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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.

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.

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.

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.

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.

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.

Leukemic cells from 89 (24%) of 369 children with newly diagnosed acute lymphoblastic leukemia (ALL) were found to have a pre-B immunophenotype. By comparison with blasts having the common ALL phenotype, the pre-B cells were more likely to have a DNA index less than 1.16 (P = 0.02), a pseudodiploid karyotype (P less than 0.001), and a chromosomal translocation (P = 0.001). Increased serum lactic dehydrogenase levels (P = 0.001) were also characteristic of pre-B ALL; otherwise, the clinical and laboratory features of the two groups were similar. A nonrandom chromosomal translocation, t(1;19)(q23;p13.3), was identified in blast cells from 16 (23%) of the 70 patients with pre-B ALL and adequate chromosome banding studies; different translocations were found in 11 of the remaining patients. The presence of any chromosomal translocation in the pre-B group was significantly related to a higher leukocyte count, an increased level of serum lactic dehydrogenase, an increased percentage of S-phase cells, black race, and a blast cell DNA index less than 1.16. Four presenting features were found to confer an increased risk of treatment failure among pre-B patients: pseudodiploidy, chromosomal translocation, black race, and higher serum lactic dehydrogenase level. In a multivariate analysis, pseudodiploidy emerged as the strongest factor for predicting relapse in pre-B ALL. The frequent association of chromosomal abnormalities of known adverse prognostic significance and high serum lactic dehydrogenase levels with pre-B-cell ALL explains, at least in part, the poor treatment outcome reported for children with this subtype of leukemia.

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.

Glucocorticoid receptor (GR) levels were quantitated in leukemic blasts from bone marrow aspirates of 249 children with acute lymphoblastic leukemia (ALL) who were entered on two St. Jude Total Therapy Studies. Of these, 235 were evaluable for analysis of the relation of GR levels to clinical outcome. For the 42 patients in the earlier Total Therapy Study IX, lower GR levels (less than 16,000 sites/cell) were associated with both induction failure and more frequent relapse (p less than 0.01) [Cancer Research, Vol. 42, p. 4801 (1982)]. When patients with 'high-risk' features (leukocyte count greater than 100 X 10(3)/mm3, positive erythrocyte rosette test, central nervous system involvement, and mediastinal mass) were excluded, lower receptor levels were still associated with early and more frequent relapse (p less than 0.02). The other 193 evaluable patients were consecutively admitted to Total Therapy Study X, in which patients with 'standard-risk' or 'high-risk' features were assigned to separate protocols--XS and XH, respectively. Induction chemotherapy in both protocols consisted of prednisone, vincristine and L-asparaginase; patients in the XH protocol received additional epipodophyllotoxin (VM-26) and cytosine arabinoside twice a week for 2 weeks preceding the conventional induction therapy. To compare the prognostic value of GR level in Study X with that of Study IX (which included both 'high-risk' and 'standard-risk' patients but did not separate them into different protocol groups), children in the XH and XS protocols were analysed together. The proportion of patients with 'standard-risk' features was the same in the two studies: 69% in Study IX and 73% in Study X. In Study X, which had a significantly better treatment result (p less than 0.001), lower receptor levels were not associated with induction failure, but were correlated with more frequent relapse (p less than 0.05). When patients in XH and XS protocols were analysed separately, however, receptor levels were no longer related to treatment outcome. Thus, GR level in childhood ALL has prognostic value, but it is not an independent factor and its importance is related to the efficacy of treatment.

We examined the leukemia cells of 81 consecutively admitted children and adolescents with acute nonlymphoblastic leukemia (ANLL) to determine the frequency and specificity of chromosomal abnormalities. Karyotypes were obtained for 73 (90%) of the 81 children, and 36 (49%) were abnormal. The modal karyotypes for the cases were tightly clustered in the diploid range; only 5 (7%) were hypodiploid, with 45 chromosomes each, and only 2 (3%) had greater than 50 chromosomes. Specific chromosomal abnormalities in the abnormal karyotypes were compared to morphologic subgroups of ANLL. An 8;21 translocation was found in 6 of 9 cases with M2 morphology but was also found in 1 case with M1 morphology. One of 4 with M3 (progranulocytic) morphology had a 15;17 translocation, and another had a 17q deletion. A structural abnormality in 11q was found in 3 of 7 patients with M5 (monoblastic) morphology, 2 of whom had a 9;11 translocation. The only case of M6 had a 22q-or Philadelphia chromosome in addition to other abnormalities. Statistical analysis of 27 abnormal karyotypes showed preferential structural rearrangement of 8q and 21q. We conclude that, in children as well as adults, specific structural abnormalities are correlated with certain morphologic subgroups of ANLL. However, other chromosomal changes associated with prior mutagenic exposure of adult ANLL were uncommon in children, which may suggest a difference in pathogenesis.

