Oncology Group Trial AAML0531 Research Articles

Pathologic, cytogenetic, and molecular features of acute myeloid leukemia with megakaryocytic differentiation: A report from the Children's Oncology Group.

Acute myeloid leukemia (AML) with megakaryocytic differentiation (AMkL) is a rare subtype of AML more common in children. Recent literature has identified multiple fusions associated with this type of leukemia. Morphology, cytogenetics, and genomic sequencing were assessed in patients from Children's Oncology Group trials AAML0531 and AAML1031 with central-pathology review confirmed non-Down syndrome AMkL. The 5-year event-free survival (EFS), overall survival (OS), and RR were evaluated in these AMkL subcategories. A total of 107 cases of AMkL (5.5%) were included. Distinct fusions were identified in the majority: RBM15::MRTFA (20%), CBFA2T3::GLIS2 (16%), NUP98 (10%), KMT2A (7%), TEC::MLLT10 (2%), MECOM (1%), and FUS::ERG (1%); many of the remaining cases were classified as AMkL with (other) myelodysplasia-related changes (MRC). Very few cases had AML-associated somatic mutations. Cases with CBFA2T3::GLIS2 were enriched in trisomy 3 (p=.015) and the RAM phenotype, with associated high CD56 expression (p<.001). Cases with NUP98 fusions were enriched in trisomy 6 (p<.001), monosomy 13/del(13q) (p<.001), trisomy 21 (p=.026), and/or complex karyotypes (p=.026). While different 5-year EFS and OS were observed in AMkL in each trial, in general, those with CBFA2T3::GLIS2 or KMT2A rearrangements had worse outcomes compared to other AMkL, while those with RBM15::MRTFA or classified as AMkl-MRC fared better. AMkL with NUP98 fusions also had poor outcomes in the AAML1031 trial. Given the differences in outcomes, AMkL classification by fusions, cytogenetics, and morphology may be warranted to help in risk stratification and therapeutic options.

Occurrence of Cardiotoxicity and the Impact on Outcomes Among Children Treated on the AAML0531 Clinical Trial: A Report from the Children's Oncology Group

Background: Much of the literature on anthracycline-associated cardiotoxicity has focused on late effects of exposure among childhood cancer survivors. Given the high anthracycline exposure in front-line therapy for pediatric acute myeloid leukemia (AML), it is crucial to gain a better understanding of the risk factors for early cardiotoxicity and its impact on subsequent treatment outcomes.Methods: Between August 2006 and June 2010, Children's Oncology Group trial AAML0531 enrolled patients less than 30 years of age for frontline treatment of de novo AML. These analyses excluded Down syndrome patients. Cardiac events over the course of treatment and off-protocol follow-up were ascertained through a combination of passive (traditional adverse event (AE) case report forms) and active (targeted requests for echocardiograms for patients with an AE report for a cardiac event or life-threatening bloodstream infection) adverse event monitoring. The primary outcome of cardiotoxicity was defined as grade 2 or higher left ventricular systolic dysfunction (LVSD) based on Common Terminology Criteria for AE Version 3 definitions (i.e., ejection fraction <50% or fractional shortening <24%). We evaluated risk factors for incident LVSD using multivariable Cox regression analyses. Cox regression models were then used to compare event-free survival (EFS) and overall survival (OS) in patients with documented LVSD, classified as infection-associated and not infection-associated, relative to patients with no documented LVSD. The occurrence of LVSD was considered as a time-varying exposure to avoid immortal and immune person-time bias. Adjusted hazard ratios and corresponding 95% confidence intervals were reported. Cox model predicted survival probabilities were used to plot the OS and EFS curves.Results: These analyses included 1022 AML patients enrolled AAML0531. Compliance with echocardiographic evaluations was higher but more variable during the on-protocol (median: 61.2%, range: 41.1%-85.0%) compared with the off-protocol reporting periods (median: 53.8%, range: 39.1%-56.1%). Compliance did not differ significantly by age, gender, race, ethnicity, BMI, insurance status, AML risk classification, initial white blood cell count, or randomized treatment arm.Approximately 12% of patients had documented grade 2 or higher LVSD over the course of follow-up; 25% of incident events were classified as infection-associated. The cumulative incidence increased approximately linearly during on-protocol therapy from 1% to 8% from Induction I through Intensification III, but plateaued early during off-protocol follow-up (i.e.18 months). The overall incidence increased with age at enrollment (p-value for trend: <0.002), was higher among black compared to white patients (HR=1.73, 95% CI: 1.00, 2.99), among obese compared to normal weight patients (HR=1.64, 95% CI: 1.01, 2.65), and in the setting of a bloodstream infection (HR=1.86, 95% CI: 1.12, 10.9). These overall trends, with the exception of obesity, were driven by on-protocol toxicities.Five-year EFS and OS were significantly lower in patients who experienced on-protocol cardiotoxicity (Table 1, Figure 1). The impact on EFS was similar whether the incident event was determined to be in the presence or absence of infection (absolute differences of 17.5% and 16.1%, respectively), whereas the impact on OS was more pronounced for cardiac toxicity in the absence of infection than cardiac toxicity in the presence of infection (absolute differences of 16.8% and 7.7%, respectively).Conclusions: Our findings demonstrate that early treatment-related cardiotoxicity is associated with decreased EFS and OS possibly through associated reductions in anthracycline exposure. The suggested heterogeneity in the effect on OS by infection status implies that patients who experience LVSD in the context of infection may be more salvageable upon relapse than patients experiencing non-infection related cardiotoxicity. Efforts to improve the outcomes for children with AML should include increased attention to the prevention and mitigation of on-protocol cardiac toxicity. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Acute erythroid leukemia is enriched in NUP98 fusions: a report from the Children's Oncology Group

