Expert Discusses Promise of Quizartinib in AML

Mark Levis, MD, PhD

As a monotherapy, quizartinib is an extremely promising agent for patients with FLT3-ITD—positive relapsed acute myeloid leukemia (AML), according to Mark Levis, MD, PhD.

“Quizartinib is a very different drug from [the FLT3 targeted-agent] midostaurin,” said Levis, an associate professor at Johns Hopkins Medical Center. “It is much more selective, much more potent, and you can inhibit the target as a monotherapy. It still has the single-highest response rate of any drug out there that I’ve seen.”

Levis recently discussed the investigational tyrosine kinase inhibitor (TKI) quizartinib as part of a focus group held at the European Congress on Hematology: Focus on Lymphoid Malignancies, an event hosted by Physician’ Education Resources (PER) in Paris, France, from November 4 to 5, 2016.

Quizartinib selectively inhibits FLT3-ITD, which is a growth driver of abnormal cells that contribute to the development of AML. Several trials are currently investigating quizartinib, including the ongoing phase III randomized QuANTUM-R study (NCT02039726). This trial was designed to determine whether quizartinib monotherapy prolongs overall survival compared with salvage chemotherapy for patients with relapsed/refractory FLT3-ITD—positive AML.

The phase III randomized, double-blind, placebo-controlled QuANTUM-First trial (NCT02668653) is examining quizartinib combined with induction and consolidation chemotherapy and then as a maintenance monotherapy in newly diagnosed elderly patients with FLT3-ITD—positive AML.

“In theory, this combination will be synergistic and antileukemic,” said Levis. “But more importantly, it will need to suppress that FLT3-addicted clone from coming out.”

It is unclear how the results of QuANTUM-First will compare to the phase III RATIFY trial, said Levis, which found that the addition of midostaurin—which also targets FLT3—to standard chemotherapy reduced the risk of death by 23% compared with chemotherapy alone in patients with AML who harbored a FLT3 mutation.

It may be easier for patients to stay on quizartinib than midostaurin and it may better suppress FLT3, said Levis, but that is yet to be determined.

The effectiveness of quizartinib as a monotherapy is most likely due to its c-Kit inhibition abilities, said Levis.

“It rarely wouldn’t work in the relapsed setting,” he said. “The blasts would go down, and routinely patients get a complete response [CR] or CR with incomplete marrow recovery [CRi]. In trials, everybody cleared peripheral blasts, and then it was how much they cleared the marrow that determined partial response or CR/CRi, but most patients were CRi.”

However, c-Kit inhibition has its downsides, he added. It can cause skin nodules and the patients hair to turn white, in addition to other marrow-related side effects.

“The Kit inhibition is a good and a bad thing; I think there is an antileukemic effect there but also clearly a marrow-suppressive effect,” said Levis. “We tested a number of TKIs for their Kit inhibitory effect and it correlates with its ability to oppress a marrow progenitor, so it’s poisonous to red and white cell progenitors.”

In theory, a KIT inhibitor in a patient with a normal marrow environment would simply lower white blood cell counts slightly. However, in the marrow of a patient with AML residual disease that has further been impacted by chemotherapy, a KIT inhibitor often cases patients to require transfusions.

Differentiation syndrome can also occur when a selective FLT3 inhibitor is used. In the focus group, Levis described how he dealt with a patient with this challenge.

“I have a patient right now who just did this,” he said. “His allelic, if anything, went up after he responded. The pathologist read the marrow, no evidence of disease, morphemically normal, and obviously now the patient is transfusion dependent.”

“The FL3-ratio went up—and you see this with any selective drug—you can get differentiate syndrome. So those neutrophils will come out just like in acute promyelocytic leukemia and they will go hit some little focus of infection and make it get large. This particular patient I actually calmed that down with steroids. That worked beautifully, she is alive today and this example was from a relapsed FLT3 patient 5 years ago.”