By Christine Duncan, MD
The story of the treatment of pediatric acute lymphoblastic leukemia (ALL) is one of tremendous progress, with overall survival rates now exceeding 80 percent. Unfortunately, that progress has not been mirrored in pediatric acute myeloid leukemia (AML). Dedicated investigators continue to wage a battle against AML on multiple fronts: refining risk stratification, improving standard chemotherapy regimens, and introducing new molecularly targeted therapies.
The pediatric AML therapy Oral Session today at 4:30 p.m. (rooms 343-345) will highlight recent advances in AML therapy. The results of three multi-center trials — from the Associazione Italiana Ematolgia Oncologia Pediatric (AIEOP), the International Berlin-Frankfurt-Münster (BFM) Study Group, and a consortium led by St. Jude Children’s Research Hospital — will be presented.
Risk stratification is the foundation for pediatric AML therapy. The AIEOP has further refined risk-group stratification, with positive results. The group stratified children with newly diagnosed AML as having standard-risk disease (i.e., patients with AML1-ETO fusion transcript or anomalies of CBFβ who achieved complete remission after the first induction); all other patients were considered high-risk. Allogeneic or autologous stem cell transplantation in first remission was offered to all patients in the high-risk category. The authors report event-free survival rates greater than 50 percent and low transplant-related mortality regardless of donor type.
Risk stratification is not limited to features present at diagnosis. Dr. Jeffrey Rubnitz of St. Jude Children’s Research Hospital will discuss the results of the multi-center AML02 trial, which used the presence of post-induction minimal residual disease (MRD) to direct therapy (abstract #16). All patients received initial induction with daunorubicin and etoposide and were randomized to receive either high-dose or low-dose cytarabine also. Induction II consisted of low-dose cytarabine, with gemtuzumab ozogamicin added if >1 percent MRD was present following induction I. The encouraging results included an overall CR rate of 95 percent following two cycles of induction chemotherapy and three-year overall survival of 70 percent.
Relapsed AML remains a major therapeutic challenge. Dr. G.J.L. Kaspers of the Dutch Childhood Oncology Group will present the results of the randomized International BFM Study Group trial, which added liposomal daunorubicin to a FLAG (fludarabine, cytarabine, and G-CSF) regimen for reinduction (abstract #18). The addition of liposomal daunorubicin led to a 12 percent higher early good response compared with patients who received FLAG alone. The study reports a 35 percent probability of overall survival at four years.
Autologous stem cell rescue following high-dose chemotherapy in the treatment of AML has been limited by the potential for leukemic contamination of the stem cell product and the loss of viable progenitor cells during purging. Researchers from the University of Florida, Gainesville, may have a solution to this challenge: the myxoma virus, an oncolytic poxvirus that selectively targets leukemic cells while sparing healthy progenitor cells. Using in vitro and murine in vivo experiments, the group has shown the safety and efficacy of ex vivo purging of leukemic cells from autologus stem cells.
Dr. Anna Sergeeva from the University of Texas M. D. Anderson Cancer Center and her colleagues are investigating a monoclonal antibody (8F4) specific to PR1, an HLA-A2-restricted peptide derived from myeloid leukemia antigens (abstract #15). 8F4 induced in vitro dose-dependent cell-mediated lysis of blasts from patients with HLA-A2 positive AML. Data from a murine AML model supported the specificity of 8F4 lysis of PR1/HLA-A2 positive blasts and leukemic stem cells.
Dr. Wei Liu of Cincinnati Children’s Hospital Medical Center will present work on a small molecule that specifically inhibits activity of Cdc42, a Rho GTPase family member that is a central regulator of cell proliferation, adhesion, and migration (abstract #13). The molecule has been shown to mobilize and lead to apoptosis of leukemia-initiating cells. We await the further development of this promising agent and the other projects presented at the oral session.
Dr. Duncan indicated no relevant conflicts of interest.
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