|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 90 No. 1 (July 1), 1997:
pp. 28-35
Clinical Features and Treatment Outcome of Children With Myeloid Antigen Positive Acute Lymphoblastic Leukemia: A Report From the Children's Cancer Group
By
Fatih M. Uckun,
Harland N. Sather,
Paul S. Gaynon,
Diane C. Arthur,
Michael E. Trigg,
David G. Tubergen,
James Nachman,
Peter G. Steinherz,
Martha G. Sensel, and
Gregory H. Reaman
From the Children's Cancer Group ALL Biology Reference Laboratory and Hughes Institute, St Paul, MN; the Department of Preventive Medicine, University of Southern California, Los Angeles; the Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD; the Department of Pediatric Hematology-Oncology, University of Wisconsin, Madison; the Department of Pediatric Hematology-Oncology, University of Iowa Hospital and Clinics, Iowa City; the Department of Pediatrics, M.D. Anderson Cancer Center, Houston, TX; the Department of Pediatric Hematology-Oncology, University of Chicago, Chicago, IL; the Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY; the Department of Hematology-Oncology, Children's National Medical Center, and the George Washington University, Washington, DC; and the Group Operations Center of the Children's Cancer Group, Arcadia, CA.
 |
ABSTRACT |
Leukemic cells from a significant number of children with acute lymphoblastic leukemia (ALL) express protein antigens characteristic of both lymphoid and myeloid cells, yet the clinical significance of this immunophenotype has remained controversial. In the current study, we have determined relationships between myeloid antigen expression and treatment outcome in a large cohort of children with newly diagnosed ALL. A total of 1,557 children enrolled on risk-adjusted Children's Cancer Group studies were classified as myeloid antigen positive (My+) or myeloid antigen negative (My-) B-lineage ALL (BL) or T-lineage ALL (TL), according to expression of CD7, CD19, CD13, and CD33 antigens on the surface of their leukemic cells. My+ patients in both BL and TL groups were more likely than My- patients to have favorable presenting features. Induction therapy outcome was similar for My+ and My- patients in both the BL and TL categories. Importantly, 4-year event-free survival (EFS) was similar for My+ BL (77.0%, standard deviation [SD] = 4.0%) versus My- BL (75.9%, SD = 1.8%) and for My+ TL (72.7%, SD = 7.1%) versus My- TL (70.1%, SD = 5.7%). An overall relative hazard rate (RHR) of 0.89 (P = .49) was determined by a cross strata analysis for My+ versus My- patients. Moreover, similar EFS and RHR also were found when My+ and My- BL patients were compared according to National Cancer Institute risk classification. Thus, patients with My+ ALL have similar treatment outcomes as My- ALL patients. In contrast to previous studies, this result was independent of treatment risk category, demonstrating that myeloid antigen expression was not an adverse prognostic factor for childhood ALL.
| |
INTRODUCTION |
ACUTE LYMPHOBLASTIC leukemia (ALL) is an immunophenotypically heterogeneous group of diseases. Leukemic cells from the majority of patients with ALL express on their surface a variety of protein antigens that are found at discrete stages of maturation on normal B- or T-lymphocyte precursors.1-6 Thus leukemic clones from ALL patients are thought to originate from normal lymphoid progenitor cells arrested at early stages of B- or T-lymphocyte ontogeny.7-9 Recent improvements in immunofluorescence and flow cytometry, as well as the availability of monoclonal antibodies that recognize lineage-associated cell surface molecules, have motivated more detailed investigations of immunophenotypic heterogeneity in childhood ALL. It is now clear that leukemic cells from a 5% to 20% of children with ALL also express myeloid differentiation antigens.5,10-20 The expression of myeloid antigens by ALL cells is speculated to reflect either lineage infidelity due to aberrant gene expression, neoplastic transformation of rare bilineage lymphoid/myeloid progenitor cells, or transformation of a multipotent lymphohematopoietic precursor cell.6,21-23
The clinical significance of myeloid antigen expression in pediatric ALL has remained controversial. Several studies5,14,15,20 have reported poor outcome for children with ALL of mixed myeloid/lymphoid phenotype, whereas others have found similar induction and treatment outcomes for patients with myeloid antigen negative and myeloid antigen positive ALL.10,11,13,16-19,24 Because of these conflicting reports regarding prognosis and treatment outcome, there has been no consensus among pediatric oncologists regarding assignment of patients to risk-directed ALL chemotherapy protocols, employment of therapies directed at acute myelogenous leukemia (AML), or necessity for bone marrow transplantation in first remission.
Herein, we report the results of a prospective study of myeloid antigen expression in a large cohort of 1,557 children with newly diagnosed ALL who were enrolled on risk-adjusted treatment protocols of the Children's Cancer Group (CCG). The presenting features and treatment outcomes of both myeloid antigen positive (My+) B-lineage (BL) and My+ T-lineage (TL) ALL patients were compared with those of myeloid antigen negative (My-) BL and My- TL controls. Our results provide new insights regarding the clinical relevance of myeloid antigen expression in childhood ALL by demonstrating that regardless of treatment protocol, My+ ALL and My- ALL patients have similar treatment outcomes.
| |
MATERIALS AND METHODS |
Study patients.
