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PURPOSE: To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management. PATIENTS AND METHODS: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography. RESULTS: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity. CONCLUSION: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

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OBJECTIVE: To assess the effect of parenteral amino acid solutions on plasma amino acid concentrations in patients with acute nonlymphocytic leukemia (ANLL) receiving parenteral nutrition (PN). DESIGN: Ten patients were studied at diagnosis, on the morning PN was started, and three times during PN therapy coinciding with the sequential administration of three different amino acid solutions (Aminosyn, FreAmine HBC, and TrophAmine). The order of amino acid solution administration in each patient was by a randomized, block design. RESULTS: The patients were undergoing identical intensive induction therapy. There was no significant difference in the number of days they received PN or the amount of protein or calories received during the three PN study periods. At diagnosis, phenylalanine and glutamic acid concentrations were elevated compared with previously published normal values and remained elevated at all observation times. During PN, asparagine, aspartic acid, and tyrosine concentrations were significantly lower with all three amino acid solutions compared with their concentrations at diagnosis. Glycine and threonine concentrations were also significantly lower with FreAmine HBC and TrophAmine administration and cysteine concentrations were significantly lower with FreAmine HBC administration than at the time of diagnosis. Aminosyn was associated with plasma amino acid concentrations most similar to those measured at diagnosis. CONCLUSIONS: These results indicate that most amino acid concentrations fall within the normal range at diagnosis in the ANLL patients studied. Plasma concentrations for certain amino acids can be influenced by the amino acid solution used in PN. Further understanding of the derangements in amino acid metabolism and the influence of parenterally administered amino acid solutions on plasma amino acid concentrations may lead to improvements in the nutritional support of cancer patients.

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Thirty cases of newly diagnosed pediatric acute myeloblastic leukemia (AML) with French-American-British (FAB) M2 morphology were analyzed with cytogenetics and a comprehensive panel of monoclonal antibodies reactive with lymphoid-, natural killer (NK)-cell-, and myeloid-associated antigens. The t(8;21)(q22;q22), or t(8;21;V)(q22;q22;V), translocation was identified in 16 of the 30 cases. Cases with the t(8;21) did not differ significantly from the remaining M2 cases with respect to expression of CD11b, CD13, CD14, CD15, CD33, CD34, CD36, CD41a, CD42b, CDw65, TdT, or HLA-DR. Expression of the B-cell antigen CD19 was detected in 13 of the 16 t(8;21) cases (81%), but in only 1 of the 14 (7%) other M2 cases (P = .00006). Expression of the CD56 NK-cell antigen was also significantly more frequent among t(8;21) cases (63% v 14%; P = .01). Coexpression of CD19 and CD56 was found only in the t(8;21) group (9 of 16 cases, P = .0009). Furthermore, this phenotype was not found in 48 evaluable cases of de novo AML of the FAB M1, M3, M4, M5, or M7 subtypes. The 14 M2 AML cases lacking the t(8;21) commonly expressed CD2 (n = 5) or CD7 (n = 8). However, no case with the t(8;21) expressed either antigen (P = .01 and .0005, respectively). Thus, the t(8;21) biologic subgroup of pediatric M2 AML has distinct immunophenotypic characteristics that distinguish it from other types of de novo AML.

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Thiopurine methyltransferase deficiency, inherited as an autosomal codominant trait, is associated with aberrant mercaptopurine metabolism leading to excessive cellular accumulation of 6-thioguanine nucleotides, the active metabolites of mercaptopurine. We describe a case of severe thiopurine methyltransferase deficiency (activity less than 1 U/8 x 10(8) erythrocytes) in a young girl with acute lymphocytic leukemia. The level of 6-thioguanine nucleotide in the patient's erythrocytes was seven times the population median value, and she had intolerable hematologic toxic effects during postremission therapy with a standard dosage of mercaptopurine (75 mg/m2 per day). Subsequent therapy with 6% of this dosage (10 mg/m2 three times weekly) yielded erythrocytic 6-thioguanine nucleotide concentrations consistently above the population median but not associated with prohibitively toxic effects. This case demonstrates that thiopurine methyltransferase deficiency does not absolutely contraindicate mercaptopurine therapy, and it also provides insight into the mechanism of excessive toxic effects of mercaptopurine sometimes observed in children with acute lymphocytic leukemia.

