High concordance from independent studies by the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) associating favorable prognosis with combined trisomies 4, 10, and 17 in children with NCI Standard-Risk B-precursor Acute Lymphoblastic Leukemia: a Children's Oncology Group (COG) initiative.

Chromosome aberrations have a major role in pediatric acute lymphoblastic leukemia (ALL) risk assignment. The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) independently assessed the significance of trisomy for chromosomes 4, 10, and 17 in National Cancer Institute (NCI) Standard- and High-Risk ALL. Data from 1582 (CCG) and 3902 (POG) patients were analyzed. Eight-year event-free survivals (EFS) of 91% (CCG) and 89% (POG) (P < 0.001) were achieved in patients assigned to NCI Standard Risk whose leukemic cells had simultaneous trisomies 4, 10, and 17. Both groups showed the degree of favorable prognostic importance increased with the actual number of favorable trisomies. POG analyses also demonstrated hyperdiploidy (> or =53 chromosomes) was less of an independently significant prognostic factor in the absence of these key trisomies. This finding supported conclusions from previous CCG and POG studies that specific trisomies are more important than chromosome number in predicting outcome in pediatric B-precursor ALL. In NCI Higher Risk patients, the number of favorable trisomies was not prognostically significant, but showed the same trend. Moreover, specific trisomies 4, 10, and 17 remain associated with favorable prognosis in Standard-Risk B-precursor ALL, even in the context of very different treatment approaches between the groups.     

Significance of commonly used prognostic factors differs for children with T cell acute lymphocytic leukemia (ALL), as compared to those with B-precursor ALL. A Pediatric Oncology Group (POG) study.

T cell acute lymphocytic leukemia (T-ALL) and B-precursor ALL differ significantly in the clinical characteristics of the patients at presentation and in laboratory-defined characteristics of the leukemic cells. We assessed for pediatric patients with T-ALL the relative importance of prognostic factors previously demonstrated to predict outcome in B-precursor ALL. Presenting clinical and laboratory features were correlated with outcome for 441 children 12 months to 21 years of age with previously untreated T-ALL, registered on the Pediatric Oncology Group (POG) T3 protocol between 1986 and 1992. These T-ALL prognostic factor analyses were then compared to similar analyses for 1993 patients with B-precursor ALL enrolled during the same time period on the POG ALinC 14 protocol. Quantitative interaction between phenotype and each prognostic factor was studied to determine the relative importance of the prognostic factor for each of the two major immunophenotypes. We also analyzed the importance of maturational stage as a T-ALL prognostic factor, using a modified Ludwig definition of maturational stage. We conclude that several of the clinical and laboratory prognostic factors, which are used reliably for B-precursor ALL, are much less predictive in T-ALL (ie age, WBC, consensus risk group, hyperdiploidy, presence of trans- locations and CALLA expression). There was no significant difference between the phenotypes in the prognostic importance of race or gender. Our data demonstrate a significant difference in outcome among the three maturational stages of T-cell ALL, with the intermediate group faring best. Using traditional risk group criteria to stratify patients with T-ALL for therapy may not be appropriate.     

Pilot studies of species-specific chemotherapy of childhood acute lymphoblastic leukemia using genotype and immunophenotype.