AbstractAcute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML) primarily affecting older adults and was previously classified into erythroid/myeloid and pure erythroid subtypes. In this pediatric AEL study, we evaluated morphologic, immunophenotypic, cytogenetic, molecular, and clinical data of 24 (1.2%) cases from all cases undergoing central pathology review in Children's Oncology Group trials AAML0531 and AAML1031. Of 24 cases, 5 had a pure erythroid phenotype, and 19 had an erythroid/myeloid phenotype. NUP98 fusions were highly enriched in patients with AEL, occurring in 7 of 22 cases for which molecular data were available (31.8% vs 6.7% in other AML subtypes). Of 5 cases of pure erythroid leukemias (PELs), 3 had NUP98 fusions, and 4 had complex karyotypes. Erythroid/myeloid leukemias were reclassified by using the 2017 World Health Organization hematopathology classification as: myelodysplastic syndrome (MDS) with excess blasts-1 (n = 3), MDS with excess blasts-2 (n = 7), AML (nonerythroid, n = 5), and unknown MDS/AML (n = 4); the 5 cases of nonerythroid AML included 1 with an NUP98–NSD1 fusion, 2 with myelodysplasia-related changes, and 1 with a complex karyotype. Three cases of MDS with excess blasts-2 also had NUP98 rearrangements. WT1 mutations were present in 5 of 14 cases, all erythroid/myeloid leukemia. Outcomes assessment revealed statistically poorer overall survival (5-year, 20% ± 36% vs 66% ± 23%; P = .004) and event-free survival (5-year, 20% ± 36% vs 46% ± 23%; P = .019) for those with PEL than those with erythroid/myeloid leukemia. Our study supports that AEL is a morphologically and genetically heterogeneous entity that is enriched in NUP98 fusions, with the pure erythroid subtype associated with particularly adverse outcomes.

Deciphering the Significance of CD56 Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group.

