Search

Background: Despite major improvements in survival, relapse is still a frequent and severe event in pediatric acute myeloid leukemia (AML). Cytogenetic abnormalities represent important predictors of outcome. Improved risk stratification encompassing the identification of novel cytogenetic subsets may allow refinements in treatment strategies and increase survival rates. Hypodiploidy, defined as a modal number (MN) below 46 chromosomes, is associated with an adverse outcome in pediatric acute lymphoblastic leukemia. In childhood AML, the predominant cause of hypodiploidy is loss of a sex chromosome accompanying t(8;21). The most commonly lost autosome is chromosome 7, associated with a poor prognosis. However, other chromosome losses in pediatric AML have not been independently explored. We aimed to investigate the occurrence, genetic characteristics, and prognostic impact of hypodiploidy in childhood AML. Methods: This study was conducted as a retrospective cohort study within the I-BFM-AML framework. Children 0-18 years of age diagnosed with de novo AML between January 2000 to December 2015 and a hypodiploid karyotype were eligible for inclusion. Patients with constitutional hypodiploidy, monosomy 7, composite karyotypes, and t(8;21) with loss of a sex chromosome were excluded. Cytogenetic review was performed according to International System for Human Cytogenetic Nomenclature. Hypodiploidy was considered clonal when occurring in at least three metaphases. The clone with the lowest MN defined the ploidy level. The log-rank test was applied for estimating difference in survival. Considering allografting in first complete remission (CR1) as a time-dependent event, the effect of stem cell transplantation (SCT) on overall survival (OS) was estimated by the Mantel-Byar method. Multivariate analyses included sex, complex karyotype (≥3 non-recurrent aberrations), FLT3-ITD mutation status, and white blood cell count as covariates. As all patients with FLT3-ITD mutations had same MN (MN=45) leading to a skewed imputation model, multiple imputation was not performed, and multivariate analyses included complete cases only (n=54). Results: Hypodiploidy was detected in 81/6,409 patients with full karyotyping from 14 collaborative study groups, yielding a frequency of 1.2% in childhood AML. The cohort displayed a balanced sex distribution (male/female: 42/39) and a median age of 6 (range: 0-17). MNs 45 (n=66), 44 (n=10) and 43 (n=5) were observed. No patient had MN below 43. Eight patients (9.8%) had chromosome loss as the only aberration. Forty-eight patients (59%) had a complex karyotype. Core-binding factor abnormalities were observed in three patients (3.7%). Four patients harbored FLT3-ITD mutations (9.3%, 54 tested). Median follow-time for patients alive was 4.5 years (range: 0.2-15.3). Five-year event-free survival (EFS) and OS were 34% (CI 95%: 23% - 45%) and 52% (CI 95%: 40% - 63%), respectively. Cumulative incidence of relapse was 50% with a median time-to-relapse of 0.8 years. Twelve out of 38 relapsed children (32%) were alive at the end of follow-up. Children with MN≤44 (n=15) had lower EFS (21%, CI 95%: 4% - 46%) and OS (33%, CI 95%: 10% - 59%) than children with MN=45 (n=66, EFS: 37%, CI 95%: 24% - 49%, OS: 56%, CI 95%: 42% - 68%). Crude hazard ratios (HR) for MN≤44 vs MN=45 were 1.8 (p=0.08) for EFS and 1.9 (p=0.1) for OS. After adjustment HRs increased to 4.9 (p=0.001) and 6.1 (p=0.003), respectively. Loss of chromosome Y (n=12) displayed a non-significant superior survival (EFS: 58%, OS: 75%). Poor survival rates were especially observed in monosomy 9 (n=11, EFS: 14%, OS 15%), 10 (n=5, EFS: 20%, OS: 20%), and 16 (n=5, EFS: 25%, OS: 25%), although not reaching statistical significance. Allogenic SCT did not offer any advantage in survival. For children receiving SCT in CR1 (n=18), crude HR for OS was 1.4, p=0.39. Multivariate analysis showed HR for OS at 1.5, p=0.42. Exclusion of children not reaching CR1 (n=7) did not significantly change HRs. This large international study reveals that hypodiploidy is rare in pediatric AML. Children with loss of chromosome 9, 10, or 16 all displayed unfavorable survival rates, whereas loss of chromosome Y did not have influence on prognosis. SCT in CR1 did not improve survival. Our results suggest that modal number has an impact on outcome and may be important for risk stratification. Disclosures No relevant conflicts of interest to declare.

