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Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 × 2 factorial design to receive either high-dose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ≥0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD0.01% had a 5-year event-free survival (EFS) of 87% ± 1% vs 74% ± 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% ± 5% 5-year disease-free survival vs 39% ± 7% for those with MRD ≥0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% ± 2% vs 58% ± 4% for MRD-negative vs positive C-MTX subjects; 88% ± 2% vs 68% ± 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725.

Summary Children and adolescents presenting with a markedly elevated white blood cell (ME WBC) count (WBC ≥200 × 109/l) comprise a unique subset of high-risk patients with acute lymphoblastic leukaemia (ALL). We evaluated the outcomes of the 251 patients (12% of the study population) with ME WBC treated on the Children's Cancer Group-1961 protocol. Patients were evaluated for early response to treatment by bone marrow morphology; those with a rapid early response were randomized to treatment regimens testing longer and stronger post-induction therapy. We found that ME WBC patients have a poorer outcome compared to those patients presenting with a WBC

Purpose In 1995, the Children's Cancer Group (CCG) opened a trial for patients with Hodgkin's lymphoma evaluating whether low-dose involved-field radiation therapy (IFRT) improved event-free survival (EFS) for patients achieving a complete response after chemotherapy. We present the long-term study outcome using final data through March 2007. Patients and Methods Between January 1995 and December 1998, 826 eligible patients were enrolled onto CCG 5942. Four hundred ninety-eight patients achieving an initial complete response to chemotherapy were randomly assigned to receive IFRT or no further therapy. EFS and overall survival (OS) were assessed from the date of study entry or random assignment, as appropriate. Results Ten-year EFS and OS rates for the entire cohort were 83.5% and 92.5%, respectively. In an as-treated analysis for randomly assigned patients, the 10-year EFS and OS rates were 91.2% and 97.1%, respectively, for IFRT and 82.9% and 95.9%, respectively, for no further therapy. For EFS and OS comparisons, P = .004 and P = .50, respectively. Bulk disease, “B” symptoms, and nodular sclerosis histology were risk factors for inferior EFS. Conclusion With a median follow-up of 7.7 years, IFRT produced a statistically significant improvement in EFS but no improvement in OS. For individual patients, the relative risks of relapse versus late effects of IFRT must be considered. Patient and disease characteristics and early response assessment will aid in deciding which patients are most likely to benefit from IFRT.

Summary Background Acute lymphoblastic leukaemia (ALL) is curable in more than 80% of children and adolescents who exhibit high-risk features. However, treatments are associated with symptomatic osteonecrosis that disproportionately affects adolescents. Based on the findings from the CCG-1882 trial, the CCG-1961 trial was designed to assess whether dexamethasone dose modification would reduce the risk of osteonecrosis. We therefore compared use of continuous versus alternate-week dexamethasone within standard and intensified post-induction treatments. Methods In the CCG-1961 trial, a multicohort cooperative group trial, 2056 patients (aged 1–21 years) with newly diagnosed high-risk ALL (age ≥10 years, white blood cell count ≥50×10 9 per L, or both) were recruited. To address osteonecrosis, a novel alternate-week schedule of dexamethasone (10 mg/m 2 per day on days 0–6 and 14–20) was compared with standard continuous dexamethasone (10 mg/m 2 per day on days 0–20) in computer-generated randomised regimens with permuted blocks within double or single delayed intensification phases, respectively. Masking was not possible because of the differences in the treatments. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002812. Findings Symptomatic osteonecrosis was diagnosed in 143 patients at 377 confirmed skeletal sites, resulting in 139 surgeries. In patients aged 1–21 years, the overall cumulative incidence of osteonecrosis at 5 years was 7·7% (SE 0·9), correlating with age at ALL diagnosis (1–9 years, 1·0% [0·5]; 10–15 years, 9·9% [1·5], hazard ratio 10·4 [4·8–22·5]; 16–21 years, 20·0% [4·3], 22·2 [10·0–49·3]; p vs boys 9·3% [1·7], 1·7 [1·2–2·4]; p=0·001). For patients aged 10 years and older with a rapid response to induction treatment, the use of alternate-week dexamethasone during phases of delayed intensification significantly reduced osteonecrosis incidence compared with continuous dexamethasone (8·7% [2·1] vs 17·0% [2·9], 2·1 [1·4–3·1]; p=0·0005), especially in those aged 16 years and older (11·3% [5·3] vs 37·5% [11·0], p=0·0003; girls 17·2% [8·1] vs 43·9% [14·1], p=0·05; boys 7·7% [5·9] vs 34·6% [11·6], p=0·0014). Interpretation Alternate-week dexamethasone during delayed intensification phases, a simple dose modification, reduces the risk of osteonecrosis in children and adolescents given intensified treatment for high-risk ALL. Its use is being evaluated in children with standard risk ALL. Funding US National Cancer Institute at the National Institutes of Health.

Background Treatment of pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) is controversial but has typically consisted of both chemotherapy and radiation. Radiation therapy is associated with potential late effects in children and adolescents. We examined the impact of radiation therapy on long-term outcome of patients with LPHL treated on CCG-5942, a large pediatric cooperative group study of Hodgkin lymphoma (HL). Procedure Eighty-two patients with LPHL were registered on CCG-5942. Fifty-two patients (63%) received chemotherapy alone; 29 patients (35%) received chemotherapy followed by involved-field radiation therapy (IFRT). Results The median follow-up of the LPHL patients is 7.7 years; 63 patients (77%) have >5 years of follow-up. The 5-year event-free survival (EFS) and overall survival (OS) were 97% and 100%. Two relapses occurred, both in patients who did not receive IFRT. There were no significant differences in EFS or OS between patients who received or did not receive IFRT. Conclusions This subset analysis demonstrates the chemosensitivity of pediatric LPHL. Patients who had a complete response to chemotherapy had an excellent EFS and OS without the addition of radiotherapy. Pediatr Blood Cancer 2012; 59: 1284–1289. © 2012 Wiley Periodicals, Inc.

Children's Cancer Group-1991 selected 2 components from the Children's Cancer Group studies shown to be effective in high-risk acute lymphoblastic leukemia and examined them in children with National Cancer Institute standard-risk acute B-precursor lymphoblastic leukemia. These were (1) vincristine and escalating IV methotrexate (MTX) without leucovorin rescue during the interim maintenance (IM) phases and (2) addition of a second delayed intensification (DI) phase. Eligible patients (n = 2078) were randomly assigned to regimens containing either oral (PO) MTX, PO mercaptopurine, dexamethasone, and vincristine or IV MTX during IM phases, and regimens with either single DI or double DI. Five-year event-free survival (EFS) and overall survival for patients on the PO MTX arms were 88.7% ± 1.4% and 96% ± 0.9% versus 92.6% ± 1.2% and 96.5% ± 0.8% for those on the IV MTX arms (P = .009, P = .66). Five-year EFS and overall survival for patients who received single DI were 90.9% ± 1.3% and 97.1% ± 0.8% versus 90.5% ± 1.3% and 95.4% ± 3.8% for those who received double DI (P = .71, P = .12). No advantage was found for a second DI; however, replacement of PO MTX, PO mercaptopurine, vincristine, and dexamethasone during IM with vincristine and escalating IV MTX improved EFS.

Glucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL), but usage differs between cooperative group protocols. All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone. Issues to consider in the choice of induction steroid include impact on event-free and overall survival, acute morbidity such as infection risk, diabetes, and behavioural disturbances and long-term complications such as avascular necrosis. It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase, but dosing schedules (intermittent versus continuous) vary. There is no consensus on the potential benefit of steroid administration during maintenance therapy. This review will summarize the current available data on steroid use in paediatric ALL, highlighting outcomes as well as major toxicities.

