Insulin-like growth factor-I and insulin-like growth factor binding protein-3 during maintenance chemotherapy of acute lymphoblastic leukemia in children.

PURPOSE: To assess the effect of maintenance chemotherapy (MT) on growth factors and growth in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Twenty-one children (10 girls, 11 boys) with standard risk pre-B ALL treated with chemotherapy had serum insulin-like growth factor-I (IGF-I), serum IGF binding protein-3 (IGFBP-3) levels, and linear growth and weight data measured every 3 months during MT. The levels of the cytotoxic metabolites of methotrexate (MTX) and 6-mercaptopurine (6MP) (i.e., erythrocyte MTX polyglutamates [E-MTX], and erythrocyte 6-thioguanine nucleotides [E-6TGN]), s-aminotransferases, and white blood counts (WBC) were measured at least monthly. RESULTS: At the beginning of MT, the median IGF-I standard deviation scores (SDS) and IGFBP-3 SDS were -0.52 and -0.09, respectively, which declined during MT to -1.67 (P < 0.001) and -1.82 (P < 0.001), respectively. At the time of diagnosis, the median height SDS was -0.4, which declined during MT to a median height SDS of -0.9 at cessation of therapy. No significant correlations were found between growth factor levels, growth and body mass index (BMI) versus the doses of MTX, and 6MP, E-MTX, E-6TGN, s-aminotransferases, or WBC. CONCLUSIONS: A significant decline in IGF-I, IGFBP-3, and growth retardation may not be directly related to the treatment intensity during MT.     

Pharmacokinetics, dose adjustments, and 6-mercaptopurine/ methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency

Two children with acute lymphoblastic leukaemia (ALL) were found to be thiopurine methyltransferase (TPMT)-deficient by both genotype and phenotype. They were monitored with haematological parameters and red blood cell concentrations of 6-thioguanine nucleotides (E-6TGN) and methotrexate (E-MTX, including MTX polyglutamates), in relation to the doses of 6-mercaptopurine (6MP) and methotrexate (MTX), during their maintenance chemotherapy. Both patients developed severe pancytopenia at the standard protocol dose of 6MP. Even at 25% and 5%, respectively, of the protocol dose of 6MP, they achieved E-6TGN values several-fold above the population median, but without unacceptable bone-marrow toxicity. Their high E-6TGN values had only a minor influence on their E-MTX values and their tolerance to oral MTX, but severe pancytopenia followed high-dose MTX infusions. Due to the risk of fatal myelo-suppression we recommend up-front determination of TPMT activity in patients treated with 6MP or azathioprine.     

Myelotoxicity, pharmacokinetics, and relapse rate with methotrexate/6-mercaptopurine maintenance therapy of childhood acute lymphoblastic leukemia

White blood cell and absolute neutrophil counts (WBC, ANC), aminotransferase (AT) levels, methotrexate (MTX) and 6-mercaptopurine (6MP) doses, metabolites in erythrocytes (E-MTX and E-6TGN), and the prognostic significance of these parameters were studied in 58 children receiving MTX/6MP maintenance therapy for acute lymphoblastic leukemia diagnosed from July 1986 to December 1991. At the end of follow-up July 1995, 13 patients had relapsed (pEFS = 0.77). Weighted means of AT, WBC, and ANC during and after maintenance therapy (mAT, mWBCON, mWBCOFF, mANCON, mANCOFF), E-MTX (mE-MTX), and E-6TGN (mE-6TGN) were calculated, as well as the product of mE-MTX and mE-6TGN (mE-MTX*6TGN), as MTX and 6MP probably act synergistically. Beyond higher MTX and 6MP doses to patients with high mWBCON, neither mWBCON, (median 3.5 x 10(9)/L), mANCON, nor mAT was correlated with the dose of MTX and 6MP, mE-MTX, mE-6TGN, or risk of relapse. Patients with mE-MTX*6TGN above or below 828 (nmol/mmol Hb)2 (median value) had pEFS values of 0.84 and 0.70, respectively (P = .16). All 5 patients who relapsed during therapy had mE-MTX*6TGN < 828 (nmol/mmol Hb)2 (P = .03). mWBCOFF and the degree of myelosuppression (= mWBCSHIFT = mWBCOFF - mWBCON; median: 2.5 x 10(9)/L) were related to age (rs = -0.50, P = .001 and rs = -0.40, P = .006, respectively). All eight relapses off therapy occurred in patients with mWBCSHIFT < 2.5 x 10(9)/L (P = .02). WBC levels during MTX/6MP therapy may underestimate the degree of MTX/6MP treatment intensity, especially in order children. Pharmacokinetic monitoring could be useful for optimizing MTX/6MP maintenance therapy.     

