Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group

We sequenced 120 candidate genes in 187 high-risk childhood B-precursor acute lymphoblastic leukemias, the largest pediatric cancer genome sequencing effort reported to date. Integrated analysis of 179 validated somatic sequence mutations with genome-wide copy number alterations and gene expression profiles revealed a high frequency of recurrent somatic alterations in key signaling pathways, including B-cell development/differentiation (68% of cases), the TP53/RB tumor suppressor pathway (54%), Ras signaling (50%), and Janus kinases (11%). Recurrent mutations were also found in ETV6 (6 cases), TBL1XR1 (3), CREBBP (3), MUC4 (2), ASMTL (2), and ADARB2 (2). The frequency of mutations within the 4 major pathways varied markedly across genetic subtypes. Among 23 leukemias expressing a BCR-ABL1-like gene expression profile, 96% had somatic alterations in B-cell development/differentiation, 57% in JAK, and 52% in both pathways, whereas only 9% had Ras pathway mutations. In contrast, 21 cases defined by a distinct gene expression profile coupled with focal ERG deletion rarely had B-cell development/differentiation or JAK kinase alterations but had a high frequency (62%) of Ras signaling pathway mutations. These data extend the range of genes that are recurrently mutated in high-risk childhood B-precursor acute lymphoblastic leukemia and highlight important new therapeutic targets for selected patient subsets.     

Prognostic factors in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.

Two hundred fifty-three children with newly diagnosed T-cell acute lymphoblastic leukemia (ALL), who were treated uniformly with modified LSA2L2 therapy, were evaluated using univariate and recursive partition analyses to define clinical or biologic features associated with risk of treatment failure. Overall event-free survival (EFS) at 4 years was 43% (SE = 4%). Factors examined included white blood cell (WBC) level, age, gender, race (black v other), presence of a mediastinal mass, hepatomegaly, splenomegaly, marked lymphadenopathy, hemoglobin level, platelet count, blast cell expression of antigens such as the common acute lymphoblastic leukemia antigen (CALLA, CD10), HLA-DR, and T-cell-associated antigens (CD3, CD4, CD8, CD7, CD5, and THY). Univariate analysis showed that age less than or equal to 5 or less than or equal to 7 years, WBC level less than 10, less than 25, less than 50 or less than 100 x 10(3)/microL, and blast cell expression of CD4, CD8, or CALLA were associated with significantly better EFS, while hepatomegaly and splenomegaly were associated with worse EFS. Recursive partitioning analysis showed that the most important single favorable prognostic factor was a WBC level less than 50 x 10(3)/microL and, for patients with WBC counts below this level, the most important predictor of EFS was blast cell expression of the pan-T antigen defined by the monoclonal antibody (MoAb), L17F12 (CD5). For patients with higher WBC levels, the most important predictor of EFS was blast cell expression of THY antigen. The recursive partitioning analysis defined three groups of patients with widely varied prognoses identified as follows: (1) those with a WBC count less than 50 x 10(3)/microL who lacked massive splenomegaly and had blasts expressing CD5 had the best prognosis (66%, SE = 7%, EFS 4 years, n = 84); (2) those with (b1) WBC counts less than 50 x 10(3)/microL with either massive splenomegaly or who had blasts lacking CD5 expression, or (b2) WBC counts greater than 50 x 10(3)/microL with expression of the THY antigen had an intermediate prognosis (39%, SE = 7% EFS at 4 years, n = 94); (3) those with WBC counts greater than 50 x 10(3)/microL and whose blasts lacked expression of THY antigen had the poorest outcome (EFS = 19% at 4 years, SE = 8%, n = 63). A three-way comparison of EFS according to these groupings showed significant differences among the three patient groups (P less than .001). The recursive partitioning was able to classify 241 (95%) of the patients.(ABSTRACT TRUNCATED AT 400 WORDS)     

Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study

Children with acute lymphoblastic leukemia (ALL) who have completed 2.5 to 3 years of initial chemotherapy have an off-therapy relapse rate of approximately 20%. In an attempt to improve the survival of children with a late bone marrow (BM) relapse (ie, occurring greater than 6 months after cessation of primary therapy), the Pediatric Oncology Group designed a randomized study to compare the efficacy of doxorubicin/prednisone and cytarabine/teniposide in a multidrug retreatment chemotherapy program. Treatment consisted of remission reinduction with vincristine, prednisone, and doxorubicin, central nervous system prophylaxis with triple intrathecal chemotherapy, and continuation therapy (for 132 weeks) with alternating cycles of oral 6- mercaptopurine/methotrexate and intravenous vincristine/cyclophosphamide. Patients received intermittent courses of either prednisone/doxorubicin (regimen 1) or teniposide/cytarabine (regimen 2) during continuation therapy and a late intensification phase with either vincristine, prednisone, and doxorubicin (regimen 1) or teniposide and cytarabine (regimen 2). One hundred two of 105 evaluable patients (97%) achieved a second complete remission. Twenty- eight of 50 patients on regimen 1 have failed compared with 28 or 52 patients on regimen 2 (log-rank analysis, P = .68), indicating that this trial was inconclusive as to which treatment regimen was superior. The overall 4-year event-free survival for children with a late BM relapse was 37% +/- 6%. Age less than 10 years at initial diagnosis (P < or = .001), white blood cell count less than 5,000/microL at relapse (P = .036) and duration of first remission greater than 54 months (P = .039) were independently associated with a more favorable outcome. While the randomized trial was inconclusive, prolonged second complete remissions were secured in more than one-third of children with a late BM relapse of ALL. The prognostic factors identified may help select children with a late BM relapse who can be successfully retreated with chemotherapy alone.     

Trisomy 21 in childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study (8602)

Of 1,036 children with newly diagnosed non-T, non-B acute lymphoblastic leukemia (ALL) and a demonstrated cytogenetic abnormality treated on the frontline Pediatric Oncology Group (POG) therapeutic trial 8602, there were 33 patients with trisomy 21 as the sole abnormality. Of these 33, 14 had Down syndrome (DS). Although the non-DS (NDS) trisomy 21 cases tended to be older than the DS cases, there were no other significant differences in clinicobiologic features nor in treatment outcomes between the DS and NDS groups, nor between the entire trisomy 21 group and the other chromosome abnormality group. Among NDS patients with +21 and one additional abnormality, +X, +16, -20, and structural abnormalities involving 6q or 12p were common findings. Kaplan-Meier event-free survival (EFS) curves showed a 4-year EFS of 80% (SE, 12%) in NDS trisomy 21 cases, 71% (SE, 22%) in DS cases with trisomy 21 as the sole abnormality, and 69% (SE, 2%) in cases with other chromosome abnormalities. Trisomy 21 as a sole acquired abnormality in NDS patients suggests a good prognosis.     

Philadelphia chromosome and monosomy 7 in childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study

During an 8-year period, 3,638 children from institutions of the Pediatric Oncology Group (POG) were diagnosed with acute lymphoblastic leukemia (ALL). Fifty-seven patients had Philadelphia chromosome-positive (Ph1) ALL. Blast cells obtained at diagnosis from 13 of these 57 cases (23%) were also found to have partial or complete monosomy 7 (-7). This subgroup of children with Ph1/-7 ALL was comprised primarily of older males with early B-lineage ALL. Bone marrow specimens from six Ph1/-7 patients were studied further using the polymerase chain reaction and primers that flank the ALL, and chronic myelogenous leukemia breakpoints to determine the molecular characteristic of the 9;22 translocation. Rearrangements were detected in RNA from bone marrow and/or peripheral blood cells of six patients, although four were in hematologic remission at the time of the analysis. Five cases showed the ALL breakpoint, while one child with Ph1/-7 showed the chronic myelogenous leukemia breakpoint. The induction failure rate was much higher in this subgroup (31%) as compared with Ph1-negative cases, and the projected duration of event-free survival reflected the aggressive nature of this subgroup because no children are projected to remain in remission at 2 years. ALL with both the 9;22 translocation and -7 appears to represent a unique and previously undescribed subgroup of childhood ALL associated with a particularly adverse outcome. Leukemic transformation in such patients may involve the interaction of a dominant oncogene (Ph1) and a tumor suppressor gene (-7).     

