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© 1999 American Society for Clinical Oncology Treatment Outcome and Prognostic Factors for Infants With Acute Lymphoblastic Leukemia Treated on Two Consecutive Trials of the Children's Cancer GroupFrom the Children's National Medical Center and George Washington University School of Medicine, Washington, DC; University of Southern California School of Medicine, Los Angeles, CA; Group Operations Center, Children's Cancer Group, Arcadia, CA; Children's Hospital of Philadelphia, Philadelphia, PA; Children's Hospital of Oakland, Oakland, CA; Indiana University School of Medicine, Bloomington, IN; University of Michigan, Ann Arbor, MI; Children's Hospital and Medical Center, Seattle, WA; University of Illinois, Chicago, IL; Primary Children's Medical Center, Salt Lake City, UT; Memorial Sloan-Kettering Cancer Center, New York, NY; University of California, Irvine, CA; University of Wisconsin, Madison, WI; Jefferson Medical College, Thomas Jefferson University, and Dupont Hospital for Children, Wilmington, DE; and Children's Cancer Group ALL Biology Reference Laboratory, Wayne Hughes Institute, St. Paul, MN. Address reprint requests to Gregory H. Reaman, MD, Children's Cancer Group, PO Box 60012, Arcadia, CA 91066-6012; email greaman{at}cnmc.org
PURPOSE: Infants represent a very poor risk group for acute lymphoblastic leukemia (ALL). We report treatment outcome for such patients treated with intensive therapy on consecutive Children's Cancer Group (CCG) protocols. PATIENTS AND METHODS: Between 1984 and 1993, infants with newly diagnosed ALL were enrolled onto CCG-107 (n = 99) and CCG-1883 (n = 135) protocols. Postconsolidation therapy was more intensive on CCG-1883. On both studies, prophylactic treatment of the CNS included both high-dose systemic chemotherapy and intrathecal therapy, in contrast to whole-brain radiotherapy, which was used in earlier studies. RESULTS: Most patients (> 95%) achieved remission with induction therapy. The most frequent event was a marrow relapse (46 patients on CCG-107 and 66 patients on CCG-1883). Four-year event-free survival was 33% (SE = 4.7%) on CCG-107 and 39% (SE = 4.2%) on CCG-1883. Both studies represent an improvement compared with a 22% (SE = 5.1%) event-free survival for historical controls. Four-year cumulative probabilities of any marrow relapse or an isolated CNS relapse were, respectively, 49% (SE = 5%) and 9% (SE = 3%) on CCG-107 and 50% (SE = 5%) and 3% (SE = 2%) on CCG-1883, compared with 63% (SE = 6%) and 5% (SE = 3%) for the historical controls. Independent adverse prognostic factors were age less than 3 months, WBC count of more than 50,000/µL, CD10 negativity, slow response to induction therapy, and presence of the translocation t(4;11). CONCLUSION: Outcome for infants on CCG-107 and CCG-1883 improved, compared with historical controls. Marrow relapse remains the primary mode of failure. Isolated CNS relapse rates are low, indicating that intrathecal chemotherapy combined with very-high-dose systemic therapy provides adequate protection of the CNS. The overall unsatisfactory outcome observed for the infant ALL population warrants the future use of novel alternative therapies.
ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) is the most common of the childhood cancers; infants with ALL comprise approximately 2% to 5% of all cases. Despite high cure rates achieved in patients 1 to 9 years of age with standard-risk ALL, extraordinarily high failure rates predominate among infants.1-7 ALL in infancy is frequently associated with known unfavorable presenting features such as hyperleukocytosis, massive organomegaly, and CNS disease, as well as immunophenotypic coexpression of myeloid-associated antigens and lack of expression of CD10.2,8-10 Numerous studies of infants have reported that the youngest infants (ages 0 to 6 months) have the worst outcome.1,2,7,10 Cytogenetic abnormalities involving ALL-1/MLL 11q23 gene rearrangements are estimated to occur in up to 70% to 80% of infants with ALL and are associated with a CD10-/myeloid+ immunophenotype.11-16 In general, infants with 11q23 rearrangements have a very poor outcome,11-14,16 although Heerema et al15 observed that the specific t(4;11) (q21;q23) translocation, rather than 11q23 rearrangements per se, was a highly significant predictor of poor outcome in infants. Overall event-free survival (EFS) estimates have ranged from 25% to 43% in studies by the various cooperative groups,1,4-7 but most of these studies involved relatively small numbers of patients. We have previously reported a 4-year EFS of 23% for 115 infants entered onto consecutive trials of the Children's Cancer Group (CCG) between 1972 and 1982,2 as well as a 4-year EFS of 36% for 27 infants treated on a CCG pilot study involving intensive multiagent chemotherapy together with cranial radiation therapy (CRT).3 Data from these studies also indicated that CRT was either inadequate for prevention of CNS relapse or, when successful, resulted in adverse neurologic sequelae in survivors. From 1984 to 1993, CCG investigators used intensive very-high-dose systemic chemotherapy together with intrathecal chemotherapy for prophylaxis of CNS leukemia as front-line treatment on two consecutive trials for infants with ALL. We now report analysis of the clinical features, treatment outcome, and prognostic variables for infants treated on these studies.