Genotype and immunophenotype can be used to define biological species of acute lymphoblastic leukemia (ALL). The purpose of these two pilot studies, conducted between 1986 and 1994, was to explore the feasibility and acceptability of classifying ALL in this manner for selection of treatment rather than using conventional risk for failure factors such as age and initial white blood cell count. The possibility that conventional risk factors would be overcome and survival improved by this approach was also considered. Flow cytometry and chromosome analysis were used to classify the ALL of 150 children into one of five biologic categories as defined by cell surface antigens, DNA index and chromosome number and arrangement. Chemotherapy regimens depended on the assigned category. There was no provision for cranial irradiation and use of alkylating agents, anthracyclines and epipodophyllotoxins was restricted in order to reduce risk of late adverse sequelae. All patients are included in the analysis regardless of presenting condition or adherence to protocol. The majority of patients were Mexican-American or African-American. Eight-year event-free survival (EFS) is 60.7% (+/-4%) and 8-year overall survival (OAS) 72.6% (+/-3.7%). EFS and OAS varied significantly among the biologic categories despite differences in chemotherapy regimens. When the patients with B-precursor ALL were retrospectively classified by current Pediatric Oncology Group (POG) criteria, 8-year EFS was 82% (+/-7.3%) for the good risk group, 68.9% (+/-5.9%) for the standard risk and 48.8% (+/-7.6%) for the poor risk, all significant differences. However, when retrospectively classified according to the Rome/NCI prognostic criteria the 8-year EFS for standard risk patients was 69.1% (+/-5.1%) and for high risk 58.8% (+/-6.9%), not a statistically significant difference. Numbers of T cell and B cell patients are too few for comparison. Gender and ethnicity influenced survival as in treatment based on prognostic factors. Initial central nervous system (CNS) relapse occurred in five patients (3%) and combined CNS and hematological relapse in six (3%). Factors significantly associated with CNS and combined relapse were leukemic pleocytosis in the initial CSF sample, pro-B immunophenotype and DNA index <1.16, but not initial white blood cell count. Only three survivors appear to have serious late adverse sequelae, the only neurologic the result of asparaginase-induced cortical vein thrombosis. The results suggest that use of biologic species as defined by immunophenotype and genotype to select therapy of ALL is feasible and acceptable but under the conditions of these studies offered no apparent therapeutic advantage over conventional risk grouping. However, the introduction of molecular genotyping and novel gene targeted therapeutic agents justify further exploration of this approach.     

Increased midkine gene expression in childhood B-precursor acute lymphoblastic leukemia

Midkine (MK) is a heparin-binding growth factor that is overexpressed in a number of solid cancers. However, expression in acute leukemia has not been clarified. We examined MK gene expression using real-time PCR in 94 children with acute leukemia. In 30 of the 41 patients with B-precursor ALL, MK gene expression was overexpressed than normal BM. MK gene was also overexpressed in more than half of patients with FAB M1 and M2 types of AML. Quantification of MK gene by real-time PCR offers particular promise as a prognostic marker and a marker for minimal residual disease in children with B-precursor ALL.     

Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23+/-+/-12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5+/-+/-5% vs 23.4+/-+/-4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88+/-+/-13 vs 46+/-14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64+/-+/-8% (high risk) vs 83+/-+/-6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.     

In vivo and in vitro expression of myeloid antigens on B-lineage acute lymphoblastic leukemia cells.

The expression of myeloid antigens has been extensively examined using two-color analysis in 43 children with B-lineage acute lymphoblastic leukemia (ALL). On pre-culture cells, CD33 expression was frequently observed in CD19+, CD10- B-precursor ALL, and CD14 was expressed only on the cells from B-precursor ALL expressing CD19, CD10 and CD20, and B-ALL. After 2 or 3 days of culture without TPA, CD13 emerged on the cells from 21 of 29 patients irrespective of the presence or the absence of fetal calf serum in the culture. Of four patients with CD10+ B-precursor ALL, which showed no expression of CD13 after culture, two had T-cell associated antigens. Whereas the addition of TPA to the culture enhanced the expression of CD13 on the cells from acute non-lymphocytic leukemia (ANLL), TPA reduced the expression of this antigen on B-precursor cells. These findings suggest that the regulatory mechanism of CD13 expression may be different between B-precursor ALL and ANLL. Co-culture with cycloheximide mostly abrogated the induction of CD13, suggesting that CD13 expression was mainly dependent on de novo protein synthesis.     

Molecular detection of minimal residual disease is a strong predictive factor of relapse in childhood B-lineage acute lymphoblastic leukemia with medium risk features. A case control study of the International BFM study group.