In patients with acute myeloid leukemia (AML), CD56 expression has been associated with adverse clinical outcome. We reported on a phenotype associated with very poor prognosis (RAM) in children enrolled in the Children's Oncology Group trial AAML0531 (Brodersen et al. Leukemia 30 (2016) 2077-2080). RAM is also characterized in part by high-intensity expression of the CD56 antigen. Herein, we investigate underlying biological and clinical differences among CD56-positive AMLs for patients in AAML0531. For 769 newly diagnosed pediatric patients with de novo AML enrolled in AAML0531, bone marrow specimens were submitted for flow cytometric analysis. For each patient, an immunophenotypic expression profile (IEP) was defined by mean fluorescent intensities of assayed surface antigens. Unsupervised hierarchical clustering analysis (HCA) was completed to group patients with similar immunophenotypes. Clusters were then evaluated for CD56 expression. Principal component analysis (PCA) was subsequently applied to determine whether CD56-positive patient groups were nonoverlapping. HCA of IEPs revealed three unique phenotypic clusters of patients with CD56-positive AML, and PCA showed that these three cohorts are distinct. Cohort 1 (N = 77) showed a prevalence of t(8;21) patients (72%), Cohort 2 (N = 52) a prevalence of 11q23 patients (69%), and Cohort 3 (RAM) (N = 16) a prevalence of patients with co-occurrence of the CBFA2T3-GLIS2 fusion transcript (63%). The 5-year event-free survival (EFS) for Cohorts 1, 2, and 3 were 69, 39, and 19%, respectively. When leukemia is considered by its multidimensional immunophenotype and not by the expression of a single antigen, correlations are seen between genotype and there are significant differences in patient outcomes. © 2019 International Clinical Cytometry Society.

Disease Characteristics and Prognostic Implications of Cell-Surface FLT3 Receptor (CD135) Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group.

Purpose: The FLT3 cell-surface receptor tyrosine kinase (CD135) is expressed in a majority of both acute lymphoid leukemia (ALL) and myeloid leukemia (AML). However, the prognostic significance of CD135 expression in AML remains unclear. We therefore evaluated the association between FLT3 surface expression and disease characteristics and outcomes in pediatric patients with AML.Experimental Design: We analyzed FLT3 receptor expression on AML blasts by multi-dimensional flow cytometry and its association with disease characteristics, clinical outcomes, and FLT3 transcript level in 367 children with AML treated on the Children's Oncology Group trial AAML0531.Results: There was high variability in blast CD135 cell-surface expression across specimens. CD135 expression measured by flow cytometry was not correlated with FLT3 transcript expression determined by quantitative RT-PCR. Overall, CD135 expression was not significantly different for patients with FLT3/WT, FLT3/ITD, or FLT3/ALM (P = 0.25). High cell-surface CD135 expression was associated with FAB M5 subtype (P < 0.001), KMT2A rearrangements (P = 0.009), and inversely associated with inv(16)/t(16;16) (P < 0.001). Complete remission rate, overall survival, disease-free survival, and relapse rates were not significantly different between patients with low and high CD135 expression.Conclusions: FLT3 cell-surface expression did not vary by FLT3 mutational status, but high FLT3 expression was strongly associated with KMT2A rearrangements. Our study found that there was no prognostic significance of FLT3 cell surface expression in pediatric AML. Clin Cancer Res; 23(14); 3649-56. ©2017 AACR.

Down Syndrome AML Is Unique in Phenotype Both at Diagnosis and in Post Chemotherapy Regeneration

