Treatment results of childhood acute lymphoblastic leukemia in Austria--a report of 20 years' experience.

Comment in: Wien Klin Wochenschr. 2002 Feb 28;114(4):141-2.

Attarbaschi A, Mann G, Dworzak M, Urban C, Fink FM, Dieckmann K, Riehm H, Gadner H; Austrian Cooperative Study Group.

St. Anna Children's Hospital, Vienna.

Between 1981 and 1999, 890 Austrian children with acute lymphoblastic leukemia (ALL) were treated in 5 consecutive trials using protocols from the Berlin-Frankfurt-Munster (BFM) Group. In the trials BFM-A (Austria) 81 and ALL A 84, treatment stratification was performed using a risk factor, which was calculated from the initial peripheral blast cell count, and size of liver and spleen. In the following studies (BFM-A 86, 90 and 95) early response to a 7-day systemic mono-therapy with prednisone (as measured by the peripheral blast cell count) was used as an overriding stratification factor; in order to reduce the need for cranial radiotherapy, all patients received high-dose methotrexate (5 g/m2) for preventive central nervous system treatment. Event-free survival (EFS) rates increased from study BFM-A 81 (n = 141, probability (p) of EFS: 59% +/- 4%) and study ALL A 84 (n = 127, pEFS: 67% +/- 4%) to 77% +/- 4% in trial BFM-A 86 (n = 142), 79% +/- 3% in trial BFM-A 90 (n = 256), and 84% +/- 3% in trial BFM-A 95 (n = 224). However, the prognosis for high-risk patients has not significantly improved within the last 20 years (pEFS: 50%). Furthermore, conventional risk factors such as leukocyte count and age at time of diagnosis, could not be used to indicate patients in the low and intermediate risk group who might eventually relapse. Thus, in trial BFM-A 2000, detection of minimal residual disease by polymerase chain reaction-based methods after 5 and 12 weeks of therapy was introduced for treatment stratification. Minimal residual disease was prospectively shown to predict relapses more precisely and, as a matter of fact, may allow a more exact definition of which patients are at risk and which patients belong to the subgroup with a good prognosis despite reduced treatment.

PMID: 12060981 [PubMed - indexed for MEDLINE]

[Severe hemolysis and SIADH-like symptoms induced by vincristine in an ALL patient with liver cirrhosis]

[Article in Japanese]

Nishihori Y, Yamauchi N, Kuribayashi K, Sato Y, Morii K, Hirayama Y, Sakamaki S, Honma H, Suzuki N, Kudo T, Niitsu Y.

Department of Internal Medicine (Section 4), Sapporo Medical University School of Medicine.

An 11-year-old boy was diagnosed as having acute lymphoblastic leukemia (ALL, L1) in 1987 and underwent treatment with an ALL high-risk protocol (prednisolone, vincristine (VCR), daunorubicin, 1-asparaginase), which resulted in complete remission. In 1990 he developed chronic hepatitis C and received interferon therapy. In December 1994, ALL recurred, and the patient was treated with VCR. He subsequently developed severe hemolysis (Hb 12.5 g/dl-->6.8 g/dl) with increases of indirect bilirubin, AST, and LDH. Furthermore, symptoms resembling a syndrome of inappropriate secretion of ADH (SIADH) and DIC developed. Upon incubation of the patient's red blood cells with VCR in vitro, extreme deformity of the cells was observed. These findings suggested that splenomegaly, due to liver cirrhosis which had developed rapidly from chronic hepatitis C while the patient was in an immunosuppressed state induced by anticancer drugs, had trapped the deformed red blood cells and resulted in severe hemolysis. The patient died on the 165th day after admission due to liver failure.

PMID: 11193445 [PubMed - indexed for MEDLINE]

Age, sex, haemoglobin level, and white cell count at diagnosis are important prognostic factors in children with acute lymphoblastic leukemia treated with BFM-type protocol.

Ng SM, Lin HP, Ariffin WA, Zainab AK, Lam SK, Chan LL.