The medium-risk B cell precursor acute lymphoblastic leukemia (ALL) accounts for 50-60% of total childhood ALL and comprises the largest number of relapses still unpredictable with diagnostic criteria. To evaluate the prognostic impact of minimal residual disease (MRD) in this specific group, a case control study was performed in patients classified and treated as medium (or intermediate)-risk according to the criteria of national studies (ALL-BFM 90, DCLSG protocol ALL-8, AIEOP-ALL 91), which includes a good day 7 treatment response. Standardized polymerase chain reaction (PCR) analysis of patient-specific immunoglobulin and T cell receptor gene (TCR) rearrangements were used as targets for semi-quantitative estimation of MRD levels: > or =10(-2), 10(-3), < or =10(-4). Twenty-nine relapsing ALL patients were matched with the same number of controls by using white blood cell count (WBC), age, sex, and time in first complete remission, as matching factors. MRD was evaluated at time-point 1 (end of protocol Ia of induction treatment, ie 6 weeks from diagnosis) and time-point 2 (before consolidation treatment, ie 3 months from diagnosis). MRD-based high risk patients (> or =10(-3) at both time-points) were more frequently present in the relapsed cases than in controls (14 vs 2), while MRD-based low risk patients (MRD negative at both time-points) (1 vs 18) showed the opposite distribution. MRD-based high risk cases experienced a significantly higher relapse rate than all other patients, according to the estimated seven-fold increase in the odds of failure, and a much higher rate than MRD-based low risk patients (OR = 35.7; P= 0.003). Using the Cox model, the prediction of the relapse-free interval at 4 years was 44.7%, 76.4% and 97.7% according to the different MRD categories. MRD-based risk group classification demonstrate their clinical relevance within the medium-risk B cell precursor ALL which account for the largest number of unpredictable relapses, despite the current knowledge about clinical and biological characteristics at diagnosis. Therefore, MRD detection during the first 3 months of follow-up can provide the tools to target more intensive therapy to those patients at true risk of relapse.     

Long-term follow-up of patients with newly diagnosed adult acute lymphoblastic leukemia: a single institution experience of 378 consecutive patients over a 21-year period.

Although the prospect of long-term leukemia-free survival (LFS) after treatment for adult acute lymphoblastic leukemia (ALL) is widely accepted, few studies have reported long-term survival data. Three hundred and seventy-eight ALL patients, referred to our hospital from 1978 to 1999, were reviewed for long-term follow-up data. The analysis included data on 351 patients treated by standard chemotherapy according to 11 different successive and/or concomitant regimens. Complete remission (CR) was achieved in 299 patients (79%). Initial performance status, LDH level, immunophenotype, age, and risk group (defined according to Hoelzer's criteria) at diagnosis were of significant prognostic value for CR achievement. Median leukemia-free survival (LFS) was 14 months with a 3-year, a 5-year, and an 8-year LFS at 30%, 26%, and 24%, respectively. LFS was better in T cell lineage ALL than in B cell lineage ALL (P = 0.05). Younger age was also a favorable prognostic factor for LFS (P = 0.001). Philadelphia-positive (Ph+) ALL displayed a poor outcome since median LFS was 7 months with only 13% of survival at 3 years. Median overall survival (OS) of the entire cohort was 18 months with a 3-year, a 5-year, and an 8-year OS at 32%, 24%, and 22% respectively. Favorable prognostic factors for OS were younger age (P < 0.0001), and T cell lineage ALL (P = 0.001). Among non-T cell lineage ALL, standard-risk ALL confirmed a significant better outcome than high-risk ALL (P = 0.0003). It was apparent from this analysis that hazard rates for death and relapse were greatest in the first year, decreased substantially between years 1 and 2, then decrease further between years 2 and 3. Rates of death and relapse were quite low after 3-4 years. All patients relapsing after 3 years of CR were B or non-B non-T cell lineage ALL. Long-term survivors (LTS), defined as survival in CR > or =3 years, represented 23% of evaluable patients. Eighty-three patients remain alive in initial CR at >3 years, while only three were LTS after a second CR. Overall, no significant improvement was shown in terms of CR achievement and survival duration over the years. However, regarding survival, a significant improvement was demonstrated in T cell lineage ALL (P = 0.03). Furthermore, patients (aged less than 50 years) transplanted while in first CR did significantly better than those receiving only chemotherapy as post-remission therapy (P < 0.0001). The 3-year OS, after allogeneic transplantation in first CR, was 74% in T cell lineage ALL, while it was less than 50% in B cell lineage ALL. This single center study on a large cohort of ALL patients reflects the degree to which ALL treatment remains unsuccessful in adults. Only T cell lineage ALL outcomes have improved over the years. The results suggest a time (3 years) at which it becomes reasonable to speak of potential cure, provided the patient is in CR.     

Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980-1997. Medical Research Council Childhood Leukaemia Working Party.

Results of three consecutive completed UK trials (1980-1997) for childhood lymphoblastic leukaemia are presented. National accrual has progressively increased so that over 90% of all the country's ALL cases were treated on the latest trial reported, UKALLXI. From 1980 to 1990, event-free and overall survival progressively improved, following adoption of an American therapy template and use of two post-remission intensification modules. Since 1990 despite demonstration of the benefit of a third intensification module overall event-free survival (EFS) has not improved further. Survival remains high due to a good retrieval rate especially for those relapsing off treatment after receipt of two intensification pulses. Possible reasons for the plateau in event-free survival (including type and dose of induction steroid, dropping of induction anthracycline, type and dose of asparaginase, gaps early in therapy following intensification, and overall lack of compliance in maintenance) are being explored in the latest protocol ALL '97. Cranial irradiation had been successfully replaced by a long course of intrathecal methotrexate injections for the majority of patients. Age (<1 year >10 years) sex (male) and white count >50 x 10(9)/l plus slow initial bone marrow clearance were consistently the most important independent prognostic indicators during this time period. Rome/NCI criteria accurately predict standard and high-risk groups for B cell lineage, but not consistently for T cell disease. This international collaborative venture might help us to define those truly at highest risk, and how we can optimise therapy for specific subgroups including T-ALL and those with unfavourable cytogenetics.     

Magnetic field exposure and long-term survival among children with leukaemia

We examined the association between magnetic field (MF) exposure and survival among children with acute lymphoblastic leukaemia (ALL) treated at 51 Pediatric Oncology Group centres between 1996 and 2001. Of 1672 potentially eligible children under treatment, 482 (29%) participated and personal 24-h MF measurements were obtained from 412 participants. A total of 386 children with ALL and 361 with B-precursor ALL were included in the analysis of event-free survival (time from diagnosis to first treatment failure, relapse, secondary malignancy, or death) and overall survival. After adjustment for risk group and socioeconomic status, the event-free survival hazard ratio (HR) for children with measurements >/=0.3 muT was 1.9 (95% confidence interval (CI) 0.8, 4.9), compared to <0.1 muT. For survival, elevated HRs were found for children exposed to >/=0.3 muT (multivariate HR=4.5, 95% CI 1.5-13.8) but based on only four deaths among 19 children. While risk was increased among children with exposures above 0.3 muT, the small numbers limited inferences for this finding.     

Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995.

Since 1968, the Children's Cancer Group (CCG) has treated more than 16,000 children with acute lymphoblastic leukemia (ALL). Herein, we report improvements obtained in CCG trials during two successive series of studies (1983-1988 and 1989-1995). Overall, 10-year EFS was 62% +/- 10% for the 1983-1988 series and 72% +/- 1% for the 1988-1995 series (P< 0.0001). Five-year cumulative rates of isolated CNS relapses were 5.9% and 4.4%. Therapy based on the Berlin-Frankfurt-Münster 76/79 study improved outcomes for intermediate and higher risk patients in the first series. For intermediate risk patients, delayed intensification (DI) was most crucial for improved outcome and cranial irradiation was safely replaced with maintenance intrathecal methotrexate, providing patients received intensified systemic therapy. In the second series, randomized trials showed better outcome with one vs no DI phase for lower risk patients, with two vs one DI phase for intermediate risk patients, and with the CCG 'augmented regimen' for higher risk patients with a slow day 7 marrow response. Cranial irradiation was safely replaced with additional intrathecal methotrexate for higher risk patients with a rapid day 7 marrow response. In a subsequent study, substitution of dexamethasone in place of prednisone in induction and maintenance improved outcome for standard risk patients. All patients received dexamethasone in DI. These successful treatment strategies form the basis for our current ALL trials.     

