A new treatment option has doubled overall survival for a difficult-to-treat subset of patients with acute myeloid leukemia (AML), according to data presented during the Presidential Symposium at the European Hematology Association (EHA) 2022 Congress in Vienna.1
Findings from the phase III QuANTUM-First trial showed that addition of the oral FLT3 inhibitor quizartinib to standard chemotherapy increased median overall survival to 31.9 months in adults with FLT3-ITD (internal tandem duplication)–positive AML, compared with 15.1 months for those who received chemotherapy alone. Patients randomly assigned to the quizartinib arm also had a better chance of relapse-free survival, and investigators identified no new safety signals with the combination therapy.
“We believe these data have the potential to change the standard of care for the treatment of adults with newly diagnosed FLT3-ITD–positive AML.”— Harry Erba, MD, PhD
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“We believe these data have the potential to change the standard of care for the treatment of adults with newly diagnosed FLT3-ITD–positive AML,” said lead study author Harry Erba, MD, PhD, clinical investigator in the Division of Hematologic Malignancies and Cellular Therapy, Duke Cancer Institute, Durham, North Carolina. “Quizartinib in combination with intensive chemotherapy with 3 years of continuation therapy should be the treatment of choice for patients with FLT3-ITD–mutated AML who are eligible for intensive curative therapy.”
As Dr. Erba explained, patients with FLT3-ITD–positive AML represent a particularly poor prognostic group. Despite the current availability of the FLT3 inhibitor midostaurin, there is an unmet need for improved treatment options.
“For patients with AML, the 5-year survival rate is only about 29%,” said Dr. Erba. He noted that approximately one in four newly diagnosed patients carry the FLT3-ITD mutation, which is associated with shorter survival and an increased risk of relapse.
“The RATIFY trial demonstrated an improvement in overall survival among patients with AML with both FLT3-ITD and FLT3-TKD [tyrosine kinase domain] mutations when midostaurin was added to standard intensive AML therapy.2 However, the prognostic significance of the FLT3-TKD mutation is unclear,” Dr. Erba explained. “Furthermore, the RATIFY trial enrolled only patients up to and including age 59.”
Study Methods
In the QuANTUM-First trial, Dr. Erba and colleagues evaluated quizartinib, a more potent and selective type 2 FLT3 inhibitor, in the poor-prognosis group with a FLT3-ITD mutation alone and included patients up to age 75. The study was designed to investigate quizartinib’s efficacy when added to standard induction and consolidation chemotherapy and given over a longer period of continuation therapy. A prior phase III study found that patients with relapsed/refractory FLT3-ITD–mutated AML had a longer overall survival when given quizartinib, as a single agent, than those treated with standard-of-care chemotherapy.3
The investigators enrolled 539 patients (median age = 56 years) with FLT3-ITD–positive AML between September 2016 and August 2019. Patients were randomly assigned to receive treatment with quizartinib at 40 mg orally once daily on days 8 to 21 (n = 268) or placebo (n = 271) after initiation of standard induction therapy with anthracycline and cytarabine. Patients who achieved complete remission or complete remission with incomplete hematologic recovery could receive up to four cycles of high-dose cytarabine plus quizartinib at 40 mg/d or placebo for 14 days. Quizartinib or placebo were continued for up to 3 years following consolidation therapy and/or allogeneic hematopoietic stem cell transplant.
Duration of Complete Response Longer With Quizartinib
As Dr. Erba reported, the addition of quizartinib provided a clinically meaningful and statistically significant improvement in overall survival compared with standard induction and consolidation therapy alone (hazard ratio [HR] = 0.776; P = .03). The median overall survival was 31.9 months with quizartinib vs 15.1 months with placebo.
During the study, 144 patients on the quizartinib arm and 128 patients on the placebo arm received an allogeneic stem cell transplant. In a sensitivity analysis, in which all treated patients were censored at the time of transplantation, investigators observed a hazard ratio consistent with the primary analysis (HR = 0.75).
Rates of complete remission were similar between study arms, but the rate of composite complete remission was numerically higher with quizartinib (71.6% vs 64.9%). The duration of complete response was approximately three times longer with quizartinib, with a median of 38.6 months for quizartinib vs 12.4 months for placebo.
KEY POINTS
- The addition of quizartinib to standard chemotherapy and up to 3 years of continuation therapy more than doubled overall survival in adults with newly diagnosed FLT3-ITD–positive AML vs the standard of care (31.9 vs 15.1 months).
- The manageable safety profile further supports the use of quizartinib in combination with standard therapy, including allogeneic hematopoietic cell transplantation, in FLT3-ITD–positive AML.
In a prespecified exploratory analysis, relapse-free survival was also longer with quizartinib than with placebo. The median relapse-free survival was 39.3 months vs 13.6 months, respectively (HR = 0.613). The cumulative incidence of relapse at 24 months was 31.2% with quizartinib vs 43.3% with placebo.
“These results indicate that the QuANTUM-First regimen may be able to prevent relapse compared with chemotherapy and consolidation therapy alone,” said Dr. Erba. In addition, he noted that at a median follow-up of 39.2 months, 58 patients remained on therapy.
Toxicity
The safety of quizartinib combined with intensive chemotherapy and as continuation monotherapy was generally manageable, with no new adverse signals.
“As expected in this population, most patients experienced at least one treatment-emergent adverse event and one grade 3 or higher adverse event, with similar incidences between treatment arms,” said Dr. Erba.
However, more patients treated with quizartinib experienced treatment-emergent adverse events with a fatal outcome (11.3% vs 9.7%), including within 30 and 60 days of study drug initiation. These events were mainly due to infection, which occurred during the induction and consolidation phases. Dr. Erba recommended prophylactic antibiotics and antifungal medication as well as myeloid growth factors during consolidation to decrease the risk of infection with this regimen. “Treatment-related mortality of intensive AML therapy is generally greater in older patients,” stated Dr Erba. “The investigators will also evaluate the safety of this regimen in younger vs older patients.”
DISCLOSURE: Dr. Erba reported financial relationships with Daiichi Sankyo and Novartis.
REFERENCES
1. Erba H, Montesinos P, Vrhovac R, et al: Quizartinib prolonged survival vs placebo plus intensive induction and consolidation therapy followed by single-agent continuation in patients aged 18-75 years with newly diagnosed FLT3-ITD+ AML. EHA 2022 Congress. Abstract S100. Presented June 11, 2022.
2. Stone RM, Mandrekar SJ, Sanford BL, et al: Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377:454-464, 2017.
3. Cortes JE, Khaled S, Martinelli G, et al: Quizartinib versus salvage chemotherapy for relapsed or refractory FLT3-ITD acute myeloid leukemia (QuANTUM-R):A multicentre, randomized, controlled, open label, phase 3 trial. Lancet Oncol 20:984-997, 2019.