Department of Paediatrics, University Hospital, Kuala Lumpur, Malaysia. ngszemay@hotmail.com

The presenting features and treatment outcome for 575 Malaysian children (< or = 12 years of age) with newly diagnosed acute lymphoblastic leukemia (ALL), admitted to the University Hospital, Kuala Lumpur, Malaysia between 1 January 1980 and 30 May 1995 were evaluated to determine their prognostic significance. Two-year overall survival was achieved in 67 per cent of all patients and 55 per cent of patients were relapse-free at 2 years. All except 10 patients, with identified French-American-British L3 morphology were treated with the modified Berlin-Frankfurt-Munster 78 treatment protocol. Univariate analyses of failure rate conferred age, sex, white cell count and hemoglobin level as potentially significant prognostic factors. All four presenting features retained their prognostic strength in a multivariate analysis. Race, platelet count, morphological subtype, liver/spleen size, lymphadenopathy, central nervous system and mediastinal mass involvement did not show any significant effect on treatment outcome. The 2-year survival rate was significantly different with regard to age, white cell count and hemoglobin level. However, sex was not significantly related to overall survival. These prognostic factors may have implications on future stratification of risk-adjusted initial treatment in the management of childhood ALL. Our analysis of Malaysian children is similar to what could be predicted based on previous studies in other populations.

PMID: 11191144 [PubMed - indexed for MEDLINE]

In vitro metabolism of 6-mercaptopurine by human liver cytosol.

Rowland K, Lennard L, Lilleyman JS.

University of Sheffield, Division of Clinical Sciences (CSUH), Royal Hallamshire Hospital, UK.

1. The aim of this study was to investigate 6-mercaptopurine (6MP) metabolism by human liver cytosol in vitro. 2. Cytosol was prepared from seven human livers (A-G). A single cytosol (C) was used to optimize incubation conditions. 3. Cytosols A-G were incubated with 6MP at 2, 10 and 500 microM for two fixed times (5 and 48 h). Parent drug, thiopurine and thionucleotide metabolites were quantitated by high performance liquid chromatography at all time points. 4. At 5 and 48 h the 2 microM and 10 microM 6MP incubations contained both 6MP and its initial nucleotide metabolite, thioinosine 5'-monophosphate (TIMP). In addition, the 10 microM 6MP 48 h incubates contained small amounts of 6-thioguanine (6TG, median 0.12 microM). At 500 microM 6MP all seven liver incubates produced a range of metabolites. At 48 h these included thiouric acid, 8-hydroxy-6-mercaptopurine and 6-methylmercaptopurine (median 31, 19.5 and 8.8 microM respectively), with TIMP, 6TG, thioxanthine and thioxanthine nucleotide at median concentrations of 61, 0.79, 2.11 and 0.80 microM respectively. Thioguanine nucleotides, major metabolites measured in vivo, were not detected. 5. These results indicate that the human liver 6MP metabolic profile is dependent upon drug concentration.

PMID: 10426560 [PubMed - indexed for MEDLINE]

Use of L-asparaginase in childhood ALL.

Muller HJ, Boos J.

Abteilung fur Padiatrische Hamatologie, Munster, Deutschland. hmuller@uni-muenster.de