THROMBOPHILIA

White blood cell and absolute neutrophil counts (WBC, ANC), aminotransferase (AT) levels, methotrexate (MTX) and 6-mercaptopurine (6MP) doses, metabolites in erythrocytes (E-MTX and E-6TGN), and the prognostic significance of these parameters were studied in 58 children receiving MTX/6MP maintenance therapy for acute lymphoblastic leukemia diagnosed from July 1986 to December 1991. At the end of follow-up July 1995,13 patients had relapsed (_p EFS = 0.77). Weighted means of AT, WBC, and ANC during and after maintenance therapy (mAT, mWBC_ON, mWBC_OFF, mANC_ON, mANC_OFF), E-MTX (mE-MTX), and E-6TGN (mE-6TGN) were calculated, as well as the product of mE-MTX and mE-6TGN (mE-MTX*6TGN), as MTX and 6MP probably act synergistically. Beyond higher MTX and 6MP doses to patients with high mWBC_ON, neither mWBC_ON, (median 3.5 × 10⁹/L), mANC_ON, nor mAT was correlated with the dose of MTX and 6MP, mE-MTX, mE-6TGN, or risk of relapse. Patients with mE-MTX*6TGN above or below 828 (nmollmmol Hb)² (median value) had_p EFS values of 0.84 and 0.70, respectively (P =. 16). All 5 patients who relapsed during therapy had mE-MTX*6TGN <828 (nmollmmol Hb)² (P =. 03). mWBC_OFF and the degree of myelosuppression (= m^WBCSSHIFT = m^WBCOFF = m^WBCON; median: 2.5 × 10⁹IL) were related to age (r, = ?0.50, P =. 001 and r, = ?0.40, P =. 006, respectively). All eight relapses off therapy occurred in patients with m^WBC_SHIFT <2.5 × 10⁹IL (P =. 02). WBC levels during MTX/6MP therapy may underestimate the degree of MTX/6MP treatment intensity, especially in older children. Pharmacokinetic monitoring could be useful for optimizing MTX/6MP maintenance therapy.     

Investigation of the mechanisms of therapy-related hypoglycaemia in children with acute lymphoblastic leukaemia

Aim: To determine the mechanisms of fasting hypoglycaemia occurring during maintenance therapy (MT) for childhood acute lymphoblastic leukaemia (ALL). Methods: Thirty-five children and adolescents with ALL, aged 2.4-17.4 y, were fasted for up to 16 h during MT. Nineteen of the children developed hypoglycaemia after 11 to 16 h of fasting. Blood samples for determination of metabolic changes were taken on completion of fasting. Nineteen patients underwent a glucagon stimulation test after 4 to 16 h of fasting during MT. Erythrocyte concentrations of the metabolites of methotrexate (E-MTX) and 6-mercaptopurine (E-TGN) were measured at the time of fasting. Fifteen out of 19 patients who became hypoglycaemic were re-studied 3 to 4 mo after cessation of therapy. Results: In the hypoglycaemia group, plasma levels of gluconeogenic amino acids alanine and glutamine were lower (medians 117 vs 190 3mol L 31 , p = 0.009, and medians 396 vs 448 3mol L 31 , p = 0.031, respectively) than in the normoglycaemia group. Serum levels of free carnitine were lower (medians 20.3 vs 29.8 3mol L 31 , p = 0.027), free fatty acids higher (medians 3.09 vs 1.23 mmol L 31 , p 3 0.001) and marked dicarboxylic aciduria was more common in the patients with hypoglycaemia (in 14/16 vs in 2/14, p 3 0.001). Impaired responses to glucagon stimulation occurred in 36% (4/11) in the hypoglycaemia group and in 12.5% (1/8) in the normoglycaemia group ( p = 0.243). No significant differences were detected in E-MTX and E-TGN between the groups. Most of the metabolic abnormalities returned to normal after cessation of chemotherapy. Conclusions: Low levels of gluconeogenic amino acids, especially of alanine, are associated with hypoglycaemia. Reduced hepatic glycogen stores may also be involved in the aetiology.     

