Willman, Cheryl L.

Abstract Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1− B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non–risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.

Summary Late relapse [>3 years from complete remission (CR)] in acute lymphoblastic leukaemia (ALL), is unusual. Data from the MRC UKALLXII/ECOG E2993 trial are presented to evaluate the incidence and characteristics of late relapse in adult ALL. Of 1,909 patients, 1,752 (92%) achieved CR and among these 757 (43·2%) relapsed; 691 (91·3%) within three years and 66 (8·7%) beyond. Among these 66 patients, median time to relapse was 47 (37–144) months. Relapse beyond three years occurred in 3·8% of all who achieved CR. The cumulative risk of relapse was 40%, 43% and 45% at three, five and ten years respectively. Out of the 1 752 patients who achieved CR, 11·7% underwent autologous and 40·6% allogeneic transplant, while in CR1. Of the autologous patients, 43·2% relapsed early and 3·4% relapsed late. However, among the allogeneic patients, 13·2% relapsed early and only 1·3% late. The five‐year overall survival from relapse was 5·8% and 20% in the early and late relapse patients respectively. In conclusion, late relapse in adults with ALL is not uncommon, and is associated with better outcome after relapse compared to early relapse.

Abstract Early response to therapy, including assessment of MRD is a powerful prognostic factor in childhood ALL. However, there are many other known prognostic factors, and the precise relationship among these and MRD has been incompletely explored. In COG protocol P9900, patients were assigned to one of 3 risk-directed therapies based on NCI risk group, as well as TEL-AML1 translocations (TEL) and simultaneous trisomies of chromosomes 4 and 10 (DT). Infants and Ph+ patients were excluded. Good risk patients (9904) comprised NCI SR patients with either TEL or DT without CNS disease. Poor risk patients (9906) included a subset of NCI HR patients with particularly unfavorable risk factors based largely on age and white count, while 9905 had both NCI SR and HR patients not eligible for 9904 or 9906, including NCI HR patients with TEL or DT. MRD was satisfactorily measured with at least .01% sensitivity by 4-color flow cytometry in the marrow at end of induction (D29) or in blood at Day 8 (D8). D29 MRD was associated with poor outcome in all studies, and in both HR and SR patients on 9905 as shown: Study 4 y EFS ± SE (n) p value MRD <.01% MRD >.01% 9904 Overall 94±1%(668) 75±6%(105) <.0001 TEL-AML1 94±2%(367) 68±12%(38) <.0001 DT 95±1%(316) 80±7%(69) <.0001 9905 NCI-Standard Risk 89±2%(462) 63±6%(119) <.0001 9905 NCI-High Risk 83±4%(292) 49±9%(73) <.0001 9906 74±6%(156) 39±8%(84) <.0001 The proportion of D29 MRD positive DT(17.9%) patients was higher than that of TEL patients (9.4%) but MRD was also prognostic when each group was considered separately; similar findings were seen in HR TEL and DT patients. TEL or DT was associated with a significantly better prognosis in both HR and SR patients who were MRD negative, but were not favorable factors in MRD positive patients. D8 blood MRD was also prognostic in all studies, with higher MRD levels generally associated with poorer outcome. Patients who were both D29 and D8 MRD negative had a good outcome overall (93% 4 y EFS); combining all favorable risk factors, including TEL, DT, NCI risk group, D8 and D29 MRD identified a group of patients (about 13% of B-precursor ALL patients) with 98± 1% 4 y EFS. In multivariate analysis, D29 MRD was the most important prognostic factor. NCI Risk group, DT and D8 blood were also significant, but TEL and day 8 morphologic assessment of marrow were not. We conclude that MRD is a major prognostic factor in childhood ALL even accounting for other risk factors. The prognostic significance of TEL and DT depends on MRD status. The combination of good risk clinical and genetic factors, and absence of MRD in both D8 blood and D29 marrow identifies a group of patients with outstanding outcome on limited therapy.

