Acute myeloid leukemia (AML) harboring FLT3 mutations commonly develops resistance to the combination of azacitidine and venetoclax. This resistance can be overcome with the addition of gilteritinib, an oral FLT3 inhibitor, resulting in high complete response (CR) rates with acceptable toxicity, according to a study published in the Journal of Clinical Oncology.
While the current standard of care for older patients with newly diagnosed (ND) FLT3-mutated AML is azacitidine plus venetoclax, this regimen does not include an FLT3 inhibitor. Remission durations with this regimen are short because FLT3 mutations lead to overexpression of BCL-xL and MCL-1, which contribute to resistance to venetoclax. Researchers therefore aimed to determine the efficacy and safety of gilteritinib when added to standard therapy in adult patients with FLT3-mutated AML.
“The data from our study suggest that the triplet combination of azacitidine, venetoclax, and gilteritinib may be a better approach in ND patients, resulting in higher response rates, more durable remissions, and better survival than expected with standard approaches. However, myelosuppression is something that needs to be monitored very carefully,” said corresponding author Nicholas Short, MD, of MD Anderson Cancer Center in Houston.
Dr. Short emphasized the mitigative strategies researchers underwent to help prevent myelosuppression. Researchers performed a bone marrow biopsy 14 days after the start of induction and held doses of venetoclax, gilteritinib, or both if bone marrow was aplastic, the sample was insufficient, or the blasts were less than 5%. They also used lower doses of azacitidine and venetoclax in consolidation cycles.
“It’s not as simple as just adding gilteritinib to your standard doses of azacitidine and venetoclax,” Dr. Short said. “You need to implement these other maneuvers to make sure that you’re delivering it safely.”
Phase I of the study included 10 patients with relapsed or refractory (R/R) AML exploring gilteritinib doses of 80 mg and 120 mg in combination with azacitidine and venetoclax. Response rates were similar in the two groups, although count recovery was better in the 80 mg cohort. Consequently, researchers determined the maximum tolerated dose of gilteritinib to be 80 mg as this dose was effective but with less myelosuppression.
Phase II included 30 patients (median age = 71 years; range = 18-86 years) with ND FLT3-mutated AML who were unsuitable for or declined intensive chemotherapy and 22 patients with R/R FLT3-mutated AML.
In the R/R cohort, 27% of patients achieved CR or complete response with incomplete count recovery (CRi), with an additional 41% of patients achieving a morphologic leukemia-free state (MLFS); the median overall survival (OS) was 5.8 months. However, patients who did not have previous exposure to a hypomethylating agent (HMA) plus venetoclax, gilteritinib, or both experienced superior OS (10.5 months vs. 4.2 months; p=0.095). Accordingly, “the triplet regimen may be a reasonable option for patients with no previous exposure to these agents,” Dr. Short said.
In the frontline cohort, the response rate was 100% (27 achieved CR, 2 achieved CRi, and 1 achieved MLFS), and 93% of evaluable patients achieved measurable residual disease (MRD) negativity by multiparameter flow cytometry. The median OS was not reached; the 18-month OS was 72%. Overall, 11 patients (37%) were bridged to transplant.
“Transplant is our ideal consolidative strategy for patients with FLT3-mutated disease, although many older patients are not suitable candidates for transplant,” Dr. Short said. “Regardless of if patients move on to transplant, we need a regimen that gets patients safely into remission, ideally with a deep MRD negativity, which we found in this study.”
These findings challenge the institution-dependent variability in treatment when it comes to administering intensive chemotherapy to patients who are 60 to 75 years old. Dr. Short suggested that “as this triplet regimen is showing 90% CR rates and a high rate of MRD negativity, our results suggest that it could be a good regimen even for patients ages 60 and 75 years with FLT3-mutated AML, whether or not they are transplant eligible, as it can spare them the potential toxicities of intensive chemotherapy.”
Researchers cited the single-center nature of the study and the small patient population as limitations.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Short NJ, Daver N, Dinardo CD, et al. Azacitidine, venetoclax, and gilteritinib in newly diagnosed and relapsed or refractory FLT3-mutated AML [published online ahead of print, 2024 January 26]. J Clin Oncol. doi: 10.1200/JCO.23.01911.
