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BACKGROUND. Patients with metastatic osteosarcoma have a poor prognosis. The objectives of the study were to determine the antitumor activity and toxicity of topotecan (daily ×5) in newly diagnosed patients with metastatic osteosarcoma followed by chemotherapy (ifosfamide, carboplatin, etoposide [ICE], alternating with cisplatin and doxorubicin [CD]). METHODS. Newly diagnosed patients (≤30 years of age) with extensive metastatic disease (primary and ≥5 pulmonary nodules and/or bone metastases) with normal hepatic, renal, and cardiac function were eligible. Patients were eligible to receive further topotecan after standard chemotherapy if they exhibited a response. Twenty-eight patients were enrolled. Seventeen had metastases to the lung only and 11 had metastases to the bone or multiple sites. Of 28 patients enrolled, 27 could be evaluated for response. A limited dose escalation was incorporated. RESULTS. No responses were seen in the 11 patients treated at 3 mg/m2/day. One partial response (PR) and 1 clinical response (CLR) were reported among 15 patients who received topotecan at 3.5 mg/m2/day. No dose-limiting toxicity was observed. Principal nondose-limiting toxicities were hematologic and gastrointestinal. The 2- and 5-year event-free survival rates were low, 7% and 4%, respectively, but the 2- and 5-year overall survival rates were 44% and 22%, respectively. CONCLUSIONS. Topotecan at dose of 3.5 mg/m2/day can be safely administered upfront to newly diagnosed patients without excessive toxicity. Insufficient activity was seen with topotecan in this schedule to warrant further studies in osteosarcoma. The combination of ICE and CD was tolerable when delivered after initial topotecan therapy. Cancer 2007. © 2007 American Cancer Society.

The International Acute Lymphoblastic Leukemia Working Group, the so-called 'Ponte di Legno Workshop' has led to substantial progress in international collaboration in leukemia research. On April 27 -28, 2005, the 8th Meeting was held in Vienna, Austria, to continue the discussions about special common treatment elements in randomized clinical trials, ethical and clinical aspects of therapy. Furthermore, collaborative projects of clinical relevance with special emphasis on rare genetic subtypes of Childhood ALL were established. The following report summarizes the achievements and aspects of possible future cooperation. © 2006 Nature Publishing Group All rights reserved.

Young adult patients with acute lymphoblastic leukaemia (ALL) represent a unique epidemiologic subgroup in that therapy may be provided by either adult or paediatric oncologists. There seem to be no differences in presenting clinical features, immunophenotypic characteristics, or cytogenetic abnormalities for young adult ALL patients treated on paediatric or adult protocols with the exception of median age (16-paediatric trials versus 19-adult trials). There is no evidence to suggest that age within the 16-21 year old subgroup has any prognostic significance. Compared with patients 1-9 years, young adult ALL patients have a lower incidence of favourable cytogenetics t(12; 21) hyperdiploidy, a slightly increased incidence of the t(9;22), and an increased frequency of T cell immunophenotype. Compared with patients >30 years, young adult ALL patients have a significantly lower incidence of the t(9; 22). In multiple studies, there is a consistent, large event-free survival and survival advantage for young adult patients treated on paediatric versus adult protocols.

Between 1995 and 2004, six International Childhood Acute Lymphoblastic Leukemia (ALL) Workshop have been held, and the completion of several collaborative projects has established the clinical relevance and treatment options for several specific genetic subtypes of ALL. This meeting report summarizes the data presented in the seventh meeting and the discussion.

Adolescents with acute lymphoblastic leukemia (ALL) have a higher incidence of T-cell immunophenotype, a higher incidence of Philadelphia chromosome positive ALL, a lower incidence of high hyperdiploidy and TEL-AML1 translocation, and a lower incidence of extramedullary bulk disease compared to younger patients. There appears to be little difference between 10-15 and 16-21 year old patients. Adolescents with ALL have a lower event free survival (EFS) compared to younger patients. Adolescents 16-21 years of age treated on pediatric ALL trials have a significantly better EFS than those treated on adult trials. Pediatric treatment protocols utilize more vincristine, steroid and L-asparaginase compared to adult trials. In a recently completed Children's Cancer Group trial, adolescents 16-21 years of age had a four-year EFS of 73.1%. Avascular necrosis of bone is an important complication of therapy in adolescents with ALL.

Monosomy 7 or deletions of 7q are associated with many myeloid disorders; however, the significance of such abnormalities in childhood acute lymphoblastic leukemia (ALL) is unknown. Among 1880 children with ALL, 75 (4%) had losses involving chromosome 7, 16 (21%) with monosomy 7, 41 (55%) with losses of 7p (del(7p)), 16 (21%) with losses of 7q (del(7q)), and two (3%) with losses involving both arms. Patients with losses involving chromosome 7 were more likely to be > or =10 years old, National Cancer Institute (NCI) poor risk, and hypodiploid than patients lacking this abnormality. Patients with or without these abnormalities had similar early response to induction therapy. Event-free survival (EFS) and survival for patients with monosomy 7 (P

The Sixth International Childhood ALL Workshop was made possible by unrestricted educational grants from Sanofi-Synethelabo Inc., Glaxosmithkline, Enzon Inc., and Ilex. Preparation of the Meeting Report was supported in part by the Österreichische Kinderkrebshilfe and private donations to the Children's Cancer Research Institute; the Associazione Italiana Ricerca sul Cancro, Fondazione Tettamanti, and Consiglio Nazionale Ricerche-Ministero Instruzione Universitá Ricerca); the Deutsche Krebshilfe, Bonn, and Madeleine Schickedanz Foundation, Fürth, Germany; Cancer Research UKJ; grants from the US National Institutes of Health (CA-21765, CA-51001, CA-31566, CA-78824, CA-29139, CA-37379, GM-61393, and GM61374), a Center of Excellence grant from the State of Tennessee, and the American Lebanese Syrian Associated Charities (ALSAC). C-H Pui is the American Cancer Society - FM Kirby Clinical Research Professor. © 2004 Nature Publishing Group. All rights reserved.

PURPOSE: Current standard therapy for children and adolescents with Hodgkin’s disease includes combination chemotherapy and low-dose involved-field radiation (LD-IFRT). Because radiation may be associated with adverse late effects, the Children’s Cancer Group (CCG) investigated whether radiation could be omitted in patients achieving a complete response to initial chemotherapy without jeopardizing the excellent outcome obtained with combined-modality therapy. PATIENTS AND METHODS: Between January 1995 and December 1998, 829 eligible patients were enrolled onto CCG 5942. A total of 501 patients who achieved an initial complete response after risk-adapted combination chemotherapy were randomized to receive LD-IFRT or no further treatment. Event-free survival (EFS) and overall survival were assessed from the date of study entry or the date of randomization, as appropriate. RESULTS: The projected 3-year EFS from study entry for the entire cohort was 87% ± 1.2%. Among patients who achieved a complete response to initial chemotherapy, 92% ± 1.9% of those randomized to receive LD-IFRT were alive and disease free 3 years after randomization, versus 87% ± 2.2% for patients randomized to receive no further therapy (stratified log-rank test; P = .057). With an “as-treated” analysis, 3-year EFS after randomization for the radiation cohort was 93% ± 1.7% versus 85% ± 2.3% for patients receiving no further therapy (stratified log-rank test; P = .0024). Three-year survival estimates for patients treated with and without LD-IFRT were 98% ± 1.1% for patients who received radiation and 99% ± 0.5% for patients who did not receive radiation. CONCLUSION: LD-IFRT after an initial complete response to risk-adapted chemotherapy improved EFS. At this time, there is no survival advantage for LD-IFRT, but follow-up remains short.

