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Can Gilteritinib Overcome FLT3 Inhibition Resistance in Patients With FLT3-Mutated AML ?
Treatment with the oral FLT3 / AXL inhibitor gilteritinib showed consistent FLT3 inhibition and high response rates in patients with FLT3-mutated , relapsed or refractory acute myeloid leukemia ( AML ) – even among patients who developed secondary FLT3 mutations associated with treatment resistance , according to the results of a phase I / II doseescalation and -expansion study published in the Lancet Oncology by Alexander E . Perl , MD , from the University of Pennsylvania – Abramson Comprehensive Cancer Center in Philadelphia , and colleagues .
This international , openlabel trial included adults with primary or secondary AML that had relapsed or was refractory to at least one cycle of induction chemotherapy . While patients were not required to have an FLT3 mutation , 10 or more patients with locally confirmed FLT3 mutation ( either an internal tandem duplication [ ITD ] or an activating point mutation ) were enrolled in expansion cohorts at each dose level . Patients were excluded if they had acute promyelocytic leukemia , BCR-ABL – positive leukemia , or malignant tumors other than AML or myelodysplastic syndromes .
A total of 265 patients ( median age = 62 years ; range = 21-90 years ) were enrolled between October 15 , 2013 , and August 27 , 2015 , from 28 sites in France , Germany , Italy , and the United States : 23 in the dose escalation phase and 229 in the dose-expansion phase . Thirteen patients did not receive gilteritinib and were excluded from the safety analysis . The remaining 252 patients were assigned to one of seven dose cohorts :
• 20 mg / day ( n = 16 )
• 40 mg / day ( n = 16 )
• 80 mg / day ( n = 24 )
• 120 mg / day ( n = 70 )
• 200 mg / day ( n = 103 )
• 300 mg / day ( n = 20 )
• 450 mg / day ( n = 3 )
The study population was heavily pretreated , the researchers noted . Seventy percent of patients ( n = 177 ) received two or more prior AML therapies , including 29 percent ( n = 73 ) who received a hematopoietic cell transplantation ( HCT ) and 25 percent ( n = 63 ) who received prior treatment with a tyrosine kinase inhibitor ( TKI ; sorafenib was most common ). Overall , 194 patients had a locally confirmed FLT3 mutation ; the most common mutations were FLT3-ITD ( n = 159 ), followed by FLT3-D835 ( n = 13 ), ITD-D835 ( n = 16 ), and other mutations ( n = 6 ).
At data cutoff ( November 24 , 2015 ), 31 patients ( 12 %) remained on treatment , with a median treatment duration of 25.9 weeks ( range = 15-50 weeks ).
The most common grade 3 / 4 adverse events ( AEs ) were febrile neutropenia ( n = 97 ; 39 %), anemia ( n = 61 ; 24 %), thrombocytopenia ( n = 33 ; 13 %), sepsis ( n = 28 ; 11 %), and pneumonia ( n = 27 ; 11 %). The most common AEs deemed related to gilteritinib were diarrhea , fatigue , elevated aspartate aminotransferase , and increased alanine aminotransferase . Serious gilteritinib-related AEs included febrile neutropenia ( n = 5 ; 2 %), acute renal failure ( n = 5 ; 2 %), pyrexia ( n = 3 ; 1 %), sepsis ( n = 2 ; 1 %), and bacteremia ( n = 1 ; < 1 %).
Twenty-five patients ( 10 %) required a dose reduction , most commonly related to diarrhea
( n = 2 ) and fatigue ( n = 3 ). The most common AEs leading to treatment discontinuation were progressive disease ( n = 15 ; 6 %) and sepsis ( n = 7 ; 3 %).
Ninety-five people died during study follow-up ; seven of the deaths were deemed “ at least possibly or probably related to gilteritinib .” The fatal events were pulmonary embolism ( at the 200 mg / day dose ), respiratory failure ( 120 mg / day ), hemoptysis ( 80 mg / day ), intracranial bleeding ( 20 mg / day ), ventricular fibrillation ( 120 mg / day ), septic shock ( 80 mg / day ), and neutropenia ( 120 mg / day ).