Patients Two hundred thirty-seven infants (< 1 year of age) with newly diagnosed ALL were enrolled between 1984 and 1993 onto two consecutive CCG infant ALL trials (CCG-107, n = 100; CCG-1883, n = 137). Diagnosis of ALL was based on morphologic, cytochemical, and immunologic features of the leukemic cells, including lymphoblast morphology on Wright-Giemsa–stained bone marrow smears, positive nuclear staining for terminal deoxynucleotidyl transferase, negative staining for myeloperoxidase, and cell surface expression of two or more lymphoid differentiation antigens (see below). Upon review, one patient on CCG-107 and two patients on CCG-1883 were found to have acute myeloid leukemia and were excluded from the current analysis. Thus, the final cohort (n = 234) included 99 patients on CCG-107 and 135 patients on CCG-1883. Each protocol was approved by the National Cancer Institute and the institutional review boards of the participating CCG-affiliated institutions. Informed consent was obtained from parents according to Department of Health and Human Services guidelines. A group of 67 infants entered between 1978 and 1983 onto the CCG-160 series of studies2 was used as a historical control.
Treatment Protocols
Immunophenotyping
Cytogenetic Analysis
Statistical Methods The primary end point examined was EFS from entry on study; EFS events included induction failure (failure to achieve M1 or M2 marrow status by day 28 or death during induction), leukemic relapse at any site, death, or second malignant neoplasm, whichever occurred first. Patients not experiencing an event at the time of EFS analysis were censored at the time of last contact. This analysis used the intent-to-treat philosophy; thus, patients were not censored or excluded from analysis for deviations, including bone marrow transplantation, from protocol therapy. A secondary end point, disease-free survival (DFS), was defined as the time from the end of induction to the time of relapse, death, or second malignant neoplasm among patients who achieved M1 or M2 status by day 28 of induction. For cause-specific failure analysis, DFS events were classified as (1) relapse involving the marrow, with or without other sites; (2) relapse involving only the CNS; (3) relapse involving sites other than the marrow or CNS; or (4) death in remission. In some analyses, outcome for the current cohort was compared with a historical series, as described below. These comparisons were adjusted for age and WBC count.
Historical Controls Treatment for infants on the CCG-162 and CCG-163 protocols has been described in detail previously.24 Briefly, therapy involved induction/intensification with VCR, prednisone (PRED), L-asparaginase (L-ASP), and mercaptopurine (6-MP), as well as CRT (18 Gy) and intrathecal MTX as presymptomatic treatment of the CNS. For maintenance (same duration as current studies), infants were randomized to one of several regimens, all of which were based on standard therapy with daily oral 6-MP, weekly oral MTX, and intravenous VCR plus oral PRED. Intensification of standard maintenance involved various schedules of additional drugs, including ARA-C, cyclophosphamide, intravenous MTX, and doxorubicin, or reinduction with VCR, PRED, and L-ASP. In general, overall therapy was less intensive on the CCG-160 series compared with CCG-107 or CCG-1883, except that the CCG-160 series included CRT. The historical controls were similar to the current cohorts with respect to presenting features, with the exception of a higher rate of hepatomegaly than observed on CCG-107 or CCG-1883 (P < .01). Follow-up requirements differed somewhat for the historical and current series. Marrow examinations were required with similar frequency before maintenance in all three cohorts. On the CCG-160 studies, marrow examinations were required every 12 weeks during maintenance, but on CCG-107 and CCG-1883, they were required only at the end of maintenance or when clinically indicated. In all three series, CSF examinations were required frequently before maintenance and at least every 3 months during maintenance, which provided similar follow-up during the period in which nearly all isolated CNS relapses occurred. After therapy, regular CSF examinations were required on the CCG-160 series and were optional on CCG-107 and CCG-1883.
