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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.

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.

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.

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.

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.

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.

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.

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.

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.

The authors observed Auer rods in mature neutrophils, bands, and metamyelocytes in two children with AML with maturation (FAB M2). In order to determine if this rare finding was characteristic of AML M2, the authors reviewed the bone marrows and peripheral blood smears of 50 children with AML M2 and 50 children with other AML subtypes (FAB M1, M3, M4, and M5). They found Auer rods in mature neutrophils and band forms in 10 of 50 patients (20%) with AML M2 but in none of 50 patients with non-M2 AML. This finding was not related to the frequency of mature cells in the specimen or to the frequency of Auer rods in blasts. Cytogenetics did not show a consistent abnormality. The presence of Auer rods in mature granulocytes is unique to FAB M2 AML in the authors' series and supports the concept that in AML at least some of the mature myeloid cells are involved in the leukemic process.

We prospectively studied the effect of amphotericin B therapy on aminoglycoside clearance in 20 consecutive children during the remission-induction phase of chemotherapy for acute myelocytic leukemia. Increases (greater than 50%) in the half-life for aminoglycoside excretion were not associated with antileukemic or aminoglycoside therapy alone but occurred in 12 of 17 children when amphotericin B was added to the antimicrobial regimen. Seven children had impaired aminoglycoside clearance without increases (greater than 50%) in serum creatinine; hence the resulting adjustments in aminoglycoside dosage would not have been made had we relied solely on serial measurements of serum creatinine. Evidence for increased excretion of the renal enzymes N-acetyl-beta-D-glucosaminidase and alanine aminopeptidase during amphotericin B therapy suggested that damage to proximal tubular cells may contribute to the renal impairment that has been associated with this drug. Our findings underscore the value of monitoring serum aminoglycoside concentrations in children being treated with amphotericin B.

Clonogenic cells from 41 children with newly diagnosed acute myeloid leukemia (AML) were tested in vitro for their sensitivity to cytarabine (Ara-C) and daunorubicin (DNR). The findings were then compared with the patients' responses to induction chemotherapy that uniformly included Ara-C and DNR. Light-density marrow cells were incubated with either or both drugs for one hour and cultured over leukocyte feeder layers; clusters and colonies were scored on days 7, 10, and 14. Only the percentage of cell kill in the presence of 1.8 mumol/L DNR was significantly associated with responses to induction therapy: median of 45% (range, 0% to 98%) for patients achieving complete remission v 16% (range, 4% to 23%) for nonresponders (P = .007). The relationship between clonogenic cell kill less than or equal to 23% and clinical responses was striking. Of the 11 evaluable patients with in vitro findings in this category, ten either failed induction therapy or relapsed within 1 year after attaining remission. Kaplan-Meier analysis of relapse-free survival times indicated longer durations of remission for patients whose blast cells showed increased sensitivity in vitro to Ara-C alone, DNR alone, or a combination of the two agents. Seven of 11 patients with cell kills of greater than or equal to 49% in the presence of 1.25 mumol/L Ara-C remain free of leukemia, compared with only one of 12 whose cells were less sensitive to the drug (P = .006). We conclude that the in vitro sensitivity of clonogenic leukemic progenitors to DNR and Ara-C correlates with treatment outcome in children with newly diagnosed AML.

We studied the clinical and biologic features of 10 cases of acute leukemia that met standard French-American-British (FAB) criteria for acute myeloid leukemia (AML) but in which the blast cells also expressed the T-cell-associated CD2 surface antigen. All cases had greater than 3% myeloperoxidase and Sudan black B-positive leukemic blasts, and blasts from seven cases contained Auer rods. Reactivity of the cells with a panel of monoclonal antibodies (MAbs) indicated that leukemic cells in all cases expressed myeloid-associated (CD11b, CD13) surface antigens, further supporting the diagnosis of AML. However, blasts from every patient coexpressed the T-cell-associated surface CD2 and CD7 as well as cytoplasmic CD3 antigens. Blasts from five patients expressed surface CD25, whereas blasts from only one expressed surface CD3. Five patients had rearranged T-cell receptor beta-chain genes, whereas only three had rearranged T-cell receptor gamma-chain genes. This pattern of lineage-related gene expression appears to define a distinct subtype of AML with T-lymphoid features (CD2+ AML) and could reflect either aberrant gene expression in leukemic blasts or transformation of a pluripotent stem cell having a flexible pattern of gene expression. Clinically, these 10 patients presented at an older age with a higher leukocyte count and a higher frequency of lymphadenopathy than did children whose blast cells were characteristic of myeloid leukemia. Patients with CD2+ AML also had poorer responses to remission induction therapy (50% v 80% entered complete remission, P = .05). However, each of the five children who failed induction chemotherapy on AML protocols had a striking response to drug combinations usually reserved for lymphoid leukemia. We conclude that this leukemia with mixed lymphoid and myeloid characteristics is a distinct biologic and clinical entity.

