Abstract
Acute myeloid leukemia harboring internal tandem duplication of fms-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis, but the previous studies have reported that the inferior outcome is only confined to those with high allelic ratio (AR) of ITD/wild type (WT). In our previous AML99 study (2000-2002), AMLFLT3-ITD showed a poor outcome compared to the WT cases (5-year OS; 35% vs. 84%, P<0.0001). We, therefore, assigned all the patients with AMLFLT3-ITD to receive hematopoietic stem cell transplantation (HSCT) in first remission (1CR) in the JPLSG AML-05 study.
AML-05 study, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, is a Japanese nation-wide multi-institutional study for children (age<18 years) with de novo AML and enrolled 443 eligible patients from Nov. 2006 to Dec. 2010. Cases with acute promyelocytic leukemia or Down syndrome were excluded. FLT3-ITD was examined centrally for all the patients. After the 2 consecutive induction chemotherapies [(ECM: etoposide, Ara-C, and mitoxantrone) and (HCEI: HD Ara-C, etoposide, and idarubicin)], all the AMLFLT3-ITD patients were allocated to the high risk group and further received intensification therapy including HD Ara-C followed by HSCT in 1CR. All DNA samples were extracted from the first diagnostic bone marrow or peripheral blood and subjected to PCR and direct sequencing. AR of FLT3-ITD/WT was examined by GeneScan, and defined AR >0.4 as high and AR ≤ 0.4 as low as previously reported (Meshinchi S. Blood2006).
We found 47 patients (10.6%) with AMLFLT3-ITD in this study (30 males, 17 females, and median age of 11 years at diagnosis). The median WBC count was 65,300/ml (3,690 - 522,050/mL). FAB classification included M1 (n=10), M2 (n=9), M4 (n=9), and M5 (n=11), and AML with normal karyotype was dominant (19/47, 40.4%).
Of the 29 patients (61.7%) who achieved CR, twenty-seven received HSCT in 1CR and 19 patients survived (19/27, 70.4%). On the other hand, 14/16 non-CR patients received HSCT, but only 4 survived. The only demographic difference between the 29 CR and 16 non-CR cases was the median WBC count at diagnosis (19,000 vs. 124,000/μL, P<0.001), and rapid clearance of bone marrow blasts after single induction course was observed in the CR group (median blast percentage dropped from 73% to 1.1% in the CR group, while that was 85% to 30.6% in the non-CR group). Finally, five-year OS, DFS and EFS for all 47 AMLFLT3-ITD patients were 41.3%, 58.4% and 36.1%, respectively.
AR was analyzed in 44 patients with median ratio of 0.68 (range, 0.11 to 4.47). Median AR was not different between CR vs. non-CR cases (0.53 vs. 0.72). There were no difference in 5-year OS (52.8% vs. 42.5%, P=0.302), DFS (54.5% vs. 64.5%, P=0.524), and EFS (50.0% vs. 34.4%, P=0.283) between patients with low (n=12) and high AR (n=32), however, induction rate was significantly higher in the low AR patients (91.7% vs. 53.1%, P=0.018).
It was rather surprising that all FLT3-ITDs were found only in JM domain and not in TKI domain in the current trial. In addition, six of 47 (12.8%) AMLFLT3-ITD patients had NPM1mutation simultaneously, and all received HSCT at 1CR and survived.
We observed a different induction rate between AMLFLT3-ITD patients with low and high AR, but poor final outcomes in both. Regardless of the level of AR, patients with AMLFLT3-ITD, especially who fail to achieve remission, have dismal outcome and effective therapy combined with novel FLT3 inhibitor is urgently needed to overcome the disease.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
