Can Adding Quizartinib to Intensive Chemotherapy Improve OS in Older Adults with AML?

Sequentially adding quizartinib to intensive chemotherapy did not lead to improved survival in older patients with acute myeloid leukemia (AML), according to results from the NCRI AML18 trial.

Steven Knapper, MRCP, FRCPath, DM, of Cardiff University, and colleagues conducted the study and presented their findings during the 2023 European Hematology Association Congress.

They conducted the study to determine if adding quizartinib—a class III receptor tyrosine kinase inhibitor with “potent activity against FLT3 and clinical activity” in relapsed or refractory FLT3-ITD AML—as a maintenance therapy after intensive chemotherapy would improve survival in older patients with AML. The median patient age was 68 years.

Quizartinib has been approved by the US Food and Drug Administration (FDA) in combination with cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy. The approval is for the treatment of adults with newly diagnosed AML who have FLT3-ITD as detected by an FDA-approved test.

Patients initially received daunorubicin 60 mg/m²  on days one, three, and five; and cytarabine 100 mg/m² twice daily on days one through 10 with one or two doses of gemtuzumab ozogamicin. The study’s investigators then randomized 464 patients 1:1 to receive quizartinib (n=233) or not (n=231), irrespective of FLT3 status. Most patients (73%) had wild-type FLT3, while 22% had FLT3-ITD, 5% had FLT3-TKD, and less than 1% had FLT3-ITD-TKD. Dr. Knapper and colleagues balanced all characteristics, including FLT3 mutation type, allelic burden, and NPM1 comutation status, between arms.

However, after receiving interim advice from the independent data monitoring committee in June 2019, the study’s investigators restricted the quizartinib randomizations to patients with FLT3 mutations.

The patients receiving quizartinib were additionally randomized 1:1 to receive short (n=117) or long (n=116) therapy. Patients received quizartinib 40 mg daily for 14 days immediately following the second and third chemotherapy cycles and for an additional 28 days after recovery from the final course. Patients in the long therapy group received 12 additional 28-day cycles of maintenance, including after allogeneic hematopoietic stem cell transplantation (HSCT).

Most patients (68%) were in complete remission (CR) at the time of randomization, while 9% had a CR with incomplete hematologic recovery. More than half (57%) of patients with available data were negative for measurable residual disease (MRD) at randomization, while 43% were positive for MRD by flow cytometry. The MRD status was unknown in 56 patients.

There was no difference in the median overall survival (OS) between treatment groups, as it was 29 months in patients who received quizartinib and 29 months in those who did not (hazard ratio [HR], 1.035; P=.768). The median OS was 27 months in patients who received a short treatment with quizartinib and was 29 months in those who received a long treatment with quizartinib.

There was a “nonsignificant trend” toward improved OS in patients with FLT3 mutations who received quizartinib, as they had a median OS of 33 months, while those who did not receive quizartinib had a median OS of 26 months (HR, 0.69; P=.123), according to Dr. Knapper and colleagues. However, there was no difference in OS between short and long treatments in patients with FLT3 mutations.

There were no differences in the median relapse-free survival between patients who received quizartinib and those who did not in the whole study population, nor in patients with FLT3 mutations.

Around one-third (36%) of patients received allogeneic HSCT. After the study’s investigators censored for HSCT, there was no significant differential effect of quizartinib on OS in the whole population, nor in the patients with FLT3 mutations.

The researchers observed a “minimal difference in toxicity” with rates of grade ≥3 adverse events and supportive care requirements being similar between groups, with no difference in time to neutrophil or platelet recovery.

“In older AML patients, the sequential addition of [quizartinib] to [intensive chemotherapy] was well-tolerated but did not lead to improved survival,” the study’s authors concluded. “Although not powered to assess benefit, a subgroup analysis of FLT3-mutated patients showed a nonsignificant trend to survival benefit consistent with the results of the QuANTUM-First trial.”

Reference

Knapper S, Thomas A, King S, et al. A randomised assessment of the sequential addition of the kinase inhibitor quizartinib to intensive chemotherapy in older acute myeloid leukaemia (AML) patients: results from the NCRI AML18 trial. Abstract #S131. Presented at the 2023 European Hematology Association Congress. June 8-15, 2023; Frankfurt, Germany.