Abstract Background: Retrospective analyses have demonstrated significantly improved survival for AYA ALL patients (pts) aged 16-21 years (yrs) when treated on pediatric versus adult U.S. NCI Cooperative group regimens where 2-yr event-free survivals (EFS) have been only 35-40%. The purpose of C10403, a large prospective US intergroup trial, was to evaluate the feasibility and effectiveness [with EFS as a primary endpoint), of treating AYA ALL pts (ages 16-39 yrs) using the standard arm of the successful Children's Oncology Group regimen (COG AALL0232) . Methods: Newly diagnosed AYA patients with B-precursor (B-ALL) or T-precursor (T-ALL) ALL were eligible to enroll on C10403. Burkitt type and Ph+ ALL were excluded. The regimen was identical to the Capizzi methotrexate arm of COG AALL0232 (Larsen E. JCO 2011; 29 suppl:3) and consisted of four intensive courses: remission induction, remission consolidation, interim maintenance, delayed intensification, and prolonged maintenance therapy. Pts with M2 marrow response (>5% but < 25% lymphoblasts) after remission induction received an extended remission induction course of therapy. Events were defined as induction failure (M3 [³25% blasts] day 29 of induction or M2 day 43 of extended induction), death, relapse, or second malignancy. Key correlative science studies in a subset of the total accrued population included assessment of Minimal Residual Disease (MRD) using quantitative real-time PCR of clonal IgH or TCR gene rearrangements as well as Low Density Microarray (LDA) assays designed to detect a previously validated gene expression profile (Harvey, R; ASH 2013, abstract 826) which can prospectively identify ALL pts with Ph-like (BCR-ABL1-like) ALL. Results: 318 pts were enrolled on C10403 from 11/2007 to 8/2012; 22 withdrew prior to therapy. Of 296 evaluable pts, the median age at diagnosis was 24 yrs (range: 17 to 39): 25% were 17-20 yrs, 53% were 21-29 yrs, and 22% were 30-39 yrs. The majority had B-ALL (76%) and were male ( 61%). Approximately 25% were non-Caucasian and 15% were Hispanic or Latino. 32% of pts were obese (BMI³30). There were 5 (2%) treatment-related deaths during protocol therapy: liver failure (n=2, both during induction), infection (1 in induction, 1 in consolidation), and ventricular arrhythmia (1 in induction). Overall, treatment toxicities were similar to those reported in the standard arm of COG AALL0232, with an increased thrombosis and early hyperbilirubinemia for C10403 pts, as reported previously (Advani A, ASH 2013, abstract 303). To date, 70 deaths have been reported and 87 pts remain on protocol therapy. With a median follow-up of 28 months for surviving pts, 105 events have been observed. The median EFS overall is 59.4 months (95% CI: 38.4 to NR) and the 2-yr EFS rate overall is 66% (95% CI: 60 – 72%) [Fig 1a] with similar 2-yr EFS rates for B and T- ALL pts (65%, and 68%). The 2-yr OS rate is 78% (95% CI: 72 – 83%)[Fig 1b], which is similar for B (78%, 95% CI: 72 – 84%) and T-ALL, (80%, 95% CI: 70 – 91%). These results allow rejection of the null hypothesis of this Phase II trial that the true median EFS is, at most, 32 months. In multivariable analysis of presenting clinical features, age > 20 years and initial WBC count ³ 30k/microliter were significantly associated with worse EFS and OS. Presence of MRD at day 28 following initiation of induction therapy and presence of a Ph-like gene expression signature were significantly associated with both worse EFS and OS. Notably, absence of detectable MRD noted in 22/58 [38%] evaluable pts at day 28 of induction was associated with 100% EFS (p=0.0006). The Ph-like like signature was detected in 28% of pts tested on C10403 and the 2 yr EFS for these patients was only 52%, compared to 81% for those without Ph-like disease (p = 0.04). Conclusions: This large prospective US adult intergroup trial (C10403) for pts 16-39 years old employing an intensive pediatric regimen demonstrates a significant improvement (compared to historical controls) in AYA EFS and OS and validates this approach for treatment of AYA with ALL by adult hematologists. The improved clinical outcomes and the predictive value of the correlative studies in this trial lay the foundation for the design of future trials, where incorporation of novel agents to eradicate MRD, and/or use of tyrosine kinase inhibitors to target the frequently detected Ph-like ALL in AYA pts may further improve survival for young adults with ALL. Figure 1a Figure 1a. Figure 1b Figure 1b. Disclosures Stock: Sigma-Tau: Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Sigma Tau: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees. Liedtke:Onyx: Membership on an entity's Board of Directors or advisory committees. Larson:Novartis: Consultancy, Research Funding.