Prognostic significance of methotrexate and 6-mercaptopurine dosage during maintenance chemotherapy for childhood acute lymphoblastic leukemia.

Tolerance of full-dose methotrexate/6-mercaptopurine (MTX/6MP) maintenance therapy for childhood acute lymphoblastic leukemia (ALL) without side effects could reflect insufficient systemic drug exposure, and drug withdrawals due to toxicity might reduce the chance of cure. The present study included 122 children with non-B cell acute lymphoblastic leukemia with a median follow-up of 84 months. Leukopenia and hepatotoxicity were calculated as weighted means of all white cell counts and all serum aminotransferase measurements, respectively, registered for each patient. Forty-five patients relapsed (30 in bone marrow). Patients tolerating an average dose of MTX of more than 75% of the recommended protocol doses and having cumulated drug withdrawals of less than 1% of the period of maintenance therapy had an increased risk of hematological relapse (p = 0.008) as well as of any relapse (p = 0.03) when compared to the remaining patients. Patients with a cumulative withdrawal of MTX or of 6MP for greater than 10% of the maintenance therapy period had an increased risk of hematological relapse (MTX: p = 0.009, 6MP: p less than 0.0001) and of any relapse (MTX: p = 0.16, 6MP: p = 0.0002). Liver toxicity was the main reason for cumulative long-term drug withdrawals. However, patients with a mean aminotransferase level above the upper normal limit (40 IU/l) who were kept on therapy (cumulative withdrawals of neither drug for more than 5% of their maintenance therapy period) had a significantly lower risk of hematological relapse (p = 0.02) as well as of any relapse (p = 0.06) than the remaining children. The concept of treating to toxicity seems warranted for maintenance therapy of childhood lymphoblastic leukemia.     

6-Mercaptopurine Cumulative Dose: A Critical Factor of Maintenance Therapy in Average Risk Childhood Acute Lymphoblastic Leukemia

A multivariate survival analysis including gender, age, log white blood cell (WBC) count, liver and spleen size at diagnosis, mean log WBC count during maintenance therapy, and the prescribed cumulative doses of 6-mercaptopurine (6-MP), methotrexate (MTX), vincristine (VCR), and prednisom (PDN) during maintenance therapy was performed on 53 children with average-risk acute lymphoblastic leukemia (ALL). The 6-MP cumulative dose prescribed during maintenance therapy resulted in the most important statistically significant independent prognostic factor. Patients who received less than the median cumulative dose of 6-MP (86% of planned protocol dose) fared significantly worse than the other patients, regardless of WBC count at diagnosis, gender, age, and other factors studied. Therefore, 6-MP cumulative dose during maintenance therapy may be the critical factor for effective maintenance therapy in childhood ALL.     

