Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232.

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 MRD <0.01% 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 MRD >0.1% 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.

Increased post-induction intensification improves outcome in children and adolescents with a markedly elevated white blood cell count (≥200 × 10(9) /l) with T cell acute lymphoblastic leukaemia but not B cell disease: a report from the Children's Oncology Group.

Children and adolescents presenting with a markedly elevated white blood cell (ME WBC) count (WBC ≥200 × 10(9) /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 <200 × 10(9) /l (5-year event-free survival 62% vs. 73%, P = 0·0005). Longer duration of therapy worsened outcome for T cell ME WBC with a trend to poorer outcome in B-ALL ME WBC patients. Augmented therapy benefits T cell ME WBC patients, similar to the entire study cohort, however, there appeared to be no impact on survival for B-ALL ME WBC patients. ME WBC was not a prognostic factor for T cell patients. In patients with high risk features, B lineage disease in association with ME WBC has a negative impact on survival.

Osteonecrosis in childhood ALL.

Kawedia et al report a 71% incidence of osteonecrosis (ON) in a cohort of children and young adult acute lymphoblastic leukemia (ALL) patients who underwent routine magnetic resonance imaging (MRI) screening at various time points on study. A majority of cases were asymptomatic. Older age, increased treatment intensity, low serum albumen, elevated lipid levels, and decreased dexamethasone clearance were risk factors associated with an increased incidence of osteonecrosis.

Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group.

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.

Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial.

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<0·0001) and sex of the patients aged 10-21 years (girls 15·7% [2·5] 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.

Impact of low-dose involved-field radiation therapy on pediatric patients with lymphocyte-predominant Hodgkin lymphoma treated with chemotherapy: a report from the Children's Oncology Group.

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.

The optimal use of steroids in paediatric acute lymphoblastic leukaemia: no easy answers.

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.

A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children's Oncology Group.

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.

Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy.

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

Extracorporeal membrane oxygenation after stem cell transplant: clinical decision-making in the absence of evidence.

OBJECTIVE: To discuss the ethical dilemmas that arise in considering innovative therapies for critically ill children when there is little data to support their use. DESIGN: Case report of a 13-yr-old patient after autologous peripheral blood stem cell transplant for stage III neuroblastoma with sepsis and hemodynamic instability who survived to discharge after a 6-day course of extracorporeal membrane oxygenation (ECMO) support. The case serves as a source of discussion of the following: the use of available data in deciding to proceed with an unproved therapy, the approach to conversations to obtain informed consent, and the need for institutional oversight and hypothesis-driven data collection to advance pediatric critical care. SETTING: Pediatric intensive care unit at a university hospital. PATIENT: One adolescent with stage III neuroblastoma. RESULTS: Despite a lack of data to support the use of ECMO in a neutropenic oncology patient after autologous peripheral blood stem cell transplant, our patient had clinical features that suggested he was a reasonable ECMO candidate. His family gave informed consent to use ECMO and he survived. It is ethical to consider and use innovative therapies when patient characteristics are suggestive that the therapy may be successful even in the absence of evidence. This requires physicians' attention to the best interest of the patient and should occur in the setting of informed consent and rigorous data collection. CONCLUSIONS: The boundaries among standard therapy, innovative therapy, and research can be quite fluid. This case illustrates the ethical imperative to consider therapies that may be appropriate for a critically ill child even without evidence predictive of success, to have entry criteria and treatment protocols for such therapies, and to collect data from such experiences to advance the standard of care.

Adolescents with acute lymphoblastic leukemia: a new "age".

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

What is the best treatment for children with limited-stage Hodgkin lymphoma?

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.

Young adults with acute lymphoblastic leukemia have an excellent outcome with chemotherapy alone and benefit from intensive postinduction treatment: a report from the children's oncology group.

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 > or = 50,000/microL and/or age > or = 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/microL 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.

Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group.

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 x 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/mm3 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.

Stem cell transplantation in pediatric leukemia and myelodysplasia: state of the art and current challenges.

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.

Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia.

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.

Thrombocytopenia in children with severe iron deficiency.

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

Abnormalities of chromosome bands 15q13-15 in childhood acute lymphoblastic leukemia.

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.