Data from a phase 2 trial show that quizartinib plus omacetaxine mepesuccinate may better position patients to proceed to consolidative transplantation.
Combining quizartinib (Vanflyta) with omacetaxine mepesuccinate (Synribo; QUIZOM) demonstrated efficacy and feasibility in a small cohort of patients with acute myeloid leukemia (AML) harboring FLT3-ITD mutations, according to findings from a phase 2 trial (NCT03135054) published in Nature Communications.1
Among 40 evaluable patients, data revealed a composite complete remission (CRc) rate of 83% (n = 33/40), which included CRs in 15% (n = 6/40) and CRs with incomplete hematologic recovery (CRi) in 68% (n = 27/40). Specifically, the CRc rates were 60% and 86% among patients with frontline disease and relapsed/refractory disease, respectively. CRc rates were also higher for patients with NPM1 mutations (95% vs 67%; P = .038), DNMT3A mutations (95% vs 67%; P = .038), and WT1 wild-type disease (91% vs 20%; P = .002).
Regarding 33 patients who experienced a remission, 39% (n = 13) proceeded to allogeneic hematopoietic stem cell transplantation (HSCT) after a median of 143 days (range, 53-367). Additionally, the median leukemia-free survival (LFS) and overall survival (OS) were 10 months (range, 0.7-68.2) and 12.9 months (range, 1.8-69.2), respectively. According to univariate analysis, patients who had an age of 60 years or younger, CRc, prior FLT3 inhibitor exposure, allogenic HSCT, and WT1 wild-type disease were more likely to experience higher OS.
“The QUIZOM combination therapy provides an effective and feasible treatment option for patients with FLT3-mutated AML who are unfit for conventional chemotherapy,” corresponding study author Anskar Leung Yu-hung, chair professor in the Department of Medicine of the School of Clinical Medicine at the University of Hong Kong (HKUMed), stated in a press release regarding these findings.2 “By improving the remission rate, patients are better positioned to proceed to HSCT as consolidation therapy. With post-transplant maintenance and monitoring, the majority of patients can achieve sustained remission.”
After performing single-cell gene expression profiling, investigators also noted that the QUIZOM regimen could disrupt protein metabolism in cancer cells, thereby inhibiting their growth while activating T-cell immune systems. Additional data showed that drug-resistant leukemic cells formed in some patients who experienced a relapse, which developed resistance based on PLD1-mediated phospholipid metabolism. These findings suggested that adding a PLD1 inhibitor may help suppress the regenerative function of these leukemic cells and boost overall treatment efficacy.
In the phase 2 trial, patients 18 years and older with relapsed/refractory FLT3-ITD–mutated AML and or those 65 years and older with newly diagnosed disease AML unfit for chemotherapywere assigned to receive quizartinib at 30 mg orally each day plus omacetaxine mepesuccinate at 2 mg intravenously each day for 7 days on the first cycle or 5 days on each subsequent cycle every 21 to 28 days until HSCT or progressive disease. The trial’s primary end point was CRc rate per ELN 2022 criteria. Secondary end points included the percentage of patients bridged to HSCT, LFS, and OS.
Investigators noted 2 early deaths on QUIZOM treatment among patients without responses; the causes of death were linked to pneumonia plus pulmonary hemorrhage, as well as pneumonia, respectively. The most common grade 3/4 adverse effects (AEs) included cytopenia and febrile neutropenia. Additionally, 20% of patients experienced grade 4 sepsis, which required management with intravenous antibiotics.
“This study demonstrates the clinical potential of QUIZOM, enabling more high‑risk patients to become eligible for HSCT, and provides a comprehensive understanding of its mechanisms. It provides a clear and promising therapeutic direction for overcoming drug resistance in leukemia. The research team has filed a patent application regarding the discovery of PLD1 inhibition in leukemia, aiming to improve treatment regimens for acute leukemia and ultimately benefitting more patients with hematological malignancies,” Leung concluded.2