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.

Leukemic blast cells are thought to arise from clonal expansion of a single transformed hematopoietic cell. This generality is supported by the rarity of convincing reports on acute myeloblastic leukemia (AML) with two karyotypically independent clones. Relying on sequential cytogenetic analyses, we identified such clones in two children with relapsed AML. The first case, classified as M2 leukemia in the French-American-British (FAB) classification system, had a t(8;21) (q22;q22) at diagnosis; 16 months later, at relapse, the leukemic cells had uniform morphologic features similar to those observed at diagnosis, except that two independent clones were present: one with the original t(8;21) and the other with t(11;22)(q23;q13) [corrected]). The second case was initially classified as FAB M1 leukemia with a t(8;21) (q22;q22). At relapse, 16 months later, the blast cells appeared morphologically uniform and similar to the diagnostic specimen; however, in addition to the original t(8;21) clone, there was a t(1;11) (p32;q23) [corrected]. These findings suggest that separate leukemogenic events affecting different progenitor cells can occur in rare cases of AML. The presence of two karyotypically independent clones could also be explained by multistep leukemogenesis; that is, more than one cell from a common pool of preleukemic cells could be affected by the transforming event, resulting in two independent clones. Alternatively, in light of recent reports of therapy-related leukemias with an 11q23 translocation, the new independent clone in these two patients could represent a therapy-related secondary malignancy. Thus, 11q23 translocations may occur preferentially in stem cells that are more susceptible to treatment-induced malignant transformation.

Bone marrow cells from 99 patients with acute myeloid leukemia were cloned in either agar stimulated by leukocyte feeder layers (AG/F) or methylcellulose supplemented with medium conditioned by phytohemagglutinin stimulation of leukocytes (MC/P). Although cell growth in the two systems was correlated (r = 0.74, p less than 0.0001), there was increased formation and size of clusters and colonies in AG/F, suggesting that the clonogenic cells from children with AML are more readily assayed in AG/F. The number and size of clones in either system did not show a relationship to the morphologic subtype of leukemia. Depending on the scoring system used, increased growth in MC/P was related to abnormal karyotype. Also dependent on scoring system, the ability of leukemic cells to form small clusters in AG/F was associated with resistance to induction therapy: cells of patients with resistant disease were more likely to produce small clusters (p = 0.02). Our results suggest that clonogenic cells from children with AML grow more readily in AG/F than in MC/P, but that neither culture system supports the growth of cells from all patients. Depending on scoring criteria, in-vitro growth patterns in AG/F correlate with response to induction therapy.

The combination of teniposide (VM-26) and amsacrine (AMSA) was evaluated in a dose-finding and efficacy study in 58 patients with relapsed or refractory acute leukemia. Both agents were given as simultaneous continuous infusions for 72 h through separate i.v. lines. All patients were evaluable for toxicity and 57 were evaluable for response; only 2 of 20 with acute lymphoblastic leukemia (ALL), acute mixed-lineage leukemia, or chronic myelogenous leukemia in blast crisis achieved a complete remission (CR). More encouraging was a second-remission rate of 43% (13 complete and 3 partial) in the 37 patients with acute nonlymphoid leukemia (ANLL). Responses occurred only in patients who received VM-26 doses of greater than or equal to 200 mg/m2 per day and AMSA doses of greater than or equal to 100 mg/m2 per day. Thus, the CR rate for relapsed ANLL patients who received the higher doses of both agents was 40% (13 of 33). All responders had previously received epipodophyllotoxin therapy and 40% had also received AMSA. All but one patient had severe leukopenia (less than 2.0 x 10(9) leukocytes/l) and thrombocytopenia (less than 50.0 x 10(9) platelets/l) as a results of therapy. Severe mucositis (grade 3 or 4) was the dose-limiting toxicity. Our results indicate that VM-26 plus AMSA, given by continuous infusion, is effective in the treatment of ANLL. Further phase II studies should consider using VM-26 at 200 mg/m2 per day and AMSA at 100 mg/m2 per day, but the best administration schedule remains unclear.