Harry Erba, MD, PhD
An estimated 19,520 new cases of acute myeloid leukemia (AML) are expected in the United States in 2018, representing approximately 1.1% of all new US cancer cases.1 Until 2017, there was little drug development in AML—treatment largely revolved around standard chemotherapy regimens, as it had for the past 40 years. By the end of 2017, however, there were 4 new drug approvals by the FDA , as well as many other agents showing promise in clinical trials (Table2-9
). These treatment advances have been attributed to increased understanding of molecular drivers of AML. During an OncLive Peer Exchange®
moderated by Harry Erba, MD, PhD, a panel of AML experts discussed these newly approved agents and provided insight on how they are rapidly changing the standard of care for various AML subgroups. They also provided insight on several promising agents on the horizon.
Newly Approved Agents
All 4 newly approved AML drugs are targeted agents, but each targets the disease in different ways. “CPX-351 [Vyxeos] is the liposomal daunorubicin/cytarabine formulation that’s targeted to a clinically defined group of patients: those with treatment-related AML and AML with myelodysplasia-related changes. Then there are 2 drugs targeted to mutations: midostaurin [Rydapt], for patients with previously untreated AML with FLT3
-ITD or FLT3
-TKD mutations, and enasidenib [Idhifa], which is the oral IDH2 inhibitor approved for IDH2
-mutated AML in relapsed or refractory disease. Finally, we have a different kind of targeted therapy, an antibody–drug conjugate against CD33: gemtuzumab ozogamicin [Mylotarg],” Erba said.Midostaurin
Midostaurin was approved in combination with chemotherapy based on data from the phase III RATIFY trial.2,10
In the study, 717 patients were randomly assigned to midostaurin (n = 360) or placebo (n = 357). Randomization was stratified by FLT3
mutation subtype: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with a high ratio (>0.7) or a low ratio (0.05-0.7) of mutant to wild-type alleles. The FLT3
-ITD subtype was ITD high in 214 patients, ITD low in 341 patients, and TKD in 162 patients. Compared with patients in the placebo group, those in the midostaurin group had significantly longer overall survival (OS) (HR for death, 0.78; one-sided P
= .009) and event-free survival (HR for event or death, 0.78; one-sided P
= .002). The benefit was consistent across all FLT3
“This is the first agent, when added to chemotherapy, to really show a benefit,” Eunice Wang, MD, said, “and that was a 4-year overall survival benefit. Survival curves were distinct, and they remain distinct. In fact, when you look carefully at the curves, the difference in the overall survival curve seems to separate out shortly after induction and continue along the therapy during induction and consolidation."
Based on RATIFY findings, adding midostaurin has become the standard of care for newly diagnosed AML patients with FLT3
mutations who are receiving induction chemotherapy with anthracycline and cytarabine and in combination with consolidation. Midostaurin's benefit in a larger subgroup of AML patients has yet to be investigated, but it may be helpful because it also targets multiple tyrosine kinases. “[Midostaurin] was developed as a pan-tyrosine inhibitor,” Wang explained.
The panelists discussed 2 key considerations with use of midostaurin in clinical practice. First, the companion diagnostic test for FLT3
-ITD and TKD mutations, which is a polymerase chain reaction (PCR) assay, might show a positive result, whereas next-generation sequencing might show a negative result. This is because technical challenges with sequencing can cause FLT3
mutations to be missed. “That’s a practical lesson here: A PCR-based assay should be done for FLT3
at the time of diagnosis because the next-generation sequencing panel may miss it,” Erba said.
Table. Newly Approved and Investigational Targeted Agents in AML2-9
Second, the panelists warned about midostaurin toxicities and drug interactions. “One of the issues we’ve had practically is that it can cause QTc prolongation. It interacts with azoles. Part of that may be because it’s such a broad spectrum in pan-kinase inhibition,” Wang said. Dose reduction is rarely necessary, she noted, and interval assessments of QT by electrocardiogram are often sufficient in patients taking midostaurin concurrently with medications that can prolong the QT interval.Enasidenib