The Children’s Cancer Group enrolled 13,298 young people age < 21 years on one of 16 protocols between 1983 and 2002. Outcomes were examined in three time periods, 1983–1988, 1989–1995, 1996–2002. Over the three intervals, 10-year event-free survival (EFS) for Rome/NCI standard risk and higher risk B-precursor patients was 68% and 58%, 77% and 63%, and 78% and 67%, respectively; while for standard risk and higher risk T-cell patients, EFS was 65% and 56%, 78% and 68%, and 70% and 72%, respectively. Five-year EFS for infants was 36%, 38%, and 43%, respectively. Seminal randomized studies led to a number of important findings. Stronger post induction intensification improved outcome for both standard and higher risk patients. With improved systemic therapy, additional IT methotrexate effectively replaced cranial radiation. For standard risk patients receiving three-drug induction, iso-toxic substitution of dexamethasone for prednisone improved EFS. Pegylated asparaginase safely and effectively replaced native asparaginase. Thus, rational therapy modifications yielded better outcomes for both standard and higher risk patients. These trials provide the platforms for current Children’s Oncology Group trials.

Purpose Patients 16 to 21 years of age with acute lymphoblastic leukemia (ALL) have an inferior outcome compared with younger children, leading some medical oncologists to advocate allogeneic stem-cell transplantation in first remission for these patients. We examined outcome for young adults with ALL enrolled onto the Children's Cancer Group (CCG) 1961 study between 1996 and 2002. Patients and Methods CCG 1961 entered patients with ALL 1 to 21 years of age with initial WBC count ≥ 50,000/μL and/or age ≥ 10 years. Randomly assigned therapies evaluated the impact of postinduction treatment intensification on outcome. We examined outcome and prognostic factors for 262 young adults with ALL. Results Five-year event-free and overall survival rates for young adult patients are 71.5% (SE, 3.6%) and 77.5% (SE, 3.3%), respectively. Rapid responder patients (< 25% bone marrow blasts on day 7) randomly assigned to augmented therapy had 5-year event-free survival of 81.8% (SE, 7%), as compared with 66.8% (SE, 6.7%) for patients receiving standard therapy (P = .07). One versus two interim maintenance and delayed intensification courses had no significant impact on event-free survival. WBC count more than 50,000/μL was an adverse prognostic factor. Conclusion Young adult patients with ALL showing a rapid response to induction chemotherapy benefit from early intensive postinduction therapy but do not benefit from a second interim maintenance and delayed intensification phase. Given the excellent outcome with this chemotherapy, there seems to be no role for the routine use of allogeneic stem-cell transplantation in first remission for young adults with ALL.

We performed a retrospective comparison of presenting features, planned treatment, complete remission (CR) rate, and outcome of 321 adolescents and young adults (AYAs) ages 16 to 20 years with newly diagnosed acute lymphoblastic leukemia (ALL) who were treated on consecutive trials in either the Children's Cancer Group (CCG) or the Cancer and Leukemia Group B (CALGB) from 1988 to 2001. CR rates were identical, 90% for both CALGB and CCG AYAs. CCG AYAs had a 63% event-free survival (EFS) and 67% overall survival (OS) at 7 years in contrast to the CALGB AYAs, in which 7-year EFS was only 34% (P < .001; relative hazard rate [RHR] = 2.2) and OS was 46% (P < .001; RHR = 1.9). While CALGB AYAs aged 16 to 17 years achieved similar outcomes to all CCG AYAs with a 7-year EFS of 55%, the EFS for 18- to 20-year-old CALGB patients was only 29%. Comparison of the regimens showed that CCG AYAs received earlier and more intensive central nervous system prophylaxis and higher cumulative doses of nonmyelosuppressive agents. There were no differences in outcomes of those who reached maintenance therapy on time compared with those who were delayed. Based on these observations, a prospective study for AYAs with ALL using the more successful approach of the CCG has been initiated.

As glucocorticoid use increased in acute lymphoblastic leukemia, osteonecrosis became an increasingly frequent complication. Besides increased age, host risk factors are poorly defined. We tested whether 12 polymorphisms were associated with osteonecrosis among patients 10 years and older treated on the CCG1882 protocol. Candidate genes (TYMS, MTHFR, ABCB1, BGLAP, ACP5, LRP5, ESR1, PAI-1, VDR, PTH, and PTHR) were chosen based on putative mechanisms underlying osteonecrosis risk. All children received dexamethasone, with doses varying by treatment arm. A PAI-1 polymorphism (rs6092) was associated with risk of osteonecrosis in univariate (P = .002; odds ratio = 2.79) and multivariate (P = .002; odds ratio = 2.89) analyses (adjusting for gender, age, and treatment arm). Overall, 21 of 78 (26.9%) children with PAI-1 GA/AA genotypes, versus 25 of 214 (11.7%) children with GG genotype, developed osteonecrosis. PAI-1 polymorphisms and PAI-1 serum levels have previously been associated with thrombosis. We conclude that PAI-1 genetic variation may contribute to risk of osteonecrosis.

One-hundred thirty-nine patients with acute lymphoblastic leukemia (ALL) and hypodiploidy (fewer than 45 chromosomes) were collected from 10 different national ALL study groups and single institutions. Patients were stratified by modal chromosome number into 4 groups: 24 to 29 (N = 46); 33 to 39 (N = 26); 40 to 43 (N = 13); and 44 (N = 54) chromosomes. Nine patients were Philadelphia chromosome (Ph) positive (4 cases: 44 chromosomes; 5 cases: 40-43 chromosomes) and were not considered further. Event-free survival (EFS) and overall survival (OS) of the remaining 130 patients were 38.5% ± 4.4% and 49.8% ± 4.2% at 8 years, respectively. There were no significant differences in outcome between patients with 24 to 29, 33 to 39, or 40 to 43 chromosomes. Compared with patients with fewer than 44 chromosomes, patients with 44 chromosomes had a significantly better EFS (P = .01; 8-year estimate, 52.2% vs 30.1%) and OS (P = .017; 69% vs 37.5%). For patients with 44 chromosomes, monosomy 7, the presence of a dicentric chromosome, or both predicted a worse EFS but similar OS. Doubling of the hypodiploid clone occurred in 32 patients (24-29 chromosomes [n = 25] and 33-39 chromosomes [n = 7]) and had no prognostic implication. Children and adolescents with ALL and hypodiploidy with fewer than 44 chromosomes have a poor outcome despite contemporary therapy.

The role of stem cell transplantation in the treatment of leukemia and myelodysplasia (MDS) in children has changed over the past decade. In pediatric acute lymphoblastic leukemia (ALL), the overall cure-rate is high with conventional chemotherapy. However, selected patients with a high-risk of relapse are often treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission (CR1). Patients with a bone-marrow relapse who attain a second remission frequently receive HSCT. High minimal residual disease (MRD) levels directly prior to HSCT determines the relapse risk. Therefore, MRD positive patients are eligible for more experimental approaches such as intensified or experimental chemotherapy pre-HSCT, as well as immune modulation post-HSCT. In pediatric acute myeloid leukemia (AML) the role of allo-HSCT in CR1 is declining, due to better outcome with modern multi-agent chemotherapy. In relapsed AML patients, allo-HSCT still seems indispensable. Targeted therapy may change the role of HSCT, in particular in chronic myeloid leukemia, where the role of allografting is changing in the imatinib era. In MDS, patients are usually transplanted immediately without prior cytoreduction. New developments in HSCT, such as the role of alternative conditioning regimens, and innovative stem cell sources such as peripheral blood and cord blood, will also be addressed.