Purpose Thrombocytopenia has been reported in some children with severe iron deficiency anemia, but the validity of the association and the mechanism of the thrombocytopenia are not well established. Six children with severe iron deficiency and thrombocytopenia are described, and the literature is reviewed. Patients and methods Clinical, hematologic, and morphologic data were collected and analyzed for six patients referred for evaluation of severe microcytic anemia and thrombocytopenia. Results The children ranged in age from 14 months to 17 years (median age 27 months) and were otherwise healthy. The iron deficiency was nutritional in four patients younger than 3 years of age and resulted from menstrual blood loss in two teenage girls. The mean initial hemoglobin was 2.5 g/dL (range 1.6-4.7) and the mean initial platelet count was 64 x 109/L (range 11-102). Bone marrow examinations were performed in three patients and showed increased numbers of megakaryocytes. After treatment with therapeutic doses of oral iron, all the patients showed rapid increases in their platelet counts. Conclusions These observations validate and extend previous reports of an association between severe iron deficiency and thrombocytopenia. The increased numbers of megakaryocytes and the extremely rapid increase in platelet counts after initiation of iron therapy suggest an essential role for iron in a late stage of thrombopoiesis.

Cancers in mouse and man express multiple tumor-specific as well as tumor-associated antigens. Immunodominance in the host response to these antigens can result in successive selection of heritable antigen loss variants. Immunodominance may also prevent the development of responses to new tumor-specific antigens that may arise during tumor progression. Some tumor-specific antigens are retained during tumor progression possibly because they are essential for survival of the malignant phenotype. Immunodominance may allow cancer cells to escape even after loss of a single MHC Class I allele because cross-presentation of the retained antigen by this allele that must be expressed on the surrounding antigen presenting cells sustains the immunodominant response. This prevents effective responses to secondary antigens that may remain as potential targets. Immunization with in vitro selected cancer cell variants that lack the immunodominant antigen can break the immunodominance and prevent escape of cancers from host immunity.

Recurring breakpoints in chromosome bands 15q13-15 occur infrequently in leukemia. To the authors' knowledge, the clinical significance of these breakpoints in childhood acute lymphoblastic leukemia (ALL) has not been previously investigated.Centrally reviewed karyotypes of children with newly diagnosed ALL enrolled on Children's Cancer Group protocols from 1988 to 1995 formed the basis of the current report. Statistical analyses used chi-square tests for homogeneity of proportions, and outcome was analyzed using life table methods and associated statistics.Of 1946 cases with centrally reviewed and accepted cytogenetic analyses, 23 cases (1%) had breakpoints in chromosome bands 15q13-15. Most patients with 15q13-15 breakpoints had standard risk ALL, although breakpoints in 15q13-15 occurred more frequently in infants than in older children. The majority of these patients (16 patients; 70%) had balanced 15q13-15 rearrangements. Additional chromosomal abnormalities not involving 15q included abnormal 12p, abnormal 9p, Philadelphia chromosome, deletion 6q, and an 11q23 breakpoint. Thirteen (57%) 15q13-15 breakpoints occurred in pseudodiploid karyotypes; five (22%) were in hyperdiploid karyotypes with 47-50 chromosomes; two (9%) were in hyperdiploid karyotypes with50 chromosomes; and three (13%) were in hypodiploid karyotypes. Of the 23 patients with 15q13-15 breakpoints, 21 were survivors, 18 survived event-free for 2.2-9.3 years, and 3 were alive 1 to 3 years after a relapse at time of writing.The current study suggests that genes at 15q13-15 may be involved in the leukemogenesis of some cases of childhood ALL, but that with current intensive therapy such aberrations do not confer increased risk of treatment failure.

Osteonecrosis is a severe glucocorticoid-induced complication of acute lymphoblastic leukemia treatment. We prospectively screened children (n = 364) with magnetic resonance imaging of hips and knees, regardless of symptoms; the cumulative incidence of any (grade 1-4) versus symptomatic (grade 2-4) osteonecrosis was 71.8% versus 17.6%, respectively. We investigated whether age, race, sex, acute lymphoblastic leukemia treatment arm, body mass, serum lipids, albumin and cortisol levels, dexamethasone pharmacokinetics, and genome-wide germline genetic polymorphisms were associated with symptomatic osteonecrosis. Age more than 10 years (odds ratio, = 4.85; 95% confidence interval, 2.5-9.2; P = .00001) and more intensive treatment (odds ratio = 2.5; 95% confidence interval, 1.2-4.9; P = .011) were risk factors and included as covariates in all analyses. Lower albumin (P = .05) and elevated cholesterol (P = .02) associated with symptomatic osteonecrosis, and severe (grade 3 or 4) osteonecrosis was linked to poor dexamethasone clearance (P = .0005). Adjusting for clinical features, polymorphisms of ACP1 (eg, rs12714403, P = 1.9 × 10−6, odds ratio = 5.6; 95% confidence interval, 2.7-11.3), which regulates lipid levels and osteoblast differentiation, were associated with risk of osteonecrosis as well as with lower albumin and higher cholesterol. Overall, older age, lower albumin, higher lipid levels, and dexamethasone exposure were associated with osteonecrosis and may be linked by inherited genomic variation.

‘Educational symposium on long-term results of large prospective clinical trials for childhood acute lymphoblastic leukemia (1985–2000)’

PURPOSE: Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (> 50 chromosomes) have improved outcome compared with other ALL patients. We sought to identify cytogenetic features that would predict differences in outcome within this low-risk subset of ALL patients. MATERIALS AND METHODS: High-hyperdiploid ALL patients (N = 480) were enrolled between 1988 and 1995 on Children’s Cancer Group (CCG) trials. Karyotypes were determined by conventional banding. Treatment outcome was analyzed by life-table methods. RESULTS: Patients with 54 to 58 chromosomes had better outcome than patients with 51 to 53 or 59 to 68 chromosomes (P = .0002). Patients with a trisomy of chromosome 10 (P < .0001), chromosome 17 (P = .0002), or chromosome 18 (P = .004) had significantly improved outcome compared with their counterparts who lacked the given trisomy. Patients with a trisomy of chromosome 5 had worse outcome than patients lacking this trisomy (P = .02). Patients with trisomies of both chromosomes 10 and 17 had better outcome than those with a trisomy of chromosome 10 (P = .09), a trisomy of chromosome 17 (P = .01), or neither trisomy (P < .0001). Multivariate analysis indicated that trisomy of chromosome 10 (P = .001) was the most significant prognostic factor for high-hyperdiploid patients, yet trisomy of chromosome 17 (P = .02) or chromosome 5 (P = .01) and modal chromosome number (P = .02) also had significant multivariate effects. CONCLUSION: Trisomy of chromosomes 10 and 17 as well as modal chromosome number 54 to 58 identify subgroups of patients with high-hyperdiploid ALL who have a better outcome than high-hyperdiploid patients who lack these cytogenetic features. Trisomy of chromosome 5 confers poorer outcome among high-hyperdiploid patients.

In this issue of Blood, Claviez and colleagues report on the outcomes of 91 patients younger than 18 years of age who underwent an allogeneic bone marrow transplantation for HL between 1987 and 2005. The outcomes were reported to the European Group for Blood and Marrow Transplantation.1

PURPOSE: We sought to determine if molecular abnormalities involving the Ikaros gene could contribute to the development of acute lymphoblastic leukemia (ALL) in children. PATIENTS AND METHODS: We studied Ikaros gene expression in normal human bone marrow, normal thymocytes, normal fetal liver–derived immature lymphocyte precursor cell lines, eight different ALL cell lines, and leukemic cells from 69 children with ALL (T-lineage ALL, n = 18; B-lineage ALL, n = 51). Expression of Ikaros protein and its subcellular localization were examined by immunoblotting and confocal laser-scanning microscopy, respectively. Polymerase chain reaction (PCR) and nucleotide sequencing were used to identify the specific Ikaros isoforms expressed in these cells. Genomic sequencing of splice junction regions of the Ikaros gene was performed in search for mutations. RESULTS: In each of the ALL cases, we found high-level expression of a non–DNA-binding or aberrant DNA-binding isoform of Ikaros with abnormal subcellular compartmentalization patterns. In contrast, only wild-type Ik-1 and Ik-2 isoforms with normal subcellular localization were found in normal bone marrow cells and thymus-derived or fetal liver–derived normal lymphocyte precursors. In leukemic cells expressing the aberrant Ikaros coding sequences with the 30-base-pair deletion, genomic sequence analysis of the intron-exon junctions between exons 6 and 7 yielded the wild-type sequence. We identified a single nucleotide polymorphism (SNP) affecting the third base of the triplet codon for a proline (CCC or CCA) in the highly conserved bipartite activation region (viz, A or C at position 1002 numbering from the translation start site of Ik-1) within our Ikaros clones. Bi-allelic expression of truncated and/or non–DNA-binding isoforms along with wild-type isoforms was observed in leukemic cells, which implicates trans-acting factor(s) affecting splice site recognition. CONCLUSION: Our findings link specific molecular defects involving the Ikaros gene to childhood ALL. Posttranscriptional regulation of alternative splicing of Ikaros RNA seems to be defective in leukemic lymphocyte precursors from most children with ALL. Consequently, leukemic cells from ALL patients, in contrast to normal lymphocyte precursors, express high levels of non–DNA-binding Ikaros isoforms that are reminiscent of the non–DNA-binding Ikaros isoforms that lead to lymphoblastic leukemia in mice.