DNA Ploidy and S-phase Fraction Analysis in Paediatric B-cell Acute Lymphoblastic Leukemia Cases: a Tertiary Care Centre Experience

DNA ploidy is an important prognostic parameter in paediatric B-ALL, but the significance of the S-phase fraction is unclear. In present study, DNA ploidy was assessed in 40 pediatric B-ALL cases by flow cytometry. The DI (DNA index) and percentage of cells in S-phase were calculated using Modfit software. Aneuploidy was noted in 26/40 (65%) cases. A DI of 1.10-1.6 (hyperdiploidy B) was noted in 20/40 (50%) and 6/40 (15%) had a DI>1.60 (triploid and tetraploid range). Some 14/40 (35%) cases had a diploid DI between 0.90-1.05. None of the cases had a DI <0.90 (hypodiploid) or in the 1.06-1.09 (hyperdiploid A) range. The mean S-phase fraction was 2.6%, with 24/40 (60%) having low and 16/40 (40%) high S-phase fractions. No correlation was noted with standard ALL risk and treatment response factors with DI values or S-phase data, except for a positive correlation of low S-phase with high NCI risk category (p=0.032). Overall frequency of hyperdiploidy in our cohort of B-ALL patients was very high (65%). No correlation between hyperdiploidy B and low TLC or common B-phenotype was observed in our study as 42% cases with DI 1.10-1.6 had TLC> 50 x 109 and 57.1% CD 10 negativity. The study also highlighted that S-phase fraction analysis does not add any prognostic information and is not a useful parameter for assessment in ALL cases. However, larger studies with long term outcome analysis are needed to derive definitive conclusions.     

Prognostic significance of cytogenetic abnormalities of chromosome arm 12p in childhood acute lymphoblastic leukemia: a report from the Children's Cancer Group

BACKGROUND: The authors have determined the prognostic significance of cytogenetically detectable 12p abnormalities, which are frequent in children with acute lymphoblastic leukemia (ALL), in a large cohort of patients treated on risk-adjusted protocols of the Children's Cancer Group (CCG). METHODS: The presence of an abnormal 12p was identified among 1880 children with newly diagnosed ALL; outcome was assessed by standard life table methods. RESULTS: A total of 174 cases (9%) had cytogenetically detectable 12p abnormalities; the majority of cases had a balanced translocation, a del(12p), or an add(12p). In the overall cohort, event free survival (EFS) at 6 years was similar for patients with or without a 12p abnormality (76%, SD = 6%, vs. 75%, SD = 2%, respectively; P = 0.60). Among patients with pseudodiploidy, an abnormal 12p conferred improved outcome (P = 0.008; relative risk = 0.51; 95% confidence interval [CI], 0.31-0.85). There was a trend for improved EFS for those with abnormalities in both chromosome 12 homologues (P = 0.16; relative risk = 0.39; 95% CI, 0.10-1.55) and those with low hyperdiploidy (P = 0.07; relative risk = 0.44; 95% CI, 0.18-1.09). Among T-lineage ALL patients, there was a trend for worse outcome for abnormal versus normal 12p (P = 0.14; relative risk = 1.97; 95% CI, 0.78-4.93). There was no difference in EFS for the 12 patients with a dic(9;12) compared with patients lacking an abnormal 12p. CONCLUSIONS: These data suggest that although a cytogenetically detectable 12p aberration is a favorable risk factor for children with ALL and pseudodiploidy, it is not prognostic for the overall group of pediatric ALL patients treated with contemporary therapies of the CCG.     

High prevelance of chronic magnesium deficiency in T cell lymphoblastic leukemia and chronic zinc deficiency in children with acute lymphoblastic leukemia and malignant lymphoma