Owing to the high efficacy of L-asparaginase in the treatment of acute lymphatic leukaemia the enzyme was introduced into the chemotherapy schedules for remission induction of this disease shortly after results of large-scale clinical trials had become available. Since asparaginase monotherapy was associated with a high response rate but short remission duration, the enzyme is currently employed within the framework of combination chemotherapy schedules which achieve treatment response in about 90% and long-term remissions in the majority of patients. Recently initiated clinical trials have still confirmed the eminent value of asparaginase in the combination chemotherapy of acute lymphatic leukaemia and of some subtypes of non-Hodgkin lymphoma, and its important role as an essential component of multimodal treatment protocols. Despite the unique mechanism of action of this cytotoxic substance which shows relative selectivity with regard to the metabolism of malignant cells, some patients experience toxic effects during asparaginase therapy. Immunological reactions toward the foreign protein include enzyme inactivation without any clinical manifestations as well as anaphylactic shock. Severe functional disorders of organ systems result from the impaired homeostasis of the amino acids asparagine and glutamine. The changes affecting the proteins of the coagulation system have considerable clinical impact as they may induce bleeding as well as thromboembolic events and may be associated with life-threatening complications when the central nervous system is involved. Risk factors predisposing to thromboembolic complications are hereditary resistance against activated protein C and any other hereditary thrombophilia. Other organ systems potentially affected by relevant functional disorders are the central nervous system, the liver, and the pancreas, with patients who have a history of pancreatic disorders carrying an especially high risk of developing pancreatitis. Studies on the mechanisms of action and the occurrence of resistance phenomena have shown that a treatment response may only be expected if the malignant cells are unable to increase their asparagine synthetase activity to an extent providing enough asparagine to the cell; one may thus conclude that the enzyme-induced asparagine depletion of the serum constitutes the decisive cytotoxic mechanism. Independent of the asparagine depletion related cytotoxicity however, there are other mechanisms of clinical relevance like induction of apoptosis. Besides this, further influences on signal transduction cannot be excluded. Only few publications have dealt with the question of minimum trough activities to be ensured before each subsequent asparaginase dose in order to maintain uninterrupted asparagine depletion under treatment, and answers to this problem are not definitive. Clinical studies using enzymes from E. coli strains indicate that a trough activity of 100 U/l will suffice for complete asparagine depletion of the fluid body compartments with the preparations studied. These findings have been transferred to enzymes from other E. coli strains as well as those isolated from Erwinia chrysanthemi and to the PEG-conjugated E. coli asparaginases. It might be desirable to countercheck the results for confirmation or correction. The dosage and administration schedule of the various enzyme preparations required for complete asparagine depletion over a period of time have been insufficiently defined. While pharmacokinetic studies showed clinically relevant differences in biological activity and activity half-lives for enzymes from different biological sources, the findings of recently published clinical trials indicate that the therapeutic efficacy is affected when different asparaginase preparations are given by identical therapy schedules. (ABSTRACT TRUNCATED)

Publication Types: Review Review, Tutorial

PMID: 9768345 [PubMed - indexed for MEDLINE]

Critical study of prognostic factors in childhood acute lymphoblastic leukaemia: differences in outcome are poorly explained by the most significant prognostic variables. Fralle group. French Acute Lymphoblastic Leukaemia study group.

Donadieu J, Auclerc MF, Baruchel A, Leblanc T, Landman-Parker J, Perel Y, Michel G, Cornu G, Bordigoni P, Sommelet D, Leverger G, Hill C, Schaison G.

Departement de Biostatistique et d'Epidemiologie, Institut Gustave Roussy, Villejuif, France.

We determined the proportion of survival variability explained by the usual prognostic factors in childhood acute lymphoblastic leukaemia (ALL) during a prognostic study of 1552 patients enrolled in three consecutive Fralle group protocols (Fralle 83, Fralle 87 and Fralle 89). The event-free survival rates at 5 years were 54.8% (SD 1.9), 43.1%) (SD 2.7) and 55.6% (SD 2.2), respectively. In the univariate analysis the following variables were predictive of poor outcome: male gender, elevated leucocytosis (> 50 x 10(9)/l), circulating blastosis. haemoglobin >12 g/dl, platelet count <100 x 10(9)/l, age under 1 year or over 9 years, enlarged mediastinum, nodes, spleen and liver, T phenotype, absence of CD10+ cells; testicular and meningeal involvement, poor response to induction therapy (CCSG M3), and LDH >400 U/l. Among the cytogenetic features, hyperdiploidy had a protective effect, whereas hypodiploidy, translocation and other structural abnormalities had a negative influence, particularly in cases of t(9;22) or t(4;11). Multivariate analysis summarized the prognostic information in terms of four variables: age, gender, leucocytosis and cytogenetic features. Missing data had little influence on the results. However, despite their significance in the multivariate analysis, these four variables each had very low predictive power (1.1% for gender, 2.0% for age, 3.5% for leucocytosis, and 1.6% for cytogenetic features). Thus, the most significant prognostic factors in childhood ALL each explain no more than 4% of the variability in prognosis. This may explain the disappointing practical value of these factors and underlines the need for prognostic tools in childhood ALL.