The sample for these analyses included pediatric patients (<21 years of age) with newly diagnosed ALL enrolled between January 1, 1989 and December 31, 1993 on risk-adjusted treatment protocols of the CCG for whom a complete immunophenotyping profile of specified lymphoid and myeloid antigens (see below) was obtained. Diagnosis of ALL was based on morphological, biochemical, and immunological features of the leukemic cells, including lymphoblast morphology on Wright-Giemsa stained bone marrow smears, positive nuclear staining for terminal deoxynucleotidyl transferase (TdT), negative staining for myeloperoxidase, and cell surface expression of two or more lymphoid differentiation antigens (see below). Degree of organomegaly (moderate or marked enlargement) was as defined previously.25 CCG risk-adjusted ALL protocols were as follows: CCG 1881 (low-risk protocol for children age 2 to 9 years and white blood cell count [WBC] < 10,000/µL); CCG 1882 (high-risk protocol for patients 1 to 9 years of age with WBC  50,000/µL or age 10 years); CCG 1883 (protocol for infants less than 1 year of age), 1891 (intermediate risk protocol for children aged 2 to 9 years and WBC 10,000 to 49,999/µL or age 1 year and WBC < 50,000/µL) and CCG 1901 (high-risk protocol for patients with lymphomatous features). Lymphomatous features are essentially as described by the revised criteria of Steinherz et al.25 Each protocol was approved by the National Cancer Institute (NCI), as well as the Institutional Review Boards of the participating CCG-affiliated institutions. Informed consent was obtained from parents, patients, or both, as deemed appropriate, according to Department of Health and Human Services guidelines. For comparisons of presenting features, antigen expression, and therapy outcomes, patients were classified as myeloid antigen positive (My+) B-lineage leukemia (BL), myeloid antigen negative (My-) BL, My+ T-lineage leukemia (TL) and My- TL, as described below. A small number of patients (24 BL and 3 TL) were excluded from the current analyses because they failed to meet the criteria given by the algorithm. Analyses performed using these 27 patients indicated similar presenting characteristics and outcome compared with the patients included in this report. Thus, there appears to be no selection bias associated with the removal of these patients. B-lineage My+ and My- patients were also grouped according to recently published NCI risk classification criteria.26 These criteria classify patients age 1 to 9 years and WBC < 50,000/µL as standard risk and all other patients as high-risk.
Immunophenotyping.
Highly blast-enriched mononuclear cell fractions containing 90% leukemic cells were isolated from pretreatment bone marrow aspirate samples by centrifugation on Ficoll-Hypaque density gradients. Immunophenotyping was performed centrally in the CCG ALL Biology Reference Laboratory by indirect immunofluorescence and flow cytometry using monoclonal antibodies reactive with B-lymphoid-associated (CD19, CD20, CD21, CD22, CD72), T-lymphoid-associated (CD1, CD2, CD3, CD4, CD5, CD7, CD8), myeloid-associated (CD13, CD33), and nonlineage-associated (CD9, CD10, CD24, CD34, CD40) differentiation antigens, as previously described.27,28 Antigen expression data are presented as the mean ± standard error (SE) and median percentages of leukemic cells scored positive for expression of a given antigen. Cells were scored positive based on increased immunofluorescence observed with an antigen-specific monoclonal antibody compared with that observed with an irrelevant antibody. The term "expression frequency" is used throughout to indicate the percentage of leukemic cells expressing a given antigen. Patients were classified as BL if 30% of the isolated leukemic cells were positive for CD19 and < 30% were positive for CD2, CD5, and CD7. Likewise, patients were classified as TL if 30% of the isolated blasts were positive for CD2, CD5, or CD7 and <30% were positive for CD19. For patients exceeding 30% positivity for both criteria, the immunological surface marker results were examined further and classified according to the lineage marker of higher expression frequency, as well as the composite immunophenotype (ie, expression frequencies of other lineage-restricted antigens). BL and TL patients were classified as My+ if 30% of the isolated leukemic cells were positive for CD13 or CD33, or both. The majority of the 1,557 patients (85.4%) had BL, whereas 14.6% had TL. Overall, 13.9% patients were classified as My+ BL, 71.5% were My- BL, 2.8% were My+ TL, and 11.8% were My- TL.
Statistical methods.
My+ BL and My+ TL patients were compared with their respective My- BL and My- TL controls for similarity of clinical, demographic, and laboratory features, as well as induction therapy outcome using global chi-square tests for homogeneity of proportions. Comparisons of antigen expression frequency distributions were performed using the Kruskal-Wallis nonparametric rank test.29 Most of the outcome analyses used life table methods and associated statistics. The primary endpoint was event-free survival (EFS) from the date of study entry. An event was defined as induction failure (no response to therapy or death during induction), leukemic relapse at any site, death during remission, or the development of a second malignant neoplasm, whichever occurred first. Patients not experiencing an event at the time of analysis were censored in the EFS analysis at the time of their last contact. Data analysis was performed in July 1996.
Life-table estimates were calculated by the Kaplan-Meier (KM) procedure, and the standard deviation (SD) of the life table estimate was obtained using Greenwood's formula.30 To indicate precision, the KM estimate of EFS and its SD were given for selected follow-up time points. An approximate 95% confidence interval can be obtained by using the life-table estimate ± 1.96 SDs. Life-table comparisons of EFS outcome pattern for patient groups used the log-rank statistic.31,32 Stratified log-rank tests were sometimes used to adjust for the possible modifying effects of other factors on the comparison of interest.32,33 P values for life-table comparisons are based on the pattern of outcome across the entire period of patient follow-up, although EFS estimates at specific time points may be given for comparative purposes. Estimates of the life-table relative hazard rate (RHR) for a particular event were calculated by the O/E method for log-rank analyses.34
| |
RESULTS |
Immunophenotypic features of primary leukemic cells from children with My+ and My- ALL.
