Acute Megakaryoblastic Leukemia in Children without Down’s Syndrome.
Authors: Reinhardt Dirk , Diekamp Sylke , Ritter Joerg , Langebrake Claudia , Fleischhack Gudrun , Dworzak Michael , Stary Jan , Harbott Jochen , Ludwig Wolf-Dieter , Creutzig Ursula 
Published: October 2019

Abstract
Acute megakaryoblastic leukemia (AMKL) in children without Down’s syndrome occurs in less than 10% of childhood AML. Data on clinical presentation, immunological and genetic features and treatment strategies are rare.
Between 6/1987 and 7/2003 89 children with AMKL (m=46; f=43) were treated according to the AML-BFM trials 87 (n=19), 93 (n=39) and 98 (n=31). AML FAB M7 was centrally confirmed by immunophenotyping (n=86) or immunohistology (n=3). The median age at diagnosis (1.5 yrs) was significantly lower compared to other children with AML (total group n=1,149; median age 7.8 yrs; p<0.004). The percentage of AMKL in the AML-BFM trials was 6%. Children with AMKL presented with anemia (93%), thrombocytopenia (88%) and hepatomegaly (83%). Hyperleukocytosis (> 100,000/μl) was less frequent (13%) compared to other AML subtypes (21%; p<0.0001). Immunophenotyping revealed the co-expression of stem cell antigens such as CD34 (61%) and CD117 (82%), myeloid antigens (CD33/CD13) and megakaryocytic antigens (CD41/CD42/CD61). The aberrant expression of CD7 (92%) was significantly increased (other AML subtypes 29%; p<0.0001). Cytogenetics revealed several aberrations such as t(1;22) (14%), monosomy 7 (12%) and trisomy 8 or 21 (7%), but mostly not isolated.
The complete remission rate increased from 58% in study AML-BFM 87 to 77% and 83% in AML-BFM 93 and 98 (p<0.05), respectively. The outcome of all children with AMKL was as follows: 5-year event-free survival (EFS) 40±5%; disease-free survival (DFS) 49±6%; overall survival (OS) 42±6%. Compared to children with high risk (HR)-AML (n=714) treated in the AML-BFM studies, the EFS was similar (40±6% vs. 43±2%; p= 0.44). Due to poor response to relapse treatment, the OS tended to be inferior (AMKL 44±6% vs. HR-AML 52±2%; p=0.13).
The treatment intensification in AML-BFM 93 and 98 with high-dose cytarabine and mitoxantrone (HAM) as second induction resulted in a significantly improved EFS (46±6%), DFS (58±7%) and OS (49±6%) compared to AML-BFM 87 (11±7%, 18 ±12%. 21±9%; p<0.009).
There was no significant difference of outcome between children treated with chemotherapy only (n=54) or allogeneic stem cell transplantation (alloSCT) in 1st CR (n=13 ) DFS 50±7 vs 37±14; p=0.49; OS 54±7 vs 43±15%; p=0.47).
Considering gender, age, WBC, blast percentage, immunophenotype or cytogenetic subgroup (available n=74; 83%) no prognostic factor could be identified. Children with poor response (n=19) or relapse (n=33) had a very unfavorable outcome. Only 5 of these children survived. Two children stayed alive in CR after relapse chemotherapy (follow-up 12.8 and 11.3 years), two after alloSCT (follow-up 1.4 and 2.4 years) and one child was alive with disease after alloSCT and relapse (follow-up 0.6 years). In conclusion, in children with AMKL intensive chemotherapy enabled a remission rate and a long-term survival comparable to other childhood HR-AML. AlloSCT seemed not to improve outcome. Therefore new approaches for the treatment of AMKL in children are needed.