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ASH 2012: Quizartinib for FLT3-ITD positive AML after second-line chemo or stem cell transplant

Research suggests that a new targeted therapy, quizartinib, may be a safe and effective option to treat a subset of patients with treatment-resistant acute myeloid leukaemia (AML).

AML is a fast-growing blood cancer in which patients produce an excessive amount of abnormal, immature white blood cells that are unable to adequately fight infection.

Following AML diagnosis, leukaemia cells from patients undergo genetic testing to identify the mutation driving the disease, which helps determine the appropriate treatment protocol.

Of the many types of genetic mutations that can occur in AML, one of the most threatening is the FLT3-ITD (internal tandem duplication), which effects 34% of AML patients, makes the leukaemia even more aggressive and typically leads to failure of standard chemotherapy treatment response.

“The FLT3 mutation is essentially a power switch that leukaemia cells use to spread more aggressively, which helps them to grow back immediately after chemotherapy,” said Mark J. Levis, MD, PhD, lead author and Associate Professor of Oncology, Pharmacology, and Medicine at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore.

“The only way to treat this type of mutation is to find a way to turn the switch off — a feat that has eluded researchers for far too long.”

Patients with the FLT3-ITD mutation can achieve remission with standard chemotherapy but tend to relapse very quickly.

An important treatment option is a stem cell transplant, but only if the patient is in some form of remission; otherwise, transplant failure rates are high.

Given the barriers to treatment in this patient population, researchers have been examining the efficacy of the investigational oral agent quizartinib, which is designed to “turn off” the mutated FLT3 enzyme, thus forcing the immature cancer cells to either die immediately or undergo maturation (and eventually die). This eliminates enough leukaemia cells to make it possible for patients to undergo stem cell transplants that can cure their disease.

In order to assess the efficacy and safety of quizartinib as a single agent (drug used alone in treatment) in AML patients with the FLT3-ITD mutation, researchers conducted a Phase II study among 333 patients that were divided into two treatment cohorts.

Cohort 1 consisted of patients age 60 or over with the FLT3-ITD mutation who failed to achieve remission with standard chemotherapy, or who had recently relapsed for the first time. Cohort 2 consisted of patients over age 18 with the FLT3-ITD mutation who presented with relapsed or refractory AML and had been administered salvage chemotherapy after failing to respond to prior treatment, or had relapsed after a stem cell transplant. Most patients in this study had the FLT3-ITD mutation, but a small number in each cohort lacked the mutation.

Study results from Cohort 2 were based on an analysis of 137 patients (99 with mutation and 38 without) who received continuous treatment with quizartinib at a fixed dose during 28-day cycles. The primary endpoint of the study was the composite complete remission rate (CRc) of all patients, which includes complete remission (CR; no active disease), complete remission with incomplete platelet recovery (CRp, no active disease but abnormal platelet count), and complete remission with incomplete hematologic recovery (Cri, no active disease but abnormal red and white blood cell counts) of the patients following treatment with quizartinib.

Following one to three cycles of quizartinib treatment, researchers observed a CRc rate of 44 percent (4% CR, 0 CRp, and 40% CRi) in patients with the FLT3-ITD mutation with a median duration of response of 11.3 weeks and median overall survival of 23.1 weeks. In patients without the mutation, researchers observed a 34 percent CRc rate (3% CR, 3% CRp, and 29% CRi) with a median duration of response of five weeks and median overall survival of 25.6 weeks. Of those patients in both cohorts who did not respond to their last AML therapy, 47 percent of those with FLT3-ITD and 31 percent of those without achieved a CRc with quizartinib. In both cohorts, 34 percent of patients were successfully bridged to a potentially curative allogeneic transplant.

Common adverse effects of treatment with quizartinib (observed in more than 20% of patients) included QT prolongation (26%), a heart complication associated with some medications and managed by reducing dosage, as well as nausea (38%), vomiting (26%), anemia (29%), fever (25%), diarrhea (20%), and fatigue (20%). These results demonstrate that quizartinib can produce a high treatment response rate in a group of very poor-prognosis AML patients with the FLT3-ITD mutation with manageable toxicity.

“Quizartinib is the first and only single-agent drug that has produced a clinical benefit in AML patients with this deadly mutation who have failed previous therapy,” said Dr. Levis. “The number of patients bridged to a stem cell transplant was very significant. We plan on using these encouraging results to design and conduct additional randomized trials that will hopefully lead to the approval of quizartinib to make it accessible to those patients who previously had no hope for a cure.”


Source: ASH

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ecancer Global Foundation