In accordance with the algorithm used for immunophenotypic classification, all BL patients showed high expression frequency for CD19 and all TL patients showed high expression frequency of CD7 (Table 1). Leukemic cells from BL patients were negative for T-lineage differentiation antigens and leukemic cells from TL patients were negative for B-lineage differentiation antigens (data not shown). The median expression frequencies of CD13 and CD33 were greater for My+ BL and My+ TL patients compared with My- BL and My- TL patients.
View larger version (17K):
[in this window]
[in a new window]
| Fig 1.
EFS of children with ALL according to BL immunophenotype. Percentages of 217 My+ BL (hatched line) and 1,113 My- BL (solid line) patients achieving EFS during 6 years of follow-up were calculated as described in Materials and Methods. The number of patients in each group remaining in follow-up at the indicated time points is shown in the inset.
|
|
Within the BL group, My+ and My- patients had identical 88% median expression frequencies of CD10. Median expression frequencies for the CD34 and CD40 antigens were significantly higher in the My+ BL group than in the My- BL group (P < .0001 for both comparisons). Similar immunophenotypic comparisons were performed for My+ TL and My- TL patients (Table 1). Expression frequencies of CD2 and CD10 were similar for both groups. In contrast, the median expression frequency of CD5 was significantly lower for My+ TL patients compared with My- TL patients (78% v 93%, P = .001). As was observed for BL patients, the median expression frequency of CD34 was significantly higher for the My+ TL patients compared with the My- TL control group (60% v 8%, P = .0002).
Presenting features of children with My+ and My- BL ALL.
Clinical and laboratory features of My+ BL and My- BL patients were compared by a global chi-square statistic (Table 2). WBC differed significantly between the two groups due to a higher percentage of My+ BL patients presenting with a low (<20,000/µL) WBC (68.7% v 58.1%; P = .006). The median WBC counts for My+ BL and My- BL patients were 9,900 (range, 800 to 507,800) and 14,400 (range, 300 to 1,000,000), respectively. My+ BL patients were less likely than My- BL patients to present with splenomegaly (47.0% v 57.2%; P = .0002) or lymphadenopathy (36.4% v 48.6%; P = .004). Platelet count also was significantly different (P = .01) between the two groups: My+ BL patients less often had low (<50,000/µL) and more often had high (150,000/µL) platelet counts at presentation. Centrally reviewed cytogenetic analysis was performed on leukemic cells from a subset of 71 My+ BL and 386 My- BL patients. Within this subset, there were two significant differences between the groups. First, chromosome number differed significantly (P = .003) due both to the greater frequency of My+ BL patients presenting with a normal diploid karyotype (43.7% v 24.1%) and to the lower frequency of My+ BL patients presenting with high hyperdiploid (>50 chromosomes) karyotype (12.7% v 29.0%). Second, chromosomal aberrations were more frequent in the My- BL group (75.9% v 53.6%, P = .001).
View larger version (16K):
[in this window]
[in a new window]
| Fig 2.
EFS of children with ALL according to TL immunophenotype. Percentages of 43 My+ TL (hatched line) and 184 My- TL (solid line) patients achieving EFS during 5 years of follow-up were calculated as described in Materials and Methods. The number of patients in each group remaining in follow-up at the indicated time points is shown in the inset.
|
|
Presenting features of children with My+ and My- TL ALL.
Clinical and laboratory features of My+ TL and My- TL patients were compared in a similar manner (Table 3). Age distribution was significantly different (P = .003) for the My+ TL versus My- TL groups largely due to a higher percentage of My+ TL patients (55.8% v 31.0%) presenting with 10 years of age. A higher percentage of My+ TL patients than My- TL patients presented with a normal liver and spleen; however, these differences did not reach statistical significance. My+ TL patients were less likely than My- TL patients to present with lymphadenopathy (58.2% v 76.1%, P = .05), a mediastinal mass (32.5% v 58.1%, P = .008), or high (11 g/dL) hemoglobin values (20.9% v 41.1%, P = .02). Cytogenetic data was available for only a small subset of patients (17 My+ TL and 82 My- TL patients), and within this subset, there were no significant differences between the My+ TL and My- TL patients.
Treatment outcomes for children with My+ and My- ALL.
Induction therapy outcomes were similar for My+ and My- controls. At the end of induction chemotherapy, 98.6% of My+ BL patients and 98.3% of My- BL patients achieved a remission (P = .97). Similarly, 97.6% of My+ TL patients and 96.6% of My- TL patients achieved remission (P = .85). EFS outcomes of My+ BL and My+ TL patients were compared with those of My- BL and TL patients using life-table methods, as described in Materials and Methods. Follow-up for event-free survivors ranged from 1 to 73 months (median, 32 months). My+ and My- BL patients had similar outcomes (P = .32; Fig 1), with 4-year EFS estimates of 77.0% (SD = 4.0%) and 75.9% (SD = 1.8%), respectively. Similarly, the My+ TL and My- TL groups had similar outcomes (P = .64; Fig 2 ), with 4-year EFS estimates of 72.7% (SD = 7.1%) and 70.1% (SD = 5.7%), respectively. The estimated RHR values for My+ BL versus My- BL and My+ TL versus My- TL were 0.83 and 1.18, respectively (Table 4). An overall RHR estimate of 0.89 (P = .49) was determined for My+ patients compared with My- patients by a stratified analysis across lineage groups (Table 4).