Biopterin and neurotransmitter amine metabolism in children with acute lymphoblastic leukemia receiving methotrexate therapy

To test the hypothesis that some of the neurologic sequelae of treatment for acute lymphoblastic leukemia (ALL) might be related to abnormalities in biopterin metabolism associated with methotrexate (MTX) therapy, total biopterin levels in cerebrospinal fluid (CSF) and plasma, and homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) were measured in a cross-sectional study of 80 children with ALL. For comparison, biopterins were also measured in a group of children of similar age undergoing investigation for neurologic disease. In children with ALL studied before therapy, no significant difference was found between the means of plasma biopterin or CSF biopterin concentrations and the means in the control group. In children receiving MTX, plasma biopterin values were higher in the group given maintenance therapy than in children observed before treatment. CSF levels were significantly increased only in those patients who had completed 2 years of maintenance therapy. CSF concentrations of HVA and 5HIAA in patients with ALL who had received no treatment (median values 52 and 18 ng/ml, respectively) showed a wide scatter and were inversely related to age. In patients receiving MTX, concentrations of these metabolites were higher than in the untreated group, again reaching a peak in patients just completing 2 years of treatment (median HVA 110 ng/ml, 5HIAA 34 ng/ml). These results provide no support for the idea that neurotransmitter amine deficiency occurs in children with ALL receiving MTX, and indicate, rather, that amine and biopterin synthesis increases in such patients.     

Liver histology after current intensified therapy for childhood acute lymphoblastic leukemia: microvesicular fatty change and siderosis are the main findings

BACKGROUND: During modern intensified therapy for childhood acute lymphoblastic leukemia (ALL) serum liver enzymes reach fairly high levels. Since no recent data on liver histopathology after therapy are available, we conducted a study of the subject. PROCEDURE: Liver biopsy specimens were evaluated and serum liver function tests and lipid profiles measured from 27 consecutive children, aged 3.5-17.6 years, treated according to the regimens for standard (SR) and intermediate risk (IR) ALL. RESULTS: None of the patients had entirely normal liver histology. Fatty infiltration was detected in 25 out of 27 (93%) and siderosis in 19 out of 27 patients (70%). Fourteen (52%) had both. Three (11%) also had mild portal and/or periportal fibrosis in addition to fatty change and siderosis. Fatty change was mainly microvesicular. Siderosis was in most cases grade II/IV to III/IV (in 16/19 or 84%). No hepatitis or cirrhosis was found. Serum total and LDL-cholesterol levels were higher in the patients with fibrosis than in the patients with fatty change (P = 0.036, P = 0.042) or with siderosis +/- fatty change (P = 0.036, P = 0.042). In serial ALT measurements a value of 300 U/L or more was oftener reached in the fibrosis than in the fatty change or siderosis groups (in 33 vs. in 12 or in 4% of the measurements, respectively, P = 0.014, in Kruskall-Wallis test). CONCLUSIONS: Microvesicular fatty change and siderosis are the main liver findings after current therapy for childhood ALL. Fibrosis occurs rarely. High values in serial serum ALT measurements repeatedly or a disturbed serum lipid profile may facilitate decisions about the need for a liver biopsy.     

Thiopurine methyltransferase deficiency in childhood lymphoblastic leukaemia: 6-mercaptopurine dosage strategies

Daily 6-mercaptopurine (6MP) forms the backbone of continuing chemotherapy for childhood lymphoblastic leukaemia (ALL). A major metabolic route is catalysed by thiopurine methyltransferase (TPMT). TPMT deficiency occurs in 1 in 300 individuals and results in high concentrations of thioguanine nucleotides (TGNs), cytotoxic 6MP metabolites. A leukaemic child taking 6MP repeatedly developed profound pancytopenias. TPMT deficiency was confirmed. TGN formation was then studied on attenuated 6MP dosages. Four weekly oral doses of 75 mg/m² 6MP produced TGNs of 2348 pmol/8 × 10⁸ red cells, nearly double the maximum TGNs recorded in ALL children with TPMT activity taking long term daily 75 mg/m² 6MP. Grossly elevated TGN concentrations were also produced at 10% standard 6MP dosage (7.5 mg/m² daily), accompanied by unacceptable 6MP toxicity (neutropenia, diarrhoea, vomiting). The child was eventually stabilised on 10% alternate day therapy and after 15 weeks TGNs were 1670 pmol, just above the upper end of the TGN range for ALL children with TPMT activity. Med. Pediatr. Oncol. 29:252–255, 1997. © 1997 Wiley-Liss, Inc.     

Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis.