The researchers established 300 mg / day as the maximum tolerated dose , as two of the patients receiving 450 mg / day experienced dose-limiting toxicities ( diarrhea and hepatic transaminase elevation ). Among the 249 patients with evaluable data , 100 ( 40 %) achieved a complete remission ( CR ), 46 ( 18 %) achieved CR with incomplete hematologic recovery ( CRi ), 25 ( 10 %) achieved partial remission ( PR ), and 10 ( 4 %) achieved CR with incomplete platelet recovery ( CRp ; TABLE ).
Among the 191 patients with FLT3 mutation , 70 ( 37 %) achieved a composite CR ( including CRi and CRp ). Most of the remissions occurred in patients who received ≥80 mg / day ( n = 69 ; 41 %). More CRs and PRs occurred in patients with FLT3 mutations ( n = 88 ; 52 %), compared with FLT3 wild-type ( n = 7 ; 12 %; p value not reported ).
“ In FLT3-mutated patients , gilteritinib doses of 80 mg / day or higher were associated with antileukemic activity both in subgroups of patients who had never received treatment with TKI and in those who had previously been treated with these drugs ,” the authors wrote . At these doses , the overall response rate was 55 percent in patients with ITD , 17 percent with D835 , and 62 percent with ITD-D835 .
“ These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory AML ,” the authors concluded , even among patients with acquired point mutations associated with treatment resistance . Based on these results , the researchers selected gilteritinib 120 mg / day as the starting dose for future studies , and this is being tested in phase III trials .
The study is limited by its nonrandomized , single-arm , openlabel study design , as well as the small number of patients in each dose cohort .
The research was funded by Astellas Pharma US , the manufacturer of gilteritinib . ●
The authors report financial support from Astellas Pharma US .
REFERENCE
Perl AE , Altman JK , Cortes J , et al . Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia : a multicenter , first-in-human , open-label , phase 1-2 study . Lancet Oncol . 2017 ; 18:1061-75 .
TABLE . Responses to Gilteritinib , Overall and by FLT3 Mutation Status
Full Analysis Set ( n = 249 )
Complete remission ( CR ) 19 ( 8 %) 95 % CI 5-12
CR with incomplete platelet recovery
CR with incomplete hematologic recovery
10 ( 4 %) 95 % CI 2-7
46 ( 18 %) 95 % CI 14-24
Partial remission 25 ( 10 %) 95 % CI 7-15
Composite CR 75 ( 30 %) 95 % CI 25-36
Overall response 100 ( 40 %) 95 % CI 34-47
Duration of response ( weeks )
17 95 % CI 14-29
Overall survival ( weeks ) 25 95 % CI 20-30
FLT3 Wild-Type ( n = 58 )
1 ( 2 %) 95 % CI 0-9
All patients ( n = 191 )
18 ( 9 %) 95 % CI 6-15
0 10 ( 5 %) 95 % CI 3-9
4 ( 7 %) 95 % CI 2-17
2 ( 3 %) 95 % CI 0-12
5 ( 9 %) 95 % CI 3-19
7 ( 12 %) 95 % CI 5-23
12 95 % CI 3-17
17 95 % CI 11-21
42 ( 22 %) 95 % CI 16-29
23 ( 12 %) 95 % CI 8-18
70 ( 37 %) 95 % CI 30-44
93 ( 49 %) 95 % CI 41-56
20 95 % CI 14-33
30 95 % CI 23-33
FLT3 Mutation-Positive ( n = 191 )
Patients receiving ≥80 mg / day ( n = 169 )
18 ( 11 %) 95 % CI 6-16
10 ( 6 %) 95 % CI 3-11
41 ( 24 %) 95 % CI 18-31
19 ( 11 %) 95 % CI 7-17
69 ( 41 %) 95 % CI 33-49
88 ( 52 %) 95 % CI 44-60
20 95 % CI 14-33
31 95 % CI 24-59
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