In addition, outcomes remained similar when BL patients were compared across NCI standard and poor risk group categories (P = .35 and P = .85, respectively; Fig 3). By this analysis, 4-year EFS estimates for My+ and My- patients were 85.7% (SD = 3.9%) and 83.2% (SD = 2.1%), respectively, within the standard risk group, and 58.7% (SD = 9.1%) and 64.5% (SD = 3.2%), respectively, within the poor risk group. Estimates of RHR for My+ versus My- patients in standard and poor-risk groups were 0.77 and 0.95, respectively. A stratified risk analysis was also performed to compare patients on CCG protocols with less intensive therapy (CCG 1881 and CCG 1891) with those on protocols with more intensive therapies (CCG 1882, CCG 1883, and CCG 1901). This analysis also showed similar outcome for My+ and My- patients in low and high intensity treatment categories (P = .44 and P = .94, respectively; data not shown).
View larger version (16K):
[in this window]
[in a new window]
| Fig 3.
EFS of children with My+ and My- BL ALL according to NCI risk classification. (Top) Standard risk: 138 My+ BL (hatched line) and 657 My- BL (solid line) patients were followed for 6 years. (Bottom) Poor risk: 79 My+ BL (hatched line) and 456 My- BL (solid line) were followed for 5 years. Percentages of patients achieving EFS during follow-up were calculated as described in Materials and Methods. The number of patients in each group remaining in follow-up at the indicated time points is shown in the inset.
|
|
| |
DISCUSSION |
We have examined the clinical importance of myeloid antigen expression in a large cohort of children enrolled in risk-adjusted treatment protocols of the CCG. In general, children with My+ ALL compared with My- ALL had similar or more favorable presenting features, including low WBC levels and normal karyotypes, as well as absence of splenomegaly, lymphadenopathy, and mediastinal mass. Importantly, we observed that remission induction rates, as well as EFS outcomes, were virtually identical for the My+ patients and My- patients, demonstrating that myeloid antigen expression was not an adverse risk factor in this cohort.
Patients analyzed herein were defined according to coexpression of the myeloid differentiation antigens CD13 and CD33 together with either B (CD19) or T-(CD7) lymphoid-associated antigens. CD13, CD33, CD14, CD15, and CDw65 are the myeloid-associated antigens most frequently expressed on the surface of leukemic cells from ALL patients.35 Moreover, Drexler and Ludwig35 found that among ALL patients from numerous studies, similar percentages were positive for each of the individual myeloid antigens. Also, previous studies have documented the expression of various combinations of these myeloid-associated antigens in 5% to 20% of pediatric ALL patients,5,10-20 and differences in outcome do not appear to be related to the choice of antigens examined. Thus, analysis of CD13 and CD33 should be representative of overall myeloid antigen expression.
My+ ALL patients in the current study showed higher expression frequency of both CD34 and CD40 than My- ALL patients. Similarly, Borowitz et al36 and Guyotat et al37 observed that in pediatric and adult patients, CD34 expression was correlated with myeloid antigen expression. Saeland et al38 reported that CD40 is also present on CD34+ immature myeloid progenitor cells, but is lost on interleukin-3 (IL-3) induced myeloid differentiation. CD34 is a 110 kD integral membrane protein thought to be expressed normally by immature hematopoietic progenitor cells,39,40 and CD40, a member of the nerve growth factor receptor superfamily, plays a role in proliferation and differentiation of normal B-lineage lymphoid cells.41-44 Therefore, expression of the CD34 and CD40 antigens by My+ ALL cells further supports the hypothesis that My+ ALL arises via transformation of an immature progenitor cell.
The clinical significance of myeloid antigen expression in children with ALL is controversial. In a single institution study involving 53 children with My+ ALL and 183 children with My- ALL, Wiersma et al20 reported 3-year EFS estimates of 84% for My- patients with WBC <50,000/µL, 57% for My- patients with WBC 50,000/µL, 47% for My+ patients with WBC<50,000/µL, and 26% for My+ ALL patients with WBC 50,000/µL. These differences were statistically significant and multivariate analysis indicated that myeloid antigen expression was the most important predictor of a poor EFS outcome. Wiersma's study concurs with reports by Cantu Rajnoldi et al,14 Kurec et al,5 and Fink et al.15 Interestingly, these results also were consistent with preclinical observations that leukemic cells from My+ ALL patients were more resistant to glucocorticoid-induced killing than cells from My- ALL patients.45
Although the studies described above demonstrated a poor outcome associated with myeloid antigen expression in childhood ALL, numerous investigators have reported conflicting results. Bradstock et al13 and Mirro et al24 reported that myeloid antigen expression in pediatric ALL was not correlated with induction outcome, and other studies later showed no effect of myeloid antigen expression on treatment outcome.10,11,16,19 Likewise, Pui et al17 reported that myeloid antigen expression in 61 of 372 children with newly diagnosed ALL treated at the St. Jude Children's Hospital had no effect on either induction outcome or EFS. In a follow-up study, myeloid antigen expression again lacked prognostic significance in 25 children with My+ ALL.18 Subsequently, Pui et al46 reported that the estimated 3-year EFS estimates for 50 children with My+ ALL and 260 children with My-ALL were 85% and 75%, respectively. The St Jude researchers concluded that myeloid antigen expression in childhood ALL is not associated with poor outcome if intensive chemotherapy regimens are used. Our results are generally consistent with these studies in showing that myeloid antigen expression does not correlate with poor outcome for children with ALL. In conclusion, this study provides new insight on the clinical significance of myeloid antigen expression in childhood ALL and shows that regardless of risk classification, ALL patients who are My+ have treatment outcomes similar to those who are My-.
| |
FOOTNOTES |
Submitted September 9, 1996;
accepted February 18, 1997.