Publication Types: Multicenter Study

PMID: 9722300 [PubMed - indexed for MEDLINE]

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

Berkovitch M, Matsui D, Zipursky A, Blanchette VS, Verjee Z, Giesbrecht E, Saunders EF, Evans WE, Koren G.

Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Canada.

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.

PMID: 8531858 [PubMed - indexed for MEDLINE]

Plasma and urine levels of methotrexate and 7-hydroxymethotrexate in children with ALL during maintenance therapy with weekly oral methotrexate.

Skoglund KA, Soderhall S, Beck O, Peterson C, Wennberg M, Hayder S, Bjork O.

Department of Pediatric Oncology, Karolinska Hospital, Stockholm, Sweden.

A new high-performance liquid chromatographic assay was used to determine methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OH-MTX), in the plasma (n = 17) and urine (n = 14) of children (age 3-12 years) on maintenance therapy for acute lymphocytic leukemia (n = 14) or non-Hodgkin's lymphoma (n = 3). Each child received oral doses of weekly MTX (4.0-29 mg/m2) and daily 6-mercaptopurine (40-111 mg/m2). Plasma samples were collected daily from two children during the 1-week dose interval. A limited sampling strategy was designed, whereby 2 days of blood sampling were used in the other 15 patients. Morning urine samples were collected daily for 1 week following MTX intake from 14 of the children. MTX was detectable in all plasma and urine samples for the entire dose interval. The main metabolite, 7-OH-MTX, could be detected in plasma and urine from all patients on the first day after dose intake but only in a few patients during the whole dose interval. Interpatient variability of MTX and 7-OH-MTX levels was high at all points during the week. Significant correlation were found between the urinary MTX levels on days 2 and 7 and plasma MTX levels on day 2 after intake. No significant correlation was found between drug levels in plasma or urine and liver function tests in the children showing signs of mild liver injury. This assay provides a tool for further studies on the role of pharmacokinetics for the clinical effects of weekly oral low-dose MTX given alone or in combination with 6-mercaptopurine.

Publication Types: Clinical Trial

PMID: 8272008 [PubMed - indexed for MEDLINE]

Liver function studies in children with acute lymphocytic leukemia after cessation of therapy.

Bessho F, Kinumaki H, Yokota S, Hayashi Y, Kobayashi M, Kamoshita S.

Department of Pediatrics, University of Tokyo Hospital, Japan.

We investigated liver function in 27 children with acute lymphocytic leukemia (ALL) after cessation of therapy. Induction therapy consisted of prednisolone+vincristine (VP regimen) alone (16 patients) or with addition of daunorubicin (4 patients) or L-asparaginase (7 patients). Patients treated with VP regimen received short courses of VP regimen every 12 weeks for the first year of maintenance. Twenty-five patients remained in first complete remission and had completed 3-year maintenance therapy with methotrexate (MTX) and 6-mercaptopurine (6-MP) 1-7 years prior to this study. Twenty-three patients had received transfusions of packed red blood cells or fresh whole blood (1-11 units; median: 2 units) but none had evidence of either hepatitis B or hepatitis C. Alanine aminotransferase (ALT), which was measured every 3 months during maintenance therapy, had values more than three times the upper limit of the normal range in 25% of the measurements in more than half of the patients. However, by 3 months after the completion of maintenance therapy, ALT had normalized in all patients and remained normal in all but two patients until the time of this study. Serum bilirubin, serum albumin, and prothrombin time were all within normal limits. Fasting and 2-hour postprandial total serum bile acids were high in 5 of 13 patients and in 6 of 13 patients, respectively. The ratio of cholic acids+deoxycholic acids to chenodeoxycholic acids+lithocholic acids was below 1 in all but two patients, whereas this ratio was above 1 in all controls. Our bile acid profile results indicate the necessity of careful long-term follow-up of survivors of ALL treated with hepatotoxic chemotherapy during childhood.