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A total of 161 cases of pediatric de novo acute myeloblastic leukemia (AML) have been reviewed, for which complete karyotyping was available and three cases (2%) were identified with t(10;11)(p14;q21). Two of the three children were infants with monoblastic (FAB M5) leukemia and the third was an adolescent with undifferentiated myeloid (FAB M1) leukemia. Both infants presented with increased levels of lactate dehydrogenase. None of these cases had increased eosinophils. One of the infants is in remission 18+ months after diagnosis and intensive chemotherapy; the two other children attained brief initial remissions but succumbed to their disease within 11 months of diagnosis. The prognosis of such children appears to be similar to that of cases of AML lacking this translocation.

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A 15-year-old boy with acute lymphoblastic leukemia (ALL) developed disseminated fusarium infection with meningoencephalitis following a contaminated skin wound. With antifungal therapy, the cutaneous lesions cleared but central nervous system (CNS) infection persisted causing a fibrosing meningitis and a brain granuloma. Fusaria are soil saprophytes that are more commonly associated with superficial eye and skin lesions, but may also cause severe systemic infections with CNS involvement in immuno-compromised patients. The organism may be confused with Aspergillus in tissue sections, and can only be diagnosed by culture.

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To evaluate its toxicity and clinical efficacy in children with relapsed or refractory leukemia, we performed a phase I trial of 2-chloro-2'-deoxy-adenosine (2-chlorodeoxyadenosine; 2-CDA) given as a continuous 5-day infusion at doses of 3 to 10.7 mg/m2/d. In this study of 31 children with acute leukemia, the only dose-limiting toxicity was myelosuppression. At the highest dose level, three of seven patients developed fatal systemic bacterial or fungal infections. At dose levels above 6.2 mg/m2/d, significant oncolytic responses occurred in all patients. In addition, there was a significant correlation between both the responsiveness by cell type and dose of 2-CDA, such that more oncolytic responses were noted in acute myeloid leukemia (AML) patients than acute lymphoblastic leukemia (ALL) patients (P = .02). Although this was a phase I trial in heavily pretreated patients with refractory disease, two AML patients treated at 5.2 and 10.7 mg/m2/d, respectively, had complete hematologic responses, and one patient treated at 10.7 mg/m2/d had a partial response. In addition, there was a dose-response relationship in all patients with improved cytoreduction of peripheral blast cells at higher doses of 2-CDA. In vitro evaluation of 2-CDA uptake and anabolism by leukemic blast cells from 22 patients demonstrated that 2-chloro-2'-deoxyadenosine (Cld-AMP) and 2-chloro-2'-deoxyadenosine 5'-striphosphate (CldATP) reached concentrations close to steady-state levels within 1 hour. Intracellular nucleotide disappearance rates were high with half-lives of 1.29 and 2.47 hours for CldAMP and CldATP, respectively. This suggests that continuous infusion is necessary to maintain the desired plasma concentration. The results of this study confirm the antileukemic activity of 2-CDA and the lack of prohibitive nonhematologic toxicity. Phase II trials in patients with AML and ALL are warranted.

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Improvement in therapies for childhood acute lymphocytic leukemia has resulted in cure for the majority of young people with this disease. Recent therapeutic advances have focused on testing more extensive treatments for cases with adverse clinical/biologic features, or pharmacologic studies to maximize dose intensity. The latter includes a trial of alternating high-dose intravenous methotrexate with high-dose intravenous 6-mercaptopurine given for the first year postremission in an attempt to circumvent the patient's natural variability of absorption and metabolism of these drugs. Patients with acute myeloid leukemia continue to fare much worse and only one in three are long-term survivors. Acute myeloid leukemia therapies emphasize the use of intensive toxic courses of cytarabine, etoposide, and an anthracycline to cytoreduce the leukemic clone. Acute progranulocytic leukemia, however, now appears to be responsive in vitro to the differentiation agent all-trans retinoic acid. For this disease, complex responses are now obtained without the use of conventional antineoplastics.