Supported in part by research grants including CCG Chairman's Grants No. CA-13539, CA-51425, CA-42633, CA-42111, CA-60437, and CA-27137 from the National Cancer Institute, National Institutes of Health, Bethesda, MD. F.M.U. is a Stohlman Scholar of the Leukemia Society of America.
Address reprint requests to Fatih M. Uckun, MD, Children's Cancer Group ALL Biology Reference Laboratory, Hughes Institute, 2657 Patton Rd, St Paul, MN 55113.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hearly marked
``advertisment'' in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
| |
REFERENCES |
1.
Pullen DJ,
Boyett JM,
Crist WM,
Falletta JM,
Roper M,
Dowell B,
Van Eys J,
Jackson JF,
Humphrey GB,
Metzgar RS,
Cooper MD:
Pediatric oncology group utilization of immunologic markers in the designation of acute lymphocytic leukemia subgroups: Influence on treatment response.
Ann NY Acad Sci
428:26,
1984[Medline]
[Order article via Infotrieve]
2.
Bene MC,
Castoldi G,
Knapp W,
Ludwig WD,
Matutes E,
Orfao A,
vant Veer MB:
Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL).
Leukemia
9:1783,
1995[Medline]
[Order article via Infotrieve]
3.
Pui CH,
Behm FG,
Crist WM:
Clinical and biologic relevance of immunologic marker studies in childhood acute lymphoblastic leukemia.
Blood
82:343,
1993[Abstract/Free Full Text]
4. Sallan SE, Ritz J, Pesando J, Gelber R, O'Brien C, Hitchcock S, Coral F, Schlossman SF: Cell surface antigens: Prognostic implications in childhood acute lymphoblastic leukemia. Blood 55:395, 1980
5.
Kurec AS,
Belair P,
Stefanu C,
Barrett DM,
Dubowy RL,
Davey FR:
Significance of aberrant immunophenotypes in childhood acute lymphoid leukemia.
Cancer
67:3081,
1991[Medline]
[Order article via Infotrieve]
6.
Ludwig WD,
Bartram CR,
Ritter J,
Raghavachar A,
Hiddemann W,
Heil G,
Harbott J,
Seibt Jung H,
Teichmann JV,
Riehm H:
Ambiguous phenotypes and genotypes in 16 children with acute leukemia as characterized by multiparameter analysis.
Blood
71:1518,
1988[Abstract/Free Full Text]
7.
Champlin R,
Gale RP:
Acute lymphoblastic leukemia: Recent advances in biology and therapy [see comments].
Blood
73:2051,
1989[Free Full Text]
8.
Greaves MF:
Differentiation-linked leukemogenesis in lymphocytes.
Science
234:697,
1986[Abstract/Free Full Text]
9.
Reinherz EL,
Kung PC,
Goldstein G,
Levey RH,
Schlossman SF:
Discrete stages of human intrathymic differentiation: Analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage.
Proc Natl Acad Sci USA
77:1588,
1980[Abstract/Free Full Text]
10.
Ludwig WD,
Teichmann JV,
Sperling C,
Komischke B,
Ritter J,
Reiter A,
Odenwald E,
Sauter S,
Riehm H:
Incidence, clinical markers and prognostic significance of immunologic subtypes of acute lymphoblastic leukemia (ALL) in children: Experiences of the ALL-BFM 83 and 86 studies.
Klin Padiatr
202:243,
1990[Medline]
[Order article via Infotrieve]
11.
Ludwig WD,
Harbott J,
Bartram CR,
Komischke B,
Sperling C,
Teichmann JV,
Seibt Jung H,
Notter M,
Odenwald E,
Nehmer A,
Thiel E,
Riehm H:
Incidence and prognostic significance of immunophenotypic subgroups in childhood acute lymphoblastic leukemia: Experience of the BFM study 86.
Recent Results Cancer Res
131:269,
1993[Medline]
[Order article via Infotrieve]
12. Ludwig WD, Reiter A, Loffler H, Gokbuget, Hoelzer D, Riehm H, Thiel E: Immunophenotypic features of childhood and adult acute lymphoblastic leukemia (ALL): Experience of the German Multicentre Trials ALL-BFM and GMALL. Leuk Lymphoma 1:71, 1994 (suppl 1)
13.
Bradstock KF,
Kirk J,
Grimsley PG,
Kabral A,
Hughes WG:
Unusual immunophenotypes in acute leukaemias: Incidence and clinical correlations.
Br J Haematol
72:512,
1989[Medline]
[Order article via Infotrieve]
14.
Cantu Rajnoldi A,
Putti C,
Saitta M,
Granchi D,
Foa R,
Schiro R,
Castagni M,
Valeggio C,
Jankovic M,
Miniero R,
Paulucci P,
Basso G:
Co-expression of myeloid antigens in childhood acute lymphoblastic leukaemia: Relationship with the stage of differentiation and clinical significance [see comments].