Abstract Background: Down syndrome (DS) acute myeloid leukemia (DS-AML) is predominantly found in young children (under the age of 4) and responds well to chemotherapy. The difference in clinical features suggests that despite the predominance of megakaryoblastic disease, DS-AML blasts are different from non-DS AML blasts with megakaryoblastic morphology (AMKL). The immunophenotypes of DS-AML blasts at diagnosis were compared to those of non-DS AML patients using unsupervised hierarchical clustering analysis (HCA) and assessed for their immunophenotypic overlap with known morphologic subgroups. In addition, residual disease monitoring of non-DS AML patients using "Difference from Normal" flow cytometry has been applied to DS-AML with unexpected results. Methods: A standardized antibody panel was used to define quantitative gene product (antigen) expression in bone marrow (BM) specimens from patients with AML at diagnosis and following chemotherapy. The quantitative phenotypic expression of multiple cell surface markers and physical characteristics defined a position in 15 dimensional data space for each patient. HCA was performed to mathematically cluster DS-AML patients enrolled on Children's Oncology Group study AAML1531 with non-DS patients from study AAML0531 based on 15 dimensional profiles. Five patients with DS who were older than 4 years of age and therefore treated on AAML0531 were also included. Data regarding morphology were appended to the data set. The same antibody panel was used to assess measurable residual disease (MRD) in 147 follow up BM aspirates from 50 DS patients ages 1 to 21 undergoing treatment for either AML or B-ALL (n=46, n=4 respectively) who were not included in the clinical studies. When possible, cell sorting was performed for FISH or SNP/CGH microarray studies. Results: Diagnostic Clustering: HCA of 17 DS-AML diagnostic phenotypes with 769 non-DS AML patients revealed a tight immunophenotypic correlation between 12 (71%) DS-AML patients (Figure 1). Further analysis of this diagnostic subset showed a consistent mean antigen expression profile that was distinct from non-DS AML diagnostic phenotypes. Similarly, the DS-AML patients clustered separately from the 5 older DS patients (&gt;4 years of age) with AML, who were treated on AAML0531 and exhibited consistently different identifying diagnostic markers despite the shared constitutional trisomy 21. Additionally, the phenotype associated with the DS-AML cluster does not match that of patients with AMKL morphology. The largest immunophenotypic cluster of non-DS patients with AMKL morphology were classified with the RAM phenotype[1], which segregate into a mathematically unique branch of the dendogram distinct from the DS-cluster. Observation of a consistent DS-specific non-leukemic myeloid regenerative phenotype: Of the 147 post chemotherapy specimens submitted for MRD analysis off clinical study, 141 (96%) had a clearly identifiable CD34+/CD56+ population present between 0.06-6.0% total non-erythroid composition. A second abnormal population expressing CD34+ but not HLA-DR was also observed in these patients but at a lower level (0.02-2.66%) compared to the CD34+/CD56+ cell population. Two patients had a reproducible absence of 56+, DR- progenitors across all follow up specimens (6/147) and may represent unique clinical cases with disease features beyond our knowledge. In four DS patients undergoing treatment for B-ALL, the same immunophenotypic features (CD34+/CD56+ and negative HLA-DR) were observed. Genetic data: In 4 cases, cell sorting of CD34+/CD56+ post treatment progenitors revealed a lack of cytogenetic markers present in the clone of leukemic blasts at diagnosis. Conclusions: The blasts of patient with typical DS-AML (i.e under the age of 4 years at diagnosis) are immunophenotypically distinct from those of non-DS-AML patients and exhibit consistent immunophenotypic features that differ from DS patients with AML who are older than 4 years of age. The normal myeloid progenitors in DS patients who have undergone chemotherapy for AML or ALL express an immunophenotype that is different from normal BM of non-DS patients recovering from chemotherapy. [1] Brodersen, Lisa Eidenschink, et al. "A Recurrent Immunophenotype at Diagnosis Independently Identifies High Risk Pediatric AML: A Report from the Children's Oncology Group Trial AAML0531." Disclosures Wilson: Hematologics: Employment. Brodersen:Hematologics: Employment. Zehentner:Hematologics: Employment, Equity Ownership. Pardo:Hematologics, Inc: Employment. Wells:Hematologics: Employment, Equity Ownership. Loken:Hematologics: Employment, Equity Ownership.

Early discharge as a mediator of greater ICU-level care requirements in patients not enrolled on the AAML0531 clinical trial: a Children's Oncology Group report.

