The second-generation FLT3 inhibitor quizartinib has recently emerged as a treatment option for patients with acute myeloid leukemia (AML) in both FLT3-ITD–wild-type and FLT3-ITD–mutated cases. At the European Hematology Association (EHA) 2023 Hybrid Congress, several studies demonstrated the potential of quizartinib in improving overall survival rates, enhancing allogeneic hematopoietic cell transplantation success, and presenting possible benefits for older patients with FLT3-mutated AML. Two of those studies are summarized here.1,2
Potential Benefits in Older Patients
Results from NCRI AML18 showed no significant improvement in overall survival with the addition of quizartinib across the entire study population of older patients with AML. However, a subgroup analysis in patients with FLT3-mutated disease revealed a nonsignificant trend toward a survival benefit.1 According to the study authors, this trend was consistent with the results of the QuANTUM-First study.
“The NCRI AML18 study provided insights into a nonsignificant trend toward survival benefit in FLT3-mutated patients and revealed potential benefits with short exposure to the drug,” said lead study author Steven Knapper, MD, Professor of Cancer and Genetics at Cardiff University School of Medicine.
The multicenter, open-label trial enrolled nearly 2,000 participants (aged > 60 years) who were fit for intensive chemotherapy at 85 sites over 8 years. A total of 464 patients were randomly assigned to receive quizartinib in addition to chemotherapy.
The trial compared quizartinib at a dose of 40 mg for 14 days with a control group receiving no quizartinib. The quizartinib cohort was further divided into two groups with short and long exposure to quizartinib.
The study compared the quizartinib and control groups among patients with FLT3-mutated and FLT3–wild-type AML. Patient characteristics such as age, performance status, type of AML, and genetics were well matched across the groups.
“It’s important to note that the AML18 study was a trial for older adults with newly diagnosed AML who were considered suitable for intensive therapy,” emphasized Dr. Knapper. “The quizartinib randomization was not restricted on the basis of FLT3 mutation status (ie, patients with both wild-type and mutated FLT3 were eligible), but that radomization didn’t take place until the patient had recovered from cycle 1 of intensive chemotherapy—so the quizartinib was introduced only from cycle 2 onwards.”
Major findings revealed that in patients with FLT3-mutated disease (including both internal tandem duplication [ITD] and tyrosine kinase domain mutations), there were trends toward improved overall survival and relapse-free survival. However, these improvements fell short of reaching statistical significance.
According to Dr. Knapper, the addition of quizartinib was generally well tolerated in the older patient population, although there was a slight increase in cardiac toxicity among quizartinib-treated patients. No significant differences were observed in supportive care requirements, such as neutrophil and platelet recovery, the number of transfusions, or hospitalization.
“Further research to better understand the potential benefits and optimal dosing strategies for quizartinib in older patients with FLT3-mutated AML is needed,” Dr. Knapper concluded.
In the Setting of Allogeneic Hematopoietic Stem Cell Transplantation
A post hoc analysis of the QuANTUM-First study showed that adding quizartinib to standard treatments improved survival in patients with AML harboring FLT3-ITD mutations who were undergoing allogeneic hematopoietic transplantation in first complete remission.
“The addition of quizartinib provides a clinically meaningful and statistically significant improvement in overall survival compared with standard induction and consolidation therapy,” said lead study author Richard Schlenk, MD, of the Cleveland Clinic, Ohio. “This outcome is especially true for patients who undergo allogeneic hematopoietic stem cell transplantation in their first complete remission,” he added.
For this study, Dr. Schlenk and colleagues aimed to determine the impact of quizartinib on the overall survival of patients with AML undergoing allogeneic hematopoietic stem cell transplantation. The study included 539 participants (aged 18–75) who had FLT3-ITD–positive disease and had received either quizartinib or a placebo.
The major findings, presented at the EHA 2023 Hybrid Congress,2 demonstrated a 58% reduction in the risk of death with the addition of quizartinib among patients who received allogeneic hematopoietic stem cell transplantation and a 23% risk reduction in death overall for patients treated with quizartinib compared with placebo. Quizartinib also yielded benefits in patients with measurable residual disease (MRD), indicating its potential role in boosting the effectiveness of allogeneic hematopoietic stem cell transplantation regardless of prior MRD status.
“Irrespective of pretransplant MRD status, longer survival was observed in the quizartinib arm, but the most significant benefit was seen in those patients who achieved MRD positivity,” Dr. Schlenk observed.
Based on these results, the authors recommended incorporating quizartinib into the standard treatment plan for patients with AML undergoing allogeneic hematopoietic stem cell transplantation. This could significantly improve the survival rate and quality of life for this high-risk group of patients, Dr. Schlenk concluded.
DISCLOSURE: Dr. Knapper reported financial relationships with AbbVie, Astellas, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier. Dr. Schlenk reported financial relationships with AbbVie, Daiichi Sankyo, Jazz Pharmaceuticals, Pfizer, BerGenBio, Novartis, AstraZeneca, Boehringer Ingelheim, PharmaMar, and Roche.
REFERENCES
1. 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 leukemia patients: Results from the NCRI AML18 trial. EHA 2023 Hybrid Congress. Abstract S131. Presented June 8, 2023.
2. Schlenk R, Montesinos P, Romero-Aguilar A, et al: Impact of allogeneic hematopoietic cell transplantation in first complete remission plus FLT3 inhibition with quizartinib in acute myeloid leukemia with FLT3-ITD: Results from QuANTUM-First. EHA 2023 Hybrid Congress. Abstract S137. Presented June 8, 2023.