The Children's Cancer Group (CCG) 1952 clinical trial for children with standard-risk acute lymphoblastic leukemia (SR-ALL) compared intrathecal (IT) methotrexate (MTX) with IT triples (ITT) (MTX, cytarabine, and hydrocortisone sodium succinate [HSS]) as presymptomatic central nervous system (CNS) treatment. Following remission induction, 1018 patients were randomized to receive IT MTX and 1009 ITT. Multivariate analysis identified male sex, hepatomegaly, CNS-2 status, and age younger than 2 or older than 6 years as significant predictors of isolated CNS (iCNS) relapse. The 6-year cumulative incidence estimates of iCNS relapse are 3.4% +/- 1.0% for ITT and 5.9% +/- 1.2% for IT MTX; P = .004. Significantly more relapses occurred in bone marrow (BM) and testicles with ITT than IT MTX, particularly among patients with T-cell phenotype or day 14 BM aspirate containing 5% to 25% blasts. Thus, the estimated 6-year event-free survivals (EFS) with ITT or IT MTX are equivalent at 80.7% +/- 1.9% and 82.5% +/- 1.8%, respectively (P = .3). Because the salvage rate after BM relapse is inferior to that after CNS relapse, the 6-year overall survival (OS) for ITT is 90.3% +/- 1.5% versus 94.4% +/- 1.1% for IT MTX (P = .01). It appears that ITT improves presymptomatic CNS treatment but does not improve overall outcome.

We investigated the anti-asparaginase antibody (Ab) and asparaginase enzymatic activity in the sera of 1,001 patients (CCG-1961) with high-risk acute lymphoblastic leukemia (HR-ALL). Patients received nine doses of native Escherichia coli asparaginase during induction. Half of rapid early r

BACKGROUND 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. METHODS 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. RESULTS 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 with > 50 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. CONCLUSIONS 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. Cancer 2002;94:1102–10. © 2002 American Cancer Society. DOI 10.1002/cncr.10325

This article describes case studies of five children treated with vasopressin for refractory hypotension. In addition, physiology and pharmacology of vasopressin are reviewed in a comprehensive survey of the literature from 1966 until the present. In all five children, blood pressure increased immediately after vasopressin administration. The preliminary success of vasopressin for hypotension the setting of vasodilatory shock is promising. This limited use of vasopressin in the setting of refractory hypotension in these patients appears to be safe; the appropriate patient population and dose regimen are not yet determined.

PURPOSE: To determine whether consolidation therapy with high-dose melphalan, etoposide, and total-body irradiation (TBI) with autologous stem-cell support would improve the prognosis for patients with newly diagnosed metastatic Ewing’s sarcoma (ES). PATIENTS AND METHODS: Thirty-two eligible patients with newly diagnosed ES metastatic to bone and/or bone marrow were enrolled onto this study. Treatment was initially comprised of five cycles of induction chemotherapy (cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide) and local control. Peripheral-blood stem-cell collection was performed after the second cycle of chemotherapy, with delay if the bone marrow was persistently involved. If patients had a good response to initial therapy, they proceeded to consolidation therapy with melphalan, etoposide, TBI, and stem-cell support. RESULTS: Of the 32 eligible patients, 23 proceeded to high-dose therapy consolidation. Of the nine patients who did not proceed to consolidation, four were secondary to progressive disease and two were secondary to toxicity. Three patients died from toxicity during the high-dose phase of the therapy. The majority of the patients who underwent high-dose consolidation therapy experienced relapse and died with progressive disease. Two-year event-free survival (EFS) for all eligible patients is 20%. The 2-year post–stem-cell reconstitution EFS for the subset of 23 patients who received consolidation therapy is 24%. Analysis of peripheral-blood stem-cell collections by molecular techniques for minimal residual disease showed contamination of at least some samples by tumor cells in all three patients with available data. CONCLUSION: Consolidation with high-dose melphalan, etoposide, TBI, and autologous stem-cell support failed to improve the probability of EFS in this cohort of patients with newly diagnosed metastatic ES.

PURPOSE: We used duration of hospitalization as a surrogate for cost and event-free survival as a measure of effectiveness to estimate the cost-effectiveness ratios of various treatment regimens on Children’s Cancer Group trials for acute lymphoblastic leukemia. PATIENTS AND METHODS: The analyses included 4,986 children (2 to 21 years of age) with newly diagnosed acute lymphoblastic leukemia enrolled onto risk-adjusted protocols between 1988 and 1995. Analyses were based on a model of 100 patients. The marginal cost-effectiveness ratio (hospital days per additional patient surviving event-free) was the difference in total duration of hospitalization divided by the difference in number of event-free survivors at 5 years for two regimens. Relapse-adjusted marginal cost of frontline therapy was the difference in total duration of hospitalization for frontline therapy plus relapse therapy divided by the difference in number of event-free survivors at 5 years on the frontline therapy for two regimens. RESULTS: One or two delayed intensification (DI) phases, augmented therapy, and dexamethasone all improved outcome. Marginal cost-effectiveness of these regimens compared with the control regimens was 133 days per patient for DI, 117 days per patient for double DI, and 41 days per patient for augmented therapy. Dexamethasone resulted in 17 fewer days per patient. Relapse-adjusted marginal costs were 68 days per patient for DI and 52 days for double DI. Augmented therapy and dexamethasone-based therapy resulted in 16 and 82 fewer hospital days, respectively. The estimated cost-effectiveness for treating any first relapse was 250 days per patient. CONCLUSION: DI, double DI, augmented therapy, and dexamethasone-based therapy are cost-effective strategies compared with current treatment of first relapse.

PURPOSE: Little is known about nonrandom deletions of chromosome bands 13q12 to 13q14 (13q12–14) in acute lymphoblastic leukemia (ALL). We determined the prognostic significance of cytogenetically identified breakpoints in 13q12–14 in children with newly diagnosed ALL treated on Children’s Cancer Group protocols from 1988 to 1995. PATIENTS AND METHODS: Breakpoints in 13q12–14 were identified in 36 (2%) of the 1,946 cases with accepted cytogenetic data. Outcome analysis used standard life-table methods. RESULTS: Seventeen patients (47%) with an abnormal 13q12–14 were classified, according to the National Cancer Institute (NCI), as poor risk, and 15 patients (42%) were standard risk; four (11%) were infants less than 12 months of age. Eight cases had balanced rearrangements of 13q12–14, 27 patients had a partial loss of 13q, and one had both a partial gain and a partial loss. The most frequent additional abnormalities among these patients were an abnormal 12p, a del(6q), a del(9p), a 14q11 breakpoint, and an 11q23 breakpoint. Nineteen patients were pseudodiploid, 10 were hyperdiploid, and seven were hypodiploid. Patients with an abnormal 13q12–14 had significantly worse event-free survival than patients lacking such an abnormality, with estimates at 6 years of 61% (SD = 14%) and 74% (SD = 1%), respectively (P = .04; relative risk = 1.74). Overall survival, however, was similar for the two groups (P = .25). The prognostic effect of an abnormal 13q was attenuated in a multivariate analysis adjusted for NCI risk status and ploidy (P = .72). CONCLUSION: Aberrations of 13q12–14 may contribute to leukemogenesis of childhood ALL and confer increased risk of treatment failure but are associated with other poor-risk features.

While it has been known for decades that the growth of tumor transplants can be enhanced immunologically, the potential significance of these previous findings to the development of primary tumors and the mechanisms of tumor enhancement has remained obscure. This review will summarize recent experiments indicating that primary tumor development can be enhanced by active immunization. The evidence suggests that antibodies, B cells and CD4+ T cells can play a critical role in enhancing the development of primary, tumors, whereas endogenous interferon-gamma (IFNgamma) can counteract enhancement. Thus, we envision two possible functions of IFNgamma: (i) preventing B cell and antibody enhancement and (ii) counteracting tumor promotion independent of T and B cells.