The efficacy of orally administered sucralfate suspension in preventing and treating chemotherapy-induced mucositis was evaluated in a double-blind trial. Forty-eight children and adolescents with newly diagnosed acute nonlymphocytic leukemia were randomized to receive suspensions of either sucralfate or placebo orally every 6 hours during the first 10 weeks of intensive remission-induction chemotherapy. Patients given sucralfate suspension were less likely than subjects receiving placebo to acquire colonization with potentially pathogenic microorganisms: 14 (58%) of 24 versus 22 (92%) of 24, respectively (p = 0.008). However, no effect on preexisting colonization was noted. Subjective reporting of discomfort, objective scoring of the severity of mucositis, and the maximal percent of body weight lost during therapy were similar; 58% of patients receiving sucralfate reported no oral pain compared with 25% receiving placebo (p = 0.06). Ten episodes of gastrointestinal bleeding, 25 documented infections, and 886 days with fever were also equally distributed between sucralfate and placebo groups. We conclude that sucralfate suspension is of limited, if any efficacy, in the prevention and treatment of chemotherapy-induced mucositis. Sucralfate administration can, however, reduce acquisition of alimentary colonization with potential pathogens, perhaps by interfering with adherence to mucosal membranes.

Certain types of chromosomal abnormalities have been shown to exert strong independent influence on treatment outcome in acute lymphoblastic leukemia (ALL). To identify the changes most closely associated with prognosis, we analyzed the completely banded blast cell karyotypes of 161 children with this disease. One hundred twenty-five cases had one or more chromosomal abnormalities, with 45 showing translocations. The frequency of translocations was highest (58%) among patients with pseudodiploid karyotypes and lowest (0%) in the hyperdiploid group defined by 51 or more chromosomes. During the maximum 6-year follow-up period, 30 of the 45 patients with a translocation failed therapy, compared with only 27 of the 116 who lacked this feature. Life-table estimates of event-free survival indicate that only 14% of the translocation group will be in complete remission at 3 years. The percentages of failures associated with random and nonrandom translocations were virtually identical (68% v 65%). When entered in a Cox proportional hazards model with seven other types of chromosomal abnormalities, and then with 11 clinical and laboratory variables of known prognostic value in ALL, translocation emerged as the strongest single predictor of treatment outcome (P less than 0.0001). The model indicated that translocation increases the risk of treatment failure six times by comparison with the absence of this feature. These findings offer an explanation for the majority of early treatment failures in childhood ALL, including those previously attributed to ploidy classification.

Reinduction therapy consisting of cyclophosphamide (250 mg/m2 orally daily for 4 days) followed by etoposide (250 mg/m2 iv daily for 3 days) was administered to 14 children with refractory or recurrent acute nonlymphocytic leukemia. Five complete remissions were achieved in eight patients who had relapsed in the bone marrow 1-27 months after cessation of initial therapy, which included anthracyclines, cytarabine, etoposide, and 5-azacitidine. Reinduction attempts were unsuccessful in patients who had failed to achieve an initial remission and in those whose relapses occurred while receiving therapy. Toxicity, including myelosuppression and mucositis, was within acceptable limits. This drug combination deserves further assessment in therapeutic protocols for patients with acute nonlymphocytic leukemia.

