Venetoclax Plus Gilteritinib in FLT3-Mutated Relapsed or Refractory Acute Myeloid Leukemia

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In a phase Ib study reported in the Journal of Clinical Oncology, Naval Daver, MD, and colleagues found that the doublet of venetoclax plus gilteritinib produced a high modified composite complete response rate in patients with FLT3-mutated relapsed or refractory acute myeloid leukemia. Dose interruptions for cytopenias were common.

Naval Daver, MD

Naval Daver, MD

Study Details

In the U.S. multicenter study, 61 patients, including 56 with FLT3-mutated disease, were enrolled between October 2018 and December 2020; 15 (10 with FLT3 mutations and 5 with wild-type FLT3) were enrolled in the dose-escalation phase and 46 (all with FLT3 mutations) were enrolled in the dose-expansion phase. Patients received 400 mg of venetoclax once daily and gilteritinib at 80 mg or 120 mg once daily during dose escalation, with the recommended phase II dose being venetoclax at 400 mg and gilteritinib at 120 mg. 

The primary efficacy outcome measure was rate of modified composite complete response, consisting of complete response, complete response with incomplete blood count recovery, complete response with incomplete platelet recovery, and morphologic leukemia-free state.


Median follow-up was 17.5 months (range = 0.8–27.5 months). Among the 56 patients with FLT3-mutant disease treated at any dose, modified composite complete response occurred in 42 (75%, complete response in 18%). Median time to response was 0.9 months and median remission duration was 4.9 months. Median overall survival was 10.0 months. FLT3 molecular response (< 10-2) was achieved in 15 (60%) of 25 evaluable patients with modified composite complete response.

Modified composite complete response was observed in 14 (67%, complete response in 29%) of 21 patients with no prior FLT3 tyrosine kinase inhibitor exposure and in 28 (80%, complete response in 11%) of 35 patients with prior tyrosine kinase inhibitor exposure. Median overall survival was 10.6 months and 9.6 months, respectively. 


  • Modified composite complete response was achieved in 75% of patients.
  • Response rates were 67% and 80% among patients without and with previous FLT3 tyrosine kinase inhibitor exposure.

Adverse Events

Among all 61 patients receiving treatment, grade 3 or 4 adverse events occurred in 97%, most commonly cytopenias (80%). Adverse events led to venetoclax and gilteritinib interruptions in 51% and 48% of patients, and to discontinuation of treatment in 15% and 13%. Serious adverse events occurred in 75% of patients, most commonly febrile neutropenia (44%) and pneumonia (13%). No cases of posterior reversible encephalopathy syndrome or differentiation syndrome were observed. Adverse events led to death in 10 patients; causes consisted of complicated fungal infection, Aspergillus pneumonia, multiorgan failure, respiratory failure, and typhlitis in patients who were in modified composite complete response, and sepsis, multiorgan failure, pseudomonal bacteremia, subdural hematoma, and death of unknown cause among patients not in response.

The investigators concluded, “The combination of venetoclax and gilteritinib was associated with high modified composite complete response and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.”

Jessica K. Altman, MD, of Robert H. Lurie Comprehensive Cancer Center, Northwestern University, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by AbbVie, Genentech, and Astellas. For full disclosures of the study authors, visit

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