In the present study, the clinical outcome of the BHAC-based regimen, consisting of BHAC, idarubicin, and 6-TG, are comparable to that of the cytarabine-based regimen for childhood AML. In a phase II study, BHAC monotherapy for adult AML produced a 36% CR rate and adverse events such as nausea and vomiting were less than for cytarabine (17
). In a comparative study between BHAC and cytarabine in combination induction and consolidation therapy for adults with de novo AML, the efficacy of BHAC given with daunorubicin was found to be inferior to that of cytarabine in combination with daunorubicin (14
). However, the dose of BHAC was not equivalent to that of cytarabine in terms of the mean leukocyte nadir of both groups (18
). In Korea, the combination regimen consisting of IDA and BHAC has been widely used for induction or post-remission therapy for adult and childhood AML since 1996. Park et al. (13
) reported that IDA-BHAC combination regimen for previously untreated adult and childhood AML showed a high CR rate (75%), which was similar or superior to results obtained with cytarabine and other anthracyclines. However, a small number of children (22%) were included in their study and follow-up duration was too short to draw a complete conclusion.
The anti-leukemic efficacy of IDA-BHAC regimen in remission induction appears to be effective, with a high CR rate (85.2%) compared to the CR rate (71.7%) of cytarabine-based regimen in our study. The proportion of NR is comparable between the 2 groups after remission induction chemotherapy (4% in the BHAC group; 4.7% in the cytarabine group). In the present study, children in the two groups have a similar 5-yr estimate of OS (55% in the BHAC group; 53% in the cytarabine group). These results are comparable to previously summarized results of the AML-BFM93, UK-MRC AML10, CCG-2891, and NOPHO-AML93, which enrolled patients between 1988 and 2001 (2
). Children with de novo AML in these studies showed CR rates of 78-93%, induction death rates of 2-7%, proportion of NR of 3-18%, and 5-yr estimates of OS of 47-66%. The addition of other agents to the standard "7+3" induction regimen did not improve the remission rate, OS or EFS in children and adolescents with AML in UK-MRC AML10 trial and CCG-213 study (2
). In our results, the addition of etoposide improves the remission rate. However, children who received the three types of induction regimen have shown similar long-term outcome in terms of OS and EFS.
Since the cytotoxic effect of cytarabine is time-dependent and S-phase specific, the standard dose of cytarabine is thought to have better therapeutic effects when administered by continuous IV infusions rather than by short-time IV infusion (7
). Because BHAC, a new cytarabine analogue, has a long plasma half-life after IV administration and releases cytarabine slowly, it may give the same effect as continuous cytarabine infusion (19
). Studies of Nara et al. (10
) have demonstrated that BHAC is rapidly taken into leukemic blasts and converted to cytarabine, and has a suppressive activity on self-renewal of leukemic blast progenitors in vitro. Therefore, BHAC may contribute to these results which are comparable to those of cytarabine-based chemotherapy.
In our study, the 5-yr estimates of EFS and OS for children appear to be much lower in the chemotherapy group than in the transplantation group. In this retrospective survey, the chemotherapy group includes induction deaths and has more nonresponders than the transplantation group. Although autologous and allogeneic HSCT represent approaches to dose intensification, several randomized studies in pediatrics have shown no advantage of autologous HSCT compared to chemotherapy alone and the majority of clinical trials have demonstrated a consistent advantage for allogeneic HSCT in terms of disease-free survival, but not always for OS (3
). In our study period, allogeneic HSCT was recommended to all patients in first remission with HLA-matched familial or unrelated donors and autologous HSCT was performed for patients without an available donor. The patients who were not candidates for HSCT received intensive chemotherapy according to the institutional principle. Therefore, our study is not a prospective randomized trial comparing chemotherapy with HSCT and our results may have a selection bias in survival analysis. For this reason, our results do not suggest the superiority of transplantation over intensive chemotherapy but the comparable outcomes of IDA plus BHAC and 6-TG versus idarubicin plus cytarabine-based regimen in childhood de novo AML regardless of post-induction therapy.
The cytogenetic aberrations in our study show a high proportion of children with t(8;21) compared to other studies (2
). In our pediatric population, the children with favorable karyotypes such as t(8;21) or inv(16) appear to show a better outcome than those with an unfavorable kayrotype in both the BHAC and cytarabine group. However, recent reports suggest that t(8;21) and inv(16) AMLs seem to be distinct clinical entities and should be stratified and reported separately when considering race, secondary cytogenetic abnormalities (23
). Karyotype markers with unfavorable implications also have been identified, such as -5/del(5q) and -7/del(7q) (3
). In our data, the patients with -7/del(7q) show a very poor prognosis compared to the reported figure (21
). Only two patients had -5/del(5q), a rare cytogenetic abnormality in children, so it appears difficult to draw any conclusion. This issue needs to be elucidated further in the future, as well as the other prognostic implications such as FLT3 internal tandem duplications (FLT3-ITDs) (25
This study is limited by its retrospective nature. Patients are not equally randomized into the BHAC group and cytarabine group in induction or post-remission therapy at each institution. There is a little heterogeneity in the induction regimen and post-remission therapy in terms of administration schedule of cytarabine, addition of etoposide, and different consolidation schedule. However, the main point of our investigation is that BHAC shows a similar efficacy compared to cytarabine in combination chemotherapy in view of induction response and long term survival. Another limitation is that the information for adverse events during induction therapy is not enough to compare the two groups in terms of regimen-related toxicity. Since childhood AML is a rare disease, further studies with a prospective, randomized, multiinstitutional cohort are required to validate the results of our study and additional studies about risk-directed therapy including post-remission intensive chemotherapy and HSCT are warranted.