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The clinical course and other distinctive features of five children who developed a testicular relapse 4 months to 25 months after the diagnosis of acute nonlymphoblastic leukemia (ANLL) are described. The chief presenting feature at relapse was painless testicular enlargement, as is also seen in children with acute lymphoblastic leukemia who relapse in the testes. By French-American-British convention, the malignant cells were classified as M4 (myelomonoblastic) in four cases and M2 (myeloblastic) in one. All children received a course of multiagent reinduction chemotherapy and all but one received local irradiation to the testes. Only one of these children, whose relapse was a late event after elective cessation of therapy, is a long-term survivor. A comparison with six previously published cases shows similar clinical characteristics and outcome. Given the poor responses of such patients to conventional treatment, it seems worthwhile to consider the use of intensive reinduction chemotherapy with concomitant bilateral testicular irradiation followed by remission intensification and an autologous or allogenic marrow transplant.

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Forty-one children with refractory acute nonlymphocytic leukemia (ANLL) were treated from March 1975 to February 1979 with a schedule-dependent combination of methotrexate (MTX) and L-asparaginase. Intravenous (IV) MTX was followed 24 hours later by IV L-asparaginase (10,000 units [U]/m2). The MTX dose was started at 60 to 100 mg/m2 and was escalated by 20 to 40 mg/m2 as tolerated. This sequence was repeated every 7 to 10 days. Eight patients (20%) achieved a complete remission (CR) and six others had a partial response (PR), with clearance of blasts from the peripheral blood and reduction of bone marrow blasts to less than 25% of nucleated marrow cells. Responding patients received a median maximum MTX dose of 120 mg/m2 (range, 60 to 220 mg/m2). The median number of courses required to achieve a CR was 6 (range, 2 to 13 courses). Toxicity consisted of allergic reactions to L-asparaginase (n = 12), stomatitis (n = 6), minimal elevation of hepatic enzymes (n = 2), and hyperglycemia (n = 1). Treatment was given on an outpatient basis in 95% of all courses. The data indicate that this combination therapy has antileukemic activity and is relatively nontoxic in childhood ANLL.

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Eighty-seven consecutive children and young adults with acute nonlymphocytic leukemia (ANLL) were treated uniformly with induction chemotherapy based on daunorubicin and cytarabine (ara-C), with the addition of etoposide (VP-16) and azacytidine (5-Az) for refractory patients. Of the 65 patients who entered complete remission, 42 were eligible for assessment of response to intensive chemotherapy consisting of four pairs of drugs administered in sequential fashion. Nineteen others with available histocompatibility locus antigen (HLA)-compatible donors were assigned to receive allogeneic bone marrow transplants within 16 weeks from their dates of complete remission. Durations of continuous complete remission (CCR) in the two groups were not significantly different at a median follow-up time of 6 years (P = .30 by log-rank analysis). Kaplan-Meier estimates of CCR probabilities (+/- SE) at 6 years were 43% +/- 13% (transplantation) and 31% +/- 7% (sequential chemotherapy). Postremission failures in the sequential chemotherapy group resulted from bone marrow relapse in 23 of 29 patients (79%), whereas in the transplantation group, failures were equally divided between marrow relapse and transplantation-related complications of graft-versus-host disease (GVHD) or infection due to the immunosuppressive effects of ablative chemotherapy. Comparison of hematologic remission curves indicated a significant advantage for marrow transplantation in terms of systemic leukemia control (P = .06). Thus, in programs of intensive chemotherapy of the type described here, allogeneic marrow transplantation should be seriously considered as alternative therapy for patients in first remission who have an HLA-matched sibling donor, provided that effective methods for control of transplant-related complications are available.