Abstract Purpose: Clinical trials in APL have generally reported similar outcomes for children and adults. However, sub-group analysis of pediatric patients treated on 2 consecutive trials of the European APL group demonstrated that children <5 years (yr) had an increased risk of relapse (Bally et al., JCO, 2012). Here we report the effect of age < 5 yr on outcome for the North American Intergroup Study C9710. Methods: Outcomes were compared among young children (age <5 yr, n=16) to those of older age (5-12 yr, n=25 and 13-18 yr, n=45) enrolled on C9710. Treatment on C9710 included induction with daunorubicin, cytarabine and ATRA followed by two consolidation cycles with daunorubicin and ATRA and maintenance for one year with ATRA +/- mercaptopurine and methotrexate. Patients of age ≥15 yr were randomized to receive or not receive two 5-week cycles of arsenic trioxide (ATO) before the chemotherapy consolidation. However, analysis in this study of young children compared to those of older age was restricted to patients who did not receive ATO. Results: Clinical remission (CR) rates were similar between the 3 age groups (age <5 yr= 88%, age 5-12 yr= 80%, age 13-18 yr= 82%; P=0.93). Overall survival (OS) Kaplan-Meier estimates were not significantly different (log rank P=0.84), and 5 yr OS rates were 77% (age <5 yr), 80% (age 5-12 yr), and 84% (age 13-18 yr). Similarly, event-free survival (EFS) Kaplan-Meier estimates were not significantly different (log rank P=0.48), and 5 yr EFS rates were 56% (age <5 yr), 47% (age 5-12 yr), and 59% (age 13-18 yr). Young children did not have a higher relapse rate (5-yr cumulative incidence of relapse by age: <5 yr=29%, 5-12 yr=49%, 13-18 yr=29%). Conclusions: Results of this intergroup trial demonstrate that ATRA administration during induction, consolidation and maintenance leads to CR rates >80% and 5 yr OS rates >75%. These results are superior to recently published results of pediatric non-APL acute myeloid leukemia and confirm results from the prior APL intergroup trial (INT0129) that demonstrated that ATRA in induction and/or maintenance significantly improved outcomes for pediatric APL (Gregory et al., Ped Blood and Cancer, 2009). Our sub-group analysis showed no association of age with outcomes in children treated with this regimen. Disclosures Off Label Use: Daunorubicin- labeled for use in AML for adults and for pediatric ALL (not pediatric AML) Arsenic Trioxide- labeled for use in relapsed/refractory APL (not de novo APL) Mercaptopurine and Methotrexate- labeled for use in pediatric ALL (not APL).