Br J Haematol
79:40,
1991[Medline]
[Order article via Infotrieve]
15.
Fink FM,
Koller U,
Mayer H,
Haas OA,
Grumayer Panzer ER,
Urban C,
Dengg K,
Mutz I,
Tuchler H,
Gatterer Menz I,
Knapp W,
Gadner H:
Prognostic significance of myeloid-associated antigen expression on blast cells in children with acute lymphoblastic leukemia. The Austrian Pediatric Oncology Group.
Med Pediatr Oncol
21:340,
1993[Medline]
[Order article via Infotrieve]
16.
Hsu PN,
Tien HF,
Wang CH,
Chen YC,
Shen MC,
Lin DT,
Lin KH,
Liang DC,
Lin KS:
A subset of acute lymphoblastic leukemia with coexpression of myeloid antigens: Prevalence and clinical significance.
J Formosan Med Assoc
90:225,
1991[Medline]
[Order article via Infotrieve]
17.
Pui CH,
Behm FG,
Singh B,
Rivera GK,
Schell MJ,
Roberts WM,
Crist WM,
Mirro J Jr:
Myeloid-associated antigen expression lacks prognostic value in childhood acute lymphoblastic leukemia treated with intensive multiagent chemotherapy.
Blood
75:198,
1990[Abstract/Free Full Text]
18.
Pui CH,
Raimondi SC,
Head DR,
Schell MJ,
Rivera GK,
Mirro J Jr,
Crist WM,
Behm FG:
Characterization of childhood acute leukemia with multiple myeloid and lymphoid markers at diagnosis and at relapse [see comments].
Blood
78:1327,
1991[Abstract/Free Full Text]
19.
Urbano Ispizua A,
Matutes E,
Villamor N,
Ribera JM,
Feliu E,
Montserrat E,
Granena A,
Vives Corrons JL,
Rozman C:
Clinical significance of the presence of myeloid associated antigens in acute lymphoblastic leukaemia.
Br J Haematol
75:202,
1990[Medline]
[Order article via Infotrieve]
20.
Wiersma SR,
Ortega J,
Sobel E,
Weinberg KI:
Clinical importance of myeloid-antigen expression in acute lymphoblastic leukemia of childhood [see comments].
N Engl J Med
324:800,
1991[Abstract]
21.
Greaves MF,
Chan LC,
Furley AJ,
Watt SM,
Molgaard HV:
Lineage promiscuity in hemopoietic differentiation and leukemia.
Blood
67:1,
1986[Abstract/Free Full Text]
22.
Smith LJ,
Curtis JE,
Messner HA,
Senn JS,
Furthmayr H,
McCulloch EA:
Lineage infidelity in acute leukemia.
Blood
61:1138,
1983[Abstract/Free Full Text]
23.
McCulloch EA,
Smith LJ,
Alder S:
Cellular lineages in normal and leukemic hemopoiesis.
Prog Clin Biol Res
134:229,
1983[Medline]
[Order article via Infotrieve]
24.
Mirro J,
Zipf TF,
Pui CH,
Kitchingman G,
Williams D,
Melvin S,
Murphy SB,
Stass S:
Acute mixed lineage leukemia: Clinicopathologic correlations and prognostic significance.
Blood
66:1115,
1985[Abstract/Free Full Text]
25.
Steinherz PG,
Siegel SE,
Bleyer WA,
Kersey J,
Chard R Jr,
Coccia P,
Leiken S,
Lukens J,
Neerhout R,
Nesbit M,
Miller DR,
Reaman G,
Sather H,
Hammond D:
Lymphomatous presentation of childhood acute lymphoblastic leukemia.
Cancer
68:751,
1991[Medline]
[Order article via Infotrieve]
26.
Smith M,
Arthur D,
Camitta B,
Carroll AJ,
Crist W,
Gaynon P,
Gelber R,
Heerema N,
Korn EL,
Link M,
Murphy S,
Pui CH,
Pullen J,
Reamon G,
Sallan SE,
Sather H,
Shuster J,
Simon R,
Trigg M,
Tubergen D,
Uckun F,
Ungerleider R:
Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia [see comments].
J Clin Oncol
14:18,
1996[Abstract]
27.
Uckun FM,
Ledbetter JA:
Immunobiologic differences between normal and leukemic human B-cell precursors.
Proc Natl Acad Sci USA
85:8603,
1988[Abstract/Free Full Text]
28.
Uckun FM,
Muraguchi A,
Ledbetter JA,
Kishimoto T,
O'Brien RT,
Roloff JS,
Gajl Peczalska K,
Provisor A,
Koller B:
Biphenotypic leukemic lymphocyte precursors in CD2+CD19+ acute lymphoblastic leukemia and their putative normal counterparts in human fetal hematopoietic tissues.
Blood
73:1000,
1989[Abstract/Free Full Text]
29. Hollander M, Wolfe D: Nonparametric Statistical Methods. New York, NY, Wiley, 1973
30.
Kaplan E,
Meier P:
Nonparametric estimation from incomplete observations.
J Am Stat Assoc
53:457,
1958
31.
Mantel N:
Evaluation of survival data and two new rank order statistics arising in its consideration.
Cancer Chemother Rep
50:163,
1966[Medline]
[Order article via Infotrieve]
32.
Peto R,
Pike MC,
Armitage P,
Breslow N,
Cox DR,
Howard SV,
Mantel N,
McPherson K,
Peto J,
Smith PG:
Design and analysis of randomized clinical trials requiring prolonged observation of each patient, II. Analysis and examples.