Children with Philadelphia (Ph) chromosome positive (+) acute lymphoblastic leukemia (ALL) represent a subgroup at very high risk for treatment failure. This study included 1322 children enrolled between 1988 and 1994 on CCG risk-adjusted studies for ALL who had centrally reviewed cytogenetic data. Thirty patients had a t(9;22) and are referred to as Ph+; 1292 were Ph-; 23 of these 30 patients were treated on the CCG-1882 high risk ALL protocol. The event-free survival (EFS) outcome in CCG-1882 was significantly worse for Ph+ compared with Ph- patients, with 4-year estimates of 11.3% (SD = 9.8%) and 73.4% (SD = 2.3%), respectively (p < 0.0001).

PURPOSE Intensified intrathecal (i.t.) chemotherapy without cranial radiation therapy (CRT) prevents CNS relapse in children with low-risk and intermediate-risk acute lymphoblastic leukemia (ALL). In the current study, high-risk ALL patients who achieved a rapid early response (RER) to induction chemotherapy were randomized to receive intensive systemic chemotherapy and presymptomatic CNS therapy that consisted of either i.t. methotrexate (MTX) and CRT or intensified i.t. MTX alone. PATIENTS AND METHODS Children (n = 636) with high-risk ALL (aged 1 to 9 years and WBC count > or = 50,000/microL or age > or = 10 years, excluding those with lymphomatous features) who achieved an RER (< or = 25% marrow blasts on day 7) to induction therapy and lacked CNS disease at diagnosis were randomized to receive systemic therapy with either i.t. MTX and CRT (regimen A, n = 317) or intensified i.t. MTX alone (regimen B, n = 319). RESULTS Interim analysis in July 1993 revealed 3-year event-free survival (EFS) estimates of 82.1% +/- 4.0% (SD)and 70.4% +/- 4.2% for patients treated on regimens A and B, respectively (P = .004). As of January 1996, outcome had changed: 5-year EFS estimates were 69.1% +/- 3.4% and 75.0% +/- 2.7% for regimens A and B, respectively (P = 0.50). Marrow relapses comprised 57 events on regimen A and 43 events on regimen B. Fewer late events occurred on regimen B. CONCLUSION For high-risk pediatric ALL patients who show an RER to induction therapy and are treated with systemic Children's Cancer Group (CCG)-modified Berlin-Frankfurt-Munster (BFM) chemotherapy, presymptomatic CNS therapy that consists of either i.t. MTX plus CRT or intensified i.t. MTX alone results in a similar 5-year EFS outcome. Furthermore, intensified i.t. MTX may protect against late bone marrow relapse.

PURPOSE The nonrandom translocation t(1;19) has been associated with poor outcome in pediatric B-lineage acute lymphoblastic leukemia (ALL). Because most patients treated by contemporary therapies now achieve improved outcomes, we have reassessed the prognostic significance of t(1;19). PATIENTS AND METHODS Cytogenetic data were accepted for 1,322 children (RESULTS Translocation (1;19)+ patients were more likely than t(1;19)- patients to be 10 years of age or greater (P < .001) or CD10+ CD19+ CD34- (P < .0001), or nonwhite (P = .02). Patients with a balanced t(1;19) were less likely to be hyperdiploid than patients with an unbalanced der(19)t(1;19). Event-free survival (EFS) was similar for the overall group of t(1;19)+ and t(1;19)- patients, with 4-year estimates of 69.5% (SD, 6.8%) and 74.8% (SD, 1.3%; P = .48), respectively. However, patients with unbalanced der(19)t(1;19) had significantly better outcomes than patients with balanced t(1;19): 4-year EFS were 80.6% (SD, 7.1%) and 41.7% (SD, 13.5%), respectively (P = .003). These differences were maintained within the individual studies analyses and after exclusion of t(1;19)+ patients whose cells were hyperdiploid with more than 50 chromosomes. CONCLUSION The overall group of t(1;19)+ patients, as well as the subgroup with an unbalanced der(19)+ (1;19) had outcomes similar to that of t(1;19)- patients, whereas patients with balanced t(1;19) had poorer outcomes. Thus, although the overall prognostic significance of t(1;19) has been obviated by contemporary risk-adjusted protocols, the balanced t(1;19) translocation remains an adverse prognostic factor.

We used reverse transcriptase polymerase chain reaction (RT-PCR) assays to examine primary leukemic cells in on-study diagnostic bone marrow specimens from 642 children with newly diagnosed acute lymphoblastic leukemia (ALL) for the expression of MLL-AF4, E2A-PBX1, and BCR-ABL fusion transcripts. All PCR assays were performed centrally in the Children's Cancer Group ALL Biology Reference Laboratory. MLL-AF4 transcript was found in only 0.7% of the study population which excluded infants. E2A-PBX1 transcript was found in 2.5% of the study population and 3.3% of B-precursor cases. Expression was associated with massive hepatomegaly. BCR-ABL transcript was found in 2.3% of cases and correlated with older age, induction failure, and inferior event-free survival (EFS). RT-PCR assays allow rapid identification of patients with MLL-AF4 and BCR-ABL positive ALL. These patients have a poor outcome with contemporary therapy and rapid identification facilitates timely allocation to innovative treatment programs.

PURPOSE Compared with previous Children's Cancer Group (CCG) acute lymphoblastic leukemia (ALL) trials, therapy based on the Berlin-Frankfurt-Munster (BFM) 76 trial has effected an improvement in event-free survival (EFS). In an attempt to improve EFS further, CCG investigators formulated an augmented BFM (A-BFM) regimen that provides prolonged, intensified postinduction chemotherapy relative to the CCG-modified BFM regimen. PATIENTS AND METHODS We tested A-BFM in 101 patients with ALL and unfavorable presenting features that showed slow early response (SER) to induction therapy who attained remission on day 28. Their outcome was compared with that of 251 concurrent patients with unfavorable presenting features, a rapid early response to therapy (RER), and remission by day 28, treated with CCG-BFM with or without cranial radiation (CRT). RESULTS The 4-year EFS rate from the end of induction for SER patients treated with A-BFM was 70.8% +/- 4.6%. Seventeen patients remain in continuous remission beyond 5 years. Vincristine (VCR) neurotoxicity developed in 50% of patients, but was rarely debilitating. Allergies to Escherichia coli L-asparaginase (L-ASP) occurred in 35% of patients. Avascular necrosis of bone (AVN) developed in 9% of patients. In comparison, a concurrent RER group treated with standard BFM +/- CRT had a 4-year EFS rate of 73.1% +/- 4.6%. CONCLUSION The toxicity of A-BFM is significant, but acceptable. Compared with historical control SER patients treated with CCG-modified BFM, A-BFM therapy appears to produce a significant improvement in EFS. This is the first study to show that intensive chemotherapy, as given in the A-BFM regimen, can abrogate the adverse prognostic significance of SER.