Abstract Purpose: Recent studies have demonstrated differential outcomes for adolescents and young adults (AYAs) vs. children treated for acute myeloid leukemia. Here we analyze outcomes by age group for APL patients treated on the North American Intergroup Study C9710. Methods: Patient characteristics and outcomes were compared between children (<15 yr, n=55) vs. AYAs (15-31 yr, n=42). To control for differences in treatment center, only young adults registered at Children’s Oncology Group (COG) treatment sites were included. Treatment included induction with daunorubicin, cytarabine and ATRA. All patients (pts) received two consolidation cycles with daunorubicin and ATRA and maintenance for one year with ATRA +/- mercaptopurine and methotrexate. Pts ≥15 yr were randomized to an additional two cycles of arsenic trioxide (ATO). Sub-group analysis was also performed to exclude pts ≥15 yr who received ATO and thus compare only patients <15 yr vs. ≥15 yr who had not received ATO. Results: Children and AYAs had similar characteristics of gender, race/ethnicity, Sanz risk grouping and M3v histology. Among all pts enrolled at COG sites on the study, complete response (CR) rates were similar (<15yr =85% vs. ≥15yr =81%, P=0.59). AYAs had improved 5 yr disease-free survival (DFS) from time of CR compared to younger pts (<15 yr =47% vs. ≥15 yr =70%, log rank P=0.05), and there was a trend toward difference in 5 yr event-free survival (EFS) (<15 yr =46% vs. ≥15 yr =63%, log rank P=0.13). Overall survival (OS) at 5 years was not significantly different (<15 yr =82% vs. ≥15 yr =75%, log rank P=0.47). Twenty-three of 42 pts ≥15 yr received ATO consolidation cycles, which may have contributed to their improved DFS and EFS. Thus, we analyzed outcomes by removing from the analysis patients ≥15 yr who received ATO consolidation cycles, and compared pts <15 yr who did not receive ATO (n=55) to pts ≥15 yr who were randomized to no ATO (n=19). CR rates were again similar (<15 yr =85% vs. ≥15 yr no ATO =84%, P=1.0). There was no significant difference in other outcomes including 5-yr DFS from time of CR (<15 yr =47% vs. ≥15 yr no ATO =63%, log rank P=0.31), 5-yr EFS (<15 yr =46% vs. ≥15 yr no ATO=53%, log rank P=0.89), or 5-yr OS (<15 yr =82% vs. ≥15 yr no ATO=79%, log rank P=0.78). Conclusions: The C9710 study demonstrated improved EFS, DFS and OS among adult patients receiving ATO consolidation compared to those who did not receive ATO (Powell et al., Blood, 2010). The current analysis of results for AYAs versus younger pediatric pts showed improved DFS among the whole AYA cohort (of which 55% received ATO consolidation) compared to pts <15 yr (of which 0% received ATO). When the analysis was restricted to AYA pts not receiving ATO, however, the results of this intergroup APL trial showed similar CR, DFS, EFS and OS for AYAs and younger pts. Thus, unlike other subtypes of AML, APL appears to have a consistent response across the pediatric and AYA age groups. The most recent COG clinical trial in APL is now evaluating whether pediatric patients can also benefit from ATO consolidation. Disclosures Off Label Use: Daunorubicin- labeled for use in AML for adults and for pediatric ALL (not pediatric AML) Arsenic Trioxide- labeled for use in relapsed/refractory APL (not de novo APL) Mercaptopurine and Methotrexate- labeled for use in pediatric ALL (not APL).