PMID: 8202032 [PubMed - indexed for MEDLINE]

6-Mercaptopurine cumulative dose: a critical factor of maintenance therapy in average risk childhood acute lymphoblastic leukemia.

Dibenedetto SP, Guardabasso V, Ragusa R, Di Cataldo A, Miraglia V, D'Amico S, Ippolito AM.

Division of Pediatric Hematology-Oncology, University of Catania, Italy.

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 prednisone (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.

PMID: 8060809 [PubMed - indexed for MEDLINE]

Prophylaxis of bacterial infection by sulfamethoxazole-trimethoprim (SMX-TMP) during chemotherapy in patients with childhood acute leukemia.

Tono-oka T, Nakayama M, Ohkawa M, Nakajima T, Takeda T, Matsumoto S.

A combination of sulfamethoxazole and trimethoprim was given orally to 13 children with acute leukemia on 16 occasions of hospitalization during remission induction chemotherapy for the prophylaxis of bacterial infection. Frequency of episodes of persistent fever in this group of patients was markedly low, namely 0.38 per one hospitalization, whereas that in control group which was given no drug was 0.98. Furthermore, frequency of episodes of definite bacterial infection in the patients given SMX-TMP was 0.25 per one hospitalization. This was significantly low as compared with control patients whose frequency was 0.84. Although, there occurred slight rash and liver dysfunction as the side effects, they were reversible. These results suggest that the prophylactic use of SMX-TMP in children with acute leukemia during chemotherapy is effective and valuable for the protection from bacterial infection.

PMID: 7314104 [PubMed - indexed for MEDLINE]

Incidence of childhood tumors in Shanghai, 1973-77.

Tu J, Li FP.

Data of the Shangai Tumor Registry were analyzed for incidence of cancer in children under 15 years of age, 1973-77. The incidence of all malignant neoplasms combined was 104.7 per million boys and 89.2 per million girls. Leukemia, brain tumors, and lymphomas comprised 70% of all childhood tumors in Shangai. Compared with U.S. whites, Shangai children had higher rates of myeloid leukemia and liver cancer and lower rates of lymphoid cancers and tumors of the kidney, eye, soft tissue, and testis. Effects of migration on tumor rates among Chinese children are largely unknown and merit additional study.

PMID: 6572746 [PubMed - indexed for MEDLINE]

A population-based case-control study of childhood leukemia in Shanghai.

Shu XO, Gao YT, Brinton LA, Linet MS, Tu JT, Zheng W, Fraumeni JF Jr.

Shanghai Cancer Institute, Epidemiology Department, People's Republic of China.

A population-based case-control interview study of 309 childhood leukemia cases and 618 healthy population control children was conducted in urban Shanghai, China. Like some studies in other countries, excess risks for both acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL) were associated with intrauterine and paternal preconception diagnostic x-ray exposure, and with maternal employment in the chemical and agricultural industries during pregnancy. ANLL was linked to maternal occupational exposure to benzene during pregnancy, whereas both ALL and ANLL were significantly associated with maternal exposure to gasoline and the patient's prior use of chloramphenicol. New findings, previously unsuspected, included an association of ANLL with younger maternal age at menarche (odds ratio [OR] = 4.3; 95% confidence interval (CI) = 1.3-13.9); a protective effect for long-term (greater than 1 year) use of cod liver oil containing vitamins A and D for both ALL (OR = 0.4; 95% CI = 0.2-0.9) and ANLL (OR = 0.3; 95% CI = 0.1-1.0); and excess risks of ANLL among children whose mothers were employed in metal refining and processing (OR = 4.6; 95% CI = 1.3-17.2) and of ALL associated with maternal occupational exposure to pesticides (OR = 3.5; 95% CI = 1.1-11.2). No relationships were found with late maternal age, certain congenital disorders, or familial occurrence, which have been related to childhood leukemia in other studies. In contrast with other reports, an excess of leukemia, primarily ANLL, occurred among second or later-born rather than firstborn children.