10001 Background: Response to initial therapy is a powerful prognostic factor in pediatric ALL. Traditionally, slow early response (SER) has been defined by marrow morphology 8 or 15 days after start of induction therapy. More recently, MRD has been identified as the most important predictor of adverse outcome. The value of morphologic assessment of response in the setting of MRD has not been established. Methods: In COG studies AALL0331 (for NCI Standard Risk (SR) B ALL patients (pts)) and AALL0232 (High Risk (HR) B ALL pts), SER was defined by morphology as either ≥5% blasts in a day 15 marrow, or by flow cytometry as ≥0.1% MRD in a d29 marrow (SER MRD). Assignment to treatment arms also depended upon cytogenetic findings and extramedullary disease; each protocol had randomized treatment questions. SER pts were non-randomly assigned to receive augmented BFM therapy (ABFM) with 2 interim maintenance and delayed intensification phases (and CNS radiation for HR SER pts only). All pt treatment groups were combined for these analyses. Rapid early responders (RER) had a better outcome than SER pts (Table). However, pts who were SER only by morphology had a 5y DFS that was not significantly different from that of RER pts, and superior to that of pts who were SER MRD, or SER by both morphology and MRD. In multivariate analysis, SER by morphology was not an adverse prognostic factor after adjusting for risk group and MRD, or separately in SR or HR pts after adjusting for MRD. However, pts with .01-.1% MRD who were SER by morphology had a better 5y DFS than the.01-.1% MRD pts who were RER (90±6%, n=91 vs 77±3%, n=592). Only the former group received ABFM, suggesting intensification based on response rescues some poor risk pts. We conclude that a day 15 marrow is not needed to assess response if MRD is measured at end induction, provided that SER MRD is defined using a .01% cutoff, the threshold for intensifying therapy in current COG ALL trials. Clinical trial information: NCT00103285, NCT00075725. [Table: see text]

CRA9508 Background: Historically, AYA patients (>16yrs of age) with HR-ALL have an inferior outcome compared to HR-ALL patients 1-15 yrs old, due to increased rates of both relapse and toxicity. Methods: AALL0232 was a phase III randomized trial for patients 1-30 years of age with newly diagnosed B-precursor HR-ALL that utilized a 2 x 2 factorial design with an augmented intensity Berlin-Frankfurt-Münster (BFM) backbone. Patients were randomized to receive dexamethasone versus prednisone during Induction and high dose methotrexate versus escalating Capizzi methotrexate during Interim Maintenance I. A total of 2,574 eligible, evaluable, non-Down Syndrome, non-very high risk patients were randomized between January 2004 and January 2011. AYA patients comprised 20% of this group (n=501; 16-21 yrs: 466 and 22-30 yrs: 35). Results: The 5-yr event-free survival (EFS) and overall survival (OS) rates were 68.0% and 79.8% for AYA patients compared to 80.9% and 88.4% for younger patients (p

Abstract 1510 Historically, AYA patients (>16yrs of age) with HR-ALL have lower event free survival and overall survival compared to younger patients (1–15 yrs of age) with HR-ALL. This inferior outcome is related to both a higher relapse rate and increased toxicity of therapy. Several underlying factors have been identified that may contribute to these differences including leukemia biology, host pharmacodynamics, relative intensity of treatment protocols, adherence to therapy, and supportive care measures, although their relative importance is largely unknown. AALL0232 was a Phase 3 randomized trial for patients 1–30 years old with newly diagnosed B-precursor HR-ALL that utilized a 2 × 2 factorial design with an augmented intensity Berlin- Frankfurt-Münster (BFM) backbone. Patients were randomized to receive dexamethasone versus prednisone during Induction and high dose methotrexate versus escalating Capizzi methotrexate during Interim Maintenance I. The study accrued 3051 eligible, evaluable, non-Down Syndrome patients between January 2004 and January 2011. AYA patients comprised 20% of study enrollments (n=601) with 555 patients in the 16–21 year range and 46 patients in the 22–30 year range. Toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE version 4.0) and all grades 3 and 4 are reported. Bone toxicities including avascular necrosis are not included in this analysis. During Induction, AYA patients when compared to younger patients had lower rates of febrile neutropenia (7.0% versus 13.4%, p Post-induction, AYA patients experienced higher rates of oral mucositis secondary to methotrexate during Interim Maintenance I (18.5% versus 11.3%, p=0.0002), and higher rates of peripheral motor neuropathy during protocol therapy (11.5% versus 7.4%, p=0.0015). Despite lower rates of febrile neutropenia throughout protocol therapy (35.6% versus 48.6%, p In conclusion, AYA patients experienced higher rates of hyperbilirubinemia and hyperglycemia during Induction, oral mucositis during Interim Maintenance I, and peripheral motor neuropathy throughout protocol therapy. Importantly, AYA patients experienced a higher rate of death during remission, predominantly due to infectious etiologies. Further analyses are needed to determine reasons for the increase in treatment related mortality, including, an evaluation of the responsible organisms, identification of periods of increased vulnerability because of concomitant mucositis, neutropenia, and/or delivery of specific chemotherapeutic agents. Disclosures: No relevant conflicts of interest to declare.

Abstract 1440 Improved Post-Induction Chemotherapy Does Not Abrogate Prognostic Significance of Minimal Residual Disease (MRD) for Children and Young Adults with High Risk Acute Lymphoblastic Leukemia (ALL). A Report from Children's Oncology Group (COG) Study AALL0232. Minimal residual disease is one of the strongest prognostic factors in pediatric ALL. COG AALL0232 was a phase 3 randomized trial for patients 1–30 years old with newly diagnosed NCI HR B precursor ALL that used a 2×2 factorial study design comparing dexamethasone (DEX) versus(vs.) prednisone(PRED) during induction, and high dose methotrexate (HD-MTX) vs. Capizzi methotrexate (C-MTX) during interim maintenance 1(IM-1). We previously reported improved event-free survival (EFS) for patients receiving HD-MTX vs. C-MTX (J Clin Oncol 29: 6s, 2011) and for DEX vs. PRED among patients =0.1% MRD at end induction, as well as patients with morphologic slow early response or specific adverse genetic features received intensified therapy including IM-2 and a second delayed intensification, and then had MRD determined at end consolidation, (about 13 weeks post diagnosis). End induction MRD > =0.01% was highly predictive of inferior outcome, though patients with 0.1–1% MRD who received intensive therapy had very low rates of early relapse and a much higher rate of late relapse. 5 year EFS for end-induction MRD positive (>=0.01%) patients was 63±5% vs. 86±2% for MRD negative patients. However, patients who were MRD positive at end induction who became negative by end consolidation had improved 5y EFS of 79±9%(n=136) compared to 52±14% for those who remained MRD positive(n=52) (p=.0012). Both end induction MRD positive and negative patients benefitted from HD-MTX vs. C-MTX, though the effect was small and did not reach statistical significance for MRD positive patients. By contrast, end-induction MRD was highly predictive of outcome for patients receiving either HD-MTX or C-MTX. 5 y EFS as a function of MRD status and IM regimen.End induction MRDCapizziHDMTXP value.01%59 ± 6%67 ± 7%.12P value End induction MRD negative patients 10y showed no difference. However, DEX patients Disclosures: Borowitz: BD Biosciences: Research Funding. Wood:BD Biosciences: Research Funding.

3 The full, final text of this abstract will be available in Part II of the 2011 Annual Meeting Proceedings, distributed onsite at the Meeting on June 4, 2011, and as a supplement to the June 20, 2...

9504 Background: When compared to PRED, the administration of DEX during Induction has been associated with improved outcomes in patients with ALL. However, DEX has also been associated with an increased risk of osteonecrosis (ON) and when given in combination with an anthracycline has an increased risk of induction mortality. Methods: AALL0232 was a Phase 3, randomized trial for patients 1-30 years of age with NCI high risk B-precursor ALL that utilized a 2 x 2 factorial design with an augmented intensity BFM backbone. Patients were randomized to receive DEX 10 mg/m2/day for 14 days versus PRED 60 mg/m2/day for 28 days during Induction and high dose methotrexate (HD MTX) versus Capizzi escalating methotrexate plus PEG asparaginase (C-MTX-ASNase) during Interim Maintenance 1, forming four arms: DH, DC, PH, and PC. In June 2008, the study was amended to exclude patients > 10 years of age from the Induction steroid randomization due to an excessive incidence of ON. Results: Between January 2004 and Septembe...

