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Gilteritinib plus azacitidine: an effective alternative to intensive induction chemotherapy in newly diagnosed acute myeloid leukaemia patients harbouring a FLT3 mutation?

The phase III LACEWING trial is an ongoing study assessing the efficacy and safety of first line gilteritinib plus azacitidine (AZA) in FLT3 mutated acute myeloid leukaemia (AML) patients who are ineligible for intensive induction chemotherapy. Mature data in the safety cohort of this trial reveal a promising complete remission rate of 33%.  When also CR patients with an incomplete hematologic recovery, or with a partial hematologic remission are considered, this response rate increased to 67%. If the results of the randomized part of this trial conform these findings and provide convincing evidence on the tolerability of this regimen, gilteritinib + AZA might become an alternative to intensive induction chemotherapy in the treatment of unfit newly diagnosed, FLT3 mutated AML.


Gilteritinib is an oral, highly selective inhibitor of FMS-like tyrosine kinase 3 (FLT3). In the phase III ADMIRAL trial, gilteritinib proved to be effective and tolerable in adult patients with relapsed/refractory FLT3-mutated acute myeloid leukaemia (AML), leading to its registration in this setting in October 2020. In other studies, the hypomethylating agent azacitidine (AZA) was shown to be associated with a better overall survival (OS), compared to conventional chemotherapy, in patients with high-risk myelodysplastic syndrome and in older patients with AML. Preclinical studies have shown that combining gilteritinib with AZA inhibits tumour growth and induces apoptosis in FLT3 ITD AML cell lines. Interestingly, both agents proved to have synergistic activity in AML xenograft models. The LACEWING phase III trial is an ongoing, open-label, randomized trial evaluating this gilteritinib-AZA combination in adults with newly diagnosed FLT3 mutated AML who are ineligible for intensive induction chemotherapy. The first part of the study aims at establishing the appropriate dose of gilteritinib through the recruitment of a safety cohort (N=15). Safety cohort participants received oral gilteritinib 80mg/d on days 1-28, escalating to 120mg/d, plus AZA 75mg/m2/d on days 1-7. Initially, LACEWING was a 3-arm study comparing gilteritinib + AZA to either gilteritinib or AZA monotherapy. However, following a protocol revision, the gilteritinib monotherapy was removed. As such, a total of 250 patients will be randomised in a 2:1 ratio to receive in 28-day cycles oral gilteritinib 120mg/d on days 1-28, plus AZA 75mg/m2/d on days 1-7 via subcutaneous injection or intravenous infusion, or AZA monotherapy in the same dosing schedule. Patients are treated until a lack of efficacy is observed, or until unacceptable toxicity. The primary endpoint of the study will be overall survival (OS), with event-free survival (EFS) as a key secondary study objective. Other secondary endpoints include best response, remission rates (complete remission [CR], CR with incomplete hematologic recovery [CRi], CR with partial hematologic remission [CRp], composite CR [CRc; sum of CR, CRi, and CRp]), response duration, transfusion conversion and maintenance rates, leukaemia-free survival, patient-reported fatigue, and safety and tolerability. At ASH 2020, mature results of the safety cohort were presented in addition to preliminary results of the randomization cohort.


As of June 2020, 14 out of 15 participants in the safety cohort had died, with 1 patient continuing treatment for over 3 years. The median age of the 15 patients was 75 years, ranging from 65 to 86 years.  Two thirds of patients harbored an ITD only FLT3 mutation. Median (range) treatment duration was 6 (<1-34) cycles, with 40% of patients receiving at least 12 cycles of therapy. In this safety cohort, 9 patients received a gilteritinib dose of 80mg/d, while the remaining 6 received it at a dose of 120mg/d. A CR was observed in 5 (33%) patients with a CRc observed in 10 subjects (67%) patients. Among the patients who obtained CRc, the median duration of remission was 10.4 months (95%CI: 0.95-NR). All 15 patients within the safety cohort experienced treatment-emergent adverse events. The most common grade ≥3 TEAEs were anemia (40%), febrile neutropenia (53.3%), neutropenia (53.3%) and thrombocytopenia (40%). In total, 40% of patients experienced TEAE that led to treatment withdrawal.

Based on the results from the safety cohort, a gilteritinib dose of 120mg/d plus AZA was adopted for the randomization cohort. As of June 29th 2020, a total of 136 patients were randomized in the study. The median age of these patients was 77 and 79% of patients had an ITD alone FLT3 mutational status. At the time of the analysis, the median (range) treatment duration was 4 (<1-31) cycles, with 54 (40%) patients having received 6 or more cycles. As of June 2020, 83 (61%) patients in the randomization cohort had died.


In summary, the ongoing LACEWING study continues to evaluate gilteritinib + AZA in patients with newly diagnosed FLT3 mutation-positive AML. Mature results of the safety cohort of this trial indicate promising remission rates to gilteritinib + AZA, with a CR in one third of patients and a CRc in 67%. Responses also proved to be durable with a median duration of response of 10.4 months in the CRc patients. Overall, the treatment was tolerable, but still 40% of patients had to discontinue therapy due to an AE. Results of the randomization cohort of LACEWING are eagerly awaited.


Wang ES, Montesinos P, Minden MD, et al. Phase 3, multicenter, open-label study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in newly diagnosed FLT3 Mutated (FLT3mut+) acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy. Presented at ASH 2020; Abstract 27.

Speaker Eunice Wang

Eunice S. Wang

Eunice S. Wang, MD, Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States.


See: Keyslides


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