Previous data suggest that patients enrolled on clinical trials for treatment of cancer have better overall survival than patients who do not enroll; however, short‐term outcomes relative to trial enrollment and corresponding mediators have not been assessed. A cohort of pediatric patients with newly‐diagnosed acute myeloid leukemia was assembled from the Pediatric Health Information System. We evaluated whether patients not enrolled onto Children's Oncology Group trial AAML0531 had greater intensive care unit (ICU)‐level requirements than enrolled patients and whether early discharge after chemotherapy administration mediated this association. Patients not enrolled on AAML0531 were more likely to be discharged early (aOR = 1.40, 95% confidence interval [CI]: 1.02, 1.90) and to require ICU‐level care (aOR = 2.00, 95% CI: 1.06, 3.78) than enrolled patients, but early discharge explained only a small proportion (12.3%) of the absolute difference in ICU‐level care risk. The direct effect of nonenrollment on the need for ICU‐level care was significant (aOR = 1.89, 95% CI: 1.00, 3.94), whereas the indirect effect mediated through early discharge was not (aOR = 1.07, 95% CI: 0.95, 1.19). Factors other than postchemotherapy discharge strategy drive the difference in ICU utilization by trial enrollment status.

A Recurrent Immunophenotype at Diagnosis Independently Identifies High Risk Pediatric AML: A Report from the Children's Oncology Group Trial AAML0531

Background: Risk stratification of pediatric patients with acute myeloid leukemia (AML) combines cytogenetics and molecular markers at diagnosis with detection of measurable residual disease (MRD) by multidimensional flow cytometry (MDF) after initial induction chemotherapy (EOI1). However, using MDF to distinguish between favorable and poor risk groups by diagnostic immunophenotype has not been sufficiently reproducible for clinical implementation.Objective: We sought to characterize a recurrent, unique diagnostic immunophenotype identified among patients treated on Children's Oncology Group trial AAML0531 and determine the clinical characteristics, frequency, and outcome of patients with this immunophenotype in a large cohort.Patients and Methods: Of the 1022 newly diagnosed pediatric patients with de novo AML who enrolled in protocol AAML0531 (exclusive of patients with promyelocytic leukemia and Down syndrome), 812 who submitted a specimen for MDF at diagnosis and gave consent to MRD testing were eligible for the study.Results: A recurrent diagnostic phenotype was identified by a combination of high intensity CD56 expression, a lack of HLA-DR, dim to negative CD38 expression and dim to negative CD45 expression (designated as RAM phenotype). At diagnosis 19 patients (2.3%) expressed this phenotype and MRD was subsequently detected by MDF in 16/19 patients at EOI1 at a level of 0.02%-41% (median 0.3). Eleven patients with this phenotype submitted bone marrow specimens for MDF analysis at all 3 additional monitoring time points during therapy and in 8 patients MDF analysis