Magnesium and zinc are the elements having essential roles in regulation of cell growth, division and differentiation. There have been some studies in the literature suggesting an association between the deficiency of these elements and the development of malignant disorders. In this study hair and serum zinc and magnesium levels were investigated in children with acute lymphoblastic leukemia (ALL) and malignant lymphoma (ML) at the time of initial diagnosis. Ten children with T-cell ALL, 10 children with B-precursor ALL, 5 children with Burkitt's Lymphoma (BL), 11 children with Hodgkin's lymphoma (HL), 10 children with non-Burkitt non-Hodgkin's lymphoma (NBNHL) and 12 age and sex matched healthy children as a control group were included in the study. Mean hair magnesium levels in all of the groups of the patients were lower than the levels in the control group but the difference was statistically significant only in the children with T cell ALL comparable to the controls (28.9+/-3.9 microg/g and 87.6+/-18.5 microg/g respectiveley, p<0,05). Mean serum magnesium levels in all the cohorts were not significantly different than those in controls (p>0.05 in each comparison). Mean hair zinc levels in the patients with T-cell, B-precursor ALL, BL, HL, NBNHL were 103.4+/-14.6 microg/g, 100.9+/-7.8 microg/g, 91.1+/-19 microg/g, 72.5+/-9.1 microg/g, 103.2+/-12.2 microg/g respectively. Each of these levels were significantly lower than the mean hair zinc levels of the control group (141.2+/-9.6 microg/g, p<0.05 in each comparison). Although mean serum zinc levels in all of the groups were also decreased, the differences were statistically significant only in the groups with B-precursor ALL, HL and NBNHL (75.9+/-5.29 microg/dl, 68.6+/-7.3 microg/dl, 85.7+/-5.5 microg/dl respectively) when compared with controls (105.1+/-9.9 microg/dl, p<0.05 in each comparison). Hair magnesium and zinc levels showed a positive correlation with each other in all the groups (r congruent with 0.5). No significant difference was found in the mean hair/serum magnesium and zinc levels between malnourished and nonmalnourished patients. In conclusion, regarding the results of our study and previous data in the literature chronic magnesium and zinc deficiency seems to be associated with the development of ALL and malignant lymphoma in a group of patients.     

Absolute lymphocyte count is a novel prognostic indicator in ALL and AML: implications for risk stratification and future studies

BACKGROUND: Leukemia is the leading cause of disease-related death in children, despite significant improvement in survival and modern risk stratification. The prognostic significance of absolute lymphocyte counts (ALC) was evaluated in young patients with acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL). METHODS: In all, 171 consecutive de novo cases of AML and ALL, age 350 cells/microL carries an excellent prognosis, with a 5-year overall survival (OS) of 85% (HR 0.2, P= .012). Similarly in ALL, an ALC-15 <350 cells/microL predicts poor survival, with a 6-year RFS of 43% (HR 4.5, P= .002), whereas an ALC-15 >350 cells/microL predicts excellent outcome, with a 6-year OS of 87% (HR 0.2, P= .018). Importantly, ALC remains a strong predictor in multivariate analysis with known prognostic factors. CONCLUSIONS: ALC is a simple, statistically powerful measurement for patients with de novo AML and ALL. The results, when combined with previous studies, demonstrate that ALC is a powerful new prognostic factor for a range of malignancies. These findings suggest a need for further exploration of postchemotherapy immune status and immune-modulating cancer therapies.     

Review of the incidence and clinical relevance of myeloid antigen-positive acute lymphoblastic leukemia

An increasing number of papers document cases of acute leukemia in which individual blast cells co-express markers normally restricted to a single cell lineage. Numerous terms are used to refer to cases with unscheduled expression of lineage-foreign proteins; the best defined categories were hybrid acute leukemia and acute mixed-lineage leukemia. The incidence of phenotypically variant acute leukemia varies with the quality and quantity of parameters used and the stringency of the criteria employed for its definition. Considerable interest has focused on acute lymphoblastic leukemia (ALL) cells expressing one or several myeloid lineage-associated antigens (My+ ALL), CD13, CD14, CD15, CD33, and CDw65. Owing to legitimate and cryptic expression on lymphoid cells, CD11b and CD15 reagents may not be considered as specific indicators of myeloid differentiation. The reported incidence ranged from 5 to 46% in 14 studies on My+ ALL, totalling 3817 patients. Several detailed reports documented a higher incidence of My+ ALL in adults (realistically in the range 10-20%) than in children (5-10%) and in B-lineage ALL as opposed to T-lineage ALL. My+ ALL cases are more likely to display unique cytogenetic [t(9;22), 11q23, 14q32] features than My-neg ALL. There appears to be no predominant expression of a single myeloid-associated antigen among those analyzed. As the morphological diagnosis of a leukemia subtype is often imprecise, some T-neg B-neg My+ ALL cases might actually contain FAB AML-M0 populations. While the expression of myeloid-associated antigens has no apparent prognostic significance in the majority of childhood ALL subtypes, in adults myeloid antigens seem to identify a high risk group of ALL patients with a poorer response to standard ALL therapy.     

