptomatic morning hypoglycemia induced by 6MP (which was diagnosed after excluding all other possible causes). Successful management included changing the time of 6MP administration from evening to morning. Other management options are also discussed.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Child; Female; Humans; Hypoglycemia; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Inadequate myelosuppression during maintenance therapy for acute lymphoblastic leukemia (ALL) is associated with an increased risk of relapse. One mechanism is skewed metabolism of 6-mercaptopurine (6MP), a major component of maintenance therapy, which results in preferential formation of the hepatotoxic metabolite (6-methyl mercaptopurine [6MMP]) with low levels of the antileukemic metabolite, 6-thioguanine nucleotides (6TGN). Allopurinol can modify 6MP metabolism to favor 6TGN production and reduce 6MMP.. Patients in maintenance were considered for allopurinol treatment who had the following features: (a) Grade ≥3 hepatotoxicity; (b) Grade ≥2 nonhepatic gastrointestinal (GI) toxicity; or (c) persistently elevated absolute neutrophil count (ANC) despite >150% protocol dosing of oral chemotherapy.. From 2013 to 2017, 13 ALL patients received allopurinol: nine for hepatotoxicity, five for inadequate myelosuppression, and three for nonhepatic GI toxicity (four met multiple criteria). Allopurinol was well tolerated, without significant adverse events. Allopurinol resulted in a significant decrease in the average 6MMP/6TGN ratio (mean reduction 89.1, P = .0001), with a significant increase in 6TGN (mean 550.4, P = .0008) and a significant decrease in 6MMP (mean 13 755, P = .0013). Patients with hepatotoxicity had a significant decrease in transaminase elevation after starting allopurinol (alanine transaminase [ALT] mean decrease 22.1%, P = .02), and all with nonhepatic GI toxicity had improved symptoms. Those with inadequate myelosuppression had a significant increase in the time with ANC in goal (mean increase 26.4%, P = .0004).. Allopurinol during ALL maintenance chemotherapy is a safe, feasible, and effective intervention for those who have altered metabolism of 6MP causing toxicity or inadequate myelosuppression.

Topics: Allopurinol; Antimetabolites; Bone Marrow Diseases; Child; Child, Preschool; Female; Follow-Up Studies; Gastrointestinal Diseases; Humans; Infant; Male; Mercaptopurine; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Retrospective Studies; Survival Rate

Low-dose thiopurine-allopurinol (LDTA) combination therapy is a commonly applied optimisation strategy in IBD patients with a skewed thiopurine metabolism.. To assess continued LDTA maintenance treatment at annual intervals and explore risk factors for treatment cessation METHODS: Adult IBD patients treated with LDTA between 2009 and 2016 were retrospectively included. Data on the incidence of clinical and laboratory adverse events (AEs), including hepatotoxicity and myelotoxicity resulting in imposing LDTA therapy cessation and associated risk factors were collected.. In total, 221 IBD patients (46% male, median age 42 years) were included. Maintenance LDTA treatment was continued in 78% of patients at 1 year (n = 145), 66% at 2 years (n = 83), 57% at 3 years (n = 52) and 52% at 4 years (n = 33). Treatment in patients receiving LDTA therapy for AEs during thiopurine monotherapy was more often continued than in patients initiating LDTA for other indications (eg, ineffectiveness of thiopurine monotherapy, routinely discovered skewed metabolism) (P = 0.016). Myelotoxicity during thiopurine monotherapy resolved in 87% and hepatotoxicity in 86% after median of 1.2 and 1.4 months after LDTA initiation. Cumulative incidence of AEs during LDTA resulting in therapy cessation within total follow-up of 449 treatment-years was 7% for clinical AEs, 4% for myelotoxicity and 1% for hepatotoxicity.. LDTA therapy is a safe and beneficial optimisation strategy in IBD patients. Continued maintenance LDTA treatment is 52% after 4 years of treatment and most commonly affected by ineffectiveness of LDTA rather than LDTA-attributed toxicity. LDTA optimisation strategy is most advantageous in patients failing thiopurine monotherapy due to AEs.