To evaluate the adverse effects associated with long-term methotrexate (MTX) therapy in children with juvenile rheumatoid arthritis, we conducted a retrospective review of 62 patients with polyarticular juvenile rheumatoid arthritis, treated from 84 to 296 weeks with MTX weekly. Pulmonary function testing was performed before MTX therapy on 46 patients older than 6 years of age; 26 patients had serial pulmonary function testing, and no abnormalities were detected. In all 62 patients, liver function (alanine aminotransferase and aspartate aminotransferase activity) was monitored every 3 months. Transient liver function abnormalities developed in nine patients during treatment. Twelve patients underwent percutaneous liver biopsies after receiving 815 to 2980 mg of MTX; none had fibrosis or cirrhosis. Macrocytic anemia developed in one child receiving simultaneous long-term trimethoprim-sulfamethoxazole therapy and resolved after the trimethoprim-sulfamethoxazole was discontinued. No stomatitis or rashes were observed. Six patients were able to discontinue MTX therapy when their disease remitted; 56 continue MTX therapy. No child permanently discontinued MTX therapy because of an adverse effect. These data suggest that MTX may be better tolerated in children with juvenile rheumatoid arthritis than in adults with rheumatoid arthritis.     

Hepatic ultrastructure in leukemic children treated with methotrexate and 6-mercaptopurine

Methotrexate (MTX) and 6-mercaptopurine (6MP), the two drugs most commonly used for maintenance treatment of childhood leukemia, are both potent hepatotoxins. In order to assess MTX-6MP-induced damage, we obtained biopsies from 11 children with acute lymphocytic leukemia (ALL) for light microscopic and transmission electron microscopic study. Prednisone, vincristine, and L-asparaginase were used for induction of remission in all patients. Although light microscopic findings were minimal, we found significant ultrastructural abnormalities in all patients. Changes included nuclear abnormalities, disruption of rough and smooth endoplasmic reticulum, a variety of mitochondrial changes, steatosis, fibrosis, and changes in peroxisomes and lysosomes. These abnormalities could not have been predicted from liver function tests or histopathology. Three of the eleven patients studied had also received cyclophosphamide and cytosine arabinoside during maintenance therapy. The ultrastructural abnormalities in this group were not distinguishable from those observed in the group that did not receive these additional chemotherapeutic agents. The long-term clinical significance of these findings is not known.     

Immunocompetence and prognosis in children with acute lymphoblastic leukemia: Combination of two different maintenance therapies

Intensive chemotherapy in patients with leukemia produces immunosuppression. The level of immunocompetence correlates with prognosis. The immunological function of 29 children with acute lymphoblastic leukemia (ALL) in complete remission and on 2 different maintenance therapies was evaluated and compared with 16 normal children (Group A). Sixteen children (Group B) with ALL received 6 mercaptopurine (6MP) daily and methotrexate (MTX) twice a week, and 13 children (Group C) received 6MP and MTX weekly for maintenance. There was depression of both cellular immunity, measured by the number of T cells and skin tests, and humoral immunity, measured by number of B cells, primary antibody production to typhoid vaccine, and levels of immunoglobulins. However, continuous maintenance therapy (Group B) produced significantly more severe immunosuppression of cellular immunity than the intermittent therapy (Group C). Humoral immunity was equally depressed in both groups of leukemia patients, but was less altered than cellular immunity. Concomitantly, patients with intermittent maintenance chemotherapy had less hematologic depression, fewer episodes of infection, and fewer died in complete remission. Patients of both groups with higher levels of immunocompetence had better prognosis with longer duration of complete remission than patients with severe immunosuppression. Out of 6 patients with “favorable immunocompetence” only 1 relapsed at 7 months and the other 5 remain in complete remission from 8 to 31 months. Among 23 leukemic patients with “unfavorable immunocompetence,” 15 relapsed and 8 remain in complete remission from 9 to 26 months.     