Relapse of TEL-AML1--positive acute lymphoblastic leukemia in childhood: a matched-pair analysis.

PURPOSE: The aim of this study was to investigate whether, in relapsed childhood acute lymphoblastic leukemia (ALL), the frequent genetic feature of TEL-AML1 fusion resulting from the cryptic chromosomal translocation t(12;21)(p13;q22) is an independent risk factor. PATIENTS AND METHODS: A matched-pair analysis was performed within a homogeneous group of children with first relapse of BCR-ABL-negative B-cell precursor (BPC) ALL treated according to relapse trials ALL-Rezidiv (REZ) of the Berlin-Frankfurt-Münster Study Group. A total of 249 patients were eligible for this study: 53 (21%) were positive for TEL-AML1, and 196 (79%) were negative. Positive patients were matched for established most-significant prognostic determinants at relapse, time point, and site of relapse, as well as age and peripheral blast cell count at relapse. RESULTS: Fifty pairs matching the aforementioned criteria could be determined. The probabilities with SE of event-free survival and survival at 5 years for matched TEL-AML1 positives and negatives are 0.63 +/- 0.10 versus 0.38 +/- 0.10 (P =.09) and 0.82 +/- 0.09 versus 0.42 +/- 0.19 (P =.10), respectively. These results were confirmed by multivariate analysis, revealing an independent prognostic significance of time point and site of relapse (both P <.001) but not of TEL-AML1 expression (P =.09). CONCLUSION: TEL-AML1 expression does not constitute an independent risk factor in relapsed childhood BCP-ALL after matching for relevant prognostic parameters. It undoubtedly characterizes genetically an ALL entity associated with established favorable prognostic parameters. High-risk therapeutic procedures such as allogeneic SCT should be considered restrictively.     

Long-term follow-up of childhood acute lymphoblastic leukemia in Tokyo Children's Cancer Study Group 1981-1995.

The objectives were as follows: Firstly, to estimate the overall probability of event-free survival (EFS) and isolated CNS relapse in the studies for children with acute lymphoblastic leukemia (ALL) during the 1980s and 1990s. Secondly, to report the EFS according to presenting features and lineage. Thirdly, to evaluate the treatment results re-classified by the risks of NCI criteria. Four consecutive protocol studies were performed in the Tokyo Children's Cancer Study Group: L81-10 protocol (1981-1984, 189 patients), L84-11 (1984-1989, 484 patents), L89-12 (1989-1992, 418 patients) and L92-13 (1992-1995, 347 patients). Overall EFS at 5 years in each protocol was 56.5 +/- 3.8(1 s.e.)%, 71.0 +/- 2.1%, 67.8 +/- 2.3%, and 63.4 +/- 2.7%, respectively. The cumulative isolated CNS relapse rate at 5 years was 8.1 +/- 2.1%, 3.5 +/- 0.9%, 3.6 +/- 1.0%, 1.0 +/- 0.6. The EFS in SR/HR (standard risk/high risk) according to the NCI criteria in B-precursor ALL at 5 years was 61.9 +/- 4.3%/41.4 +/- 7.4% (lineage was not confirmed.), 72.5 +/- 2.6%/63.4 +/- 5.0%, 77.4 +/- 2.7%/56.3 +/- 4.7%, and 67.8 +/- 3.4%/56.7 +/- 5.4% in each protocol. Also EFSs according to NCI SR/HR at 5 years of T-ALL in protocols L84-11, L89-12 and L92-13 were 55.6 +/- 16.6%/60.9 +/- 10.1%, 72.7 +/- 13.4%/51.6 +/- 9.1%, and 77.1 +/- 14.4%/53.6/10.1%, respectively. The truncation of maintenance therapy to 6 months resulted in a decreased EFS in L92-13, particularly due to an increase of bone marrow relapse after cessation of therapy in SR and HR. The NCI risk criteria work properly even in the patients treated by different intensities, so that it makes the comparison possible among the patients in various groups. The overall EFSs in childhood ALL improved in 1980s, but it seemed stable or decreased in 1990s. The short maintenance therapy resulted in poor outcome in SR on the L92-13 protocol. Many of these late relapsers were effectively rescued and overall survival remained at a high level. The proportion of patients who received cranial irradiation reduced without any increase of the CNS events.