9534 Background: L-ASP is an important component of the multi-agent chemotherapy in children and young adults for treatment of acute lymphoblastic leukemia (ALL). The pegylated E. coli derived form, Oncaspar (PEG-ASP) is most commonly used because of its longer half-life; however, clinical hypersensitivity reactions can occur in 10-30% of patients requiring its discontinuation. Erwinia L-ASP (E) is an L-ASP derived from a different bacterium and is immunologically distinct from the E. coli L-ASP. We conducted a compassionate use trial of E in patients with ALL and hypersensitivity to PEG-ASP to collect safety information. Methods: Patients were ≥ 1 year of age with ALL who developed a clinical hypersensitivity reaction to PEG-ASP. Patients with a history of pancreatitis, previous allergic reaction to E, or pregnant, were excluded. E was administered at 25,000 IU/m2 IM/IV/SC 3 times per week on a Monday/Wednesday/Friday schedule for 2 weeks to replace each dose of PEG-ASP. The study was IRB approved at eac...

Abstract 497 DS is associated with a high incidence of ALL that is linked to unique biological and clinical features. In some studies these children have had an inferior outcome and have demonstrated unusual sensitivity to the side effects of chemotherapy, particularly methotrexate (MTX). CCG-1991 aimed to: 1) determine in a randomized fashion the benefit of double delayed intensification (DI) over single DI in a modified BFM therapy that uses dexamethasone as the sole corticosteroid and 2) compare the outcome of treatment that included escalating-dose intravenous (IV) MTX without leucovorin, and vincristine, to one that contains oral (PO) MTX, mercaptopurine, vincristine and dexamethasone during the interim maintenance phases (IM) of therapy. Patients received a 3-drug induction with vincristine, pegylated asparaginase, dexamethasone, and intrathecal cytarabine and MTX. This was followed by consolidation, delayed intensification, interim maintenance, and maintenance phases of therapy. Slow early responders by bone marrow morphology (Day 7/14 M3-M3, or M3-M2; or M2 at Day 28 Induction) and patients with unfavorable cytogenetics [(t(9;22)(q34;q11), (4;11)(q21;q23), balanced t(1;19)(q23;p13) or hypodiploidy with < 45 chromosomes] were non-randomly assigned to a COG augmented BFM therapy regimen (N Engl J Med 1998; 338:1663). Rapid early responders with no unfavorable cytogenetics or CNS leukemia were randomized in a 2 × 2 factorial design to one of the 4 regimens -Table 1. Three thousand fifty four children with NCI SR ALL were enrolled on CCG-1991; 2078 non-T ALL eligible patients were randomized. A total of 108 patients with DS were enrolled, 77 patients were randomized to one of the 4 regimens; 45 patients were randomized to the arms containing PO MTX during IM (OS+OD), and 32 to the ones containing IV MTX (IS+ID) during IM. IV methotrexate, as given in this study, was generally well tolerated, but the mean total dose was lower in patients with DS. There was no increased hepatic toxicity, seizures or leukoencephalopathy in patients with DS during IM on either the IV or PO MTX arms, as compared to those without DS. Similarly, the incidence of systemic infections was not higher in patients with DS. The incidence of mucositis, however, was increased in patients with DS as compared with patients without DS, particularly in those who received IV MTX. Five-year EFS and overall survival (OS) for patients with DS randomized to the IV MTX and PO MTX arms are listed in Table 2. The overall 5-year EFS and OS of randomized patients with DS are 90.1% ± 4.9% and 94.8% ± 3.7% respectively. We conclude that patients with DS and SR-ALL without adverse features can be cured with COG BFM-modified therapy with escalating-dose IV MTX without leucovorin rescue during the interim phases of therapy. Disclosure: Matloub: Bristol-Myers Squibb: Previous employment.

Abstract 767 Introduction: Optimal therapy for favorable risk HL in children and adolescents continues to evolve. Although the great majority of children will be cured, the potential for long-term adverse sequelae of treatment remains significant. Current regimens seek to define less toxic approaches that effectively treat low risk HL patients. The Children's Oncology Group (COG) HL studies have focused on the use of a response based paradigm for reduction of therapy. Methods: COG protocol AHOD0431 was a single arm study designed to investigate: 1) the rate at which three cycles of doxorubicin, vincristine, prednisone and cyclophosphamide (AVPC) induces complete response (CR), 2) whether achieving CR after 3 cycles of chemotherapy alone allows elimination of involved-field radiation therapy (IFRT), while maintaining excellent disease control and 3) whether very early response as measured by [18F]–fluorodeoxyglucose-positron emission tomography (FDG-PET) after the first course of chemotherapy is predictive of outcome. Eligibility requirements were: ages 0–21 years with newly diagnosed Stages IA and IIA HL without bulk and without lymphocyte predominance (LP) histology. All subject received chemotherapy. Patients who achieved a CR after 3 cycles of AVPC received no further therapy. Those with a partial response (PR) received 21 Gy IFRT. CR was defined as at least 80% reduction in the size of each of the nodal masses, or return to normal size, and negative findings on FDG-PET or Gallium scanning. Imaging studies were centrally reviewed. Results: 287 subjects were enrolled between February, 2006 and December, 2008. 9 subjects were subsequently found to be ineligible, and an additional 3 were inevaluable for 3-cycle response. The CR rate after 3-cycles of AVPC was 63.6%, lower than the goal rate of 80%. However, event free survival (EFS) for the entire cohort at 2 years was 84%, and overall survival (OS) was 100%. Analysis by CR vs. PR status after 3 cycles of chemotherapy showed a 2 yr EFS of 80% for those achieving CR after 3 cycles of AVPC (no IFRT) vs. 88% for those achieving PR and therefore receiving IFRT (p=0.11). 227 subjects had evaluable FDG-PET results after one cycle of chemotherapy (PET1). Among subjects who achieved a CR (no IFRT) the 2 year EFS for PET1 positive/equivocal vs. negative was 65% vs. 87% (p=0.005). Among subjects who achieved a PR after 3 cycles of chemotherapy and received IFRT per protocol, 2 year EFS for PET1 positive/equivocal vs. negative was 82% vs. 96% (p=0.047). In December, 2008 the Study Committee recommended IFRT for all CR patients who were PET1 positive or PET1 status unknown, and were within one year of completing chemotherapy. 12 subjects received IFRT based on this recommendation, and all remain in CR. At a median f/u of 25 months, 46% of the entire cohort remain in CR without receiving any radiation therapy. Conclusions: Low risk HL in pediatric and adolescents is well recognized to be a highly curable malignancy, however late toxicities of therapy are frequent and may be life threatening or substantially affect quality of life. Nearly half of our patients have not received radiation therapy on this protocol. These outcomes are similar to other published pediatric regimens for low risk HL (excluding LP histology), even those that incorporated radiation therapy for all or most patients. The OS of 100% suggests that those who did recur after limited therapy were quite salvageable, many without aggressive salvage regimens or stem cell transplant. CR status after 9 weeks of chemotherapy may not optimally identify patients in whom IFRT can be avoided. Very early response, as measured by FDG-PET after 3 weeks of therapy, had significant prognostic implications in both CR and PR subjects, suggesting that this assessment may have a role in identifying a cohort of patients for whom limited volume/low dose RT remains an important component of therapy. Alternatively, AVPC may require intensification to optimize EFS while limiting need for IFRT. The role of a limited intensity chemotherapy regimen with low-dose IFRT for those subjects that experience localized recurrence after chemotherapy alone is the subject of an ongoing investigation. Disclosures: No relevant conflicts of interest to declare.