Perspectives
Older adults with AML have historically poor outcomes due to toxicity and lack of efficacy with standard cytotoxic chemotherapy regimens. Although the approval of venetoclax in combination with HMAs has revolutionized the treatment of older adults with AML, relapse rates remain high, and OS is low.
Newer approaches are investigating whether adding targeted therapies to HMA plus venetoclax can improve efficacy and duration of response. Preclinical studies suggest synergy of gilteritinib with venetoclax,1 providing the rationale for this trial adding gilteritinib to HMA plus venetoclax for patients with FLT3-mutated AML.
Although many combination approaches are strongly backed by scientific rationale, historically toxicities such as myelosuppression have limited their applicability.2,3,4 Therefore, the investigators shortened the duration of venetoclax during both induction (14 days) and consolidation (seven days). Rates of myelosuppression and toxicity were low, and despite the abbreviated venetoclax course, in ND patients, CR rates and MRD negativity were high (90% and 93%, respectively), with 18-month OS of 72%. This is in line with emerging evidence that shorter courses of venetoclax (seven or 14 days) may have similar efficacy and decreased toxicity as compared to standard dosing schedules.5,6
Despite this therapy being targeted to an unfit older adult population, a large proportion of patients underwent allogeneic hematopoietic cell transplant (alloHCT) in first remission. Although survival remained high, even among patients not undergoing alloHCT, randomized trials will be needed to confirm the benefit of this approach. Given these results, it is worth considering whether this triplet therapy may be a beneficial approach even for younger, fit adults, but further investigation in future clinical trials is needed.
Overall, this trial adds to the growing evidence that adding targeted therapies to chemotherapy backbones, whether intensive or non-intensive, may improve outcomes for patients with AML. Future studies are needed to confirm these findings and refine this dosing strategy, but the results of this trial should inform the design of future clinical trials with combination approaches.
Emily Curran, MD
Assistant Professor
Division of Hematology/Oncology,
Department of Internal Medicine
University of Cincinnati Cancer Center
References
- Ma J, Zhao S, Qiao X, et al. Inhibition of Bcl-2 synergistically enhances the antileukemic activity of midostaurin and gilteritinib in preclinical models of FLT3-mutated acute myeloid leukemia. Clin Cancer Res. 2019;25(22):6815-6826.
- Short N, DiNardo CD, Daver N, et al. Updated results from a phase I/II study of the triplet combination of azacitidine, venetoclax and gilteritinib for patients with FLT3-mutated acute myeloid leukemia. Blood. 2022;140(Suppl. 1):2007-2009.
- Daver N, Senapati J, Maiti A, et al. Phase I/II study of azacitidine (AZA) with venetoclax (VEN) and magrolimab (Magro) in patients (pts) with newly diagnosed (ND) older/unfit or high-risk acute myeloid leukemia (AML) and relapsed/refractory (R/R) AML. Blood. 2022;140(Suppl. 1):141-144.
- Lane AA, Stein AS, Garcia JS, et al. Safety and efficacy of combining tagraxofusp (SL-401) with azacitidine or azacitidine and venetoclax in a phase 1b study for CD123 positive AML, MDS, or BPDCN. Blood. 2021;138(Suppl. 1):2346-2346.
- Aiba M, Shigematsu A, Suzuki T, et al. Shorter duration of venetoclax administration to 14 days has same efficacy and better safety profile in treatment of acute myeloid leukemia. Ann Hematol. 2023;102(3):541-546.
- Karrar O, Abdelmagid M, Rana M, et al. Venetoclax duration (14 vs. 21 vs. 28 days) in combination with hypomethylating agent in newly diagnosed acute myeloid leukemia: comparative analysis of response, toxicity, and survival. Am J Hematol. 2024;99(2):E63-E66.
Conflicts of Interest
Dr. Curran has served on the advisory board for Kite and Jazz; received honoraria from Dava Oncology, Creative Education Concepts, and Clinical Care Options; and done research for Servier and Jazz.
