Unconventional Strategies May Be Required for TP53-Mutated AML

Unconventional strategies and targeted therapeutics may be required to overcome the adverse risks associated with TP53-mutated acute myeloid leukemia (AML), according to John Sutton Welch, MD, PhD, of Washington University School of Medicine in St. Louis, Missouri. At the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago, an educational session was held that reviewed core binding factor (CBF)-AML (the good), secondary AML (the bad), and TP53-mutated AML (the ugly). Dr. Welch presented what currently is known about treating TP53-mutated AML and what is on the horizon in, “The Ugly: p53-Mutated Acute Myeloid Leukemia-Can It Be Solved?”

Welch noted that identifying the good, the bad, and the ugly forms of AML is helping clinicians better select patients likely to require more aggressive therapeutic intervention following induction chemotherapy. “TP53-mutated AML appears to be a subcategory of AML. In multiple series, these patients [have] very poor outcomes with cytotoxic chemotherapy. We found that there is not an adverse outcome when these patients receive decitabine, and that they may respond more consistently to decitabine,” said Welch.

However, he noted that decitabine by itself does not lead to deep molecular remissions. “Relapse is the norm as new subclones emerge that have gained decitabine resistance,” said Welch. Subsequently, TP53-mutated AML is a subset of AML with consistently dismal outcomes and one that will need a different approach.

“The molecular mechanisms that facilitate acquired decitabine resistance have not yet been defined, but it is clear that additional consolidation therapy is required using stem cell transplant or novel therapies that are being developed,” said Welch.

The US Food and Drug Administration (FDA) approval of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, for the treatment of newly diagnosed therapy-related AML (t-AML) and AML with myelodysplastic syndrome (MDS)-related changes now marks an important step forward. The FDA has also approved gemtuzumab ozogamicin as a first-line treatment for CBF-AML.

Welch said that the FDA approval of gemtuzumab ozogamicin and CPX-351, coupled with the impressive results of decitabine in TP53-mutated AML, is ushering in a new era. An improved and growing understanding of the molecular and biologic underpinnings of AML is allowing clinicians to view AML in an increasingly nuanced way.

David Sallman, MD, of the malignant hematology department at the Moffitt Cancer Center & Research Institute in Tampa, Florida, said looking at each type of AML separately helps to tailor therapy and better categorize patients as being high risk, intermediate risk, or low risk.

“We understand from a prognostic standpoint that TP53-mutant AML represents a molecular cohort with poor overall survival and significant decreased benefit for all standard-of-care therapies. Novel therapeutics are urgently needed for this molecular subgroup,” said Sallman. “One exciting clinical trial option is the combination of azacitidine with the p53 reactivator APR-246, which is currently enrolling for patients with high-risk MDS and AML.”