Topics: Adult; Allopurinol; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medication Adherence; Mercaptopurine; Middle Aged; Netherlands; Retrospective Studies; Withholding Treatment

We describe the case of an 8-year-old girl with common precursor B-cell acute lymphoblastic leukemia who presented with severe pancytopenia during maintenance therapy with methotrexate and 6-mercaptopurine. The bone marrow smear showed moderate hypocellularity and trilinear dysplastic changes consistent with a diagnosis of drug toxicity, with no evidence of lymphoblasts. Flow cytometric immunophenotyping was negative for leukemic cells. Blood cell counts normalized after treatment with folinic acid. Maintenance therapy was gradually restarted and she remained well at follow-up visits. Myelotoxicity from methotrexate and 6-mercaptopurine may represent an unpredictable incident during an otherwise uneventful maintenance therapy, and may occur independently of other organ toxicities.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Child; Disease Management; Female; Follow-Up Studies; Humans; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis

Topics: Aged; Allopurinol; Azathioprine; Biotransformation; Bone Marrow Diseases; Crohn Disease; Drug Interactions; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methyltransferases; Xanthine Oxidase

An increased understanding of the genetic basis of disease creates a demand for personalized medicine and more genetic testing for diagnosis and treatment. The objective was to assess the incremental cost-effectiveness per life-month gained of thiopurine methyltransferase (TPMT) genotyping to guide doses of 6-mercaptopurine (6-MP) in children with acute lymphoblastic leukemia (ALL) compared to enzymatic testing and standard weight-based dosing.. A cost-effectiveness analysis was conducted from a health care system perspective comparing costs and consequences over 3 months. Decision analysis was used to evaluate the impact of TPMT tests on preventing myelosuppression and improving survival in ALL patients receiving 6-MP. Direct medical costs included laboratory tests, medications, physician services, pharmacy and inpatient care. Probabilities were derived from published evidence. Survival was measured in life-months. The robustness of the results to variable uncertainty was tested in one-way sensitivity analyses. Probabilistic sensitivity analysis examined the impact of parameter uncertainty and generated confidence intervals around point estimates.. Neither of the testing interventions showed a benefit in survival compared to weight-based dosing. Both test strategies were more costly compared to weight-based dosing. Incremental costs per child (95% confidence interval) were $277 ($112, $442) and $298 ($392, $421) for the genotyping and phenotyping strategies, respectively, compared to weight-based dosing.. The present analysis suggests that screening for TPMT mutations using either genotype or enzymatic laboratory tests prior to the administration of 6-MP in pediatric ALL patients is not cost-effective.

Topics: Antimetabolites, Antineoplastic; Bone Marrow Diseases; Child, Preschool; Clinical Enzyme Tests; Cost-Benefit Analysis; Decision Trees; Drug Dosage Calculations; Genetic Testing; Genotype; Humans; Mercaptopurine; Methyltransferases; Models, Econometric; Ontario; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sensitivity and Specificity; Survival Analysis

Topics: Adrenal Cortex Hormones; Adult; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Asparaginase; Bone Marrow Diseases; Diagnosis, Differential; Doxorubicin; Humans; Ischemia; Leukemic Infiltration; Male; Mercaptopurine; Methotrexate; Myelitis, Transverse; Paraplegia; Paresthesia; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Salvage Therapy; Spinal Cord; Vincristine

We sought to assess the activity of thiopurine methyltransferase (TPMT) in 14,545 Spanish patients with different diseases amenable to treatment with azathioprine/6-mercaptopurine (6-MP), and to evaluate the proportion of patients with low TPMT activity and therefore a higher risk of myelotoxicity with these drugs. TPMT activity in red blood cells (RBCs) was measured by a radiochemical method. The association between several clinical variables and TPMT activity was assessed by multiple linear regression. We included 14,545 patients: autoimmune hepatitis (n=359 patients), inflammatory bowel disease (n=7,046), multiple sclerosis (n = 814), myasthenia gravis (n=344), pemphigus (n=133), and other diseases (n=5,849). Mean TPMT activity was 20.1 +/- 6 U/mL, but differed depending on the disease (P<.001). TPMT distribution was low (<5) in 0.5%; intermediate (5.0-13.7) in 11.9%; or high (>or=13.8) in 87.6%. Only when TPMT activity was considered separately in each disease did it reveal a normal distribution. In the multivariate analysis, gender, hematocrit, and treatment with 5-aminosalicylates/steroids/azathioprine/6-MP statistically influenced TPMT activity, although, probably, in a clinically irrelevant manner. This study shows, in a large sample of 14,545 patients, that 0.5% had low TPMT activity, indicating a higher risk of myelotoxicity with azathioprine/6-MP, a figure similar or slightly higher than that reported in other areas. Nevertheless, the trimodal distribution of TPMT activity varied depending on disease, and the proportion of patients with low activity values ranged from 0-0.8%. The drugs prescribed for the treatment of autoimmune diseases, including azathioprine/6-MP, modified TPMT activity, but the magnitude of this effect was very small and the differences found are probably irrelevant from the clinical point of view.