revealed disease persistence throughout treatment. The experimental cohort (RAM cohort, N=19) and 2 control cohorts, one consisting of all other patients with CD56 positive AML (CD56+ control, N=166) and the other of patients with CD56 negative AML (CD56- control, N=627), were analyzed for clinical outcomes.Patients in the RAM cohort were significantly younger with a median age at diagnosis of 1.26 years [range 0.75-16.89] than those in the CD56+ control (median 7.57 years [range 0.01-29.8], p=0.002) and the CD56- control (median 10.64 [range 0.02-23.94], p<0.001). All patients in the RAM cohort were classified as standard risk per study protocol compared to 55% (p<0.001) for the CD56+ control and 46% (p<0.001) for the CD56- control. Patients in the RAM cohort were FLT3-ITD- and wild type for CEBPA, NPM1, and WT1. Of them, 7 had normal cytogenetics, 1 had trisomy 8, and 11 had other cytogenetic abnormalities not associated with prognostic subgroups, including the 11q23/MLL rearrangement. According to morphology, patients in the RAM cohort were more often classified as having megakaryoblastic AML (38%) compared to the CD56+ control (2.0%, p<0.001) and the CD56- control (4.0%, p<0.001).MDF analysis detected MRD in 84% of RAM cohort compared to 29% (p<0.001) for the CD56+ control and 33% (p<0.001) for the CD56- control cohorts. MRD detected at EOI1 was compared to morphologic complete remission (CR). Morphologic CR at EOI1 was achieved in 11 (58%) patients in the RAM cohort (58%) versus 71% of patients in the CD56+ (p=0.250) and 74% of patients in the CD56- (p=0.116) control cohorts. Patients in the RAM cohort had a 3-year event free survival (EFS) of 16% versus 52% for those in the CD56+ (p=0.003) and 51% for those in the CD56- (p<0.001) control cohorts. The 3-year overall survival (OS) for patients in the RAM cohort was 26% versus 66% for those in the CD56+ (p<0.001) and 70% for those in the CD56- (p<0.001) control cohorts. Multivariable Cox regression analysis revealed that the diagnostic RAM immunophenotype was an independent predictor of adverse outcome (hazard ratios [and 95% confidence intervals]: OS= 3.4 (1.84 - 6.18), relapse risk from CR=4.97 (2.67 - 9.24), DFS from CR=4.27 (2.04 - 8.95)).Conclusions: A definitive diagnostic phenotype is identified that is highly predictive of poor outcome in pediatric AML. The survival of patients with the RAM phenotype is similar to or worse than those with high-risk molecular features. It occurs in 10% of infants (<1 year old) with AML who lack known risk factors, do not respond to standard therapy, and have extremely poor outcomes. This phenotype can be identified rapidly at diagnosis, allowing clinicians to predict failure before initiating therapy, and thereby allowing administration of more effective alternative therapies and minimizing exposure to non-efficacious treatment. DisclosuresBrodersen:Hematologics Inc.: Employment. Menssen:Hematologics Inc.: Employment. Pardo:Hematologics Inc.: Employment. Voigt:Hematologics Inc.: Employment. Loken:Hematologics Inc.: Equity Ownership.