Presenting Features of Infants With ALL on CCG Studies 107 and 1883 Demographic, clinical, and biologic characteristics at diagnosis of infants on the CCG-107 and CCG-1883 studies are listed in Table 1. Presenting features were similar for infants on the two studies, with the exception of a lower frequency of patients with high platelet count on CCG-1883 (P < .05). A predominance of girls was noted for both study groups, consistent with previous reports.1,2 Centrally reviewed cytogenetic data were available for 38 patients on CCG-107 and 56 patients on CCG-1883. Among this subset, 33 had a t(4;11) translocation, 12 had an 11q23 abnormality not involving chromosome 4, and 49 had normal chromosomes or other abnormalities. Complete cytogenetic data for infants on CCG-107 have been reported15; complete data for infants on CCG-1883 will be reported separately (Heerema et al, manuscript submitted for publication).
Immunophenotypic analysis (Table 2) of leukemic cells was based solely on the quality and quantity of marrow received. Although immunophenotyping was performed during both study eras, it should be noted that during the CCG-107 study, CD24, rather than CD19, was used as a B-lineage marker. Because CD24 is a less precise marker for B-lineage ALL, a large percentage of patients on CCG-107 were classified as having a null immunophenotype, whereas the majority of patients on CCG-1883 were classified as B-lineage. Patients on CCG-1883 were more frequently CD10+ than their counterparts on CCG-107, yet the majority of patients on both studies were CD10-. Cytoplasmic µ was absent in the majority of the analyzed patients from studies 107 and 1883. Together, these data suggest an early B-precursor immunophenotype for the majority of these infants. Myeloid antigen (CD13 or CD33) expression data were available for 65 patients on CCG-1883. Among such patients, only five were myeloid antigen positive.
Treatment Outcome of Infants With ALL on CCG Studies 107 and 1883 EFS outcome was similar for patients on CCG-107 and CCG-1883, with a 4-year EFS of 33% (SE = 5%) and 39% (SE = 4%), respectively (P = .63, log-rank test) (Fig 2). Follow-up for event-free survivors ranged from 46 to 141 months for CCG-107 and from 48 to 91 months for CCG-1883. By comparison, 67 infants treated on the preceding CCG-162 and CCG-163 studies for high-risk ALL had a 4-year EFS of 22% (SE = 5%). After adjustment for age and WBC count in a Cox regression analysis, EFS for infants on either CCG-107 or CCG-1883 was significantly improved, compared with those in the historical control group (P < .01, both comparisons) (Fig 2). Overall survival estimates for infants on CCG-107 and CCG-1883 at 4 years also were similar to each other (45%, SE = 5% and 51%, SE = 4%, respectively; P = .43) and were significantly improved compared with a 31% (SE = 6%) survival at 4 years for those in the historical control group (Cox regression analysis, P = .01 and P < .01, respectively).
A total of 150 events (67 on CCG-107; 83 on CCG-1883) (Table 3) occurred among the overall cohort of infants on CCG-107 and CCG-1883. Ten of these events were induction failures; seven were remission deaths. Of the remaining 133 events, the majority were isolated marrow relapses (35 on CCG-107; 54 on CCG-1883) or concurrent relapses in the marrow and other sites (11 on CCG-107; 12 on CCG-1883). A total of 15 and 11 CNS relapses occurred on CCG-107 and CCG-1883, respectively. Of these, seven on each study were concurrent CNS/marrow relapses; an isolated CNS relapse occurred in only eight patients on CCG-107 and four patients on CCG-1883.
After completion of induction therapy, the 4-year cumulative probability of having a marrow relapse, either alone or concurrent with an extramedullary relapse, was 49% (SE = 5%) on CCG-107 and 50% (SE = 5%) on CCG-1883 (Table 4). The 4-year cumulative probability of isolated CNS relapse was 9% (SE = 3%) on CCG-107 and 3% (SE = 2%) on CCG-1883 (Table 4). By comparison, the 4-year cumulative probabilities of any marrow relapse or an isolated CNS relapse on the CCG-160 series were 63% (SE = 6%) and 5% (SE = 3%), respectively (data not shown). The majority of all first relapses (65%, CCG-107; 72%, CCG-1883) occurred less than 1 year after the start of consolidation. These early relapses were the primary cause of death among patients on both studies: 88% of CCG-107 and 76% of CCG-1883 patients who experienced such a relapse succumbed to disease.