Disposition of oral methotrexate in children with acute lymphoblastic leukemia and its relation to 6-mercaptopurine pharmacokinetics

We studied the disposition pharmacokinetics of methotrexate (MTX) given orally to 16 children with acute lymphoblastic leukemia (ALL) and its relation to the pharmacokinetics of 6-mercaptopurine (6MP) in the same children. There was an eightfold variability in area-under-concentration time-curve (AUC) of MTX achieved by the same dose. Excellent correlation existed between peak concentrations and AUC0----infinity (r = 0.95, P less than 0.001). Elimination T1/2 was between 1.34 and 5 hours (mean 2.16 +/- 0.23 hr, mean +/- SE). A weak correlation existed between AUC achieved by 1 mg/m2 MTX and patients' age or body weight. Weak but significant correlation existed between AUC achieved by 1 mg/m2 of MTX vs. 6MP (r = 0.54, P less than 0.05). In 13/16 patients peak concentrations were achieved at 60 minutes. There was a significantly larger AUC of 6MP achieved by a standardized dose in longer therapy (greater than 15 mo) vs. short therapy (less than 12 mo) (462 +/- 75 and 246 +/- 58 ng.ml-1.min.mg-1.m2, P less than 0.025). No statistical differences in AUC of MTX were found between short and long therapy. The large interpatient variability in MTX pharmacokinetics supports the possibility that differences in absorption and/or clearance of the drug may affect the clinical response. Because of the excellent correlation between peak and AUC of MTX, and because 3 measurements, at 30, 60, and 90 minutes will almost invariably identify the peak, this measurement can be used to estimate AUC for purpose of correlation with clinical outcome.     

Prolylhydroxylase and procollagen type III in long-term survivors of acute lymphoblastic leukemia (ALL): a biochemical approach to HCV-related liver disease

BACKGROUND: We examined two proteins, prolylhydroxylase (hPH) and procollagen type III (PIIIP), as possible non-invasive HCV-related markers of liver disease. The purpose of this study was to assess whether the measurement of these proteins could serve to monitor HCV related liver damage in acute lymphoblastic leukaemia (ALL) patients. PROCEDURE: A total of 34 ALL patients, 24 HCV-seropositive and 10 HCV-seronegative, who had had increased transaminase values (ALT) for almost 6 months were studied. Serum hPH concentrations were determined by an immuno-enzymatic assay kit. PIIIP was assayed by the radioimmunoassay method. RESULTS: Both hPH and PIIIP were increased in ALL patients with chronic hepatitis C. Serum hPH levels were significantly elevated in those with chronic hepatitis C with either normal or high transaminases when compared to those who never were HCV seropositive. The sensitivity and specificity of these protein measurements to evaluate hepatic fibrosis were not supported by histologic confirmation because only 6 out of 12 patients with chronic hepatitis had a liver biopsy. CONCLUSIONS: Our study suggests that PIIIP and hPH values are significantly higher in ALL patients with chronic HCV with either normal or high transaminases. This might suggest that the liver damage is more marked in patients with chronic hepatitis and that the liver damage is related to the HCV rather than chemotherapy. Future studies correlating histologic findings with the serum biochemical markers are required to establish the sensitivity and specificity of hPH and PIIIP in predicting hepatic fibrosis and to confirm this association.     

Liver disease does not affect lipolysis as measured with the 13C-mixed triacylglycerol breath test in children with cystic fibrosis

BACKGROUND: Liver disease associated with cystic fibrosis may not only limit the solubilisation and absorption of the products of fat digestion, but also may depress the activity of pancreatic lipase. The purpose of this study was to measure the effect of liver disease on triacylglycerol lipolysis using the 13C-mixed triacylglycerol breath test. METHODS: Forty children with cystic fibrosis took 13C-mixed triacylglycerol with a standard breakfast and the child's normal pancreatic enzyme replacement therapy. Breath samples were collected before and every 30 minutes after ingestion for 6 hours. The cumulative percentage dose of 13C recovered at 6 hours was calculated from sequential measurements of 13C enrichment of breath CO2, measured by isotope ratio mass spectrometry. Liver abnormalities and portal hypertension were defined by ultrasound scan and clinical examination. RESULTS: Twenty-four children had liver abnormalities, including 5 with portal hypertension. No difference was found between cumulative percentage dose of 13C recovered at 6 hours in 16 children with no liver abnormality (mean, 21.4%+/-11.1%), 19 children with liver abnormalities (22.2%+/-10.0%) and 5 children with portal hypertension (20.9%+/-7.1%). CONCLUSION: Intestinal lipolysis is not reduced in cystic fibrosis liver disease when measured using the 13C mixed triacylglycerol breath test. These findings affirm the test's use as an indirect measure of fat digestion that is not affected by inadequate intraluminal bile salts or liver disease.     