Abstract 3529 Introduction: High hyperdiploidy (51–67 chromosomes) is one of the most common cytogenetic abnormality patterns in childhood B-cell precursor acute lymphoblastic leukemia (ALL) and the clinical and cytogenetic features are well characterized. High hyperdiploidy in pediatric acute myeloid leukemia (AML), however, is a rare cytogenetic finding. It is most often categorized as a complex karyotype, which is considered associated with an unfavorable outcome. The group of complex karyotypes is heterogeneous and the significance of multiple additional chromosomes with or without structural abnormalities among the pediatric hyperdiploid AML patients is relatively unknown. Current knowledge in this field is based on small adult series or case reports. In this descriptive study we describe the clinical - and cytogenetic features in childhood hyperdiploid AML with a modal chromosome number at 50 or more. We report a series of 29 children from the Nordic Countries diagnosed with high hyperdiploid (50+) AML along with 105 cases identified from the literature. Material and Method: Children age 0–18 years diagnosed with AML and treated according to the NOPHO –AML-93 or 2004 protocols from 1993 to 2010 and with a karyotype including at least one clone with a modal number of 50 or more were identified in the NOPHO-AML database. They were compared to all non-hyperdiploid AML children diagnosed in the Nordic countries and treated according to same NOPHO protocols. Furthermore we conducted a literature study searching for hyperdiploid childhood AML (50+) cases using the Mitelman, PubMed, and Scopus databases. The 105 patients from the literature study were compared to the hyperdiploid NOPHO-AML patients. The total cohort of 134 hyperdiploid cases were used to characterize hyperdiploid AML in children Results: Clinical: The 29 hyperdiploid patients from the population based NOPHO-AML database constituted 6% of all childhood AML cases. Compared to all other NOPHO-AML patients, the hyperdiploid had similar sex distribution (45% boys) but were younger, median age 3 years vs. 6.5, had a lower WBC, median WBC 9.5 vs. 19.0, and an excess of M7 28% vs. 6%, (p Cytogenetics: In the total hyperdiploid cohort 100 (75%) were near diploid (modal number 50–57), 8 (6%) were near triploid (58–80), 24 (18%) were near tetraploid (81–103). Only 2 cases were pentaploid (modal number of 117 and 127). Modal number 50 (25%), 51 (19%) and 52 (13%) were most common. The most frequently gained chromosomes were chromosome 8 (78%), chromosome 19 (67%), chromosome 6 (63%) and chromosome 21(58%). (figure 1) Survival data were available for 94 patients: 29 from the NOPHO and 65 from the literature. All chromosomes were represented as additional chromosomes and they were all analyzed for prognostic significance. Additional chromosome 8 indicated favorable outcome (log rank 0.09), whereas additional chromosome 21 was unfavorable (log rank Conclusion: Hyperdiploidy (50+) is found in 6% of childhood AML and is associated with young age, low WBC, and AML M7. Most patients had a modal number of 50, 51 and 52, and the most frequently gained chromosomes were 6, 8,19, and 21; a distinctively different pattern from the high-hyperdiploid ALL. Overall survival in the hyperdiploid patients seems similar to the non-hyperdiploids. Gain of chromosome 8 was associated with favorable outcome whereas gain of chromosome 21 was associated with an inferior outcome. Disclosures: Hasle: Pfizer: Research Funding.