Toxicities Two patients on CCG-107 and five patients on CCG-1883 died during remission. Causes of death for patients on CCG-107 included sepsis (one patient) and CNS toxicity (one patient). All five remission deaths on CCG-1883 followed bone marrow transplantation that was performed off study on patients in first remission. Documented causes of remission deaths for patients on CCG-1883 included cardiac arrest (one patient); Pneumocystis infection (one patient); multiple infection due to Enterobacter cloacae, Pseudomonas aeruginosa, Candida albicans, and S maltophilia (one patient); hemorrhage in the CNS (one patient); and interstitial pneumonitis of unknown etiology (one patient). Among patients on CCG-107, 125 episodes of hematologic toxicities, primarily leukopenia, thrombocytopenia, and neutropenia, were reported during induction and consolidation. Neutropenia and leukopenia continued to occur through later stages of therapy. Liver toxicities (transient elevation of transaminases) occurred mainly during consolidation (49 episodes). Fewer toxic episodes were reported for patients on CCG-1883; the majority were transient liver toxicities associated with induction (16 episodes), consolidation (88 episodes), interim maintenance (15 episodes), and delayed intensification (28 episodes). Long-term neurologic sequelae were examined in a subset of infants on CCG-107.25 Preliminary data suggested a decrease in the incidence of psychoneurologic dysfunction in these infants, compared with those treated on previous CCG ALL protocols. Definitive analyses of treatment effects on neurologic development are currently in progress and will be reported elsewhere (Kaleita, manuscript in preparation).
Prognostic Factors Notably, among the subset of patients with centrally reviewed cytogenetic data, those with a t(4;11) translocation had significantly worse outcomes than those with either normal cytogenetics or structural abnormalities other than t(4;11): 4-year EFS estimates were 3% (SE = 2%), 49% (SE = 7%), and 50% (SE = 14%), respectively (P < .001, log-rank test) (Fig 3). Patients with an M1 day-14 marrow status had improved DFS outcome, compared with patients having an M2/M3 day-14 marrow status, with 4-year estimates of 43% (SE = 4%) and 6% (SE = 4%), respectively (P < .001, log-rank test).
To determine the independent prognostic significance of univariate prognostic factors, we initially used multivariate Cox regression analyses that did not include t(4;11) status. In an analysis of EFS that included age, WBC count, FAB morphology, hepatomegaly, and hemoglobin status, significantly increased risk was observed for younger patients (P < .01) and for those with WBC counts of more than 50,000/µL (P < .05) (Table 5, model A). Hemoglobin, FAB morphology, and hepatomegaly were not statistically significant in this model, although the results were consistent with higher failure rate for L2 morphology and increased liver size.
After adjustment for age and WBC count, infants who were CD10- had increased risk with respect to EFS (P < .05) (Table 5, model B), and those who had M2 or M3 day-14 marrow status had increased risk with respect to DFS (P < .001) (Table 5, model C). The prognostic importance of day- 14 marrow in predicting DFS was maintained after additional adjustment for CD10 status in the 114 patients with complete data on all variables (P < .001; parameter estimates not shown).
Additional multivariate analyses were performed to assess the independent prognostic importance of age, WBC count, CD10 status, and day-14 marrow status in the context of t(4;11) or other 11q23 abnormalities. These analyses were complicated because of the reduced number of patients with complete data on all variables as well as the strong associations between age, WBC count, CD10 status, and t(4;11) status: 24 (73%) of 33 patients with t(4;11), compared with 19 (31%) of 61 patients without t(4;11), were under 6 months of age (P < .001, Because of the complete absence of patients who were t(4;11)+/CD10+, the prognostic significance of CD10 status in predicting EFS was assessed in two additional analyses. The first analysis, which included WBC count and age, compared t(4;11) status among 44 CD10- patients with complete data. This analysis indicated that the presence of t(4;11) was associated with increased risk of failure (RHR, 2.5; 95% CI, 0.95 to 6.4; P = .053). The second analysis, also adjusted for age and WBC count, compared CD10 status among the 40 t(4;11)- patients with complete data. In this model, there was no indication that CD10 negativity was associated with increased risk (RHR, 1.0; 95% CI, 0.4 to 2.6; P > .9). Hence, it appears from these data that t(4;11) status rather than CD10 status is the more important determinant of prognosis. In contrast to CD10 status, day-14 marrow status remained a significant predictor of DFS after adjustment for t(4;11) and CD10 status. In a Cox regression analysis adjusting for age, WBC count, and t(4;11) status, the day-14 marrow effect was statistically significant among 78 patients with complete data on all variables (P < .001), with relative risk comparable to that shown in Table 5. Furthermore, this effect was also evident in a similar analysis restricted to the subset of 38 patients who were CD10- (P < .05).
