Azacitidine, venetoclax, and gilteritinib in patients with FLT3-mutated AML

Azacitidine plus venetoclax is the standard-of-care treatment for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy; however, patients with FLT3-mutated AML may be resistant to this treatment.¹ The triple combination of azacitidine, venetoclax, and gilteritinib, an FLT3 inhibitor, may improve outcomes in this patient population.¹ Here, we summarize results from a single center phase I/II trial (NCT04140487) evaluating the safety and efficacy of this triplet combination in patients with newly diagnosed and relapsed/refractory (R/R) FLT3-mutated AML, published by Short et al.¹ in Journal of Clinical Oncology.

Study design and patient population¹

• The phase I portion (n = 10) included patients with R/R FLT3-mutated AML.
• In the phase II portion (n = 52), the R/R cohort included patients with:
  • R/R FLT3-mutated AML (n = 21)
  • Other myeloid malignancies (chronic myelomonocytic leukemia, n = 1)
• The first-line cohort included patients with newly diagnosed FLT3-mutated AML who were ineligible for intensive chemotherapy (n = 30)
• In Cycle 1, patients received azacitidine 75 mg/m² once daily on Days 1–7, venetoclax with ramp-up to 400 mg once daily on Days 1–28, and gilteritinib once daily on Days 1–28 (phase I, 80/120 mg; phase II, 80 mg).
• From Cycle 2 onwards, patients received azacitidine 75 mg/m² once daily on Days 1–5, 400 mg venetoclax once daily on Days 1–7, and gilteritinib once daily on Days 1–28 (phase I, 80/120 mg; phase II, 80 mg).
• The primary endpoints included:
  • Maximum tolerated dose of gilteritinib (phase I)
  • Combined complete remission (CR)/CR with incomplete hematological recovery rate within two cycles (phase II)

Key findings¹

Phase I

• Six patients received 80 mg once daily, and four patients received 120 mg gilteritinib once daily.

• No dose-limiting toxicities were observed at the 80 mg dose; one patient had prolonged Grade 4 myelosuppression in the 120 mg cohort.
• A maximum tolerated dose was not established. However, due to good clinical activity, superior count recovery, and concerns for myelosuppression at 120 mg dose, 80 mg was chosen as the recommended phase II dose.

Phase II

• In the first-line and R/R cohorts, CR/CR with incomplete hematological recovery was achieved by 96% and 27% of patients, respectively (Figure 1).

CR, complete remission; CRi, CR with incomplete hematologic recovery; MLFS, morphologic leukemia-free state; PR, partial remission; R/R, relapsed/refractory.
*Data from Short, et al.¹

• Of the 27 evaluable patients in the first-line cohort, 93% achieved measurable residual disease negativity by flow cytometry (Table 1).

Table 1. MRD response in the first-line and R/R cohorts*

C1, Cycle 1; FLT3, FMS‐like tyrosine kinase 3; MRD, measurable residual disease; PCR, polymerase chain reaction; R/R, relapsed/refractory. *Adapted from Short, et al.1
MRD response, % (unless otherwise specified)	First-line cohort (n = 30)	R/R cohort (n = 22)
MRD by flow cytometry (after C1), n	16	9
Negative	56	11
Positive	44	89
MRD by flow cytometry (best response), n	27	11
Negative	93	45
Positive	7	55
MRD by PCR for FLT3 (after C1), n	30	11
Negative	37	27
Positive	63	73
MRD by PCR for FLT3 (best response), n	30	14
Negative	90	43
Positive	10	57

• Overall, 43% of patients in the first-line cohort and 23% in the R/R cohort underwent allogeneic hematopoietic stem cell transplantation in the first remission.
• Median follow-up was 19.3 months and 30.7 months in the first-line and R/R cohorts, respectively
  • Median relapse-free survival (RFS) and overall survival (OS) were not reached in the first-line cohort
  • 6-, 12-, and 18-month RFS and OS rates in the first-line cohort are shown in Figure 2
  • Median RFS was 4.3 months and OS was 5.8 months in the R/R cohort

OS, overall survival; RFS, relapse-free survival.
*Data from Short, et al.¹

• The most common Grade ≥3 non-hematologic adverse events were infection (62%) and febrile neutropenia (38%)
  • Of patients in the first-line cohort, 53% and 33% experienced Grade ≥3 infection and febrile neutropenia, respectively
  • Of patients in the R/R cohort, 73%, 45%, and 23% experienced Grade ≥3 infection, febrile neutropenia, and sepsis, respectively

Key learnings

The triplet combination of azacitidine, venetoclax, and gilteritinib was associated with promising response rates and survival outcomes in newly diagnosed patients with FLT3-mutated AML who are ineligible for intensive chemotherapy.