Abstract Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared to pediatric ALL. Age, as a continuous variable, is negatively correlated with prognosis, in spite of risk-adapted combination chemotherapy. To better understand the etiology of ALL in this age group, we performed the first genome-wide association study (GWAS) to comprehensively examine germline single nucleotide polymorphisms (SNPs) for their association with susceptibility to B-ALL in AYAs. In the discovery GWAS, we compared genotype frequency at 635,297 SNPs between 308 AYA ALL cases (age 16-39 years, treated on the Children’s Oncology Group [COG], the Alliance-Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, MD Anderson Cancer Center, and St. Jude Children’s Research Hospital trials) vs. 6,661 non-ALL controls. The association between genotypes at each SNP and ALL susceptibility was tested by using a logistic regression model after adjusting for genetic ancestries to control for population stratification. SNPs that reached P≤ 5×10-8 in the discovery GWAS were tested in an independent cohort of 82 AYA ALL cases from the COG protocols and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus on 10p14 signified by two SNPs within the GATA3 gene: rs3824662, P=2.8x10-10, odds ratio (OR)=1.77; rs3781093, P=3.2x10-9, OR=1.73, both of which were validated in the replication cohort (P=1.9x10-8 and P=4.3x10-5, respectively). We also examined the association signals in AYAs for susceptibility loci previously identified in pediatric ALL: ARID5B, IKZF1 and PIP4K2A variants were nominally significant in AYAs in the discovery GWAS and/or in the replication analysis, whereas CEBPE or CDKN2A/CDKN2B were not significant. These results imply both similarities and differences in genetic predisposition to ALL between children and AYAs. At the GATA3 locus, rs3824662 risk variant was over-represented in Philadelphia chromosome (Ph)-like ALL in AYAs (P=0.02), confirming our previous report of Ph-like ALL susceptibility variants in GATA3 (Nat Genet 45:1494). Importantly, even after excluding Ph-like cases, rs3824662 remained associated with the risk of developing ALL in AYAs, suggesting that the influence of the GATA3risk variant on ALL susceptibility in AYAs extends beyond the predisposition to Ph-like subtype. We next examined the relationship between GATA3 risk allele frequency and age at diagnosis in a cohort of unselected childhood and adolescent ALL cases enrolled in the COG P9900 protocols (N=1,827). Dividing patients into four consecutives age groups (<5, 5-10, 10-15 and >15 years), we observed a clear progressive increase in the risk allele frequency at rs3824662 (P=6.29×10-11) with increasing allelic odds ratio (i.e. relative risk of ALL conferred by each copy of the risk allele). This correlation between genotype and age was evident regardless of genetic ancestry, although the risk variant was more common among individuals with higher Native American ancestry. In contrast, the frequency of ALL susceptibility variant in ARID5B decreased progressively with increasing age at diagnosis (P=0.006), whereas PIP4K2A, CDKN2A/CDKN2B, IKZF1 and CEBPE variants were not related to age. Finally, we compared rs3824662 risk variant frequency by age in the COG P9900 protocols after stratifying the ALL cases into TCF3-PBX1, ETV6-RUNX1, hyperdiploid, MLL-rearranged and B-other. There was a trend that the risk allele was more frequent in cases older than 16 years compared to those below 16 in the five subtypes examined. In conclusion, we have identified inherited GATA3 genetic variants that strongly influence ALL susceptibility in adolescent and young adults, indicating potential age-related differences in ALL biology. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 1038 The relationships of inherent disease-related characteristics and of treatment to the nature of APL cell clones that emerge at disease relapse are poorly understood. We studied these relationships in 45 patients who relapsed after ATRA/chemotherapy treatment on the non-arsenic trixoxide arm of intergroup phase III trial C9710 (Powell, et al. Blood, Epub). Four variably-expressed APL cell clonal markers were assessed: PML-RARA ligand binding domain mutations (LBD-M), FLT3 internal tandem duplication mutations (ITD), FLT3 receptor tyrosine kinase mutations (D835; RTK-M) and additional chromosome abnormalities (ACA), i.e., in addition to the hallmark t(15;17). The methods for mutation analysis of PML-RARA and FLT3 have been reported and were RNA transcript-initiated supplemented by selected quantitative FLT3 mutation analyses initiated from DNA. Karyotype data were derived by standard cytogenetic methods. Four