Protocol Deviations and Bone Marrow Transplantation
In the current report, we present outcome and prognostic factor analyses for the largest cohort of infants with ALL ever reported. Patients were enrolled between 1984 and 1993 on two consecutive CCG treatment protocols, CCG-107 and CCG-1883, and received five-phase intensive systemic chemotherapy on both regimens; overall, treatments on CCG-1883 were generally more intensive than those on CCG-107. Toxicities were tolerable on both studies and were rarely responsible for patient death. EFS outcomes for infants on CCG-107 and CCG-1883 were 33% and 39%, respectively. By comparison, 4-year EFS was 22% for infants treated on the CCG-162 and CCG-163 high-risk ALL studies that immediately preceded CCG-107. Thus, in the context of such historical controls, there appeared to be a progressive improvement in outcome from the earliest to the most recent CCG studies, although, when using such a historical comparison, one cannot entirely exclude the possibility that the observed improvement may be attributable to nontherapeutic factors. Consistent with previous reports of prognostic factors in infant ALL, we observed heterogeneity in outcome among infants, with very poor EFS for those who were less than 3 months of age or were CD10-.2,8-10 As we reported previously for children more than 1 year of age with ALL,26,27 M2 or M3 day-14 marrow status predicted a significantly increased risk of postinduction treatment failure, compared with M1 status. Also, the specific nonrandom translocation t(4;11), but not other 11q23 rearrangements, was a significant adverse factor among the subset of patients with cytogenetic data. This observation was reported previously for the subset of CCG-107 patients included in the current analysis.15 We and others have reported a higher incidence of MLL gene rearrangements among patients assessed by molecular techniques, compared with those evaluated cytogenetically.13,14,16,28 In infants with ALL, the existence of an MLL gene rearrangement was associated with an inferioroutcome, although correlation with specific chromosomal aberrations, ie, t(4;11) or other 11q23 abnormalities, was incompletely assessed.16,28 A definitive evaluation of the relative prognostic significance of MLL rearrangements and the specific translocation t(4;11) is being addressed in the current CCG trial for ALL in infants. Multivariate analysis not including cytogenetic data indicated that younger age, high WBC count, CD10 negativity, and M2/M3 day-14 marrow status were significant adverse prognostic factors for the overall group of patients. Multivariate analyses of EFS for the subset of patients with cytogenetic data using a model containing the other relevant variables indicated that although presence of t(4;11) was the most important adverse risk factor, it did not appear to explain completely the prognostic importance of WBC count or age in this small sample. The t(4;11) translocation did appear to explain completely the effect of CD10 negativity in this group. Similarly, we previously noted improved outcome for the subgroup of infants on the CCG-1883 study who had a CD10+CD19+CD34+ B-progenitor immunophenotype.29 Multivariate analyses of DFS indicated that day-14 marrow status remained prognostically significant after adjustment for t(4;11) status, age, WBC count, and CD10 status. As was the case in our previous report,2 early marrow relapse continued to be the major cause of treatment failure in the current studies. The cumulative probability of isolated CNS relapse on CCG-1883 was decreased, compared with CCG-107, and was similar to the rate observed for the CCG-160 series that used CRT. A higher percentage of infants in our previous report2 experienced a CNS relapse (isolated or concurrent with other sites), but these events occurred primarily on studies conducted before the CCG-160 series that used CRT, minimal or no intrathecal therapy, and less intensive systemic therapy. Together, these data indicate that intensive systemic chemotherapy, particularly the very high-dose protracted MTX and high-dose ARA-C infusions combined with intrathecal agents and without CRT, were effective in preventing CNS relapse. The use of CRT previously was associated with long-term adverse neurologic sequelae,2 and preliminary analysis of