PURPOSE: To determine the incidence, risk factors, and morbidity for osteonecrosis (ON) in children with acute lymphoblastic leukemia (ALL) treated with intensive chemotherapy including multiple, prolonged courses of corticosteroid. PATIENTS AND METHODS: The occurrence of symptomatic ON was investigated retrospectively in 1,409 children ages 1 to 20 years old receiving therapy for high-risk ALL on Children’s Cancer Group (CCG) protocol CCG-1882. RESULTS: ON was diagnosed in 111 patients (9.3% ± 0.9%, 3-year life-table incidence). The incidence was higher for older children (≥ 10 years: 14.2% ± 1.3% v < 10 years: 0.9% ± 0.4%; P < .0001), especially females 10 to 15 years old and males 16 to 20 years old (19.2% ± 2.3% and 20.7% ± 4.7%, respectively). In patients 10 to 20 years old, the incidence of ON was higher for females versus males (17.4% ± 2.1% v 11.7% ± 1.6%, respectively; P = .03) and for patients randomized to receive two 21-day dexamethasone courses versus one course (23.2% ± 4.8% v 16.4% ± 4.3%, respectively; P = .27). Among ethnic groups, whites had the highest incidence and blacks the lowest, with other groups intermediate (16.7% ± 1.4% v 3.3% ± 2.3% v 6.7% ± 2.2%, respectively; P = .003). There was no difference in event-free survival in patients with or without ON. ON was diagnosed within 3 years of starting ALL therapy in all but one patient, involved weight-bearing joint(s) in 94% of patients, and was multifocal in 74% of patients. Symptoms of pain and/or immobility were chronic in 84% of patients, with 24% having undergone an orthopedic procedure and an additional 15% considered candidates for surgery in the future. CONCLUSION: Children ages 10 to 20 years who receive intensive ALL therapy, including multiple courses of corticosteroid, are at significant risk for developing ON.

BACKGROUND The authors have determined the prognostic significance of cytogenetically detectable 12p abnormalities, which are frequent in children with acute lymphoblastic leukemia (ALL), in a large cohort of patients treated on risk-adjusted protocols of the Children's Cancer Group (CCG). METHODS The presence of an abnormal 12p was identified among 1880 children with newly diagnosed ALL; outcome was assessed by standard life table methods. RESULTS A total of 174 cases (9%) had cytogenetically detectable 12p abnormalities; the majority of cases had a balanced translocation, a del(12p), or an add(12p). In the overall cohort, event free survival (EFS) at 6 years was similar for patients with or without a 12p abnormality (76%, SD = 6%, vs. 75%, SD = 2%, respectively; P = 0.60). Among patients with pseudodiploidy, an abnormal 12p conferred improved outcome (P = 0.008; relative risk = 0.51; 95% confidence interval [CI], 0.31–0.85). There was a trend for improved EFS for those with abnormalities in both chromosome 12 homologues (P = 0.16; relative risk = 0.39; 95% CI, 0.10–1.55) and those with low hyperdiploidy (P = 0.07; relative risk = 0.44; 95% CI, 0.18–1.09). Among T-lineage ALL patients, there was a trend for worse outcome for abnormal versus normal 12p (P = 0.14; relative risk = 1.97; 95% CI, 0.78–4.93). There was no difference in EFS for the 12 patients with a dic(9;12) compared with patients lacking an abnormal 12p. CONCLUSIONS These data suggest that although a cytogenetically detectable 12p aberration is a favorable risk factor for children with ALL and pseudodiploidy, it is not prognostic for the overall group of pediatric ALL patients treated with contemporary therapies of the CCG. Cancer 2000;88:1945–54. © 2000 American Cancer Society.

We have compared outcome for 167 (9.0%) children with a del(6q) and 1713 (91%) children without a del(6q) treated on Children's Cancer Group (CCG) risk-adjusted treatment protocols for acute lymphoblastic leukemia (ALL). Thirty-three patients had a del(6q) as the sole aberration; 22 patients had a del(6q) only as a secondary abnormality. Thirty-six cases had a del(6q) and high hyperdiploidy (50 chromosomes). Six patients with a del(6q) also had +16 and 8 patients had loss of a sex chromosome. Frequent recurring breakpoints were q13, q15, q21, q23, and q25. Patients with a del(6q) were more likely to have T-lineage ALL (p0.001), a mediastinal mass (p = 0.01), and higher WBC counts (p = 0.04), although only half of these patients were classified as poor risk. Event-free survival at 6 years was similar for patients with or without a del(6q), with estimates of 77% (SD = 5%) and 74% (SD = 2%), respectively (p = 0.44). This finding was also observed within NCI poor and standard risk groups. Thus, cytogenetically detectable del(6q) is not associated with adverse risk in pediatric ALL.

Purpose: To assess the role of consolidative radiation therapy (CRT) in conjunction with myeloablative therapy with or without total body irradiation (TBI) in children and young adults with metastatic or recurrent sarcoma. Methods and Materials: Twenty-one pediatric sarcoma patients with metastatic (10) or recurrent (11) disease were entered on a prospective feasibility study of intensive myeloablative therapy with or without TBI. Median patient age was 17.8 years (range, 9.4–24.7 years). Primary histologies included Ewing’s (12) , PNET (3) , and other soft tissue sarcomas (6) . Twenty patients received induction chemotherapy. Myeloablative therapy consisted of TBI in 11 patients with either high dose melphalan/etoposide (9) or high dose cytoxan/thiotepa (2) . TBI consisted of 12 Gy in 2 Gy fractions delivered twice daily over 3 days. Ten patients received high dose chemotherapy alone, either with thiotepa/carboplatinum/etoposide (8) or cytoxan/carboplatinum (2) . Myeloablative therapy was followed by autologous stem cell rescue (ASCR) 24 to 48 hours after completing chemotherapy. Fourteen patients (67%) received CRT either prior to (5) or following (9) myeloablative therapy. Median CRT dose was 37.2 Gy (range, 20–60). Fifty-one disease sites were present prior to myeloablative therapy. Twelve (24%) were bulky (> 8 cm) and 18 (35%) underwent surgical debulking. The median follow-up of surviving patients was 15 months (range, 8–20) with 25% of patients having been followed for more than 20 months. Results: The 3-year actuarial disease-free (DFS) and overall survival (OS) rates for the entire group were 36% and 27%, respectively. Following myeloablative treatment, responses were: 11 complete, 6 partial, 1 stable, and 3 progressive disease. Sixteen patients (71%) have relapsed. The most common site of relapse was the lung (13) . Of the 51 disease sites present prior to myeloablative therapy, 36 sites (71%) were amenable to CRT. Non-amenable sites were: multiple lung metastases (13) and bone marrow (2) . Twenty-six amenable sites (51%) received CRT either prior to (14) or following (12) ASCR. Amenable sites treated with CRT had a better 3-year actuarial local control (80 vs 37%) ( p = 0.0065) than amenable sites not treated with CRT. Factors associated with improved disease-free survival (DFS) in univariate analysis were induction chemotherapy response ( p = 0.002) and extent of surgical resection ( p = 0.045). There was a trend toward improved DFS on univariate analysis with the use of TBI as part of myeloablative therapy ( p = 0.07). The one factor associated with improved OS on univariate analysis was induction chemotherapy response ( p = 0.007). Multivariate analysis revealed that induction chemotherapy response is the only factor that remains significant for DFS ( p = 0.032) as well as for OS ( p = 0.017). Patients with complete response to induction therapy had 40% probability of survival versus all other patients who had 10% survival ( p = 0.05). Conclusion: Consolidative radiotherapy is feasible in primary metastatic or recurrent pediatric sarcoma patients treated with myeloablative therapy with or without TBI. CRT to sites amenable to irradiation provided an improved 3-year actuarial local control than that seen in sites amenable to CRT that did not undergo radiotherapy. There was a trend for improved DFS with the use of TBI. Improved DFS and OS can be predicted by response to induction therapy. This intensive regimen may improve the cure rate of advanced pediatric sarcomas in select patients.