Late effects in survivors of childhood acute lymphoblastic leukemia: a study from Thai Pediatric Oncology Group

Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk of long-term late effects. Therefore, systematic screenings of the late complications are essential. The objective of this study was to determine the prevalence of late effects of Thai children and adolescents after completion of ALL therapy. We performed a cross-sectional study for evaluation of the late effects in ALL survivors who came for follow-up at 10 pediatric oncology centers in Thailand. We evaluated the treatment-related late complications of children and adolescents who had finished ALL treatment for at least 2 years. Demographic data, treatment modalities, and late effects were recorded and analyzed. There were 258 survivors with a median age of 12.2 years (range 3.6–23.3 years). The median follow-up time was 7.2 years (range 2–17.5 years). Forty-seven percent (122 cases) suffered from at least one late effect. Overweight/obesity was the most common late effect. Radiation of central nervous system was a significant risk factor for overweight/obesity (OR 1.97, 95% CI 1.02–3.81) and educational problems (OR 4.3, 95% CI 1.32–14.02). Our data have demonstrated a significant prevalence of late effects after childhood ALL therapy. A long-term follow-up program for survivors of childhood cancer is therefore needed in our country.     

Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201

Pediatric Oncology Group (POG) protocol 9201 enrolled children with lesser-risk B-lineage acute lymphoblastic leukemia (ALL) defined by age (1-9), white blood cell count (WBC) less than 50 x 10(9)/L (50,000/microL), DNA findings of trisomies 4 and 10 (or DNA index > 1.16), and lack of overt central nervous system (CNS) leukemia. After vincristine, prednisone, and asparaginase induction, 650 of 653 eligible patients attained remission (3 induction deaths) and received 6 courses of intravenous methotrexate (1 g/m(2)) with daily mercaptopurine. Weekly intramuscular methotrexate was added during maintenance; pulses of vincristine and prednisone were administered with periodic intrathecal chemotherapy. Treatment duration was 2.5 years. No alkylators, epipodophylotoxins, anthracyclines, or radiation were given. The 6-year event-free survival (EFS) was 86.6% with overall survival (OS) of 97.2%. Patients with less than 5% marrow blasts on induction day 15 had superior EFS. A difference not reaching conventional statistical significance (P = .068) was noted for superior outcomes in patients with trisomies of chromosomes 4 and 10 versus those lacking double trisomies. Sex, ethnicity, CNS status, and WBC were not predictive. This indicates the great majority of children with lesser-risk B-lineage ALL are curable without agents with substantial late effects.     

Postrelapse survival in childhood acute lymphoblastic leukemia is independent of initial treatment intensity: a report from the Children's Oncology Group

While intensification of therapy has improved event-free survival (EFS) and survival in newly diagnosed children with acute lymphoblastic leukemia (ALL), postrelapse outcomes remain poor. It might be expected that patients relapsing after inferior initial therapy would have a higher retrieval rate than after superior therapy. In the Children's Oncology Group Study CCG-1961, significantly superior EFS and survival were achieved with an augmented (stronger) versus standard intensity regimen of postinduction intensification (PII) for children with newly diagnosed high-risk ALL and rapid day 7 marrow response (EFS/survival 81.2%/88.7% vs 71.7%/83.4%, respectively). This provided an opportunity to evaluate postrelapse survival (PRS) in 272 relapsed patients who had received randomly allocated initial treatment with augmented or standard intensity PII. As expected, PRS was worse for early versus late relapse, marrow versus extramedullary site, adolescent versus younger age and T versus B lineage. However, no difference in 3-year PRS was detected for having received augmented versus standard intensity PII (36.4% ± 5.7% vs 39.2% ± 4.1%; log rank P = .72). Similar findings were noted within subanalyses by timing and site of relapse, age, and immunophenotype. These findings provide insight into mechanisms of relapse in ALL, and are consistent with emergence of a resistant subclone that has acquired spontaneous mutations largely independent of initial therapy. This study is registered at www.clinicaltrials.gov as NCT00002812.     