a subset of patients from the current studies suggests that neurologic abnormalities now have been reduced.25 Thus, the combination of intrathecal therapy and very-high-dose systemic MTX appears to represent a superior and effective treatment strategy for prevention of CNS disease without adverse neurologic effects. In general, the other pediatric cancer cooperative groups also have reported poor outcomes for infants with ALL,4-7although Silverman et al,30 using a regimen that included postinduction intensification with high-dose MTX, ARA-C, and L-ASP plus VCR and 6-MP, recently reported a 5-year EFS of 54% ± 11% for a group of 23 infants, 48% of whom were CD10+. The true efficacy of such a regimen will require further study with a larger cohort. It is also notable that the regimen used by Silverman et al included CRT and resulted in adverse neuropsychologic effects in nine of the 11 assessed long-term survivors. In contrast, a recent Pediatric Oncology Group study reported a 4-year EFS of 28% (SE = 5%) for 82 infant ALL patients treated with a regimen that emphasized pulse doses of cyclophosphamide, ARA-C, and teniposide and used triple intrathecal therapy for CNS therapy.1 Despite the progressive improvement in EFS outcome achieved for the majority of children with ALL treated on increasingly intensive multiagent chemotherapy regimens, the outcome for patients less than 1 year of age remains decidedly inferior. Furthermore, the elucidation of adverse predictive indicators, such as age under 6 months, WBC count of more than 50,000/µL, lack of CD10 expression, presence of a t(4;11) translocation, and a slow early response to induction therapy, defines a subgroup of infants who have a dismal prognosis on current intensive therapies. The evaluation of novel therapeutic approaches, including stem-cell transplantation strategies31 and targeted immunotherapy with agents such as anti-CD19 immunoconjugates,32,33 should be considered.
Supported by the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and Human Services (grant no. CA-13539).
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Reaman G, Zeltzer P, Bleyer WA, et al: Acute lymphoblastic leukemia in infants less than one year of age: A cumulative experience of the Children's Cancer Study Group. J Clin Oncol 3:1513-1521, 1985 3. Reaman GH, Steinherz PG, Gaynon PS, et al: Improved survival of infants less than 1 year of age with acute lymphoblastic leukemia treated with intensive multiagent chemotherapy. Cancer Treat Rep 71:1033-1038, 1987[Medline] 4. Ferster A, Bertrand Y, Benoit Y, et al: Improved survival for acute lymphoblastic leukaemia in infancy: The experience of EORTC-Childhood Leukaemia Cooperative Group. Br J Haematol 86:284-290, 1994[Medline] 5. Ishii E, Okamura J, Tsuchida M, et al: Infant leukemia in Japan: Clinical and biological analysis of 48 cases. Med Pediatr Oncol 19:28-32, 1991[Medline] 6. Bucsky P, Reiter A, Ritter J, et al: [Acute lymphoblastic leukemia in infancy: Results of 5 multicenter ALL-BFM therapy studies 1970-1986]. Klin Padiatr 200:177-183, 1988[Medline] 7. Chessells JM, Eden OB, Bailey CC, et al: Acute lymphoblastic leukaemia in infancy: Experience in MRC UKALL trials—Report from the Medical Research Council Working Party on Childhood Leukaemia. Leukemia 8:1275-1279, 1994[Medline] 8. Basso G, Putti MC, Cantu Rajnoldi A, et al: The immunophenotype in infant acute lymphoblastic leukaemia: Correlation with clinical outcome—An Italian multicentre study (AIEOP). Br J Haematol 81:184-191, 1992[Medline] 9. Ludwig WD, Bartram CR, Harbott J, et al: Phenotypic and genotypic heterogeneity in infant acute leukemia: I. Acute lymphoblastic leukemia. Leukemia 3:431-439, 1989[Medline] 10. Pui CH, Ribeiro RC, Campana D, et al: Prognostic factors in the acute lymphoid and myeloid leukemias of infants. Leukemia 10:952-956, 1996[Medline] 11. Cimino G, Rapanotti MC, Rivolta A, et al: Prognostic relevance of ALL-1 gene rearrangement in infant acute leukemias. Leukemia 9:391-395, 1995[Medline]
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Pui CH, Behm FG, Downing JR, et al: 11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. J Clin Oncol 12:909-915, 1994 13. Taki T, Ida K, Bessho F, et al: Frequency and clinical significance of the MLL gene rearrangements in infant acute leukemia. Leukemia 10:1303-1307, 1996[Medline]