Treatment of 11q23/MLL + AML with Gemtuzumab Ozogamicin: Results from the Randomized Phase III Children's Oncology Group Trial AAML0531

CD33 is variably expressed on acute myeloid leukemia (AML) blasts and is the target of gemtuzumab ozogamicin (GO). We previously demonstrated the clinical benefit of GO treatment in children with AML treated on COG AAML0531 in which patients were randomized to receive standard Medical Research Council-based chemotherapy with or without GO. We also demonstrated that CD33 expression is highly variable in pediatric AML and that children with 11q23 translocations involving the KMT2A gene, previously known as the mixed lineage leukemia gene and referred to here as MLL+, have significantly higher CD33 expression, as defined by mean fluorescent intensity (MFI) values, than patients without 11q23/MLL + leukemia (MLL-) [median CD33 MFI: MLL + 229.13 (range 6-1351) vs. MLL-129 (range 2.68-1225.87) P <0.001.] Given significantly elevated levels of CD33 expression in MLL + AML and our previous findings showing an association between high CD33 expression and improved response to GO, we evaluated MLL + AML patients treated on COG AAML0531 to determine whether GO treatment improved their clinical outcomes.COG AAML0531 included 1022 eligible patients ages 1 month-29.99 years of which 215 harbored a 11q23/MLL rearrangement that was confirmed by central cytogenetic review (including G-banding and FISH). Analysis of overall outcomes revealed similar complete remission (CR) rates after Induction I for MLL + and MLL-patients (71% vs. 73%, P = 0.494). However, MLL + patients had lower 5-year overall survival (OS) and event-free survival (EFS) than MLL-patients (OS 58% vs. 66%, P =0.012, EFS 38% vs. 51%, P =<0.001) as well as higher rates of relapse (RR) (52% vs. 36%, P =<0.001) and lower disease-free survival (DFS) (46% vs. 58%, P =0.002).Of the 215 MLL + patients, 107 were treated with conventional chemotherapy only (No-GO) and 108 with chemotherapy and GO (GO). CD33 expression data from flow cytometry analysis were available for 170 MLL + patients. The median CD33 MFI was similar for MLL + patients on both treatment arms [No-GO: 226.5 (range 6-911), GO 237.345 (range 7.6-1351), P = 0.648]. CR rate was higher for MLL + patients treated with GO vs. No-GO (77% vs. 64%; P =0.035). Evaluation of clinical outcomes for patients in the MLL + cohort by treatment arm revealed a superior outcome for GO recipients. EFS at 5 years from study entry was 48% for patients in the GO group vs. 28% for those in the No-GO group (P =0.002) with a corresponding OS of 64% vs. 53% (P =0.053). MLL-patients had similar EFS and OS regardless of GO exposure (P =0.435 and P =0.861, respectively, Figure 1). In MLL + patients who achieved CR, GO exposure translated to lower RR (40% vs. 66% No-GO, P =0.001) and improved DFS (57% vs. 33% No-GO, P =0.002) demonstrating that MLL + patients receiving GO treatment have improved outcomes.In COG AAML0531 a subset of patients was allocated to receive allogeneic hematopoietic stem cell transplant (HSCT) in 1st CR based on donor availability and risk status. This allowed us to evaluate the effect of HSCT in MLL+ patients in the context of GO exposure as any MLL+ patient with a matched family donor or poor induction response (>15% blasts) underwent HSCT. HSCT was conducted in 19 of 83 MLL+ patients (23%) in the GO group after one course of intensification therapy and in 11 of 73 (15%) patients in the No-GO group. Patients in the GO group who received HSCT consolidation had better outcomes than those not receiving HSCT. Specifically, MLL+ patients who received HSCT after prior treatment with GO had a RR of 28% at 5 years from HSCT compared with a RR of 73% for MLL + patients who received HSCT without GO prior (P =0.006). The corresponding DFS at 5 years from HSCT for patients in the GO and No-GO groups was 72% vs. 27% (P =0.004) respectively. These results highlight that the clinical impact of induction GO maintains clinical significance in the post-HSCT setting.Our analysis of data from AAML0531 suggests that pediatric MLL + AML might benefit from the addition of GO to conventional chemotherapy. HSCT might further enhance GO benefit in this subset of patients. Future studies, utilizing GO or other novel CD33 targeted agents, should be considered for MLL + pediatric AML given the superior outcomes observed. [Display omitted] DisclosuresAplenc:Sigma Tau: Honoraria. Loken:Hematologics Inc.: Equity Ownership.

Prevalence and Prognostic Significance of KIT Mutations in Pediatric Core Binding Factor AML Patients Treated with Gemtuzumab Ozogamicin: Results from the Randomized Phase III Children's Oncology Group Trial AAML0531

