A new phase II clinical trial is investigating the use of quizartinib in combination with intensive salvage chemotherapy for patients with relapsed or refractory acute myeloid leukemia (AML) carrying FLT3-ITD mutations. The multicenter Q-HAM study, published in the journal Trials in 2023, aims to assess the efficacy of adding the FLT3 inhibitor quizartinib to standard salvage chemotherapy and as maintenance therapy in this difficult-to-treat patient population.
The open-label, randomized phase II trial is being conducted across up to 20 academic centers in Germany that are part of the Study Alliance Leukemia (SAL) network. The study is co-financed by funds from Heidelberg University Hospital and Daiichi Sankyo Europe GmbH, with the latter also providing the study drug free of charge. Additional funding comes from the German Research Organization (DFG).
Patients with relapsed or refractory AML carrying FLT3-ITD mutations have a particularly poor prognosis, with median overall survival of less than 4 months in some studies. While the FLT3 inhibitor midostaurin has shown efficacy in newly diagnosed FLT3-mutated AML when combined with chemotherapy, it has minimal activity in the relapsed/refractory setting. More potent and selective FLT3 inhibitors like quizartinib have demonstrated single-agent activity in relapsed/refractory FLT3-mutated AML, but survival beyond 2 years remains poor. The Q-HAM study aims to evaluate if combining quizartinib with intensive salvage chemotherapy can improve outcomes in these patients.
The trial has a planned enrollment of up to 80 patients aged 18-75 years with relapsed or refractory AML and FLT3-ITD mutations. Key inclusion criteria are AML according to 2016 WHO classification, relapse or refractoriness to prior therapy including hematopoietic cell transplantation, FLT3-ITD mutation with allelic ratio ≥0.05, ECOG performance status 0-2, and adequate organ function. Patients with acute promyelocytic leukemia, active CNS leukemia, isolated extramedullary AML, or hyperleukocytosis are excluded.
All enrolled patients will receive salvage chemotherapy with high-dose cytarabine and mitoxantrone (HAM regimen) plus quizartinib 40 mg orally daily for 28 days. The primary endpoint is achievement of complete remission (CR), CR with incomplete hematologic recovery (CRi), or CR with partial hematologic recovery (CRh) after this salvage therapy. This will be compared to historical controls using a novel matched threshold crossing statistical approach.
Patients who achieve remission are then randomized 1:1 to either prophylactic quizartinib maintenance or measurable residual disease (MRD)-triggered preemptive quizartinib. In the prophylactic arm, patients receive quizartinib continuously. In the MRD-triggered arm, quizartinib is only given if MRD becomes detectable. A key secondary endpoint is to compare event-free survival between these two post-remission strategies.
The study utilizes an adaptive two-stage design with an interim analysis planned after enrollment of the first 20 patients. This allows for potential early stopping for futility or sample size re-estimation based on the observed response rate. The maximum sample size is set at 80 patients to provide adequate power for the primary endpoint analysis.
By using matched historical controls rather than a randomized design for the primary endpoint, the study aims to maximize the number of patients receiving the experimental therapy while still allowing for statistical comparison. The matched threshold crossing approach adjusts for key prognostic factors like age and cytogenetic risk to enable a fair comparison to historical data.
As of the publication date, 11 patients (13% of planned enrollment) had been recruited to the study since it opened in October 2020. Patient accrual has been slower than initially projected, likely impacted by the COVID-19 pandemic and increasing use of gilteritinib in this patient population. The authors note that the recruitment period may need to be extended beyond the original 2-year plan to reach the target enrollment.
In addition to evaluating clinical efficacy endpoints, the study incorporates extensive correlative analyses. Serial bone marrow and blood samples will be collected to assess MRD and study biomarkers of response and resistance. Quality of life assessments using validated questionnaires are also included as secondary endpoints.
The study has several strengths in its design. The use of quizartinib in combination with intensive salvage chemotherapy builds on promising phase I data and has strong scientific rationale. Incorporating both prophylactic and MRD-triggered maintenance strategies addresses an important clinical question about optimal post-remission therapy. The adaptive design with an interim analysis allows for efficient evaluation of efficacy.
There are also some limitations to note. The lack of a randomized control group for the primary endpoint analysis could introduce bias, although this is mitigated somewhat by the matched historical control approach. The open-label design may impact assessment of subjective endpoints. As a phase II study, the sample size is relatively small and may not be powered to detect modest differences in survival endpoints.
The authors conclude that this study will provide important data on the efficacy and safety of combining quizartinib with intensive salvage therapy in relapsed/refractory FLT3-mutated AML. If positive, it could support further evaluation of this approach in larger phase III trials. The comparison of prophylactic versus MRD-triggered maintenance could also inform optimal post-remission strategies with FLT3 inhibitors.
The potential clinical impact of this study is significant. Relapsed/refractory FLT3-mutated AML remains an area of high unmet medical need with very poor outcomes using current therapies. If adding quizartinib to salvage chemotherapy substantially improves remission rates, it could enable more patients to proceed to potentially curative allogeneic stem cell transplantation. Effective post-remission strategies are also critically needed to prevent relapse and improve long-term survival.
More broadly, this trial may provide insights into how to optimally incorporate targeted therapies like FLT3 inhibitors into AML treatment paradigms. The comparison of prophylactic versus MRD-guided maintenance addresses a key question relevant to other targeted agents in AML as well. The correlative studies may uncover biomarkers to help further refine patient selection and elucidate resistance mechanisms.
While the results of this phase II study will require confirmation in larger trials, they have the potential to impact clinical practice for this high-risk AML population. Medical professionals treating relapsed/refractory AML patients should be aware of this ongoing trial as a potential option for eligible patients. The outcome of this study may also inform the design of future trials incorporating FLT3 inhibitors in AML.
In summary, the Q-HAM study is an important clinical trial evaluating a rational combination approach of adding quizartinib to intensive salvage chemotherapy for relapsed/refractory FLT3-mutated AML. Its results will provide valuable data to guide further development of FLT3 inhibitor-based treatment strategies for this challenging patient population. Medical professionals should look forward to the publication of results from this trial in the coming years to see how it may impact the standard of care for relapsed/refractory FLT3-mutated AML.
References
Jaramillo S, Le Cornet L, Kratzmann M, et al. Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD. Trials. 2023;24(1):591. Published 2023 Sep 15. doi:10.1186/s13063-023-07421-x