Outcome after relapse in childhood acute lymphoblastic leukemia

Among 157 children with acute lymphoblastic leukemia (ALL) who experienced relapse at 54 institutes participating in the Japan Association of Childhood Leukemia Study, we analyzed the outcomes after relapse in 103 and 30 eligible cases with bone marrow (BM) and central nervous system (CNS) relapse, respectively. Reinduction rates in BM and CNS relapse cases were 72.3% and 83.3%, respectively. High reinduction rates were observed in B-precursor (B-pre) phenotype ALL in both relapse groups and in late (more than 24 months from onset) BM-relapse patients. After BM relapse, the overall 5-year survival rate was superior in the allogeneic stem cell transplantation (SCT) group compared to the non-SCT group (41.9%+/-8.2% versus 13.6%+/-6.5%, P < .0001). In contrast, the 4-year overall survival rate was not significantly different between the SCT (allogeneic plus autologous) and non-SCT groups after CNS relapse (26.8%+/-14.2% versus 61.9%+/-12.3%, P = .252). The late BM-relapse patients showed a significantly higher survival rate than did early-relapse patients, and survival rates were similar between the allogeneic and autologous group when the patients underwent SCT during a second complete remission. Moreover, B-pre ALL patients classified in the standard-risk group according to National Cancer Institute/Rome's criteria at onset had a good prognosis after allogeneic SCT. Improving the cure rate in relapsed ALL patients requires more intensive reinduction therapy and efforts to succeed with SCT in early BM-relapse patients as well as the establishment of a treatment strategy including indications of SCT for CNS-relapse patients.     

Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study

Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of event-free survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n = 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5-year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups.     

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study

Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Children's Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0.01% to 0.1% day-29 MRD had poor outcome compared with patients negative for MRD patients (59% +/- 5% vs 88% +/- 1% 5-year EFS). Presence of good prognostic markers TEL-AML1 or trisomies of chromosomes 4 and 10 still provided additional prognostic information, but not in National Cancer Institute high-risk (NCI HR) patients who were MRD(+). The few patients with detectable MRD at end of consolidation fared especially poorly, with only a 43% plus or minus 7% 5-year EFS. Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy. These studies are registered at www.clinicaltrials.gov as NCT00005585, NCT00005596, and NCT00005603.     

Ethnicity and survival in childhood acute myeloid leukemia: a report from the Children's Oncology Group

We evaluated differences in outcome by ethnicity among children with acute myeloid leukemia (AML). We analyzed 791 children in the CCG 2891 trial and confirmed positive findings in 850 children in the CCG 2961 trial. Hispanic and black children treated with chemotherapy in CCG 2891 had significantly inferior overall survival (OS) from study entry compared with white children (37%+/- 9% vs 48%+/- 4% [P = .016] and 34% +/- 10% vs 48% +/- 4%, [P = .007], respectively). Significantly fewer black children had related donors. Analyses of CCG 2961 confirmed that black children had significantly decreased OS rates compared with white children (45% +/- 12% vs 60% +/- 4%; P = .007) The difference in OS rates between Hispanic and white children approached statistical significance (51% +/- 8% vs 60% +/- 4%; P = .065) Only 7.5% of black children on CCG 2961 had an available family donor. In conclusion, Hispanic and black children with AML have worse survival than white children. Access to chemotherapy, differences in supportive care or leukemia phenotype, and reduced compliance are unlikely explanations for this difference because therapy was given intravenously according to CCG protocols. Fewer black children than expected had an available family marrow donor.     

Reinduction therapy in 297 children with acute lymphoblastic leukemia in first bone marrow relapse: a Pediatric Oncology Group Study

Many children with acute lymphoblastic leukemia (ALL) develop a marrow relapse during or shortly following initial continuation chemotherapy. Achievement of a second complete remission is the initial step in a successful retreatment effort. Reinduction results using two or three drugs have been unsatisfactory, and previous reports of four-drug reinduction programs have included relatively small numbers of patients. Pediatric Oncology Group protocol 8303 was designed for patients with ALL in first marrow relapse during or within 6 months after cessation of chemotherapy. The results of reinduction therapy in 297 study patients are described here. Four-drug reinduction therapy consisted of daily oral prednisone, weekly vincristine and daunorubicin, and asparaginase three times weekly for 4 weeks (PVDA). CNS retreatment consisted of two doses of triple intrathecal chemotherapy. Of the 297 patients receiving reinduction, 245, or 82%, entered second complete remission, six died of infection or progressive disease, and 46 others still had M2 or M3 bone marrow status. Forty of these latter patients received four doses (during a 2-week period) of teniposide and cytarabine, after which 13 (32%) achieved complete remission status. Thus, the overall second complete remission rate with PVDA with or without teniposide/cytarabine was 258 of 297, or 87%. The treatment program was generally well tolerated. Among the numerous factors analyzed by using logistic regression, only female sex (P = .035), the presence of blasts on the blood smear at the time of relapse (P = .0002), and a length of initial complete remission less than 12 months (P = .021) were independent predictors of failure to enter second remission. We conclude that the intensive reinduction program described here is a highly effective first step in the delivery of salvage therapy to patients with ALL in first marrow relapse. The current challenge is to develop improved continuation treatment for these children.     

Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group

Minimal residual disease (MRD) as a marker of antileukemic drug efficacy is being used to assess risk status and, in some cases, to adjust the intensity of therapy. Within known prognostic categories, the determinants of MRD are not known. We measured MRD by flow cytometry at day 8 (in blood) and at day 28 (in bone marrow) of induction therapy in more than 1000 children enrolled in Pediatric Oncology Group therapy protocols 9904, 9905, and 9906. We classified patients as "best risk" if they had cleared MRD by day 8 of therapy and as "worst risk" if they had MRD remaining in bone marrow at day 28, and tested whether MRD was related to polymorphisms in 16 loci in genes hypothesized to influence response to therapy in acute lymphoblastic leukemia (ALL). After adjusting for known prognostic features such as presence of the TEL-AML1 rearrangement, National Cancer Institute (NCI) risk status, ploidy, and race, the G allele of a common polymorphism in chemokine receptor 5 (CCR5) was associated with more favorable MRD status than the A allele (P = .009, logistic regression), when comparing "best" and "worst" risk groups. These data are consistent with growing evidence that both acquired and host genetics influence response to cancer therapy.     

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.     

Prognostic importance of the pre-B-cell immunophenotype and other presenting features in B-lineage childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study

We report the prognostic significance of the pre-B-cell immunophenotype and other presenting features, including blast cell karyotype, in a randomized clinical trial conducted from 1981 to 1986 for children with early pre-B (n = 685) or pre-B (n = 222) acute lymphoblastic leukemia (ALL). Patients greater than or equal to 1 year and less than or equal to 21 years of age who attained complete remission were stratified by conventional risk criteria and immunophenotype and then randomized to receive continuation therapy with either of two regimens of intensive chemotherapy, designated S (standard) and SAM (standard plus intermediate-dose methotrexate, 1 g/m2 every 8 weeks). The proportions of subjects achieving complete remission in the two phenotypically defined subgroups were identical, 96%. At a median follow-up time of 42 months, the overall probability of 4-year event-free survival (+/- SE) was 63% +/- 2% (pre-B = 51% +/- 5% and early pre-B = 66% +/- 3%). Children with pre-B ALL had significantly shorter durations of continuous complete remission (P = .0004); this association included both bone marrow and CNS remissions (P = .0004 and P = .02, respectively). In a univariate Cox regression analysis of potentially important prognostic factors, the pre-B immunophenotype was significantly related to a poorer outcome, as were other recognized biologic and clinical features (eg, pseudodiploidy, older age, male sex, black race, and a higher WBC). It retained its prognostic strength in a multivariate model based on age, WBC, ploidy, and sex. The risk of failure at any point in the clinical course of a child with the pre-B immunophenotype was 1.8 times as great as that in a patient lacking this feature but otherwise having an equivalent risk status. It should be stressed that the predictive value of any of the significant characteristics identified in this study could diminish in the context of another, more effective treatment program. Nevertheless, our major conclusion, that children with pre-B ALL fare worse than those with early pre-B disease in a contemporary clinical trial has implications for stratified randomization of patients and the design of risk- specific treatment protocols.     

Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia

Leukemic cells from 31 (7.6%) of 409 children with newly diagnosed acute lymphoblastic leukemia (ALL) had a hypodiploid karyotype. The patients' ages ranged from 0.8 to 17 years (median, 5 years) and their initial leukocyte counts from 1.0 to 132 X 10(9)/L (median, 12.7 X 10(9)/L). Modal chromosome numbers for the leukemic stem lines were 45 in 26 cases, 28 in two cases, and 26, 36 and 43 in one case each. Seven cases had one to three additional abnormal lines due to clonal evolution. Chromosome 20 was lost most frequently (nine cases). Structural abnormalities--including chromosomal translocations (21 cases), deletions (ten cases), duplications (two cases), or inversions (one case)--were common findings; the nonrandom translocations consisted of the t(1;19)(q23;p13.3) in two pre-B cases and tdic(9;12)(p1?1;p1?2) in three cases of common ALL. When compared with hyperdiploid cases (greater than 50 chromosomes), ALL with hypodiploidy was found to have a poorer outcome and was more likely to be associated with chromosomal translocations, higher serum lactic dehydrogenase levels, and age less than 2 or greater than or equal to 10 years. Moreover, patients with hypodiploid ALL fared as poorly as those with pseudodiploid karyotypes, even though their leukocyte counts and serum lactic dehydrogenase levels were lower and they had a comparable frequency of leukemic cell translocations. Hypodiploidy is therefore an unfavorable karyotypic feature in childhood ALL.     

Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group

The clinical and cytogenetic features associated with T-cell acute lymphoblastic leukemia (T-ALL) are not predictive of early treatment failure. Based on the hypothesis that microarrays might identify patients who fail therapy, we used the Affymetrix U133 Plus 2.0 chip and prediction analysis of microarrays (PAM) to profile 50 newly diagnosed patients who were treated in the Children's Oncology Group (COG) T-ALL Study 9404. We identified a 116-member genomic classifier that could accurately distinguish all 6 induction failure (IF) cases from 44 patients who achieved remission; network analyses suggest a prominent role for genes mediating cellular quiescence. Seven genes were similarly upregulated in both the genomic classifier for IF patients and T-ALL cell lines having acquired resistance to neoplastic agents, identifying potential target genes for further study in drug resistance. We tested whether our classifier could predict IF within 42 patient samples obtained from COG 8704 and, using PAM to define a smaller classifier for the U133A chip, correctly identified the single IF case and patients with persistently circulating blasts. Genetic profiling may identify T-ALL patients who are likely to fail induction and for whom alternate treatment strategies might be beneficial.     

Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children's Oncology Group study

As controversy exists regarding the prognostic significance of genomic rearrangements of CRLF2 in pediatric B-precursor acute lymphoblastic leukemia (ALL) classified as standard/intermediate-risk (SR) or high-risk (HR), we assessed the prognostic significance of CRLF2 mRNA expression, CRLF2 genomic lesions (IGH@-CRLF2, P2RY8-CRLF2, CRLF2 F232C), deletion/mutation in genes frequently associated with high CRLF2 expression (IKZF1, JAK, IL7R), and minimal residual disease (MRD) in 1061 pediatric ALL patients (499 HR and 562 SR) on COG Trials P9905/P9906. Whereas very high CRLF2 expression was found in 17.5% of cases, only 51.4% of high CRLF2 expressors had CRLF2 genomic lesions. The mechanism underlying elevated CRLF2 expression in cases lacking known genomic lesions remains to be determined. All CRLF2 genomic lesions and virtually all JAK mutations were found in high CRLF2 expressors, whereas IKZF1 deletions/mutations were distributed across the full cohort. In multivariate analyses, NCI risk group, MRD, high CRLF2 expression, and IKZF1 lesions were associated with relapse-free survival. Within HR ALL, only MRD and CRLF2 expression predicted a poorer relapse-free survival; no difference was seen between cases with or without CRLF2 genomic lesions. Thus, high CRLF2 expression is associated with a very poor outcome in high-risk, but not standard-risk, ALL. This study is registered at www.clinicaltrials.gov as NCT00005596 and NCT00005603.     

Cytogenetically different leukemic clones at relapse of childhood acute lymphoblastic leukemia

Sequential analysis of blast cell chromosomes in 98 cases of acute lymphoblastic leukemia (ALL) disclosed entirely different karyotypes for nine patients at the time of relapse. The presenting clinical, immunophenotypic, and cytogenetic features of this subgroup were similar to those of the 89 patients without major karyotypic shifts. The median length of initial remissions in these nine patients, all of whom received intensive multiagent therapy, was 24 months (range, 6 to 35); responses to subsequent treatment have been uniformly poor. Prominent cytogenetic changes included a gain of modal chromosome numbers in five cases, a loss of chromosomes in two, and the acquisition of an 11q23 rearrangement in three. We propose several different mechanisms to account for these findings. In one, the presence of an entirely different ALL karyotype at relapse may represent induction of secondary leukemia analogous to the well- described entity of epipodophyllotoxin-related secondary acute myeloid leukemia (AML).