Leukemia cell karyotypes were determined at diagnosis for 136 of 159 consecutive patients with acute lymphoblastic leukemia (ALL) who were followed for up to 35 mo. Ninety patients (67%) had abnormal karyotypes. Five chromosome categories were designated, based on the distribution of modal numbers: hyperdiploid greater than 50 (n = 41), hyperdiploid 47-50 (n = 18), pseudodiploid (n = 28), normal (n = 46), and hypodiploid (n = 3). Treatment response was assessed for the categories in terms of time to failure (induction failure, first relapse, or death). Children in the hyperdiploid greater than 50 category had the best responses to treatment, with only 2 failures, and those in the pseudodiploid category had the poorest (p less than 0.001). The remaining 3 chromosome categories had intermediate responses and formed a third prognostic group. This same influence of chromosome number on time to failure was evident within the 2 clinical prognostic groups: high risk, signified by a leukocyte count greater than 100 X 10(9)/liter, meningeal leukemia, mediastinal mass, or the presence of blasts that formed rosettes with sheep erythrocytes at 37 degrees C, and standard risk, indicated by the absence of these features. The influence of chromosome number on time to failure was also the same within the historically favorable prognostic group that had common ALL. Results of a multivariate analysis indicated that chromosome number was the strongest single predictor of outcome (p less than 0.001) and was the only variable that added significant prognostic information to leukocyte count (p less than 0.001). The combination of chromosome number and leukocyte count should more clearly distinguish patients with ALL at low or high risk of relapse.

Twenty-four (5.7%) of 424 children with newly diagnosed acute lymphoblastic leukemia (ALL) were found to have blast cells that expressed HLA-DR antigens but not the common ALL antigen (CALLA), E-rosette receptors, T-cell antigens, or cytoplasmic or surface immunoglobulins. Each of the eight cases tested expressed the B-cell associated antigen B4, but not B1 or B2 antigen. Myeloid-associated antigens were not present in any of the 10 cases tested. By comparison with common (CALLA+ B-cell precursor) ALL, patients having this immunophenotype were more likely to be children less than 2 yr of age (p less than 0.001), to have higher initial leukocyte counts (p less than 0.001), and to have blast cells with a DNA index less than 1.16 (p = 0.05), a pseudodiploid karyotype (p = 0.01) and a chromosomal translocation (p = 0.003). The presence of any chromosomal translocation in these CALLA- ALL was related to measures of increased leukemic cell burden including higher leukocyte counts, larger liver and spleen sizes and higher serum lactic dehydrogenase levels. While the patients were entered into several treatment arms of two protocols, the CALLA- cases appeared to have lower remission rate (p = 0.06) and shorter event-free survival time (p = 0.05) than did those with common ALL. The association with clinical and laboratory features of known adverse prognostic significance provides some explanation for the poor treatment outcome of CALLA- ALL.

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.

The value of intensified chemotherapy for improving event-free survival rates in childhood lymphoblastic leukemia (ALL) is now widely accepted among leukemia therapists. Still to be determined are (1) the optimal method of intensification, (2) the subset or subsets of patients for whom such treatment may be excessive, and (3) whether or not cure rates in ALL can be further improved by alternative approaches to intensification. St. Jude Total Therapy Study XI, based on predictions of the Goldie-Coldmand model of drug resistance, addresses some of these questions by use of rotational "non-cross-resistant" drug pairs throughout the course of therapy. A new method of risk classification has been developed to refine distinctions among prognostic subgroups, especially to identify patients with biologically unfavorable ALL. Unacceptable toxicity noted in the first 134 children enrolled in this study led to two protocol modifications. One hundred thirty-two patients have been treated subsequently without undue toxicity. The treatment is now being delivered safely. Our early experience with this regimen demonstrates some of the hazards of intensive multidrug combination treatment, but gains in leukemia control appear to justify this approach.

Childhood nonlymphocytic leukemia comprises a minority (25%) of pediatric leukemia cases, yet contributes a significant proportion of overall leukemia mortality. Improvements in supportive care (antibiotics, antifungals, nutrition, and blood products) along with aggressive induction therapies have significantly improved remission induction rates over the past two decades. Ideal treatment to completely eliminate residual disease following remission is not yet known. In most series, only one out of three patients are long-term survivors of this disease. Recent advances in allogeneic bone marrow transplantation and improved techniques for autologous engraftment leave promise for significant improvements in postinduction disease control. Biologic studies of surface immunophenotype have contributed to our understanding of the heterogeneity of this family of disorders and allowed identification and characterization of leukemias of mixed myeloid/lymphoid lineage. Karyotype studies have identified important subsets of ANLL with distinctive clinical and biologic properties, for which tailored therapies someday may be developed. In addition, studies of oncogenes provide insight into regulation of leukemic hematopoiesis with potential of identifying future methods to regulate proliferation of the leukemic clone.