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Behm FG, Raimondi SC, Frestedt JL, et al: Rearrangement of the MLL gene confers a poor prognosis in childhood acute lymphoblastic leukemia, regardless of presenting age. Blood 87:2870-2877, 1996
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Hilden JM, Frestedt JL, Moore RO, et al: Molecular analysis of infant acute lymphoblastic leukemia: MLL gene rearrangement and reverse transcriptase-polymerase chain reaction for t(4;11)(q21;q23). Blood 86:3876-3882, 1995
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Uckun FM, Ledbetter JA: Immunobiologic differences between normal and leukemic human B-cell precursors. Proc Natl Acad Sci USA 85:8603-8607, 1988
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Uckun FM, Muraguchi A, Ledbetter JA, et al: Biphenotypic leukemic lymphocyte precursors in CD2+CD19+ acute lymphoblastic leukemia and their putative normal counterparts in human fetal hematopoietic tissues. Blood 73:1000-1015, 1989 19. Heerema NA, Palmer CG, Baehner RL: Karyotypic and clinical findings in a consecutive series of children with acute lymphocytic leukemia. Cancer Genet Cytogenet 17:165-179, 1985[Medline] 20. Mitelman F: ISCN: An International System for Human Cytogenetic Nomenclature. Basel, Switzerland, Karger, 1995 21. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, John Wiley and Sons, 1980 22. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35:1-39, 1977[Medline] 23. Gaynor J, Feuer E, Tan C, et al: On the use of cause-specific failure and conditional failure probabilities: Examples from clinical oncology data. J Am Stat Assoc 88:400-409, 1993 24. Coccia PF, Bleyer WA, Siegel SE, et al: Development and Preliminary Findings of Children's Cancer Study Group Protocols (161, 162 and 163) for Low-, Average- and High-Risk Acute Lymphoblastic Leukemia in Children, in Murphy S, Gilbert J (eds): Leukemia Research: Advances in Cell Biology and Treatment. Amsterdam, the Netherlands, Elsevier Science Publishing Co, 1983 25. Kaleita TA, MacLean WE, Reaman GH, et al: Neurodevelopmental outcome of children diagnosed with all during infancy: A preliminary report from the Children's Cancer Study Group. Med Pediatr Oncol 20:385, 1992
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Steinherz PG, Gaynon PS, Breneman JC, et al: Cytoreduction and prognosis in acute lymphoblastic leukemia-the importance of early marrow response: Report from the Children's Cancer Group. J Clin Oncol 14:389-398, 1996 27. Gaynon PS, Bleyer WA, Steinherz PG, et al: Day 7 marrow response and outcome for children with acute lymphoblastic leukemia and unfavorable presenting features. Med Pediatr Oncol 18:273-279, 1990[Medline]
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Rubnitz JE, Link MP, Shuster JJ, et al: Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: A Pediatric Oncology Group study. Blood 84:570-573, 1994 29. Uckun F, Sather H, Gaynon P, et al: Prognostic significance of the CD10+CD19+CD34+ B-progenitor immunophenotype in children with acute lymphoblastic leukemia: A report from the Children's Cancer Group. Leuk Lymphoma 27:445-457, 1997[Medline] 30. Silverman L, McLean T, Gelber R, et al: Intensified therapy for infants with acute lymphoblastic leukemia. Cancer 80:2285-2296, 1997[Medline] 31. Appelbaum FR: Allogeneic hematopoietic stem cell transplantation for acute leukemia. Semin Oncol 24:114-123, 1997[Medline]
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Uckun FM, Evans WE, Forsyth CJ, et al: Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases. Science 267:886-891, 1995 Submitted March 9, 1998; accepted October 8, 1998. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
90%) of leukemic cells were isolated from pretreatment bone marrow aspirate samples by centrifugation on Ficoll-Hypaque gradients. Immunophenotyping was performed centrally in the CCG ALL Biology Reference Laboratory using monoclonal antibodies reactive with CD2, CD3, CD5, CD7, CD10, CD19, and CD24, as previously described.
2 tests for homogeneity. Outcome was analyzed using survival analysis methods, including the product-limit (Kaplan-Meier) estimate of survival probability, stratified and unstratified log-rank tests, Cox regression analysis, and cause-specific failure analysis.