Acute lymphoblastic leukemia (ALL) of childhood is frequently characterized by a hyperdiploid karyotype. Typically, most of the affected chromosomes in the abnormal clone are present in three copies. We have studied two patients with hyperdiploid ALL whose leukemic cells were atypical in that all or most of the chromosomes were present in either two or four copies, raising a suspicion that the observed karyotype arose through duplication of chromosomes in a precursor cell with a near-haploid chromosome number. Analysis of restriction fragment length polymorphisms confirmed that both cases arose from a near-haploid cell; all informative disomic chromosomes tested had loss of heterozygosity. Furthermore, the hyperdiploid karyotypes did not arise via a perfect haploid cell with exactly 23 chromosomes, because tetrasomic chromosomes remained heterozygous. These two patients probably are classified best as near-haploid cases, which often are observed to have a co-existing hyperdiploid clone with a duplicated chromosome set. The distinction between typical hyperdiploidy and hyperdiploidy arising via a near-haploid cell may be clinically important, because the prognosis for patients with a hyperdiploid karyotype is favorable in comparison to that of patients with a near-haploid karyotype.

Abstract 320 Three thousand fifty four children with NCI standard-risk (SR) ALL were enrolled on CCG-1991; 2075 non-T ALL eligible patients were randomized and began treatment with IT cytarabine, vincristine, dexamethasone, and pegylated asparaginase. Bone marrow status was assessed at Day 7, 14, and 28 of Induction. Slow early responders (Day 7/14 M3-M3 and M3-M2; or M2 at Day 28 Induction) and patients with unfavorable cytogenetics were non-randomly assigned to a COG augmented BFM therapy regimen (N Engl J Med 1998; 338:1663).Thirteen hundred and thirty patients were analyzed for the presence of trisomy 4 and trisomy 10 (DT); and 1041 patients were evaluated for the presence of TEL/AML1 (ETV6/RUNX1) (TEL) fusion transcript. Twenty four percent of patients were positive for DT, and 41% were positive for TEL. Among the randomized subset, 23.8% had DT, and 40.8% had TEL. Six year event-free survival (EFS) and overall survival (OS) rates are given in the tables below for all patients and also separately for the randomized patients, by DT and TEL status. There was a significant different in EFS and OS between patients that were DT+ vs. DT- and also between patients that were TEL+ vs. TEL-.The overall 6-year EFS and OS for all patients with B-lineage ALL are 88.1±1.1% and 94.7±0.8%; and for the randomized patients they are 89.4±2.4% and 95.9±0.8%. We conclude that COG risk-adapted therapy is curative for patients with NCI-SR criteria and DT and/or TEL. ALL PATIENTS Event-Free Survival p-value DT+ vs. DT- (n1=317, n2=1013) 93.6±2.2% vs. 85.5±1.7% 0.0007 TEL+ vs. TEL- (n1=425, n2=616) 90.8±2.7% vs. 87.7±2.5% 0.0401 DT+ and/or TEL+ vs. DT- and TEL- (n1=737, n2=248) 92.0±1.8% vs. 85.1±4.0% 0.0017 Overall Survival p-value DT+ vs. DT- (n1=317, n2=1013) 98.6±1.1% vs. 94.1±1.2% 0.0063 TEL+ vs. TEL- (n1=425, n2=616) 97.2±1.6% vs. 93.9±1.9% 0.0494 DT+ and/or TEL+ vs. DT- and TEL- (n1=737, n2=248) 97.8±1.0% vs. 93.8±2.7% 0.019 RANDOMIZED PATIENTS Event-Free Survival p-value DT+ vs. DT- (n1=224, n2=724) 94.5±2.2% vs. 87.1±1.8% 0.0023 TEL+ vs. TEL- (n1=324, n2=434) 92.9±2.6% vs. 88.7±2.7% 0.0174 DT+ and/or TEL+ vs. DT- and TEL- (n1=546, n2=172) 93.6±1.7% vs. 85.5±4.3% 0.0007 Overall Survival p-value DT+ vs. DT- (n1=224, n2=724) 98.6±1.1% vs. 94.9±1.2% 0.04 TEL+ vs. TEL- (n1=324, n2=434) 98.8±1.1% vs. 94.6±1.9% 0.0037 DT+ and/or TEL+ vs. DT- and TEL- (n1=546, n2=172) 98.8±0.8% vs. 94.0±2.9% 0.002 Disclosures: No relevant conflicts of interest to declare.

In this issue of Blood , Rubnitz and colleagues from St Jude Children's Research Hospital provide important information concerning the immunophenotypic, cytogenetic, gene expression, and response to therapy characteristics of 35 patients with so-called mixed lineage leukemia. Identification of

Treatment with DEX, rather than prednisone (PRED), improves outcome for children with standard risk ALL. However, DEX exposure is strongly associated with the development of therapy-related ON, particularly in adolescents. Previous COG HR-ALL studies have shown a lower ON risk for patients receiving 1 vs. 2 delayed intensification (DI) phases, and for DI using discontinuous DEX (days 1–7 & 15–21) vs. continuous DEX (days 1–21), suggesting a strategy for giving the drug with acceptable toxicity. The HRALL study COG AALL0232 utilizes a modified augmented BFM backbone that compares in a 2x2 randomized design: induction DEX (10 mg/M2/day x14 days) vs PRED (60 mg/M2/day x28 days), and interim maintenance (IM) escalating-dose “Capizzi” methotrexate vs. high-dose (HD) MTX. Induction rapid early responders (RER) receive single DI while slow responders receive double DI; all patients receive monthly 5-day DEX pulses during maintenance. To limit ON risk in adolescents, in the initial study design children ≥ 13y received discontinuous DEX during single or double DI; those

A substantial number of relapses derive from the NCI standard risk population. CCG-1991 tested two components of the successful COG augmented “BFM” regimen (N Engl J Med1998; 338:1663) in this subset in a 2 × 2 factorial design. Patients received a 3-drug Induction: vincristine (V), pegylated asparaginase, dexamethasone (D), and intrathecal (IT) cytarabine and methotrexate (M). Patients with an unfavorable early marrow response by morphology (> 25% blasts at day 14, or >25% blasts at day 7 and >5% blasts at day 14) were assigned rescue daunorubicin and “augmented BFM” therapy. Other patients, termed rapid early responders (RER), received Consolidation (daily oral mercaptopurine (MP) and weekly IT M) and were randomized to receive either single or double delayed intensification (DI) phases, and D pulses, oral daily MP, weekly M and monthly V (Reg O) or V and intravenous (IV) escalating dose M with no leukovorin every 10 days for two months preceding and following the DI phase (Reg I). Induction Consolidation Interim Maintenance Delayed Intensification (DI #1) Interim Maintenance Reg O Oral MP/M/D Reg O Oral 6MP/M/D Maintenance DI #2 Maintenance Reg I V/IV M Reg I V/IV M Maintenance DI #2 Maintenance CCG-1991 enrolled a total of 3026 patients between 6/1/00 and 1/31/05 with 2078 eligible randomized non-T ALL patients. The overall 5-year event free (EFS) and overall survival (OS) for the randomized patients was 90.5% (SE = 1.0 %), and 96.0% (SE = 1.0%). We previously reported the double DI randomization (Blood2006; 108: abstract #146). Events were 71/1042 patients in Regimen I, and 100/1036 patients in Regimen O. For Reg I and Reg O, 5-year EFS was 92.1% and 88.7% (p = 0.02; RHR = 0.69 respectively. Comparison by type of events: isolated and combined marrow relapse (55 and 54), isolated CNS relapse (10 and 25), testes relapse (0 and 5), death in remission (1 and 5), secondary neoplasm (2 and 6), and other (2 and 4). The benefit was shown in both sexes. The overall survival was 96% on either arm. We therefore conclude that Reg I was superior for children with B-precursor SR-ALL with RER. We saw decreases in CNS and testes relapse with no decrease in marrow relapse. At this time, we find no difference in OS between the two arms.