Mutations of KIT (KIT +) occur in children and adults with core binding factor (CBF) acute myeloid leukemia (AML) and cluster within exons 8 and 17. We previously reported a 19% prevalence of KIT mutations in pediatric CBF AML and lack of prognostic significance in serial pediatric cooperative trials. We also determined that gemtuzumab ozogamicin (GO) improves outcomes for a subset of CBF AML patients with higher CD33 expression enrolled on AAML0531, a randomized trial of conventional chemotherapy with or without GO. Thus, in this study, we determined whether the clinical outcome of patients with KIT + CBF AML is affected by GO treatment.COG AAML0531 enrolled 1022 eligible pediatric de novo AML patients of which 247 had CBF AML [137 t(8;21) and 110 inv(16)/t(16;16)] based on central cytogenetic review. Of these 247 patients, 218 had evaluable samples for KIT mutational analysis. Analysis included PCR amplification of exons 8 and 17 and fragment length analysis and direct sequencing to identify all missense and size mutations. Mutations were detected in 55 patient samples (25%); 27 (49%) involved exon 8, 26 (47%) involved exon 17 and 2 (4%) involved both exons. Breakdown by exon and CBF translocation type demonstrated exon 8 mutations in 12/121 (10%) t(8;21) samples and 17/97 (18%) inv(16)/t(16;16)patient samples. Exon 17 mutations were found in 18/121 (15%) t(8;21) and 10/97 (10%) inv(16)/t(16;16) patient samples.Overall outcome analysis among the 218 CBF AML samples analyzed for KIT mutations revealed similar complete remission (CR) rates after induction I for KIT + vs. KIT- patients (83% vs. 82%, p=0.796). Five-year event-free survival (EFS) from study entry for KIT + vs. KIT- was 54% and 70%, respectively (p=0.029) with a corresponding overall survival (OS) of 76% vs. 83% (p=0.380). Notably, KIT + patients who achieved CR had a relapse risk (RR) of 45% vs. 23% for KIT- patients (p=0.010). Disease-free survival (DFS) for KIT + vs. KIT- was 51% and 72%, respectively (p=0.021).We also compared the clinical impact of exon 8 vs. exon 17 mutations. Outcomes of CBF AML patients with exon 8 mutations were similar to CBF AML patients without these mutations (OS 90% vs. 80%, p=0.277, EFS 55% vs. 68%, p=0.224, DFS 58% vs. 68%, p= 0.419, RR 42% vs. 26%, p= 0.112). In contrast, outcomes of patients with exon 17 mutations were inferior to those CBF AML patients without exon 17 mutations [OS 64% vs. 84%, p=0.035; DFS 43% vs. 70%, p=0.016) and higher RR was observed (48% vs. 26%, p=0.057).The impact of GO treatment on outcome was subsequently evaluated. KIT + CBF AML patients who did not receive GO had inferior OS and EFS from study entry compared to KIT-patients (OS 64% vs. 86%, p= 0.034, EFS: 46% vs. 69%, p=0.037). Higher RR (55% vs. 31%, p= 0.046) and inferior DFS (45% vs. 66%, p= 0.094) were also observed. In contrast, KIT + and KIT-patients receiving GO treatment had comparable outcomes (OS 88% vs. 80%, p=0.393; EFS 62% vs. 72%, p=0.438) as well as RR (33% vs. 15%, p=0.103) and DFS (57% vs. 77%, p=0.109).Analysis by mutation subtype revealed that outcomes of patients with exon 8 mutations were similar to exon 8 wild-type (WT) patients when treatment did not include GO (OS 81% vs. 80%, p=0.910; EFS 50% vs. 65%, p= 0.185). DFS and RR were also similar (DFS 57% vs. 62%, p= 0.752, RR 43% vs. 36%, p= 0.632). Treatment of exon 8 mutations with GO resulted in significant improvement in OS at 5 years from study entry compared to those without exon 8 mutations (100% vs. 80%, landmark p value <0.001) but other outcome parameters were not significantly improved (EFS 62% vs. 71%, p= 0.707; DFS 58% vs. 75%, p=0.382; RR 42% vs. 16%, p=0.056).For patients with exon 17 mutations, treatment without GO resulted in inferior outcomes when compared to CBF AML patients without exon 17 mutations (OS 56% vs. 85%, p= 0.019; EFS 44% vs. 66%, p=0.154; DFS 33% vs. 65%, p=0.049; RR 67% vs. 32%, p=0.031). Adding GO abrogated this negative impact. Specifically, OS, EFS, DFS and RR for patients with exon 17 mutations were comparable to that of CBF AML patients with WT exon 17 when treated with GO (OS 77% vs. 83%, p= 0.542; EFS 62% vs. 71%, p=0.516; DFS: 56% vs. 74%, p=0.195; RR 22% vs.19%, p=0.898).This analysis suggests that pediatric KIT + CBF AML has negative prognostic impact within the context of AAML0531. This effect was abrogated, particularly for patients with exon 17 mutations, with GO treatment. CD33-targeted agents may be beneficial, at least for a subset of these patients, in future clinical trials. DisclosuresAplenc:Sigma Tau: Honoraria.

Standardized costs and outcome in children treated with gemtuzumab on the AAML0531 trial: A report from the Children’s Oncology Group.

7086 Background: NCI-funded cooperative group oncology group trials report clinical outcomes but do not report cost estimates. The Children’s Oncology Group trial AAML0531 randomized 1,022 de novo ...