Azacitidine-Venetoclax-Gilteritinib Regimen Produces Durable Responses in FLT3-Mutated AML

Long-term follow-up from a single-center phase 1/2 trial (NCT04140487) indicates that azacitidine (Vidaza; Bristol Myers Squibb), venetoclax (Venclexta; AbbVie, Genentech), and gilteritinib (Xospata; Astellas Pharma) may produce deep and durable responses in adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.¹

After a median follow-up of 41.5 months, the median overall survival (OS) was 29.7 months and the estimated 3-year OS rate was 46%. These findings support continued investigation of a targeted triplet strategy designed to address FLT3-mediated resistance to azacitidine and venetoclax; however, the researchers emphasized that randomized studies are needed before the regimen can be compared definitively with currently established treatment approaches.¹

FLT3 Mutations Create a High-Risk Treatment Challenge

AML is an aggressive hematologic malignancy identified through the rapid accumulation of abnormal myeloid cells in the bone marrow and blood. Mutations involving FMS-like tyrosine kinase 3 (FLT3) are among the most clinically important molecular alterations in AML and are generally divided into internal tandem duplication (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD) mutations.²

Constitutive activation of FLT3 signaling promotes leukemic-cell proliferation and survival. Patients with FLT3-ITD–mutated AML have experienced particularly high rates of relapse, however, prognosis is also influenced by allelic burden, co-occurring mutations, treatment selection, and access to allogeneic stem cell transplantation.²

Azacitidine plus venetoclax is an established frontline treatment for adults aged 75 years or older or these with comorbidities that preclude intensive induction chemotherapy. Venetoclax inhibits B-cell lymphoma 2, or BCL-2, an antiapoptotic protein that helps malignant cells survive, whereas azacitidine is a hypomethylating agent that can restore the activity of genes involved in cellular differentiation and death.³

Despite the activity of azacitidine-venetoclax, FLT3 mutations can contribute to treatment resistance and disease recurrence. Adding a FLT3 inhibitor may therefore suppress a pathway that allows leukemic cells to survive BCL-2–directed treatment.⁴

Gilteritinib is an oral small-molecule tyrosine kinase inhibitor that blocks FLT3 signaling, including signaling associated with FLT3-ITD and certain FLT3-TKD mutations. The FDA approved gilteritinib as monotherapy for adults with relapsed or refractory FLT3-mutated AML, but its use with azacitidine and venetoclax in newly diagnosed disease remains under investigation.⁵

Triplet Regimen Produces Long-Term Survival in Phase 2 Trial

The trial had enrolled 30 adults with newly diagnosed FLT3-mutated AML who were considered ineligible for intensive chemotherapy. Patients received azacitidine at 75 mg/m² on days 1 through 7, venetoclax at 400 mg on days 1 through 28, and gilteritinib at 80 mg on days 1 through 28 of the initial treatment cycle.¹

A bone marrow assessment was conducted on day 14. Venetoclax and gilteritinib could be held when bone marrow blasts had fallen below 5% or when the marrow was aplastic or otherwise insufficient for evaluation. Treatment duration was also shortened during subsequent cycles to reduce prolonged myelosuppression.¹

Previously reported data demonstrated a composite complete remission rate of 96%, including a complete remission rate of approximately 92%. Among evaluable patients with FLT3-ITD mutations, 65% achieved a molecular measurable residual disease level below 10^-5 within 4 treatment cycles.⁶

With the longer follow-up, the median relapse-free survival (RFS) was about 23.4 months, and the estimated 3-year RFS rate was 43%. Median OS was 29.7 months, with an estimated 3-year OS rate of 46%.¹

Outcomes differed according to the type of FLT3 alteration. Among patients with FLT3-ITD mutations, median RFS and OS were 17.0 and 21.8 months, respectively. The corresponding 3-year RFS and OS rates were 32% and 36%. For patients with FLT3-TKD mutations, median RFS was about 38.5 months, median OS had not been reached, and the estimated 3-year RFS and OS rates were both 75%.¹

At relapse, 6 of 9 evaluable patients no longer had a detectable FLT3 mutation by polymerase chain reaction. Additionally, 6 of 8 patients who underwent cytogenetic and molecular testing displayed evidence of clonal evolution. These findings suggest that although the triplet may effectively suppress FLT3-driven clones, relapse can occur through the emergence or expansion of alternative leukemia clones.¹

Myelosuppression and Infection Require Close Management

No unexpected safety signals emerged during longer follow-up, but clinically significant infectious and hematologic complications remained important. The most common grade 3 or higher nonhematologic adverse event was infection (63%). Grade 3 or higher febrile neutropenia (40%) and sepsis (17%) were also observed.¹

These findings reinforce the need for proactive supportive care and close coordination among pharmacists, hematologists, nurses, and patients. Venetoclax-based AML regimens can produce substantial neutropenia and thrombocytopenia, requiring frequent complete blood cell counts, bone marrow assessments, treatment interruptions, cycle delays, and reductions in venetoclax duration after remission.³

Pharmacists should also review treatment plans for clinically important drug interactions. Venetoclax is metabolized predominantly through cytochrome P450 3A, and its dose must be reduced when administered with moderate or strong CYP3A inhibitors, including commonly used azole antifungals.³

Gilteritinib exposure can also increase with strong CYP3A inhibitors. It carries warnings for differentiation syndrome, posterior reversible encephalopathy syndrome, QT-interval prolongation, pancreatitis, and embryo-fetal toxicity.⁵

Tumor lysis syndrome prophylaxis and monitoring are essential when initiating venetoclax, particularly in patients with high circulating blast counts or substantial disease burden. Pharmacists can help ensure appropriate hydration, antihy peruricemic therapy, electrolyte monitoring, antimicrobial prophylaxis, and adjustment of interacting medications.³

REFERENCES

1. Short NJ, Kantarjian HM, Daver NG, et al. Long-Term Outcomes of Azacitidine, Venetoclax and Gilteritinib in Newly Diagnosed FLT3-Mutated AML. Blood Adv. Published online May 27, 2026. doi:10.1182/bloodadvances.2026019841

2. Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33(2):299-312. doi:10.1038/s41375-018-0357-9

3. Venclexta. Prescribing information. AbbVie Inc; 2026. Updated February 2026. Accessed June 29, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/208573s031lbl.pdf

4. Konopleva M, Thirman MJ, Pratz KW, et al. Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia. Clin Cancer Res. 2022;28(13):2744-2752. doi:10.1158/1078-0432.CCR-21-3405

5. Xospata. Prescribing information. Astellas Pharma US, Inc; 2019. Updated January 2022. Accessed June 29, 2026. https://astellas.us/docs/xospata.pdf

6. Short NJ, Daver N, Dinardo CD, et al. Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML. J Clin Oncol. 2024;42(13):1499-1508. doi:10.1200/JCO.23.01911