Between April 1986 and March 1989, ten patients under 21 years of age with histologically confirmed malignant astrocytoma, received marrow-ablative chemotherapy with either thiotepa and Etoposide (five patients) or thiotepa, Etoposide and BCNU (five patients), followed by bone marrow ‘rescue’. Nine patients had glioblastoma multiforme (GBM), and one patient had an intrinsic brain stem anaplastic astrocytoma (AA). Seven patients were treated for recurrent tumor. Two patients who developed GBM as second malignancies were treated directly following surgical resection. One patient had received irradiation only for recently diagnosed cervical spinal cord GBM. Thiotepa was administered at a total dose of 600–900 mg/M2 over three days, Etoposide was administered at a total dose of 1500 mg/M2 over three days, and BCNU was administered at a total dose of 600 mg/M2 over four days. Non-hematopoietic toxicities have been mainly transient, predictable and acceptable, consisting of oropharyngeal mucositis, cutaneous hyperpigmentation, erythema and desquamation. Four patients achieved complete responses (CR), as determined by radiographic evaluation (CT and/or MRI) on day 28 post-marrow infusion. The mean remission duration of those with CR is 290 + days; two patients presently remain in remission. Two patients achieved partial responses (PR, greater than 50% tumor shrinkage) by day 28 post-marrow infusion; both developed disease progression, at day 61 and 94 post-marrow infusion, respectively. One patient, with a brain stem AA, had stable disease maintained for 13 months post-marrow infusion. With a total (CR + PR) response rate of 60%, these regimens merit evaluation in broader categories of recurrent brain tumor patients, as well as in patients with newly-diagnosed GBM.

Sixty-four patients aged 2 to 18 years with advanced-stage Hodgkin's disease (HD) were treated on a Children's Cancer Study Group (CCSG) pilot toxicity study (521-P). Therapy consisted of 12 courses of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), bleomycin, vinblastine, and dacarbazine (ABVD), followed by low-dose (2,100 cGy in 12 fractions) regional irradiation (RT). All patients were monitored for toxicity with particular attention to the pulmonary system. Six patients (9%) developed grade 3 or 4 pulmonary toxicity. Three had grade 3 toxicity based solely on changes in carbon monoxide diffusing capacity (DLCO) and remained well for more than 3 years after diagnosis. There was one fatality among the three symptomatic cases. In five cases, toxicity occurred prior to RT. One occurred after seven courses of ABVD, one after nine courses, and three after 10 courses. In one of these five cases, ABVD was stopped. The patient was given nitrogen mustard (mechlorethamine), vincristine, prednisone, and procarbazine (MOPP). This patient subsequently developed recurrence of HD and died of overwhelming sepsis. The other four continued on study and completed their chemotherapy. Three patients had no further bleomycin, and one continued bleomycin at 50% of the assigned dose. They all received mantle RT following chemotherapy, one with a boost dose to the mediastinum to 3,800 cGy and one with added RT to both lungs (1,050 cGy). In the sixth case of pulmonary toxicity, symptoms were first noticed 2 weeks after mantle RT to 3,500 cGy. This patient died of progressive respiratory failure. The event-free survival (EFS) and overall survival is 87% at 3 years. These early results indicate that this therapy is effective in advanced HD in children but has a 9% incidence of acute pulmonary toxicity.

9511 Background: Numerous studies have shown that SER in ALL has a negative impact on outcome. Children's Cancer Group CCG-1882 demonstrated that post-induction intensification greatly improved the outcome of children with high-risk ALL and SER. Five year event-free-survival (EFS), and overall survival (OS) for the augmented regimen was 75 ± 4% vs 55 ± 4.5%, and 78 ± 4% vs 67 ± 5% for the standard regimen, p 5% blasts, and their day-14 marrow >25%. COG-1991 used the same criteria for SER, but also added patients whose day-7 marrow had >25% blasts and their day-14 marrow had >5% blasts to the SER group. This was based on the unfavorable outcome of this subgroup in COG-1952. The augmented therapy in COG-1991 like the CCG-1882 and COG-1952, was based on a COG-modified ABFM, but differed in using dexamethasone as the sole steroid and pegylated asparaginase as the asparaginase preparation, as compared to prednisone in induction and maintenance, and native E coli asparaginase. Results: Comparative groups with days 7 and 14 M3 marrows and unfavorable cytogenetics included 126 patients from COG-1991 and 81 from the COG-1952 were assigned to their corresponding ABFM regimens. Four year EFS and OS were 85% ± 5% and 90 ± 4% for CCG-1991 vs 61 ± 5.6% and 75 ± 5% for CCG-1952, p = 0.003 and 0.04 respectively. Conclusion: We conclude that the use of dexamethasone, and pegylated asparaginase greatly improves the outcome of children with NCI-SR with SER treated on a modified augmented BFM therapy, thus supporting the use of these agents in ALL therapy. No significant financial relationships to disclose.

Intensification of therapy has improved outcome of children with ALL. CCG 1891 demonstrated that children with intermediate risk ALL (a subset of SR-ALL) had a superior outcome with DDI vs SDI using a modified Berlin-Frankfurt-Muenster (BFM) backbone therapy that included prednisone, in a 3 drug induction (Blood.2002;99:825–33). This benefit was limited to patients with > 5% marrow blasts on Day 7 of induction. CCG-1921 best arm had similar outcome with dexamethasone in induction, and SDI (Blood.2003;101:3809–17). The question remained as to whether DDI would benefit SR patients if they received dexamethasone in induction. Therefore, one hypothesis tested by CCG-1991 was that a regimen with DDI phases would have a superior event free survival (EFS) and overall survival (OS) compared with one that had a SDI phase in children with SR-ALL treated with a modified BFM backbone therapy that included dexamethasone in induction. SR-ALL patients with an unfavorable early response (> 25% marrow blasts at day 14, or >25% marrow blasts at day 7 and >5% marrow blasts at day 14) were not eligible for randomization and were assigned to receive augmented therapy. CCG-1991 used a 2 X 2 factorial design to compare outcome in patients who received SDI vs DDI phases, and oral vs escalating intravenous methotrexate without leucovorin rescue during the interim maintenance phases of therapy. The results of the methotrexate question remain blinded at this time. There were 52 relapses among the 1029 patients randomized to the SDI regimens vs 58 among the 1021 patients randomized to the DDI regimens. Four year EFS was 88.3% (SE = 3.6) for the SDI regimens, and 88.1% (SE = 3.9) for the DDI regimens, p = 0.45, RHR 1.15. The 4 year OS estimate is 96.2% for the SDI, and 94.2% for the DDI; p = 0.25, RHR 1.41. We conclude that there are no benefits to DDI vs SDI in children with SR-ALL and a favorable early marrow response to induction chemotherapy.

In prior studies, children and adolescents with markedly elevated (ME) WBC≥200,000 had a poor outcome. We examined the outcome of these patients enrolled on CCG l961 (n=250) and compared them to other patients with WBC

8513 Background: There is scant data in the literature concerning the outcome of YA pts 16–21 years of age with HD. Methods: Newly diagnosed YA HD pts (N=227) were entered on the CCG 5942 study. Following clinical staging, YA pts received risk adapted chemotherapy. Group I patients had Stage I or IIA, no bulk disease, no hilar adenopathy and < 4 nodal regions involved. Group III patients had stage 4 disease. Initial therapy for Group I patients consisted of 4 cycles of the COPP/ABV Hybrid while Group 2 patients received 6 cycles of COPP/ABV. Group III patients received two cycles each of high dose ARA-C/VP-16. COPP/ABV, and CHOP. Patients who achieved a complete response to initial chemotherapy were randomized to receive no further treatment or IFRT (2100 RADS). Patients with partial response were nonrandomly assigned to IFRT. Results: Five year EFS for YA pts was 81% ± 2.8%; 5 year survival was 91.4% ± 2.1%. Events included 3 - progressive disease, 36 - relapse, and 1 second malignancy. Sixty and 56 YA p...