Fifty-six children with refractory acute lymphocytic leukemia (ALL) were assessed for remission-induction responses to VM-26 (250 mg/m2 per week) in combination with prednisone (40 mg/m2 per day) and vincristine (1.5 mg/m2 per week). Each child had been treated intensively with steroids, vincristine, daunorubicin and L-asparaginase. In fact, all patients had failed to respond to previous reinduction therapy with prednisone-vincristine or had relapsed while receiving vincristine. Our intent in this study was to test whether or not addition of VM-26 to prednisone-vincristine would overcome clinical resistance to these established agents. Complete remissions were induced in 17 patients (0.30) over 4 to 6 weeks. Five of these children, all clinically unresponsive to prednisone-vincristine alone, had complete remissions that lasted longer than 1 year; two remain in remission for 2 1/2 years and both are now off therapy. Myelosuppression, the most serious treatment complication, was documented in 20 of 26 evaluable patients. The median time to recovery of normal marrow function was 15 days. These results demonstrate further the potential of VM-26 in combined-drug treatment of refractory ALL. Whether the effectiveness of this combination represents potentiation of prednisone and vincristine activity by VM-26 or some other, as yet unidentified interaction, remains to be determined.

The presenting features and clinical outcome of acute nonlymphoblastic leukemia (ANLL) in infants and older children were compared to identify any differences that might suggest methods to improve therapy. Twelve of the 29 infants were boys and 17 were girls, with ages ranging from two days to 12 months (median, 7 months). By comparison with 222 patients greater than 1 year of age, infants were significantly more likely to have monoblastic or myelomonoblastic leukemia (P less than .0001), chloroma (P less than .0001), marked hepatomegaly (P = .001), and high leukocyte count (P = .005) and were less likely to have Auer rods (P less than .001). Each of these features except leukocyte count showed an association with infant ANLL in a multivariate analysis. Twenty-four (83%) of the infants attained a complete remission, a rate that was not significantly different from that of the older children. Even though infants had a significantly higher CNS relapse rate (P = .003), their event-free survival times were no different than those of older children (P = .74). Ten of the infants remain in initial complete remission for 5+ to 112+ months (median, 52+ months). Infants with ANLL did not have a poorer prognosis than older patients in our study; future protocols for this age group should emphasize more effective systemic therapy, preferably including an epipodophyllotoxin, as well as improved treatment for subclinical CNS leukemia.

The authors reviewed 250 consecutive children with ALL to determine if the periodic acid-Schiff (PAS) score was a useful, independent predictor of time to failure. PAS stains were scored from 0 to 400 and divided into low- and high-score groups using a variance-ratio test (F test) to optimize any effect of PAS on prognosis. Although the effect of PAS score considered alone approached significance for time to failure, the PAS score lost all significance when the patients were divided into standard-risk and high-risk groups on the basis of peripheral white count, central nervous system involvement, mediastinal mass, or E-rosette positivity at diagnosis. A Cox regression analysis was performed on a subgroup of 198 patients for whom cytogenetic studies were also available. The PAS score again approached the level of significance when considered alone but was of no significance after the effects of peripheral white count, pseudodiploidy, mediastinal mass, and E-rosette positivity were removed. The authors conclude that the PAS stain has no independent prognostic significance in childhood ALL.

Four children developed mycotic cervical lymphadenitis while receiving cytotoxic chemotherapy for acute leukemia. Neutropenia, oral mucositis, and broad-spectrum antibiotic administration preceded the appearance of lymphadenitis in each case. Enlarged tender cervical lymph nodes of mycotic origin were not clinically distinguishable from lymphadenitis of bacterial or viral origin. Although cervical lymphadenitis was the initial clinical manifestation of deep fungal infection, computerized tomography of the chest and abdomen subsequently demonstrated asymptomatic pulmonic, splenic, or hepatic lesions characteristic of fungal abscesses in all four children. These findings demonstrate the importance of microbiologic identification of the etiologic agents of cervical lymphadenitis following mucositis and neutropenia in children with leukemia.

