Treatment advances over the past 40 years have led to improved prognoses for children and adolescents who are diagnosed with acute myeloid leukemia (AML). However, there are many opportunities for the further improvement of survival and quality of life, including the creation of more effective and less intensive chemotherapy regimens, the addition of targeted therapies to chemotherapy, and a shift away from hematopoietic stem cell transplant (HSCT), which is associated with long-term sequelae.

The survival of pediatric patients with AML has recently been reported to be as high as 80%. While these data may be accurate in the United States, they are actually restricted to a very small number of patients who are admitted to protocols and may not reflect what occurs in real-world treatment, especially in developing nations.

Transplant medicine has progressed a lot, with fewer complications, a better understanding of graft-versus-host disease, and the ability to provide post-transplant treatments such as donor lymphocyte infusion. This seems wonderful, but, if we start looking at the late side effects in children who have undergone HSCT, we start having second thoughts. A study from St. Jude of patients with AML who were more than 10 years from diagnosis and at least 18 years of age at the time of evaluation looked for chronic conditions, neurocognitive function, and functional impairment. Those who underwent HSCT experienced more cumulative burden compared with those who received chemotherapy. So, in pediatric patients, I think that it is a major problem to focus only on transplant; we need to be working to discover other options.

We know from very early studies that we can cure some patients with very low-risk AML using mild chemotherapy. If we can better identify these low-risk patients, then they can receive much less therapy. I estimate that approximately 25% of patients may fall into this category and can be treated with chemotherapy alone. Now, can we improve chemotherapy? For many years, cytarabine plus anthracycline was the only combination that proved to be effective. In 2007, however, we began seeing more options for chemotherapy agents and the so-called molecularly targeted therapies.

How can we integrate these medications in ways that are effective in pediatric patients? We know that combining targeted therapies with chemotherapy is not enough. For example, the phase 3 AAML1031 study looked at patients with de novo AML to see if increasing treatment intensity with the addition of bortezomib to standard chemotherapy would improve survival. The addition of bortezomib did not improve survival, but it did increase toxicity. The phase 3 AAML0531 trial evaluating the addition of the antibody-drug conjugate gemtuzumab ozogamicin to chemotherapy for de novo AML reported significantly improved event-free survival but no improvement in overall survival.

In conclusion, we can estimate that 70% to 80% of children with AML living in developed nations now survive. We also know that intensifying conventional chemotherapy will not improve these results and may be associated with long-term sequelae. Right now, HSCT is very important, but we have to be concerned with what our other options will be. Future research is needed to understand the mechanism of leukemia resistance to chemotherapy. We also have to determine the role of the new targeted drugs and how to integrate them with conventional chemotherapy.