Topics: Adult; Autoimmune Diseases; Azathioprine; Bone Marrow Diseases; Erythrocytes; Female; Humans; Immunosuppressive Agents; Linear Models; Male; Mercaptopurine; Methyltransferases; Middle Aged; Risk Assessment; Risk Factors; Spain

Thiopurine methyltransferase (TPMT) is the main enzyme responsible for inactivating toxic products of azathioprine (AZA) metabolism. Patients with homozygous deficiency of this enzyme have no enzyme activity and ideally should not be given AZA. Patients with heterozygous deficiency have 50% of enzyme activity and have been shown to respond well and tolerate half a standard dose. We describe a patient with homozygous deficiency of TPMT who developed life threatening neutropenic sepsis, and advocate that all patients should be tested for TPMT activity prior to starting AZA therapy.

Topics: Aged; Arthritis, Rheumatoid; Azathioprine; Bone Marrow Diseases; Diagnostic Tests, Routine; Female; Homozygote; Humans; Immunosuppressive Agents; Inactivation, Metabolic; Mercaptopurine; Methylation; Methyltransferases; Neutropenia; Prodrugs; Sepsis; United Kingdom

Thiopurines are used in the treatment of inflammatory bowel disease. They are metabolised via methylation by thiopurine-S-methyltransferase (TPMT), which displays a genetically determined polymorphic activity. Subjects with reduced TPMT activity have a higher concentration of active thiopurine metabolites and may be at increased risk of bone-marrow suppression.. To evaluate the relevance of TPMT genotyping in the management of thiopurines therapy in inflammatory bowel disease patients.. Adverse effects and clinical response were determined retrospectively and correlated with TPMT genotype in 70 paediatric inflammatory bowel disease patients.. Nineteen patients (27.1%) developed adverse effects; of the 51 who did not, 34 (66.7%) responded to treatment. Five patients (7.1%) were heterozygous for a variant TPMT allele; two of these (40%) were intolerant to thiopurines, compared to 17 of the 65 patients (26.2%) with a wild type gene (O.R. 1.88, 95% CI 0.29-12.2, p=0.61); among the 34 responders, the median dosage of the drug required to obtain remission was lower for mutated than for wild type patients (1.6mgkg(-1)day(-1) versus 2.0mgkg(-1)day(-1), p=0.043).. There was no significant association between adverse effects of thiopurines and TPMT heterozygous genotype, but TPMT genotyping could be useful in establishing the most appropriate dose of thiopurines to start treatment.

Topics: Adolescent; Adult; Azathioprine; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Genotype; Humans; Immunosuppressive Agents; Infant; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Pancreatitis; Polymorphism, Genetic

Arsenic trioxide (As2O3) therapy at a daily dose of 0.15 mg/kg was given to a 60-yr-old Japanese male with refractory acute promyelocytic leukemia. White blood cell (WBC) of 6.6 x 10(3)/microl increased to 134 x 10(3)/microl following the administration of As2O3. Daily hydroxyurea (HU), and 6-mercaptopurine (6-MP) were added on days 7 and 19, respectively. Both HU and 6-MP were discontinued on day 28, when WBC declined to 54.0 x 10(3)/microl. He developed unexplained fever and profound cytopenia requiring multiple blood products transfusions. Bone marrow examination on day 42 revealed massive necrosis. Pharmacokinetics confirmed a mean maximum plasma arsenic concentration (Cpmax) and a half-life time (t1/2) of 6.9 microm and 3.2 h, respectively, in the therapeutic range. This is the first case of bone marrow necrosis after standard-dose As2O3 therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Bone Marrow; Bone Marrow Diseases; Fever; Humans; Hydroxyurea; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Middle Aged; Necrosis; Oxides; Pancytopenia; Remission Induction

Thiopurine methyltransferase (TPMT), one of the enzymes involved in azathioprine metabolism, exhibits a wide range of activity in the normal population. We prospectively evaluated the monitoring of erythrocyte TPMT activity (using a radiochemical method) in kidney transplant recipients with regard to the efficacy of azathioprine. Three patterns in TPMT activity variation were observed. In group 1 patients, TPMT activity rose as early as 8 days after transplantation and steadily until month 3. In group 3 patients, TPMT activity remained unchanged. In group 2 patients, TPMT activity rose at month 1 after transplantation. Interestingly, the incidence of acute rejection was significantly (P < 0.01) different among the 3 groups, with the lowest incidence in group 1 and the highest in group 3. We hypothesized that TPMT activity increase was induced by azathioprine in the patients with the lowest incidence of acute rejection. The inducibility of TPMT activity would then appear to be an interesting marker of azathioprine-induced immunosuppression.