Hepatotoxicity of 6-mercaptopurine in childhood acute lymphocytic leukemia: Pharmacokinetic characteristics

Treatment with 6-mercaptopurine (6MP) is associated with adverse gastrointestinal (GI) and hepatic effects. Four patients, ages 6.9 ± 2.6 (mean ± S.D.) years, with acute lymphocytic leukemia (ALL) on maintenance chemotherapy including 6MP, developed nausea, vomiting, abdominal pain, elevated liver enzymes, and hyperbilirubinemia after 1.4 ± 1.0 (range 0.5–2) years. Liver biopsy in 1 patient was suggestive of drug-induced intrahepatic cholestatis. Symptoms resolved and liver function returned to normal after discontinuation of 6MP. Pharmacokinetic data of the symptomatic patients were compared with those of 25 ALL patients on the same protocol but without GI symptoms or hepatotoxicity. Levels of 6-thioguanine nucleotides (6-TGN) and the methylated metabolites of 6MP in red blood cells of the patients with hepatotoxicity, were not significantly different when compared to patients without hepatotoxicity, suggesting similar absorption of 6MP in both groups. Time to achieve peak 6MP levels was significantly longer in the symptomatic patients compared to the asymptomatic patients (P = 0.005). Peak levels and standardized concentration versus time curve (AUC) per 1 mg of 6MP per m² of body surface area were significantly lower in the patients with hepatotoxicity (P = 0.016; P = 0.037, respectively). A significant correlation between peak 6MP levels and standardized AUC (r = 0.729, P < 0.0001) was found. These results suggest accumulation of 6MP and its metabolites in the liver of the patients with GI symptoms, leading to hepatotoxicity. © 1996 Wiley-Liss, Inc.     

Delta Virus and Childhood Leukemia

We studied 145 children with acute lymphocytic leukemia (ALL) in remission who had been off chemotherapy for at least 2 years, to assess the prevalence of hepatitis delta virus (HDV) infection, and to determine whether HD V infection was associated with more severe chronic liver disease. The prevalence of chronic HBV infection was 41.5% (60/145). The prevalence of HDV infection among these patients with chronic HBV infection was 50% (30/60). Eighty-five patients were HBsAg-negative. There was evidence that HDV-infected children had more severe chronic liver disease than did HBsAg-positive, anti-HDV-negative patients: (1) their serum ALT levels were significantly more likely to be elevated at long-term follow-up (27/30 vs. 10/26, p = 0.0001); (2) their mean ALT levels were significantly higher 3 years after the cessation of chemotherapy (128 vs. 84 IU/L, p = 0.001); and (3) they were more likely to have either chronic acute hepatitis or cirrhosis when liver biopsy was done (18/23 vs. 6/18, p = 0.0038). Children who were HBsAg-negative had the lowest alanine aminotransferase (ALT) levels and were least likely to have chronic active hepatitis or cirrhosis (3/31).

We conclude that infection with HDV in children with ALL is associated with serious chronic liver disease. In long-term survivors, HDV infection is a major cause of morbidity and an adverse prognostic factor in terms of leukemia-free survival.     