Br J Cancer
35:1,
1977[Medline]
[Order article via Infotrieve]
33. Breslow N: Comparison of survival curves, in Buyse M, Staquet M, Sylvester M (eds): Cancer Clinical Trials: Methods and Practice. Oxford, UK, Oxford, 1988, p 381
34.
Breslow N:
Analysis of survival data under the proportional hazards model.
Int Stat Rev
43:45,
1975
35.
Drexler HG,
Ludwig WD:
Incidence and clinical relevance of myeloid antigen-positive acute lymphoblastic leukemia.
Recent Results Cancer Res
131:53,
1993[Medline]
[Order article via Infotrieve]
36.
Borowitz MJ,
Shuster JJ,
Civin CI,
Carroll AJ,
Look AT,
Behm FG,
Land VJ,
Pullen DJ,
Crist WM:
Prognostic significance of CD34 expression in childhood B-precursor acute lymphocytic leukemia: A Pediatric Oncology Group study.
J Clin Oncol
8:1389,
1990[Abstract]
37.
Guyotat D,
Campos L,
Shi ZH,
Charrin C,
Treille D,
Magaud JP,
Fiere D:
Myeloid surface antigen expression in adult acute lymphoblastic leukemia.
Leukemia
4:664,
1990[Medline]
[Order article via Infotrieve]
38.
Saeland S,
Duvert V,
Caux C,
Pandrau D,
Favre C,
Valle A,
Durand I,
Charbord P,
de Vries J,
Banchereau J:
Distribution of surface-membrane molecules on bone marrow and cord blood CD34+ hematopoietic cells.
Exp Hematol
20:24,
1992[Medline]
[Order article via Infotrieve]
39. Greaves MF, Brown J, Molgaard HV, Spurr NK, Robertson D, Delia D, Sutherland DR: Molecular features of CD34: A hemopoietic progenitor cell-associated molecule. Leukemia 1:31, 1992 (suppl 6)
40.
Simmons DL,
Satterthwaite AB,
Tenen DG,
Seed B:
Molecular cloning of a cDNA encoding CD34, a sialomucin of human hematopoietic stem cells.
J Immunol
148:267,
1992[Abstract]
41.
Banchereau J,
Bazan F,
Blanchard D,
Briere F,
Galizzi JP,
van Kooten C,
Liu YJ,
Rousset F,
Saeland S:
The CD40 antigen and its ligand.
Annu Rev Immunol
12:881,
1994[Medline]
[Order article via Infotrieve]
42.
Stamenkovic I,
Clark EA,
Seed B:
A B-lymphocyte activation molecule related to the nerve growth factor receptor and induced by cytokines in carcinomas.
EMBO J
8:1403,
1989[Medline]
[Order article via Infotrieve]
43.
Ledbetter JA,
Shu G,
Gallagher M,
Clark EA:
Augmentation of normal and malignant B cell proliferation by monoclonal antibody to the B cell-specific antigen Bp50 (Cdw40).
J Immunol
138:788,
1987[Abstract]
44.
Uckun FM,
Gajl Peczalska K,
Myers DE,
Jaszcz W,
Haissig S,
Ledbetter JA:
Temporal association of CD40 antigen expression with discrete stages of human B-cell ontogeny and the efficacy of anti-CD40 immunotoxins against clonogenic B-lineage acute lymphoblastic leukemia as well as B-lineage non-Hodgkin's lymphoma cells.
Blood
76:2449,
1990[Abstract/Free Full Text]
45.
Kaspers GJ,
Kardos G,
Pieters R,
Van Zantwijk CH,
Klumper E,
Hahlen K,
de Waal FC,
van Wering ER,
Veerman AJ:
Different cellular drug resistance profiles in childhood lymphoblastic and non-lymphoblastic leukemia: A preliminary report.
Leukemia
8:1224,
1994[Medline]
[Order article via Infotrieve]
46. Pui C, Schell M, Raimondi S, Head D, Rivera G, Crist W, Behm F: Myeloid antigen expression in childhood acute lymphoblastic leukemia. N Engl J Med 325:1378, 1991 (letter)
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
J. E. Rubnitz, M. Onciu, S. Pounds, S. Shurtleff, X. Cao, S. C. Raimondi, F. G. Behm, D. Campana, B. I. Razzouk, R. C. Ribeiro, et al.
Acute mixed lineage leukemia in children: the experience of St Jude Children's Research Hospital
Blood,
May 21, 2009;
113(21):
5083 - 5089.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Vitale, A. Guarini, C. Ariola, M. Mancini, C. Mecucci, A. Cuneo, F. Pane, G. Saglio, G. Cimino, A. Tafuri, et al.
Adult T-cell acute lymphoblastic leukemia: biologic profile at presentation and correlation with response to induction treatment in patients enrolled in the GIMEMA LAL 0496 protocol
Blood,
January 15, 2006;
107(2):
473 - 479.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. L. Carroll, D. Bhojwani, D.-J. Min, E. Raetz, M. Relling, S. Davies, J. R. Downing, C. L. Willman, and J. C. Reed
Pediatric Acute Lymphoblastic Leukemia
Hematology,
January 1, 2003;
2003(1):
102 - 131.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. A. Heerema, H. N. Sather, M. G. Sensel, M. K. Lee, R. J. Hutchinson, J. B. Nachman, G. H. Reaman, B. J. Lange, P. G. Steinherz, B. C. Bostrom, et al.