Contemporary intensive therapies are effective for the majority of pediatric T-lineage acute lymphoblastic leukemia (ALL) patients, thus current challenge is to identify patients who may benefit from alternative treatment modalities. Previously, we demonstrated that human leukemic cell growth in the severe combined immunodeficiency (SCID) mouse was a significant prognostic factor for very high risk B-lineage ALL patients. In the current report we show that primary leukemic cells from 24 of 88 (27%) T-lineage ALL patients (SCID+) caused histopathologically detectable leukemia in SCID mice. These SCID+ patients were similar to SCID- (n = 64) patients with respect to virtually all presenting features, including age, sex, race, and leukocyte count. Growth of primary leukemic cells in SCID mice was not a significant predictor of outcome for the aggregate population of T-lineage ALL patients. Two-year event-free survival (EFS) outcomes for SCID+ patient and SCID- patients were 76.2% (SD = 5.6%) and a 64.0% (SD = 10.4%; p = 0.20). Overall survival also was similar between the two groups (p = 0.36). Among the subset of patients with M1 or M2 marrow status by day 7 of induction chemotherapy (rapid early responders), those who were SCID+ had poorer outcomes than those who were SCID-, with a 2-year EFS of 68.4% (SD = 11.9%) vs. 85.7% (SD = 6.0%) and relative hazard rate of 3.06 (p = 0.06). These data suggest that leukemic cell growth in SCID mice may identify a subset of T-lineage ALL patients who are at higher risk for relapse despite achieving a rapid early response to induction chemotherapy.

BACKGROUND Children with Philadelphia (Ph) chromosome positive (+) acute lymphoblastic leukemia (ALL) represent a subgroup at very high risk for treatment failure. In this report, the authors assessed the outcome of Ph+ ALL in a large cohort of children treated on contemporary intensive chemotherapy protocols of the Children's Cancer Group (CCG). METHODS This study included 1322 children enrolled between 1988-1995 on CCG risk-adjusted studies for ALL who had centrally reviewed cytogenetic data. Thirty patients had a t(9;22)(q34;q11) translocation and were referred to as Ph+; 1292 were Ph negative(-). Outcome analyses used standard life table methods. RESULTS Compared with Ph- ALL patients, Ph+ ALL patients were more likely to be black (P = 0.008), age >10 years (P = 0.02), and have a leukocyte count ≥50,000/L (P < 0.0001). Nearly all Ph+ (96.7%) and Ph- (98.3%) patients achieved remission after induction therapy, yet event free survival outcome was significantly worse for Ph+ patients compared with Ph- patients, with 4-year estimates of 20.1% (standard deviation [SD] = 9.1%) and 75.8% (SD = 1.2%), respectively (P < 0.0001). This difference was maintained among patients regardless of presenting leukocyte count, age, or early response to therapy. Ten Ph+ patients underwent bone marrow transplantation (BMT) at the time of first remission; six of these patients remained event free at the time of analysis, and represent the majority (six of eight) of patients surviving event free. CONCLUSIONS The findings of the current study confirm that Ph chromosome positivity represents a significant independent adverse risk factor for childhood ALL that has not been abrogated by current intensive chemotherapy programs. BMT at the time of first remission, as well as other alternative strategies employing biotherapeutic agents, should be considered in future front-line trials for pediatric patients with Ph+ ALL. Cancer 1998;83:2030-2039. © 1998 American Cancer Society.

Children with high-risk acute lymphoblastic leukemia (ALL) who have a slow response to initial chemotherapy (more than 25 percent blasts in the bone marrow on day 7) have a poor outcome despite intensive therapy. We conducted a randomized trial in which such patients were treated with either an augmented intensive regimen of post-induction chemotherapy or a standard regimen of intensive post-induction chemotherapy.Between January 1991 and June 1995, 311 children with newly diagnosed ALL who were either 1 to 9 years of age with white-cell counts of at least 50,000 per cubic millimeter or 10 years of age or older, had a slow response to initial therapy, and entered remission at the end of induction chemotherapy were randomly assigned to receive standard therapy (156 children) or augmented therapy (155). Those with lymphomatous features were excluded. Event-free survival and overall survival were assessed from the end of induction treatment.The outcome at five years was significantly better in the augmented-therapy group than in the standard-therapy group (Kaplan-Meier estimate of event-free survival [+/-SD]: 75.0+/-3.8 vs. 55.0+/-4.5 percent, P0.001; overall survival: 78.4+/-3.7 vs. 66.7+/-4.2 percent, P=0.02). The difference between treatments was most pronounced among patients one to nine years of age, all of whom had white-cell counts of at least 50,000 per cubic millimeter (P0.001). Risk factors for an adverse event in the entire cohort included a white-cell count of 200,000 per cubic millimeter or higher (P=0.004), race other than black or white (P0.001), and the presence of a t(9;22) translocation (P=0.007). The toxic effects of augmented therapy were considerable but manageable.Augmented post-induction chemotherapy results in an excellent outcome for most patients with high-risk ALL and a slow response to initial therapy.

Untreated patients with Hurler syndrome (MPSIH) experience progressive neurologic deterioration and early death. Allogeneic bone marrow transplantation (BMT) ameliorates or halts this course. The Storage Disease Collaborative Study Group was formed to evaluate the effectiveness and toxicity of BMT. Effectiveness was defined as engrafted survival with continuing cognitive development. Fifty-four patients deficient in leukocyte α-l-iduronidase enzyme activity (median age, 1.8 years; range, 0.4 to 7.9) received high-dose chemotherapy with or without irradiation and BMT from HLA-genotypically identical sibling (GIS) or HLA-haploidentical related (HIR) donors between September 16, 1983 and July 14, 1995; all children were included in this report. Thirty-nine of 54 patients (72%) engrafted following the first BMT. The probability of grade II to IV acute graft-versus-host disease (GVHD) at 100 days was 32% for GIS and 55% for HIR patients. The probability of extensive chronic GVHD was 0% for GIS and 24% for HIR patients. The actuarial probability of survival at 5 years was 64% for all patients, 75% for GIS patients, 53% for HIR patients, and 53% for patients with donor marrow engraftment. The baseline Mental Developmental Index (MDI) was examined both for children less than and greater than 24 months of age at BMT. Children transplanted before 24 months had a mean baseline MDI of 78, while those transplanted after 24 months had a mean baseline MDI of 63 (P = .0002). Both baseline and post-BMT neuropsychologic data were available for 26 of 30 engrafted survivors. Of 14 patients transplanted before 24 months of age, nine demonstrated developmental trajectories that were normal or somewhat slower than normal. In contrast, of 12 patients transplanted after 24 months of age, only three showed developmental trajectories that were normal or somewhat slower than normal (P = .01). For children with a baseline MDI greater than 70, there was a significant correlation between the MDI at follow-up study and leukocyte α-l-iduronidase enzyme activity (P = .02). Children were more likely to maintain normal cognitive development if they were fully engrafted following BMT from a donor with homozygous normal leukocyte α-l-iduronidase enzyme activity. Children who developed acute GVHD of grade II or worse had significantly poorer cognitive outcomes (P

BACKGROUND Early response to therapy is defined as the initial response prior to Day 28 of treatment, the conventional time of marrow evaluation. The number of reports linking early response to therapy with the ultimate outcome of childhood acute lymphoblastic leukemia is substantial and growing. When this study began, these experiences had yet to be comprehensively reviewed. METHODS A comprehensive search of the published literature yielded contributory reports of 14 trials conducted in the United States and Europe. In addition, unpublished data from one Children's Cancer Group trial were made available. Outcome measures were standardized by conversion to ratios of the incidence of adverse events among poorer and better responders. RESULTS Early response to therapy was an independent prognostic factor in each of the 15 trials, which together included more than 10,000 patients. The incidence of slower early response ranged from 2-33%, with various measures and criteria used in different trials. Patients with a slower early response were 1.5-6.1 times (median, 2.7) more likely to have an adverse event than patients with a more rapid early response, however defined. Early response maintained prognostic significance after the exclusion of induction failure and within risk strata defined by age, white blood cell count, and/or immunophenotype. Its significance was also maintained in multivariate analyses where performed. CONCLUSIONS Early response to therapy, whether determined by evaluation of bone marrow or peripheral blood, is a consistent, independent prognostic factor in childhood acute lymphoblastic leukemia. Slower early response may serve as a useful surrogate for outcome, a more complex end point, in investigations of the cellular and molecular determinants of resistance to therapy. It may also allow early identification of a patient subpopulation for whom current therapy is less effective and alternative strategies may be justified. Cancer 1997; 80:1717-26. © 1997 American Cancer Society.

PURPOSE Leukemic cells from T-lineage acute lymphoblastic leukemia (ALL) patients are thought to originate from T-lymphocyte precursors corresponding to discrete stages of T-cell ontogeny. Here we sought to determine the influence of leukemic cell apparent maturational stage on treatment outcomes in pediatric T-lineage ALL. PATIENTS AND METHODS From 1983 through 1993, 407 pediatric T-lineage ALL patients were enrolled onto two sequential series of risk-adjusted treatment protocols of the Children's Cancer Group. In the current analysis, T-lineage ALL patients were immunophenotypically classified as follows: CD7+ CD2- CD5- pro-thymocyte leukemia (pro-TL), CD7+ (CD2 or CD5)+ CD3- immature TL, and CD7+ CD2+ CD5+ CD3+ mature TL. RESULTS Similar induction outcomes of 91.4%, 97.1%, and 98.3% were obtained by the pro-, immature, and mature TL groups, respectively. Four-year event-free survival (EFS) was lower for pro-TL patients (57.1%; SD = 8.4%,) compared with immature and mature TL patients (68.5%; SD = 3.5%; and 77.1%; SD = 4.0%, respectively) with an overall significance of .05 (log-rank test) or .04 (log-rank trend test). Relative hazards rates (RHR) were 2.11 and 1.22 for pro-TL and immature TL versus mature TL, respectively. Highly significant differences were found for overall survival (P = .005, log-rank test; P = .009, log-rank trend test). Multivariate analysis confirmed that the prognostic influence of ontogeny grouping was independent of that of other prognostic factors. CONCLUSION Leukemic cells of the pro-TL maturation stage identify a small subgroup of T-lineage ALL patients who have a significantly worse EFS outcome than patients whose cells are of a more mature stage of development.

We found a marked variation in BCL-2 oncoprotein expression levels of primary leukemic cells from 338 children with newly diagnosed acute lymphoblastic leukemia (ALL). None of the high-risk features predictive of poor treatment outcome in childhood ALL, such as older age, high white blood cell (WBC) count, organomegaly, T-lineage immunophenotype, ability of leukemic cells to cause overt leukemia in severe combined immunodeficient (SCID) mice, presence of MLL-AF4, and BCR-ABL fusion transcripts were associated with high levels of BCL-2 expression. Overall, high BCL-2 levels were not associated with slow early response, failure to achieve complete remission, or poor event-free survival. High BCL-2 levels in primary leukemic cells predicted slow early response only in T-lineage ALL patients, which comprised approximately 15% of the total patient population. Even for this small subset of patients, the level of BCL-2 expression did not have a significant impact on the short-term event-free survival.

PURPOSE The specific aims of this study were to improve event-free survival (EFS) in patients with newly diagnosed nonmetastatic osteosarcoma of an extremity using the histologic response to neoadjuvant chemotherapy to determine postoperative chemotherapy; to evaluate a uniform histologic grading system that measures tumor response; and to identify patient characteristics that might influence EFS and survival. PATIENTS AND METHODS Two hundred sixty-eight patients with nonmetastatic osteosarcoma of the extremity were entered between August 1983 and October 1986. Preoperative chemotherapy consisted of four courses of high-dose methotrexate (MTX) and one course of bleomycin, cyclophosphamide, and dactinomycin (BCD). Histologic response to preoperative chemotherapy was determined by morphometric analysis. Good histologic responders (< 5% residual viable tumor) were treated postoperatively with MTX, BCD, and doxorubicin (DOX); poor histologic responders were treated with BCD, DOX, and cisplatin (CDDP). RESULTS The 8-year EFS and survival rates were 53% and 60%, respectively. Two hundred six patients had their tumors assessed for histologic response: 28% displayed a good histologic response to preoperative chemotherapy. Good histologic responders had an 8-year postoperative EFS rate of 81% and survival rate of 87%; those with a poor histologic response had an 8-year postoperative EFS rate of 46% and survival rate of 52%. A primary tumor site in the proximal humerus or proximal femur and an elevated serum alkaline phosphatase level were associated with an increased risk of an adverse event, whereas the type of surgical procedure was not. CONCLUSION EFS and survival appear to be directly related to histologic response to neoadjuvant chemotherapy.

Leukemic cells from most patients with B-lineage acute lymphoblastic leukemia (ALL) appear to originate from normal B-lymphocyte precursors. The earliest B-cell progenitors coexpress the antigens CD10, CD19, or CD34 on their cell surfaces. In a large cohort of 2028 children with ALL, we compared treatment outcomes of a subset of B-lineage ALL patients with CD10+CD19+CD34+ immature B-progenitor leukemia (BPL) to the treatment outcomes of the remaining CD19+ B-lineage ALL patients. Pediatric B-lineage ALL cases enrolled on risk-adjusted ALL treatment protocols of the Children's Cancer Group were immunophenotypically classified as BPL or non-BPL. Patients were stratified further into age groups ofor = 1 year and12 months. Event-free survival (EFS) outcomes were calculated by standard life table methods. BPL patients in both age groups generally had more favorable presenting characteristics than non-BPL controls. Within the age group ofor = 1 year, BPL patients had a slightly better EFS outcome than non-BPL patients, with 3-year estimates of 83.9% (SD = 1.1%) vs. 78.8% (SD = 1.8%), respectively (P = 0.10). Infants with BPL, representing one-fifth of the total infant patient population, had a significantly better EFS outcome than infants with non-BPL (three-year EFS: 82.4%, SD = 9.2% vs. 34.4%, SD = 5.9%, P = 0.006). In univariate analyses, the relative hazard rate (RHR) was 3.73 for non-BPL vs BPL and this marked difference in EFS outcome was maintained at 5 years of follow-up. The favorable prognostic influence of the BPL immunophenotype for infants remained significant in multivariate analyses with an RHR of 2.72 for non-BPL vs BPL (P = 0.05). CD10+CD19+CD34+ immature B-progenitor immunophenotype is associated with favorable characteristics for children with ALL and identifies a subset of infants who achieve favorable EFS outcomes.