Topics: Azathioprine; Bone Marrow Diseases; Erythrocytes; Evaluation Studies as Topic; Genotype; Glutathione Transferase; Humans; Immunosuppressive Agents; Kidney Transplantation; Mercaptopurine; Methyltransferases; Prospective Studies

Plasma levels of 6-mercaptopurine were determined in 22 consecutive children with acute lymphoblastic leukemia on oral remission maintenance therapy during the time period of August 1984 to January 1988. Each child received the drug once daily for up to 3 years and was studied repeatedly (1-12 times). An HPLC method was used for drug analysis. We found large interpatient variations in the mean peak plasma concentration (range of 50-424 ng/ml) and in the mean area under the concentration vs. time from 0-4 h curve (range of 82-637 ng ml-1 h). There were also pronounced variations between different sampling occasions in the same patient. Nine of the 22 patients had complications during the maintenance therapy. Five children with a mean peak plasma level below 135 ng/ml and a mean area under the curve (AUC) value below 251 ng ml-1 h relapsed (three in the central nervous system and two in the bone marrow). Both children with a bone marrow relapse died. Relapse risk was related to the AUC (p less than 0.05). Four children with a mean peak plasma level above 166 ng/ml and a mean AUC value above 363 ng/ml/h developed severe myelotoxicity, which necessitated a temporary cessation of the maintenance therapy. In addition, two patient relapsed 6 and 11 months after termination of maintenance therapy. Their mean peak and AUC values were not low but the concentrations decreased markedly towards the end of the maintenance period. The results indicate that the plasma levels of 6-mercaptopurine, when determined repeatedly, might be of significance for the outcome of the remission maintenance treatment.

Topics: Adolescent; Bone Marrow Diseases; Child; Child, Preschool; Female; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Remission Induction; Risk Factors

We assess toxicity related to 6-mercaptopurine in the treatment of inflammatory bowel disease by reporting our experience with 396 patients (120 patients with ulcerative colitis, 276 with Crohn disease) observed over 18 years. Follow-up data for a mean period of 60.3 months were obtained for 90% of the patients. Toxicity directly induced by 6-mercaptopurine included pancreatitis in 13 patients (3.3%), bone marrow depression in 8 (2%), allergic reactions in 8 (2%), and drug hepatitis in 1 (0.3%). These complications were reversible in all cases with no mortality. Most cases of marrow depression occurred earlier in our experience, when the initial drug doses used were higher. Infectious complications were seen in 29 patients (7.4%), of which 7 (1.8%) were severe, including one instance of herpes zoster encephalitis. All infections were reversible with no deaths. Twelve neoplasms (3.1%) were observed, but only 1 (0.3%), a diffuse histiocytic lymphoma of the brain, had a probable association with the use of 6-mercaptopurine. Our data, showing a low incidence of toxicity in 396 patients, coupled with the previously demonstrated efficacy of 6-mercaptopurine in the treatment of inflammatory bowel disease, indicate that the drug is a reasonable alternative in the management of patients with intractable inflammatory bowel disease.

Topics: Adolescent; Adult; Aged; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Child; Colitis, Ulcerative; Crohn Disease; Double-Blind Method; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Infections; Male; Mercaptopurine; Middle Aged; Neoplasms; Pancreatitis; Pregnancy; Time Factors

Between 1964 and 1982, 862 patients with acute leukemia who were collected from medical institutions throughout the country had a survival of 5 years or longer. Their remission has been achieved mainly with a combination therapy of vincristine and prednisone in childhood acute leukemia and daunomycin, cytosine arabinoside, 6-mercaptopurine, prednisone (DCMP) regimen in adult acute leukemia. Among 320 relapsed patients, 88 (38.8%) of 227 children had a primary relapse in the marrow, 85 in the central nervous system (CNS), 37 in the testis/ovary, and 13 in a combined site. The large majority of adult relapsed patients relapsed in the marrow. Ninety-three patients who experienced only one relapse had a much longer prolongation of survival, not yet reaching a median over 14 years after diagnosis, compared to those experiencing two or more relapses. Survival curves in five groups of patients divided by length of maintained remission were investigated by the life table method. In children as well as adults, survival duration in patients on 5 or more years maintained remission was significantly longer than that in the other maintained groups. With respect to relation between frequency of CNS relapse and type of CNS prophylaxis, there was no statistically significant difference between patients who received CNS prophylaxis and patients who did not. However, a better survival was observed in patients who received CNS prophylaxis with cranial radiation plus intrathecal methotrexate. Thus, long-term clinical follow-up might provide important information for the therapeutic strategy against acute leukemia.

