Epidemiology, Cytogenetic and Molecular Abnormalities and Outcome of Childhood Acute Myeloid Leukemia- an Israeli Retrospective Multicenter Study

Introduction

Acute myeloid leukemia (AML) contributes to 18% of childhood leukemia cases and about 50% of all deaths of pediatric leukemia in the United States .In high-income countries, intensive therapy has increased survival rates to 60-70% . Contributing factors to the improved survival include refinement in the diagnosis of AML and advancement in therapeutic approaches.

In light of the ethnic diversity in the Israeli population, we reviewed patient's data and investigate whether the clinical, biologic and molecular features differ between Israeli Arab and Jewish AML patients.

Patients and Methods

We performed a retrospective epidemiological and clinical study including patients younger than 18 years of age, treated at all six Israeli pediatric oncology centers between 2000-2015. Down syndrome and secondary AML were excluded . The clinical characteristics such as gender, age, subtype of FAB, leukocyte count at diagnosis, cytogenetics and molecular markers were analyzed in correlation with their prognosis between different characteristics groups and different ethnicity. Survival analyses were calculated by Kaplan-Meier survival curves and the log rank test. Multivariate analyses on categorized data were performed using Cox proportional hazards model.

Results

We analyzed 175 patients, 46% females and 54%, males, 15 % younger than 2 years old, 35% from 2 to 10 years and 50% older than 10 years (median age 9.3±5.6 years ). According to FAB subtype, the majority subtypes were M2 and M4 for 26% and 27% respectively , 40% of patients presented WBC count below 10 X 10⁹/L at diagnosis while 13% of patients higher than 100 X 10⁹/L. The most common cytogenetic abnormalities in these children, including t(8;21)(q22;q22), inv(16)(p13.1q22) and 11q23/MLL-rearranged abnormalities were detected, with the occurrence of 18% , 8% and 13% respectively.

Acute promyelocytic leukemia (APL) was diagnosed in 14% of the children. Molecular data such as FLT3 were not evaluated due to small numbers.

No statistical difference was observed regarding ethnicity as to age, white blood cell (WBC) and central nervous system (CNS) involvement. However, the Arab patients presented with a significantly higher incidence of M2 (42% vs 23% p=0.035), while the Jewish population demonstrated significantly higher incidence of M4 (33% vs. 10% p=0.011). The high incidence of M3 was common to both ethnic groups. In addition, cytogenetic subtype distribution was similar in both ethnic groups.

Out of 175 patients, 114 patients were treated in accordance with the same protocol, namely BFM98 . The demographic characteristics of these 114 pts, as well as their WBC, FAB and cytogenetics were distributed similarly to the whole cohort.

Among the 114 AML patients, 105 pts achieved complete remission (CR) (92%) after one course of chemotherapy. Of those who achieved CR after 2 induction cycles, 62 pts are alive and free of disease, 38 pts relapsed, 4 pts died in CR ( 3 due to bacterial infection and 1 due to post transplant lymphoproliferative disease) , one patient developed myelodysplastic syndrome after treatment for APL . Six patients did not go into remission after two induction phases. Three patients had early death (within six weeks of diagnosis), all due to bleeding- 2 were APL and one with MLL split and hyperleukocytosis.

The median follow-up was 6.3 years (0.7y-16y), with a 5-year event free survival (EFS) and overall survival (OS) of 54% and 67% respectively.

There was no prognostic significance in EFS and OS related to gender, age and ethnicity.

As to risk stratification, there was a statistical difference in EFS and OS in the standard risk (SR) and the high risk (HR) group: 5 year EFS SR group 83% and 39% for HR group (p<0.0001) 5 year OS for SR group 98% and 52% for HR group (p<0.0001).

Conclusions

In this retrospective study of pediatric AML patients in Israel,the clinical, laboratory and cytogenetic characteristics were not significantly different between Jewish and Arab patients, with a similar outcome. We report a 14% incidence of APL - an incidence that is higher than that reported for the European and American populations. It may be of interest to further investigate this increased rate of APL in the Israeli population and possibly identify underlying genetic predisposing factors.

The pts treated according to AML-BFM-98 protocol without pCRT have a 5y EFS and OS of 54% and 67%, respectively. These outcomes are similar to those reported for BFM98.