Pseudallescheria boydii, a common soil organism, is best known as the causative agent of mycetoma. Isolation of the organism from sites other than the extremities is relatively uncommon. However, the use of corticosteroids and cancer chemotherapy has been associated with an increasing frequency of localized superinfection as well as disseminated disease. Recently, an increased number of disseminated P boydii infections, primarily associated with immunosuppressed patients, has been reported in the literature. We diagnosed an additional case of P boydii in a 16-year-old boy who had acute lymphoblastic leukemia and manifested a disseminated infection during reinduction chemotherapy. The unusual features of this case were the extent of organ involvement, which was more wide-spread than previously noted in the literature, and the presence of conidia in sections of an endocardial thrombus.

Transient leukemoid reactions that resemble acute leukemia have been well described for infants with trisomy 21 (Down syndrome). We report a phenotypically normal 3-day-old boy with hepatosplenomegaly, leukocytosis, and circulating myeloblasts. On chromosome analysis, trisomy 21 was found in all blood and bone marrow cells. However, only 4% of cultured skin fibroblasts were trisomic and the other 96% were normal, thus indicating mosaicism. Without treatment, the leukocyte count gradually returned to normal and the organomegaly diminished. Subsequently, chromosome analysis of blood and bone marrow disclosed a predominance of cells with a normal karyotype. These findings suggest that mosaicism could be responsible for the transient leukemoid reactions in some newborns--i.e., the trisomic cells may temporarily gain a proliferative advantage over the normal cells, perhaps by inhibiting their growth. Serial cytogenetic studies, as well as chromosome analysis of more than one tissue, may help to distinguish transient leukemoid reactions from acute leukemia in infants.

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.

Sequential studies in children with acute lymphoblastic leukemia have demonstrated that at diagnosis or relapse there is defective utilization of complement by the alternative pathway. Thus, the sera of 17/18 patients fail to completely consume C3 to C9 when incubated with zymosan or cobra venom factor (CoF). This underutilization is due to a specific inhibitor of C3 activation which has been partially isolated. By remission, the inhibotor disappears and the CoF and zymosan assays return to normal. In addition, serum levels of C3 and factor B are elevated at the time of diagnosis or relapse but fall to below 3 S.D. from the mean in nearly 60 per cent of the cases during induction therapy. Similarly, serum C4 levels which are normal at diagnosis fall to less that 3 S.D. from the mean in 7/12 cases during treatment. Low C3 levels correlate well with factor B values, suggesting that if C3 to C9 are utilized after the inhibitor has been eliminated, such utilization occurs primarily through the alternative pathway. Presumably, as illustrated by the low C4 levels, this activity is mediated by the ampliciation loop of the alternative pathway involving classical pathway generation of C3b.

Using a whole-cell assay, we found glucocorticoid receptors (GR) in all 43 consecutive assessable children with newly diagnosed acute non-lymphocytic leukemia (ANLL). The receptor levels ranged from 2146 to 81,308 sites/cell (median = 18,105); these results were similar to those for acute lymphocytic leukemia. Receptor levels were not related to any of these clinical or biological features at diagnosis: age, sex, race, initial leukocyte count, liver or spleen size, presence of CNS disease or Auer rods, [3H] thymidine ( [3H]TdR) labelling index, French-American-British morphology or terminal deoxynucleotidyl transferase activity. Receptor levels also were not related to the initial treatment response or remission duration after therapy that did not include a glucocorticoid. We conclude that GR level has no clinical utility as a marker protein in childhood ANLL.

Leukemic cell chromosomal findings in 27 infants were analyzed. Among the 18 cases of acute nonlymphoblastic leukemia (ANLL), all but two were classified as monocytic or myelomonocytic. The remaining nine cases were acute lymphoblastic leukemia (ALL), seven lacking the common ALL antigen and two having cytoplasmic immunoglobulin (pre-B phenotype). Twenty-five cases (93%) had an abnormal karyotype, 21 (84%) being pseudodiploid. Chromosomal translocations were detected in 67% of the ANLL cases and in 78% of the ALL cases. Nonrandom chromosomal abnormalities included the t(9;11)(p21-22;q23) in three cases of monocytic leukemia, inversion of chromosome 16 in three cases of myelomonocytic leukemia with bone marrow eosinophilia, and t(4;11)(q21;q23) in one case of ALL. Chromosomal regions preferentially involved in infant leukemia included 11q23-25 (13 cases), 9p21-22 and 10p11-13. All but one of the 24 cases with chromosomal breakage or rearrangement had breakpoints that corresponded to known fragile sites, half of which were at 11q23-25, a finding that may have pathogenetic importance. The CALLA- or pre-B phenotype and the presence of chromosomal translocations in most infants with ALL provide a biological explanation for their poor prognosis.