Abnormalities of Chromosome Bands 13q12 to 13q14 in Childhood Acute Lymphoblastic Leukemia
J. Clin. Oncol.,
November 15, 2000;
18(22):
3837 - 3844.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. M. Uckun, L. Stork, N. Seibel, M. Sarquis, C. Bedros, H. Sather, M. Sensel, G. H. Reaman, and P. S. Gaynon
Residual Bone Marrow Leukemic Progenitor Cell Burden after Induction Chemotherapy in Pediatric Patients with Acute Lymphoblastic Leukemia
Clin. Cancer Res.,
August 1, 2000;
6(8):
3123 - 3130.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
Y. Toyoda, A. Manabe, M. Tsuchida, R. Hanada, K. Ikuta, Y. Okimoto, A. Ohara, Y. Ohkawa, T. Mori, K. Ishimoto, et al.
Six Months of Maintenance Chemotherapy After Intensified Treatment for Acute Lymphoblastic Leukemia of Childhood
J. Clin. Oncol.,
April 7, 2000;
18(7):
1508 - 1516.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Kantarjian, S. O’Brien, T. L. Smith, J. Cortes, F. J. Giles, M. Beran, S. Pierce, Y. Huh, M. Andreeff, C. Koller, et al.
Results of Treatment With Hyper-CVAD, a Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia
J. Clin. Oncol.,
February 1, 2000;
18(3):
547 - 547.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. A. Heerema, J. B. Nachman, H. N. Sather, M. G. Sensel, M. K. Lee, R. Hutchinson, B. J. Lange, P. G. Steinherz, B. Bostrom, P. S. Gaynon, et al.
Hypodiploidy With Less Than 45 Chromosomes Confers Adverse Risk in Childhood Acute Lymphoblastic Leukemia: A Report From the Children's Cancer Group
Blood,
December 15, 1999;
94(12):
4036 - 4045.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Sun, P. A. Goodman, C. M. Wood, M.-L. Crotty, M. Sensel, H. Sather, C. Navara, J. Nachman, P. G. Steinherz, P. S. Gaynon, et al.
Expression of Aberrantly Spliced Oncogenic Ikaros Isoforms in Childhood Acute Lymphoblastic Leukemia
J. Clin. Oncol.,
December 1, 1999;
17(12):
3753 - 3766.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. M. Uckun, Y. Messinger, C.-L. Chen, K. O'Neill, D. E. Myers, F. Goldman, C. Hurvitz, J. T. Casper, and A. Levine
Treatment of Therapy-Refractory B-Lineage Acute Lymphoblastic Leukemia with an Apoptosis-inducing CD19-directed Tyrosine Kinase Inhibitor
Clin. Cancer Res.,
December 1, 1999;
5(12):
3906 - 3913.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. M. Uckun, P. S. Gaynon, D. O. Stram, M. G. Sensel, M. B. Sarquis, K. H. Lazarus, and M. Willoughby
Paucity of Leukemic Progenitor Cells in the Bone Marrow of Pediatric B-Lineage Acute Lymphoblastic Leukemia Patients with an Isolated Extramedullary First Relapse
Clin. Cancer Res.,
September 1, 1999;
5(9):
2415 - 2420.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Felix and B. J. Lange
Leukemia in Infants
Oncologist,
June 1, 1999;
4(3):
225 - 240.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
L. Sun, N. Heerema, L. Crotty, X. Wu, C. Navara, A. Vassilev, M. Sensel, G. H. Reaman, and F. M. Uckun
Expression of dominant-negative and mutant isoforms of the antileukemic transcription factor Ikaros in infant acute lymphoblastic leukemia
PNAS,
January 19, 1999;
96(2):
680 - 685.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-H. Pui and W. E. Evans
Acute Lymphoblastic Leukemia
N. Engl. J. Med.,
August 27, 1998;
339(9):
605 - 615.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Putti, R. Rondelli, M. G. Cocito, M. Arico, L. Sainati, V. Conter, C. Guglielmi, A. Cantu-Rajnoldi, R. Consolini, A. Pession, et al.
Expression of Myeloid Markers Lacks Prognostic Impact in Children Treated for Acute Lymphoblastic Leukemia: Italian Experience in AIEOP-ALL 88-91 Studies
Blood,
August 1, 1998;
92(3):
795 - 801.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. M. Uckun, K. Herman-Hatten, M.-L. Crotty, M. G. Sensel, H. N. Sather, L. Tuel-Ahlgren, M. B. Sarquis, B. Bostrom, J. B. Nachman, P. G. Steinherz, et al.
Clinical Significance of MLL-AF4 Fusion Transcript Expression in the Absence of a Cytogenetically Detectable t(4;11)(q21;q23) Chromosomal Translocation
Blood,
August 1, 1998;
92(3):
810 - 821.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. M. Uckun, M. G. Sensel, L. Sun, P. G. Steinherz, M. E. Trigg, N. A. Heerema, H. N. Sather, G. H. Reaman, and P. S. Gaynon
Biology and Treatment of Childhood T-Lineage Acute Lymphoblastic Leukemia
Blood,
February 1, 1998;
91(3):
735 - 746.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Rubnitz and C.-H. Pui
Childhood Acute Lymphoblastic Leukemia
Oncologist,
December 1, 1997;
2(6):
374 - 380.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract