Children's Cancer Group Protocol Research Articles

Clinical Features and Treatment Outcome of Children With Biphenotypic CD2+CD19+ Acute Lymphoblastic Leukemia: A Children's Cancer Group Study

AbstractLeukemic cells from a subset of children with acute lymphoblastic leukemia (ALL) express lymphoid antigens of both T lineage and B lineage, but the clinical significance of this immunophenotype is unknown. We now report the first comprehensive comparison of treatment outcomes among a large cohort of children with CD2+CD19+ biphenotypic ALL (N = 77), B-lineage ALL (BL) (N = 1,631), or T-lineage ALL (TL) (N = 347) ALL who were treated on risk-adjusted Children's Cancer Group (CCG) protocols. CD2+CD19+ patients were more similar to BL than TL patients with respect to presenting features and antigen expression. The percentages of patients achieving successful induction therapy outcome were 98.7%, 97.8%, and 97.3% for CD2+CD19+, BL, and TL patients, respectively. Univariate comparisons of 4-year event-free survival (83.7%, 72.8%, 75.2% for CD2+CD19+, BL, and TL patients, respectively) achieved borderline significance (CD2+CD19+ B, P = .08; CD2+CD19+v T, P = .07). Relative hazard rate (RHR) estimates for BL and TL compared with CD2+CD19+ were 1.79 and 1.90, respectively, implying a better outcome for biphenotypic patients. However, multivariate adjusted RHRs for BL and TL compared with CD2+CD19+ were 1.43 (P = .29) and 1.16 (P = .76), respectively, suggesting a significant reduction in risk for BL or TL patients once adjustment was made for the more favorable characteristics of the CD2+CD19+ group. Thus, pediatric ALL patients treated on contemporary CCG protocols who present with CD2+CD19+ biphenotypic leukemia generally have good treatment outcomes, due in part to their favorable presenting features.

A prospective study of the hypothalamic-pituitary-adrenal axis in children with acute lymphoblastic leukemia receiving chemotherapy

BackgroundGlucocorticoids are essential in protocols of therapy of acute lymphoblastic leukemia (ALL).ObjectivesTo assess the incidence, severity, morbidity, and risk factors of hypothalamic-pituitary-adrenal axis (HPA) suppression in children with ALL, and the time course of recovery.DesignForty standard risk ALL children treated in the Pediatric Hematology/Oncology Unit, Ain-Shams University, Egypt, were classified into dexamethasone (DXM) group: 20 patients on children cancer group protocol and prednisone (PDN) group: 20 patients on modified Berlin-Frankfurt-Muenster (BFM) study group 90 protocol. Patients were followed clinically and by laboratory assessment of morning s.ACTH, basal and after low-dose adrenocorticotrophic hormone stimulation test of cortisol and DHEAS, at diagnosis and every 2 weeks till adrenal recovery.ResultsHPA recovery was earlier in PDN than DXM group (P < 0.05). In induction phases 1 and 2: 65 and 75% of PDN group recovered on week 2, while 45 and 50% of DXM group recovered in week 4. Adrenal recovery was predicted 2 weeks earlier by normalized s.DHEAS. Children below 5 years of age had earlier recovery in PDN group (P = 0.04), no age effect in DXM group.ConclusionAdrenal suppression is an inevitable consequence of ALL therapy. Monitoring of cortisol levels and steroid coverage during stress is recommended, and gradual steroid tapering is suggested.

Phase II study of pre‐irradiation chemotherapy for childhood intracranial ependymoma. Children's Cancer Group protocol 9942: A report from the Children's Oncology Group

Standard therapy for childhood intracranial ependymoma is maximal tumor resection followed by involved-field irradiation. Although not used routinely, chemotherapy has produced objective responses in ependymoma, both at recurrence and in infants. Because the presence of residual tumor following surgery is consistently associated with inferior outcome, the potential impact of pre-irradiation chemotherapy was investigated. Between 1995 and 1999, the Children's Cancer Group undertook a Phase II trial of pre-irradiation chemotherapy in children 3-21 years of age with intracranial ependymoma and radiological evidence of post-operative residual tumor. Of 84 patients, 41 had residual tumor, and were given four cycles of cisplatin-based chemotherapy prior to irradiation. Of 35 patients fully evaluable for response to chemotherapy, 14 (40%) demonstrated complete response, 6 (17%) partial response, 10 (29%) minor response or stable disease, and 5 (14%) demonstrated progressive tumor growth. For the entire group, 5-year overall survival (OS) and event-free survival (EFS) was 71 ± 6%, and 57 ± 6%, respectively. The pre-irradiation chemotherapy group demonstrated EFS comparable to that of patients with no residual tumor who received irradiation alone (55 ± 8% vs. 58 ± 9%, P = 0.45). Any benefit of chemotherapy was restricted to patients with greater than 90% tumor resection. Children with near total resection of ependymoma may benefit from pre-irradiation chemotherapy. Patients with subtotal resection have inferior outcome despite responses to chemotherapy, and should be considered for second-look surgery prior to irradiation. Pediatr Blood Cancer 2012; 59: 1183-1189. © 2012 Wiley Periodicals, Inc.

Donor-Derived Myelodysplastic Syndrome and Acute Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Incidence, Natural History and Treatment Response

AbstractAbstract 1306Donor-derived myelodysplastic syndrome (DD-MDS) and acute leukemia (DD-AL) are rare complications of allogeneic HSCT with approximately 40 cases identified in the literature. While the estimated incidence of DD-MDS/AL is between 0.12–5% for recipients of allogeneic HSCTs, more precise estimates by HSCT source have been impaired by differences in follow-up and changes in diagnostic tools over time. To this end, we evaluated all allogeneic transplants performed at the University of Minnesota between 1992 and 2009 in whom molecular assays for chimerism were performed. Patients transplanted for malignancy also had routine marrow examinations for evidence of recurrent disease. During this interval, there were 226 related donor transplants (47 marrow, 164 peripheral blood, 3 marrow and peripheral blood, 12 umbilical cord blood [UCB]), and 1254 unrelated donor transplants (436 marrow, 16 peripheral blood, 802 UCB). Of the entire cohort, 73% had a malignant and 27% had a non-malignant disease with 60% male, and 57% aged >18 years. The median follow-up among survivors was 3.5 years (range, 0.5 to 15.1). Eight cases of DD-MDS/AL were identified with the event diagnosed between 3 months and 15 years (median 33 months) after transplant. At 5 years, the incidence of DD-MDS/AL by donor type was 3.4% after matched sibling donor, 0% after unrelated marrow/peripheral blood donor and 0.4% after unrelated UCB donor transplant. Main characteristics of the 8 cases are described in Table 1. Four patients had CMV reactivation during their post-transplant course requiring antiviral therapy; three had poor hematopoietic recovery with prolonged courses of hematopoietic growth factor therapy. Five had monosomy 7, including all 4 UCB cases. Time to DD-MDS/AL varied by HSCT source: 22 months for UCB and 50 months for MSD cases. Underlying mechanisms are not yet known but have been postulated to include inherited or chemotherapy-induced marrow stroma and microenvironment abnormalities, bystander injury due to residual low-level chemotherapy and radiation damage, impaired tumor surveillance, chronic antigenic stimulation, premature aging of donor cells, transfer of oncogenic material from host to donor cells and the presence of preleukemic clones found rarely in UCB samples. Interestingly, one patient with DD-MDS had a sustained complete remission and loss of the cytogenetic clone by removing GCSF. The patient with DD-acute lymphocyte leukemia completed Children's Cancer Group protocol 1961 and remains disease-free currently out 43 months from DD-AL occurrence. Two of the DD-acute myeloid leukemia cases were treated with high dose Ara-C containing regimens and one patient went on to a second HSCT. Two of the DD-MDS cases were treated with a second HSCT, while one was given decitabine. These 8 cases illustrate the rarity of the event and potentially provide more accurate estimates of the risk of this complication by HSCT source for counseling patients. Furthermore, therapeutic interventions are limited but removal of hematopoietic growth factor may alone be effective in some cases. Disclosures:No relevant conflicts of interest to declare.

Twenty‐five years of treatment for childhood acute lymphoblastic leukaemia in Western Australia: how do we compare?

To compare survival among the subgroup of children with acute lymphoblastic leukaemia (ALL) who were treated at Princess Margaret Hospital for Children (PMH) in Perth, Western Australia, over 25 years under 15 consecutive protocols of the Children's Cancer Group (CCG) with survival for the entire cohort of children in multiple centres treated under CCG protocols in that period; and to highlight the benefits of membership of a large cooperative research group conducting multicentre randomised controlled trials. Retrospective review of the outcomes of all 311 children with newly diagnosed ALL treated at PMH between 1983 and 2008. 4-year event-free survival; and 10-year overall survival. Four-year event-free survival for the entire PMH cohort increased from 66% (SE, 6%) for 1983-1987 to 88% (SE, 6%) for 2002-2005, while overall survival over the same period improved from 78% (SE, 5%) to 94% (SE, 4%). Comparisons of outcomes of children treated at PMH with those of the entire CCG cohort, protocol by protocol, revealed similar outcomes. Outcomes of children treated at PMH over the 25-year period are equivalent to those of the larger CCG cohort.

The presence of central nervous system disease at diagnosis in pediatric acute myeloid leukemia does not affect survival: A Children's Oncology Group study

The presence of central nervous system (CNS) disease in pediatric acute myeloid leukemia (AML) is often thought to confer a worse prognosis. This study examined the outcome of children with AML who had CNS disease at diagnosis. Patients enrolled on Children's Cancer Group protocols 2861, 2891, 2941, and 2961 being treated for de novo AML were classified for the presence of CNS disease at diagnosis as CNS1 (<5 WBC in the CSF without blasts), CNS2 (<5 WBC in the CSF with blasts), or CNS3 (> or =5 WBC in the CSF with blasts). CNS disease at diagnosis was then analyzed regarding patient characteristics and outcome. There was an incidence of CNS disease (i.e., CNS3 status) of 11% in the 1,459 patients analyzed in this study. The risk factors found are young age, high white cell count, hepatomegaly or splenomegaly at diagnosis, M4 subtype, chromosome 16 abnormalities, and hyperdiploid cytogenetics. There were no significant differences in overall survival, event free survival, or remission rates between the groups; however, a significant difference was seen between the CNS1 and CNS3 groups in disease free survival and isolated CNS relapse risk. Patients with CNS disease at diagnosis have similar survival to those without CNS disease, although they have an increased incidence of isolated CNS relapse. Patients with CNS disease at diagnosis may warrant more aggressive CNS directed therapy.

Weight patterns in children with higher risk ALL: A report from the Children's Oncology Group (COG) for CCG 1961.

This retrospective analysis defined and described patterns and predictors of weight change during treatment in children with acute lymphocytic leukemia (ALL) with high-risk features who received treatment on Children's Cancer Group protocol CCG 1961. Patients (1,638) were enrolled in CCG 1961 from November 1996 to May 2002. Weight was measured as BMI percent (%), specific for age and gender, and defined as 100 x ln(BMI/median BMI). By the end of treatment, 23% of children were obese (BMI >or=95%), compared with 14% at diagnosis. Children who received post-induction intensified therapy (arms C, D, SER with Doxorubicin or Idarubicin) had higher gastrointestinal toxicities and lower BMI% from consolidation through interim maintenance 1. BMI% then increased for all arms between delayed intensification and maintenance 1 or 2. Children who were of Black or Hispanic race, obese at diagnosis, or who had grade 3 or 4 pancreatitis/glucose toxicities during induction had higher BMI% throughout treatment. Children were more likely to be obese at the end of the study if they were aged 5-9 years at diagnosis or female gender. Cranial radiation was not a predictor of obesity. Successful treatment of higher risk childhood ALL was associated with obesity, independent of cranial irradiation. The beginning of maintenance therapy may be the best time to intervene with nutritional and behavioral interventions, particularly for children who are obese or aged 5-9 years at diagnosis, female, Black or Hispanic, or those with metabolic toxicities during induction.

Analysis of Infectious Complications in Infants With Acute Lymphoblastic Leukemia Treated on the Children's Cancer Group Protocol 1953

Infants with acute lymphoblastic leukemia have a poor prognosis. The Children's Cancer Group (CCG) 1953 protocol tested the hypothesis that intensification of therapy would improve outcome for these patients. This intensified therapy resulted in better disease control, but resulted in greater toxicity. In this paper, we report the infectious complications associated with this intensified therapy. We retrospectively analyzed the infectious complications reported on the case report forms of all 115 patients enrolled on CCG 1953. Overall 495 infectious complications were identified in 115 patients. Bacterial infections occurred most frequently (74%), followed by viral (13%), fungal (11%), and protozoan (1%). Infection related mortality disproportionately occurred with viral (31%) and fungal (19%) infections. Twenty-three percent (n=26) of patients died of infectious complications, with the majority occurring during induction/intensification. Lower respiratory infections contributed to death in 12 patients and were most commonly viral (n=6) and fungal (n=3). Intensification of therapy resulted in increased infectious complications and deaths compared with previous studies. Future studies will need to focus on: (1) decreasing intensification during the first month of therapy, (2) developing targeted therapies, and (3) improving measures designed to prevent, quickly diagnose, and appropriately treat infections.

Pediatric Patients with Extramedullary Leukemia Involving the Central Nervous System Have a Superior Outcome.

Purpose: Extramedullary leukemia (EML), formally known as chloroma, is discrete collections of leukemia cells outside of the bone marrow. EML is often seen within the central nervous system (CNS) and these are often treated in a similar fashion as leukemia cells within the cerebral spinal fluid (CSF). We previously demonstrated that the presence of leukemia cells within the CSF (CNS leukemia) does not affect overall survival. We sought to determine the outcome of patients with central nervous system EML and compare these patients with those with CNS disease and non CNS EML.Methods: Patients enrolled on Children's Cancer Group protocols 2861, 2891, 2941 and 2961 being treated for de novo acute myeloid leukemia (AML) with intensive timing chemotherapy were classified for the presence of CNS disease as CNS1 (<5 wbc in the CSF without blasts), CNS2 (<5 wbc in the CSF with blasts), or CNS3 (≥ 5 wbc in the CSF with blasts), as well as EML in the CNS (eg orbit, brain, etc) or non-CNS EML (eg skin, lung, etc). These patient's outcomes were then analyzed.Results: A total of 1459 patients treated with intensive timing chemotherapy were analyzed in this study. At diagnosis, 1113 (76%) were CNS1, 143 (13%) CNS2, 154 (11%) CNS3, 48 (3%) had CNS EML, 57 (4%) had a non-CNS EML, and only 6 patients (0.4%) with CNS EML had CNS3 status. Patients with CNS EML had a significantly higher overall survival from study entry compared to patients with non-CNS EML (83% vs 38%, p<0.001), and compared to CNS3 patients (83% vs 50%, p<0.001). The patients with CNS EML also had a significantly higher event free survival compared to patients with non-CNS EML (65% vs 34%, p<0.001), and compared to CNS3 patients (65% vs 34%, p<0.001). There was no significant difference in relapse risk, bone marrow relapse, isolated CNS relapse, or EML relapse comparing patients with CNS EML and non-CNS EML. CNS EML patients had a significantly lower relapse risk compared to CNS3 patients (29% vs 49%, p=0.025). There was not a significant difference in bone marrow relapse, isolated CNS relapse, or EML relapse comparing these 2 groups of patients.Conclusion: Patients with extramedullary leukemia involving the CNS had a significantly better survival than patients with non-CNS EML or patients with CNS leukemia at diagnosis. This should reassure clinicians caring for these often challenging patients.

Polymorphisms in the MGMT Gene as Predictors of Leukemia Risk and Response to Therapy in Children with AML.

Approximately 40% of patients treated with chemotherapy for pediatric AML will relapse after initial treatment and 8–10% will die of toxic side effects of chemotherapy. This highly variable response to standardized treatment protocols is due in part to genetic variation among patients in the metabolism of chemotherapeutic agents and in the response to the DNA damage they induce. We have analyzed polymorphisms in the coding region of the DNA alkylation repair gene O6-Methylguanine-DNA Methyltransferase (MGMT) in 356 patients with de novo pediatric AML to determine whether naturally occurring MGMT variant alleles correlate with leukemia susceptibility, treatment efficacy, and the incidence of adverse effects of chemotherapy. The polymorphism rs2308321 (Ile143Val) has been shown to modify biochemical properties of the MGMT protein, with altered substrate specificity of the rare valine allele (G genotype) compared with the isoleucine allele (A genotype) (Margison et al, Carcinogenesis , 26;1473, 2005). All patients were treated on Children's Cancer Group protocols 2941 and 2961. Outcomes were examined stratified by genotype. All patients received intensively timed induction therapy with IDA-DCTER (idarubicin, dexamethasone, Ara-C, thioguanine, etoposide and daunomycin) given on days 0 to 3 followed by DCTER given on days 10 to 13. On recovery of ANC and platelet counts, patients were randomized to consolidation therapy with a further course of IDA-DCTER/DCTER or IDA-FLAG (idarubicin, fludarabine, Ara-C and G-CSF). Patients received intensification with a single course of high dose Ara-C and L-asparaginase unless a family donor was available when allogeneic transplant was performed after busulfan and cyclophosphamide. Black children were significantly more likely to have a homozygous wild-type AA genotype than white children (p=0.002). When compared to a healthy control population, there was no correlation between MGMT polymorphisms and the risk of AML overall. However, in a case-case comparison of genetic sub-types of AML, children with a variant allele (AG or G/G genotype) were significantly more likely to have monosomy 7 than AA cases (9% vs 1%; p=0.01); in contrast, children with trisomy 8 were significantly more likely to have an AA genotype (8% vs 0%; p=0.028). The presence of at least one G allele was associated with a significant reduction in the incidence of relapse. There was no effect on treatment-related mortality (TRM). In a multivariate Cox model adjusted for race, the increased risk of relapse (RR) associated with the variant G allele remained significant (hazard ratio 1.72 95% CI 1.03–2.86; p=0.037). These results suggest that genotyping at the rs2308321 polymorphism in the MGMT gene could be useful in the risk stratification of patients with AML prior to therapy.A/AA/G+G/GN% ± 2 SEN% ± 2 SEp-value5yr OS from end of course 128054 ± 67671 ± 110.0315yr RR from end of course 128043 ± 67627 ± 110.0145yr TRM from end of course 128014 ± 47614 ± 80.11

Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCG-E08

Among pediatric non-Hodgkin lymphomas, one of the most frequent types is lymphoblastic lymphoma (LBL). Specific chromosome abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia, but have not been evaluated for prognostic value in pediatric LBL. For the Children's Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, 13 patients were enrolled with cytogenetic analysis of LBL and on treatment protocol CCG-502. Pathology material and karyotypes at initial diagnosis were given central review. The patients were aged 6–13 years (median 9 years), with a male-to-female ratio of 12:1. All patients had advanced disease. Disease relapsed in six patients (event-free survival 54% ± 14%, median 10.8 years). Chromosome abnormalities were identified in 11 (85%), and translocations at 14q11.2 likely involving the T-cell receptor α/δ locus (TCR A/D) occurred in 4 (31%). For patients with relapse, four had translocations t(1;14)(p32;q11.2), t(8;14)(q24.1;q11.2), t(11;14)(p13;q11.2), or t(9;17)(q34;q23), involving breakpoints in the regions of TAL1, MYC, LMO2, and NOTCH1, respectively. Pediatric advanced LBLs have a high frequency of chromosome abnormalities; in this limited study, these often involved translocations at 14q11.2, the site of TCR A/D. Translocations possibly involving TAL1, MYC, LMO2, or NOTCH1 may have contributed to poor outcome. Further studies are warranted in larger cohorts of children and adolescents with LBL to evaluate the prognostic significance.

Complex secondary chromosome abnormalities in advanced stage anaplastic large cell lymphoma of children and adolescents: a report from CCG-E08

Among pediatric non-Hodgkin lymphomas, one of the most distinctive types is anaplastic large cell lymphoma (ALCL). Specific chromosomal abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia, but chromosome abnormalities have not been evaluated for prognostic value in pediatric ALCL. For Children's Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, three patients were enrolled with cytogenetic analysis of ALCL and simultaneously enrolled on treatment protocol CCG-552. Pathology material and karyotypes at initial diagnosis underwent central review. Demographics included ages of 9, 12, and 14 years, and a male/female ratio of 1:2. All patients had advanced disease (stage III). Disease progressed or relapsed in two patients, and one died. Chromosomal abnormalities, including t(2;5)(p23;q35), the ALK/NPM fusion gene, and complex karyotypes with multiple additional abnormalities, were identified in all three patients. In two patients with progressive disease or relapse, additional chromosomal abnormalities at 1q21 and 10q24, possibly involving MCL1 and HOX11/ TCL3, respectively, may have contributed to worse outcome. Pediatric ALCL cases frequently have complex karyotypes and usually involve ALK/NPM translocations in this limited study. Additional chromosome abnormalities may be involved in the pathogenesis of ALCL. Further studies are warranted in larger cohorts of children and adolescents with ALCL.

Cytidine Deaminase Genotype Modifies the Toxicity of Therapy for Childhood AML.

Cytosine arabinoside (Ara-C), given at standard or high dose, is an important component of AML therapy. A major catabolic pathway of Ara-C is deamination by cytidine deaminase (CDD) to the non-toxic metabolite uridine arabinoside. A non-synonymous single nucleotide polymorphism, A79C, in CDD changes a lysine residue to glutamine. In-vitro studies indicate reduced activity of the variant glutamine allele compared with the lysine allele. We hypothesized that children with the low activity CC CDD genotype would have increased toxicity of Ara-C based therapy for AML. CDD A79C genotype frequencies were determined for 457 children with de novo AML treated on Children's Cancer Group protocols 2941 and 2961. Outcomes were examined stratified by genotype. All patients received intensively timed induction therapy with IDA-DCTER (idarubicin, dexamethasone, Ara-C (800 mg/m2 total dose), thioguanine, etoposide and daunomycin) given on days 0 to 3 followed by DCTER given on days 10 to 13. On recovery of ANC and platelet counts, patients were randomized to consolidation therapy with a further course of IDA-DCTER/DCTER or IDA-FLAG (idarubicin, fludarabine, Ara-C (7590 mg/m2 total dose Ara-C) and G-CSF). Patients received intensification with a single course of high dose Ara-C (24,000 mg/m2 total dose) and L-asparaginase unless a family donor was available when allogeneic transplant was performed.Genotype frequencies did not differ according to WBC at diagnosis, FAB group, cytogenetics or gender. The CDD variant C allele was more frequent in white children (36%) compared with black (9%), Hispanic (26%) and Asian children (11%), p= 0.00002. No significant differences in overall survival (OS) or event-free survival (EFS) were observed according to CDD genotype (5 yr OS 52 ± 7% for AA, 46 ± 8% for AC, 55 ± 15% for CC; p=0.56), (5 year EFS 40 ± 7% AA, 37 ± 7% AC, 41 ± 15% CC; p=0.90). However cumulative incidence of treatment related mortality (TRM) after two courses of chemotherapy was significantly elevated in children with the low activity CC genotype compared with AA and AC genotypes (5 year TRM 17 ± 13% CC (n=36) vs 7 ± 4% AA, 5 ± 4% AC (n=257), p= 0.019), reflecting events during intensification when the large majority of Ara-C therapy was given (24,000 mg/m2). TRM after 2 courses of chemotherapy, analyzed according to prior randomized therapy, was significantly increased in those children randomized to IDA-FLAG consolidation (5 year TRM 24 ± 20% CC vs 6 ± 6% AA, 6 ± 6% AC, p=0.017) but the increase was not statistically significant in those randomized to IDA-DCTER/DCTER prior to intensification (5 year TRM 15 ± 20% CC vs 8 ± 6% AA, 4 ± 6% AC; p=0.261). Relapse-free survival was increased in children with the CC genotype treated with IDA-FLAG but this was not statistically significant (76 ± 20% CC vs 59 ± 12% AA and 55 ± 14% AC; p= 0.104). These data suggest that children with a low activity CDD genotype are at increased risk of treatment-related mortality when treated with Ara-C based therapy for AML.

A SERPINE1 (PAI-1) Single Nucleotide Polymorphism Predicts Osteonecrosis in Children Treated for Acute Lymphoblastic Leukemia: Results of the Children's Oncology Group (COG) Study AALL03B2.

As intensity of glucocorticoid use has increased, osteonecrosis has become an increasingly frequent complication of modern intensive chemotherapy for pediatric patients with acute lymphoblastic leukemia (ALL). Although patient age > 10 years is a well-known risk factor, other host risk factors that may predispose to this complication are not well described. We tested whether 12 polymorphisms in 11 candidate genes were associated with osteonecrosis among up to 344 patients ≥ 10 years old treated on the Children's Cancer Group protocol CCG 1882 for newly diagnosed high-risk ALL, adjusting for gender, age, and treatment arm (augmented versus standard treatment). Genes tested (TYMS, ER, MTHFR, ABCB1, BGLAP (osteocalcin), ACP5, LRP5, ESR, SERPINE1, VDR, PTH, and PTHR) were chosen because they are candidates based on the putative mechanisms underlying osteonecrosis risk, including involvement in antifolate pharmacodynamics, drug pharmacokinetics, thrombosis risk, and possible hormonal influence on glucocorticoid effects. All children received dexamethasone during the delayed intensification phase of therapy, with doses varying by treatment arm (one dexamethasone pulse in the standard chemotherapy arm vs. two dexamethasone pulses in the augmented chemotherapy arm). Of the 11 candidate polymorphisms, a single nucleotide polymorphism (dbSNP rs6092) in the SERPINE1 gene (plasminogen activator inhibitor type 1 or PAI-1) was the only polymorphism associated with an increased risk of osteonecrosis in both univariate (p=0.0039) and multivariate (p=0.0019) analyses (adjusting for gender, age, and treatment arm), with an odds ratio of 2.51 (95% CI 1.32 to 4.74). Overall, 23.9% of the 88 children heterozygous or homozygous for the SERPINE1 T allele, versus 11.1% of the 234 children homozygous for the C allele, developed osteonecrosis. The combined CT or TT genotypes were present in a greater percentage (27%) of whites than in blacks (12%, p = 0.016), consistent with a higher risk (p = 0.003) of osteonecrosis in whites than blacks that was originally reported for CCG-1882 (J Clin Oncol 18:3262–72, 2000). In a multivariate analysis, only the SERPINE1 polymorphism and sex predicted AVN, with the incidence of osteonecrosis lower in boys (odds ratio 0.49, 95% confidence interval 0.25 to 0.96, p = 0.034). No statistically significant gene-gene interactions between SERPINE1 and any other tested genotype were noted. SERPINE1 polymorphisms and PAI-1 serum levels have previously been associated with a clinical pro-thrombotic state. We conclude that polymorphisms in SERPINE1 may contribute to the risk of osteonecrosis in patients treated with glucocorticoids.

Favorable Prognosis for Patients 12 to 18 Months of Age With Stage 4 Nonamplified MYCN Neuroblastoma: A Children's Cancer Group Study

The long-term survival of children between age 12 and 24 months with stage 4 neuroblastoma and nonamplified MYCN (MYCN-NA) has not been defined previously. Survival for stage 4 MYCN-NA neuroblastoma patients enrolled onto Children's Cancer Group (CCG) protocols 321P2 (1986 to 1991) and 3891 (1991 to 1996) was analyzed. Treatment consisted of intensive alkylator-based induction chemotherapy with or without autologous bone marrow transplantation (ABMT) with or without 13 cis-retinoic acid. Survival was analyzed by age strata less than 12, 12 to 18, 18 to 24, and more than 24 months at diagnosis. Patients younger than 12 months were treated on the moderate-intensity CCG protocol 3881. Forty-three patients with stage 4 MYCN-NA disease enrolled onto CCG-321P2 (n = 17) or CCG-3891 (n = 26) were between 12 and 24 months of age at diagnosis. After a median follow-up of 94 months (range, 4 to 140 months), the 6-year event-free survival (EFS) for the 12- to 18-month age group was superior to that of the 18- to 24-month age group (74% +/- 8% v 31% +/- 12%; P = .008). The EFS for children older than 24 months with stage 4 MYCN-NA neuroblastoma was 23% +/- 3%, and for children younger than 12 months was 92% +/- 3%. Children diagnosed with stage 4 MYCN-NA neuroblastoma in the second year of life form a transitional group between infants and older children in terms of prognosis. Patients between 12 and 18 months of age have significantly better long-term survival than that of older children treated with intensive chemotherapy with or without ABMT. These patients may not benefit from additional intensification of therapy beyond that provided in earlier clinical trials and may even maintain this high survival rate with less intensive therapy.

Cognitive and Adaptive Outcome in Low-Grade Pediatric Cerebellar Astrocytomas: Evidence of Diminished Cognitive and Adaptive Functioning in National Collaborative Research Studies (CCG 9891/POG 9130)

Clinicians often assume that children with posterior fossa tumors are at minimal risk for cognitive or adaptive deficits if they do not undergo cranial irradiation. However, small case series have called that assumption into question, and have also suggested that nonirradiated cerebellar tumors can cause location-specific cognitive and adaptive impairment. This study (1) assessed whether resected but not irradiated pediatric cerebellar tumors are associated with cognitive and adaptive functioning deficits, and (2) examined the effect of tumor location and medical complications on cognitive and adaptive functioning. The sample was composed of 103 children aged 3 to 18 years with low-grade cerebellar astrocytomas, who underwent only surgical treatment as part of Children's Cancer Group protocol 9891 or Pediatric Oncology Group protocol 9130. The sample was divided into three groups based on primary tumor location: vermis, left hemisphere, or right hemisphere. Data were collected prospectively on intelligence, academic achievement, adaptive skills, behavioral functioning, and pre-, peri-, and postsurgical medical complications. The sample as a whole displayed an elevated risk for cognitive and adaptive impairment that was not associated consistently with medical complications. Within this group of children with cerebellar tumors, tumor location had little effect on cognitive, adaptive, or medical outcome. We did not replicate previous findings of location-specific effects on cognitive or adaptive outcome. However, the elevated risk of deficits in this population runs contrary to clinical lore, and suggests that clinicians should attend to the functional outcomes of children who undergo only surgical treatment for cerebellar tumors.

Significance of HOX11L2/TLX3 expression in children with T-cell acute lymphoblastic leukemia treated on Children's Cancer Group protocols

Significance of HOX11L2/TLX3 expression in children with T-cell acute lymphoblastic leukemia treated on Children's Cancer Group protocols

Fusion of SFQP to ABL in a Patient with a T(1;9)(p34;q34) and Acute Lymphocytic Leukemia.

We have investigated a child who presented with pre-B ALL and an acquired t(1;9)(p34;q34). BCR-ABL was not detected by RT-PCR or FISH analysis, however FISH did indicate that the ABL gene at 9q34 was disrupted. To identify the putative partner locus in this case, a modified 5′RACE strategy was employed that selected against normal ABL transcripts. Several clones were recovered in which ABL was fused to SFPQ (also known as PSF), a gene mapping to 1p34 that encodes a polypyrimidine tract-binding protein-associated splicing previously identified as a fusion partner of the helix-loop-helix transcription factor TFE3 in papillary renal cell carcinomas. Both SFPQ-ABL and reciprocal ABL-SFPQ transcripts were detectable by RT-PCR, and disruption of these two genes was further confirmed by amplification and sequencing of the forward genomic breakpoint. SFPQ-ABL, the likely oncogenic product, is predicted to encode a protein that retains the coiled coil domain of SFPQ and the entire tyrosine kinase domain and C-terminal sequences of ABL. The breakpoint in ABL was downstream of that seen for other ABL fusion genes and the chimeric protein is predicted to lack the ABL-encoded SH3 domain and part of the SH2 domain. The patient was treated according to the Children's Cancer Group Protocol 1961 and subsequently received augmented BFM therapy with doxorubicin and double delayed intensification. He achieved complete remission but suffered extramedullary testicular relapse at 4.5 years. Following orchiectomy and intensive chemotherapy he remains in complete remission more than 6 years after diagnosis. We conclude that SFPQ-ABL is a novel fusion gene associated with ALL. Although the patient here responded to conventional chemotherapy, SFPQ-ABL is likely to be sensitive to imatinib and use of this agent might be considered in further cases.

Biology-Driven Classification of Childhood Acute Lymphoblastic Leukemia: A Combined Analysis of Prognostic Markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG).

Risk adapted therapy, tailoring treatment to the likelihood of relapse, has constituted a significant advance in the treatment of childhood ALL. The recent merger of the POG and CCG provided an opportunity to reassess previous approaches and to develop a new biology driven classification system based on data from both legacy groups. All children (age 12 months to 21.99 years) with newly diagnosed B-precursor (ALL), consecutively enrolled on CCG (December 1988 to August 1995, N = 3056) and POG (January 1986 to November 1999, N = 6800) protocols, were evaluated for the impact of numerous clinical and laboratory variables on event free survival at 5 and 8 years in each group separately, thereby superseding differences in treatment approaches. Infants and patients with a T- cell phenotype were excluded from the analyses. Very high risk was defined as the group for which myeloablative therapy might be indicated with an anticipated 5 year EFS <45%, while a reduction in therapy could be justified for the lowest risk patients with a >85% 5 year EFS. Patients identified as being at very high risk for relapse had hypodiploidy (<45 chromosomes) (CCG 34.8%, POG 46.5% - 5 year EFS), induction failure (CCG 11.3% 5 year EFS) or t(9;22) or BCR/ABL (POG 27.5%, CCG 29.6% 5 year EFS). Patients identified as low risk for relapse were NCI standard risk patients with either t(12;21) (TEL-AML1) (CCG 86%, POG 85% 5 year EFS) or all three trisomies of 4, 10, and 17 (CCG 91.5%, POG 89.3% 5 year EFS). Certain NCI high risk patients were identified as having a higher risk for relapse but did not fall into the VHR category: t(4;11)(POG 49.9%, CCG 50.0% 5 year EFS),CNS3 (CCG 59.3%, POG 67.8% 5 year EFS) and slow early response (SER) defined by M2/3 at day 14 (Standard risk 66% SER versus 84% and for high risk ALL 63% SER versus 75%). Other potential VHR factors that require confirmation included, slow early responder t(4;11) (CCG 11.1% 5 year EFS) and monosomy 7 (CCG 44%, POG 66.6% 5 year EFS). A balanced t(1;19) had only a minor unfavorable effect on EFS. The COG has identified a risk classification system that builds on the previous NCI risk classification system for childhood ALL, incorporating the cytogenetic and molecular genetic features of the blasts, as well as rapidity of clinical response. The division of B-precursor ALL patients into low risk (18%), standard risk (49%), high risk (30%) and very high risk (3%) groups will : 1) identify those patients for whom therapy might be reduced without sacrificing overall cure rates, 2) determine those patients who will require intensified therapy and 3) suggest underlying biological pathways that mediate cure or treatment failure.

Chromosome abnormalities may correlate with prognosis in Burkitt/Burkitt-like lymphomas of children and adolescents: a report from Children's Cancer Group Study CCG-E08.

Among pediatric non-Hodgkin lymphomas, the most frequent type is small noncleaved-cell lymphoma (including Burkitt and Burkitt-like). Specific chromosome abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia (ALL); however, chromosome abnormalities have not been evaluated for prognostic value in pediatric Burkitt and Burkitt-like lymphomas. For Children's Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, 19 patients were enrolled with cytogenetic analysis of Burkitt or Burkitt-like lymphoma and simultaneously enrolled on treatment protocols CCG-503 or CCG-552. Pathology material and karyotypes at initial diagnosis underwent central review. Demographics included an age range of 2 to 14 years (median 8 years) and a male:female ratio of 14:5. All patients had advanced disease (stages III and IV, or ALL). Disease relapsed in five patients (event-free survival 74%, median follow-up 10.4 years). Chromosome abnormalities were identified in 18 patients (95%) including t(8;14)(q24.1;q32) in 12 (63%); t(8;22)(q24.1;q11.2) in 1 (5%); partial duplication of 1q in 7 (37%); and 13q32 abnormalities in 2 (11%). In patients who had relapses, in addition to the t(8;14)(q24. ;q32), two had abnormalities of 13q32 and two had partial duplication of 1q. CMYC translocations were absent in Burkitt-like lymphomas from all three patients. Burkitt and Burkitt-like lymphomas in children have a high frequency of chromosome abnormalities. Burkitt lymphoma abnormalities often involve CMYC translocations, usually a t(8;14)(q24.1;q32). Additional chromosome abnormalities that involved 13q32 and partial duplication of 1q were associated with poor prognosis. Burkitt-like lymphomas were not associated with CMYC translocations. Further studies are warranted in larger cohorts of children and adolescents with Burkitt and Burkitt-like lymphomas.