To evaluate the patterns of failure and outcome of patients undergoing high-dose chemotherapy, total body irradiation (TBI), and bone marrow transplantation (BMT) for advanced/relapsed pediatric neuroblastoma, with emphasis on the impact of a radiotherapy boost to primary and metastatic sites.Between May 1986 and June 1993, 26 patients with advanced neuroblastoma underwent high-dose chemotherapy and TBI followed by BMT at our institution. The majority of patients were over the age of 2 years (73%) and were Stage IV at diagnosis (81%). Multiple metastatic sites were involved including bone (17), bone marrow (15), distant nodes (11), liver (5), lung (4) and brain (1). Twenty patients (77%) received cyclophosphamide (50 mg/kg x 4 days) and TBI as consolidation therapy. TBI was delivered to a total dose of 12 Gy given in 2 Gy twice daily (b.i.d.) fractions over the 3 days preceding bone marrow infusion. A local radiotherapy boost of 8-24 Gy was given to 13 out of 26 patients (50%) to the primary and/or metastatic sites immediately prior to or following induction chemotherapy according to physician judgement. Sites not amenable to a radiotherapy boost included the bone marrow, diffuse/bilateral lung involvement, and multiple bone metastases (four sites).The actuarial overall survival of the 26 patients was 40.4% at 3 and 5 years, with a progression-free survival at 5 years of 38.5%. Six patients died of transplant-related toxicity (23%). The use of cyclophosphamide as high-dose consolidation chemotherapy was significantly better than other multidrug regimens used in terms of overall survival (p0.0001) and progression-free survival (p = 0.0004). The presence of liver involvement prior to BMT was a significant adverse prognostic factor by multivariate analysis. Of the 20 patients surviving the transplant, 10 (50%) underwent a local radiotherapy boost. The patterns of failure were as follows: 3 out of 10 "boost" patients failed overall, none in previous (old) sites of disease only, 1 in new sites only, and 2 in old and new sites; 6 out of 10 "no boost" patients failed overall, 4 in old sites only, none in new sites only, and 2 in old and new sites. There was a trend toward improved 5-year progression-free survival in patients surviving the transplant that received a boost (68% vs. 33%, p = 0.24). A failure analysis was also performed for each of the 59 initially involved sites, of which the majority (64%) were amenable to a radiotherapy boost. Overall, there is a trend toward less failure in sites amenable to a radiotherapy boost that were irradiated (1 out of 10) vs. those not irradiated (6 out of 28). Failure in the liver occurred in three out of four of the patients with liver involvement that did not receive boost radiotherapy, whereas all seven patients with distant nodal involvement were controlled without a boost. Long-term sequelae include learning difficulties (2), cataract formation (1), and hearing loss (2). Sequelae attributable to a radiotherapy boost occurred in only one patient who received whole brain radiotherapy and developed a cataract and learning difficulties.We have found an actuarial 5-year survival rate of 40.4% for patients with advanced neuroblastoma treated with BMT, which compares favorably with results of other published series. Disease recurrence following BMT was most common in previous sites of disease. The majority (64%) of these sites were amenable to a radiotherapy boost. An analysis of failure suggests that a low-dose radiotherapy boost improves control of these sites.

Treatment of pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) is controversial but has typically consisted of both chemotherapy and radiation. Radiation therapy is associated with potential late effects in children and adolescents. We examined the impact of radiation therapy on long-term outcome of patients with LPHL treated on CCG-5942, a large pediatric cooperative group study of Hodgkin lymphoma (HL).Eighty-two patients with LPHL were registered on CCG-5942. Fifty-two patients (63%) received chemotherapy alone; 29 patients (35%) received chemotherapy followed by involved-field radiation therapy (IFRT).The median follow-up of the LPHL patients is 7.7 years; 63 patients (77%) have5 years of follow-up. The 5-year event-free survival (EFS) and overall survival (OS) were 97% and 100%. Two relapses occurred, both in patients who did not receive IFRT. There were no significant differences in EFS or OS between patients who received or did not receive IFRT.This subset analysis demonstrates the chemosensitivity of pediatric LPHL. Patients who had a complete response to chemotherapy had an excellent EFS and OS without the addition of radiotherapy.

Hereditary pyropoikilocytosis (HPP) is a recessively inherited hemolytic anemia characterized by severe poikilocytosis and red blood cell fragmentation. HPP red blood cells are partially deficient in spectrin and contain a mutant alpha or beta-spectrin that is defective in terms of spectrin self-association. Although the nature of the latter defect has been studied in considerable detail and many mutations of alpha-spectrin and beta spectrin have been identified, the molecular basis of spectrin deficiency is unknown. Here we report two mechanisms underlying spectrin deficiency in HPP. The first mechanism involves a thalassemia-like defect characterized by a reduced synthesis of alpha-spectrin as shown by studies involving synthesis of spectrin in two unrelated HPP probands and their parents: One parent carries the elliptocytogenic spectrin mutation, whereas the other parent is fully asymptomatic. Peripheral blood mononuclear cells as a source of erythroid burst-forming unit (BFUe) were cultured in a two-phase liquid culture system that gives rise to terminally differentiated erythroblasts. Pulse-labeling studies of an equal number of erythroblasts or morphologically identical maturity showed that the synthesis of alpha-spectrin as well as the mRNA levels as measured by the competitive polymerase chain reaction (PCR) method are markedly reduced in the presumed asymptomatic carriers and the HPP probands. In contrast, the synthesis and mRNA levels of beta-spectrin were normal. These results constitute a direct demonstration of an alpha-spectrin synthetic defect in a subset of asymptomatic carriers of HPP and HPP probands. The second mechanism underlying spectrin deficiency involves increased degradation of mutant spectrin before its assembly on the membrane. This is evidenced by pulse labeling studies of erythroblasts from a patient with HPP associated with a homozygous state for spectrin alpha I/46 mutation (leu-pro mutation at AA 207 of alpha-spectrin). These studies showed that although spectrin is synthesized in the cytosol in normal amounts, the rate of turnover of alpha-spectrin is faster resulting in about 40% to 50% reduced assembly of alpha-spectrin and beta-spectrin on the membrane. Thus, spectrin deficiency in this case is at least in part caused by increased susceptibility of the mutant spectrin to degradation before its assembly on the membrane. We conclude that at least two separate mechanisms underlie the molecular basis of spectrin deficiency in HPP.

Background. Scant data are available on event-free survival (EFS) for young adults with leukemia who were 16-21 years of age at diagnosis. In acute lymphoblastic leukemia (ALL), it is well recognized that children have a better EFS compared with adults, whereas for acute myelocytic leukemia (AML), EFS results seem to be similar. To determine the appropriate treatment for young adults with leukemia, outcome data are essential. Methods. Young adults entered on the Childrens Cancer Group (CCG) 100 series ALL protocols and the CCG 213 AML protocol were analyzed for EFS and survival. Prognostic factors for EFS also were determined. Results. The actuarial EFS for 143 young adults with ALL treated on the CCG 100 series ALL protocols was 64±4% at 4 years and 59±4% at 6 years

Limited-stage Hodgkin lymphoma remains a challenging problem for pediatric oncologists. Published and investigative treatment regimens represent varied approaches to balance the excellent overall and event-free survival with the substantial potential for long-term sequelae of effective treatment modalities. Regimens incorporating low-dose radiation to smaller fields and chemotherapy that limits cumulative exposure to the agents most closely associated with long-term complications have been shown to be effective for most patients. Investigative approaches to optimize overall therapy focus on identifying which patients require more or less therapy. A recent example is the use of response-based therapy as a means of limiting or omitting radiation for those with an early, rapid response to chemotherapy. Biologic markers that influence risk for treatment failure or treatment-related toxicities have been only minimally defined. This paper reviews recently published treatment regimens for children and adolescents and presents some considerations for choosing a treatment approach for individual patients.

We have studied 20 children with therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who were 3 months to 16 years old at diagnosis of their primary neoplasm and 1 to 24 years old at diagnosis of their secondary neoplasm. The median interval from initial treatment for the first malignancy to diagnosis of therapy- related MDS or AML was 46 months (range, 12 to 116 months). Twelve patients had chromosomal abnormalities resulting in loss of material from the long arm of chromosomes 5 and/or 7, three patients had abnormalities of chromosome 11 band q23, one patient had both classes of abnormalities, three patients had other abnormalities, and one patient had a normal karyotype. Ten of 12 patients with chromosome 5 and/or 7 abnormalities had been exposed to an alkylating agent, and two of three patients with 11q23 abnormalities had been exposed to an epipodophyllotoxin. The patient with both classes of abnormalities had been exposed to both types of therapy. We conclude that abnormalities of chromosomes 5 and/or 7 are common in children with therapy-related MDS or AML. The proposed relationships between exposure to alkylating agents and abnormalities of chromosomes 5 and/or 7 and between exposure to epipodophyllotoxins and abnormalities of 11q23 are supported in this pediatric series.