Influence of different cytotoxic drugs on T and B lymphocytes in children with ALL during remission maintenance therapy

The influence of four different cytotoxic drugs (MTX, CYC, 6 MP, and ARA-C) on T, B, and O-lymphocytes was investigated in 20 children with ALL in complete remission during cyclic remission maintenance therapy. Each of the four drugs causes a marked reduction of the absolute number of T and B cells whereas the relative number lies within the normal range with the exception of CYC, which leads to a depression of the percentage of both T and B cells. The percentage of O cells is markedly increased by CYC and slightly increased by MTX, 6 MP, and ARA-C. The data are interpreted with care since the function of the immune system and especially tumor rejection depends on the interaction between the different lymphocyte subpopulations.

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Zusammenfassung Der Einfluß von 4 verschiedenen Cytostatica (MTX, 6 MP, CYC und ARA-C) auf T-, B- und O-Lymphozyten wurde bei 20 Patienten mit ALL in Vollremission während einer cyklischen Erhaltungstherapie untersucht. Während der Anwendung aller Cytostatica ist die absolute Anzahl von T- und B-Lymphozyten deutlich erniedrigt, während die relative Anzahl von T und B Zellen im unteren Normbereich liegt mit Ausnahme von CYC, welches zu einer deutlichen Senkung der relativen Anzahl von T und B Lymphozyten führt. Entsprechend ist der Prozentsatz von O Zellen unter CYC deutlich erhöht und unter MTX, 6 MP und ARA-C nur leicht erhöht.Die Ergebnisse werden mit Vorsicht interpretiert, da die Funktion des Immunapparates und insbesondere die immunologische Tumorabwehr auf der Interaktion zwischen den verschiedenen Lymphozytensubpopulationen beruht.

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Abbrevations used in this paper ALL acute lymphocytic leukemia - ARA-C arabinosyl cytosine - B cell nonthymus-derived lymphocyte - CYC cyclophosphamide - MEPA methotrexate-cyclophosphamide-6 mercaptopurine-arabinosyl cytosine - 6 MP 6 mercaptopurine - MTX methotrexate - T cell thymus-derived lymphocyte Supported by the Deutsche Forschungsgemeinschaft (Oe 27/20)Parts of this work were presented at the 12. Arbeitstagung für pädiatrische Forschung, Göttingen, März 1976     

High-dose methotrexate improves clinical outcome in children with acute lymphoblastic leukemia: St. Jude Total Therapy Study X

High-dose methotrexate (HDMTX, 1,000 mg/m2) and cranial irradiation/sequential chemotherapy (RTSC) were compared for ability to extend complete remission durations in children with acute lymphoblastic leukemia (ALL). Three hundred thirty patients were enrolled in the study, according to our criteria for standard-risk ALL: a leukocyte count less than 100 X 10(9)/L, no mediastinal mass, no leukemic involvement of the central nervous system (CNS), and blast cells lacking sheep erythrocyte receptors and surface immunoglobulin. Prednisone-vincristine-asparaginase induced complete remissions in 95% of the patients, who were then randomized to receive either HDMTX (n = 154) or RTSC (n = 155). HDMTX was administered with intrathecal MTX for the first 3 weeks following remission induction, and then every 6 weeks with daily mercaptopurine (MP) and weekly oral MTX for a total of 18 months. The RTSC regimen consisted of 1,800 cGy cranial irradiation and intrathecal MTX for 3 weeks, followed by MP/MTX, cyclophosphamide/doxorubicin, and teniposide/cytarabine administered sequentially over 18 months. The final 12 months of treatment for both groups was MP and oral MTX; all patients received intrathecal MTX every 12 weeks. With a median follow-up of 5 years, complete remission durations have been significantly longer among children treated with HDMTX, compared with RTSC (P = .049) or historical institutional control regimens (P = .002). Approximately 67% of the patients receiving HDMTX and 56% of those receiving RTSC are expected to be in continuous complete remission at 4 years. Overall, isolated CNS relapse rates were similar (P = .17) in the two treatment groups, although by newer risk criteria cranial irradiation could be expected to provide better protection in patients with an unfavorable prognosis. These findings indicate that addition of intermittent HDMTX infusions to conventional chemotherapy is an effective method for extending complete remissions in children with ALL.