Recent CCG and POG treatment stategies for patients with T-ALL are significantly different. POG treats T-ALL patients on a separate protocol from that used for B precursor ALL (B-ALL) while CCG treats T-ALL patients on the same protocols utilized for B-ALL patients with protocol assignment determined by the NCI risk classification. We recently reviewed the outcome of patients with T-ALL and high-risk features (age ≥ 10 years and/or initial WBC > 50,000/ul) treated on either the CCG-1961 or POG-9404 clinical trials. POG utilized an intensive anthracycline based multidrug regimen based on the DFCI treatment program and randomized patients at registration to receive or not receive additional high dose methotrexate(HDMTX) with leucovorin rescue. All patients received cranial irradiation (CRT). CCG therapy for high risk T-ALL was based on CCG modified BFM(S-BFM) and Augmented BFM(A-BFM). Patients with

Children with T-ALL have generally had a poorer prognosis than patients with precursor-B ALL. Patients with T-ALL are more likely than those with B-precursor ALL to be > 9 years and present with WBC > 50,000/ul, bulky lymphadenopathy and mediastinal mass. Since 1996, the former CCG has stratified protocol eligibility for patients with ALL based on NCI defined Standard Risk (SR = age between 1-9.99 years; WBC < 50,000/ul) or High Risk (HR) groups, regardless of immunophenotype. In contrast, the former POG has treated all T-cell patients on protocols separate from those for precursor-B ALL. This report compares the outcomes among children with T-cell ALL treated on recently completed or ongoing CCG and POG phase III trials for ALL. CCG-1952 enrolled 2176 eligible children with SR ALL between 1996 and 2000; 106 (5%) had T-cell immunophenotype. Treatment was a standard BFM regimen with prednisone and 2 phases of delayed intensification (DI) with a 2x2 randomization of IT methotrexate (MTX) v ITT and MP v TG. From June 2000 to March 2004, CCG-1991 has enrolled 1794 SR ALL patients: 80 (4%) had T-ALL. Treatment included a similar BFM backbone with substitution of dexamethasone and a 2x2 randomization between escalating IV v oral MTX and 1 v 2 DIs. POG-9404 (opened 1996; closed 2001) was developed exclusively for T-cell disease and enrolled 363 patients with T-ALL; 84 (23%) fit the NCI SR group criteria. On the latter protocol, patients received treatment similar to that developed by the Dana-Farber Leukemia Consortium for high risk B-precursor ALL, with randomization to ± 4 cycles of high dose MTX (5 Gm/m2) and leucovorin. All patients on 9404 received 1800 cGy prophylactic cranial radiation while CCG patients did not. Outcome for T-ALL on CCG-1952 is substantially worse than for B-precursor ALL, with 5 year event-free survival (EFS) of 73% compared to 82% (p = 0.007). Interim analysis of CCG-1991 also shows a significantly worse outcome for T-ALL compared to B-precursor ALL: 3y estimated EFS 78% v 90%, p = 0.0002. In contrast, estimated 5y EFS for patients with SR T-ALL on POG-9404 is 88% (90% on the superior high dose MTX regimen). Comparison of the SR v HR T-ALL patients treated on POG 9404 shows a significant advantage for the SR group (5y EFS of 90% v 75%, p < 0.004). This is in contrast to comparison of T-ALL patients on CCG-1952 (SR) v the concurrent CCG-1961 HR study where T-ALL patients have similar outcome (5y EFS 73% v 72%, p = 0.77). These data suggest that patients with T-ALL and SR features have better EFS when treated with more intensified chemotherapy regimens. Because early EFS for T-cell patients treated on CCG-1991 is worse than on POG 9404, the former study was closed to further accrual of patients with T-ALL. The COG ALL Committee is developing a study for exclusive enrollment of patients with T-ALL using intensive therapy based on the current COG HR ALL regimen, regardless of SR or HR features.

AYA Patients 16–21 years of age with ALL are treated on both pediatric and adult ALL protocols. Recent publications have suggested that AYA patients treated on pediatric protocols have a significantly better outcome than those treated on adult protocols. From November 1996 to May 2002, 262 AYA ALL patients were entered on the CCG 1961 protocol. Treatment was based on the following observations from the previous CCG 1882 Protocol (1989–1995). 1) For patients with rapid early response (< = 25% blasts in a day seven bone marrow aspirate-RER), in the context of CCG modified BFM therapy (S-BFM), pre-symptomatic central nervous system therapy with intensive intrathecal (IT) methotrexate (MTX) alone provided equivalent results to standard IT MTX and cranial radiation (CRT). 2) For patients with slow early response (> than 25 blasts on day 7-SER), the augmented BFM (A-BFM) regimen produced a significant improvement in outcome compared to S-BFM. A-BFM featured a significant increase in dose intensity for vincristine (VCR), L-asparaginase (L-ASP), and steroid, the use of intravenous MTX without rescue in conjunction with VCR and L-ASP in interim maintenance (IM), and a second IM and delayed intensification (DI) phase. RER patients on 1961 were randomized to one of four arms; S-BFM, S-BFM with a second standard IM and DI phase, A-BFM with only 1 IM/DI phase, and full A-BFM. SER patients were randomized to A-BFM or A-BFM with Idarubicin/Cytoxan pulses added to the 2 DI phases. One hundred ninety patients had < 50K WBC (73.4%) and 21% had T cell immunophenotype. Seven patients had a t (9/22) and three patients had a t (4/11). Five year EFS for AYA patients treated on CCG 1961 was 68% ± 3.7% and the five-year survival was 77% ± 3.2%. The majority of events were isolated bone marrow relapses. For RER AYA patients, five year EFS for patients treated on the augmented intensity arms (N=87) was 83.2% compared to 60.8% for patients treated on the standard intensity arms (N=76) (P = .10). Within the augmented intensity arms, there was no difference in EFS for patients randomized to one or two DI phases. There was no difference in EFS for the 2 SER treatment arms. 5 year EFS was 78% for the Idarubicin/Cytoxan arm and 74% for the ABFM arm. Five year EFS for AYA patients with < 50K WBC was 73.2% (N=190) versus 54% for AYA patients with > 50K WBC. Unlike younger patients, there was no difference in outcome for males and females. Conclusions: 1) AYA patients with ALL have a 68% 5 year EFS when treated with BFM based chemotherapy. 2) WBC < 50K predicts for a favorable outcome. 3) Early augmented intensity therapy appears to improve outcome for AYA ALL patients showing a rapid response to induction therapy.

Purpose: Two-thirds of neuroblastoma patients present in advanced stages of disease. The treatment of advanced or recurrent neumblastoma remains controversial, with the roles of bone marrow transplant (BMT), total body irradiation (TBI), and local boost radiotherapy (RT) currently undefined. The purpose of this study is to review our experience with TBI and BMT, and to examine the role of local boost RT. Methods Between 5/86 and 6/93,26 patients with advanced nemoblastoma underwent high-dose chemotherapy and TBI followed by BMT at our institution. The majority of the patients (20/26) received Cytoxan alone as their induction regimen. TBI was delivered using 18 MV photons at an extended SSD, a dose rate of 12 cGy/min, a Lexan spoiler, custom partial transmission lung blocks, and bolus to improve homogeneity around the head, neck, and legs. The total dose delivered was 1200 cGy given in 200 cGy fractions BID via opposed lateral fields over the 3 days preceding the BM infusion. A local RT boost was given to 13/26 patients prior to TBI with doses of 8002400 cGy, in 200 cGy daily fractions. Results: The actuarial overall survival (OS) of the 26 patients was 40.4% at 3 and 5 years, with a progression-free survival (PFS) at 5 years of 28.1%. Six patients died of transplant-related toxicity (23%) leaving 20 patients evaluable for treatment response. Neither the extent of resection (gross total vs. subtotal/none) or BMT type (autologous vs. allogeneic) was significant in terms of OS or PPS. Of the 20 evaluable patients, 10 underwent a local RT boost and had an improved 5 year PFS (67.5%) than those who had no boost (0%) @=0.04). A local RT boost had no significant impact on OS (60% vs. 43.8% at 5 years, p=O.61). ‘Ihe patterns of failure were as follows: 3/10 “boost” patients failed overall, O/10 in old sites only, l/IO in new sites only, and 2/10 in old+new sites; 8/10 “no boost” patients failed overall, 5/10 in old sites only, l/10 in new sites only and 2/10 in old+new sites. A failure analysis was also performed for all 59 initially involved sites and is shown in the table. Overall, their is a trend towards decreased failure in irradiable sites that were irtadiated (l/10) vs. those not irradiated (7/28). The single patient who failed in an irradiated site failed simultaneously in the lungs, liver, and diffusely throughout the abdomen (including the irradiated primary site).