patients were excluded from analysis because the sample level of PML-RARA, as determined by quantitative RT-PCR, was insufficient to exclude possible false-negative mutation results. In 41 evaluable patients, the marker incidences were: LBD-M, 44%; ITD, 37%; RTK-M, 12%; ACA (22 tested), 59%. At presentation, the corresponding incidences were: LBD-M, 0% (by high-sensitivity testing a minor subclone of the relapse mutation was found in 2/7 patients tested); ITD, 43% (37 tested); RTK-M, 22% (37 tested); ACA, 24% (34 tested). The low frequency of RTK-M impeded further analysis. The other markers, using relapse determinations, were assessed for potential associations between the markers and with the following parameters: age, sex, presenting WBC count, PML-RARA type, time to relapse, relapse on or off ATRA treatment (on = taking or within 30 days of discontinuing) and post-relapse survival. The most essential positive findings are summarized below:Association of Marker with Parameter or Other MarkerCases with ParameterCases without Parameterp-valuePretreatment parameters: LBD-M with WBC count < 5,000/uL12/18 (67%)7/23 (30%)0.030 ITD with WBC count >10,000/uL10/15 (67%)5/26 (19%)0.006 ITD with S-form PML-RARA15/15 (100%)10/26 (38%)<0.0001Relapse parameters: ITD with lack of ACA1/7 (14%)12/15 (80%)0.007 LBD with relapse On-ATRA11/18 (61%)7/23 (30%)0.064 Off-ATRA only: LBD with lack of ITD0/7 (0%)9/16 (56%)0.019 The results confirm reports, which tested pretreatment samples, of a strong association between FLT3ITD mutations present at relapse and high WBC count and S-form PML-RARA. At relapse, there was, also, divergent selection of ITD-harboring vs ACA-harboring clones. LBD-M occurred more frequently in patients with low presenting WBC counts. They, also, occurred in patients who relapsed while on ATRA, consistent with an ATRA selective role for clones harboring LBD mutations. A significant segregation of patients with LBD-M or ITD was observed after relapse off ATRA treatment (p = 0.019), while no segregation was observed in overall relapse patients (p = 0.346) or after relapse on ATRA (p = 0.316). In 2 patients who relapsed on ATRA, quantitative analysis indicated that LBD-M and ITD mutations must be present in the same APL cell clone. There were no significant survival differences related to any clonal marker (post-relapse survival = 66%). Although the small number of cases is cautionary, the overall data suggest that LBD-M may have an overriding, dominant APL clone selection role in relapse that occurs on ATRA therapy. Other inherent clinicopathologic characteristics of APL may predispose to divergent molecular pathways of disease progression and relapse in patients alternatively harboring clones with LBD-M or ITD after the termination of ATRA selection pressure. Disclosures: No relevant conflicts of interest to declare.

Abstract Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.

AbstractBackgroundAcute promyelocytic leukemia (APL) is a unique leukemia subtype requiring specialized treatment including all‐trans retinoic acid (ATRA). A prior report demonstrated worse outcome among young children <5 years old compared with older children.MethodsWe evaluated outcomes for pediatric patients (<18 years old; N = 83) with APL treated on North American intergroup study CALGB 9710 at Children's Oncology Group sites. Induction and consolidation included ATRA, cytarabine, and anthracyclines. Patients ≥15 years old were randomized to addition of arsenic trioxide (ATO) consolidation. All patients were randomized to ATRA maintenance with versus without oral chemotherapy.ResultsThe estimated 5‐year overall survival (OS) rate was 82%, and the event‐free survival (EFS) rate was 54%. Seven patients (8.4%) died during induction due to coagulopathy. Maintenance randomization demonstrated that addition of oral chemotherapy to ATRA significantly reduced relapse rate, but difference in EFS did not reach statistical significance (P = 0.12; 5‐year rates [95% CI]: 41% [17%–64%] ATRA only vs 72% [56%–88%] ATRA plus chemotherapy). There was no difference (P = 0.93) in EFS for age <5 years versus 5–12.99 years versus 13–17.99 years (5‐year rates: 56%, 47%, and 45%, respectively). Among adolescents 15–17.99 years old in the ATO randomization, there was a significantly lower relapse risk at 5 years for those receiving ATO (0% ATO vs 44% no ATO; P = 0.02).ConclusionOur data demonstrate that intensified ATRA, cytarabine, and anthracycline chemotherapy is effective for pediatric APL including very young patients, but early deaths and relapses remain barriers to cure. Further improvements are likely with incorporation of ATO into pediatric APL regimens.