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Twenty-eight children with Down syndrome (DS) and acute lymphocytic leukemia (ALL) were compared to non-DS control leukemics matched by age, white blood cell (WBC) count, and treatment protocol to evaluate presenting manifestations, toxicity, and outcome. The DS children with ALL did not have unique clinical or biologic characteristics to distinguish their disease from that of non-DS patients. Eleven of the DS patients had successfully banded cytogenetic studies of their leukemic cells with the distribution of model chromosome number of 46 (n = 1), 47 (2), 48 (5), and greater than 50 (3). The abnormal leukemic line involved an isochromosome of the long arm of chromosome 9[i(9q)] in 3 cases. Multiagent chemotherapies induced complete remissions in 25 patients (85%), yet overall 5 year event-free survival was only 23 +/- 8% when compared to 64 +/- 9% for control children receiving similar therapies (P less than 0.01). A significant cause of treatment failure was late marrow recurrence in the DS children. Host toxicity was striking in these children. Severe congenital heart disease present in one-third contributed to 2 deaths during antileukemia therapy. Hyperglycemia secondary to diabetogenic agents and repeated bronchitis were common toxicities. Intolerance to the antifolate methotrexate with severe gastrointestinal and skin toxicities was universal. We conclude that the poor prognosis for the child with DS and ALL stems in part from their increased risk of complications and toxicity from intensive modern leukemia therapies, specifically antifolates.

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Reports of close associations between recurring chromosomal abnormalities and the clinical behavior of acute nonlymphocytic leukemia (ANLL) have stimulated efforts to define this disease in cytogenetic terms. Here we report on the leukemic cell karyotypes of 155 children with ANLL who were treated from 1980 to 1987 in consecutive programs of chemotherapy at this institution. Of 121 cases with adequate banding, 20% were normal, 30% had miscellaneous clonal abnormalities, and 50% were classified into known cytogenetic subgroups: inv(16)/del(16q) (n = 15), t(8; 21) (n = 14), t(15;17) (n = 9), t(9;11) (n = 9), t(11;V)/del(11q) (n = 7) and -7/del(7q) (n = 6). The inv(16)/del(16q) cases showed a nearly equal distribution of myelocytic and monocytic French-American-British (FAB) subtypes; only four of these patients presented with M4Eo morphology. Despite a 100% remission induction rate, patients with inv(16)/del(16q)-positive ANLL fared no better overall than the entire group; only 40% of this subgroup were event-free survivors at 2 years from diagnosis (P = .23). Patients with inv(16)/del(16q) frequently had CNS involvement at diagnosis (eight of 15) or initially relapsed in this site (three of eight). Event-free survival (EFS) was clearly superior for young patients with FAB M5 leukemia and the t(9;11) (P = .041). These patients were clinically indistinguishable from others with the FAB disease subtype, yet their responses to etoposide-containing therapies were noteworthy. By contrast, children with structural abnormalities involving 11q23, other than t(9;11), were infants (median age, 6 months) with FAB M4 or M5 leukemia, hyperleukocytosis, and frequent coagulation abnormalities. Patients with such changes [t(11;V) or del(11q)] relapsed early during postremission therapy: none remained disease-free more than 16 months from diagnosis. Because of resistant leukemia, patients with monosomy 7/del(7q) had a poor remission induction rate (17%; P = .0015); patients with the t(15;17) were also poor responders to induction therapy (44%; P = 0.02) because of hemorrhagic deaths. These results identify several cytogenetic subtypes of pediatric ANLL that may represent unique disease processes for which more effective early cytoreduction [-7/del(7q), t(11;V)], better supportive care measures [t(15;17)], or more effective CNS prophylaxis [inv(16)/del(16q)] would be warranted.

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Hyperuricemia is an unusual presenting feature of acute lymphoblastic leukemia (ALL) and is generally associated with a large leukemic cell burden. We describe three children with T-cell ALL who presented with acute renal failure and very high serum uric acid concentrations, despite a relatively small leukemic cell burden. Two of the three patients had normal complete blood counts without circulating blasts or other physical evidence of leukemia. An isolated renal relapse in one case was associated with hyperuricemia, increased renal excretion of uric acid, and renal dysfunction. An unusually high rate of purine catabolism of the lymphoblasts may cause hyperuricemia in these cases. Unexplained hyperuricemia should prompt a search for occult malignancy.

