Clinical Evaluation of Antibody-drug Conjugates and Targeted Cancer Agents for Acute Myeloid Leukemia (AML)

Acute myeloid leukemia (AML) accounts for roughly 20 percent of all diagnosed childhood leukemias in the US. Current intensive cytotoxic chemotherapy regimens achieve long-term cure in only 60 percent of AML pediatric patients. Relapsed and chemotherapy-refractory AML accounts for more than half of annually reported childhood leukemia-related deaths.

Because of the success treating adult cancers with antibody drug conjugates and targeted small molecule drugs, researchers at the Center for Childhood Cancer Research, under the direction of Richard Aplenc, MD, PhD, MSCE, are currently evaluating these therapies in Phase III clinical trials as treatments for AML. These two national Phase III trials are being conducted by the Children’s Oncology Group (COG)

The results from a randomized Phase III clinical trial (AAML0531) involving 1,022 children and adolescents newly diagnosed with AML revealed that gemtuzumab-ozogamicin (GO), a humanized monoclonal antibody immunoconjugate directed against CD33, combined with conventional chemotherapy improved event-free survival by reducing AML relapse risk. CD33 is expressed in most leukemic cancer cells. These results suggested that GO treatment, rather than chemotherapy dose escalation, may help to improve long-term clinical outcomes for children and adolescents with AML. Dr. Aplenc was the Vice-chairman of this trial and is leading several secondary analyses of AAML0531 data.

Another COG-sponsored, randomized Phase III clinical trial (AAM1031) is underway at the Center for Childhood Cancer Research to evaluate the safety and efficacy of the targeted cancer agents bortezomib or sorafenib tosylate in combination with conventional chemotherapy on children and young adults with newly diagnosed AML. Bortezomib is a proteasome inhibitor, whereas sorafenib tosylate inhibits tyrosine and serine kinases. Both agents have been approved as targeted therapies to treat a variety of adult cancers. Dr. Aplenc is the Chair of this trial and is leading the analyses of clinical data from this trial.

Additional clinical trials are currently being developed to evaluate new immunotherapies and targeted cancer drugs to treat children and young adults with AML.