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Single-agent treatment with quizartinib improved survival over salvage chemotherapy in adults with relapsed acute myeloid leukemia (AML) and FLT3-internal tandem duplication (ITD), a new study found.

Among the 367 patients with FLT3-ITD-positive AML, those treated with quizartinib had a median overall survival of 6.2 months compared with 4.7 months for those treated with standard salvage chemotherapy regimens (HR 0.76, 95% CI 0.58-0.98, P=0.0177), reported lead investigator Jorge Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.

"In relapsed/refractory AML with FLT3-ITD mutations, these findings represent the first reported clinical data demonstrating that a single agent can significantly improve overall survival," Cortes said in a statement. "Additionally, in the study, a higher proportion of patients received a stem cell transplant in the quizartinib arm compared to the chemotherapy arm."

At a median follow-up of nearly 2 years, the estimated 1-year survival rate was 27% with quizartinib versus 20% with investigator's choice of chemotherapy.

The results of the phase III study were presented at the European Hematology Association meeting in Stockholm.

“I think the story of FLT3 is an exciting one because that’s a mutation that’s probably seen in approximately a third of patients with acute myeloid leukemia and is a poor prognostic marker,” John Mascarenhas, MD, of the Tisch Cancer Institute at Mount Sinai in New York City, told 51成人动漫.

Mascarenhas, who was not involved in the study, noted that quizartinib appeared to provide a “modest improvement” and seemed to be as tolerable as traditional chemotherapeutic approaches.

“An advantage of having an oral therapy like this is that it makes the patient more ambulatory, which is nice, and less tethered to an IV and an infusion center,” he added.

A common driver mutation in AML, FLT3-ITD is associated with high relapse risk, decreased response to salvage regimens, and worse overall survival. While the FDA approved the first FLT3 inhibitor -- midostaurin (Rydapt) -- last year for the first-line treatment of AML, there are currently no approved targeted therapies for FLT3-ITD-associated AML in the relapsed setting.

“We know patients can respond to these inhibitors, but we also know they’re not curative,” Mascarenhas said, but he added that these novel agents “can be used as bridges to transplant.”

A presented at the meeting included a small number of AML patients treated with quizartinib in two phase II trials who had previously had midostaurin exposure, and reported similar response rates:

• Study A: 67% with prior midostaurin versus 75% without
• Study B: 45% with prior midostaurin versus 69% without

The current study randomized patients 2:1 to once-daily quizartinib (n=245) or standard salvage chemotherapy with low-dose cytarabine (n=29); fludarabine, cytarabine, and granulocyte-colony stimulating factor with idarubicin (n=53; up to 2 cycles); or mitoxantrone, etoposide, and intermediate-dose cytarabine (n=40; up to 2 cycles). Patients were treated with quizartinib until unacceptable toxicity, lack of efficacy, or hematopoietic stem cell transplant.

Prior midostaurin treatment was also allowed in this study. Median age of patients was 55 in the quizartinib arm and 57 in the chemotherapy arm. Roughly one-third of patients in both arms were refractory with the remaining two-thirds having relapsed after an initial complete remission of 6 months or less prior to the enrollment.

Common adverse events (AEs) of any grade (>30%) occurred more frequently in the quizartinib arm and included nausea, fatigue, thrombocytopenia, anemia, musculoskeletal pain, febrile neutropenia, neutropenia, vomiting, and hypokalemia. Pyrexia was more common with chemotherapy.

Common grade 3 or higher AEs (>10%) also occurred more frequently with quizartinib and included thrombocytopenia, neutropenia, febrile neutropenia, anemia, leukopenia, pneumonia, and hypokalemia. Sepsis was more common in the chemotherapy arm. Eight quizartinib-treated patients had QTcF >500 msec, with two patients discontinuing due to QTcF prolongation, though no cases were grade 4.

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