Gilteritinib Plus Azacitidine in Newly Diagnosed FLT3 Mutated (FLT3mut+) Acute Myeloid Leukaemia Patients Ineligible for Intensive Induction Chemotherapy: Preliminary Findings from the Safety Cohort - European Medical Journal


Gilteritinib Plus Azacitidine in Newly Diagnosed FLT3 Mutated (FLT3mut+) Acute Myeloid Leukaemia Patients Ineligible for Intensive Induction Chemotherapy: Preliminary Findings from the Safety Cohort

| Hematology
*Jordi Esteve,1 Rik Schots,2 Teresa Bernal del Castillo,3 Je-Hwan Lee,4 Eunice S. Wang,5 Shira Dinner,6 Mark D. Minden,7 Olga Salamero,8 Jorge Sierra,9 Goichi Yoshimoto,10 Kamel Laribi,11 Janusz Halka,12 Pau Montesinos,13 Shufang Liu,14 Domique Talbert,14 Justine Kennedy,14 Elizabeth Shima Rich,14 Erkut Bahceci14

Jorge Sierra has received grants from Novartis, and personal fees from Abbvie, Daiichi-Sankyo, Janssen, Jazz Pharmaceuticals, Novartis, and Pfizer. Shufang Liu currently is a permanent employee of Astellas.

EMJ Hematol. ;7[1]:50-52. AR No. AR4 .

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

Search of more effective treatment for patients with acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy remains challenging. Monotherapy with hypomethylating agents (HMT) constitute the backbone therapy in this patient population, associated with a modest clinical benefit.1,2 Recently, the combination of HMT with agents against determinate novel targets has resulted in unprecedented response rates with a low toxicity profile. In this context, FLT3 inhibitors, targeting one of the most recurrently mutated genes in AML, have demonstrated significant activity in different clinical settings, such as frontline chemotherapy combined with intensive chemotherapy (midostaurin),3 as monotherapy for salvage therapy (quizartinib, gilteritinib),4-6 or as maintenance to prevent relapse after allogeneic hematopoietic cell transplantation (sorafenib).7

Gilteritinib is a type I FLT3 inhibitor with capability to bind both the monomeric (ITD mutation) and dimeric (D835 TKD mutation) forms of the FLT3 receptor. Pre-clinical work suggests a possible synergistic antileukaemic effect of gilteritinib when combined with azacytidine (AZA),8 and supports the clinical evaluation of this combination. This was the basis of a Phase I/II clinical trial aimed to explore the added benefit of combination of gilteritinib plus AZA in newly diagnosed FLT3mut+ AML ineligible for intensive induction chemotherapy.9 This trial consisted of an initial phase with a safety cohort, which evaluated feasibility and was aimed to define the recommended dose of gilteritinib in combination to AZA for a randomised phase, currently on-going. In this abstract, the results of a safety cohort of 15 patients are presented. Patients enrolled in this safety cohort received escalating doses of oral gilteritinib (80 or 120 mg/day) on Days 1–28 in combination with AZA (75 mg/m2/day) on Days 1–7. Treatment was continued in 28-day cycles until lack of a clinical benefit or unacceptable toxicity. Safety and tolerability were the primary endpoints of the safety cohort; antileukaemic activity was also assessed.

Fifteen patients (median age: 76 [range: 65–86]) were enrolled into the safety cohort (80 mg gilteritinib, n=9; 120 mg gilteritinib, n=6). All except one patient harbored a FLT3 mutation (ITD alone, n=10; TKD alone, n=3; ITD and TKD, n=1; none, n=1). Despite a high frequency of adverse events (AE) observed, frequent (>25% of patients) grade ≥3 AE corresponded to common events in this patient population, such as febrile neutropenia and cytopenias. Eight patients experienced fatal AE, none of which were related to treatment; three patients died in an early treatment phase due to septic shock (Day 2), respiratory failure (Day 6), and cerebral haemorrhage (Day 17). No patient presented a severe increase of liver enzymes (i.e., aminotransferase/alanine aminotransferase >3 X Upper Limit of Normal [ULN] and/or total bilirubin >2 X ULN) or significant QTcF interval prolongation, >500 msec. Only one dose limiting toxicity (DLT) consisting of an early episode of tumour lysis syndrome was observed in a patient who received 80 mg gilteritinib plus AZA, with no further episodes at the same or higher gilteritinib dosing. Given this unique DLT episode from the 11 DLT evaluable patients, the decision to proceed to the randomised portion (AZA plus gilteritinib versus AZA) at a dose of 120 mg gilteritinib for the combination treatment arm was adopted.

In this cohort of patients, 10 out of 15 patients (67%) achieved as best response as composite complete remission (CR; with incomplete haematological recovery: CRi), including four bona fide CR and six CRi. Two additional patients achieved a partial response (PR), giving an overall response rate (CR+CRi+PR) of 80%. Six of these CR/CRi patients maintained their response at last follow-up, between 220 and 377 days after treatment start (Figure 1). More than half (n=8/15; 56%) of the patients had a treatment duration lasting more than 6 months, while nine patients discontinued treatment (death, n=4; relapse; AE; physician decision; sponsor decision; subject withdrawal, n=1 each) and six patients remained on treatment.

Figure 1: Graph depicting response obtained and treatment duration of the combination of azacytidine and gilteritinib in the trial safety cohort.
CR: complete remission; CRi: complete response with incomplete haematological recovery; CRp: complete response without complete platelet recovery; PR: partial response.

In conclusion, gilteritinib was safely combined with AZA without unexpected toxicity in this population of elderly, unfit AML patients, and 120 mg gilteritinib was the chosen dose for the randomised Phase II of the trial. Moreover, this combination therapy induced a significant proportion of antileukaemic responses in newly diagnosed FLT3mut+ AML patients, suggesting an added benefit and warranting further exploration.

Kantarjian HM et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30(21):2670-7. Dombret H et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126(3):291-9. Stone RM et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454-64. Cortes JE et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): A multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):984-97. Perl AE et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: A multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017;18(8):1061-75. Perl AE et al. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial. Abstract CT184. AACR Annual Meeting, 29th March-3rd April, 2019. Burchert A et al. Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: Results from the randomized, double-blind, placebo-controlled multicentre Sormain Trial. Blood. 2018;132:661. Ueno Y et al. Evaluation of gilteritinib in combination with chemotherapy in preclinical models of FLT3-ITD+ acute myeloid leukemia. Oncotarget. 2019;10:2530-45. Astellas Pharma Global Development, Inc. A study of ASP2215 (gilteritinib) by itself, ASP2215 combined with azacitidine or azacitidine by itself to treat adult patients who have recently been diagnosed with acute myeloid leukemia with a FLT3 gene mutation and who cannot receive standard chemotherapy. NCT02752035.