PMID: 3164642 [PubMed - indexed for MEDLINE]

Vincristine overdose: experience with 3 patients.

Comment in: Pediatr Hematol Oncol. 1991 Apr-Jun;8(2):ix.

Kosmidis HV, Bouhoutsou DO, Varvoutsi MC, Papadatos J, Stefanidis CG, Vlachos P, Scardoutsou A, Kostakis A.

Department of Oncology, Children's Hospital, A. Kyriakou, Athens, Greece.

Vincristine overdose (7.5 mg/m2) was accidentally administered to 3 children with acute lymphoblastic leukemia. Treatment included double-volume exchange transfusion, phenobarbital administered prophylactically, and folinic acid rescue 18 mg every 3 hours for 16 doses. Vincristine levels were also assayed and showed a dramatic decline in postexchange levels in the 2 patients who survived and an almost unchanged value in the patient who succumbed. Early signs of toxicity in the 2 survivors were peripheral neuropathy (day 4), bone marrow toxicity (day 5), gastrointestinal toxicity (days 6 and 7), and hypertension (days 7 and 8). Marrow aplasia lasted for 4 and 10 days, peripheral neuropathy for 15 and 42 days, gastrointestinal toxicity for 3 and 5 days, and hypertension for 5 and 14 days. The 2 children were discharged on days 13 and 16 and cytostatic therapy was restarted on days 18 and 25. Both are alive without evidence of leukemia. The third patient developed liver and marrow toxicity on day 3 and died on day 9. Postmortem examination showed leukemia infiltration of the liver and spleen.

PMID: 1863543 [PubMed - indexed for MEDLINE]

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

Erratum in: Pediatr Hematol Oncol 1992 Apr-Jun;9(2):following 198

Schmiegelow K.

Department of Pediatrics, University Hospital, Copenhagen, Denmark.

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.

PMID: 1782110 [PubMed - indexed for MEDLINE]

High-dose methotrexate administration and acute liver damage in children treated for acute lymphoblastic leukemia. A prospective study.

Locasciulli A, Mura R, Fraschini D, Gornati G, Scovena E, Gervasoni A, Uderzo C, Masera G.

Clinica Pediatrica, Universita di Milano, Ospedale S. Gerardo, Monza, Italy.

BACKGROUND. Methotrexate-induced hepatotoxicity following chronic low-dose administration has been extensively reported. Current protocols now include high-dose methotrexate (HDMTX), but there are few studies providing data on its acute hepatotoxicity in childhood leukemia. METHODS. To evaluate the prevalence of HDMTX-induced acute hepatotoxicity, sixty-eight consecutive children with ALL were prospectively studied from diagnosis to the end of HDMTX courses with biochemical and clinical evaluation performed at regular intervals. RESULTS. Prevalence of HDMTX-induced acute hepatotoxicity was 1.47% (1/68 patients). ALT values did not change in 22% (15/68) and decreased in 76.4% (52/68) after HDMTX infusion. Mean ALT levels calculated in all the patients decreased significantly during HDMTX administration when compared to the values reached during induction (p less than 0.0001). Direct hyperbilirubinemia was present only in the child with HDMTX-related hepatotoxicity. CONCLUSIONS. The use of HDMTX in the treatment of childhood ALL is not associated with major evidence of direct acute hepatotoxic effects, while it may modify the pattern of preexisting liver diseases.

PMID: 1398282 [PubMed - indexed for MEDLINE]