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Presenting features of 120 consecutive children with T-cell acute lymphoblastic leukemia (ALL), representing 15% of all patients diagnosed as having ALL during the study period, were analyzed to determine relationships with treatment outcome. Patients' ages ranged from 1.7 to 18.8 years (median, 10.3 years) and their leukocyte counts from 1.7 to 1,070 x 10(9)/L (median, 100 x 10(9)/L). Central nervous system (CNS) leukemia was present in 12.5% of the cases, a mediastinal mass in 61%, and L2 lymphoblast morphology in 32%. A relatively high proportion of cases, 26%, had normal karyotypes at presentation. Of the cases tested, membrane CD1 expression was found in 38% of cases, CD3 in 33%, CD4 in 50%, CD5 in 94%, CD8 in 55%, and CD10 in 35%. Four presenting features were found to confer an increased risk of treatment failure: age greater than or equal to 15 years, L2 lymphoblast morphology, abnormal karyotype, and membrane CD3 expression. This study illustrates the heterogeneity of presentations of childhood T-cell ALL and suggests that the relative importance of risk factors in ALL differs according to immunophenotype and treatment strategy.

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We studied the risk of the development of acute myeloid leukemia (AML) during initial remission in 733 consecutive children with acute lymphoid leukemia (ALL) who were treated with intensive chemotherapy. This complication was identified according to standard morphologic and cytochemical criteria in 13 patients 1.2 to 6 years (median, 3.0) after the diagnosis of ALL. At three years of follow-up, the cumulative risk of secondary AML during the first bone marrow remission was 1.6 percent (95 percent confidence limits, 0.7 and 3.5 percent); at six years, it was 4.7 percent (2 and 10 percent). The development of secondary AML was much more likely among patients with a T-cell than a non-T-cell immunophenotype (cumulative risk, 19.1 percent [6 and 47 percent] at six years). Sequential cytogenetic studies in 10 patients revealed entirely different karyotypes in 9, suggesting the induction of a second neoplasm. In eight of these patients, the blast cells had abnormalities of the 11q23 chromosomal region, which has been associated with malignant transformation of a pluripotential stem cell. There was no evidence of loss of DNA from chromosome 5 or 7, a karyotypic change commonly observed in cases of AML secondary to treatment with alkylating agents, irradiation, or both. We conclude that there is a substantial risk of AML in patients who receive intensive treatment for ALL, especially in those with a T-cell immunophenotype, and that 11q23 chromosomal abnormalities may be important in the pathogenesis of this complication.

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Interest in more precise subclassification of the acute leukemias by cytogenetic criteria led us to identify and characterize the full range of chromosomal abnormalities in 121 children with de novo acute nonlymphocytic leukemia (ANLL). Only 21% of the cases had normal karyotypes; 62% had consistent or recurrent alterations, most commonly inv(16) or del(16), t(8;21), t(15;17), t(9;11), t(11;V) or del(11), and -7 or 7q-; and 17% had miscellaneous, apparently random, clonal abnormalities. Statistically significant associations between chromosomal abnormalities and the morphologic/cytochemical subtypes of ANLL, defined by criteria of the French-American-British (FAB) cooperative group were demonstrated for the t(8;21) in M1 and M2 leukemia, t(15;17) in M3, t(9;11) in M5, and translocations involving 11q23 other than t(9;11) [t(11;V)] or del(11q) in M4 and M5. The chromosome 16 inversion was not restricted to the M4 subtype, as is generally reported, and was not uniformly associated with increased and/or abnormal marrow eosinophils. None of these 121 cases were characterized by the Philadelphia chromosome, nor did any have the t(6;9), t(16;16), or inv(3), which have been noted previously in this disease. In addition to confirming several recognized correlations between recurrent structural chromosome abnormalities and FAB subtypes, this study identified novel abnormalities that have not been reported by others. It also disclosed an unusual heterogeneity of chromosome 16 abnormalities with respect to their distribution among FAB subtypes, their association with marrow eosinophilia, and their participation with other chromosomes in translocations.

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