Results
The majority of cases were negative for the 43 fusion genes identifiable in leukemia at the time of the study, with only two cases positive for the fusion protein AML1/ETO.
The 5-year OS and EFS rates of the 15 cases were each 80±10% (Fig. 1). There were 2 cases of recurrence (13.3%) and 1 case of chemotherapy-related death (6.7%) (Table I).
All cases had varying degrees of myelosuppression after HDCT, as expected. Approximately one-half had fever, myalgia and bone pain, and occasionally chest pain, maculopapular rash, conjunctivitis and other symptoms 6-12 h after administration. The general condition of the patients was satisfactory, although antibiotics were not effective for patients with a high fever (n=2), suggesting they had the rare post-cytarabine syndrome, which is characterized by a fever, malaise, myalgia, arthralgia and/or a rash (9). In this case, corticosteroids were used for prevention and treatment.
Discussion
The prognosis of pediatric AML has been improving over the years; however, in most collaborative groups, the 5-year OS rate after chemotherapy alone remains at ~75% (10). Schweitzer et al (11) found that treatment using the AML-Berlin-Frankfurt-Münster (BFM) 2004 protocol (not with chemotherapy alone) yielded a 5-year OS rate as high as 70% in patients with acute megakaryoblastic leukemia, where patients received a randomized induction therapy of Ara-C, liposomal daunorubicin (L-DNR) and etoposide. Similarly, Rubnitz et al (12) reported 3-year OS and EFS rates of 75 and 66%, respectively, in children aged 0 to 9 years who underwent AML-02 treatment [high-dose cytarabine (3 g/m2 every 12 h on days 1, 3 and 5) or low-dose cytarabine (100 mg/m2 every 12 h on days 1-10) plus daunorubicin (50 mg/m2 on days 2, 4, and 6) and etoposide (100 mg/m2 on days 2-6)]. The primary cause of treatment failure in AML is the high risk of recurrence, and thus increasing the intensity of consolidation treatment after remission might be beneficial (13). Notably, the application of high-dose Ara-C in the consolidation phase has resulted in better outcomes (14).
In the present study, HDCT therapy was improved upon by increasing the dosage of Ara-C and combining consolidation and maintenance therapy. In 2002, treatment with Ara-C was started for pediatric AML, using standard induction therapy followed by HDCT as aforementioned. The cumulative dose of 108 g/m2 cytarabine is 3 times the maximum dosage suggested by Herzig et al (1983) (5). A complete regimen of HDCT achieved 5-year EFS and OS rates of 80%.
In recent years, the application of high-dose cytarabine in the consolidation phase has resulted in better AML treatment outcomes worldwide. The treatment regimens used by the various collaborative groups are basically similar, and these have been found to achieve a remission rate of ~90% (15).
Although only a small number of patients were enrolled in the present study, the follow-up time was long at up to 20 years. This allowed a long-term assessment of efficacy, proving the durability of the curative effect. One patient (male, 4 years old, M2 type) was admitted to the hospital and received only one course of treatment, in January 2001. The patient was withdrawn from the therapy in the early intensive phase for economic reasons and therefore was excluded from the analysis.
AML is still known as a threat to humans, and in China, investigators keep exploring better therapeutic approaches for the disorder. In recent years, some significant advances have occurred in the treatment for AML, such as the addition of gemtuzumab ozogamicin (GO) or bortezomib to traditional chemotherapy, which have improved the prognosis (EFS, 48% with GO vs. 29% without; OS, 63% with GO vs. 53% without) (16), but the outcomes are still not satisfactory. Cytarabine, daunorubicin and etoposide (ADE) is an effective induction regimen for pediatric patients with relapsed AML, and a study by Garg et al obtained 2-year EFS and OS rates of 29% (±7%) and 34% (±7%) at the first relapse, with a complete remission rate of 66% (17).
HDAC improves OS and relapse-free survival rates in induction therapy while reducing the relapse rate in consolidation therapy, especially for the favorable-risk group. In one study, patients randomly assigned HD cytarabine treatment obtained 6-year OS rates of 42.5%, compared with 38.7% for those receiving standard cytarabine (18). The median OS time of patients with AML in a study also using high-dose cytarabine in Brazil was 23.5 months for the M0, M1 and M2 subtypes, 97.7 months for M3, and 7.4 months for M4, M5, M6 and M7, with a poor prognosis in most patients (19).
It has been noted that Ara-C in a dosage of 3 g/m2 twice daily provides a maximal therapeutic effect in consolidation chemotherapy for adult patients with AML, associated with grade 3-4 non-hematological toxicity (20), but the optimal dosage for pediatric patients with AML is still controversial. Studies have evaluated high-dose cytarabine in induction therapy for children with de novo AML in Japan, adopting HD-ADE therapy, and suggested that Ara-C in a dosage of 3 g/m2 twice daily obtains a good outcome with improved disease-free survival rates (21). In Saudi Arabia, the 5-year OS rates for the low-risk, intermediate-risk and high-risk groups were 72.0±6.9, 59.8±6.2 and 45.1±7.4%, and the EFS rates were 50.5±8.0, 46.3±6.4 and 23.3±6.4% (22).
Notably, the HDCT regimen developed in this study is clinically safe and effective, with relatively low cost, as it successfully reached 5-year EFS and OS rates of 80%. It should be emphasized that this regimen not only has great therapeutic value, but that also its EFS and OS rates for pediatric AML reach the current international leading level, and even the international leading academic level for hematological malignancies. HDCT seems an optimal option for childhood leukemia with chemotherapy alone.
According to a summary of treatments for AML from 8 international organizations involving the Children's Oncology Group, Berlin-Frankfurt-Munster, the Italian Association of Pediatric Hematology Oncology, and the European Organization for Research and Treatment of Cancer, the 5-year EFS rate ranges from 55.5 to 77.7% (23-26). This indicates that in the world, the highest 5-year EFS rate reaches ~77%, which is the result of not only chemotherapy, but also immune and targeted therapy. Thus similarly high or slightly higher rates of long-term remission are achieved by more complex regimens. However, these may not be available in numerous parts of China, for various reasons, including difficulties in finding a fully matched donor for transplantation, expense of medical care and the presence of a number of complications. Another issue is that AML is prone to relapse. As in most developing countries, most Chinese people usually only accept chemotherapy for leukemia, so it is imperative to seek a low-cost and efficient chemotherapy regimen.
In conclusion, HDCT therapy is clinically safe, effective and relatively low cost, and thus should be strongly considered in limited access (remote) or underserved areas.