The presence of a chromosomal translocation in the leukemic cells at diagnosis of acute lymphoblastic leukemia (ALL) in children is associated with a high risk for treatment failure. We have reexamined the relationship between translocations and prognosis in 146 children with ALL who received risk-based therapy such that high-risk patients were treated with intensive drug schedules. In univariate analysis, multiple factors were associated with a relatively poor event-free survival (EFS) including age less than 2 years or greater than 10 years (combined group), WBC count greater than 10 x 10(9)/L, French-American-British (FAB) morphologic classification L2, absence of common ALL antigen (CALLA, CD10) expression, absence of hyperdiploidy with a chromosome number of 50 to 60, and presence of the specific translocations t(4; 11)(q21;q23) or t(9;22)(q34;q11) (combined group). However, there was no disadvantage with respect to EFS in patients with translocations compared with those who lacked translocations (73% at 4 years in both groups). Furthermore, when patients with specific cytogenetic abnormalities for which the prognostic significance has been well established (hyperdiploid 50 to 60, t(4;11), and t(9;22] were removed from the analysis, the remaining group with other translocations had a better EFS than the remaining group lacking translocations, although this was not statistically significant (81% v 65% at 4 years, P = .24). In a multivariate analysis, a model including WBC count and FAB classification was the strongest predictor of EFS. The presence or absence of translocations was not an independent predictor of EFS and did not contribute to the ability of any model to predict EFS. In conclusion, when effective intensive therapy is used to treat childhood ALL with high-risk clinical features, categorization of patients on the basis of chromosomal translocations without attention to the specific abnormality is not useful as a prognostic factor.

Bone marrow cells from two pediatric patients completing therapy for acute lymphoblastic leukemia were studied using in situ hybridization with an alpha-satellite DNA probe specific for chromosome 17. Morphologic analysis of the end-therapy specimens from each patient had shown small numbers (7.5%, 8.5%) of cells that were suspicious for residual or recurrent disease. These cells could not be morphologically or immunophenotypically distinguished with certainty from immature lymphoid cells (hematogones), which may be present normally, sometimes in increased numbers, in the bone marrow specimens of children. In situ hybridization with a probe to chromosome 17 was used because the leukemic cells from each patient had originally been shown to have an extra copy of this chromosome. In one patient, in situ studies showed a population of cells (106 of 1,000 cells) with three hybridization signals indicating trisomy 17, and thus residual/recurrent leukemia. In the other patient trisomy 17 could not be detected. Additional hybridizations to previously stained bone marrow aspirate smears permitted a direct correlation of the cytogenetic findings with the suspicious cells on a cell-to-cell basis. The questionable cells were identified, photographed, and then re-examined after hybridization. In one patient, 13 of 18 (72%) of the suspicious cells were found to have trisomy 17, whereas in the other patient 0 of 24 (0%) demonstrated an extra copy of this chromosome. These cases illustrate a clinical application of interphase cytogenetic analysis and demonstrate how this technology can be used for direct correlation of cytogenetic findings with cell morphology. This technique should prove useful for the detection of minimal residual disease and for lineage studies in leukemia and myelodysplasia.

The recurring chromosomal 9;II translocation [t(9; II) (p22;q23)] typically is associated with acute monoblastic leukemia, but a number of patients with acute lymphoblastic leukemia also have been reported to have the t(9; II). To investigate the cell lineage in the latter cases, we analyzed DNA from the leukemic cells of an 8-year-old girl with acute lymphoblastic leukemia and a t(9;I I) for rearrangements of the immunoglobulin and T-cell receptor genes. Rearrangements of both immunoglobulin heavy-chain loci and of one lambda light-chain gene were detected, as well as deletions affecting both alleles of the kappa light-chain genes; T-cell receptor genes were in germline configuration. These results provide further evidence that the 9; I I translocation is not limited to myeloid lineage leukemia and may be observed in acute lymphoblastic leukemia.

An 8-year-old boy with a granulocytic sarcoma of the proximal ileum metastatic to mesenteric lymph nodes was placed into complete remission with surgical excision of the primary tumor and conventional induction chemotherapy with daunorubicin and cytosine arabinoside. He was then treated with high dose cytosine arabinoside, fractionated total body irradiation, and allogeneic marrow transplantation from his 22-month-old brother who was completely matched at the major histocompatibility complex. Methotrexate was given following the transplant to prevent graft-versus-host disease (GVHD). His post-transplantation course was complicated by a transient autoimmune hemolytic anemia related to an ABO blood group incompatibility and hepatic fungal microabscesses which responded to Amphotericin therapy. Four years following the transplant the patient remains in complete remission. The prognosis for patients with granulocytic sarcoma has been poor although, perhaps, improved over the past decade. This is the first published case report of successful treatment of a granulocytic sarcoma of the ileum by allogeneic marrow transplantation.

The radiobiological parameters of 33 tumor cell lines were studied in biopsy samples obtained from patients prior to radiotherapy. Epithelial tumor cells derived from head and neck cancer patients were more radioresistant than tumor cell lines derived from patients with sarcoma regardless of method of analysis. The presence of radioresistant tumor cell lines was associated with local failure in some patients. However, the presence of radiosensitive tumor cells did not necessarily predict local control. Our data suggest radiocurability is complex and inherent radiobiological parameters of tumor cells may be only one factor in radiotherapy outcome.

Bilateral testicular biopsies were performed on 708 males with acute lymphoblastic leukemia completing 24 to 30 months of maintenance chemotherapy in continuous remission. The 73 patients (10.3%) with occult testicular leukemia (TL) had a significantly increased risk of subsequent relapse (P = .0001) and death (P less than .0001) when compared with patients with negative biopsies. Protocol-specified therapy for occult TL included reinduction therapy with concurrent bilateral testicular radiation, and 2 years of maintenance therapy. Four-year event-free survival for patients with negative biopsies was 78.2% +/- 4% versus 65% +/- 14% for patients with occult TL who received protocol-specified therapy (P = .05). This study suggests that (1) occult TL occurs in 10% of males completing 2 years of maintenance therapy; (2) occult TL significantly increases risk for subsequent relapse and death; (3) treatment results for occult TL and isolated overt off therapy TL (no previous biopsy) are similar; and (4) given current therapy, documentation of occult TL after 2 years of therapy does not improve disease-free survival.

Childhood non-Hodgkin's lymphomas can be divided into two broad groups based on histologic findings: lymphoblastic and nonlymphoblastic. Lymphoblastic lymphomas often appear with a mediastinal mass and have a propensity for relapse in the bone marrow and CNS. Nonlymphoblastic lymphomas occur primarily in the abdomen and head-neck region. Relapses tend to occur within the first year and may be either local or systemic. Marrow and/or CNS involvement at diagnosis, bulk disease (reflected as elevated serum lactic dehydrogenase levels), and mediastinal occurrences are adverse prognostic features for nonlymphoblastic lymphomas. Chemotherapy is the treatment of choice for both types of childhood non-Hodgkin's lymphomas. In general, radiation therapy is not necessary for optimal treatment of these tumors. Localized non-Hodgkin's lymphomas of either histologic type are highly curable with short-course chemotherapy. Disseminated non-Hodgkin's lymphomas, particularly those with marrow and/or CNS involvement, remain a major treatment challenge.

Longer and more intensive postinduction intensification (PII) improved the outcome of children and adolescents with “higher risk” acute lymphoblastic leukemia (ALL) and a slow marrow response to induction therapy. In the Children's Cancer Group study (CCG-1961), we tested longer versus more intensive PII, using a 2 × 2 factorial design for children with higher risk ALL and a rapid marrow response to induction therapy. Between November 1996 and May 2002, 2078 children and adolescents with newly diagnosed ALL (1 to 9 years old with white blood count 50 000/ or more, or 10 years of age or older with any white blood count) were enrolled. After induction, 1299 patients with marrow blasts less than or equal to 25% on day 7 of induction (rapid early responders) were randomized to standard or longer duration (n = 651 + 648) and standard or increased intensity (n = 649 + 650) PII. Stronger intensity PII improved event-free survival (81% vs 72%, P < .001) and survival (89% vs 83%, P = .003) at 5 years. Differences were most apparent after 2 years from diagnosis. Longer duration PII provided no benefit. Stronger intensity but not prolonged duration PII improved outcome for patients with higher-risk ALL. This study is registered at http://clinicaltrials.gov as NCT00002812.