Topics: Actuarial Analysis; Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; Health Surveys; Humans; Infant; Japan; Leukemia; Leukemia, Lymphoid; Male; Mercaptopurine; Middle Aged; Nervous System Neoplasms; Prednisolone; Recurrence; Testicular Neoplasms

Numerous agents induce differentiation and maturation of neoplastic and dysplastic myeloid cells in vitro and some of these agents have been used with limited success in the treatment of patients with myelodysplastic syndromes (MDS) and myeloid leukaemias. We recently proposed that physiological and pharmacological agents which enhance differentiation and maturation in vitro act by two fundamentally different routes: (1) by hastening the progression through various differentiation/maturation steps; (2) by slowing proliferation (usually by inhibition of DNA synthesis). In order to test this thesis we looked for synergistic effects on differentiation using pairs of agents from the two groups in cultures of cells from myelodysplastic and acute myeloid leukaemia (AML) patients and from normal marrow donors. The results with three MDS, two AML and three normal samples show that combinations of differentiation inducing agents (retinoic acid, N-methylformamide) with DNA synthesis inhibitors (6-mercaptopurine, cytosine arabinoside and aphidicolin) produce a differentiation inducing effect equivalent to that of 10-100, or even 1000 fold higher concentrations of single agents. Myelotoxic effects in vitro were not synergistic. The use of these synergistic combinations should greatly enhance the usefulness of differentiation inducers in the therapy of MDS and myeloid leukaemia.

Topics: Antineoplastic Combined Chemotherapy Protocols; Aphidicolin; Bone Marrow; Bone Marrow Diseases; Cell Differentiation; Cells, Cultured; Cytarabine; Diterpenes; DNA; Drug Synergism; Formamides; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Preleukemia; Syndrome; Tretinoin

6-Mercaptopurine is extensively used in the treatment of childhood lymphoblastic leukaemia to prolong the duration of remission achieved with other drugs. The response to remission maintenance therapy varies widely. We investigated the relationship between red blood cell 6-thioguanine nucleotide, a metabolite of 6-mercaptopurine, and myelosuppression in 22 children with acute lymphoblastic leukaemia in remission. The peripheral neutrophil count was used as an index of myelosuppression. 6-Mercaptopurine dose was related to 6-thioguanine nucleotide concentration (r = 0.4; P less than 0.001; n = 90; y = 18.51 + 0.36 x). Large individual variations around the regression line are observed. Neither 6-mercaptopurine dose nor 6-thioguanine nucleotide concentration was related to the neutrophil count at the time of sampling (day 0) or 7 days later. Both 6-mercaptopurine dose and 6-thioguanine nucleotide concentration correlated with the neutrophil count at day 14 (r = -0.33; P less than 0.01; n = 90 and r = -0.3; P less than 0.01; n = 90 respectively). This delay is compatible with a cytotoxic action on bone marrow stem cells. Excluding children with other, uncontrolled, potentially myelosuppressive influences the correlation between 6-thioguanine nucleotide concentration and neutropenia improved (r = -0.6; P less than 0.001; n = 37). A significant degree of neutropenia was observed by day 14 if the 6-thioguanine nucleotide concentration (day 0) was greater than 210 pmol/8 X 10(8) RBCs. The assay of 6-thioguanine nucleotide may highlight those individuals with pharmacokinetic resistance. Two children on continuous high dose 6-mercaptopurine, had low red blood cell 6-thioguanine nucleotide concentrations and neutropenia was not observed.

Topics: Adolescent; Agranulocytosis; Bone Marrow Diseases; Child; Child, Preschool; Erythrocytes; Female; Humans; Leukemia, Lymphoid; Male; Mercaptopurine; Neutropenia; Thioguanine

Combination chemotherapy with VM-26 and ara-C was given to 14 children with acute lymphocytic leukemia who had not responded to initial treatment with prednisone, vincristine, daunomycin, and asparaginase. Nine of these patients had also received ara-C. At diagnosis, five children were classified as having standard prognostic features and nine as being at high risk for treatment failure. The drug combination was administered by vein twice a week for four weeks at dosages of 165 mg/m2 for VM-26 and 300 mg/m2 for araC. Nine complete remissions, five in patients with high-risk leukemia, were induced with acceptable toxicity; all 9 subsequently were given continuation therapy with oral mercaptopurine and methotrexate. Four of the 9 patients have relapsed at 2--21 months. All treatment was stopped in 2 patients after 30 months of complete remission. Combinations of VM-26 and ara-C represent an alternative remission induction treatment for patients who fail to attain initial remission with agents of established effectiveness. These agents may especially benefit patients with prognostic features indicating a high risk of treatment failure.