This clinical study, begun in 1975, tested the efficacy of early and delayed intensification treatments in children with acute lymphoblastic leukemia. Regardless of presenting features, all patients received 4 weeks of conventional induction therapy with daily prednisone and weekly vincristine and daunorubicin. One-third were randomized to receive, in addition, two doses of asparaginase during induction therapy, while another one-third received four doses of both asparaginase and cytarabine after remission induction. Preventive central nervous system therapy uniformly included 2400 rads cranial irradiation and five doses of intrathecal methotrexate. Remissions were maintained with daily p.o. mercaptopurine and weekly i.v. methotrexate. Of the 277 assessable patients, 254 (92%) entered complete remission, and 102 (37%) remain clinically free of leukemia for 4.6 to 8.0 years (median, 6.3 years). The three treatment groups showed no significant differences in either remission induction rate or outcome, even when the analysis was based on risk assignment. A "late intensification" phase of therapy, added to the maintenance protocol for 65 patients who had been in continuous complete remission for 14 to 30 months, failed to extend remission durations, as judged from statistical comparison with matched controls (p = 0.84). When tested as a time-dependent covariate in the Cox proportional-hazards model, delayed intensification again showed no important effect on duration of complete remission. We conclude that limited early or aggressive late intensification of therapy, as described here, does not improve outcome in childhood acute lymphoblastic leukemia.

In early 1984, we treated 13 consecutive patients with acute lymphoblastic leukemia (ALL) using an induction regimen of rapidly rotated combinations of prednisone, vincristine, asparaginase, teniposide (VM-26), cytosine arabinoside, and high-dose methotrexate (MTX) followed by leucovorin rescue. The intent of this clinical trial, designated Total Therapy Study XI, is to test the hypothesis that greater initial leukemia cell kill will decrease opportunities for the development of drug-resistant mutants, with resultant improvement in the length of disease-free survival. Five patients experienced life-threatening gastrointestinal toxicity within three weeks of the start of treatment. One died. Three other patients had severe abdominal pain, abdominal distention, diarrhea, and weight loss, but not gastrointestinal bleeding. In the remaining five patients, toxicity was rapidly reversible, and each child was able to complete the planned course of chemotherapy. The study was then amended to switch high-dose MTX from the induction phase to the consolidation phase, allowing at least one week for mucosal recovery. Among the next 28 patients who were treated, none showed evidence of severe gastrointestinal toxicity. Patients now receive high-dose MTX alone as consolidation therapy and are tolerating it adequately. Drug timing should be examined critically when intensified multiple-agent regimens are being devised for initial treatment of ALL.

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.

Treatment with a combination of daunorubicin (45 mg/m2 IV, days 1-3) and cytarabine (100 mg/m2 continuous IV infusion, days 4-10) failed to induce complete remission in 31 of 87 children (36%) with acute nonlymphocytic leukemia (ANLL). Six patients with monocytic or promyelocytic leukemia died before day 14 of therapy from complications of hyperleukocytosis and coagulopathy; an additional 10 failed because of fatal infections associated with drug-induced marrow hypoplasia, and the remaining 15 had residual leukemia despite receiving two courses of daunorubicin and cytarabine. Alternative therapy with etoposide (250 mg/m2, IV, days 1-3, 7-9) and 5-azacytidine (300 mg/m2 IV, days 4, 5, 9, 10) induced complete remission in nine (60%) of the 15 patients with resistant leukemia. Among the six children who failed to respond to either regimen, three had cytochemical and immunophenotypic features indicative of acute mixed-lineage leukemia, and one had monosomy 7 syndrome. Our findings suggest that the addition of etoposide and 5-azacytidine to a basic daunorubicin-cytarabine regimen would increase remission induction rates in childhood ANLL. Careful determination of pretreatment characteristics, including blast cell immunophenotype and cytogenetic properties, are needed to identify unusual cases of ANLL that may require selective therapy.