Topics: Adolescent; Antineoplastic Agents; Bone Marrow Diseases; Child; Child, Preschool; Cytarabine; Drug Resistance; Drug Therapy, Combination; Female; Humans; Infant; Leukemia, Lymphoid; Male; Mercaptopurine; Methotrexate; Podophyllotoxin; Remission, Spontaneous; Teniposide

Several cytotoxic drugs were tested for their ability to produce permanent residual damage to the bone marrow. A short course of the drug was given to BALB/c female mice, and the numbers of various types of bone marrow cells were determined at least two months later. Evidence of residual damage was found after administration of busulfan and 1,3-bis(chloroethyl)-1-nitrosourea, but not after administration of cyclophosphamide, 5-fluorouracil, 6-mercaptopurine, methotrexate, or vinblastine.

Topics: Animals; Antineoplastic Agents; Bone Marrow; Bone Marrow Diseases; Busulfan; Carmustine; Cell Survival; Cyclophosphamide; Drug Evaluation, Preclinical; Female; Fluorouracil; Hematopoietic Stem Cells; Mercaptopurine; Methotrexate; Mice; Mice, Inbred BALB C; Vinblastine

Topics: Bone Marrow Diseases; Bone Marrow Examination; Child; Histoplasmosis; Humans; Leukemia, Lymphoid; Male; Mercaptopurine; Neoplasm Regression, Spontaneous; Prednisone; Vincristine

Topics: Animals; Azathioprine; Body Weight; Bone Marrow Diseases; Dogs; Graft Rejection; Histocompatibility; Kidney Transplantation; Mercaptopurine; Nucleotides; Time Factors; Transplantation Immunology; Transplantation, Homologous

Topics: Anemia, Hemolytic, Autoimmune; Anti-Bacterial Agents; Antimetabolites; Blood Specimen Collection; Bone Marrow Diseases; Busulfan; Chromosome Aberrations; Diuretics; Hodgkin Disease; Humans; Karyotyping; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemoid Reaction; Mercaptopurine; Prednisone; Specimen Handling; Thrombocytopenia; Time Factors

Topics: Adolescent; Adult; Aged; Blood Cell Count; Blood Platelets; Bone Marrow Diseases; Busulfan; Child; Cobalt Isotopes; Female; Hemoglobins; Humans; Hydroxyurea; Leukemia, Myeloid; Leukocyte Count; Male; Mercaptopurine; Middle Aged; Radiotherapy; Remission, Spontaneous; Spleen; Time Factors

Topics: Adenocarcinoma; Aged; Bone Marrow Diseases; Erythrocytes; Humans; Leukemia; Lung Neoplasms; Male; Megakaryocytes; Mercaptopurine; Middle Aged; Thiotepa; Thrombocythemia, Essential

Topics: Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Bone Marrow Diseases; Bone Marrow Examination; Busulfan; Chlorambucil; Cortisone; Daunorubicin; Etiocholanolone; Female; Hematologic Diseases; Hodgkin Disease; Humans; Leukemia; Leukocyte Count; Male; Mercaptopurine; Radiation Effects; Vinblastine

Topics: Acute Disease; Aged; Aneuploidy; Bone Marrow Diseases; Busulfan; Cell Transformation, Neoplastic; Chromosome Aberrations; Chromosome Disorders; Chronic Disease; Female; Humans; Leukemia, Myeloid; Mercaptopurine; Methotrexate; Prednisolone; Vincristine

Topics: Adrenal Cortex Hormones; Animals; Bone Marrow Diseases; Dactinomycin; Dogs; Drug Synergism; Gastrointestinal Diseases; Graft vs Host Disease; Graft vs Host Reaction; Humans; Immunosuppressive Agents; Infections; Mercaptopurine; Rabbits; Transplantation, Homologous

Topics: Allopurinol; Bone Marrow Diseases; Drug Synergism; Enzyme Therapy; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Myeloproliferative Disorders; Xanthine Oxidase